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WO2008102127A2 - Gel forming compounds - Google Patents

Gel forming compounds Download PDF

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Publication number
WO2008102127A2
WO2008102127A2 PCT/GB2008/000575 GB2008000575W WO2008102127A2 WO 2008102127 A2 WO2008102127 A2 WO 2008102127A2 GB 2008000575 W GB2008000575 W GB 2008000575W WO 2008102127 A2 WO2008102127 A2 WO 2008102127A2
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WO
WIPO (PCT)
Prior art keywords
compound
amino
mmol
pyridylmethyl
general formula
Prior art date
Application number
PCT/GB2008/000575
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French (fr)
Other versions
WO2008102127A3 (en
Inventor
Vesna Caplar
Leo Frkanec
Milan Jokic
Janja Makarevic
Tomislav Portada
Mladen Zinic
Zelimir Jelcic
Original Assignee
Pliva Hrvatska D.O.O.
Bucks, Teresa Anne
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Publication date
Application filed by Pliva Hrvatska D.O.O., Bucks, Teresa Anne filed Critical Pliva Hrvatska D.O.O.
Publication of WO2008102127A2 publication Critical patent/WO2008102127A2/en
Publication of WO2008102127A3 publication Critical patent/WO2008102127A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds which are capable of forming gels when mixed with an appropriate solvent and to methods of preparing these compounds.
  • the invention also relates to the gels formed by the compounds, methods for making them, compositions comprising the gels and to the use of the gels in various applications.
  • Supramolecular hydrogels are used in many applications including food and cosmetic thickeners, formation of contact lenses, vehicles for drug delivery and tissue replacement matrices. They are of particular interest as drug delivery vehicles because of their generally favourable biocompatibility. Because of their high water content they are particularly attractive for the delivery of delicate bioactive agents such as proteins.
  • Gels may be either chemical or physical gels. Chemical gels consist of solid components which are covalently linked to one another and gel formation is irreversible. Physical gels are generally formed from smaller subunits which, are linked non-covalently into a network. Physical gels tend to be thermoreversible.
  • Hydrogels may be formed either by polymers or by low molecular weight gelators (LMWGs).
  • LMWGs low molecular weight gelators
  • the molecules are assembled in well ordered arrays and the gels are thermoreversible and strong. In addition, they tend to have low minimal gelation concentrations and high tolerance towards salts and other additives.
  • hydrogels formed from chemically cross-linked hydrophilic polymers there are many examples of documents relating to hydrogels formed from chemically cross-linked hydrophilic polymers.
  • a hydrogel is formed from a cross linked polymerised hydrophilic polymer with an olefmic bond, an amino acid polymer, a cross-linking agent and a lower alcohol.
  • WO-A-97/05185 relates to macromers which can be ionically or covalently cross- linked to form hydrogels.
  • the macromers are block co-polymers which have hydrophilic blocks and blocks which are more hydrophobic.
  • WO-A-03/089506 also relates to hydrogels as well as to hydrogel foams and superporous hydrogels. These hydrogels are said to consist of two or more interpenetrating polymer networks which provide enhanced elasticity and mechanical strength properties.
  • WO-A-2004/104021 again relates to hydrogels which, in this case, are intended to provide controlled release of active agents by utilising repeat sequence protein polymers.
  • hydrogelator compounds formed by combining 11-aminoundecanoioc acid, lauric acid and aromatic and aliphatic amino acid units in the same molecule. These molecules were low molecular weight compounds derived from amino acids and connected through amide bonds with long aliphatic chains ending in a carboxylic acid functional group and have the general formula: wherein R can be isopropyl, isobutyl, benzyl or phenyl.
  • the sodium salts of these compounds are able to form gels but the acids are not very satisfactory gelators as they tend to be insoluble in both aqueous and in some organic solvents. This means that gelation of the compounds is pH sensitive since the sodium salts exist and therefore form gels in alkaline media, whereas the free acids are insoluble in acidic solvents.
  • chiral bis(amino acid) oxalyl amides and chiral bis(amino alcohol)oxalyl amide are capable of forming hydrogels (Makarevic et al, Chem.Eur.J. 2001, 7, 3328 - 3341, Makarevic et al,. Croat. Chem. Acta. 2004, 77, 403-414).
  • the present invention relates to novel non-polymeric compounds which, in water, are able to form hydrogels without the need for chemical cross-linking.
  • the compounds are also able to form gels in solvents other than water, including organic solvents and oils and at acidic pH. It is thought that the gels are formed by the self- assembly of the molecules into nanofibrous networks.
  • R 1 is Ci- 6 alkyl, benzyl, phenyl, or indolylmethyl, any of which may be substituted with OH 5 0(C 1-6 alkyl) or S(C 1-6 alkyl); each of X and X a is independently -O-[CH 2 ] P - or -NH-[CH 2 Jr-; p is 1 to 4 except when:
  • R 1 is C 1-6 alkyl, and: n is ⁇ 6 in compounds of formula (Ia); or q is ⁇ 5 in compounds of formula (Ib); in which case, p is 2 to 4; r is 0 to 4; each of R 2 and R 2a is independently pyridyl; m is an integer of 4 to 12; n is an integer of 5 to 12; q is an integer of 4 to 11 ; or a salt thereof.
  • the compounds of general formula (Ia) and (Ib), and especially their salts have the advantages that they can form gels in both water and organic solvents and that the properties of the gels can easily be manipulated by adjusting the temperature, pH or the type and amount of solvent present. Unlike many of the prior art compounds, the compounds of general formulae (Ia) and (Ib) or salts thereof are capable of forming gels in acidic media.
  • gel forming compound refers to any molecule, whether a small organic molecule (such as the compounds of general formulae (Ia) and (Ib)) or a polymer, which forms a gel when mixed with either an aqueous or a non-aqueous solvent and, if necessary, heated and then cooled.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl 5 isobutyl, sec-butyl and n-hexyl.
  • Salts of the compounds of general formulae (Ia) and (Ib) are preferably pharmaceutically acceptable and include salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, salts of phosphoric and sulfonic acids; and salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifiuoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate,
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • R 1 is C 1-6 alkyl, phenyl, benzyl, j>-hydroxybenzyl, indolylmethyl or methylthioethyl; m is 5 to 10; p is 0 to 3;
  • X is -NH-[CH 2 ]r; and each of R 2 and R 2a is 4-pyridyl.
  • m is 7 to 10
  • n is 8 to 10
  • X is -NH-CH 2 - and R 2 is 4-pyridyl.
  • q is 1 to 3, most preferably 2, X is -NH-CH 2 - and R 2 is 4-pyridyl.
  • R 1 is isobutyl or phenyl.
  • hydrochloride salts of the compounds of general formulae (Ia) and (Ib) are particularly suitable hydrogelators.
  • the condensation reaction may make use of a coupling agent N 1 N'- dicyclohexylcarbodiimide (DCC) and is typically conducted in an organic solvent and in the presence of 4-dimethylaminopyridine (DMAP), initially at a temperature of from about -5 to 5 0 C 5 with the reaction mixture later being allowed to warm to room temperature.
  • DCC N 1 N'- dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • R 1 , m and n are as defined in general formula (Ia) and R 6 is C 1-6 alkyl; by alkaline hydrolysis, for example with an aqueous alkali metal hydroxide such as lithium hydroxide, followed by acidification, using, for example, hydrochloric acid.
  • alkaline hydrolysis for example with an aqueous alkali metal hydroxide such as lithium hydroxide, followed by acidification, using, for example, hydrochloric acid.
  • the condensation may be a DCC condensation and may be carried out in an organic solvent and in the presence of DMAP, initially at a temperature of from about -5 to 5 0 C, with the reaction mixture later being allowed to warm to room temperature.
  • This acylation reaction may be carried out in an aqueous base and initially at a temperature of from -5 to 5 0 C with the reaction mixture subsequently being allowed to warm to room temperature.
  • This reaction is particularly suitable when X is -NHCH 2 - and R is a pyridyl group, particularly 4-pyridyl and may be carried out in a polar organic solvent such as acetonitrile and in the presence of a triphenylphosphine, carbon tetrachloride and triethylamine.
  • R 2 , X and n are as defined in general formula (Ia) and P 1 is an amine protecting group such as /-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) or any other suitable protecting group.
  • BOC /-butoxycarbonyl
  • CBZ benzyloxycarbonyl
  • the method for removal of the protecting group will depend upon the particular protecting group which is used. For example, hydrogenation over a suitable catalyst, for example palladium or platinum, is particularly appropriate when P 1 is Z but when P 1 is BOC, it is more easily removed by stirring with trifluoroacetic acid.
  • n is as defined for general formula (I); using standard methods well known to those of skill in the art and described in more detail in the examples below.
  • a compound of general formula (XIII) may be prepared by deprotecting a compound of general formula (XIV):
  • Deprotection may be achieved using standard methods, which depend upon the particular protecting group used. For example, when the amine is protected with BOC, it may be removed using TFA. However, when P 1 is CBZ, hydrogenation over an appropriate catalyst is a more appropriate method for its removal.
  • R 1 is as defined for general formula (Ia) and P 1 is a protecting group as defined for general formula (X) with a compound of general formula (IX), again in a condensation reaction activated with triphenylphosphine, carbon tetrachloride and triethylamine.
  • a further method for the preparation of a compound of general formula (Ia) is by the conversion of another compound of general formula (Ia).
  • a compound of a formula similar to that of general formula (Ia) but in which, R 1 is, for example benzyloxybenzyl may be converted to a compound of general formula (Ia), for example in which R is hydroxybenzyl.
  • the condensation reaction may be of any known type, for example it may be activated with triphenyl phosphine, carbon tetrachloride and triethylamine or, alternatively, it may be a DCC activated condensation. General procedures for these reactions are given in the Examples below.
  • a compound of general formula (XXI) may be prepared by reacting a compound of general formula (XXII) :
  • a compound of general formula (Ib) may be prepared by the reaction of a compound of general formula (XX):
  • Compounds of general formula (XX) may be prepared from compounds of general formula (V) as defined above by reaction with compounds of general formula (XIX):
  • compounds of general formulae (Ia) and (Ib) and acid addition salts of these compounds are capable of forming gels when added to water or other solvents, heated and then left to cool.
  • a gel comprising a compound of formula (Ia) or (Ib) or a salt thereof mixed with a solvent and a process for preparing such a gel comprising mixing a compound of formula (Ia) or (Ib) or a salt thereof with a solvent, heating and then cooling the solution.
  • the solvent may be an aqueous solvent such as water, sodium chloride solution or aqueous acetic acid or a mixture of water with an organic solvent such as DMSO.
  • a gel may be formed in situ and in such a case, the aqueous solvent may be a physiological fluid, for example stomach acid or saliva.
  • the solvent may be an organic solvent such as DMSO, ethanol, «-decanol, propylene glycol, polyethylene glycol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, />-xylene 5 tetraline, or benzyl alcohol.
  • the compound of the present invention are also capable of forming gels in oils such as glycerine, oleic acid, octyldodecanol and cocoyl caprylocaprate, which is sold under the trade mark Cetiol LC (Cognis).
  • the compounds of the present invention have extremely good gelation properties and relatively low concentrations are needed to cause gelation, although clearly the concentration required depends on the solvent.
  • the compound of general formula (Ia) or (Ib) or the salt thereof is present in a concentration of at least 0.2 mg/mL, but more preferably at least 1 mg/mL and in ascending order of preference at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/mL.
  • the concentration of the compound needed to form a gel (minimal gelation concentration or MGC) varies according to the solvent and will, for example be different for an aqueous solution of sodium chloride and pure water.
  • MGC minimum gelation concentration
  • concentration of the solution For an aqueous solution of, for example, sodium chloride or acetic acid, the MGC also varies according to the concentration of the solution.
  • MGC was determined visually by the vial inversion method in which sample vials were put in an inverted position and the MGC was defined as the concentration just before the gel started to flow. In practice, this requires the elastic modulus of the gel to be greater than about 65 Pa.
  • the MGC also depends upon the pH of the solvent used.
  • the compounds of the invention can form gels in solutions which have acidic and neutral pH but are not so effective in alkaline solution, and particularly at pH 10 and above. More preferably, the pH of the solution is 7 or less.
  • gels formed by the compounds of general formula (Ia) or (Ib) and their salts are able to flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula or when sprayed onto a delivery site.
  • the threshold stresses of the gels are typically in the range of 1 kPa to 100 kPa.
  • the gel can be injected into a mould or extruded from a nozzle tip to form, for instance, line or sheet structures to cover a desired surface, which may be, for example, a skin surface or the surface of a body cavity.
  • the gels can be formed into desired shapes means that they are ideally suited for purposes such as support matrices for tissue replacement as they can be applied to and conform to sites on or in tissue including tissue surfaces and defined cavities such as intravertebral spaces.
  • the gels formed by the compounds of the present invention are stable at room temperature for several months, they have high water content and therefore exhibit excellent biocompatibility and they are therefore ideal for pharmaceutical and cosmetic use. Furthermore, the mucoadhesive and drug release properties of the gels can be adjusted by the degree of gelation, which is affected by the concentration above the minimal gelation concentration (MGC). Therefore, in a further aspect of the invention, there is provided a composition comprising: i. a compound of formula (Ia) or (Ib) or a salt thereof; and ii. an active agent.
  • compositions may additionally comprise a solvent, in which case they may be in gel form. In some cases, however, the composition may be a dry composition which is intended to form a gel in situ.
  • compositions may be pharmaceutical compositions, in which case the active agent is a pharmaceutically or biologically active substance. Alternatively, however, they may be intended for the administration of other active agents, for example, dietary supplements.
  • the active agent is preferably water soluble and the solvent is preferably water or an aqueous solvent.
  • the solvent is preferably water or an aqueous solvent.
  • anaesthetics such as benoxinate, bupivacaine, dibucaine hydrochloride, dyclonine hydrochloride, etidocaine cocaine, hexylcaine, lidocaine, mepivacaine, naepaine, phenacaine hydrochloride, piperocaine, prilocaine, proparacaine hydrochloride, and tetracaine hydrochloride
  • analgesics such as aspirin, acetaminophen and diflunisal
  • angiogenesis inhibitors such as aspirin, acetaminophen and diflunisal
  • antibiotics such as bacitracin, carbenicillin, cefazolin, cefoxitin, cephaloridine, chloramphenicol, chibrorifamycin, n-formamidoylthienamycin, gramicidin, neo
  • the drug delivery systems of the present invention may be designed to release appropriate biologically active substances.
  • biologically active substances should be intended for example proteins and their fragments, peptides and polynucleotides, growth factors, enzymes, vaccines and substances used in the treatment of diseases associated with genetic defects.
  • Particular water soluble polypeptides which may be used include, for example, angiotensins, adrenocorticotrophic hormone (ACTH), bacitracins, bombesin antagonists, bradykinin, calcitonin, colistins, growth hormone, growth hormone releasing factor, endomorphins, enkephalins, glucagon, gastrin, gramicidines, insulin, interferon, luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or antagonists, monoclonal antibodies, tetragastrin, pentagastrin, urogastrone, prolactin, renin, secretin, oxytocin, polymyzins, somatostatin, tyrocidin, transforming growth factor antagonists, soluble vaccines, and vasopressin.
  • angiotensins adrenocorticotrophic hormone (ACTH)
  • compositions of the invention may also contain other agents, such as preservatives and buffering agents.
  • Suitable water soluble preservatives which may be employed in the drug delivery systems of the present invention include ascorbate, benzalkonium chloride, benzylalcohol, chlorobutanol, sodium bisulfite, sodium thiosulfate, parabens, phenylethanol, phenylmercuric borate and thimerosal. These agents may be present in amounts of from 0.001 to 5% by weight and preferably 0.01 to 2%.
  • Suitable water soluble buffering agents are alkali or alkali earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. These agents may be present in amounts sufficient to maintain a pH of the system of referably from 4 up to 8. The buffering agent therefore may be much as 5% by weight of the total composition.
  • hydro gel-based drug delivery systems prepared in accordance with the present invention include, but are not limited to: inoculation or injection (e.g., intra-articular, intra-aural, intra-mammary, intra-muscular, intraperitoneal, subcutaneous, etc.), topical application (e.g., on areas, such as eyes, ears, in or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g., vaginal and other epthelial linings, gastrointestinal mucosa, etc.).
  • the compositions formulated using hydrogel matrices may include previously known pharmaceutical carriers or excipients, adjuvants, etc.
  • compositions of the present invention are particularly advantageous as the gel formed by the compound of formula (Ia) or (Ib) or a salt thereof and a solvent is an ideal matrix for the sustained release of the active agent.
  • the rate at which an active agent is released from a matrix is dependent upon several factors.
  • a major element of the release of the active agent is related to the migration of its molecules through channels formed by the gel forming molecules, which may occur by one of two mechanisms, bulk flow and diffusion.
  • the exact role of bulk flow is unclear but it is thought to take place mainly in areas adjacent to gel surfaces and therefore diffusion is thought to be the more important factor.
  • the rate of diffusion of an active agent through a gel is modified by tortuosity ( ⁇ ), which is defined by the equation:
  • compositions containing them can be formed required shapes, for instance tablets, lozenges, transdermal patches or suppositories. They can also easily be loaded into capsules.
  • the composition may be intended for topical, transdermal, rectal, buccal or sublingual administration and may be a pharmaceutical composition, in which the active agent is a biologically active compound.
  • the composition may be a cosmetic composition intended for topical administration, in which case the active agent may be a cosmetically acceptable compound, for example a natural product or a vitamin.
  • the solvent in topical, transdermal, rectal, buccal or sublingual compositions may be either an aqueous solvent, a mixture of an aqueous and an organic solvent or a pharmaceutical oil such as glycerine, oleic acid, octyldodecanol or cocoyl caprylocaprate (Cetiol ® LC).
  • Oleic acid is a particularly useful oily solvent in such compositions because it has been found to reduce the irritation associated with many transdermal and topical products which is caused by other ingredients of the composition.
  • transdermal pharmaceutical compositions for example, penetration enhancing agents such as alcohols or glycols are known to cause skin irritation but oleic acid has been shown to reduce this (US 6,319,913).
  • oleic acid is itself a penetration enhancing agent and so is particularly suitable solvent for transdermal products.
  • a composition for application to the skin may be also made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • tack is defined as the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas if the tack is too high, adhesive residue may be left on the skin after removal or the gel may cause dermal irritation.
  • a gel it is therefore preferable for a gel to have a probe tack value of at least 0.25N as if it is lower than this, the skin adhesiveness is insufficient and the gel is likely to peel off with even a small amount of movement. Adhesives with high tack may form strong bonds with the skin on initial application and may therefore be difficult to remove and if the probe tack value of the gel exceeds 1.2 N, skin irritation is likely to occur (US 6,914,169).
  • compositions may also be formulated for oral administration and they may be pharmaceutical compositions, in which case the active agent is a biologically active compound. Alternatively, however, they may be intended for the administration of, for example, dietary supplements.
  • the compounds of the first aspect of the invention are particularly useful for the formation of oral compositions as they are capable of retaining their gel structure at low pH and therefore are ideal for use as matrices for the sustained release of active agents in the stomach.
  • the solvent for the oral compositions may be an aqueous solvent, an organic solvent, a mixture of aqueous and organic solvents or oil and may be chosen according to the active compound.
  • hydrophobic compounds are preferably formulated in a gel which includes a hydrophobic solvent whereas for hydrophilic compounds an aqueous solvent may be preferred.
  • the composition may be formulated without a solvent since the compound of general formula (Ia), (Ib) or salt thereof is capable of forming a gel in the stomach so that a matrix is formed around the active agent in situ.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing predetermined amounts of the compound of general formula (Ia), (Ib) or salt thereof and active agent; as a powder or granules; as a gel composition in an aqueous liquid or a nonaqueous liquid etc.
  • Oral compositions whether pharmaceutical or not, may also include an acceptable carrier.
  • the term "acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound of general formula (Ia), (Ib) or salt thereof and active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored.
  • compositions suitable for oral administration include lozenges comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia.
  • compositions of the invention may be formed simply by mixing the compound of general formula (Ia) or (Ib) or a salt thereof with an active compound and optionally adding a solvent. This method forms yet another aspect of the present invention.
  • gels formed by compounds of general formula (Ia) or (Ib) or their salts include thickeners for foodstuffs or cosmetic compositions.
  • FIGURE 1 is a set of near infrared spectra for the hydrochloride salt of Compound 3 at concentrations of 5%, 1%, 0.5% and 0.33% wt/vol and for Compound 3 free base at a concentration of 0.33 wt/vol.
  • FIGURE 2 is a water vapour sorption/desorption curve for the hydrochloride of Compound 3 at 25 0 C.
  • FIGURE 3 is a photograph of particles of the hydrochloride salt of Compound 18 at 0% RH (dry state) and at 90% RH (with 27% adsorbed water).
  • FIGURE 4 is a typical curve of tack probe measurement: force (in kg) vs distance (or displacement in mm) .
  • Dimethyl glutamate hydrochloride was prepared starting from L-glutamic acid in 100 % yield, methyl 11-amino-undecanoate hydrochloride starting from 11-amino- undecanoic acid (97 %) and methyl 12-aminododecanoate hydrochloride starting from 12-arninododecanoic acid (88 %), in methanol with thionyl chloride, following the general procedure for preparation of methyl esters of amino acids (Houben-Weyl, Methoden der organischen Chemie, Band XV/I, Georg Thieme Verlag, Stuttgart, 1974, p. 317). Methyl 6-amino-hexanoate hydrochloride and methyl 4-amino- butyrate hydrochloride were purchased from Fluka.
  • the compound was prepared starting from D-phenylglycine (3.023 g, 20 mmol) and decanoyl chloride (4.1 mL, 20 mmol) to give 5.02 g (85 %) of the product.
  • the compound was prepared starting from L-leucine (1.00 g, 7.6 mmol) and decanoyl chloride (1.71 mL, 8.4 mmol) to give 1.51 g (70 %) of the product.
  • iV-Nonanoyl-L-phenylalanine (Pelargonyl-L-phenylalanine) The compound was prepared starting from L-phenylalanine (1.652 g, 10 mmol) and pelargonyl chloride (1.88 mL, 10 mmol) to give 2.890 g (95 %) of the product.
  • the compound was prepared starting from D,L-alanine (1.782 g, 20.0 mmol) and decanoyl chloride (4.1 mL, 20.0 mmol) to give 3.4 g (70 %) of the product.
  • the compound was prepared starting from L-valine (1.171 g, 10.0 mmol) and decanoyl chloride (2.04 mL, 10.0 mmol) to give 2.285 g (84 %) of the product.
  • iV-Decanoyl-glycine The compound was prepared starting from glycine (327 mg, 4.361 mmol) and decanoyl chloride (0.893 mL, 4.361 mmol) to give 836 mg (84 %) of the product.
  • the compound was prepared starting from D,L-methionine (2.100 g, 14.074 mmol) and decanoyl chloride (2.92 mL,14.071 mmol) to give 2.62 g (61 %) of the product.
  • the compound was prepared starting from L-tryptophan (613 mg, 3.0 mmol) and decanoyl chloride (0.66 mL, 3.0 mmol) to give 905 mg (84 %) of the product.
  • the compound was prepared starting from 11-amino-undecanoic acid (8.052 g, 40.0 mmol) and 50 % toluene solution of benzyloxycarbonyl chloride (13.4 mL, 40.0 mmol) to give 12.967 g (97 %) of the product.
  • the compound was prepared starting from lauroyl-L-leucine (831 mg, 2.651 mmol), methyl 6-amino-hexanoate hydrochloride (482 mg, 2.651 mmol), DCC (547 mg, 2.651 mmol), Et 3 N (371 ⁇ l, 2.651 mmol) and DMAP (32 mg, 0.265 mmol) to give 1.094 mg (94 %) of the product.
  • the compound was prepared starting from lauroyl-L-leucine (880 mg, 2.807 mmol), methyl 4-amino-butyrate hydrochloride (482 mg, 2.651 mmol), DCC (579 mg, 2.807 mmol), Et 3 N (393 ⁇ L, 2.807 mmol) and DMAP (34 mg, 0.281 mmol) to give 1.065 mg (92 %) of the product.
  • Methyl 6- ⁇ [(2R)-2-(dodecanoylamino)-2-phenylethanoyl]amino ⁇ hexanoate The compound was prepared starting from lauroyl-D-phenylglycine (753 mg, 2.258 mmol), methyl 4-amino-hexanoate hydrochloride (410 mg, 2.258 mmol), DCC (466 mg, 2.258 mmol), Et 3 N (316 ⁇ L, 2.258 mmol) and DMAP (28 mg, 0.226 mmol) to give 1.19O g of the crude product that was recrystallized from MeOH: 478 mg (46
  • the compound was prepared starting from methyl 11-aminoundecanoate hydrochloride (755 mg, 3.0 mmol), decanoyl-D-phenylglycine (916 mg, 3.0 mmol), DCC (619 mg, 3.0 mmol), Et 3 N (420 ⁇ L, 3.0 mmol) and DMAP (37 mg, 0.3 mmol) to give 1.434 g (95 %) of the crude product that was recrystallized from acetonitrile (20-25 mL) giving 904 mg (63 %) of the product, m.p. 101-103 0 C.
  • the compound was prepared starting from methyl 6-aminohexanoate hydrochloride (545 mg, 3.0 mmol), decanoyl-D-phenylglycine (916 mg, 3.0 mmol), DCC (619 mg,
  • the compound was prepared starting from methyl 11-aminoundecanoate hydrochloride (755 mg, 3.00 mmol), nonanoyl-D-phenylglycine (874 mg, 3.00 mmol), DCC (619 mg, 3.00 mmol), Et 3 N (0.42 mL, 3.00 mmol) and DMAP (37 mg, 0.30 mmol) to give 126 g (90 %) of the crude product that was recrystallized from EtOAc giving 813 mg (55 %) of the pure product.
  • the compound was prepared starting from methyl 12-aminododecanoate hydrochloride (797 rng, 3.00 mmol), nonanoyl-D-phenylglycine (874 mg, 3.00 mmol), DCC (619 mg, 3.00 mmol), Et 3 N (0.42 mL, 3.00 mmol) and DMAP (37 mg,
  • the compound was prepared starting from lauroyl-L-leucine, i.e. (25)-2- (dodecanoylamino)-4-methylpentanoic acid (349 mg, 1.113 mmol) and dimethyl L- glutamate hydrochloride (236 mg, 1.113 mmol), DCC (230 mg, 1.113 mmol), and Et 3 N (156 ⁇ L, 1.113 mmol) to give 397 mg (76 %) of the product.
  • lauroyl-L-leucine i.e. (25)-2- (dodecanoylamino)-4-methylpentanoic acid (349 mg, 1.113 mmol) and dimethyl L- glutamate hydrochloride (236 mg, 1.113 mmol), DCC (230 mg, 1.113 mmol), and Et 3 N (156 ⁇ L, 1.113 mmol)
  • the compound was prepared starting from dimethyl L-glutamate hydrochloride (235 mg, 1.110 mmol), lauroyl-D-phenylglycine (370 mg, 1.110 mmol), DCC (229 mg, 1.110 mmol), Et 3 N (155 ⁇ L, 1.110 mmol) and DMAP (13.5 mg, 0.111 mmol) to give 507 mg (93 %) of product.
  • the compound was prepared starting from methyl 6- ⁇ [(25)-2-(dodecanoylamino)-4- methylpentanoyl]amino ⁇ hexanoate (1.069 mg, 2.426 mmol) and IM LiOH (3.64 mL) to give 1.03I g (IOO %) of the product.
  • the compound was prepared starting from methyl 6- ⁇ [(2i?)-2-(dodecanoylamino)-2- phenylethanoyl]arnino ⁇ hexanoate (464 mg, 1.007 mmol), IM LiOH (1.5 niL) to give 445.5 mg (99 %) of the product.
  • the compound was prepared starting from methyl 6- ⁇ [(2i?)-2-(decanoylamino)-2- phenylethanoyl] amino ⁇ hexanoate (467 mg, 1.079 mmol) and IM LiOH (1.6 niL, 1.619 mmol) to give 444 mg (98 %) of product.
  • the compound was prepared starting from methyl ll- ⁇ [(2i?)-2-(decanoylamino)-2- phenylethanoyl] amino ⁇ undecanoate (875 mg, 1.740 mmol) and IM LiOH (2.6 mL, 2.611 mmol) to give 848 mg (100 %) of product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 24:1) giving 595 mg (70 %) of the pure product.
  • the compound was prepared starting from methyl l l- ⁇ [(2i?)-2-(heptanoylamino)-2- phenylethanoyl]amino ⁇ undecanoate (610 mg, 1.324 mmol), ) and IM LiOH (2.0 mL, 2.096 mmol) to give 471 mg (80 %) of the product.
  • the compound was prepared starting from methyl l l- ⁇ [(2i?)-2-(nonanoylamino)-2- phenylethanoyl]amino ⁇ undecanoate (729 mg, 1.492 mmol) and IM LiOH (1.64 mL,
  • the compound was prepared starting from methyl 12- ⁇ [(2i?)-2-(decanoylamino)-2- phenylethanoyl]amino ⁇ dodecanoate (329 mg, 0.637 mmol) and IM LiOH (1.27 mL,
  • the compound was prepared starting from dimethyl (2S)-2- ⁇ [(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino ⁇ pentanedioate (369 mg, 0.784 mmol) and IM LiOH (2.35 mL, 2.35 mmol) to give 278 mg (80 %) of the product.
  • the compound was prepared starting from dimethyl (2S)-2- ⁇ [(2R)-2- (dodecanoylamino)-2-phenylethanoyl]amino ⁇ pentanedioate (186 mg, 0.379 mmol) and IM LiOH (1.1 mL, 1.137 mmol) to give 154.5 mg (88 %) of product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(2i?)-2-
  • hydrochloride salt is water insoluble.
  • iVl-[(li?)-2-Oxo-2-( ⁇ 6-oxo-6-[(4-pyridylmethyl)amino]hexyl ⁇ amino)-l- phenylethyl]decanamide (Compound 1)
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2i?)-2-(decanoylamino)- 2-phenylethanoyl]amino ⁇ hexanoic acid (429 mg, 1.025 mmol), DCC (212 mg, 1.025 mmol), 4-picolylarnine (104 ⁇ L, 1.025 mmol) and DMAP (12.5 mg, 0.103 mmol) to give 459 mg (88 %).
  • the crude product was purified by preparative TLC (CH 2 Cl 2 - MeOH 19:1), giving 171 mg (33 %) of the pure product.
  • the base is insoluble in water and does not form gels.
  • Hydrochloride (10 mg) gelates water (1.5 mL) and makes colourless, transparent gel.
  • the warm solution (until 1 mL) is milk-white, nontransparent, but above this volume it gets more and more clear. After some days of standing, little flocculent crystals occur in the gel.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l- ⁇ [(2i?)-2-(decanoylamino)-2-phenylethanoyl]amino ⁇ undecanoic acid (499 mg, 1.021 mmol), 4-picolylamine (103 ⁇ L, 1.021 mmol), DCC (211 mg, 1.021 mmol) and DMAP (12.5 mg, 0.102 mmol) to give 279.5 mg (47 %) of crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1) giving 132 mg (22 %) of the pure product.
  • the base is insoluble in water and does not form gels.
  • Hydrochloride was prepared starting from the base (1.091 g, 1.885 mmol) to give 1.132 g (98 %) of the product; 10 mg gelates 2.4 mL of water as colourless, slightly opaque gel.
  • the hot solution is milk-white, nontransparent. 5 IR: 3306, 2921, 2851, 1637, 1538, 1369, 1417, 1228, 1194, 792, 720, 695 cm "1 .
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(25)-2- (dodecanoylamino)-3-phenylpropanoyl]amino ⁇ undecanoic acid (531 mg, 1.000 mmol), benzyl iV-[4-(2-hydroxyethyl)phenyl]carbamate (271 mg, 1.000 mmol), DCC
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(2S)-2- (dodecanoylamino)-3-phenylpropanoyl]amino ⁇ undecanoic acid (531 mg, 1.00 mmol), 4-pyridyl-propanol (137 mg, 1.00 mmol), DCC (206 mg, 1.00 mmol) and DMAP (12 mg, 0.01 mmol) to give 572 mg (88 %) of the crude product, that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1) giving 450 mg (69 %) of the pure product.
  • the base is in water insoluble and does not form gels.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino ⁇ hexanoic acid (331 mg, 0.776 mmol), 4-picolylamine (79 ⁇ l, 076 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 411 mg of the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 33:1, 2x developed), giving 232 mg (62 %) of the product.
  • Hydrochloride (10 mg) gelates 200 ⁇ l of water.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino ⁇ hexanoic acid (331 mg, 0.776 mmol), 4-hydroxymethyl-pyridine (85 mg, 076 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 342 mg (85 %) of the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1), giving 236 mg (59 %) of the product.
  • Hydrochloride is water insoluble. It is soluble in EtOH, but upon the addition of water it precipitates immediately
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(25)-2- (dodecanoylammo)-4-methylpentanoyl]amino ⁇ hexanoic acid (331 mg, 0.776 mmol), 4-dimethylaminobenzylamine dihydrochloride (173 mg, 076 mmol), Et 3 N (217 ⁇ L, 1.552 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 432 mg (99 %) of the crude product that was purified by preparative TLC (CH 2 Cl 2 - MeOH 19:1), giving 285 mg (66 %) of the product.
  • Hydrochloride is in water insoluble. It is soluble in EtOH 5 but upon the addition of water it precipitates immediately.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(2S)-2- (dodecanoylamino)-4-methylpentanoyl] amino ⁇ undecanoic acid (308 mg, 0.620 mmol), 4- ⁇ icolylamine (63 ⁇ L, 0.620 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 319 mg (88 %) of the crude product purified by preparative TLC (CH 2 Cl 2 -MeOH 25:1) giving 213 mg (59 %) of the product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(2S)-2- (dodecanoylammo)-4-methylpentanoyl]amino ⁇ undecanoic acid (308 mg, 0.620 mmol) 4-pyridyl-propanol (80 ⁇ l, 0.620 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol), to give 337 mg (88 %) of the crude product by preparative TLC (CH 2 Cl 2 -MeOH 25:1) giving 193 mg (51 %) of the pure product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from ll- ⁇ [(2£) ⁇ 2- (dodecanoylamino)-4-methylpentanoyl] amino ⁇ undecanoic acid (308 mg, 0.620 mmol), 4-hydroxypyridine (68 mg, 020 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 331 mg (91 %) of the crude product, that was purified by preparative TLC (CH 2 Cl 2 -MeOH 25:1) giving 241.5 mg (66 %) of the pure product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l- ⁇ [(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino ⁇ undecanoic acid (308 mg, 0.620 mmol), 4-(dimethylamino)benzylamine dihydrochloride (138 mg, 020 mmol), DCC (128 mg, 0.620 mmol), Et 3 N (173 ⁇ L, 1.240 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 343 mg (88 %) of the crude product, that was purified by preparative TLC (CH 2 Cl 2 -MeOH 25:1) giving 163.5 mg (42 %) of the pure product.
  • Hydrochloride is in water insoluble .
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2S)-2- (dodecanoylamino)-2-phenylethanoyl] amino ⁇ hexanoic acid (304 mg, 0.763 mmol), DCC (157 mg, 0.763 mmol), 4-picolylamine (77 ⁇ L, 0.763 mmol) and DMAP (9 mg, 0.076 mmol) to give 261 mg (70 %) of the product.
  • Hydrochloride is in water insoluble (crystallizes). It is soluble in EtOH, but upon addition of water, it crystallizes.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2S)-2- (dodecanoylamino)-2-phenylethanoyl]amino ⁇ hexanoic acid (304 mg, 0.763 mmol), DCC (157 mg, 0.763 mmol), 4-pyridyl- ⁇ ropanol (99 ⁇ l, 0.763 mmol) and DMAP (9 mg, 0.076 mmol) to give 328 mg (83 %) of the product.
  • Hydrochloride is water insoluble, and crystallizes. It is soluble in EtOH 5 but upon addition of water, it crystallizes.
  • the compound was prepared following general procedure for DCC-condensations with amines and alcohols, starting from 6- ⁇ [(2S)-2-(dodecanoylamino)-2- phenylethanoyl]amino ⁇ hexanoic acid (290 mg, 0.728 mniol), DCC (150 nig, 0.728 mmol), 4-hydroxypyridine (79 mg, 0.835 mmol) and DMAP (9 mg, 0.073 mmol) to give 328 mg (95 %) of the product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2i?)-2- (dodecanoylamino)-2-phenylethanoyl] amino jhexanoic acid (205 mg, 0.459 mrnol), DCC (95 mg, 0.0.459 mmol), 4-picolylamine (46 ⁇ L, 0.459 mmol) and DMAP (6 mg, 0.046 mmol) to give 126 mg (51 %) of the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 25:1) to give 29 mg of the pure product.
  • Hydrochloride (10 mg) gelates 1.1 mL water as opaque, nontransparent gel.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6- ⁇ [(2i?)-2- (dodecanoylamino)-2-phenylethanoyl]amino ⁇ hexanoic acid (205 mg, 0.459 mmol), DCC (95 mg, 0.0.459 mmol), 4-hydroxymethylpyridine (50 mg, 0.459 mmol) and DMAP (6 mg, 0.046 mmol) to give 145.5 mg (59 %) of the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1) giving 87 mg (35 %) of the pure product.
  • Hydrochloride (10 mg) gelates 800 ⁇ L of water.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l- ⁇ [(2i?)-2-(heptanoylamino)-2-phenylethanoyl]amino ⁇ t ⁇ ndecanoic acid (462 mg, 1.034 mmol), DCC (213 mg, 1.034 mmol), 4- ⁇ icolylamine (105 ⁇ L, 1.034 mmol) and DMAP (13 mg, 0.103 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH ) to give 97 mg (17 %) of the pure product.
  • Hydrochloride was prepared starting from the base (263 mg, 0.490 mmol) giving 266 mg (95 %) of the product; 10 mg gelates 4.0 mL of water in the form of opaque, nontransparent gel.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l- ⁇ [(2i?)-2-(nonanoylamino)-2- ⁇ henylethanoyl]amino ⁇ undecanoic acid (566 mg, .1192 mmol), DCC (246 mg, 1.192 mmol), 4-picolylamine (120 ⁇ L, 1- 192 mmol) and DMAP (15 mg, 0.120 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1, 2x)) to give 140 mg (21 %) of the pure product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 12- ⁇ [(2i?)-2- (nonanoylamino)-2-phenylethanoyl] amino jdodecanoic acid (418 mg, 0.855 mmol), DCC (176 mg, 0.855 mmol), 4-picolylamine (86 ⁇ L, 0.855 mmol) and DMAP (11 mg, 0.086 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1, 2x) to give 95 mg (20%) of the pure product.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 12- ⁇ [(2i?)-2-(decanoylamino)- 2-phenylethanoyl]amino ⁇ dodecanoic acid (253 nig, 0.427 mmol), DCC (88 mg, 0.427 mmol), 4-picolylamine (43 ⁇ L, 0.427 mmol) and DMAP (5 mg, 0.043 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1, 2x) to give 77 mg (30 %) of the pure product.
  • Hydrochloride (10 mg) gelates 2.4 mL of water in the form of opaque, nontransparent gel.
  • the compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 11-([2(.R)- (dodecanoylamino)-2-phenyletanoyl] amino ⁇ undecanoic acid (517 mg, 1.00 mmol), 4-amino-pyridine (94 mg, 1.00 mmol), DCC (206 mg, 1.00 mmol) and DMAP (12 mg, 0.10 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1) giving 65 rag (11 %) of the pure product.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l- ⁇ [(2i?)-2-(dodecanoylamino)-2-phenyletanoyl]amino ⁇ undecanoic acid (408 mg, 0.789 mmol), 4-picolylamine (80 ⁇ L, 0.789 mmol), DCC (163 mg, 0.789 mmol) and DMAP (10 mg, 0.079 mmol) to give the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 25:1, 2x) giving 119 mg (25 %) of the pure product.
  • Hydrochloride was prepared starting from the base (468 mg, 0.771 mmol) giving 462 mg (93 %) of the product; 10 mg gelates 1.2 mL of water as white, nontransparent gel.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from ( (25)-2- ⁇ [(2S)-2-(dodecanoylamino)-4- methyl ⁇ entanoyl]amino ⁇ pentanedioic acid (256 mg, 0.578 mmol), DCC (239 mg, 1.157 mmol), 4-picolylamine (117 ⁇ L, 1.157 mmol) and DMAP (14 mg, 0.116 mmol) to give 245 mg (68 %) of the crude product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1, 2x) giving 125.5 mg (35 %) of the pure product.
  • the base is in water insoluble and does not form gels.
  • Dihydrochloride (10 mg) gelates water (4.4 mL) in the form of colourless, transparent gel, after some hours of standing.
  • the hot solution up to 600 ⁇ L is clear, but above this volume of water it becomes milky white up to 2.0 mL volume; then it is more and more clear.
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from (25)-2- ⁇ [(2i?)-2-(dodecanoylamino)-2- phenylethanoyl] amino ⁇ pentanedioic acid (653 mg, 1.412 mmol), DCC (582 mg, 2.823 mmol), 4-picolylamine (286 ⁇ L, 2.823 mmol) and DMAP (35 mg, 0.282 mmol) to give 557 mg (61 %) of the crade product that was purified by preparative TLC (CH 2 Cl 2 -MeOH 19:1, 2x) giving 120 mg (13 %) of still not quite pure product.
  • the base is in water insoluble and does not form gels.
  • Dihydrochloride was prepared starting from the base (497 mg, 0.798 mmol) giving 436 mg (79 %) of the product; 10 mg gelates 1.3 mL of water in the form of colourless, transparent gel.
  • the compound was prepared following the general procedure for condensation with amines using Ph3P/CCl 4 /Et 3 N, starting from decanoyl-D-phenylglycine (500 mg, 1.637 mmol) and methyl 12-amino-dodecanoate hydrochloride (435 mg, 1.637 mmol) and Et 3 N (0.456 mL, 3.274 mmol) to give 365 mg (43 %) of the pre product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 P/CCl 4 /Et 3 N 5 starting from -V-[(benzyloxy)carbonyl]glutamic acid (8.308 g, 29.54 mmol) and 4-picolylamine (5.98 mL, 59.08 mmol) to give 10.619 g (78 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 P/CCl 4 /Et 3 N, starting from ll-[ (tert- butoxycarbonyl)amino]undecanoic acid (9.256 g, 30.708 mmol) and 4-picolylamine (3.11 mL, 30.708 mmol) to give 11.748 g (98 %) of the crude product that was purified by flash-chromatography (CH 2 Cl 2 -MeOH 30:1) giving 10.162 g (85 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using Ph S PZCCl 4 VEt 3 N, starting from 11- [(benzyloxycarbonyl)amino]undecanoic acid (300 mg, 0.894 mmol) and 4- picolylamine (90 ⁇ L, 0.894 mmol), Ph 3 P (281 mg, 0.894 mmol), Et 3 N (125 ⁇ L, 0.894 mmol) and CCl 4 (86 ⁇ L, 0.894 mmol) to give 235 mg (61 %) of the product.
  • the compound was prepared starting following the general procedure for condensation with amines using Ph 3 PZCCl 4 ZEt 3 N 5 from decanoyl-D-phenylglycine (764 mg, 2.50 mmol) and 4- ⁇ icolylamine (0.253 mL, 2.50 mniol) to give 473 mg (48 %) of the pure product.
  • Hydrochloride was prepared from the base (271 mg, 085 mmol) giving 238 mg (80 %) of the product. It crystallizes from water, and does not form hydrogel.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 PZCCl 4 ZEt 3 N, starting from decanoyl-L-leucine (1.35 g, 4.73 mmol) and l l-undecanoyl-4'-picolylamide (1.38 g, 4.73 mmol) to give 1.50 g (56 %) of the product
  • the compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l- ⁇ [(2S)-2-(dodecanoylamino)-3-phenylpropanoyl]amino ⁇ undecanoic acid (555 mg, 1.046 mmola), DCC (216 mg, 1.046 mmola), 4-picolylamine (106 ⁇ l, 1.046 mmola) and DMAP (13 mg, 0.105 mmola) to give 558 mg (86 %) of the crude product that was purified by preparative TLC (CH 2 CIi-MeOH 19:1) giving 234 mg (36 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 P/CCl 4 /Et 3 N, starting from decanoyl-L-phenylalanine (1.042 g, 3.00 mmol) and ll-undecanoyl-4'-picolylamide (874 mg, 3.00 mmol)) to give 1.317 g (75 %)of the raw product After purification on chromatographic plates (CH 2 Cl 2 -MeOH 19:1) it was obtained 828 mg (47 %) of the pure product.
  • IR (KBr): 3293, 3062, 2921, 2851, 1638, 1541, 1466, 1455, 1436, 1375, 1272, 1230, 1191, 1160, 1119, 1029, 786, 745, 721 and 698 cm “1 .
  • the compound was prepared following the general procedure for condensation with amines using PhsP/CCL/EtsN, starting from decanoyl-D,L-alanine (0.9 g, 3.7 mmol) and l l-aminoundecanoyl-4'-picolylamide (1.079 g, 3.7 mmol) to give after purification by TLC chromatography (CH 2 Cl 2 -MeOH 100 :1) 0.816 g (47 %) of the product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 PZCCl 4 ZEt 3 N, starting from pelargonyl-L-phenylalanine (1.069 g, 3.50 mmol) and ll-undecanoyl-4'-picorylamide (1.020 g, 3.50 mmol) to give 1.705 g (84 %) of the raw product After purification by flash chromatography (CH 2 Cl 2 - MeOH 30:1 and 20:1) it was obtained 1.395 g (69 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 PZCCl 4 ZEt 3 N, starting from decanoyl-D,L-methionine (1.315 g, 4.333 mmol) and ll-aminoundecanoyl-4'-picolylamide (1.265 g, 4.341 mmol) to give 1.970 g of the crude product that was purified by preparative TLC (CH 2 Cl 2 - MeOH 9:1) giving 0.982 g (39 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using Ph 3 PZCCl 4 ZEt 3 N, starting from decanoyl-L-glycine (790 mg, 3.445 mmol) and l l-undecanoyl-4'-picolylamide (1004 mg, 3.445 mmol), to give 1074 mg (62 %) of the crude product. Repeated chromatographic purification gave 240 mg (14 %) of the pure product.
  • the compound was prepared following the general procedure for condensation with amines using PhsP/CCLj/EtsN, starting from decanoyl-L-tryptophan (868 mg, 2.421 mmol) and l l-undecanoyl-4'-picolylamide (706 mg, 2.421 mmol), to give 993 mg (65 %) of the product
  • the compound was prepared following the general procedure for condensation with amines using PhsP/CCU/EtsN, starting from commercial BOC-11-aminoundecanoic acid (1.00Og, 3.138 mmol) and benzylamine (0.363 mL, 0.356 mg, 3.318 mmol) to give 922 mg (71 %) of the product
  • the compound was prepared starting from benzyl 7V-((lS)-4-oxo-4-[(4- pyridylmethyl)amino]-l- ⁇ [(4-pyridylmethyl)amino]carbonyl ⁇ butyl)carbamate (1.747 g, 3.785 mmol) giving 1.239 g (100 %) of the pure product as an oil that crystallized spontaneously.
  • the compound was prepared starting from 4- ⁇ [(benzyloxy)carbonyl]amino ⁇ phenetyl 11 - ⁇ [(2>S)-2-(dodecanoylamino)-3 -phenylpropanoyl] amino ⁇ undecanoate (374 mg, 0.477 mmol) to give 310 mg (100 %) of the pure product.
  • Hydrochloride is insoluble in water and does not form hydrogel.
  • the compound was prepared starting from Nl-(4-pyridylmethyl)-ll- ⁇ [(25)-3- [ ⁇ erizyloxy)phenyl]-2-(decanoylamino)propanoyl]amino ⁇ undecanarnide (289 mg 0.414 mmol) to give after purification by preparative TL chromatography (CH 2 Cl 2 - MeOH 20:1) 111 mg (44%) of the pure product.
  • Hydrochloride was prepared starting from the base (270 mg, 0.443 mmola) giving 286 mg (100 %) of the product.
  • the compound was prepared: a) following the general procedure for TFA-cleavage of BOC-group, starting from ll-(ter ⁇ butoxycarbonylamino)undecanoyl-4'- picolylamide (3.265 g, 8.39 mmol) to give 2.445 g (100 %) of the product.
  • the compound was prepared following the general procedure for TF-cleavage of BOC-group, starting from tert-butyl 7V-[(l,S3-l-[4-(benzyloxy)benzyl]-2-oxo-2-( ⁇ l l- oxo-ll-[(4-pyridylmethyl)ammo]undecyl ⁇ amino)ethyl]carbamate (1.282 g, 2.134 mmol) to give 1.108 g (95 %) of the product.
  • the compound was prepared following the general procedure for TFA-cleavage of BOC-group, starting from 11-BOC-ammoundecanoyl-benzylamide (697 mg, 1.786 mmol) to give 514 mg (99 %) of the product.
  • the compound was prepared following the general procedure for TFA-cleavage of BOC-group, starting from tert-butyl N-[(1S)-1-( ⁇ [1 l-(benzylamino)-l 1- oxoundecyl]amino ⁇ carbonyl)-3-methylbutyl]carbamate (533 mg, 1.06 mmol) to give 400 mg (93 %) of the product.
  • the compound was prepared foolowing the general procedure for the reaction of BOC-protected amino acid succinimide ester with 1 l-aminoundecanoyl-4 1 - picolylamide starting from commercial Boc-Tyr(OBzl)-OSu (1.073g, 2.290 mmol) and ll-aminoundecanoyl-4'-picolylamide (0.687 g, 2.357 mmol) to give 1.350 g (91
  • the compound was prepared foolowing the general procedure for the reaction of BOC-protected amino acid succinimide ester with 1 l-aminoundecanoyl-4 1 - picolylamide starting from Boc-NH-L-Leu-succinimide ester (575 mg, 1.75 mmol) and 1 l-aminoundecanoyl-4'-picolylamide (510 mg, 1.75 mmol) to give 776 mg (88
  • NIR Near infrared
  • Figure 1 is NIR spectra of Compound 2 hydrochloride in water at concentrations of 5%, 1%, 0.5% and 0.33% wt./vol. together with the NIR spectrum of Compound 2 free base at 0.33% wt/vol.
  • the four samples of the hydrochloride have formed gels but the free base is in the sol state.
  • Dynamic vapour sorption was performed to assess the ability of the gel forming compounds to interact with water molecules.
  • the water vapour sorption isotherm was determined by measuring the mass changes of the sample at various humidity conditions. At equilibrium, the reaction between water content and equilibrium humidity of a material can be displayed graphically by a curve, the so called sorption isotherm. For each humidity value, a sorption isotherm indicates the corresponding water content value at a given, constant temperature. The sorption behaviour changes if the composition or quality of the material changes.
  • Dynamic Vapour Sorption (DVS) is employed to measure the moisture sorption properties of hygroscopic gel forming compounds. The affinity of these materials for moisture is due to a degree of amorphous character present in the material.
  • highly crystalline gelators may have very low affinities for moisture sorption due to the low surface energy of the particles formed during the crystallisation process.
  • the gel forming compounds of the invention show classic sorption behaviour with a slight hysteresis between the sorption and desorption course.
  • Samples of about 10 - 20 mg were loaded on one side of the pan balance and the program set to isothermal measurements at 25 0 C in a two cycles: sorption from 0 %RH up to 90 % RH, and then desorption from 90 % RH to 0 %RH, all in 10 %RH steps.
  • Figure 2 is water vapour sorption/desorption plot for Compound 2 hydrochloride at a temperature of 25 0 C.
  • the instrument was equipped with a optional microscopy assembly that allows video tracking of sorption/desorption processes and Figure 3 illustrates Compound 10 hydrochloride particles at both 0% relative humidity (in the dry state) and at 90% relative humidity with 27% adsorbed water.
  • the maximal water vapour sorption (at 90% relative humidity, 25 0 C) was measured for several of the compounds of the present invention and the results are presented in Table 5. A maximal water vapour sorption of 5% or less indicates that the compounds are poor at forming hydrogels.
  • Buffer pH 1.658 (potassium tetraoxalate 50 mmol/L)
  • Buffer pH 4 (potassium hydrogen phthalate 50 mmol/L)
  • Buffer pH 7 (disodium hydrogen phosphate 27.5 mmol/L + potassium dihydrogen phosphate 20 mmol/L)
  • Buffer pH 10 sodium hydrogen carbonate 25mmol/L + sodium carbonate 25 mmol/L
  • Table 6 shows that all of the compounds are capable of forming gels but that gel formation is dependent upon various factors including the nature of the solvent (i.e. pure water, aqueous sodium chloride solution or aqueous acetic acid), the pH, and the salt concentration, with the different gel forming requiring different conditions for gelation.
  • Table 6 - Gel Formation in Various Solvents i.e. pure water, aqueous sodium chloride solution or aqueous acetic acid
  • the minimal gelation concentration was then determined for a selection of compounds in the solvents listed above.
  • the gel forming compounds (from 10 mg up to 50 mg) were dissolved in water (or buffers or pharmaceutical oil; from 1 up to 5 mL) to make up a concentration from 0.2 up to 5 % wt./voL.
  • the glass container (vial) was heated until the gel forming compound dissolved completely, and it was then cooled to room temperature. Gelation was observed, and the minimal gelation concentration (MGC) was determined visually by the vial-inversion method.
  • the sample vials were put in an inverted position, and the concentration was taken as MGC at the point at which the gel started to flow.
  • the gels were strong enough not to flow on inversion of the container and were found to be stable at room temperature for several months. They are pH-sensitive, forming around acidic and neutral pH but not at pH 10.0.
  • Dimethyl sulfoxide has also been shown to increase the rate and amount of transdermal diffusion (Y. Kalia, V. Merino, R. Guy; Dermatologic Clinics; 1998, 16, 289-299).
  • the binary composition of water and DMSO has even better gelation properties than single components.
  • Compound 15 hydrochloride (10 mg) can gel 1.2 mL water, or 0.1 mL DMSO. However, it can gel mix of 18 mL DMSO and 6.4 mL water.
  • Table 7 shows the minimal gelation concentration of various compounds of the invention in water measured by the vial inversion method.
  • Tables 8 and 9 show the effect of pH and salt concentration on the gelation of various compounds of the invention at a concentration of 10 mg/mL.
  • Oleic acid (cis-9-octadecenoic acid) is a monounsaturated fatty acid and has the ability of oleic acid to lessen the irritation caused by other penetration enhancing agents and/or other formulation components to a greater extent than oleyl alcohol has been described previously (United States Patent 6,319,913 Penetration enhancing and irritation reducing systems).
  • the gelled combination of oleic acid with a gelling agent (supramolecular hydrogelator), such as referred here, and/or other irritation reducing agents, can result in drug formulations that produce markedly reduced levels of skin irritation.
  • Tack is the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas excessive tack may leave adhesive residue on removal or cause dermal irritation. If the probe tack value of gel is less than 0.25 N, then the skin adhesiveness of gel becomes insufficient, so that it is likely to peel off even upon a little movement.
  • Adhesives with a very high tack could form strong initial bonds with the skin upon application and thus may be difficult to remove. If the probes tack value of gel exceeds the 1.2 N value, the skin irritation increases so much that rashes in the skin and pains upon peeling are likely to occur.
  • Measurements of probe tack were based on the method described in ASTM D2979- 01 Standard Test Method for Pressure-Sensitive Tack of Adhesives Using an Inverted Probe Machine using an inverted probe machine (Texture Analyzer TA- XTPlus, Stable Micro Systems).
  • the probe tack tester defined in ASTM D 2979-01, after one bottom face of a cylinder (probe) made of steel having a diameter of 12.5 mm and a gel layer surface are brought into contact with each other at a contact load of 4.9 ⁇ 0.01 N for a contact time of 10.0 ⁇ 0.01 seconds, the probe is separated from the adhesive layer surface in the perpendicular direction of the latter at a separating speed of 0.5 ⁇ 0.1 mm/s.
  • the probe tack value refers to the force [N] required at the time of separation.
  • FIG. 4 shows a typical curve of tack probe measurement: force (in g) vs. distance (or displacement in mm).
  • Probe tack or Adhesive Peak Force
  • the average force at maximum is average of 10 repeated measurements. Adhesion throughout the contact surface was achieved only for a short period of time, as indicated by the shape of the curve. The area under the curve of tack force vs.
  • Table 11 shows the probe tack measurements of various compounds of the invention in water, and from the table we can determine where the minimal gelation concentration (MGC) is by up-slope of the tack force values.
  • Table 12 shows the effect on the tack force of adding a buffer (pH 1.658) to the solvent.
  • Table 12 shows that many of the compounds, when mixed an aqueous solvent having a pH of 1.658, form gels which have a tack force of greater than 0.25N and less than 1.2N, which makes them ideal candidates for use in bioadhesive systems.
  • Table 13 shows the effect of acidity on the tack force by comparing the effect on the tack force of using as a solvent acetic acid of varying concentrations and therefore varying pH. The results from the table show that for all of the tested compounds, it is possible to select a pH value at which the tack force will make the gel suitable for use in bioadhesive systems.
  • Table 14 illustrates the effect of sodium chloride in gels on probe tack and show that for some compounds it is possible to form a gel using a solvent which contains sodium chloride in which the gel has a tack value which makes it suitable for use in bioadhesive systems.
  • the gels can be described as weakly adhering gels.
  • the adhesive properties of the gels are dominated by the solvent (or water). Because aqueous solutions of the gel forming compounds are freely flowing liquids at elevated temperatures, these materials can readily be moulded into different shapes at temperatures above the gel point. When these solutions are cooled to room temperature, elastic solids are formed with very weak moduli, depending on the hydrogelator concentration in the gel. Adhesion of these gels has been studied using a rigid cylindrical indenter in contact with a thin layer of the gel. The experiments indicate that adhesion of the gel is dominated by the solvent, and can be viewed as a simple wetting process, Table 15.
  • Hydrogelators 2, 10, 15 and 11 did not gel (at lOmg/1 mL) in paraffin oil, ethylene glycol, or propylene glycol. They gelation properties in other oils are given in Table 16, which show that some of the compounds form gels in some non-aqueous solvents which are suitable for use in bioadhesive systems.
  • Compounds 2, 10 and 15 all form such gels in oleic acid and Compound 3 also forms a suitable gel with Cetiol ® LC Table 16
  • the quality of gels as usable objects was checked by measuring the gel texture using the viscosity values. Viscosity often determines the flow of products and controls the productivity.
  • the flowability of the gel e.g. the ability to be extruded through a syringe
  • the flowability of the gel is the ability of the gel to be applied onto and conform to sites on or in tissue, including tissue surfaces and defined cavities (intravertebral spaces, tissue).
  • the gel flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula, when sprayed onto the delivery site, or the like.
  • the threshold stresses are typically in the range of several kPa.
  • compositions will remain generally immobile when subjected to stresses below the threshold level.
  • a minimum pressure gradient is required to extrude a given gel through orifice. Once this minimum pressure gradient is exceeded, the pressure gradient during gel extrusion is insensitive to the flow rate.
  • Measurements of extrusion were based on flow rate determination using a capillary extrusion viscosimeter with a plunger (tube length: 6, tube diameter 12.5 mm) that was attached to a texture analyzer machine (Texture Analyzer TA-XTPlus, Stable Micro Systems), and it consists of a cylindrical steel flow cell that has a steel bottom with a small size orifice (lmm in diameter).
  • the pre-test speed was 1.5 mm/second, and test speed 2 mm/second.
  • the trigger force was set at 0.00981 N. The force and stress required to extrude the gel through the orifice at the constant speed was measured and the results are shown in Table 17.
  • the force required to extrude the gel formulations is co-measurable to forces required to extrude from the collapsible tube.
  • the low values at concentrations in the vicinity of minimal gelation concentration (MGC) reveal the easy of extrusion of such gels.
  • the gel front diffusivity or penetration depth is measured from the scanned images and diffusional constant calculated. Measurements collected from analyzing these images were fit to an equation of motion for a swelling gel and conventional diffusion models to characterize the transport characteristics of these materials. The mean-square displacement (MSD), and the time lag (tlag) yielded the expected linear relationship. Using the relation:
  • permeant i.e., water in hydrogels
  • the diffusion of permeant is determined by the relative rates of diffusion and network relaxation (T. Alfrey, E.F. Gurnee and W.G. Lloyd, Diffusion in glassy polymers, J. Polym. Sd. Part C 1966, 12, 249-261.). This effect of the diffusion of permeant can determine the drug release profiles from the swelling gel matrix.
  • Peppas A simple equation for description of solute release. I. Fickian and non- Fickian release from non-swellable devices in the form of slabs, spheres cylinders or discs, J. Contr. Release 1987, 5, 23-36.; P.L. Ritger and N.A. Peppas, A Simple equation for description of solute release. I. Fickian and non-Fickian release from swellable devices, J. Contr. Release 1987, 5, 37-42.):

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Abstract

Compounds of general formula (Ia) or (Ib): general formula (Ia) or (Ib): wherein: R1 is C1-6 alkyl, benzyl, phenyl, or indolylmethyl, any of which may be substituted with OH, 0(C1-6 alkyl) or S(C1-6 alkyl); each of X and Xa is independently -O-[CH2]P- or -NH-[CH2]r; p is 1 to 4 except when: R1 is C1-6≤ alkyl, and: n is ≤ 6 in compounds of formula (Ia); or q is ≤ 5 in compounds of formula (Ib); in which case, p is 2 to 4; r is 0 to 4; each of R2 and R2a is independently pyridyl; m is an integer of 4 to 12; n is an integer of 5 to 12; q is an integer of 4 to 11; or salts thereof are capable of forming gels when added to water or to organic solvents, heated and left to cool.

Description

GEL FORMING COMPOUNDS
The present invention relates to compounds which are capable of forming gels when mixed with an appropriate solvent and to methods of preparing these compounds. The invention also relates to the gels formed by the compounds, methods for making them, compositions comprising the gels and to the use of the gels in various applications.
Supramolecular hydrogels are used in many applications including food and cosmetic thickeners, formation of contact lenses, vehicles for drug delivery and tissue replacement matrices. They are of particular interest as drug delivery vehicles because of their generally favourable biocompatibility. Because of their high water content they are particularly attractive for the delivery of delicate bioactive agents such as proteins.
Gels may be either chemical or physical gels. Chemical gels consist of solid components which are covalently linked to one another and gel formation is irreversible. Physical gels are generally formed from smaller subunits which, are linked non-covalently into a network. Physical gels tend to be thermoreversible.
Hydrogels may be formed either by polymers or by low molecular weight gelators (LMWGs). In gels formed by LMWGs, the molecules are assembled in well ordered arrays and the gels are thermoreversible and strong. In addition, they tend to have low minimal gelation concentrations and high tolerance towards salts and other additives.
There are many examples of documents relating to hydrogels formed from chemically cross-linked hydrophilic polymers. In EP-A-0212959, a hydrogel is formed from a cross linked polymerised hydrophilic polymer with an olefmic bond, an amino acid polymer, a cross-linking agent and a lower alcohol. WO-A-97/05185 relates to macromers which can be ionically or covalently cross- linked to form hydrogels. The macromers are block co-polymers which have hydrophilic blocks and blocks which are more hydrophobic.
WO-A-03/089506 also relates to hydrogels as well as to hydrogel foams and superporous hydrogels. These hydrogels are said to consist of two or more interpenetrating polymer networks which provide enhanced elasticity and mechanical strength properties.
WO-A-2004/104021 again relates to hydrogels which, in this case, are intended to provide controlled release of active agents by utilising repeat sequence protein polymers.
There are also, however, a number of documents which relate to the formation of hydrogels from LMWGs. The art is reviewed by Maaike de Loos, Ben L. Feringa, and Jan H. van Esch, Design and Application of Self-Assembled Low Molecular Weight Hydrogels Eur. J. Org. Chem. 2005, 3615-3631; and by Estroff LA. Hamilton AD., in "Water gelation by small organic molecules", Chemical Reviews. 2004, 104(3), 1201-1217,.
Fages et al, Top. Curr. Chem. 2005, 256, 77-131, describe urea derivatives which are capable of forming gels when dissolved in various organic solvents. Some of the ureido amino acid derivatives are also capable of forming gels in water, Wang et al, Chem. Commun., 2003, 310-311.
In our earlier publications (Caplar et al, Eur. J. Org. Chem., 2004(19), 4048-4059 and D'Aleo et al, Chem. Commun., 2004, 190-191) we discuss hydrogelator compounds formed by combining 11-aminoundecanoioc acid, lauric acid and aromatic and aliphatic amino acid units in the same molecule. These molecules were low molecular weight compounds derived from amino acids and connected through amide bonds with long aliphatic chains ending in a carboxylic acid functional group and have the general formula:
Figure imgf000005_0001
wherein R can be isopropyl, isobutyl, benzyl or phenyl.
The sodium salts of these compounds are able to form gels but the acids are not very satisfactory gelators as they tend to be insoluble in both aqueous and in some organic solvents. This means that gelation of the compounds is pH sensitive since the sodium salts exist and therefore form gels in alkaline media, whereas the free acids are insoluble in acidic solvents. Similarly, we report that chiral bis(amino acid) oxalyl amides and chiral bis(amino alcohol)oxalyl amide are capable of forming hydrogels (Makarevic et al, Chem.Eur.J. 2001, 7, 3328 - 3341, Makarevic et al,. Croat. Chem. Acta. 2004, 77, 403-414).
The present invention relates to novel non-polymeric compounds which, in water, are able to form hydrogels without the need for chemical cross-linking. In addition, the compounds are also able to form gels in solvents other than water, including organic solvents and oils and at acidic pH. It is thought that the gels are formed by the self- assembly of the molecules into nanofibrous networks.
Therefore, in a first aspect of the present invention there is provided a compound of general formula (Ia) or (Ib):
Figure imgf000005_0002
(Ia) (Ib)
wherein: R1 is Ci-6 alkyl, benzyl, phenyl, or indolylmethyl, any of which may be substituted with OH5 0(C1-6 alkyl) or S(C1-6 alkyl); each of X and Xa is independently -O-[CH2]P- or -NH-[CH2Jr-; p is 1 to 4 except when:
R1 is C1-6 alkyl, and: n is < 6 in compounds of formula (Ia); or q is < 5 in compounds of formula (Ib); in which case, p is 2 to 4; r is 0 to 4; each of R2 and R2a is independently pyridyl; m is an integer of 4 to 12; n is an integer of 5 to 12; q is an integer of 4 to 11 ; or a salt thereof.
When the compounds of general formula (Ia) or (Ib) or their salts are added to a solvent, it is believed that a gel is formed by means of individual molecules of the compounds forming chains and these chains becoming entangled to form nanofibrous networks. However, the effectiveness of the invention is not dependent on the correctness of this supposition.
The compounds of general formula (Ia) and (Ib), and especially their salts, have the advantages that they can form gels in both water and organic solvents and that the properties of the gels can easily be manipulated by adjusting the temperature, pH or the type and amount of solvent present. Unlike many of the prior art compounds, the compounds of general formulae (Ia) and (Ib) or salts thereof are capable of forming gels in acidic media.
In the present invention, the term "gel forming compound" refers to any molecule, whether a small organic molecule (such as the compounds of general formulae (Ia) and (Ib)) or a polymer, which forms a gel when mixed with either an aqueous or a non-aqueous solvent and, if necessary, heated and then cooled.
In the present specification "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl5 isobutyl, sec-butyl and n-hexyl.
Salts of the compounds of general formulae (Ia) and (Ib) are preferably pharmaceutically acceptable and include salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, salts of phosphoric and sulfonic acids; and salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifiuoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, lactobionate, pivolate, camphorate, undecanoate and succinate, salts of organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p- chlorobenzenesulfonate and p-toluenesulfonate.
If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
In preferred compounds of general formula (Ia) and (Ib), independently or in any combination:
R1 is C1-6 alkyl, phenyl, benzyl, j>-hydroxybenzyl, indolylmethyl or methylthioethyl; m is 5 to 10; p is 0 to 3;
X is -NH-[CH2]r; and each of R2 and R2a is 4-pyridyl.
In more preferred compounds of general formula (Ia), independently or in any combination, m is 7 to 10, n is 8 to 10, X is -NH-CH2- and R2 is 4-pyridyl.
In more preferred compounds of general formula (Ib), q is 1 to 3, most preferably 2, X is -NH-CH2- and R2 is 4-pyridyl. In these compounds, it is particularly preferred that R1 is isobutyl or phenyl.
The hydrochloride salts of the compounds of general formulae (Ia) and (Ib) are particularly suitable hydrogelators.
Among the most preferred compounds are:
1. iVl-[(li?)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyljdecanamide;
2. M-(4-Pyridylmethyl)-l l-{[(2i?)-(decanoylamino)-2-phenylethanoyl] aminojundecanamide; 3. 3-(4-Pyridyl)propyl-l l-{[(2£)-2-(dodecanoylamino)-3~phenylpropanoyl] amino } undecano ate ;
4. M-{(15)-3-Methyl-l-[({6-oxo-6-[4-pyridylmethyl)amino]hexyl}amino) carbonyl]butyl}dodecanamide;
5. M-{(15)-3-Methyl-l-[({l 1-oxo-l l-[(4-pyridylmethyl)amino]undecyl} amino)carbonyl]butyl}dodecanamide;
6. 3 -(4-Pyridylρropyl)- 11 - { [(25)-2-(dodecanoylamino)-4-methylpentanoyl] amino } undecano ate;
7. 4-Pyridylmethyl- 11 - { [(2>S)-2-(dodecanoylamino)-4-methylpentanoyl] amino } undecanoate; 8. M-[(li?)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyl]dodecanamide;
9. 4-Pyridylmethyl-6-{[(2i?)-2-(dodecanoylamino)-2-phenylethanoyl]amino} hexanoate;
10. Nl -(4-Pyridylmethyl)- 11 - { [(2i?)-(heptanoylamino)-2-phenylethanoyl]amino} undecanamide;
11. Nl -(4-Pyridylmethyl)- 11 - { [(2i?)-(nonanoylamino)-2-phenylethanoyl]amino } undecanamide; 12. -Vl-(4-Pyridylinethyl)-12-{[(2i?)-(nonanoylainmo)-2-plienylethanoyl]ainmo} dodecanamide; 13. Nl -(4-ρyridylmethyl)- 12- { [(2i?)-(deeanoylamino)-2-phenylethanoyl] amino } dodecanamide; 14. M~((li?)-2-Oxo-2-{[l 1-oxo-l l-(4-pyridylamino)undecyl]amino}-l- phenylethyl) dodecanamide;
15. Nl -[(li?)-2-oxo-2-({ 11 -oxo-11 -[4-pyridylmethyl)amino]undecyl}amino)-l - phenylethyl] dodecanamide;
16. M ,ΛT5-di(4-pyridylmethyl)-(2S)-2- { [(2S)-2-(dodecanoylamino)-4- methylpentanoyl]amino}pentanediamide;
17. M ^V5-di(4-pyridylmethyl)-(25)-2-{ [(2i?)-2-(dodecanoylamino)-2- phenylethanoyl]amino}pentanediamide;
18. M -(pyridylmethyl)- 11 - { [(2S)-(decanoylamino-4-methylpentanoyl] amino } undecanamide; 19. M-(4-Pyridymiethyl)-l l-{[(25)-2-(decanoylamino-3- methylbutanoyl] amino } undecanamide;
20. M-[(15)-l-Benzyl-2-oxo-2-({l 1-oxo-l l-[4- pyridylmethyl)amino]undecyl}amino)ethyl]dodecanamide;
21. M-(4-Pyridylmethyl)-l l-{[(2S)-2-(decanoylamino)-3- phenylproρanoyl]amino}undecanamide;
22. M-(4-Pyridylmethyl)-l l-{[(2i?,5)-(decanoylamino)-2- methylethanoyljamino} undecanamide;
23. M-(4-Pyridylmethyl)-l l-{[(2S)-2-(nonanoylamino)-3- phenylpropanoyl]amino}undecanamide; 24. M-(4-Pyridylmethyl)-l l-{[(2i?)5)-2-(decanoylamino)-4-(methylsulfanyl) butanoyl] amino} undecanamide;
25. M-(4-pyridylmethyl)-l l-{[(2S)-2-(decanoylamino)-3-(liI-3- indolyl)propanoyl]amino}undecanamide;
26. M-(4-Pyridylmethyl)-l l-{[(25)-2-(decanoylamino)-3-(4- hydroxyphenyl)propanoyl]amino }undecanamide; and salts thereof. Compounds of general formula (Ia) may be prepared from compounds of general formula (II):
Figure imgf000010_0001
(II) wherein R1, m and n are as defined in general formula (Ia); by a condensation reaction with compounds of general formula (III):
HX-R2 (III)
wherein X and R2 are as defined in general formula (Ia) and this process forms a further aspect of the present invention.
The condensation reaction may make use of a coupling agent N1N'- dicyclohexylcarbodiimide (DCC) and is typically conducted in an organic solvent and in the presence of 4-dimethylaminopyridine (DMAP), initially at a temperature of from about -5 to 50C5 with the reaction mixture later being allowed to warm to room temperature.
Compounds of general formula (III) are readily available or may be synthesised by methods well known to those of skill in the art.
Compounds of formula (II) may be prepared from compounds of general formula (IV):
Figure imgf000010_0002
(IV) wherein R1, m and n are as defined in general formula (Ia) and R6 is C1-6 alkyl; by alkaline hydrolysis, for example with an aqueous alkali metal hydroxide such as lithium hydroxide, followed by acidification, using, for example, hydrochloric acid.
Compounds of general formula (IV) may be prepared from compounds of general formula (V):
Figure imgf000011_0001
(V) wherein R1 and m are as defined in general formula (Ia); in a condensation reaction with a compound of general formula (VI):
Figure imgf000011_0002
(VI) wherein n is as defined in general formula (Ia) and R6 is as defined for general formula (IV).
The condensation may be a DCC condensation and may be carried out in an organic solvent and in the presence of DMAP, initially at a temperature of from about -5 to 50C, with the reaction mixture later being allowed to warm to room temperature.
Compounds of general formula (VI) are readily available or may be prepared by methods well known to those of skill in the art of organic chemistry.
Compounds of general formula (V) may be prepared by reacting a compound of general formula (VII):
Figure imgf000011_0003
(VII) wherein m is as defined in general formula (Ia); with an amino acid of general formula (VIII):
Figure imgf000012_0001
(VIII) wherein R1 is as defined in general formula (Ia).
This acylation reaction may be carried out in an aqueous base and initially at a temperature of from -5 to 50C with the reaction mixture subsequently being allowed to warm to room temperature.
Compounds of general formulae (VII) and (VIII) are readily available or may be prepared using methods known to those of skill in the art.
An alternative method of preparing a compound of general formula (Ia) is by reaction of a compound of general formula (V) as defined above with a compound of general formula (IX) :
Figure imgf000012_0002
(IX) wherein R2 and n are as defined for general formula (Ia).
This reaction is particularly suitable when X is -NHCH2- and R is a pyridyl group, particularly 4-pyridyl and may be carried out in a polar organic solvent such as acetonitrile and in the presence of a triphenylphosphine, carbon tetrachloride and triethylamine.
Compounds of general formula (IX) may be prepared by deprotecting a compound of general formula (X):
Figure imgf000013_0001
(X) wherein R2, X and n are as defined in general formula (Ia) and P1 is an amine protecting group such as /-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) or any other suitable protecting group. The method for removal of the protecting group will depend upon the particular protecting group which is used. For example, hydrogenation over a suitable catalyst, for example palladium or platinum, is particularly appropriate when P1 is Z but when P1 is BOC, it is more easily removed by stirring with trifluoroacetic acid.
Suitable protection and deprotection methodologies may be found, for example, in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
Protected compounds of general formula (X) may be prepared from compounds of general formula (XI):
Figure imgf000013_0002
(XI) wherein n is as defined in general formula (Ia) and P1 is as defined for general formula (X); in a condensation reaction with a compound of general formula (III) as defined above, which is typically activated with triphenylphosphine, carbon tetrachloride and triethylamine, under similar conditions to those described above for the reaction between compounds of general formulae (V) and (IX).
Protected compounds of general formula (XI) may be prepared from amines of general formula (XII):
Figure imgf000014_0001
(XII)
wherein n is as defined for general formula (I); using standard methods well known to those of skill in the art and described in more detail in the examples below.
Compounds of general formula (XII) are readily available or may be prepared by methods well known to the skilled chemist.
Yet another route for the preparation of compound of general formula (Ia) is particularly suited to the preparation of optically pure products and this method forms a further aspect of the present invention. In this process for preparing compounds of general formula (Ia), a compound of general formula (XIII):
H o
(XIII) wherein R1, R2, X and n are as defined in general formula (Ia); is reacted with a compound of general formula (VII) as defined above. This acylation reaction may be carried out in an aqueous base and initially at a temperature of from -5 to 50C with the reaction mixture subsequently being allowed to warm to room temperature.
A compound of general formula (XIII) may be prepared by deprotecting a compound of general formula (XIV):
Figure imgf000014_0002
(XIV) wherein R1, R2, X and n are as defined for general formula (Ia) and P1 is a protecting group as defined for general formula (X).
Deprotection may be achieved using standard methods, which depend upon the particular protecting group used. For example, when the amine is protected with BOC, it may be removed using TFA. However, when P1 is CBZ, hydrogenation over an appropriate catalyst is a more appropriate method for its removal.
Compounds of general formula (XIV) may be prepared by reacting a compound of general formula (IX) as defined above with a reaction of general formula (XV):
Figure imgf000015_0001
(XV) wherein R1 is as defined for general formula (Ia) and P1 is a protecting group as defined for general formula (X) in a condensation reaction with a compound of general formula (IX) as defined above, which is typically activated with triphenylphosphine, carbon tetrachloride and triethylamine, under similar conditions to those described above for the reaction between compounds of general formulae (V) and (IX).
Compounds of general formula (XIV) may be also be prepared by reacting a compound of general formula (IX) as defined above with a compound of general formula (XVII):
Figure imgf000015_0002
(XVII)
wherein R1 is as defined for general formula (Ia) and P1 is a protecting group as defined for general formula (X) with a compound of general formula (IX), again in a condensation reaction activated with triphenylphosphine, carbon tetrachloride and triethylamine.
Compounds of general formulae (XV) and (XVII) are readily available or may be prepared by methods well known to those of skill in the art.
A further method for the preparation of a compound of general formula (Ia) is by the conversion of another compound of general formula (Ia). In particular, it is possible to convert the R1 moiety of a compound of general formula (Ia) to a different R1 moiety. Alternatively, a compound of a formula similar to that of general formula (Ia) but in which, R1 is, for example benzyloxybenzyl, may be converted to a compound of general formula (Ia), for example in which R is hydroxybenzyl.
Compounds of general formula (Ib) may be prepared by the condensation of a compound of general formula (V) as defined above with a compound of general formula (XVIII):
Figure imgf000016_0001
(XVIII) wherein R2, R2a, X, Xa and q are as defined for general formula (Ib) above; and this method forms a further aspect of the invention.
The condensation reaction may be of any known type, for example it may be activated with triphenyl phosphine, carbon tetrachloride and triethylamine or, alternatively, it may be a DCC activated condensation. General procedures for these reactions are given in the Examples below.
Compounds of general formula (XVIII) may be prepared by deprotecting compounds of general formula (XXI):
Figure imgf000017_0001
(XXI) wherein R2, R2a, X, Xa and q are as defined for general formula (Ib) and P1 is a protecting group as defined for general formula (X); using either a hydrogenation method (more suitable if P1 is benzyloxycarbonyl) or by treating with trifluoroacetic acid (more appropriate if P1 is alkyl, for example tert- butyloxycarbonyl).
A compound of general formula (XXI) may be prepared by reacting a compound of general formula (XXII) :
Figure imgf000017_0002
(XXII) wherein Xa, R2a and q are as defined for general formula (Ib) and P1 is as defined for general formula (X); with a compound of general formula (III) as defined above in a condensation reaction which is typically activated by DCC in the presence of DMAP.
Compounds of general formula (XXII) are readily available or can be prepared by methods well known to those skilled in the art.
In an alternative procedure, a compound of general formula (Ib) may be prepared by the reaction of a compound of general formula (XX):
Figure imgf000018_0001
(XX) wherein R1, m and q are as defined for general formula (Ib) and R8 is C1-6 alkyl; with a compound of general formula (III) as defined above in a condensation reaction which is typically activated by DCC in the presence of DMAP, or withPh3P/CCl4/Et3N.
Compounds of general formula (XX) may be prepared from compounds of general formula (V) as defined above by reaction with compounds of general formula (XIX):
Figure imgf000018_0002
(XK) wherein q is as defined for general formula (Ib) and R8 is as defined for general formula (XX). Again, a DCC condensation reaction is typically used and is carried out in the presence of DMAP.
Compounds of general formula (XIX) are readily available or may be prepared by methods well known to those of skill in the art.
As already discussed, compounds of general formulae (Ia) and (Ib) and acid addition salts of these compounds are capable of forming gels when added to water or other solvents, heated and then left to cool.
Therefore, in further aspects of the invention, there is provided a gel comprising a compound of formula (Ia) or (Ib) or a salt thereof mixed with a solvent and a process for preparing such a gel comprising mixing a compound of formula (Ia) or (Ib) or a salt thereof with a solvent, heating and then cooling the solution.
The solvent may be an aqueous solvent such as water, sodium chloride solution or aqueous acetic acid or a mixture of water with an organic solvent such as DMSO.
Where the compound of general formula (Ia) or (Ib) or a composition containing the compound is intended to be administered to a subject in a dry form, a gel may be formed in situ and in such a case, the aqueous solvent may be a physiological fluid, for example stomach acid or saliva.
Alternatively, however, the solvent may be an organic solvent such as DMSO, ethanol, «-decanol, propylene glycol, polyethylene glycol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, />-xylene5 tetraline, or benzyl alcohol. The compound of the present invention are also capable of forming gels in oils such as glycerine, oleic acid, octyldodecanol and cocoyl caprylocaprate, which is sold under the trade mark Cetiol LC (Cognis).
Many of the compounds of the present invention have extremely good gelation properties and relatively low concentrations are needed to cause gelation, although clearly the concentration required depends on the solvent. Typically, when in an aqueous solvent, the compound of general formula (Ia) or (Ib) or the salt thereof is present in a concentration of at least 0.2 mg/mL, but more preferably at least 1 mg/mL and in ascending order of preference at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/mL.
The concentration of the compound needed to form a gel (minimal gelation concentration or MGC) varies according to the solvent and will, for example be different for an aqueous solution of sodium chloride and pure water. For an aqueous solution of, for example, sodium chloride or acetic acid, the MGC also varies according to the concentration of the solution. For the purposes of the present specification, MGC was determined visually by the vial inversion method in which sample vials were put in an inverted position and the MGC was defined as the concentration just before the gel started to flow. In practice, this requires the elastic modulus of the gel to be greater than about 65 Pa.
The MGC also depends upon the pH of the solvent used. The compounds of the invention can form gels in solutions which have acidic and neutral pH but are not so effective in alkaline solution, and particularly at pH 10 and above. More preferably, the pH of the solution is 7 or less.
Another advantageous property of gels formed by the compounds of general formula (Ia) or (Ib) and their salts is that they are able to flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula or when sprayed onto a delivery site.
The threshold stresses of the gels are typically in the range of 1 kPa to 100 kPa.
When subjected to stresses below the threshold level, however, the gels remain immobile.
These properties mean that the gel can be injected into a mould or extruded from a nozzle tip to form, for instance, line or sheet structures to cover a desired surface, which may be, for example, a skin surface or the surface of a body cavity.
The ease with which the gels can be formed into desired shapes means that they are ideally suited for purposes such as support matrices for tissue replacement as they can be applied to and conform to sites on or in tissue including tissue surfaces and defined cavities such as intravertebral spaces.
The gels formed by the compounds of the present invention are stable at room temperature for several months, they have high water content and therefore exhibit excellent biocompatibility and they are therefore ideal for pharmaceutical and cosmetic use. Furthermore, the mucoadhesive and drug release properties of the gels can be adjusted by the degree of gelation, which is affected by the concentration above the minimal gelation concentration (MGC). Therefore, in a further aspect of the invention, there is provided a composition comprising: i. a compound of formula (Ia) or (Ib) or a salt thereof; and ii. an active agent.
The compositions may additionally comprise a solvent, in which case they may be in gel form. In some cases, however, the composition may be a dry composition which is intended to form a gel in situ.
The compositions may be pharmaceutical compositions, in which case the active agent is a pharmaceutically or biologically active substance. Alternatively, however, they may be intended for the administration of other active agents, for example, dietary supplements.
The active agent is preferably water soluble and the solvent is preferably water or an aqueous solvent. Some active substances will show lesser solubility in aqueous hydrogelator systems than others and these water insoluble active substances can also be dispersed or suspended in the hydrogel with the aid of suitable suspending or viscosity enhancing agents.
A complete listing of useful water soluble, pharmaceutically active substances is not possible. However, representative are the following examples of the pharmacologically active substances that are preferred: anaesthetics (such as benoxinate, bupivacaine, dibucaine hydrochloride, dyclonine hydrochloride, etidocaine cocaine, hexylcaine, lidocaine, mepivacaine, naepaine, phenacaine hydrochloride, piperocaine, prilocaine, proparacaine hydrochloride, and tetracaine hydrochloride), analgesics (such as aspirin, acetaminophen and diflunisal), angiogenesis inhibitors, antiallergic agents, antibiotics (such as bacitracin, carbenicillin, cefazolin, cefoxitin, cephaloridine, chloramphenicol, chibrorifamycin, n-formamidoylthienamycin, gramicidin, neomycincolistin, penicillin G, polymyxin B, tetracyclines, vancomycin, and sulfonamides), anticancer, anticoagulants (such as heparin, bishydroxycoumarin, and warfarin), antidepressants (amitriptyline, chlordiazepoxide perphenazine, doxepin, imipramine and protriptyline), antidiabetic agents (such as acetohexamide, chlorpropamide insulin, tolazamide and tolbutamide), antiepileptic agents, antifungal (such as amphotericin B, miconazole, natamycin, nystatin and tlucytosine), antihypertensive agents (such as spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride and reserpine), anti- infective, anti-inflammatory (such as betamethasone, cortisone, dexamethasone sodium phosphate, fluorometholone, hydrocortisone, hydrocortisone acetate, dexamethasone, indomethacin, methylprednisolone, medrysone, prednisolone, preunisone, preunisolone sodium phosphate, triamcinolonesulindac, and its salts and analogs), antimicrobial, antipyretics, antiarrhythmic agents, antithrombotics, antituberculous agents, antitussive expectorants, antiulcer agents, antiviral (such as acyclovir, adenosine arabinoside (Ara-A), interferon, 5-iodo-2'-deoxyuridine and trifluorothymidine), bone resorption inhibitors, cholinergic or adrenergic agonists and antagonists, cardiotonics, cytostatic, haemostatics, fibrinolytics, muscle relaxants (such as melphalan, danbrolene, cyclobenzoprine, methocarbamol and diazepam), narcotic antagonists, sedatives, thrombolytics and wound healing agents. For example, the following highly water soluble drugs are suitable for delivery by hydrogels: buflomedil pyridoxalphosphate, diltiazem hydochloride, riboflavin sodium phosphate.
The drug delivery systems of the present invention may be designed to release appropriate biologically active substances. As biologically active substances should be intended for example proteins and their fragments, peptides and polynucleotides, growth factors, enzymes, vaccines and substances used in the treatment of diseases associated with genetic defects. Particular water soluble polypeptides which may be used include, for example, angiotensins, adrenocorticotrophic hormone (ACTH), bacitracins, bombesin antagonists, bradykinin, calcitonin, colistins, growth hormone, growth hormone releasing factor, endomorphins, enkephalins, glucagon, gastrin, gramicidines, insulin, interferon, luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or antagonists, monoclonal antibodies, tetragastrin, pentagastrin, urogastrone, prolactin, renin, secretin, oxytocin, polymyzins, somatostatin, tyrocidin, transforming growth factor antagonists, soluble vaccines, and vasopressin.
The compositions of the invention may also contain other agents, such as preservatives and buffering agents.
Suitable water soluble preservatives which may be employed in the drug delivery systems of the present invention include ascorbate, benzalkonium chloride, benzylalcohol, chlorobutanol, sodium bisulfite, sodium thiosulfate, parabens, phenylethanol, phenylmercuric borate and thimerosal. These agents may be present in amounts of from 0.001 to 5% by weight and preferably 0.01 to 2%.
Suitable water soluble buffering agents are alkali or alkali earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. These agents may be present in amounts sufficient to maintain a pH of the system of referably from 4 up to 8. The buffering agent therefore may be much as 5% by weight of the total composition.
Routes of administration of hydro gel-based drug delivery systems prepared in accordance with the present invention include, but are not limited to: inoculation or injection (e.g., intra-articular, intra-aural, intra-mammary, intra-muscular, intraperitoneal, subcutaneous, etc.), topical application (e.g., on areas, such as eyes, ears, in or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g., vaginal and other epthelial linings, gastrointestinal mucosa, etc.). The compositions formulated using hydrogel matrices may include previously known pharmaceutical carriers or excipients, adjuvants, etc.
Compositions of the present invention are particularly advantageous as the gel formed by the compound of formula (Ia) or (Ib) or a salt thereof and a solvent is an ideal matrix for the sustained release of the active agent. The rate at which an active agent is released from a matrix is dependent upon several factors. A major element of the release of the active agent is related to the migration of its molecules through channels formed by the gel forming molecules, which may occur by one of two mechanisms, bulk flow and diffusion. The exact role of bulk flow is unclear but it is thought to take place mainly in areas adjacent to gel surfaces and therefore diffusion is thought to be the more important factor. The rate of diffusion of an active agent through a gel is modified by tortuosity (λ), which is defined by the equation:
Figure imgf000024_0001
Where D is the diffusion coefficient in water and D* is the apparent diffusion coefficient in gel. Tortuosity summarises the hindrance imposed by gel network structures and is also sensitive to the viscosity of the matrix and to molecular size. In practice, this means that increasing the elastic modulus of the gel or the size of the active agent molecule decreases the rate at which the active agent is released from the drug matrix. The elastic modulus of gels formed from compounds of general formula (Ia) or (Ib) or their salts is relatively easy to manipulate as it is affected by the solvent, the pH and the concentration of the compound of general formula (Ia) or (Ib) or its salt.
The thixotropic nature of the gels, which is discussed above, also means that compositions containing them can be formed required shapes, for instance tablets, lozenges, transdermal patches or suppositories. They can also easily be loaded into capsules.
The composition may be intended for topical, transdermal, rectal, buccal or sublingual administration and may be a pharmaceutical composition, in which the active agent is a biologically active compound. Alternatively, however, the composition may be a cosmetic composition intended for topical administration, in which case the active agent may be a cosmetically acceptable compound, for example a natural product or a vitamin.
The solvent in topical, transdermal, rectal, buccal or sublingual compositions may be either an aqueous solvent, a mixture of an aqueous and an organic solvent or a pharmaceutical oil such as glycerine, oleic acid, octyldodecanol or cocoyl caprylocaprate (Cetiol® LC). Oleic acid is a particularly useful oily solvent in such compositions because it has been found to reduce the irritation associated with many transdermal and topical products which is caused by other ingredients of the composition.
In transdermal pharmaceutical compositions, for example, penetration enhancing agents such as alcohols or glycols are known to cause skin irritation but oleic acid has been shown to reduce this (US 6,319,913). In addition, oleic acid is itself a penetration enhancing agent and so is particularly suitable solvent for transdermal products.
A composition for application to the skin may be also made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
Some topical and transdermal products take the form of patches which must adhere to the skin and it is therefore necessary for gels which form the basis of such products to exhibit appropriate values of adhesion and mechanical strength. The ability of an adhesive to form a bond with the skin is directly related to the tack of the adhesive, where tack is defined as the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas if the tack is too high, adhesive residue may be left on the skin after removal or the gel may cause dermal irritation. It is therefore preferable for a gel to have a probe tack value of at least 0.25N as if it is lower than this, the skin adhesiveness is insufficient and the gel is likely to peel off with even a small amount of movement. Adhesives with high tack may form strong bonds with the skin on initial application and may therefore be difficult to remove and if the probe tack value of the gel exceeds 1.2 N, skin irritation is likely to occur (US 6,914,169).
The compositions may also be formulated for oral administration and they may be pharmaceutical compositions, in which case the active agent is a biologically active compound. Alternatively, however, they may be intended for the administration of, for example, dietary supplements.
The compounds of the first aspect of the invention are particularly useful for the formation of oral compositions as they are capable of retaining their gel structure at low pH and therefore are ideal for use as matrices for the sustained release of active agents in the stomach.
The solvent for the oral compositions may be an aqueous solvent, an organic solvent, a mixture of aqueous and organic solvents or oil and may be chosen according to the active compound. For example, hydrophobic compounds are preferably formulated in a gel which includes a hydrophobic solvent whereas for hydrophilic compounds an aqueous solvent may be preferred. Alternatively, the composition may be formulated without a solvent since the compound of general formula (Ia), (Ib) or salt thereof is capable of forming a gel in the stomach so that a matrix is formed around the active agent in situ.
Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing predetermined amounts of the compound of general formula (Ia), (Ib) or salt thereof and active agent; as a powder or granules; as a gel composition in an aqueous liquid or a nonaqueous liquid etc.
Oral compositions, whether pharmaceutical or not, may also include an acceptable carrier.
For compositions for oral administration (e.g. tablets and capsules), the term "acceptable carrier" includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound of general formula (Ia), (Ib) or salt thereof and active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored.
Other formulations suitable for oral administration include lozenges comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia.
The compositions of the invention may be formed simply by mixing the compound of general formula (Ia) or (Ib) or a salt thereof with an active compound and optionally adding a solvent. This method forms yet another aspect of the present invention.
Other uses for gels formed by compounds of general formula (Ia) or (Ib) or their salts include thickeners for foodstuffs or cosmetic compositions.
Further aspects of the invention therefore comprise: the use of a compound of general formula (Ia) or (Ib) in the preparation of a gel;
the use of a compound of general formula (Ia) or (Ib) in the preparation of a gel- forming composition, wherein the gel-forming composition comprises a compound of general formula (Ia) or (Ib) and an active agent;
the use of a compound of general formula (Ia) or (Ib) in the preparation of a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of general formula (Ia) or (Ib), and a biologically active agent;
the use of a compound of general formula (Ia) or (Ib) as a gastroprotective agent for an acid sensitive biologically active agent;
the use of a compound of general formula (Ia) or (Ib) as an agent for controlling the rate of release of an active agent from a composition;
the use of a compound of general formula (Ia) or (Ib) in the preparation of a cosmetic composition, wherein the cosmetic composition comprises a cosmetically acceptable compound;
the use of a compound of general formula (Ia) or (Ib) in the preparation of a dietary supplement; and
a compound of general formula (Ia) or (Ib) for use as a gastroprotective agent for an acid sensitive biologically active agent.
The invention will now be described in greater detail with reference to the following examples and to the drawings in which:
FIGURE 1 is a set of near infrared spectra for the hydrochloride salt of Compound 3 at concentrations of 5%, 1%, 0.5% and 0.33% wt/vol and for Compound 3 free base at a concentration of 0.33 wt/vol.
FIGURE 2 is a water vapour sorption/desorption curve for the hydrochloride of Compound 3 at 250C.
FIGURE 3 is a photograph of particles of the hydrochloride salt of Compound 18 at 0% RH (dry state) and at 90% RH (with 27% adsorbed water).
FIGURE 4 is a typical curve of tack probe measurement: force (in kg) vs distance (or displacement in mm) .
Examples General
1H and 13C NMR spectra were recorded on the Bruker® Avance 300 spectrometer with tetramethylsilane (TMS) as an internal standard at 300 MHz, in CDCl3 unless otherwise stated. Chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. Spin multiplicities are abbreviated as s (singlet), d (doublet), t (triplet), pt (pseudotriplet - doublet of doublets), qua (quadruplet), p (pentet) and m (multiplex). IR spectra were recorded on a FT ABB® Bomem MB 102 IR spectrometer in KBr plates with CsI optics and DTGS detector. Wavenumbers (v) are reported as reciprocal centimeters, cm"1. Melting points, tm, were determined on a Kofler hot stage and are uncorrected. Optical rotations are measured at temperature of 24 °C on Optical Activity AA-10 Automatic Polarimeter in 1 dm cells at wavelength 589 nm. The reactions were monitored on thin-leaf chromatograms on silica gel plates, the spots were detected under UV light (λ = 254 nm) or in iodine vapours. Prepared compounds were purified chromatographically by preparative TLC using silica gel Merck® HF254 and by flash column chromatography using silica 0.04-0.063 mm (Merck). Eluant was usually CH2Cl2-MeOH 19:1. Reagents were purchased from commercial suppliers (Fluka, Sigma-Aldrich, Kemika) and were used without further purification. All solvents were purified and dried according to standard laboratory procedures. Reaction yields are not optimized. Dimethyl glutamate hydrochloride was prepared starting from L-glutamic acid in 100 % yield, methyl 11-amino-undecanoate hydrochloride starting from 11-amino- undecanoic acid (97 %) and methyl 12-aminododecanoate hydrochloride starting from 12-arninododecanoic acid (88 %), in methanol with thionyl chloride, following the general procedure for preparation of methyl esters of amino acids (Houben-Weyl, Methoden der organischen Chemie, Band XV/I, Georg Thieme Verlag, Stuttgart, 1974, p. 317). Methyl 6-amino-hexanoate hydrochloride and methyl 4-amino- butyrate hydrochloride were purchased from Fluka.
Determination of gelation: 10 mg of substance was weighed into the tube of 10 mm diameter, and water was added in 100 μl portions. The tube was the stoppered, heated until solution occured, and left to achieve the room temperature. The tube was then turned down and checked the maximal gelated volume of water.
Example 1
A. General procedure for acylation of amino acids
Amino acid (10 mmol) was dissolved in IM NaOH (10 mL) and cooled in an ice- bath. Acyl chloride (10 mmol) and IM NaOH (10 mL) were simultaneously added dropwise into the reaction mixture with vigorous stirring. After 0.5 hr the ice-bath was removed and stirring continued at room temperature overnight. The reaction mixture was washed with CH2Cl2 to remove eventually unreacted acyl chloride. The aqueous layer was cooled in an ice-bath, acidified to pH = 2 with IM HCl and the precipitated product filtrated off and washed with water, or extracted into CH2Cl2, dried (Na2SO4) and evaporated to give the product. General procedure A was used to prepare the compounds set out below.
N-Dodecanoyl-D-phenylglycine flauroyl-D-phenylglycine)
The compound was prepared starting from D-phenylglycine (3.780 g, 25 mmol) and lauroyl chloride (5.93 mL, 25 mmol) to give 7.356 g (88 %) of the product. [α]o = - 81° (c 1.016, CH2Cl2). iV-Decanoyl-D-phenylglycine
The compound was prepared starting from D-phenylglycine (3.023 g, 20 mmol) and decanoyl chloride (4.1 mL, 20 mmol) to give 5.02 g (85 %) of the product.
iV-Nonanoyl-D-phenylglycine (pelargonyl-D-phenylglycine)
The compound was prepared starting from D-phenylglycine (7.560 g, 50 mmol) and pelargonyl chloride (9.4 mL, 50 mmol), to give 13.025 g (89 %) of the product. [α]o = -116° (c 1.030, CH2Cl2).
iV-Heptanoyl-D-phenylglycine
The compound was prepared starting from D-phenylglycine (7.40 g, 48.951 mmol) and heptanoyl chloride (7.5 mL, 48.951 mmol), to give 10.842 g (84 %) of the product. [α]D = -130° (c 0.994, CH2Cl2).
iV-Dodecanoyl-L-leucine (lauroyl-L-leucine)
The compound was prepared starting from L-leucine (656 mg, 5.00 mmol) and lauroyl chloride (1.19 mL, 5.00 mmol) to give 1.474 g (94 %) of the crude product that was recrystallized from MeCN, m.p. 77-79 °C, [α]D = -12° (c 1.012, MeOH).
iV-Decanoyl-L-leucine
The compound was prepared starting from L-leucine (1.00 g, 7.6 mmol) and decanoyl chloride (1.71 mL, 8.4 mmol) to give 1.51 g (70 %) of the product.
iV-Nonanoyl-L-phenylalanine (Pelargonyl-L-phenylalanine) The compound was prepared starting from L-phenylalanine (1.652 g, 10 mmol) and pelargonyl chloride (1.88 mL, 10 mmol) to give 2.890 g (95 %) of the product.
JV-Decanoyl-L-phenylalanine
The compound was prepared starting from L-phenylalanine (3.3 g, 20 mmol) and decanoyl chloride (4.1 mL, 20 mmol) to give 5.62 g (86 %) of the product. iV-Decanoyl-D,L-alanine
The compound was prepared starting from D,L-alanine (1.782 g, 20.0 mmol) and decanoyl chloride (4.1 mL, 20.0 mmol) to give 3.4 g (70 %) of the product.
JV-Decanoyl-L-valine
The compound was prepared starting from L-valine (1.171 g, 10.0 mmol) and decanoyl chloride (2.04 mL, 10.0 mmol) to give 2.285 g (84 %) of the product.
iV-Decanoyl-glycine The compound was prepared starting from glycine (327 mg, 4.361 mmol) and decanoyl chloride (0.893 mL, 4.361 mmol) to give 836 mg (84 %) of the product.
iV-Decanoyl-D,L-methionine
The compound was prepared starting from D,L-methionine (2.100 g, 14.074 mmol) and decanoyl chloride (2.92 mL,14.071 mmol) to give 2.62 g (61 %) of the product.
iV-Decanoyl-L-tryptophan
The compound was prepared starting from L-tryptophan (613 mg, 3.0 mmol) and decanoyl chloride (0.66 mL, 3.0 mmol) to give 905 mg (84 %) of the product.
ll-{[(benzyloxy)carbonyl]amino}undecanoic acid
The compound was prepared starting from 11-amino-undecanoic acid (8.052 g, 40.0 mmol) and 50 % toluene solution of benzyloxycarbonyl chloride (13.4 mL, 40.0 mmol) to give 12.967 g (97 %) of the product.
B. General procedure for DCC-condensations with ω-aminoalkanoic acids or glutamic acid
Acylamino acid (1.0 mmol) was dissolved in dry CH2Cl2 (10 mL), and under cooling in an ice-bath and stirring amino compound hydrochloride (1.0 mmol), DCC (1.0 mmol), Et3N (1.0 mmol) and DMAP (0.1 mmol) were added. After 0.5 hr ice-bath was removed and the stirring continued at room temperature overnight. The precipitate of by-product DCHU was removed, the filtrate washed with water, 5% AcOH, water, sat. NaHCθ3 and water to remove impurities, then dried (Na2SO4) and evaporated to give the product. This general procedure was used to prepare the compounds listed below.
Methyl 6-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyl]amino}hexanoate
Figure imgf000033_0001
The compound was prepared starting from lauroyl-L-leucine (831 mg, 2.651 mmol), methyl 6-amino-hexanoate hydrochloride (482 mg, 2.651 mmol), DCC (547 mg, 2.651 mmol), Et3N (371 μl, 2.651 mmol) and DMAP (32 mg, 0.265 mmol) to give 1.094 mg (94 %) of the product.
1H-NMR (CDCl3): 6.84 (t, IH, J= 5.01 Hz, NH-CH2), 6.49 (m, IH5 NH)5 4.51-4.44 (m, IH, *CH), 3.67 (m, 3H, OCH3), 3.27-3.17 (m, 2H, NH-CH2), 2.31 (t, 2H, J = 7.48 Hz5 CH2CO)5 2.19 (t, 2H, J= 7.96 Hz5 CH2CO), 1.96-1.91 (m, IH5 CH(CH3)2), 1.66-1.26 (m, 26H, other CH2), 0.93-0.86 ppm (m, 3+6H, -CH3). 13C-NMR (CDCl3): 174.00, 173.39, 172.32 (3x CONH)5 51.46 (OCH3), 49.12 (*CH), 41.14, 39.16, 36.49, 33.88, 33.76, 31.87, 29.58, 29.48, 29.30, 29.21, 28.97, 26.28, 25.65, 24.91, 24.41, 22.64 (16x CH2), 24.74, 22.79, 22.22 (-CH(CH3)2), 14.09 ppm (- CH3).
Methyl 4-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyl]amino}butyrate
Figure imgf000033_0002
The compound was prepared starting from lauroyl-L-leucine (880 mg, 2.807 mmol), methyl 4-amino-butyrate hydrochloride (482 mg, 2.651 mmol), DCC (579 mg, 2.807 mmol), Et3N (393 μL, 2.807 mmol) and DMAP (34 mg, 0.281 mmol) to give 1.065 mg (92 %) of the product.
1H-NMR (CDCl3): 7.07 (pt, IH, J= 5.23; 10.46 Hz, NH), 6.50 (pt, IH5 J= 3.92; 8.37 Hz NH)5 4.50-4.47 (m, IH5 *CH)5 3.67 (m, 3H5 OCH3), 3.29-3.24 (m, 2H, NH-CH2), 2.35 (t, 2H3 J= 7.32 Hz, CH2CO), 2.19 (t, 2H, J= 7.85 Hz, CH2CO), 1.83 (t, 2H, J=
7.06 Hz, CH2), 1.62-1.25 (m, 21H, CH and other CH2), 0.93-0.85 ppm (m, 3+6H,
CH3).
13C-NMR (CDCl3): 173.41, 172.56 (3x CONH), 51.64 and 51.46 (OCH3 and *CH),
41.24, 38.78, 36.50, 33.91, 33.76, 31.89, 31.31, 29.6O5 29.34, 29.28, 29.25, 25.66,
24.53, 22.66 (14x CH2), 24.76, 22.81, 22.21 (-CH(CH3)2), 14.09 ppm (-CH3).
Methyl 6-{[(2R)-2-(dodecanoylamino)-2-phenylethanoyl]amino}hexanoate
Figure imgf000034_0001
The compound was prepared starting from lauroyl-D-phenylglycine (753 mg, 2.258 mmol), methyl 4-amino-hexanoate hydrochloride (410 mg, 2.258 mmol), DCC (466 mg, 2.258 mmol), Et3N (316 μL, 2.258 mmol) and DMAP (28 mg, 0.226 mmol) to give 1.19O g of the crude product that was recrystallized from MeOH: 478 mg (46
%)• 1H-NMR (CDCl3): 7.41-7.29 (m, 5H, Ph), 7.01 (d, IH, J= 7.15 Hz, NH-*CH), 6.45
(m, IH, NH-CH2), 5.56 (d, IH, J= 7.04 Hz, *CH), 3.66 (m, 3H, OCH3), 3.27-3.18
(m, 2H, NH-CH2), 2.24 (t, 2x2H, J= 7.37 Hz, 2x CH2CO), 1.63-1.22 (m, 27H, CH and other CH2), 0.89 ppm (t, 3H, J= 7.04 Hz, -CH3).
13C-NMR (CDCl3): 174.02 (COO), 172.72, 170.07 (2x CONH), 138.49 (1'-Ph), 128.88 (2'-Ph), 128.18 (4'-Ph), 127.11 (3'-Ph), 56.78 (*CH), 51.52 (OCH3), 39.47,
36.51, 33.85, 33.78, 31.92, 29.62, 29.50, 29.36, 29.25, 28.25, 26.13, 25.58, 24.92,
24.30, 22.71 (15x CH2), 14.14 ppm (CH3).
Methyl ll-{[(2i?)-2-(decanoyIamino)-2-phenyIethanoyl]amino}undecanoate
O Ph
o
The compound was prepared starting from methyl 11-aminoundecanoate hydrochloride (755 mg, 3.0 mmol), decanoyl-D-phenylglycine (916 mg, 3.0 mmol), DCC (619 mg, 3.0 mmol), Et3N (420 μL, 3.0 mmol) and DMAP (37 mg, 0.3 mmol) to give 1.434 g (95 %) of the crude product that was recrystallized from acetonitrile (20-25 mL) giving 904 mg (63 %) of the product, m.p. 101-103 0C. 1H-NMR (CDCl3): 7.37-7.29 (m, 5H5 Ph), 7.02 (d, IH, J= 7.05 Hz, NH-*CH), 6.39 (m, IH, NH-CH2), 5.55 (d, IH, J= 7.10 Hz5 *CH), 3.67 (s, 3H, OCH3), 3.18 (m, 2H, NH-CH2), 2.30 (t, 2H5 J = 7.41 Hz, CH2CO), 2.23 (t, 2H5 J = 7.30 Hz, CH2CO)5 1.61-1.19 (m, 3OH, 15x CH2), 0.88 ppm (t, 3H, J= 6.871 Hz, CH3). 13C-NMR (CDCl3): 172.65, 169.96 (3x CO)5 138.50 (1'-Ph), 128.82 (2'-Ph), 128.09 (4'-Ph)5 127.07 (3'-Ph)5 56.72 (*CH), 51.43 (OCH3), 39.78, 36.47, 34.05, 33.89, 31.83, 29.40, 29.33, 29.30, 29.25, 29.22, 29.19, 29.16, 29.09, 29.06, 26.65, 25.53, 24.89, 22.63 (18x CH2), 14.08 ppm (CH3).
Methyl 6-{[(2R)-2-(decanoylamrao)-2-phenylethanoyI]amino}hexanoate
Figure imgf000035_0001
The compound was prepared starting from methyl 6-aminohexanoate hydrochloride (545 mg, 3.0 mmol), decanoyl-D-phenylglycine (916 mg, 3.0 mmol), DCC (619 mg,
3.0 mmol), Et3N (420 μL, 3.0 mmol) and DMAP (37 mg, 0.3 mmol) to give 1.143 g
(88.1 %) of the crude product that was recrystallized from MeOH (20 mL) giving
477 mg (42 %) of the product, m.p. 116-118 0C.
1H-NMR (CDCl3): 7.37-7.28 (m, 5H, Ph), 7.12 (d, IH, J= 7.27 Hz, NH-*CH), 6.86 (m, IH, NH-CH2), 5.66 (d, IH, J= 7.40 Hz, *CH-Ph), 3.64 (s, 3H5 OCH3), 3.17 (m,
2H, NH-CH2), 2.22 (dt as qua, 4H, J= 7.40 Hz, 2x CH2CO), 1.60-1.19 (m, 2OH, 10x
CH2), 0.87 ppm (t, 3H, J= 7.00 Hz, CH3).
13C-NMR (CDCl3): 173.93, 172.69, 170.10 (3x CO), 138.50 (1'-Ph)5 128.76 (2'-Ph),
128.00 (4'-Ph), 126.93 (3'-Ph)5 56.56 (*CH), 51.46 (OCH3), 39.36, 36.42, 33.71, 31.81, 29.39, 29.30, 29.20, 29.17, 28.77, 26.09, 25.53, 24.27, 22.61 (13x CH2), 14.07 ppm (CH3).
Methyl ll-{[(2i?)-2-(heptanoyIamino)-2-phenylethanoyI]ammo}undecaiioate
Ph
I H The compound was prepared starting from methyl 11-aminoundecanoate hydrochloride (928 mg, 383 mmol), heptanoyl-D-phenylglycine (970 mg, 383 mmol), DCC (760 mg, 383 mmol), Et3N (515 μL, 383 mmol) and DMAP (45 mg, 0.368 mmol) to give 106 g (100 %) of the crude product that was recrystallized from acetonitrile (10-12 mL) giving 621 mg (39 %) of the product.
1H-NMR (CDCl3): 7.38-7.28 (m, 5H, Ph), 7.02 (d, IH, J= 7.12 Hz, NH-*CH), 6.44 (m, IH5 NH-CH2), 5.56 (d, IH, J= 7.12 Hz, *CH), 3.66 (s, 3H, OCH3), 3.18 (m, 2H, NH-CH2), 2.29 (d, 2H, J = 7.58 Hz, CH2CO), 2.22 (d, 2H, J = 6.84 Hz, CH2CO), 1.63-1.19 (m, 24H, Ux CH2), 0.86 ppm (t, 3H, J= 7.10 Hz, CH3). 13C-NMR (CDCl3): 1743, 172.62, 169.99 (3x CO), 138.56 (1'-Ph)5 128.81 (2'-Ph), 128.07 (4'-Ph), 127.12 (3'-Ph), 56.78 (*CH), 51.37 (OCH3), 39.81, 36.51, 34.08, 31.48, 29.34, 29.27, 29.25, 29.15, 28.86, 26.67, 25.49, 24.91, 22.45 (15x CH2), 13.99 ppm (CH3).
Methyl ll-{[(2i?)-2-(nonanoylamino)-2-phenylethanoyl]amino}undecanoate
Figure imgf000036_0001
The compound was prepared starting from methyl 11-aminoundecanoate hydrochloride (755 mg, 3.00 mmol), nonanoyl-D-phenylglycine (874 mg, 3.00 mmol), DCC (619 mg, 3.00 mmol), Et3N (0.42 mL, 3.00 mmol) and DMAP (37 mg, 0.30 mmol) to give 126 g (90 %) of the crude product that was recrystallized from EtOAc giving 813 mg (55 %) of the pure product.
1H-NMR (CDCl3): 7.50-7.27 (m, 5+1H, Ph + NH-*CH), 6.47 (m, IH, NH-CH2), 5.54 (d, IH, *CH), 3.67 (s, 3H, OCH3), 3.38 (qua, 2H, J= 6.94 Hz, NH-CH2), 2.30 (t, 2H, J = 7.54 Hz, CH2CO), 2.24-2.21 (m, 2H, CH2CO), 1.73-1.12 (m, 28H, 14x CH2), 0.87 ppm (m, 3H, CH3).
13C-NMR (CDCl3): 128.74 (2'-Ph), 128.45 (4'-Ph), 127.59 (3'-Ph), 56.66 (*CH), 51.41 (OCH3), 39.44, 36.29, 30.91, 29.33, 29.30, 29.26, 29.22, 29.16, 29.10, 29.09, 26.85, 25.52, 25.44, 24.91, 242, 22.61 (17x CH2), 14.55 ppm (CH3). Methyl 12-{[(2i?)-2-(nonanoylamino)-2-phenylethanoyl]amino}dodecanoate
Figure imgf000037_0001
The compound was prepared starting from methyl 12-aminododecanoate hydrochloride (797 rng, 3.00 mmol), nonanoyl-D-phenylglycine (874 mg, 3.00 mmol), DCC (619 mg, 3.00 mmol), Et3N (0.42 mL, 3.00 mmol) and DMAP (37 mg,
0.30 mmol) to give the crude product that was recrystallized from EtOAc giving 660 mg (44 %) of the pure product.
1H-NMR (CDCl3): 7.42-7.29 (m, 5 H, Ph), 7.01 (d, IH, J= 7.09 Hz, NH-*CH), 6.43
(t, IH, J= 7.12 Hz, NH-CH2), 5.56 (d, IH, J= 7.09 Hz, *CH), 3.67 (s, 3H, OCH3), 3.20 (qua, 2H, J= 6.96 Hz, NH-CH2), 2.31 (d, 2H, J= 7.31 Hz, CH2CO), 2.22 (d,
2H5 J= 7.34 Hz, CH2CO), 1.62-1.20 (m5 3OH, 15x CH2), 0.88 ppm (t, 3H, J= 6.96
Hz, CH3).
13C-NMR (CDCl3): 172.69, 169.94 (3x CO), 138.53 (1'-Ph), 128.85 (2'-Ph), 128.12
(4'-Ph), 127.09 (3'-Ph), 56.73 (*CH), 51.46 (OCH3), 45.79, 39.83, 36.52, 34.11, 31.79, 29.43, 29.38, 29.29, 29.26, 29.25, 29.22, 29.15, 29.14, 28.97, 26.71, 25.56,
24.94, 22.64 (18x CH2), 14.10 ppm (CH3).
Dimethyl (25)-2-{[(2iS)-2-(dodecanoylamino)-4-methylpentanoyl]amino} pentanedioate
Figure imgf000037_0002
The compound was prepared starting from lauroyl-L-leucine, i.e. (25)-2- (dodecanoylamino)-4-methylpentanoic acid (349 mg, 1.113 mmol) and dimethyl L- glutamate hydrochloride (236 mg, 1.113 mmol), DCC (230 mg, 1.113 mmol), and Et3N (156 μL, 1.113 mmol) to give 397 mg (76 %) of the product. 1H-NMR (CDCl3): 6.89 (d, IH, J = 7.62 Hz, NH), 6.03 (d, IH, J = 8.18 Hz, NH), 4.59-4.57 (m, 2H, 2x *CH), 3.75 and 3.67 (2s, 2x OCH3), 2.41-2.33 (m, 4H5 2x CH2CO), 1.73-1.09 (m, 23 H, CH and Hx CH2), 0.94 (2d, 6H, J = 6.30 Hz, CH(CH3)2), 0.88 ppm (t, 3H, J= 7.11 Hz, CH3). 13C-NMR (CDCl3): 173.29, 172.19, 171.83 (4x CO), 52.47 and 51.80 (2x *CH), 51.73 and 51.51 (2x OCH3), 41.16, 36.59, 33.89, 31.88, 29.88, 29.59, 29.46, 29.30, 29.24, 27.08, 25.60, 24.91, 22.65 (13x CH2), 24.74, 22.80, 22.17 (CH(CHg)2), 14.06 ppm (CH3).
Dimethyl (2S)-2-{[(2R)-2-(dodecanoylamino)-2-phenylethanoyl]amino} pentanedioate
Figure imgf000038_0001
The compound was prepared starting from dimethyl L-glutamate hydrochloride (235 mg, 1.110 mmol), lauroyl-D-phenylglycine (370 mg, 1.110 mmol), DCC (229 mg, 1.110 mmol), Et3N (155 μL, 1.110 mmol) and DMAP (13.5 mg, 0.111 mmol) to give 507 mg (93 %) of product.
1H-NMR (CDCl3): 7.38-7.31 (m, 5H, Ph), 6.95-6.87 (m, 2H, 2x NH), 5.58 (d, IH, J = 7.07 Hz, *CH-Ph), 4.56 (m, IH, *CH-CH2), 3.74 and 3.61 (2s, 2x OCH3), 2.23- 1.24 (m, 24H, 12x CH2), 0.88 ppm (t, 3H, J= 6.80 Hz, CH3).
13C-NMR (CDCl3): 173.07, 172.77, 171.49, 170.25 (4x CO), 137.99 (1'-Ph), 128.98 (2'-Ph), 128.36 (4'-Ph), 127.18 (3'-Ph), 56.90 (*CH-Ph), 51.81 (*CH-CH2), 52.61 and 51.79 (2x OCH3), 36.43, 33.79, 31.87, 29.57, 29.44, 29.30, 29.28, 29.19, 25.53, 25.49, 24.87, 22.65 (12x CH2), 14.08 ppm (CH3).
C. General procedure for hydrolyses of methyl esters Methyl ester (1.0 mmol) was dissolved in a mixture of MeOH (10 mL) and CH2Cl2 (10 mL), IM LiOH (1.5 mL, 1.5 mmol, resp. 3.0 mL, 3.0 mmol for glutamic esters) added and the reaction mixture stirred at room temperature overnight. It was then cooled in an ice-bath and neutralized with IM HCl, evaporated to the half of volume, diluted with water (20 mL) and acidified with IM HCl to pH 2-2.5. The precipitated product was filtrated off and washed with water, or extracted with CH2Cl2 (3 x 10 mL), dried (Na2SO4) and evaporated to give the product. General procedure C was used to prepare the following compounds. 6-{[(2S)-2-(DodecanoyIamino)-4-methylpentanoyl]amino}hexanoic acid
Figure imgf000039_0001
The compound was prepared starting from methyl 6-{[(25)-2-(dodecanoylamino)-4- methylpentanoyl]amino}hexanoate (1.069 mg, 2.426 mmol) and IM LiOH (3.64 mL) to give 1.03I g (IOO %) of the product.
1H-NMR (CDCl3): 7.30 (m, IH5 NH-CH2), 7.12 (d, IH, J = 8.73 Hz, NH-*CH), 4.60-4.55 (m, IH, *CH), 3.26-3.17 (m, 2H, NH-CH2), 2.34 (t, 2H, J = 7.36 Hz, CH2CO), 2.21 (t, 2H, J= 7.36 Hz, CH2CO), 1.95-1.90 (m, IH, CH(CH3)2), 1.73-1.16 (m, 26H, other CH2), 0.93-0.86 ppm (m5 3+6H, CH3). 13C-NMR (CDCl3): 177.29, 173.90, 172.79 (2x CONH and COOH), 49.13 (*CH), 41.11, 39.28, 36.42, 33.99, 33.77, 31.92, 29.64, 29.54, 29.36, 29.22, 28.80, 26.23, 25.70, 25.57, 24.46, 22.70 (16x CH2), 24.78, 22.73, 22.26 (-CH(CH3)2), 14.13 ppm (CH3).
4-{[(2S)-2-(Dodecanoylamino)-4-methylpentanoyl]amino}butanoic acid
Figure imgf000039_0002
The compound was prepared starting from methyl 4-{[(26)-2-(dodecanoylamino)-4- methylpentanoyl] amino }butyrate (1.042 mg, 2.525 mmol) and IM LiOH (3.8 mL) to give 979 mg (97 %) of the product. 1H-NMR (CDCl3): 7.29 (t, IH, J= 5.64 Hz, NH-CH2), 6.84 (d, IH, J= 8.47 Hz, NH-
*CH), 4.54 (qua, IH, J= 8.47 Hz, *CH), 3.30-3.26 (m, 2H, NH-CH2), 2.38 (t, 2H, J
= 7.14 Hz, CH2CO), 2.31 (t, 2H, J = 7.53 Hz, CH2CO), 1.95-1.15 (m, 23H,
CH(CH3)2, and other CH2), 0.93-0.87 ppm (m, 3+6H, -CH3).
13C-NMR (CDCl3): 176.34 (-COOH)5 174.02, 172.77 (2x CONH), 51.63 (*CH), 41.07, 38.80, 36.49, 33.61, 31.89, 31.20, 29.59, 29.49, 29.30, 29.19, 25.61, 25.49,
24.36, 22.65 (14x CH2), 24.8O5 22.72, 22.20 (CH(CH3)2), 14.06 ppm (CH3). 6-{[(2i?)-2-(Dodecanoylamino)-2-phenylethanoyl]amino}hexanoic acid
Figure imgf000040_0001
The compound was prepared starting from methyl 6-{[(2i?)-2-(dodecanoylamino)-2- phenylethanoyl]arnino}hexanoate (464 mg, 1.007 mmol), IM LiOH (1.5 niL) to give 445.5 mg (99 %) of the product.
1H-NMR (CDCl3): 7.52 (bs, IH, NH), 7.33-7.17 (m, 5+1H, Ph + NH), 5.70 (d, IH, J = 7.90 Hz, *CH), 4.61 (bs, IH, COOH), 3.14-3.06 (m, 2H, NH-CH2), 2.16 (t, 2+2H5 J= 7.35 Hz, 2x CH2CO), 1.53-1.10 (m, 24H, 12x CH2), 0.80 ppm (t, 3H, J = 7.20 Hz5 -CH3). 13C-NMR (CDCl3): 178.21 (COOH), 173.51, 170.66 (2x CONH)5 138.07 (1'-Ph)5 128.75 (3'-Ph), 128.06 (4'-Ph), 127.09 (2'-Ph)5 56.63 (*CH), 39.29, 36.34, 34.03, 31.89, 29.60, 29.50, 29.34, 29.31, 29.22, 28.54, 25.89, 25.60, 25.56, 24.11, 22.66 (15x CH2), 14.07 ppm (CH3).
6-{[(2J?)-2-(Decanoylamino)-2-pheiiylethanoyl]ainino}hexanoic acid
Figure imgf000040_0002
The compound was prepared starting from methyl 6-{[(2i?)-2-(decanoylamino)-2- phenylethanoyl] amino }hexanoate (467 mg, 1.079 mmol) and IM LiOH (1.6 niL, 1.619 mmol) to give 444 mg (98 %) of product. 1H-NMR (CDCl3): 9.37 (bs, IH, COOH), 7.49 (d, IH, J= 8.14 Hz, NH-*CH), 7.38- 7.26 (m, 5H, Ph), 7.08 (t, IH5 J = 5.29 Hz, NH-CH2), 5.73 (d, IH, J = 7.93 Hz, *CH), 3.18 (qua, IH, J= 6.38 Hz, NH-CH2), 2.25 (t, 4H, J = 7.02 Hz, 2x COCH2), 1.60-1.23 (m, 2OH, 1Ox CH2), 0.87 ppm (t, 3H, J= 7.31 Hz5 CH3). 13C-NMR (CDCl3): 177.49, 173.29, 170.54 (3x CO), 138.22 (1'-Ph), 128.77 (2'-Ph), 128.08 (4'-Ph), 127.01 (3'-Ph), 56.66 (*CH), 39.38, 36.39, 33.68, 31.84 29.41, 29.30, 29.21, 29.19, 28.61, 25.96, 25.60, 24.09, 22.62 (13x CH2), 14.05 ppm (CH3). ll-{[(2i?)-2-(Decanoylammo)-2-phenylethanoyI]amino}undecanoic acid
O
The compound was prepared starting from methyl ll-{[(2i?)-2-(decanoylamino)-2- phenylethanoyl] amino }undecanoate (875 mg, 1.740 mmol) and IM LiOH (2.6 mL, 2.611 mmol) to give 848 mg (100 %) of product that was purified by preparative TLC (CH2Cl2-MeOH 24:1) giving 595 mg (70 %) of the pure product. 1H-NMR (CDCl3): 8.82 (bs, IH, COOH)5 7.50 (d, IH, J = 7.78 Hz5 NH-*CH), 7.49- 7.26 (m, 5H, Ph)5 6.92 (t, IH5 J = 5.50 Hz5 NH-CH2), 5.76 (d, IH, J = 7.79 Hz5 *CH), 3.17 (qua, IH5 J= 6.61 Hz5 NH-CH2), 2.32 (t, 2H, J= 7.41 Hz, CH2CO), 2.25 (t, 4H, J = 7.91 Hz5 COCH2), 1.73-1.07 (m, 30H5 15x CH2), 0.87 ppm (t, 3H, J = 7.08 Hz5 CH3).
13C-NMR (CDCl3): 178.20, 173.19, 170.52 (3x CO), 138.30 (1'-Ph), 128.76 (2'-Ph), 128.02 (4'-Ph)5 127.00 (3'-Ph)5 56.52 (*CH), 39.74, 36.36, 33.75, 31.84, 29.43, 29.33, 29.24, 29.21, 29.10, 29.00, 28.96, 28.91, 26.57, 25.61, 25.53, 24.86, 24.79, 22.64 (18x CH2), 14.09 ppm (CH3).
ll-{[(2l?)-2-(Heptanoylamino)-2-phenyIethanoyI]amino}undecanoic acid
Figure imgf000041_0001
The compound was prepared starting from methyl l l-{[(2i?)-2-(heptanoylamino)-2- phenylethanoyl]amino}undecanoate (610 mg, 1.324 mmol), ) and IM LiOH (2.0 mL, 2.096 mmol) to give 471 mg (80 %) of the product.
1H-NMR (CDCl3): 7.39-7.29 (m, 5+1H5 Ph + NH-*CH), 6.58 (t, IH5 NH-CH2), 5.69 (d, IH, *CH), 3.20 (m, 2H5 NH-CH2), 2.34 (t, 2H5 J= 7.41 Hz5 CH2CO), 2.25 (t, 2H, J = 7.91 Hz, COCH2), 1.71-1.20 (m, 24H, 12x CH2), 0.85 ppm (t, 3H5 J= 7.08 Hz5 CH3).
13C-NMR (CDCl3): 178.20, 173.14, 170.37 (3x CO), 138.28 (1'-Ph), 128.92 (2'-Ph), 128.21 (4'-Ph), 127.16 (3'-Ph), 56.72 (*CH), 39.76, 36.45, 33.73, 31.48, 29.25, 29.01, 28.85, 28.78, 28.70, 28.66, 26.45, 25.55, 24.85, 24.63, 22.46 (15x CH2), 13.97 ppm (CH3).
ll-{[(2i?)-2-(Nonanoylamino)-2-phenylethanoyl]amino}undecanoic acid
Figure imgf000042_0001
The compound was prepared starting from methyl l l-{[(2i?)-2-(nonanoylamino)-2- phenylethanoyl]amino}undecanoate (729 mg, 1.492 mmol) and IM LiOH (1.64 mL,
1.641 mmol) to give 673 mg (95 %).
1H-NMR (CDCl3): 7.39-7.27 (m, 5H, Ph), 6.94 (m, IH, NH-*CH ), 6.59 (m, IH,
NH-CH2), 5.76 (d, IH, J = 7.46 Hz, *CH), 3.17 (m, 2H, NH-CH2), 2.33 (t, 2H, J =
7.20 Hz, CH2CO), 2.25 (t, 2H, J = 7.43 Hz, COCH2), 1.60-1.12 (m, 28H, 14x CH2),
0.87 ppm (t, 3H, J= 7.12 Hz, CH3).
13C-NMR (CDCl3): 177.69, 173.17, 170.47 (3x CO), 138.30 (1'-Ph), 128.81 (2'-Ph),
128.04 (4'-Ph), 127.11 (3'-Ph)5 56.73 (*CH), 39.75, 36.41, 33.97, 33.80, 31.79,
29.28, 29.15, 29.11, 28.99, 28.84, 28.82, 28.75, 26.52, 25.59, 24.92, 24.69, 22.62
(17x CH2), 14.04 ppm (CH3).
12-{[(2R)-2-(Nonanoylamino)-2-phenylethanoyl]amino}dodecanoic acid
Figure imgf000042_0002
The compound was prepared starting from methyl 12-{[(2i?)-2-(nonanoylarnino)-2~ phenylethanoyl]amino}dodecanoate 642 (mg, 1.277 mmol) and IM LiOH (1.92 mL, 1.916 mmol) to give 495 mg (79 %) of the product.
1H-NMR (DMSO-de): 12.02 (bs, IH, COOH), 8.43 (d, IH, J = 8.83 Hz, NH-*CH ), 8.24 (t, IH, J = 5.76 Hz, NH-CH2), 7.40-7.24 (m, 5H, Ph), 5.46 (d, IH, J = 8.64 Hz *CH), 3.02 (qua, 2H, J - 5.95 Hz, NH-CH2), 2.28 (t, 2H, J = 7.29 Hz, CH2CO), 2.19 (t, 2H, J = 6.91 Hz, COCH2), 1.72-1.18 (m, 3OH, 15x CH2), 0.85 ppm (t, 3H, J = 6AA Hz, CH3).
13C-NMR (DMSO-d6): 171.82, 169.68 (2x CO), 139.33 (1'-Ph), 128.06 (2'-Ph), 127.20 (4'-Ph), 126.92 (3'-Ph), 56.10 (*CH), 38.45, 34.91, 33.73, 33.30, 31.20, 28.92, 28.87, 28.83, 28.70, 28.63, 28.58, 28.54, 26.16, 25.31, 25.25, 24.50, 24.41, 22.04 (18x CH2), 13.89 ppm (CH3).
12-{[(2i?)-2-(Decanoylamino)-2~phenylethanoyl]amino}dodecanoic acid
Figure imgf000043_0001
The compound was prepared starting from methyl 12-{[(2i?)-2-(decanoylamino)-2- phenylethanoyl]amino}dodecanoate (329 mg, 0.637 mmol) and IM LiOH (1.27 mL,
1.273 mmol) to give 298 mg (93 %) of the product.
1H-NMR (DMSO-d6): 8.42 (d, IH, J = 8.17 Hz NH-*CH ), 8.23 (t, IH, J = 59 Hz, NH-CH2), 7.41-7.25 (m, 5H, Ph), 5.45 (d, IH, J = 8.17 Hz, *CH), 3.02 (qua, 2H, J
= 6.22 Hz, NH-CH2), 2.22 (dt, 2+2H, J = 7.37 Hz, 2x CH2CO), 1.49-1.18 (m, 32H,
16x CH2), 0.86 ppm (t, 3H, J= 6.87 Hz, CH3).
13C-NMR (DMSO-d6): 171.90, 169.73 (2x CO), 139.35 (1'-Ph)5 128.13 (2'-Ph)5
127.27 (4'-Ph), 126.95 (3'-Ph), 56.09 CCH), 38.48, 34.92, 31.33, 29.04, 29.00, 28.95, 28.89, 28.82, 28.78, 28.75, 28.70, 28.62, 28.59, 26.21, 25.32, 24.54, 22.13
(19x CH2), 13.97 ppm (CH3).
(25)-2-{[(2S)-2-(dodecanoylamino)-4-methylpentaiioyl]ainino}pentaiiedioic acid
Figure imgf000043_0002
The compound was prepared starting from dimethyl (2S)-2-{[(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino}pentanedioate (369 mg, 0.784 mmol) and IM LiOH (2.35 mL, 2.35 mmol) to give 278 mg (80 %) of the product. 1H-NMR (CDCl3): 8.34 (bs, 2H, 2x COOH), 7.56 (d, IH, J= 7.26 Hz, NH)5 7.05 (d, IH, J= 8.38 Hz, NH), 4.65-4.55 (m, 2H, 2x *CH), 2.47-1.12 (m, 27 H, CH and 13x CH2), 0.92 ppm (m, 6+3H, CH(CH3)2 and CH3). 13C-NMR (CDCl3): 176.73, 174.65, 174.41, 173.03 (4x CO), 51.71 and 51.57 (2x *CH), 36.38, 33.61, 31.92, 29.64, 29.62, 29.54, 29.36, 29.34, 29.21, 25.67, 25.49, 24.81, 22.83 (13x CH2), 24.67, 22.75, 22.09 (CH(CHs)2), 14.12 ppm (CH3).
(25)-2-{[(2R)-2-(dodecanoylamino)-2-phenylethanoyl]amino}pentanedioic acid
Figure imgf000044_0001
The compound was prepared starting from dimethyl (2S)-2-{[(2R)-2- (dodecanoylamino)-2-phenylethanoyl]amino}pentanedioate (186 mg, 0.379 mmol) and IM LiOH (1.1 mL, 1.137 mmol) to give 154.5 mg (88 %) of product. 1H-NMR (CDCl3): 8.21 (bs, 2H, 2x COOH), 7.40-7.24 (m, 5H, Ph), 7.20 (pt, IH, J= 3.80, 7.20 Hz, NH), 7.11 (d, IH3 J= 7.25 Hz, NH), 5.72 (pt, IH, J= 7.76; 16.74 Hz, *CH-Ph), 3.40 (m, IH, *CH-CH2), 2.46-1.14 (m, 24 H, 12x CH2), 0.88 ppm (t, 3H, J = 6.56 Hz, CH3). 13C-NMR (CDCl3): 180.27, 176.53, 173.92, 170.86 (4x CO), 137.61 (1'-Ph), 128.07 (2'-Ph), 128.43 (4'-Ph), 127.24 (3'-Ph), 56.90 (*CH-Ph), 51.85 (*CH-CH2), 36.43, 33.79, 33.66, 31.92, 29.61, 29.59, 29.31, 29.30, 29.13, 25.58, 24.80, 22.65 (12x CH2), 14.00 ppm (CH3).
D. General procedure for DCC-condensations with amines and alcohols Acylamino-acylamino-alkanoic acid (1.0 mmol) was dissolved in a mixture of dry CH2Cl2 [10 mL, and dioxane (10 mL), if appropriate] and cooled in an ice-bath. DCC (1.0 mmol), amine or alcohol (1.0 mmol) and DMAP (0.1 mmol) were added under stirring. Ice-bath was removed and the reaction mixture was stirred at room temperature overnight. The precipitated by-product DCHU was filtrated off, the filtrate washed with water, 5% AcOH, water, sat. NaHCO3 and water to remove impurities, dried (Na2SO4) and evaporated to give the product as a base.
E. General procedure for condensation with amines using PhsP/CC^/EtsN
Protected acid (30 mmol) was dissolved in MeCN (120 mL), amino compound (30 mmol), Ph3P (9.94 g, 36 mmol), CCl4 (2.9 mL, 30 mmol), Et3N (4.2 mL, 30 mmol) were added and stirred at room temperature overnight. The solvent was evaporated, water (60 mL) and diethyl ether (120 mL) added, and the undissolved material - the pure product - filtrated. Additional quantity of product was obtained from the filtrate: the layers were separated, the product was extracted from organic layer with IM citric acid (3 x 15 mL). The acidic extract was made alkaline with NaHCO3 and the product extracted into CH2Cl2 (3 x 30 mL), dried (Na2SO4), evaporated and purified by flash chromatography (CH2Cl2-MeOH 25:1).
F. General procedure for the preparation of hydrochlorides The base (1.0 mmol) was dissolved in a minimal quantity of CH2Cl2 and MeOH, 3% HCl/MeOH added (3.0 mL) followed with diethyl ether until the onset of turbidity. To the crystallized product some more ether was added, the precipitate filtrated and dried. General procedures D to F were used to prepare the following compounds.
iVl-{(2/?)-2-[(ll-{[4-(Dimethylamino)benzyl]amino}-ll-oxoundecyl)amino]-2- oxo-l-phenylethyl}dodecanamide (Comparator Compound I)
Figure imgf000045_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(2i?)-2-
(dodecanoylamino)-2-phenylethanoyl]amino}undecanoic acid (246 mg, 0.476 mmol), 4-(dimethylamino)benzylamine dihydrochloride (106 mg, 0.476 mmol),
DCC (98 mg, 0.476 mmol), Et3N (133 μl, 0.952 mmol) and DMAP (6 mg, 0.048 mmol) to give 134 mg (43 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1), giving 80 mg of the pure product.
1H-NMR (CD3OD): 7.40-7.31 (m, 5H, Ph), 7.12 (d, 2H, J= 8.36 Hz, 2"-H), 6.73 (d, 2H, J= 8.36 Hz, 3"-H), 5.41 (s, IH, *CH), 4.2 (s, 2H, NH-CH2-Ph), 3.21-3.12 (m, 2H, NH-CH2CH2), 2.88 (s, 6H, (N(CH3)2), 2.27 (t, 2H, J= 7.39 Hz, CH2CO), 2.19 (t, 2H, J = 7.39 Hz, CH2CO), 1.89-1.07 (m, 34H, other CH2), 0.89 ppm (t, 3H, J = 6.41Hz, -CH3). 13C-NMR (CD3OD): 175.93, 175.76, 172.44 (3x CONH). 139.22 (4"-Ph and T-Ph), 129.68 and 129.60 (2'-Ph and 2"-Ph), 129.17 (4'-Ph), 128.56 (3'-Ph), 128.21 (1"-Ph)5 114.19 (3"-Ph), 59.73 CCH), 41.13 (N(CH3)2), 43.69, 40.15, 37.09, 33.06, 30.74, 30.71, 30.63, 30.84, 30.74, 30.53, 30.48, 30.46, 30.37, 30.30, 30.20, 27.76, 27.08, 26.73, 26.04, 23.72 (2Ox CH2), 14.44 ppm (-CH3).
The hydrochloride salt is water insoluble. iVl-[(li?)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyl]decanamide (Compound 1)
Figure imgf000046_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2i?)-2-(decanoylamino)- 2-phenylethanoyl]amino}hexanoic acid (429 mg, 1.025 mmol), DCC (212 mg, 1.025 mmol), 4-picolylarnine (104 μL, 1.025 mmol) and DMAP (12.5 mg, 0.103 mmol) to give 459 mg (88 %). The crude product was purified by preparative TLC (CH2Cl2- MeOH 19:1), giving 171 mg (33 %) of the pure product. The base is insoluble in water and does not form gels.
1H-NMR (CDCl3): 8.49 (bs, 2H, 2'-H py.), 7.37-7.27 (m, 5H, Ph), 7.15 (d, 2H, J = 5.05 Hz, 3'-py.), 7.08 (d, IH, J= 7.28 Hz, NH-*CH), 6.97 (t, IH, J= 5.53 Hz, NH- CH2), 6.71 (t, IH, J = 5.53 Hz, NH-CH2), 5.59 (d, IH, J = 7.64 Hz, *CH), 4.38 (d, 2H, J= 5.79 Hz, NH-CH2-py.)3 3.17 (septet, J= 6.41 Hz, NH-CH2-CH2), 2.28 (qua, 4H, J= 7.64 Hz, 2x CH2CO), 1.58-1.23 (m, 22H, Hx CH2), 0.87 (t, 3H, J= 6.85 Hz, CH3). 13C-NMR (CDCl3): 173.26, 172.88, 170.24 (3x CONH), 149.72 (2'-py.), 147.85 (41- py.), 138.23 (1'-Ph), 128.77 (2'-Ph), 128.11 (4'-Ph), 127.06 (3'-Ph), 122.29 (3'-py.), 56.77 (*CH), 42.14, 39.28, 36.39, 36.01, 31.79, 29.38, 29.28, 29.19, 29.16, 28.63, 26.12, 25.53, 24.84, 22.60 (14x CH2), 14.06 ppm (CH3).
Hydrochloride (10 mg) gelates water (1.5 mL) and makes colourless, transparent gel. The warm solution (until 1 mL) is milk-white, nontransparent, but above this volume it gets more and more clear. After some days of standing, little flocculent crystals occur in the gel.
iVl-(4-Pyridylmethyl)-ll-{[(2i?)-(decanoylammo)-2-phenylethanoyl]amino} undecanamide (Compound 2)
Figure imgf000047_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l-{[(2i?)-2-(decanoylamino)-2-phenylethanoyl]amino}undecanoic acid (499 mg, 1.021 mmol), 4-picolylamine (103 μL, 1.021 mmol), DCC (211 mg, 1.021 mmol) and DMAP (12.5 mg, 0.102 mmol) to give 279.5 mg (47 %) of crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1) giving 132 mg (22 %) of the pure product. The base is insoluble in water and does not form gels. IR: 3300, 2921, 2851, 1635, 1541, 1567, 1415, 1383, 792, 719, 695 cm"1. 1H-NMR (CDCl3): 8.52 (bs, 2H, 2'-H py.), 7.36-7.28 (m, 5H, Ph), 7.20 (d, 2H, J = 4.36 Hz, 3'-py.), 7.03 (d, IH, J= 6.92 Hz, NH-*CH), 6.46 (bs, IH, NH-CH2), 6.41 (bs, IH, NH-CH2), 5.52 (d, IH, J = 7.04 Hz, *CH), 4.45 (d, 2H, J = 6.23 Hz, NH- CH2-py.), 3.23-3.17 (m, 2H, NH-CH2-CH2), 2.28-2.21 (m, 4H, 2x CH2CO), 1.58- 1.20 (m, 3OH, 15x CH2), 0.87 (t, 3H, J= 7.33 Hz, CH3). 13C-NMR (CDCl3): 173.39, 172.63, 169.98 (3x CONH), 149.69 (2'-py.), 147.58 (41- py.), 138.49 (1'-Ph), 128.85 (2'-Ph), 128.15 (4'-Ph), 127.16 (3'-Ph), 122.39 (3'-py.), 56.84 (*CH), 42.23, 39.77, 39.38, 36.52, 36.49, 33.91, 31.82, 29.29, 29.20, 29.19, 29.15, 29.12, 29.10, 28.95, 26.56, 25.63, 25.58, 25.53, 22.62 (19x CH2), 14.06 ppm (CH3).
b) following the general procedure for condensation with amines using PhsP/CCJU/E^N, starting from decanoyl-D-phenylglycine (1.224 g, 4.00 mmol) and l l-aminoundecanoyl-4'-picolylamide (1.166 g, 4.00 mmol) to give after purification by flash-chromatography (CH2Cl2-MeOH 25 :1) 1.091 g (47 %) of the product. Nmr spectra were identical to those reported above. Compound 2 hydrochloride salt
Hydrochloride was prepared starting from the base (1.091 g, 1.885 mmol) to give 1.132 g (98 %) of the product; 10 mg gelates 2.4 mL of water as colourless, slightly opaque gel. The hot solution is milk-white, nontransparent. 5 IR: 3306, 2921, 2851, 1637, 1538, 1369, 1417, 1228, 1194, 792, 720, 695 cm"1.
1H-NMR (DMSOd6): 8.90 (d, 2H, J= 5.88 Hz, 2'-py.), 8.65 (t, IH, J = 6.37 Hz, NHCH2), 8.42 (d, IH, J = 8.17 Hz, NH*CH), 8.24 (t, IH, J = 5.39 Hz, NHCH2), 7.80 (d, 2H, J = 6.20 Hz, 3'-py.), 7.40-7.25 (m, 5H, Ph), 5.45 (d, IH, J = 8.27 Hz3 *CH), 4.50 (d, 2H, J = 5.82 Hz, NHCH2-py.), 3.02 (qua, 2H, J = 6.12 Hz,
10 NHCH2CH2), 2.20 (dt as qua, 4H, J= 7.14 Hz, 2x CH2CO)5 1.58-1.13 (m, 30H, 15x CH2), 0.85 ppm (t, 3H, J= 6.89 Hz, CH3).
13C-NMR (DMSOd6): 173.00, 171.87, 169.73 (3x CO), 160.14 (4'-py.), 141.60 (2'- py.), 139.37 (1'-Ph), 128.11 (2'-Ph), 127.26 (4'-Ph), 126.95 (3'-Ph), 124.68 (3'-py.), 56.11 (*CH), 41.67 (NHCH2-py.), 38.48 (NHCH2CH2), 35.15, 34.90, 31.30, 28.98,
15 28.95, 28.88, 28.80, 28.73, 28.67, 28.61, 26.22, 25.31, 25.16, 22.11 (17x CH2), 13.94 ppm (CH3).
4-{[(Benzyloxy)carbonyl]amino}phenetyl ll-{[(25)-2-(dodecanoylamino)-3- phenylpropanoyl]amino}undecanoate (Comparator Compound II)
Figure imgf000048_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(25)-2- (dodecanoylamino)-3-phenylpropanoyl]amino}undecanoic acid (531 mg, 1.000 mmol), benzyl iV-[4-(2-hydroxyethyl)phenyl]carbamate (271 mg, 1.000 mmol), DCC
25 (206 mg, 1.000 mmol) and DMAP (12 mg, 0.100 mmol) to give 714 mg (91 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1), giving 548 mg (70 %) of the pure product.
1H-NMR (CDCl3): 7.37-7.13 (m, 14H, arom.), 6.93 (bs, IH, NH), 6.24 (bs, IH, NH), 5.76 (bs, IH, NH), 5.19 (s, 2H, CH2-Ph), 4.58 (dt as qua, J =6.87 Hz, IH, *CH), 4.25
30 (t, J =6.87 Hz, 2H, CH2O-), 3.15-2.95 (m, 2+2H, NH-CH2 and *CH-CH2), 2.27 (t, 2H, J= 7.65 Hz, CH2CO), 2.14 (t, 2H, J = 7.65 Hz5 CH2CO)5 1.57-1.16 (m, 34H5 other CH2), 0.88 ppm (t, 3H5 J= 6.87Hz5 -CH3).
13C-NMR (CDCl3): 177.52, 173.82, 173.12 (3x CONH)5 159.15 (NH-CO-O), 136.85 (4"-Ph and T-Ph), 129.47, 129.24, 129.22, 128.62, 128.36, 128.31 (arom.), 126.94 (4'-Ph), 117.16 (3"-Ph), 67.02 and 64.71 (2x OCH2), 54.61 (*CH), 39.45, 38.66, 36.59, 34.46, 34.31, 31.92, 29.63, 29.47, 29.34, 29.29, 29.18, 29.16, 26.68, 25.58, 22.69 (2Ox CH2), 14.13 ppm (-CH3).
3-(4-PyridyI)propyl ll-{[(2S)-2-(dodecanoyIamino)-3-phenyϊpropanoyl]amino} undecanoate (Compound 3)
Figure imgf000049_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(2S)-2- (dodecanoylamino)-3-phenylpropanoyl]amino}undecanoic acid (531 mg, 1.00 mmol), 4-pyridyl-propanol (137 mg, 1.00 mmol), DCC (206 mg, 1.00 mmol) and DMAP (12 mg, 0.01 mmol) to give 572 mg (88 %) of the crude product, that was purified by preparative TLC (CH2Cl2-MeOH 19:1) giving 450 mg (69 %) of the pure product. The base is in water insoluble and does not form gels. 1H-NMR (CDCl3): 8.50 (d, 2H5 J = 3.7 Hz, 2'-py.) 7.31-7.19 (m, 5H, Ph), 7.13 (d, 2H, J = 5.74 Hz, 3'-py.), 6.41 (d, IH. J = 8.13 Hz, NH-*CH), 6.04 (t, IH, J= 5.50 Hz, NH-CH2), 4.62 (dt as qua, J =6.22 Hz5 IH5 *CH), 4.11 (t, J =6.40 Hz, 2H, CH2O-CO-), 3.20-2.95 (m, 2+2H, NH-CH2 and *CH-CH2), 2.70 (t, 2H, J= 7.30 Hz, CH2-py.), 2.30 (t, 2H, J= 7.53 Hz, CH2CO), 2.17 (t, 2H, J= 7.30 Hz, CH2CO), 2.03- 1.91 (m, 2H, CH2-CH2-Py.), 1.72-1.08 (m, 34H, other CH2), 0.89 ppm (t5 3H, J = 6.46 Hz, CH3).
13C-NMR (CDCl3): 173.82, 173.12, 170.78 (3x CONH)5 150.24 (4'-py.), 149.48 (21- py.), 136.59 (1'-Ph)5 129.27 (2'-Ph), 128.58 (3'-Ph), 126.88 (4'-Ph), 123.85 (3'-py.), 63.18 (-OCH2), 54.54 (*CH), 39.47, 38.71, 36.59, 34.30, 33.96, 31.95, 29.63, 29.47, 29.41, 29.38, 29.34, 29.24, 29.19, 29.14, 26.75, 25.62, 24.96, 22.69 (24x CH2), 14.12 ppm (CH3). Hydrochloride (10 mg) gelates 300 μl of water.
iVl-{(lS)-3-Methyl-l-[({6-oxo-6-[4-pyridylmethyl)ammo]hexyl}amino)carbonyl] butyljdodecanamide (Compound 4)
Figure imgf000050_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino}hexanoic acid (331 mg, 0.776 mmol), 4-picolylamine (79 μl, 076 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 411 mg of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 33:1, 2x developed), giving 232 mg (62 %) of the product. 1H-NMR (CDCl3): 8.54 (bs, 2H, 2'-H), 7.20 (d, 2H, J= 3.77 Hz, 3'-H), 6.77 (t, IH, J = 5.39 Hz5 NH-CH2), 6.62 (m, IH, NH), 6.31 (d, IH, J= 8.26 Hz, NH-*CH), 4.44 (d, 2+1H, J = 5.80 Hz, *CH and NH-CH2), 3.21 (m, *CH-CH2), 2.25 (t, 2H, J= 7.35 Hz5 CH2CO), 2.17 (t, 2H, J= 7.40 Hz, CH2CO), 1.73-1.25 (m, 27H5 CH(CH3)2 and other CH2), 0.93-O.86 ppm (m, 3+6H, -CH3).
13C-NMR (CDCl3): 173.52, 173.26, 172.34 (3x CONH)5 149.80 (2'-py.)5 147.80 (4'- py.), 122.33 (3'-py.), 51.56 (*CH), 42.24, 41.02, 39.05, 36.52, 36.16, 31.86, 29.58, 29.51, 29.31, 29.19, 28.80, 26.28, 25.67, 24.99, 22.66 (16x CH2), 24.76, 22.87, 22.10 (CH(CHs)2), 14.08 ppm (CH3).
Hydrochloride (10 mg) gelates 200 μl of water.
4-PyridyImethyI 6-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyI]amino} hexanoate (Comparator Compound III)
Figure imgf000050_0002
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino}hexanoic acid (331 mg, 0.776 mmol), 4-hydroxymethyl-pyridine (85 mg, 076 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 342 mg (85 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1), giving 236 mg (59 %) of the product.
1H-NMR (CDCl3): 8.63 (bs, 2H, 2'-H), 7.26 (bs, 2H, 3'-H), 6.55 (bs, IH, NH-CH2), 6.19 (d, IH, J= 6.51 Hz, NH-*CH), 5.14 (s, 2H, OCH2), 4.44 (pt, IH, J = 8.10 Hz, *CH), 3.25 (m, 2H, NH-CH2), 2.42 (t, 2H, J = 7.35 Hz, CH2CO), 2.20 (t, 2H, J = 7.12 Hz5 CH2CO), 1.74-1.26 (m, 27H, CH(CH3)2 and other CH2), 0.94-0.85 ppm (m, 3+6H, CH3).
13C-NMR (CDCl3): 173.40, 173.01 (2x CONH), 172.17 (COO), 149.92 (2'-py.), 145.09 (4'-py.), 122.03 (3'-py.), 64.14 (OCH2), 51.49 (*CH), 41.01, 39.17, 36.58, 33.88, 31.89, 29.60, 29.49, 29.32, 29.22, 29.04, 26.27, 25.66, 24.98, 24.36, 22.67 (16x CH2), 24.78, 22.83, 22.23 (CH(CH3)2), 14.10 ppm (CH3).
Hydrochloride is water insoluble. It is soluble in EtOH, but upon the addition of water it precipitates immediately
JV1-((LS)-1 - {[(6- { [4-(Dimethylamino)benzyl] amino} amino-6-oxohexyl)amino] carbonyl}-3-methylbutyl)dodecanamide (Comparator Compound TV)
Figure imgf000051_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(25)-2- (dodecanoylammo)-4-methylpentanoyl]amino}hexanoic acid (331 mg, 0.776 mmol), 4-dimethylaminobenzylamine dihydrochloride (173 mg, 076 mmol), Et3N (217 μL, 1.552 mmol), DCC (160 mg, 0.776 mmol) and DMAP (9.5 mg, 0.078 mmol) to give 432 mg (99 %) of the crude product that was purified by preparative TLC (CH2Cl2- MeOH 19:1), giving 285 mg (66 %) of the product.
1H-NMR (CDCl3): 7.16 (d, 2H, J= 8.71 Hz, 2'-H), 6.70 (d, 2H, J = 8.73 Hz, 3'-H), 6.32 (d, IH, J = 6.9 Hz, NH-*CH), 5.93 (bs, IH, NH-CH2), 4.46 (pt, IH5 J = 8.54 Hz, *CH), 4.33 (d, 2H, J= 5.21 Hz, NH-CH2-Ph)5 3.22 (m, 2H5 NH-CH2), 2.94 (s, 6H, -N(CH3)2)5 2.18 (t, 2+2H, J= 7.5 Hz5 2x CH2CO), 1.68-1.26 (m, 27H, CH(CH3)2 and other CH2), 0.94-0.87 ppm (m5 3+6H5 CH3).
13C-NMR (CDCl3): 173.41, 172.58, 172.31(3x CONH)5 150.13 (1'-Ph), 129.03 (3'- Ph)5 125.99 (4'-Ph)5 122.71 (2'-Ph)5 51.54 (*CH)5 43.24, 419, 39.14, 36.57, 33.95, 31.92, 29.63, 29.53, 29.32, 29.26, 28.87, 26.35, 25.70, 25.05, 22.18 (16x CH2), 40.64 (-N(CHs)2), 24.81, 22.92, 22.17 (CH(CH3)2), 14.12 ppm (CH3).
Hydrochloride is in water insoluble. It is soluble in EtOH5 but upon the addition of water it precipitates immediately.
Nl-{(lS)-3-Methyl-l-[({ll-oxo-ll-[(4-pyridyImethyl)amino]undecyl}amino) carbonyl]butyl}dodecanamide (Compound 5)
Figure imgf000052_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(2S)-2- (dodecanoylamino)-4-methylpentanoyl] amino }undecanoic acid (308 mg, 0.620 mmol), 4-ρicolylamine (63 μL, 0.620 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 319 mg (88 %) of the crude product purified by preparative TLC (CH2Cl2-MeOH 25:1) giving 213 mg (59 %) of the product. 1H-NMR (CDCl3): 8.53 (bs, 2H, 2'-H), 7.19 (bs, 2H, 3'-H), 6.75 (m, IH, NH-CH2), 6.57-6.35 (m, 1+lH, 2x NH)5 4.60-4.39 (m, 2+1H, *CH and NH-CH2), 3.17 (m, *CH-CH2), 2.35-2.06 (m, 2+2H5 2x CH2CO), 1.69-1.23 (m5 37H, CH(CH3)2 and other CH2), 0.93-0.84 ppm (m, 3+6H5 CH3). 13C-NMR (CDCl3): 173.45, 172.73, 172.21 (3x CONH)5 149.63 (2'-py.)5 148.11 (4'- py.), 122.41 (3 '-py.)5 51.51 (*CH), 42.23, 42.13, 41.10, 40.73, 39.42, 36.51, 32.22, 31.87, 29.58, 29.48, 29.21, 29.13, 29.05, 26.71, 25.66, 22.65 (22x CH2), 24.73 22.80, 22.24 (CH(CHa)2), 14.09 ppm (CH3).
Hydrochloride (10 mg) gelated 450 μL of water.
3-(4-Pyridylpropyl) ll-{[(25)-2-(dodecanoyIamino)-4-methylpentanoyI]amino} undecanoate (Compound 6)
Figure imgf000053_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(2S)-2- (dodecanoylammo)-4-methylpentanoyl]amino}undecanoic acid (308 mg, 0.620 mmol) 4-pyridyl-propanol (80 μl, 0.620 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol), to give 337 mg (88 %) of the crude product by preparative TLC (CH2Cl2-MeOH 25:1) giving 193 mg (51 %) of the pure product. 1H-NMR (CDCl3): 8.48 (s, 2H5 2'-H), 7.10 (d, 2H, J= 5.34 Hz, 3'-H), 6.76 (pt, IH, J = 5.57 Hz, NH-*CH), 6.38 (t, IH, J = 7.95 Hz, NH-CH2), 4.43 (dt as qua, J =8.21 Hz, IH, *CH), 4.07 (t, J =6.44 Hz, 2H, CH2O-CO-), 3.21-.3.14 (m, 2H, NH-CH2), 2.66 (t, 2H, J= 8.21 Hz, -CH2CO), 2.26 (t, 2H, J= 7.55 Hz, CH2-CO), 2.17-2.11 (m, 2H, CH2-py.), 1.95 (dt, 2H, J= 6.66 Hz, CH2-CH2-py.), 1.68-1.15 (m, 37H, CH and other CH2), 0.89-0.84 ppm (m, 6+3H, CH(CH3)2 and CH3).
13C-NMR (CDCl3): 173.80, 173.38, 172.19 (3x CO), 150.64 (4'-py.), 149.38 (2'-py.), 123.95 (3'-py.), 63.12 (-OCH2), 51.47 (*CH), 41.10, 39.46, 36.54, 34.23, 33.92, 31.85, 31.5, 29.56, 29.45, 29.40, 29.37, 29.32, 29.30, 29.27, 29.20, 29.18, 29.09, 26.80, 25.64, 24.92, 22.62 (24x CH2), 24.76, 22.80, 22.23 (CH(CH3)2), 14.03 ppm (CH3).
Hydrochloride (10 mg) gelated 200 μL of water. 4-Pyridylmethyl ll-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyI]amino} undecanoate (Compound 7)
Figure imgf000054_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from ll-{[(2£)~2- (dodecanoylamino)-4-methylpentanoyl] amino }undecanoic acid (308 mg, 0.620 mmol), 4-hydroxypyridine (68 mg, 020 mmol), DCC (128 mg, 0.620 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 331 mg (91 %) of the crude product, that was purified by preparative TLC (CH2Cl2-MeOH 25:1) giving 241.5 mg (66 %) of the pure product.
1H-NMR (CDCl3): 8.54 (s, 2H, 2'-H), 7.19 (d, 2H, J= 4.39 Hz, 3'-H), 6.76 (d, IH, J = 7.93 Hz5 NH-*CH), 6.48 (t, IH, J= 7.65 Hz, NH-CH2), 5.06 (s, 2H, OCH2), 4.38 (dt as qua, J= 5.95 Hz, IH5 *CH), 3.16-3.08 (m5 2H5 NH-CH2), 2.33 (t, J= 7.61 Hz5 2H5 CH2-CO-), 2.12 (m, 2H5 CH2-CO)5 1.63-1.18 (m, 37H5 CH and other CH2), 0.89- 0.80 ppm (m, 6+3H, CH(CH3)2 and -CH3).
13C-NMR (CDCl3): 173.32, 172.21 (3x CO), 149.81 (2'-Ph)5 145.32 (4'-Ph)5 121.96 (3!-Ph), 63.99 (OCH2), 51.51 (*CH), 41.11, 39.48, 36.57, 34.10, 33.93, 31.87, 29.57, 29.47 29.39, 29.38, 29.31, 29.29, 29.21, 29.18, 29.15, 29.04, 26.81, 25.65, 24.88, 22.63 (24x CH2), 24.78, 22.81, 22.25 (CH(CH3)2), 14.05 ppm (CH3).
Hydrochloride (10 mg) gelated 400 μL of water.
iVl-((lS)-l-{[(ll-{[4-(Dimethylamino)benzyl]amino}-ll-oxoundecyI)amino] carbonyl}-3-methylbutyI)dodecanamide (Comparator Compound V)
Figure imgf000054_0002
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from l l-{[(2S)-2- (dodecanoylamino)-4-methylpentanoyl]amino}undecanoic acid (308 mg, 0.620 mmol), 4-(dimethylamino)benzylamine dihydrochloride (138 mg, 020 mmol), DCC (128 mg, 0.620 mmol), Et3N (173 μL, 1.240 mmol) and DMAP (7.5 mg, 0.062 mmol) to give 343 mg (88 %) of the crude product, that was purified by preparative TLC (CH2Cl2-MeOH 25:1) giving 163.5 mg (42 %) of the pure product.
1H-NMR (CDCl3): 7.15 (d, 2H3 J= 8.76 Hz, 2'-H), 6.69 (d, 2H, J= 8.76 Hz, 3'-H), 6.39 (pt, IH, J= 2.92; 8.76 Hz, NH-*CH), 5.80 (t, IH, J= 5.11 Hz, NH-CH2), 4.48- 4.41 (m, 1+lH, NH and *CH), 4.32 (d, 2H, J= 5.35 Hz, NH-CH2-Ph), 3.49 (m, IH)5 3.20 (dt, 2H, J = 5.35 Hz, NH-CH2), 2.94 (s, 6H, -N(CH3)2), 2.17 (m, 2+2H, 2x CH2CO), 1.92 (m, 2H, CH2), 1.72-1.04 (m, 27H, CH(CH3)2 and other CH2), 0.93- 0.86 ppm (m, 3+6H, CH3).
13C-NMR (CDCl3): 173.31, 172.82, 172.12 (3x CONH), 150.05 (1'-Ph), 128.95 (31- Ph), 125.93 (4'-Ph), 112.64 (2'-Ph), 51.44 (*CH), 43.16, 41.05, 39.43, 36.77, 36.49, 33.91 31.85, 29.56, 29.46, 29.31, 29.28, 29.22, 29.19, 29.18, 29.09, 26.73, 25.70, 25.65, 25.59, 24.91, 22.62 (22x CH2), 40.58 (N(CH3)2), 24.91, 22.81, 22.20 (CH(CHa)2), 14.07 ppm (CH3).
Hydrochloride is in water insoluble .
M-{(lS)-3-Methyl-l-[({4-oxo-4-[(4-pyridylmethyl)amino]butyl}amino)carbonyl] butyl} dodecanamide (Comparator Compound VI)
Figure imgf000055_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2S)-2- (dodecanoylamino)-2-phenylethanoyl] amino }hexanoic acid (304 mg, 0.763 mmol), DCC (157 mg, 0.763 mmol), 4-picolylamine (77 μL, 0.763 mmol) and DMAP (9 mg, 0.076 mmol) to give 261 mg (70 %) of the product.
1H-NMR (CDCl3): 8.53 (bs, 2H, 2'-H), 7.44 (t, IH, J= 5.97 Hz, NH-CH2), 7.21 (d, 2H, J- 4.86 Hz, 3'-H), 7.13 (t, IH, J= 5.97 Hz, NH-CH2), 6.43 (d, IH, J= 7.35 Hz, NH-*CH)3 4.43 (d, 2+1H, J = 5.97 Hz, *CH and NH-CH2-py.), 3.29 (m, *CH-CH2), 2.27 (t, 2H, J= 8.27 Hz, CH2CO)5 2.16 (t, 2H, J= 7.85 Hz, CH2CO)5 1.58 (m, 2H, CH2), 1.72-1.10 (m, 23H, CH(CH3)2 and other CH2), 0.93-0.85 ppm (m, 3+6H, CH3). 13C-NMR (CDCl3): 173.80, 173.07 (3x CONH), 149.79 (2'-py.), 147.89 (4'-py.), 122.33 (3'-py.), 51.98 (*CH)5 42.27, 41.00, 38.55, 36.46, 33.91, 33.28, 31.89, 29.60, 29.50, 29.32, 29.23, 25.78, 25.66, 24.93, 22.67 (15x CH2), 24.80, 22.89, 22.03 (CH(CHs)2), 14.11 ppm (CH3).
Hydrochloride is in water insoluble (crystallizes). It is soluble in EtOH, but upon addition of water, it crystallizes.
3-(4-Pyridyl)propyl 4-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyl]amino} butanoate (Comparator Compound VII)
Figure imgf000056_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2S)-2- (dodecanoylamino)-2-phenylethanoyl]amino}hexanoic acid (304 mg, 0.763 mmol), DCC (157 mg, 0.763 mmol), 4-pyridyl-ρropanol (99 μl, 0.763 mmol) and DMAP (9 mg, 0.076 mmol) to give 328 mg (83 %) of the product.
1H-NMR (CDCl3): 8.50 (bs, 2H, 2'-H), 7.13 (d, 2H, J= 5.65 Hz, 3'-H), 6.84 (m, IH, NH-CH2), 6.31 (pt, IH, J= 2.26; 8.19 Hz, NH-*CH), 4.47 (m, IH, *CH), 4.10 (t, J =6.14 Hz, 2H, CH2O-CO-), 3.27 (m, 2H, NH-CH2), 2.69 (t, 2H, J= 4.16 Hz, -CH2), 2.32 (t, 2H, J= 6.78 Hz, -CH2), 2.20 (t, 2H, J= 7.42 Hz, CH2), 198 (dt, 2H, J = 6.36; 15.25 Hz, CH2-CH2-py.), 1.81 (t, 2H, J= 8.20 Hz, CH2), 1.69-1.18 (m, 21H, CH and 1Ox CH2), 0.93-0.85 ppm (m, 6+3H, CH(CH3)2 and CH3).
13C-NMR (CDCl3): 173.40, 173.07, 172.39 (3x CO), 150.23 (4'-py.), 149.73 (2'-py.), 123.90 (3'-py.), 63.57 (OCH2), 51.46 (*CH), 41.12, 38.77, 36.56, 31.89, 31.64, 31.47, 29.60, 29.49, 29.33, 29.23, 29.05, 25.66, 25.61, 24.57, 22.67 (15x CH2), 24.78, 22.88, 22.17 (CH(CH3)2), 14.03 ppm (CH3).
Hydrochloride is water insoluble, and crystallizes. It is soluble in EtOH5 but upon addition of water, it crystallizes.
4-Pyridylmethyl 4-{[(25)-2-(dodecanoylamino)-4-methylpentanoyI] amino] butyrate (Comparator Compound VIII)
Figure imgf000057_0001
The compound was prepared following general procedure for DCC-condensations with amines and alcohols, starting from 6-{[(2S)-2-(dodecanoylamino)-2- phenylethanoyl]amino}hexanoic acid (290 mg, 0.728 mniol), DCC (150 nig, 0.728 mmol), 4-hydroxypyridine (79 mg, 0.835 mmol) and DMAP (9 mg, 0.073 mmol) to give 328 mg (95 %) of the product. 1H-NMR (CDCl3): 7.78 (d, 2H, J = 6.82 Hz, 2'-H), 7.42 (t, IH, J = 5.04 Hz, NH- CH2), 6.98 (d, IH, J= 8.60 Hz, NH-*CH), 6.61 (d, 2H, J= 6.82 Hz, 3'-H), 4.50 (m, IH, *CH), 3.27 (qua, 2H, J= 6.26 Hz, NH-CH2), 2.36 (t, 2H, J= 6.88 Hz, -CH2CO), 2.21 (t, 2H, J = 7.76 Hz5 -CH2CO), 1.83 (dt, 2H5 J = 6.88 Hz5 CH2), 1.66-1.20 (m5 23H, CH and Hx CH2), 0.92-0.86 ppm (m, 6+3H, CH(CH3)2 and CH3). 13C-NMR (CDCl3): 176.88 (COO), 173.96, 172.89 (2x CONH), 153.65 (4'-py.), 139.13 (2'-py.), 116.66 (3'-py.), 51.83 (*CH), 41.19, 39.03, 36.47, 33.80, 31.88, 29.59, 29.50, 29.32, 29.31, 29.23, 25.69, 25.55, 24.6O5 22.65 (14x CH2), 24.82, 22.83, 22.08 (CH(CH3)2), 14.05 ppm (CH3).
Hydrochloride is in water insoluble, and crystallizes. It is soluble in EtOH, but upon addition of water, it crystallizes. M-[(lR)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyl]dodecanamide (Compound 8)
Figure imgf000058_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2i?)-2- (dodecanoylamino)-2-phenylethanoyl] amino jhexanoic acid (205 mg, 0.459 mrnol), DCC (95 mg, 0.0.459 mmol), 4-picolylamine (46 μL, 0.459 mmol) and DMAP (6 mg, 0.046 mmol) to give 126 mg (51 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 25:1) to give 29 mg of the pure product. 1H-NMR (CDCl3): 8.49 (bs, 2H, 2'-py.), 7.35-7.26 (m, 5H, Ph).7.16 (d, 2H, J= 4.89 Hz, 3'-py.), 7.01 (d, IH, J = 7.02 Hz, NH-*CH), 6.75 and 6.57 (2x bs, 2H3 2x NH- CH2), 5.52 (d, IH5 J= 7.33 Hz, *CH), 4.39 (d, 2H, J= 6.11 Hz, NHCH2-py.), 3.23- 3.13 (m, 2H, NH-CH2), 2.19 (t, 2H, J= 7.63 Hz, CH2CO)5 2.17 (t, 2H, J= 7.63 Hz5 CH2CO)5 1.60-1.22 (m, 24H5 other CH2), 0.87 ppm (t5 3H, J= 7.33 Hz, -CH3). 13C-NMR (CDCl3): 173.23, 172.9O5 170.23 (3x CONH)5 149.71 (2'-py.)5 147.88 (4'- py.), 138.23 (1'-Ph)5 128.85 (2'-Ph)5 128.19 (4'-Ph)5 127.16 (3'-Ph)5 122.36 (3'-py.)5 56.92 (*CH), 42.25, 39.32, 36.47, 36.04, 31.86, 29.55, 29.44, 29.28, 29.19, 28.63, 26.08, 25.56, 24.79, 22.63 (14x CH2), 14.05 ppm (-CH3).
Hydrochloride (10 mg) gelates 1.1 mL water as opaque, nontransparent gel.
4-Pyridylmethyl 6-{[(2R)-2-(dodecanoylamino)-2-phenylethanoyl]amino} hexanoate (Compound 9)
Figure imgf000058_0002
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 6-{[(2i?)-2- (dodecanoylamino)-2-phenylethanoyl]amino}hexanoic acid (205 mg, 0.459 mmol), DCC (95 mg, 0.0.459 mmol), 4-hydroxymethylpyridine (50 mg, 0.459 mmol) and DMAP (6 mg, 0.046 mmol) to give 145.5 mg (59 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1) giving 87 mg (35 %) of the pure product.
1H-NMR (CDCl3): 8.52 (bs, 2H, 2'-py.)3 7.30-7.15 (m, 5+2H, Ph and 3'-py.)5 7.11 (d, IH, J= 7.91 Hz5 NH-*CH), 6.99 (t, IH5 NH-CH2), 5.61 (d5 IH5 J= 7.53 Hz5 *CH)5 5.02 (s, 2H5 OCH2), 3.16-3.04 (m, 2H5 NH-CH2), 2.24 (t5 2H5 J= 7.63 Hz5 CH2CO)5 2.16 (t, 2H, J= 7.63 Hz5 CH2CO), 1.53-1.15 (m, 24H5 other CH2), 0.80 ppm (t5 3H, J = 7.06 Hz, -CH3).
13C-NMR (CDCl3): 172.83, 172.68 (2x CONH), 170.17 (COO)5 149.85 (2'-py.)5 144.97 (4'-py.)5 138.50 (1'-Ph)5 128.68 (2'-Ph)5 127.95 (4'-Ph), 126.97 (3'-Ph)5 121.87 (3'-py.), 64.02 (OCH2), 56.60 (*CH), 39.32, 36.40, 33.75, 31.81, 29.50, 29.39, 29.26, 29.22, 29.15, 28.77, 26.07, 25.51, 24.86, 24.22, 22.58 (15x CH2), 14.00 ppm (CH3).
Hydrochloride (10 mg) gelates 800 μL of water.
iVl-(4-PyridyImethyI)-ll-{[(2i?)-(heptanoylamino)-2-phenylethanoyl]amiiio} undecanamide (Compound 10)
Figure imgf000059_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l-{[(2i?)-2-(heptanoylamino)-2-phenylethanoyl]amino}tιndecanoic acid (462 mg, 1.034 mmol), DCC (213 mg, 1.034 mmol), 4-ρicolylamine (105 μL, 1.034 mmol) and DMAP (13 mg, 0.103 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH ) to give 97 mg (17 %) of the pure product.
1H-NMR (CDCl3): 8.52 (d, 2H5 2'-H-py.)5 7.36-70 (m, 5H, Ph)5 7.19 (d, 2H5 3'-H- py.), 6.91 (d, IH, J = 7.91 Hz, NH-*CH)5 6.08 (t, IH5 NH-CH2), 5.45 (d, IH, J = 7.53 Hz5 *CH), 4.45 (d, 2H, NH-CH2-py.), 3.21 (m, 2H, NH-CH2-CH2), 2.28-2.19 (m, 4H, 2x CH2CO), 1.43-1.20 (m, 24H, other CH2), 0.86 ppm (t, 3H, J = 7.06 Hz, CH3). 13C-NMR (CDCl3): 173.36, 172.66, 170.02 (3x CONH), 149.64 (2'-py.), 148.10 (4'- py.), 138.50 (1'-Ph)5 128.86 (2'-Ph), 127.15 (4'-Ph), 127.18 (3'-Ph), 122.55 (3'-py.), 56.85 (*CH), 42.29 (NH-CH2-py.), 39.80, 36.54, 36.49, 36.48, 31.47, 29.17, 29.15, 29.13, 29.11, 28.97, 28.85, 26.57, 25.63, 25.49, 22.44, (15x CH2), 13.96 ppm (CH3).
b) following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from heptanoyl-D-phenylglycine (658 mg, 2.50 mmol) and l l-aminoundecanoyl-4l-picolylamide (729 mg, 2.5 mmol) to give 933 mg (69 %) of the product after purification by preparative TLC (CH2Cl2-MeOH 10:1). Nmr-spectra were identical to those reported above.
Compound 10 Hydrochloride
Hydrochloride was prepared starting from the base (263 mg, 0.490 mmol) giving 266 mg (95 %) of the product; 10 mg gelates 4.0 mL of water in the form of opaque, nontransparent gel.
1H-NMR (DMSO-d6): 8.84 (d, 2H, J= 6.70 Hz, 2'-py.), 8.74 (t, IH, J = 5.58 Hz, NHCH2), 8.45 (d, IH, J = 7.98 Hz, NH*CH), 8.28 (t, IH, J = 5.47 Hz, NHCH2), 7.85 (d, 2H, J = 6.35 Hz, 3'-py.), 7.84-7.25 (m, 5H, Ph), 5.45 (d, IH, J = 8.37 Hz, *CH), 4.51 (d, 2H, J = 5.87 Hz, NHCH2-py.), 3.02 (qua, 2H, J = 6.45 Hz, NHCH2CH2), 2.21 (dt as qua, 4H, J= 6.92 Hz, 2x CH2CO), 1.53-1.17 (m, 24 H, 12x CH2), 0.84 ppm (t, 3H, J= 6.83 Hz, CH3).
13C-NMR (DMSO-d6): 173.00, 171.86, 169.72 (3x CO), 160.02 (4'-py.), 141.74 (T- py.), 139.36 (1'-Ph), 128.12 (2'-Ph), 127.27 (4'-Ph), 126.95 (3'-Ph), 124.63 (3'-py.), 56.10 (*CH), 41.67 (NHCH2-py.), 38.48, 35.14, 34.91, 31.01, 28.96, 28.87, 28.85, 28.78, 28.71, 28.66, 28.28, 26.20, 25.25, 25.15, 22.02 (15x CH2), 13.91 ppm (CH3).
]Vl-(4-Py ridylmethyl)-l 1- {[(2if )-(nonanoylamino)-2-phenylethanoyl] amino} undecanamide (Compound 11)
Figure imgf000060_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l-{[(2i?)-2-(nonanoylamino)-2-ρhenylethanoyl]amino}undecanoic acid (566 mg, .1192 mmol), DCC (246 mg, 1.192 mmol), 4-picolylamine (120 μL, 1- 192 mmol) and DMAP (15 mg, 0.120 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1, 2x)) to give 140 mg (21 %) of the pure product.
1H-NMR (CDCl3): 8.49 (d, 2H, J= 4.64 Hz, 2'-H py.), 7.35-7.14 (m, 5+2 + IH, Ph + 3'-py + NH-*CH), 6.92 (t, IH5 NH-CH2), 6.65 (t, IH, J = 5.94 Hz, NH-CH2), 5.62 (d, IH, J= 7.22 Hz, *CH), 4.40 (d, 2H, J= 6.03 Hz, NH-CH2-py.), 3.15 (qua, 2H, J = 6.67 Hz, NH-CH2-CH2), 2.26-2.19 (m, 4H, 2x CH2CO)5 1.63-1.17 (m, 28H, 14x CH2), 0.86 (t, 3H, J= 7.10 Hz5 CH3).
13C-NMR (CDCl3): 173.49, 172.69, 170.07 (3x CONH)5 149.74 (2'-py.), 147.85 (4(- py.)5 138.47 (1'-Ph), 128.68 (2'-Ph), 127.96 (4'-Ph)5 126.96 (3'-Ph)5 122.25 (3'-py.), 56.57 (*CH), 42.09, 39.66, 36.42, 36.38, 31.72, 29.23, 29.16, 29.12, 29.07, 28.96, 26.57, 25.52, 22.56 (18x CH2), 14.04 ppm (CH3).
b) following the general procedure for condensation with amines using Ph3P/CC]4/Et3N, starting from pelargonyl-D-phenylglycine (453 mg, 1.554 mmol), and ll-aminoundecanoyl-4'-picolylamide (453 mg, 1.554 mmol) to give 396 mg (45 %) of the pure product after chromatographical purification. Nmr spectra were identical to those reported above.
Compound 11 Hydrochloride Hydrochloride was prepared starting from the base (247 mg, 0.437 mmol) giving 228 mg (87 %) of the product; 10 mg gelates 4.6 mL of water in the form of opaque, nontransparent gel.
1H-NMR (DMSO-d6): 8.82 (d, 2H, J= 6Al Hz, 2'-py.), 8.72 (t, IH, J = 5.78 Hz5 NHCH2), 8.43 (d, IH, J = 8.38 Hz, NH*CH), 8.26 (t, IH, J = 5.50 Hz, NHCH2), 7.84 (d, 2H, J = 6.39 Hz, 3'-py.), 7.40-7.27 (m, 5H5 Ph), 5.45 (d, IH, J = 8.29 Hz5 *CH), 4.50 (d, 2H, J = 5.86 Hz, NHCH2-py.), 3.02 (qua, 2H, J = 6.31 Hz, NHCH2CH2), 2.20 (dt as qua, 4H, J= 7.48 Hz5 2x CH2CO), 1.53-1.18 (m, 28 H, 14x CH2) and 0.85 ppm (t, 3H, J= 6.23 Hz, CH3).
13C-NMR (DMSO-d6): 172.97, 171.85, 169.71 (3x CO), 141.92 (2'-py.), 139.34 (I1- Ph), 128.10 (2'-Ph)5 127.25 (4'-Ph), 126.93 (3'-Ph), 124.56 (3'-py.), 56.09 (*CH), 41.65 (NHCH2-py.)5 38.50, 35.13, 34.89, 31.22, 28.94, 28.86, 28.83, 28.77, 28.73, 28.70, 28.65, 28.61, 28.59, 26.19, 25.27, 25.13, 22.07 (17x CH2), 13.94 ppm (CH3).
7Vl-(4-PyridyImethyl)-12-{[(2i?)-(nonanoyIainino)-2-phenylethanoyl] amino} dodecanamide (Compound 12)
Figure imgf000062_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 12-{[(2i?)-2- (nonanoylamino)-2-phenylethanoyl] amino jdodecanoic acid (418 mg, 0.855 mmol), DCC (176 mg, 0.855 mmol), 4-picolylamine (86 μL, 0.855 mmol) and DMAP (11 mg, 0.086 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1, 2x) to give 95 mg (20%) of the pure product. 1H-NMR (DMSO-de): 8.48 (d, 2H, J= 4.68 Hz, 2'-H py.), 8.46 (m, IH, NH), 8.29 (t, IH, J= 5.38 Hz, NH-CH2), 7.41-7.22 (m, 5 + 2 + IH, Ph + 3'-py + NH-CH2), 5.46 (d, IH, J= 8.03 Hz, *CH), 4.27 (d, 2H, J= 5.60 Hz, NH-CH2-py.), 3.02 (qua, 2H, J = 4.87 Hz, NH-CH2-CH2), 2.19 (t, 2H, J = 6.57 Hz, CH2CO), 2.15 (t, 2H, J = 6.81 Hz, CH2CO), 1.52-1.07 (m, 3OH, 15x CH2), 0.85 (t, 3H, J= 7.06 Hz, CH3). 13C-NMR (DMSO-d6): 172.44, 171.78, 169.66 (3x CONH), 149.37 (2'-py.), 148.74 (4'-py), 139.32 (1'-Ph), 128.03 (2'-Ph), 127.17 (4'-Ph), 126.90 (3'-Ph), 122.02 (3'- py.), 56.09 (*CH), 40.98, 38.44, 35.22, 34.90, 33.98, 31.17, 28.90, 28.89, 28.86, 28.81, 28.70, 28.67, 28.63, 28.62, 28.55, 26.15, 25.29, 25.22, 25.21, 22.01 (20x CH2), 13.86 ppm (CH3).
Hydrochloride (10 mg) gelates 1.6 mL of water in the form of opaque, nontransparent gel. Λrl-(4-pyridylmethyl)-12-{[(2i?)-(decanoylamino)-2-phenylethanoyl]amino} dodecanamide (Compound 13)
Figure imgf000063_0001
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 12-{[(2i?)-2-(decanoylamino)- 2-phenylethanoyl]amino}dodecanoic acid (253 nig, 0.427 mmol), DCC (88 mg, 0.427 mmol), 4-picolylamine (43 μL, 0.427 mmol) and DMAP (5 mg, 0.043 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1, 2x) to give 77 mg (30 %) of the pure product. 1H-NMR (DMSO-d6): 8.48 (d, 2H, J = 5.62 Hz, 2'-H py.), 8.44 (m, IH, NH), 8.41 (m, IH, NH), 8.23 (t, IH, J= 5.52 Hz, NH-CH2), 7.40-7.21 (m, 5 + 2H, Ph + 3'-py), 5.45 (d, IH, J= 8.33 Hz, *CH), 4.27 (d, 2H, J= 6.12 Hz5 NH-CH2-py.), 3.02 (qua, 2H, J= 6.02 Hz, NH-CH2-CH2), 2.17 (qua, 2 + 2H, J= 7.63 Hz, 2x CH2CO), 1.52- 1.19 (m, 32H, 16x CH2), 0.86 (t, 3H, J- 7.10 Hz, CH3). 13C-NMR (DMSO-d6): 172.49, 171.87, 169.72 (3x CONH), 149.46 (2'-py.), 139.36 (1'-Ph), 128.12 (2'-Ph), 127.22 (4'-Ph), 126.94 (3'-Ph), 122.06 (3'-py.), 56.06 (*CH), 41.01, 38.47, 35.27, 34.90, 31.31, 29.03, 28.99, 28.98, 28.94, 28.80, 28.78, 28.73, 28.70, 28.61, 25.31, 25.27, 22.11 (2Ox CH2), 13.96 ppm (CH3).
Hydrochloride (10 mg) gelates 2.4 mL of water in the form of opaque, nontransparent gel.
iVl-((li?)-2-Oxo-2-{[ll-oxo-ll-(4-pyridylamino)undecyl]amino}-l-phenyIethyl) dodecanamide (Compound 14)
Figure imgf000063_0002
The compound was prepared following the general procedure for DCC- condensations with amines and alcohols, starting from 11-([2(.R)- (dodecanoylamino)-2-phenyletanoyl] amino }undecanoic acid (517 mg, 1.00 mmol), 4-amino-pyridine (94 mg, 1.00 mmol), DCC (206 mg, 1.00 mmol) and DMAP (12 mg, 0.10 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1) giving 65 rag (11 %) of the pure product. 1H-NMR (CD3OD): 10.22 (bs, IH, CONH-py.), 8.36 (bs, 2H, 2'-py.), 7.65 (d, 2H5 J = 4.12 Hz, 3'-py.), 7.44-7.30 (m, 5H, Ph)5 5.44 (s, IH5 *CH), 3.23-3.07 (m, 2H, NH- CH2), 2.40 (t, 2+2H5 J= 7.56 Hz5 2x CH2CO)5 1.70-1.15 (m, 34H5 other CH2), 0.88 ppm (t, 3H, J= 6.88 Hz5 -CH3).
13C-NMR (CD3OD): 175.91, 175.61, 172.70 (3x CONH)5 150.96 (2'-py.)5 148.44 (4'- py.)5 139.54 (1'-Ph)5 129.96 (2'-Ph)5 129.42 (4'-Ph), 128.85 (3'-Ph), 115.34 (3'-py.), 59.01 (*CH), 40.74, 38.39, 37.00, 33.34, 31.01, 30.94, 30.89, 30.84, 30.74, 30.66, 30.56, 28.07, 27.18, 26.76, 26.34, 24, 01 (2Ox CH2), 14.78 ppm (CH3).
Hydrochloride (10 mg) gelates 0.3 mL of water.
iVl-[(lif)-2-oxo-2-({ll-oxo-ll-[4-pyridylmethyl)amiiio]undecyl}amino)-l- phenylethyl]dodecanamide (Compound 15)
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l-{[(2i?)-2-(dodecanoylamino)-2-phenyletanoyl]amino}undecanoic acid (408 mg, 0.789 mmol), 4-picolylamine (80 μL, 0.789 mmol), DCC (163 mg, 0.789 mmol) and DMAP (10 mg, 0.079 mmol) to give the crude product that was purified by preparative TLC (CH2Cl2-MeOH 25:1, 2x) giving 119 mg (25 %) of the pure product.
1H-NMR (CDCl3): 8.45 (bs, 2H, 2'-py.), 7.30-7.20 (m, 5H5 Ph), 6.64 and 6.44 (2x bs, 2H, 3'-py.), 7.12 (s, 2H5 2x CONH)5 7.03 (d, IH, J= 5.71 Hz, CONH)5 5.50 (d, IH5 J = 7.07 Hz5 *CH), 4.35 (d, 2H5 J = 5.98 Hz5 NHCH2-ρy.)5 3.12-3.09 (m, 2H5 NH- CH2CH2), 2.16 (p, 2+2H, J= 7.69 Hz5 2x CH2CO)5 1.60-1.12 (m5 34H, other CH2), 0.82 ppm (t, 3H, J= 6.90 Hz5 -CH3).
13C-NMR (CDCl3): 173.51, 172.78, 170.31 (3x CONH)5 149.82 (2'-py.)5 147.95 (4'- py.), 138.55 (1'-Ph), 128.85 (2'-Ph), 128.15 (4'-Ph)5 127.17 (3'.Ph), 122.45 (3'-py.), 56.84 (*CH), 42.28, 39.81, 36.54 31.92, 29.62, 29.50, 29.34, 29.25, 29.19, 29.17, 29.02, 26.64, 25.60, 22.69 (21x CH2), 14.11 ppm (CH3).
b) following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from lauroyl-D-phenylglycine (667 mg, 2.00 mmol) and 11- aminoundecanoyl-4'-picolylamide (583 mg, 2.00 mmol) to give 873 (72 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1) giving 447 mg (37 %) of the pure product. Nmr spectra were identical to those reported above.
Hydrochloride was prepared starting from the base (468 mg, 0.771 mmol) giving 462 mg (93 %) of the product; 10 mg gelates 1.2 mL of water as white, nontransparent gel.
iVlJV5-di(4-pyridylmethyl)-(2S)-2-{[(2S)-2-(dodecanoylamino)-4- methylpentanoyl]amino}pentanediamide (Compound 16)
Figure imgf000065_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from ( (25)-2-{[(2S)-2-(dodecanoylamino)-4- methylρentanoyl]amino}pentanedioic acid (256 mg, 0.578 mmol), DCC (239 mg, 1.157 mmol), 4-picolylamine (117 μL, 1.157 mmol) and DMAP (14 mg, 0.116 mmol) to give 245 mg (68 %) of the crude product that was purified by preparative TLC (CH2Cl2-MeOH 19:1, 2x) giving 125.5 mg (35 %) of the pure product. The base is in water insoluble and does not form gels. IR: 3430, 3283, 3070, 2925, 2853, 1637, 1542, 790 ran 1. 1H-NMR (CDCl3): 8.49 (bs, 2x 2H, 2'-H py.), 8.29-8.16 (m, IH5 NH), 8.01-7.92 (m, 2H, 2xNH)5 7.46 (t5 IH, J= 6.01 Hz, NH-CH2), 7.15 (bs, 2x 2H5 3'-H py.), 6.47 (d, J = 6.85 Hz, NH-*CH), 4.40-4.33 (m, 6H5 2x *CH and 2x NH-CH2), 2.45-2.35 (m, 4H5 2x CH2CO), 2.28-2.01 (m, 4H, 2x CH2), 1.65-1.14 (m, 19H5 CH and 9x CH2), 0.92-0.85 ppm (m, 9H5 CH(CH3)2 and CH3).
13C-NMR (CDCl3): 174.56, 173.44, 172.89, 171.56 (4x CONH), 149.86 (2!-py.), 147.50 (4'-ρy.), 122.19 (3'-py.), 52.92 and 52.63 (2x *CH), 42.40, 42.31, 42.15, 36.27, 36.05, 31.86, 29.57, 29.49, 29.45, 29.32, 29.29, 29.27, 29.22, 25.50, 22.65 (15x CH2), 24.90, 22.96, 21.63 (CH(CH3)2), 14.08 ppm (CH3).
b) following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from (25)-2-{[(25)-2-(dodecanoylamino)-4- methylpentanoyl] amino }pentanedioic (317 mg, 0.716 mmol) and 4-picolylamine (145 μL, 1.432 mmol) to give 243 mg (55 %) of the crude product that was purified by preparative TLC giving 142 mg (32 %) of the product.
Dihydrochloride (10 mg) gelates water (4.4 mL) in the form of colourless, transparent gel, after some hours of standing. The hot solution up to 600 μL is clear, but above this volume of water it becomes milky white up to 2.0 mL volume; then it is more and more clear.
M^V5-di(4-pyridylmethyl)-(25)-2-{[(2R)-2-(dodecanoylamino)-2- phenylethanoyl]amino}pentanediamide (Compound 17)
Figure imgf000066_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from (25)-2-{[(2i?)-2-(dodecanoylamino)-2- phenylethanoyl] amino }pentanedioic acid (653 mg, 1.412 mmol), DCC (582 mg, 2.823 mmol), 4-picolylamine (286 μL, 2.823 mmol) and DMAP (35 mg, 0.282 mmol) to give 557 mg (61 %) of the crade product that was purified by preparative TLC (CH2Cl2-MeOH 19:1, 2x) giving 120 mg (13 %) of still not quite pure product. The base is in water insoluble and does not form gels. 1H-NMR (DMSOd6): 8.49 (d, 2x 2H, J = 64 Hz, 2'-H py.), 8.60-8.36 (m, 3H, 3x NH), 74-78 (m, 5 + 4 + IH, Ph + 3'-H py NH)5 50 (d, J= 79 Hz, *CH), 4.33-4.23 (m, 5H, *CH and 2x NH-CH2), 2.20-2.10 (m, 4H, 2x CH2CO), 1.50-1.14 (m, 21H, CH and 1Ox CH2), 05 ppm (t, 3H, J= 66 Hz, CH3).
13C-NMR (DMSO-d6): 171.99, 171.87, 171.64, 170.89 (4x CONH), 149.85 (2'-py.), 148.95 (4'-py.), 138.74 (1'-Ph), 128.63 (2'-Ph), 127.76 (4'-Ph), 127.62 (3'-Ph), 122.39 (3'-py.), 57.04 and 53.11 (2x *CH), 41.53, 41.43, 35.90, 35.16, 31.69, 29.41, 29.33, 29.31, 29.22, 29.15, 29.09, 25.82, 25.56, 22.48 (14x CH2), 14.34 ppm (CH3).
b) following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from lauroyl-D-phenylglycine (584 mg, 1.750 mmol) and M,N5-di(4-pyridyhnethyl)-(25)-2-aminopentanediamide (573 mg, 1.750 mmol) to give 911 mg (84 %) of the crude product; after purification by preparative TLC (CH2Cl2-MeOH 9:1, 2x) there was 544 mg (50 %) of the pure product. Nmr spectra were identical to those reported above.
Dihydrochloride was prepared starting from the base (497 mg, 0.798 mmol) giving 436 mg (79 %) of the product; 10 mg gelates 1.3 mL of water in the form of colourless, transparent gel.
Methyl 12-{[(2i?)-2-(decanoylamino)-2-phenylethanoyl]amino}dodecanoate
Figure imgf000067_0001
The compound was prepared following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from decanoyl-D-phenylglycine (500 mg, 1.637 mmol) and methyl 12-amino-dodecanoate hydrochloride (435 mg, 1.637 mmol) and Et3N (0.456 mL, 3.274 mmol) to give 365 mg (43 %) of the pre product. 1H-NMR (DMSO-d6): 8.43 (d, IH5 J = 8.22 Hz5 NH-*CH ), 8.23 (t, IH5 J = 5.43 Hz5 NH-CH2), 7.40-7.21 (m, 5H5 Ph)5 5.45 (d, IH5 J = 8.70 Hz5 *CH), 3.57 (s, 3H5 OCH3), 3.02 (qua, 2H, J = 6.09 Hz, NH-CH2), 2.28 (t, 2H, J= 6.96 Hz, CH2CO), 2.18 (t, 2H5 J= 7.61 Hz, CH2CO), 1.50-1.18 (m, 32H5 16x CH2), 0.85 ppm (t, 3H, J = 6.88 Hz, CH3).
13C-NMR (DMSO-d6): 171.85 169.70 (2x CO), 139.35 (1'-Ph), 128.09 (2'-Ph), 126.93 (4'-Ph)5 126.69 (3'-Ph), 56.05 (*CH), 51.15 (OCH3), 38.45, 33.26, 31.30, 29.02, 28.83, 28.86, 28.72, 28.67, 28.46, 26.18, 25.30, 24.43, 22.10 (19x CH2), 13.94 ppm (CH3).
Benzyl N-((15)-4-oxo-4-[(4-pyridylmethyI)amino]-l-{[(4-pyridylmethyl)amino ] carbonyl}butyl)carbamate
Figure imgf000068_0001
The compound was prepared following the general procedure for condensation with amines using Ph3P/CCl4/Et3N5 starting from -V-[(benzyloxy)carbonyl]glutamic acid (8.308 g, 29.54 mmol) and 4-picolylamine (5.98 mL, 59.08 mmol) to give 10.619 g (78 %) of the pure product.
1H-NMR (DMSO-d6): 8.60 (t, IH, J= 6.08 Hz5 NH), 8.48 (bs, 4H5 2x 2'-H py.), 7.60 (d, IH, J= 7.72 Hz, NH*CH), 7.40-7.30 (m, 5H, Ph), 7.24 (m, 4H, 2x 3'-H py.), 5.06 (s, 2H, OCH2), 4.34-4.27 (m5 4H, 2x NH-CH2), 4.06 (m, IH5 *CH), 2.29 (m, 2H5 CH2CO), 1.85-1.83 ppm (m, 2H, *CH-CH2).
13C-NMR (DMSO-d6): 171.78 (CONH), 156.04 (COO), 149.42 (2'-py.), 148.55 (I1- py.), 136.94 (1'-Ph), 128.29 (2'-Ph), 127.75 (4'-Ph)5 127.68 (3'-Ph), 122.02 (3'-py.), 65.50 (OCH2), 54.55 (*CH), 41.12 and 41.08 (2x NH-CH2), 31.68 and 27.59 ppm (2x CH2).
fer/-ButylN-{ll-oxo-ll-[(4-pyridylmethyl)amino]undecyl}carbamate
Figure imgf000068_0002
The compound was prepared following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from ll-[ (tert- butoxycarbonyl)amino]undecanoic acid (9.256 g, 30.708 mmol) and 4-picolylamine (3.11 mL, 30.708 mmol) to give 11.748 g (98 %) of the crude product that was purified by flash-chromatography (CH2Cl2-MeOH 30:1) giving 10.162 g (85 %) of the pure product.
1H-NMR (CDCl3): 8.50 (d, 2H5 J= 5.36 Hz, 2'-H)3 7.28 (d, 2H, J = 5.36 Hz, 3'-H), 6.73 (t, IH, J= 5.82 Hz, NHCH2-py.), 4.70 (m, IH5 NHCH2CH2), 4.43 (d, 2H5 J = 6.07 Hz, NHCH2-Py.), 3.08 (qua, 2H5 J = 6.79 Hz, NHCH2CH2), 2.26 (t, 2H5 J = 7.50 Hz5 CH2CO)5 1.66 (p, 2H, J = 7.36 Hz5 NHCH2CH2), 1.43 (s, 9H, f-Bu), 1.26 ppm (m, 14H5 7x CH2).
13C (CDCl3): 174.95 and 173.41 (2x CO), 149.89 (2'-py.)5 147.71 (l'-py.)5 122.26 (31- py.)5 78.90 (C(CH3)3), 42.19 (NHCH2-py.), 36.52 (NHCH2CH2), 29.98, 29.28, 29.20, 29.15, 29.11, 29.06, 26.63, 25.62 (9x CH2), 28.32 ppm (C(CH3)3).
Benzyl iV-{ll-oxo-ll-[(4-pyridylmethyl)amino]undecyl}carbamate
Figure imgf000069_0001
The compound was prepared following the general procedure for condensation with amines using PhSPZCCl4VEt3N, starting from 11- [(benzyloxycarbonyl)amino]undecanoic acid (300 mg, 0.894 mmol) and 4- picolylamine (90 μL, 0.894 mmol), Ph3P (281 mg, 0.894 mmol), Et3N (125 μL, 0.894 mmol) and CCl4 (86 μL, 0.894 mmol) to give 235 mg (61 %) of the product.
Nl-{(lR)-2-oxo-l-phenyl-2-[(4-pyridylmethyl)amino]ethyl}decanamide (Comparator Compound IX)
Figure imgf000069_0002
The compound was prepared starting following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N5 from decanoyl-D-phenylglycine (764 mg, 2.50 mmol) and 4-ρicolylamine (0.253 mL, 2.50 mniol) to give 473 mg (48 %) of the pure product.
1H-NMR (CDCl3): 8.43 (d, 2H, J- 4.52 Hz 2'-H), 7.42-7.33 (m, 5 + IH, Ph + NH), 6.98 (m, IH3 NH), 6.96 (d, 2H, J = 4.54 Hz, 3'-H), 5.77 (d, IH, J= 70 Hz), 4.46-4.29 (m, 2H5 NHCH2-py.), 2.21 (t, 2H, J= 7.56 Hz, CH2CO), 1.53 (p, 2H, J= 7.04 Hz, CH2CH2CO), 1.40-1.20 (m, 12H, 6x CH2) and 0.87 ppm (t, 3H, J= 7.00 Hz, CH3). 13C (CDCl3): 172.94 and 170.61 (2x CO)5 149.86 (2'-py.), 146.92 (l'-py.), 137.94 (I1- ph), 129.05 (2'-Ph)5 128.50 (4'-Ph), 127.15 (3'-Ph), 121.89 (3'-py.), 56.89 (*CH), 42.35 (NHCH2-py.)5 36.43 (NHCH2CH2), 31.83, 29.39, 29.27, 29.21, 29.16, 25.48, 22.63 (7x CH2), 14.06 ppm (CH3).
Hydrochloride was prepared from the base (271 mg, 085 mmol) giving 238 mg (80 %) of the product. It crystallizes from water, and does not form hydrogel.
iVl-(4-Pyridylmethyl)-ll-{[(25)-2-(decanoylamino-4-methylpentanoyl]amino} undecanamide (Compound 18)
Figure imgf000070_0001
The compound was prepared following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N, starting from decanoyl-L-leucine (1.35 g, 4.73 mmol) and l l-undecanoyl-4'-picolylamide (1.38 g, 4.73 mmol) to give 1.50 g (56 %) of the product
1H-NMR (CDCl3): 8.53 (d, 2H5 J= 5.91 Hz, 2'-py.), 7.23 (d, 2H, J= 5.91 Hz, 3'-py.)5 6.51- 6.49 (m, IH, NH), 6.26 (t, IH, J= 5.84 Hz, NHCH2), 6.22 (t, IH, J= 8.30 Hz, NHCH2), 4.45 (dd, 2H, J = 2.56; 6.04 Hz, NHCH2-py.), 4.44-4.41 (m, IH, Hz5 *CH), 3.20 (qua, 2H, J = 6.35 Hz5 NH-CH2CH2), 2.26 (t, 2H, J = 7.58 Hz, CH2CO), 2.18 (t, 2H, J= 7.48 Hz, CH2CO), 1.69-1.21 (m, 33H, CH and other CH2), 0.91 ppm (dd, 6H, J= 6.16; 10.17 Hz, CH(CH3)2), 0.87 ppm (t, 3H5 J= 6.98 Hz, CH3).
Hydrochloride was prepared: a) following General procedure for the preparation of hydrochlorides (F) starting from the base (1.50 g, 2.68 mmol) giving 900 mg (56 %). b) To the solution of JVl -benzyl- 1 l-{[(25)-2-amino-4- methylpentanoyl]amino}undecanamide (400 mg, 0.98 mmol) in dry CH2Cl2 (5 mL) Na2Cθ3 (116 mg, 1.1 mmol) was added in an argon atmosphere.The reaction mixture was cooled in ice.bath and decanoyl chloride (=.2 mL) was added under stirring. Additional CH2Cl2 (20 ml) was added and the reaction mixture stirred at 30-35 0C for 6 hours. Once more CH2Cl2 (20 ml) was added, the mixture warmed up to 40 0C and filtrated to remove inorganic salts. The filtrate was evaporated, dry MeOH (5 mL) and 3% HCl/MeOH were added. The hydrochloride product was precipitated by addition of dry ether, filtrated and dried giving 425 mg (73 %) of pale-yellow precipitate, m.p. 111-113 0C. [α]D = -18 (c = 1, MeOH).
1H-NMR (CDCl3): 8,72 (d, 2H, J= 5.55 Hz, 2'-H)5 8.28 (br s, IH, NH), 7.98 (d, 2 H, J- 5.87 Hz, 3'-H), 6.96 (d, IH. J= 6.85 Hz, NH-CH*), 4.69 (d, 2 H5 J= 4.89 Hz, NH-CH2-Py), 4.49 (qua, IH5 J= 8.05 Hz, C*H), 3.19 (m, 2H, NHCH2CH2), 2.36 (t, 2H, J= CH2CO), 2.25 (dt, 2H, J= 7.48, 10.38 Hz, CH2CO), 1.70-1.55 (m, 8 H), 1.48 (t, 2H, J= 6.81 Hz, CH2) 1.35-1.16 (m, 28 H5 other CH2), 0.96- 0.84 ppm (m, 9H, CH3). 13C-NMR (CDCl3): 174.55, 173.91, 172.84 (3 x CONH), 161.48 (4'-py), 140.38 (2'- py), 125.92 (3'-py), 52.08 (*CH), 42.74 (NH-CH2-py), 41.21, 39.56, 36.46, 36.09, 31.87, 29.49, 29.39, 29.26, 29.05, 26.75, 25.79, 25.53, 22.66 (19 x CH2), 24.86, 22.91, 22.16 (CH(CH3)2), 14.08 (CH3).
M-(4-Pyridylmethyl)-ll-{[(25)-2-(decanoylamino-3- methylbutanoyl]ammo}undecanamide (Compound 19)
Figure imgf000071_0001
The compound was prepared following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N5 starting from decanoyl-L-valine (1.086 g, 4.00 mmol) and 1 l-undecanoil-4'-picolylamide (1.166 g, 4.00 mmol) to give 1.40 g (64 %) of the product after purification by FC chromatography (CH2Cl2-MeOH 30 : 1 and 20 : 1 ) 1H-NMR (DMSO-d6): 8.48 (d, 2H5 J = 5.95 Hz5 2'-py.), 8.39 (t, IH, J = 6.18 Hz, NH-CH2), 7.87(t5 IH, J= 5.60 Hz, NH-CH2), 7.75 (d, IH, J= 9.22 Hz, NH-C*H)5 7.22 (d, 2H5 J= 5.83 Hz, 3'-py), 4.27 (d, 2H, J= 5.95 Hz, NHCH2-py.), 4.07 (dd, IH, J= 7.35, 9.10 Hz, Hz5 *CH), 3.08-2.96 (m, 2H, NH-CH2CH2), 2.19-1.82 (m, 5H, 2 x CH2CO and CH(CH3)2), 1.57-1.14 (m, 30H5 other CH2), 0.87-0.80 ppm (m5 9H5 CH(CH3)2 and CH3).
13C (DMSO-dβ): 172.49, 172.12 and 170.90 (3 x CO), 149.45 (2'-py.)5 148.77 (4'- py.)5 122.06 (3'-py.), 57.76 (*CH), 41.02 (NHCH2-ρy.)5 38.03 (NHCH2CH2), 35.27, 35.13, 31.30, 30.36, 28.99, 28.96, 28.91, 28.80, 28.78, 28.72, 28.70, 28.67, 28.61, 26.33, 25.41, 24.26, 22.11 (17x CH2), 29.01, 19.22 and 18.30 (CH(CH3)2), 13.94 ppm (CH3).
Hydrochloride was prepared starting from the base (396 mg, 0.727 mmol) giving 418 mg (99 %) of the product. 1H-NMR (DMSO-d6): 8.84 (d, 2H, J= 6.00 Hz, 2'-py.-H), 8.76 (t, IH, J= 6.00 Hz, NHCH2), 7.93 (t, IH, J= 5.83 Hz, NHCH2), 7.85 (d, 2H, J = 6.18 Hz5 3'-py.-H), 7.82 (d, IH, J= 8.87 Hz, C*HNH), 4.51 (d, 2H5 J= 5.91 Hz5 NHCH2-py.), 4.o6 (t, IH, J = 8.35 Hz, *CH), 3.12-2.92 (m, 2H, NH-CH2CH2), 2.21 (t, 2H, J= 7.43 Hz, CH2CO)5 2.12 (t, 2H5 J= 6.88 Hz, CH2CO), 2.02-184 (m, IH, CH(CH3)2), 1.57-1.12 (m, 30H, other CH2), 0.88-0.79 ppm (m, 9H, CH(CH3)2) and CH3). 13C-NMR (DMSO-d6): 173.0I5 172.14, 170.95 (3x CO), 160-11 (4'-py), 141.64 (21- py.)5 124.68 (3'-py.), 57.87 (*CH), 41.69 (NHCH2-py.), 38.32 (NH-CH2CH2),, 35.15, 35.16, 31.30, 29.01, 28.96, 28.90, 28.89, 28.74, 28.67, 28.62, 26.35, 25.43, 25,16, 22.11 (17 x CH2), 30.36, 19.24 and 18.33 (CH(CH3)2), 13.95 ppm (CH3).
iVl-[(lS)-l-BenzyI-2-oxo-2-({ll-oxo-ll-[4-pyridylmethyl)amino]undecyl}amino) ethyl] dodecanamide (Compound 20)
Figure imgf000072_0001
The compound was prepared: a) following the general procedure for DCC-condensations with amines and alcohols, starting from 1 l-{[(2S)-2-(dodecanoylamino)-3-phenylpropanoyl]amino}undecanoic acid (555 mg, 1.046 mmola), DCC (216 mg, 1.046 mmola), 4-picolylamine (106 μl, 1.046 mmola) and DMAP (13 mg, 0.105 mmola) to give 558 mg (86 %) of the crude product that was purified by preparative TLC (CH2CIi-MeOH 19:1) giving 234 mg (36 %) of the pure product.
IR (KBr): 3292, 2919, 2850, 1638, 1542, 1468, 1416, 1384, 1275, 1220, 1188, 698 cm"1. 1H-NMR (CDCl3): 8.52 (d, 2H, J= 5.53 Hz, 2'-py.-H), 7,27-7.17 (m, 5+2H3 Ph i 3'- py.-H), 6.44 (d, IH, J= 7.86 Hz, C*H-NH), 6.31 (t, IH, J= 6.12 Hz, NHCH2), 6.11 (t, IH, J= 5.68 Hz, NHCH2), 4.62 (q, IH, J= 7.14 Hz, *CH), 4.44 (d, 2H, J= 6.14 Hz, NHCH2-py.), 3.13-3.00 (m, 2+2H, 2x NH-CH2), 2.26 (t, 2H, J= 7.62 Hz, CH2CO), 2.14 (t, 2H, J= 7.86 Hz, CH2CO), 1.69 (t, 2H, J= 7.29 Hz, CH2), 1.54 (t, 2H, J= 7.17 Hz, CH2), 1.30-1.18 (m, 3OH, other CH2), 0.88 ppm (t, 3H, J= 6.88 Hz, -CH3).
13C-NMR (CDCl3): 173.38, 173.12, 170.81 (3x CONH)9 149.86 (T- py), 147.77 (41- py), 136.84 (l'-Ph.), 129.21 (2'-Ph), 128.53 (4'-Ph), 126.86 (3'-Ph), 122.29 (3'- py), 54.49 (*CH), 42.20, 39.4O5 38.59, 36.53, 31.87, 29.59, 29.57, 29.43, 29.32, 29.30, 29.22, 29.15, 29.03, 26.64, 25.64, 25.57, 22.64 (22x CH2), 14.08 ppm (-CH3).
b) following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from l l-{[(25)-2-(dodecanoylamino)-3- phenylpropanoyl]amino}undecanoic acid (931 mg, 1.754 mmol) and 4-picolylamine (0.177 mL, 1.754 mmol), to give 277 mg (25 %) of the pure product after chromatographic purification.
Hydrochloride (10 mg) gelates 900 μL of water as white, non-transparent gel. IR (KBr): 3291, 2929, 2850, 1638, 1540, 1466, 1374, 1274, 1119, 697 cm4. 1H-NMR (DMSO-de): 8.81 (d, 2H, J= 5.60 Hz, 2'-py.-H), 8.67 (t, IH, J= 5.83 Hz, NHCH2), 8.00 (dd, IH, J= 3.33; 8.33 Hz, NHCH2), 7.88 (d, IH, J= 5.83 Hz,
C*HNH), 7.82 (d, 2H, J = 5.60 Hz, 3'-py.-H), 7.23-7.19 (m, 5H, Ph), 4.5 (d, 2H, J= 5.83 Hz5 NHCH2-py.), 4.45 (q, IH, J= 4.44 Hz, *CH), 3.07-2.68 (m, 2+2H, 2x NH- CH2), 2.27 (t, 2H5 J= 7.45 Hz, CH2CO), 2.1 (t, 2H, J= 7.45 Hz, CH2CO), 2.01 (t, 2H5 J= 7.62 Hz5 CH2), 1.56-1.12 (m, 32H5 other CH2), 0.88 ppm (t, 3H, J= 6.24 Hz, -CH3).
13C-NMR (DMS0-d6): 172.97, 171.90, 170.97 (3x CO), 142.26 (2'-py.), 138.05 (I1- Ph), 129.10 (2'-Ph)5 127.90 (3'-Ph), 126.09 (4'-Ph), 124.46 (3'-py.), 53.89 (*CH), 41.64 (NHCH2-Py.), 38.41, 37.87, 35.16, 35.13, 33.25, 31.29, 29.02, 28.98, 28.95, 28.92, 28.81, 28.71, 28.44, 28.29, 26.25, 25.19, 25.14, 34.43, 22.09 (21x CH2), 13.94 ppm (CH3).
iVl-(4-PyridyImethyl)-ll-{[(2S)-2-(decanoylamino)-3-phenylpropanoyI]amino} undecanamide (Compound 21)
Figure imgf000074_0001
The compound was prepared following the general procedure for condensation with amines using Ph3P/CCl4/Et3N, starting from decanoyl-L-phenylalanine (1.042 g, 3.00 mmol) and ll-undecanoyl-4'-picolylamide (874 mg, 3.00 mmol)) to give 1.317 g (75 %)of the raw product After purification on chromatographic plates (CH2Cl2-MeOH 19:1) it was obtained 828 mg (47 %) of the pure product.
IR (KBr): 3287, 3061, 3026, 2919, 2850, 1651, 1538, 1468, 1383, 1228,1197, 1119, 1029, 993, 793, 747, 699 and 606 cm 1. 1H-NMR (DMSO-d6): 8.48 (d, 2H, 3J= 5.94 Hz, Hpy-2'), 8.40 (t, IH, 3J= 5.84 Hz, NH-CH2-py), 8.00 (d, IH, 3J= 8.48 Hz, NH-C*H), 7.88 (t, IH, 3J= 5.84 Hz, NH- CH2 ), 7.26-7.17 (5+2H5 m, Ph i Hpy-3' ), 4.50-4.40 (m, IH, *CH ), 4.27 (d, 2H, 2J= 5.96 Hz, CH2-Ph ), 3.08-2.96 (m, 2H, NH-CH2 ), 2.92 (dd, IH, 2J^ = 13.51 Hz, 3Ja5NH = 5.16 Hz, CH23 - py), 2.72 (dd, IH, 2Jb,a = 13.51 Hz, 3Jb;NH = 5.16 Hz, CH2b - py), 2.15 (t, 2H, 3J= 7.25 Hz, CH2CO ), 2.01 (t, 2H, 3J= 7.19 Hz, CH2CO ), 1.51 (t, 2H, 3J= 7.10 Hz, CH2 ), 1.37 (t, 2H, 3J= 7.60 Hz, CH2), 1.32 (t, 2H, 3J= 7.38 Hz, CH2 ), 1.28-1.10 (m, nH, otheri CH2 ), 0.85 (t, 3H, 3J= 6.90 Hz, CH3 ). 13C-NMR (DMSO-d6): 172.43, 171.89, 170.91 (3xCONH), 149.40 (2'- py), 148.71 (41 -py), 138.01 (1'-Ph), 129.05 (2'-Ph), 127.86 (3'-Ph), 126.04 (4'-Ph), 122.03 (3'- py), 53.82 (*CH), 41.02, 38.43, 37.86, 35.26, 35.18, 31.24, 28.93, 28.91, 28.87, 28,82, 28.76, 28.72, 28.70, 28.65, 28.61, 28.43, 26.24, 25.21, 25.15 and 22.03 (2OxCH2, 13.87 PPm(CH3).
Hydrochloride was prepared starting from the base (212mg, 0.36 mmol) giving 210 mg, 92%) of the product.
IR (KBr): 3293, 3062, 2921, 2851, 1638, 1541, 1466, 1455, 1436, 1375, 1272, 1230, 1191, 1160, 1119, 1029, 786, 745, 721 and 698 cm"1.
1H-NMR (DMSOd6): 8. 82 (d, 2H, 3J= 6.16 Hz, Hpy-2'), 8.69 (IH, t, 3J= 5.80 Hz, NH-CH2-py), 8.02 (IH, d, 3J= 8.35 Hz, NH-C*H), 7.90 (IH, t, 3J= 5.43 Hz, NH- CH2 ), 7.83 (d, 2H, 3J= 6.16 Hz, Hpy-3'), 7.25-7.14 (5H, m, Ph), 4.50 (2H, d, 2J= 5.80 Hz, CH2-Py ), 4.48-4.38 (IH, m, *CH ), 3.07-2.97 (2H, m, NH-CH2 ), 2.92 (lH,dd, 2Ja,b = 13.46 Hz, 3J3, C*H = 5.11 Hz, CH2a - Ph), 2.73 (IH, dd, 2Jb,a = 13.46 Hz, 3Jb; C*H = 9.60 Hz, CH2b - Ph), 2.20 (2H, t, 3J= 7.30 Hz, CH2CO ), 2.01 (2H, t, 3J= 7.22 Hz, CH2CO ), 1.53 (2H, t, 3J= 6.65 Hz, CH2 ), 1.35 (2H, t, 3J= 7.24 Hz3 CH2), 1.32 (2H, t, 3J= 7.38 Hz, CH2 ), 1.29-1.10 (22H, m, Hx CH2 ), 0.85 ppm (3H, t, 3J= 6.83 Hz, CH3 ),
13C-NMR (DMSO-d6):173.43, 172.39, 171.48 (3xCONH), 160.11 (C-4' py), 142.52 (CH-21 py.), 138.52 ( C-I1 ph.), 129.57 ( CH-2' ph.), 128.38 (CH-31 ph.), 126.57 (CH- 4' ph.), 124.98 (CH-31 py.)5 54.36 (*CH), 42.11, 38.90, 38.34, , 35.64, 35.60, 31.76, , 29.44, 29.36, 29,35, 29.28, 29.62, 29.21, 29.18, 29.15, 28.91, 26.75, 25.66, 25.60 and 22.57 (2OxCH2), 14.43 ppm (CH3).
Λ^l-(4-Pyridylmethyl)-ll-{[(27?,S)-(decanoylammo)-2-methylethanoyl] amino} undecanamide (Compound 22)
Figure imgf000075_0001
The compound was prepared following the general procedure for condensation with amines using PhsP/CCL/EtsN, starting from decanoyl-D,L-alanine (0.9 g, 3.7 mmol) and l l-aminoundecanoyl-4'-picolylamide (1.079 g, 3.7 mmol) to give after purification by TLC chromatography (CH2Cl2-MeOH 100 :1) 0.816 g (47 %) of the product.
1H-NMR (DMSO-d6): 8.85 (d, 2H, J= 6.33 Hz, 2'-H py.), 8.78 (t, IH, J= 5.94 Hz5 NH-CH2), 7.94 (d, IH, J= 7.92 Hz, NH-*CH), 7.88 (d, 2H, J= 6.33 Hz, 3'-py.), 7.80 (t, IH, J = 5.60 Hz, NH-CH2), 4.52 (d, 2H, J = 5.82 Hz, NH-CH2-py.), 4.26-4.16 (m, IH, *CH), 3.04-2.98 (m, 2H, NH-CH2-CH2), 2.21 (t, 2H, J = 7.50 Hz, CH2CO), 2.09 (t, 2H5 J = 7.40 Hz5 CH2CO), 1.58-1.17 (m, 30H5 15x CH2), 1.15 (d, 2H5 J = 7.16 Hz5 CH3-AIa)5 0.84 (t, 3H5 J= 6.90 Hz5 CH3).
13C-NMR (DMSO-d6): 173.46, 172.63, 172.32 (3x CONH), 161.01 (4'-py.), 141.74 (2'-py.)5 125.25 (3'-py.), 48.54 (*CH), 42.16, 38.84, 35.59, 35.57, 31.74, 29.50, 29.45, 29.39, 29.35, 29.29, 29.24, 29.19, 29.14, 29.10, 26.75, 25.66, 25.60, 22.62 (18x CH2), 18.86 (CH3-AIa) and 14.06 ppm (CH3).
Compound 22 hydrochloride salt Hydrochloride was prepared starting from the base (0.400 g, 0.792 mmol) to give 0.416 g (97 %) of the product.
1H-NMR (DMSO-d6): 8.48 (d, 2H, J= 5.10 Hz, 2'-py.), 8.39 (t, IH5 J= 5.95 Hz5 NH- CH2), 7.87 (d, IH5 J= 7.65 Hz, NH-*CH), 7.74 (t, IH, J= 5.53 Hz5 NH-CH2), 7.80 (d, 2H5 J = 5.10 Hz5 3'-py.), 4.27 (d, 2H5 J = 5.95 Hz, NHCH2-py.), 4.26-4.17 (m, IH, *CH), 3.02 (qua, 2H, J = 6.25 Hz5 NHCH2CH2), 2.16 (t, 2H, J = 7.40 Hz, CH2CO)5 2.09 (t, 2H, J= 7.35 Hz, CH2CO)5 1.58-1.18 (m, 30H, 15x CH2), 1.15 (d, 2H, J= 7.10 Hz5 CH3-AIa)5 0.84 (t, 3H5 J= 6.90 Hz5 CH3).
13C-NMR (DMSO-d6): 172.93, 172.58, 172.30 (3x CONH), 149.91 (2'-py.)5 149.23 (4'-py.)5 122.52 (3'-py.)5 48.45 (*CH), 41.47, 38.84, 35.72, 35.56, 31.75, 29.50, 29.44, 29.39, 29.30, 23.29, 29.2O5 29.15, 29.10, 26.74, 25.72, 25.66, 22.59 (17x CH2), 18.84 (CH3-AIa) and 14.40 ppm (CH3).
Nl-(4-PyridyImethyl)-ll-{[(2S)-2-(nonanoyIamino)-3-phenylpropanoyl] amino}undecanamide (Compound 23)
Figure imgf000077_0001
The compound was prepared following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N, starting from pelargonyl-L-phenylalanine (1.069 g, 3.50 mmol) and ll-undecanoyl-4'-picorylamide (1.020 g, 3.50 mmol) to give 1.705 g (84 %) of the raw product After purification by flash chromatography (CH2Cl2- MeOH 30:1 and 20:1) it was obtained 1.395 g (69 %) of the pure product. 1H-NMR (CDCl3): 8.51 (bs, 2H, 2'-py.-H), 7,28-7.17 (m, 5+2H, Ph i 3'-ρy.-H), 6.60 (d, IH, J= 7.86 Hz, C*H-NH), 6.52 (t, IH, J= 5.74 Hz, NHCH2), 6.39 (q, IH, J= 3.53 Hz, NHCH2), 4.65 (q, IH, J= 7.59 Hz, *CH), 4.43 (d, 2H, J= 6.07 Hz, NHCH2-py.), 3.12 (septet, 2H, J= 5.99 Hz, *CH-CH2), 3.00 (d, 2H, J= 7.12 Hz,
NH-CH2), 2.25 (t, 2H, J= 7.69 Hz5 CH2CO), 2.14 (t, 2H, J= 7.41 Hz, CH2CO), 1.66 (t, 2H, J= 7.41 Hz, CH2), 1.53 (t, 2H, J= 6.84 Hz, CH2), 1.33-1.23 (m, 26H, other CH2), 0.87 ppm (t, 3H, J= 6.92 Hz, -CH3). 13C-NMR (CDCl3): 173.48, 173.16, 170.92 (3x CONH), 149.86 (C-21 py.), 147.85 (C-41 py.), 136.89 (C-I1 ph.), 129.24 (C-21 ph.), 128.52 (C-3' ph.), 126.49 (C-41 ph.), 122.33 (C-31 py.), 54.43 (*CH), 42.20, 39.43, 38.66, 36.53, 36.51, 31.81, 29.30, 29.21, 29.20, 29.17, 29.15, 29.12, 29.10, 26.71, 25.70, 25.60, 22.63 (21x CH2), 14.09 ppm (-CH3).
Hydrochloride was prepared starting from the base (408 mg, 0.705 mmol) to give 378 mg (87 %) of the product.
1H-NMR (DMSO-d6): 8.81 (d, 2H, J= 5.60 Hz, 2'-py.-H), 8.67 (t, IH, J= 5.83 Hz, NHCH2), 8.00 (dd, IH, J= 3.33; 8.33 Hz, NHCH2), 7.88 (d, IH, J= 5.83 Hz, C*HNH), 7.82 (d, 2H, J = 5.60 Hz, 3'-py.-H), 7.23-7.19 (m, 5H, Ph), 4.5 (d, 2H, J= 5.83 Hz, NHCH2-py.), 4.45 (q, IH, J= 4.44 Hz, *CH), 3.07-2.68 (m, 2+2H, 2x NH- CH2), 2.27 (t, 2H, J= 7.45 Hz, CH2CO), 2.1 (t, 2H, J= 7.45 Hz, CH2CO), 2.01 (t, 2H, J= 7.62 Hz, CH2), 1.56-1.12 (m, 32H5 other CH2), 0.88 ppm (t, 3H, J= 6.24 Hz5 -CH3). 13C-NMR (DMSOd6): 172.97, 171.90, 170.97 (3x CO), 142.26 (2'-py.), 138.05 (I1- Ph), 129.10 (2'-Ph), 127.90 (3'-Ph), 126.09 (4'-Ph), 124.46 (3'-py.), 53.89 (*CH), 41.64 (NHCH2-py.), 38.41, 37.87, 35.16, 35.13, 33.25, 31.29, 29.02, 28.98, 28.95, 28.92, 28.81, 28.71, 28.44, 28.29, 26.25, 25.19, 25.14, 34.43, 22.09 (21x CH2), 13.94 PPm (CH3).
M-(4-Pyridylmethyl)-ll-{[(2i?,S)-2-(decaiioylammo)-4-(methylsulfanyl) butanoyl] amino} undecanamide (Compound 24)
Figure imgf000078_0001
The compound was prepared following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N, starting from decanoyl-D,L-methionine (1.315 g, 4.333 mmol) and ll-aminoundecanoyl-4'-picolylamide (1.265 g, 4.341 mmol) to give 1.970 g of the crude product that was purified by preparative TLC (CH2Cl2- MeOH 9:1) giving 0.982 g (39 %) of the pure product. 1H-NMR (CDCl3): 5.83 (d, 2H, J= 5.2 Hz, 2'-H), 7.19 (d, 2H, J= 5.2 Hz, 3'-H), 6.61 (t, IH, J= 5.3 Hz, NH), 6.52 (d, IH, J= 7.9 Hz, NH), 6.24 (t, IH, J= 5.5 Hz, NH), 4.61-4.51 (m, IH, C*H), 4.45 (d, 2H, J= 6.0 Hz, NH-CH2-py), 3.27-3.17 (m, 2H, NHCH2CH2), 2.63-2.40, 2.16-2.84 (2m, 2+2 H, CH2CH2S), 2.26, 2.19 (2t, 2+2H, J = 7.5. 2 Hz, 2xCH2CO), 2.09 (s, 3H, SCH3), 1.74-1.14 (28 H, m, other CH2), 0.88 (t, 3H, J= 63, CH2CH3);
Hydrochloride salt
Hydrochloride was prepared starting from the base (420 mg, 0.728 mmol) giving 402 mg (90 %) of the product. 1H-NMR (DMSO-d6): 8.85 (d, 2H, J= 6.2, 2'-py), 8.78 (t, IH, J= 5.6, NH), 8.01 (d, IH, J= 8.3 Hz, NH), 7.88 (d, 2H, J= 6.2 Hz, 3'-py), 4.52 (d, 2H, J= 5.8 Hz, NHCH2-Py), 4.33^.23 (dt, IH, J= 8.3, 5.2 Hz, C*H), 3.10-2.91 (m, 2H, NHCH2CH2), 2.47-2.31, 1.93-1.66 (2m, 2+2H, CH2CH2S), 2.22 (t, 2H, J= 7.5 Hz, CH2CO), 2.12 (dt, 2H5 J= 7.3, 1.4 Hz, CH2CO), 2.02 (s, 3H5 SCH3), 1.61-0.96 (m,
28H5 other CH2), 0.85 ppm (t, 3 H, J- 6.6 Hz5 CH2CH3).
13C-NMR (DMSO-(I6): 173.5, 172.7, 171.6 (3x CONH)5 160.8 (4'-py), 141.9 (2'-py),
126.2 (3'-py), 52.3 (C*H), 38.9, 35.6, 32.4, 31.8, 30.2, 29.46, 29.41, 29.35, 29.28,
29.25, 29.18, 29.13, 29.05, 26.8, 25.7, 25.6, 22.6 (2IxCH2), 15.1 (CH3S) and 14.4
(CH3).
iVl-(4-Pyridylmethyl)-ll-{[2-(decanoyIamino)acetyl]ainino}undecanamide (Comparator Compound X)
Figure imgf000079_0001
The compound was prepared following the general procedure for condensation with amines using Ph3PZCCl4ZEt3N, starting from decanoyl-L-glycine (790 mg, 3.445 mmol) and l l-undecanoyl-4'-picolylamide (1004 mg, 3.445 mmol), to give 1074 mg (62 %) of the crude product. Repeated chromatographic purification gave 240 mg (14 %) of the pure product.
1H-NMR (DMSO-d6): 8.47 (d, 2H, J = 6.02 Hz, 2'-H py.), 8.10 (bs, IH, NH), 7.64 (bs, IH, NH), 7.40 (bs, IH, NH), 7.22 (d, 2H, J = 6.03 Hz, 3'-py.), 4.28 (d, 2H, J = 5.96 Hz5 NH-CH2-py.), 3.65 (d, 2H, J= 5.75 Hz, NHCH2CO), 2.17 (t, 2H, J= 7.24 Hz, CH2CO), 2.13 (t, 2H, J= 7.59 Hz, CH2CO), 1.60-1.20 (m, 32H5 16x CH2), .87 (t, 3H5 J= 6.99 Hz5 CH3).
13C-NMR (DMSO-d6): 172.03, 172.02, 168.30 (3x CONH), 157.84 (4'-py.), 148.93 (2'-py.), 121.66 (3'-py.), 41.93, 40.83, 38.14, 34.95, 34.89, 30.71, 28.59, 28.38, 28.36, 28.31, 28.23, 28.17, 28.05, 25.85, 24.7O5 24.60, 21.44 (2Ox CH2), 13.20 ppm (CH3).
M-(4-pyridylmethyI)-ll-{[(2S)-2-(decanoylamino)-3-(lJϊ-3-indolyl)propanoyl] amino}undecanamide (Compound 25)
Figure imgf000079_0002
The compound was prepared following the general procedure for condensation with amines using PhsP/CCLj/EtsN, starting from decanoyl-L-tryptophan (868 mg, 2.421 mmol) and l l-undecanoyl-4'-picolylamide (706 mg, 2.421 mmol), to give 993 mg (65 %) of the product
1H-NMR (DMSOd6): 8.89 (s, IH N(I)-H), 8.50 (d, 2H, J = 5.81 Hz, 2'-H), 7.70 (d, IH, J= 7.78 Hz, 2-H), 7.33 (IH, d, J = 8.00 Hz, 4-H), 7.20-7.07 (m, 2 + 1+1 H, 3'-H, 5-H, i 6-H)5 7.01 (d, IH, J= 2.21 Hz5 7-H)5 6.48 (d, IH5 J= 7.58 Hz, NH-*CH), 6.43 (t, 2H, J= 6.00 Hz, NH-CH2CH2), 5.87 (t, IH, J= 5.82 Hz, NH-CH2-py.)5 4.70 (dt, IH, J= 5.54; 8.03 Hz, *CH), 4.43 (d, 2H, J = 6.23 Hz5 CH2-py.)5 3.13-2.97 (m, 2H, *CH-CH2), 2.26 (t5 2H, J = 7.55 Hz, CH2CO), 2.16 (t, 2H5 J = 7.87 Hz5 CH2CO)5 1.70-0.99 (m, 32 H5 16 x CH2), 0.87 ppm (t, 3H, J= 7.03 Hz, CH3). 13C-NMR (DMSO-d6): 175.53, 173.10 and 171.15 (3 x CO), 149.81 (C-2')5 147.78 (C-4')5 136.26 (C-7a), 127.33 (C-3a), 123.05 (C-2), 122.27 (C-6), 122.08 (C-3% 119.57 (C-5), 118.83 (C-4), 111.26 (C-7), 110.73 (C-3), 53.85 (*CH), 42.20 (NHCH2-py.)5 39.40 (NHCH2CH2), 36.60, 36.46, 31.82, 29.39, 29.31, 29.23, 29.19, 29.07, 29.06, 29.02, 29.00, 28.97, 28.68, 26.49, 25.58, 25.53, and 22.63 (18 x CH2), 14.09 ppm (CH3).
Hydrochloride was prepared starting from the base (449 mg, 0.710 mmol) to give 480 mg (96 %) of the product
1H-NMR (CDCl3): 10.82 (s, IH N(I)-H), 8.85 (d, 2H5 J = 6.66 Hz, 2'-H), 8.730 (t, IH, J= 5.08 Hz, NH-CH2), 7.95 (IH, d, J= 8.43 Hz, 2-H), 7.88 (d, 2H, J= 6.75 Hz, 3'-H), 7.57 (d, IH, J= 7.98 Hz, 4H), 7.30 (d, IH, J = 8.09 Hz, 7H), 7.09 (br s, IH5 NH-CH2-py.), 7.04 (t, 2H, J= 7.31 Hz5 NH-CH2CH2), 6.95 (t, IH, J= 7.41 Hz), 4.52 d, 2H5 J= 6.31 Hz5 CH2-py.), (dd, IH, J= 8.51; 14.55 Hz, *CH), 3.06-2.99 (m, 2H5 *CH-CH2), 2.20 (t, 2H, J= 7.14 Hz5 CH2CO), 2.02 (dt, 2H, J= 7.41 Hz, CH2CO)5 1.54-0.86 (m, 32 H, 16 x CH2), 0.84 ppm (t, 3H, J= 7.13 Hz5 CH3). 13C-NMR (CDCl3): 173.00, 171.95 and 171.40 (3 x CO), 141.46 (C-2'-py), 136.02 (C-7a ind.), 127.33 (C-3a ind.), 124.71 (C-3' py.), 123.34 (C-2 hid.), 120.69 (C-6 ind.), 118.37 and 118.03 (C-5, C-4 ind.) 111.15 (C-7 ind.), 110.27 (C-3 ind.), 53.46 (*CH), 41.71 (NHCH2-py.), 38.47 (NHCH2CH2), 35.23, 35.12, 31.22, 28.90, 28.88, 28.80, 28.75, 28.72, 28.68, 28.66, 28.60, 28.49, 27.94, 26.24, 25.12, 25.08, and 22.02 (19 x CH2), 13.98 ppm (CH3).
tert-Butyl iV-[ll-(benzylammo)-ll-oxoundecyl]carbamate
Figure imgf000081_0001
The compound was prepared following the general procedure for condensation with amines using PhsP/CCU/EtsN, starting from commercial BOC-11-aminoundecanoic acid (1.00Og, 3.138 mmol) and benzylamine (0.363 mL, 0.356 mg, 3.318 mmol) to give 922 mg (71 %) of the product
1H-NMR (DMSO-d6): 8.29 (t, U, J = 5.35 Hz, NH), 7.33-7.22 (m 5H5 Ph), 6.75 (t, IH, J= 5.49 Hz, NH), 4.25 (d, 2H, J= 6.05 Hz, NHCH2-Ph.), 2.89 (t, 2H, J= 6.34 Hz, NHCH2), 2.12 (t, 2H, J = 7.32 Hz, CH2CO), 1.51 (t, 2H, J = 6.486 Hz, CH2), 1.37 (s, 9H, t-Bu), 1.23 ppm (m, 14H, 7x CH2). 13C (DMSO-d6): 172.20 (CO), 139.79 (C-I1), 128.25 (C-2'), 127.17 (C-31), 126.70 (C-41), 77.30 (C(CH3)3), 41.98 (NHCH2-Ph), 39.85, 35.38, 29.51, 28.99, 28.93, 28.79, 26.76, 28.69, 26.31, 25.35 (10 x CH2) and 28.30 ppm (C(CH3)3).
G. General procedure for hydrogenolytic deprotection [(Benzyloxy)carbonyl] amino compound (10 mmol) was dissolved in MeOH (40 mL) or in a solvent mixture MeOH-dioxane (1:1), the catalyst 10% Pd/C (50 mg) added and hydrogenated overnight in a Parr apparatus. The catalyst was filtrated off through the celite pad and the filtrate evaporated to give the pure product. The following compounds were made using General procedure G.
iVl^V5-di(4-pyridylmethyl)-(2S)-2-aminopentanediamide
Figure imgf000081_0002
The compound was prepared starting from benzyl 7V-((lS)-4-oxo-4-[(4- pyridylmethyl)amino]-l-{[(4-pyridylmethyl)amino]carbonyl}butyl)carbamate (1.747 g, 3.785 mmol) giving 1.239 g (100 %) of the pure product as an oil that crystallized spontaneously.
1H-NMR (DMSO-d6): 8.47 (d, 6H, J= 5.57 Hz, 2x 2'-H py. and NH2), 7.26 (pt, 4H, J = 4.39 Hz, 2x 3'-H py.), 4.33-4.27 (m, 5H, *CH and 2x NH-CH2), 2.29 (m, 2H, CH2CO), 1.95- 1.67 ppm (m, 2H, * CH-CH2).
13C-NMR (DMSOd6): 175.41, 172.37 (2x CONH)5 149.40 (2'-py.)3 148.68 (l'-py.), 122.01 (3'-py.), 54.51 (*CH), 41.02 and 40.92 (2x NH-CH2), 31.90 and 31.03 ppm (2x CH2).
4-Aminophenyl H-{[(2S)-2-(dodecanoyIamino)-3-phenylpropanoyl] amino} undecanoate (Comparator Compound XI)
Figure imgf000082_0001
The compound was prepared starting from 4-{[(benzyloxy)carbonyl]amino}phenetyl 11 - { [(2>S)-2-(dodecanoylamino)-3 -phenylpropanoyl] amino}undecanoate (374 mg, 0.477 mmol) to give 310 mg (100 %) of the pure product.
1H-NMR (CDCl3): 7.28-7.20 (m, 5H, Ph), 7.01 (d, 2H5 J= 8.19 Hz, 2"-Ph), 6.63 (d, 2H, J= 8.19 Hz, 3"-Ph), 6.42 (d, IH, J = 8.19 Hz, NH-*CH), 6.04 (t, IH, J= 5.91 Hz, NH-CH2), 4.63 (dt as qua, J =8.19 Hz, IH, *CH), 4.23 (t, J =6.87 Hz5 2H, CH2O)5 3.18-2.95 (m, 2+2+2H, NH-CH2, * CH-CH2 and NH2), 2.83 (t, 2H5 J= 7.73 Hz, CH2), 2.29 (t, 2H, J= 7.73 Hz, CH2CO), 2.17 (t, 2H5 J= 7.28 Hz, CH2CO)5 1.65- 1.11 (m5 34H, other CH2), 0.89 ppm (t, 3H5 J= 5.91 Hz5 CH3). 13C-NMR (CDCl3): 177.52, 173.82, 173.12 (3x CONH), 159.15 (NH-CO-O), 136.85 (C-4" and C-I1), 129.47, 129.24, 129.22, 128.62, 128.36, 128.31 (arom.), 1126.94 (4'- Ph)5 117.16 (3"-Ph)5 67.02 and 6471 (2x OCH2), 54.61 (*CH), 39.45, 38.66, 36.59, 34.46, 34.31, 31.92, 29.63, 29.47, 29.34, 29.29, 29.18, 29.16, 26.68, 25.58, 22.69 (2Ox CH2), 14.13 ppm (CH3).
Hydrochloride is insoluble in water and does not form hydrogel.. M-(4-PyridyImethyI)-ll-{[(2S)-2-(decanoylamino)-3-(4-hydroxyphenyl) propanoyl]amino}undecanamide (Compound 26)
Figure imgf000083_0001
The compound was prepared starting from Nl-(4-pyridylmethyl)-ll-{[(25)-3- [φerizyloxy)phenyl]-2-(decanoylamino)propanoyl]amino}undecanarnide (289 mg 0.414 mmol) to give after purification by preparative TL chromatography (CH2Cl2- MeOH 20:1) 111 mg (44%) of the pure product.
1HNMR (DMSOd6): 9.44 (1 H5 s, OH)5 8.49 (2 H, dd5 J= 1.15, 4.85 Hz5 Hz5 2'-py), 8.44 (1 H, t, J= 8.43 Hz5 NH-CH2), 8.00 (1 H, d, J= 7.98 Hz, NH-C*H), 7.89 (1 H, t, J= 7.87 Hz5 NH-CH2) 7.22 (2 H5 d5 J= 4.83 Hz5 3'-py), 6.98, 6.61 (2d, 2H each, J=8.3 Hz5 T- Ph and 3"-Ph)5 4.35 (1 H5 dd, J= 5.51 Hz5 *CH), 4.27 (2 H5 d5 J=5.73 Hz5 NH-CH2-Py)5 3.00-2.99 (2 H5 m, NHCH2CH2), 2.79 (IH5 dd, J= 5.73, 13.15 Hz5 C*HCH2A), 2.61 (IH, dd, J= 9.12, 13.56 Hz5 C*HCH2B), 2.16, 2.02 (2t, 2H each, J = 7.16 Hz, 2x CH2CO), 1.57-1.08 (30 H5 m, other CH2), 0.85 ppm (3 H, t, J= 7.10 Hz5 CH3).
13C NMR (DMSO-d6): 172.53, 171.92, 171.22 (3x CO)5 155.85 (4'-Ph)5 149.47 (T- py)5 148.82 (4'-py)5 129.98 (2'-Ph)5 127.96 (1'-Ph), 122.08 (3'-py), 114.77 (3'-Ph)5 54.32 (*CH)5 41.02 (NHCH2-py), 39.51, 38.42, 35.28, 35.21, 31.33, 29.02, 28.97, 28.93, 28.87, 28.80, 28.74, 28.72, 28.55, 26.33, 25.29, 22.15 (19x CH2), 14.00 (CH3).
Hydrochloride was prepared starting from the base (270 mg, 0.443 mmola) giving 286 mg (100 %) of the product.
1H NMR (DMSO-d6): 8.82 (d, 2H, J = 6.57 Hz, 2'-py), 8.75 (t, IH, J = 5.94 Hz, NH CH2), 7.95 (d, IH, J = 8.51 Hz, NHC*H), 7.86 (t, IH5 J = 5.53, NHCH2), 7.84 (d, 2H5 J= 8.40 Hz, 3'-py), 6.98, 6.61 (2d, 2H each, J=8.4 Hz, 2"-Ph and 3"-Ph), 4.50 (d, 2H5 J= 6.01 Hz, NHCH2-Py), 4.34 (dd, IH5 J= 3.71, 5.49 Hz5 *CH), 3.00-2.98 (2 H5 m, NHCH2CH2), 2.79 (dd, IH5 J= 5.48, 13.60 Hz, C*HCH2A)), 2.61 (dd, IH5 J= 9.13, 13.79 Hz, C*HCH2B), 2.21, 2.02 (2t, 2H each, J= 7.32 Hz, 2x CH2CO), 1.53- 1.08 (m, 30 H, other CH2), 0.85 ppm (t, 3H5 J= 7.00 Hz, CH3). 13C NMR (DMSO-d6): 173.02, 171.92, 171.21 (3x CO), 160.02 (4'-py), 155.74 (4"- Ph), 147.77 (2'-py), 129.96 (2"-Ph), 128.02 (1"-Ph), 124.63 (3'-py), 114.75 (3"-Ph), 54.32 (*CH), 41.70 (NHCH2-py), 38.43, 35.22, 35.15, 31.30, 29.00, 28.93, 28.90, 28.84, 28.80, 28.76, 28.74, 28.71, 28.53, 26.32, 25.23, 25.16, 22.12 (19x CH2), 13.98 ppm (CH3).
H. General procedure for f-butoxycarbonyl protection of ω-aminoalkanoic acids ω-Aminoalkanoic acid (10 mmol) was suspended in a mixture of dioxane (20 mL) and water (10 mL) and IM NaOH (10 mL) was added. The solution was cooled in an ice-bath and (BOC)2 (12 mmol) and NaHCO3 (10 mmol) were added. After half an hour ice-bath was removed and the stirring continued at room temperature overnight. To the reaction mixture EtOAc (40 mL) was added and acidified with IM KHSO4. The layers were separated, the aqueous extracted with 2 x 20 mL of EtOAc, dried and evaporated to give the product.
I. General procedure for TFA-cleavage of BOC -group BOC-compound (10 mmol) was dissolved in a mixture of dry CH2Cl2 (10 mL) and TFA (10 mL) and stirred at room temperature overnight. The reaction mixture was evaporated and to the residue some water (25 mL) and diethyl ether (50 mL) added. The layers were separated, and aqueous one made alkaline with IM NaOH. The precipitated product was filtrated off, washed with water and air-dried. The following compounds were made using General procedure I.
iVl(4-pyridylmethyl)-ll-aminoundecanamide (Comparator Compound XII)
Figure imgf000084_0001
The compound was prepared: a) following the general procedure for TFA-cleavage of BOC-group, starting from ll-(ter^butoxycarbonylamino)undecanoyl-4'- picolylamide (3.265 g, 8.39 mmol) to give 2.445 g (100 %) of the product. 1H-NMR (CDCl3): 8.50 (d, 2H5 J= 6.02 Hz, 2'-H), 7.17 (d, 2H5 J = 5.76 Hz5 3'-H)5 8.82 (m, IH5 NH)5 4.42 (d, 2H5 J= 6.02 Hz5 NHCH2-py.)5 2.66 (t5 2H5 J- 6.93 Hz5 NHCH2), 2.25 (t, 2H5 J= 7.85 Hz5 CH2CO) 1.66 (t, 2H5 J = 7.06 Hz5 CH2), 1.42- 1.27 ppm (m5 14H5 7x CH2).
13C (CDCl3): 173.50 (CO)5 149.70 (2'-py.)5 147.85 (l'-ρy.)5 122.18 (3'-py.)5 42.01 (NHCH2-py.)5 36.42 (NHCH2CH2), 29.39, 29.30, 29.27, 29.72 26.72 and 25.62 ppm (9x CH2).
b) following the general procedure for hydrogenolytic deprotection, starting from benzyl N-{ll-oxo-ll-[(4-pyridylmethyl)amino]undecyl}carbamate (196 mg, 0.456 mmol) to give 133 mg (100 %) of the product. The nmr spectra were identical to those given above.
Hydrochloride was prepared starting from the base (182 mg, 0.624 mmol) giving 207 mg (91 %) of the product.
Neither the free base nor the hydrochloride salt formed gels.
A^l-(4-pyridylmethyl)-ll-({(l«S)-2-amino-2-[4-(benzyIoxy)phenyl]propanoyl} amino)undecanamide
Figure imgf000085_0001
The compound was prepared following the general procedure for TF-cleavage of BOC-group, starting from tert-butyl 7V-[(l,S3-l-[4-(benzyloxy)benzyl]-2-oxo-2-({l l- oxo-ll-[(4-pyridylmethyl)ammo]undecyl}amino)ethyl]carbamate (1.282 g, 2.134 mmol) to give 1.108 g (95 %) of the product. 1H NMR (DMSO-d6): 8.47 (d, 2H5 J=5.6 Hz , 2'-py), 7.75 (t, IH, J=6.3 Hz, NH CH2.),7.42-7.38 (m, 5+1+1 H, Ph+NHCH2+NHCH2), 7.21 (d, 2H, J=5.2 Hz, 3'-py), 7.09, 6.90 (2d, 2H each, J=8.5 Hz, 2"-Ph and 3"-Ph), 5.05 (s, 2H, CH2Ph), 4.26 (d, 2H, J=5.9 Hz, NHCH2-Py), 3.07-2.93 (m, 2H, NHCH2CH2X 2.85-2.53 (m, 2 H, m, C*HCH2), 2.15 (t, 2H, J=7.48 Hz, CH2CO), 1.58-1.14 ppm (m, 18H, other CH2). 13C NMR (DMSOd6): 174.12, 172.51 (2x CO)5 156.80 (4'+-Ph), 149.46 (2'-py), 148.81 (4'-py), 137.25 (4"'-benzyl), 130.86 (1"-Ph), 130.26 (2"-Ph), 128.40 and 127.56 (2'" and 3'", benzyl), 122.09 (3'-py), 114.35 (3"-Ph), 69.11 (CH2Ph), 56.43 (*CH), 41.01 (NHCH2N-py), 38.27, 35.26, 29.12, 28.98, 28.96, 28.78, 28.69, 26.38, 25.26 ppm (CH2).
JVl-Benzyl-11-aminoundecanamide
Figure imgf000086_0001
The compound was prepared following the general procedure for TFA-cleavage of BOC-group, starting from 11-BOC-ammoundecanoyl-benzylamide (697 mg, 1.786 mmol) to give 514 mg (99 %) of the product.
1H-NMR (DMSO-d6): 8.31 (t, U, J= 6.20 Hz, NH), 7.33-7.22 (m 5H, Ph), 4.25 (d,
2H, J = 6.04 Hz, NHCH2-Ph.), 2.57 (t, 2H, J = 6.33 Hz, NHCH2), 2.12 (t, 2H, J =
7.36 Hz, CH2CO), 1.51 (t, 2H, J = 6.62 Hz, CH2), 1.39-1.24 ppm (m, 14H, 7x CH2). 13C (DMSO-d6): 172.10 (CO), 139.78 (C-I'), 128.19 (C-2')3 127.13 (C-31), 126.63
(C-41), 41.94 (NHCH2-Ph), 40.99, 35.33, 31.87, 28.98, 28.91, 28.89, 26.77, 28.66,
26.29, 25.31 ppm (10 x CH2).
M-(4-Pyridylmethyl)-ll-{[(2S)-2-amino-4-methyIpentanoyl] aniinojundecanamide
Figure imgf000086_0002
The compound was prepared following the general procedure for TFA-cleavage of BOC-group, starting from tert-butyl N-[(1S)-1-({[1 l-(benzylamino)-l 1- oxoundecyl]amino}carbonyl)-3-methylbutyl]carbamate (533 mg, 1.06 mmol) to give 400 mg (93 %) of the product.
1HNMR (300 MHz; CDCl3) δ ppm: 8,55 (d, 2 H), 7,20 (d, 2 H), 6,13 (br, IH), 4,47 (d, 2 H) 3,36 (m, IH) 3,23 (q, 2H), 2,27 (t, 2H), 1,72 - 1,61 (m, 6 H), 1,50 (br t 3 H) 1,30 (br m 18 H) 0,95 (q, 7 H)
J. General procedure for the reaction of BOC-protected amino acid succinimide ester with ll-aminoundecanoyl-4'-picolylamide
BOC-protected amino acid succinimide ester (2.0 mmol) and ll-aminoundecanoyl- 4'-picolylamide (2.0 mmol) were dissolved in dry THF (30-40 ml) and stirred at room tempeature overnight. The solvent was then evaporated, the residue dissolved in CH2Cl2 and washed with water. Organic layer was dried (Na2SO4) and evaporated to give the product. The following compounds were made using General procedure J.
tert-ButylA?-[(l1S)-l-[4-(benzyloxy)benzyl]-2-oxo-2-({ll-oxo-ll-[(4- pyridylmethyl)amino]undecyl}amino)ethyl]carbamate
Figure imgf000087_0001
The compound was prepared foolowing the general procedure for the reaction of BOC-protected amino acid succinimide ester with 1 l-aminoundecanoyl-41- picolylamide starting from commercial Boc-Tyr(OBzl)-OSu (1.073g, 2.290 mmol) and ll-aminoundecanoyl-4'-picolylamide (0.687 g, 2.357 mmol) to give 1.350 g (91
%) of the product.
1HNMR (CDCl3): 8.57-8.46 (m, 2H, 2'-py), 7.46-7.27 (m, 5H, Ph), 7.18 (d, 2H, .7=5.1 Hz, 3'-py), 7.10, 6.89 (2d, 2H each, .7=8.4 Hz, T- and 3"-Tyr), 6.29 (t, IH5
J=6.0 Hz, NH-CH2-ρy), 5.93 (t, IH, .7=5.1 Hz, NH-CH2), 5.24-5.09 (m, IH5 NH-
CH), 5.02 (s, 2H5 CH2-Ph)5 4.28-4.16 (m, IH, *CH), 4.43 (d, 2H5 J=6.0 Hz5 CH2- py), 3.23-3.06, 3.05-2.88 (2m, IH each, C*H-CH2), 2.28-2.20 (m, 2H, NH-CH2 CH2), 1.40 (s, 9H5 C(CH3), 1.73-1.09 ppm (m, 18H, other CH2). 13C NMR (CDCl3): 173.4, 171.1 (NHCO), 157.8 (NHCOO), 148.0, 139.9, 129.1, 130.4, 128.6, 128.0, 127.4, 122.4, 115.0 (atom.), 70.0 (CH2-py), 56.1 (CH*), 42.2 (NHCH2-Py), 39.4, 37.9, 36.5, 29.29, 29.25, 29.16, 29.06, 26.7, 25.7 (other CH2), 28.3 ppm (C(CH3)).
iVl-BenzyI-ll-{[(2if)-(nonanoyIamino)-2-phenyletanoyl]amino}undecanainide (Comparator Compound XIII)
Figure imgf000088_0001
The compound was prepared foolowing the general procedure for the reaction of
BOC-protected amino acid succinimide ester with ll-aminoundecanoyl-4'- picolylamide, starting from 2,5-dioxotetrahydro-lH-l-pyrrolyl (2R)-2- (nonanoylamino)-2-phenyletanoate (pelargonyl-D-phenyglycine succinimide ester) (493 mg, 1.27 mmol) anad ll-aminoundecanoyl-4'-picolylamide (369 mg, 1.27 mmol) to give 515 mg (72 %) of the product.
1HNMR (DMSO-d6): 8.41 (t, 1Η, .7=8.41 Ηz, NΗ*CΗ), 8.29 (d, IH, d, J=5.94, NHCH2), 8.22 (t, IH, J=5.32 Hz, NHCH2), 7.40-7.22 (m, 5+5H, 2x Ph), 5.45 (d, IH, d, J= 8.44 Hz, *CH), 4.25 (d, 2 H, J=5.62 Hz, CH2Ph), 3.02 (t, 2H, J= 6.16 Hz, NHCH2), 2.19 (t, 2H, J=7.34 Hz, CH2CO), 2.12 (t, 2H, J=7.43 Hz, CH2CO), 1.49 (m, 4H, 2x CH2), 1.38-1,14 (m, 24H, 12x CH2), 0.85 (t, 3H, J=7.10 Hz, CH3). 13CNMR (DMSO-d6): 172.10, 171.86, 169.70 (3x CO), 139.78, 139.37 (Carom), 128.21, 128.12, 127.27, 127.14, 126.92, 126.66(CHaT0n,), 56.02, (*CH), 41.94 (CH2- py), 38.47, 35.34, 34.89, 31.25, 28.95, 28.89, 28.79, 28.75, 28.68, 28.64, 28.61, 26.20, 25.33, 25.30, 22.10 (other CH2), 13.96 ppm (CH3). tert-ButyliV-[(15)-l-({[ll-(benzylamino)-ll-oxoundecyI]amino}carbonyl)-3- methylbutyl]carbamate
Figure imgf000089_0001
The compound was prepared foolowing the general procedure for the reaction of BOC-protected amino acid succinimide ester with 1 l-aminoundecanoyl-41- picolylamide starting from Boc-NH-L-Leu-succinimide ester (575 mg, 1.75 mmol) and 1 l-aminoundecanoyl-4'-picolylamide (510 mg, 1.75 mmol) to give 776 mg (88
%) of the product.
1HNMR (300 MHz; CDCl3) δ = 8.54 (d, 2H, J= 5.96 Hz, 2'-py), 7.19 (d, 2H5 J= 5.88 Hz5 3'-py), 6.26 (2t as br qua, 2H5 J= 5.70 Hz3 2x NHCH2), 5.0 (d, IH5 J= 7.00
Hz, C*H), 4.46 (d, 2H, J= 5.97 Hz5 NHCH2-py), 4.17- 3.98 (m, 2H5 CH2), 3.21 (qua,
J= 6.18 Hz, 2H, CH2), 2.27 (t, 2H, J= 7.69 Hz, CH2CO), 1.84 (m, 2H5 CH2), 1.66
(m, 5 H5 CH and 2xCH2)5 1.49-1.38 (m, other CH2 and C(CH3)3), 0.93 ppm (dd, 6
H5 J= 3.16, 5.89 Hz5 CH(CH3)2).
K. Other reactions iVl-(4-pyridylmethyl)decanamide (Comparator Compound XIV)
Figure imgf000089_0002
To the solution of 4-picolylamine (0.51 mL5 5.00 mmol) and Et3N (0.733 mL5 5.25 mmol) in dry CH2Cl2 (15 rnL) under cooling in an ice-bath and stirring, decanoyl chloride (1.02 mL, 5.00 mmol) was added. The reaction mixture was stirred at room temperature overnight and diluted with water (10 mL) and CH2Cl2 (10 mL). The layers were separated, aqueous layer extracted with 2 x 5 mL CH2Cl2; the combined extracts dried (Na2SO4) and evaporated to give the crude product that was purified by flash-chromatography (CH2Cl2-MeOH 25:1) to give 934 mg (71 %) of the pure product.
1H-NMR (CDCl3): 8.52 (d, 2H, J= 4.97 Hz5 2'-H)5 7.27 (d, 2H, J = 4.97 Hz5 3'-H)5 6.23 (m, IH, NH)5 4.44 (d, 2H, J= 6.05 Hz5 NHCH2-py.), 2.26 (t, 2H, J = 7.66 Hz5 CH2CO), 1.67 (t, 2H, J = 6.99 Hz, CH2CH2CO), 1.31-1.26 (m, 12H, 6x CH2), 0.88 ppm (t, 3H, J= 6.58 Hz, CH3).
13C-NMR (CDCl3): 173.35 (CO), 149.93 (2'-py.), 147.67 (l'-py.), 122.26 (3'-py.), 42.25 (NHCH2-py.), 36.61 (NHCH2CH2), 31.81, 29.40, 29.29, 29.21, 25.69 and 22.61 (7x CH2), 14.03 ppm (CH3).
Hydrochloride was prepared starting from the base (389 mg, 1.482 mmol) giving 413 mg (93%) of the product.
iVl-(4-pyridylmetliyl)-ll-(decanoylamino)undecanainide (Comparator Compound XV)
Figure imgf000090_0001
To the suspension of ll-aminoundecanoyl-4l-picolylamide (253 mg, 0.868 mmol) and Et3N (0.121 mL, 0.868 mmol) in dry CH2Cl2 (10 mL) under cooling in an ice- bath and stirring, decanoyl chloride (0.177 mL, 0.868 mmol) was added. The reaction mixture was stirred at room temperature overnight and diluted with water
(10 mL) and CH2Cl2 (10 mL). The undissolved material was filtrated and air-dried:
242 mg (62 %).
1H-NMR (DMSO-d6): 8.48 (d, 2H, J = 4.97 Hz, 2'-H), 8.41 (st, IH, J = 6.12 Hz, NH), 7.74 (t, IH, J= 5.66 Hz, NH), 7.22 (d, 2H, J = 5.89 Hz, 3'-H), 4.27 (d, 2H, J=
6.06 Hz, NHCH2-py.), 3.26 (m, 2H, NHCH2CH2), 3.00 (m, 2H, CH2), 2.15 (t, 2H, J
= 7.45 Hz, CH2CO), 2.01 (t, 2H, J = 7.36 Hz, CH2CO), 1.54-1.13 (m, 28H, 14x
CH2), 0.85 ppm (t, 3H, J= 6.94 Hz, CH3).
13C-NMR (DMSO-d6): 172.49, 171.88 (2x CO), 149.42 (2'-py.)5 148.82 (l'-py.), 122.08(3'-py.), 45.54 (NHCH2-py.), 41.01 (NHCH2CH2), 38.30, 35.42, 35.26, 31.29,
29.16,, 28.99, 28.95, 28.91, 28.78, 28.76, 28.67, 28.60, 26.39, 25.35, 25.26 and 22.10
(17x CH2), 13.96 ppm (CH3).
Hydrochloride was prepared starting from the base (232 mg, 0.520 mmol) giving 236 mg (94%) of the product. 1H-NMR (DMSO-d6): 8.84 (d, 2H5 J = 6.46 Hz, 2'-H), 8.73 (st, IH5 J - 6.10 Hz, NH)5 7.86 (t5 IH5 J= 6.46 Hz5 NH)5 7.75 (d, 2H5 J = 5.74 Hz5 3'-H)5 4.51 (d, 2H, J = 5.75 Hz5 NHCH2-py.)5 3.09-2.97 (m, 4H, 2x CH2), 2.21 (t5 2H, J= 7.42 Hz5 CH2CO)5 2.02 (t5 2H5 J= 7.27 Hz, CH2CO), 1.55-1.16 (m, 28H5 14x CH2), 0.85 ppm (t, 3H, J = 6.96 Hz5 CH3).
13C-NMR (DMSOd6): 172.99, 171.89 (2x CO), 160.17 (l'-py), 141.65 (2'-py.)5 124.67 (3'-py.)5 45.35 (NHCH2-py.)5 41.68 (NHCH2CH2), 38.30, 35.41, 35.13, 31.28, 29.17, 29.01, 28.95, 28.90, 28.78, 28.75, 28.72, 28.66, 28.60, 26.40, 25.35, 25.14 and 22.10 (17x CH2), 13.95 ppm (CH3).
iVl-(4-Pyridylmethyl)-l 1- { [(2iS)-3-[(benzyloxy)phenyl]-2-(decanoylamino) propanoyl]amino}undecanamide (Comparator Compound XVI)
Figure imgf000091_0001
tert-Butyl JV-[(lS)-l-[benzyloxy)benzyl]-2-oxo-2-({ 11-oxo-l l-[(4- pyridylmethyl)amino]undecyl}amino)ethyl]carbamate (1.096 g, 2.012 mmol) was suspeded in dry CH2Cl2 (20 ml) and cooled in an ice-bath. TEA (0.280 ml, 2.012 mmol) and decanoyl chloride (0.411 ml, 2.012 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue suspended in water. The indissolved material was filtrated, washed with water and air-dried to give 1.104 g (79 %) of the crude product that was purified by FC chromatography (CH2Cl2-MeOH 30:1 to 10:1) giving 644 mg (46 %) of the pure product.
1H NMR (DMSO-d6): 8.48 (d, 2H, J=5.1 Hz, 2'-H), 8.40 (t, IH, J=5.7 Hz, NH-CH2), 7.95 (d, IH, J=8.5 Hz, NH-C*H), 7.85 (t, IH, J=5.6 Hz5 NH-CH2), 7.46-7.27 (m, 5H5 m5 Ph)5 7.22 (d, 2H, d, J=5.1 Hz, 3'-H), 7.12, 6.88 (2d, 4H, J=8.4 Hz, 2"-H and 3"-H), 5.03 (s, 2H, CH2-Ph)5 4.46-4.34 (m, IH5 *CH), 4.27 (d, 2H, J=5.7 Hz5 CH2- py)5 3.10-2.91 (m, 2H5 NHCH2CH2), 2.85 (dd, IH, J=5.4, 13.5 Hz, C*H-CHA), 2.66 (dd, IH, J=9.6, 13.5 Hz5 C*H-CHB), 2.16 (dt, 2H, J=7.5; 9.2 Hz, CH2CO)5 2.01 (t, 2H, J=I 2 Hz, CH2CO), 1.62-0.95 (m, 36H, other CH2), 0.83 ppm (t, 3H, J=6.8 Hz, CH3).
13C NMR (DMSO-d6): 172.9, 172.4, 171.1 (3xC0NH), 157.0, 148.6, 137.0, 130.0 (Carom), 149.3, 130.1, 128.3, 127.6, 127.3, 122.0, 114.2 (CHaT01n), 69.3 (CH2-Ph), 54.1 (*CH), 41.3(CH2-ρy), 38.7, 35.6, 37.2, 35.6, 31.5, 29.12, 29.09, 29.05, 28.98, 28.91, 28.77, 26.5, 25.42, 25.38, 22.3 (other CH2), 14.0 ppm (CH3).
Preparation of suceinimide ester
2,5-Dioxotetrahydro-l.H-l-pyrrolyl (2i?)-2-(nonanoylamino)-2-phenyIetanoate (Pelargonyl-D-phenyglycine suceinimide ester)
Figure imgf000092_0001
Pelargonyl-D-phenylglycine (600 mg, 2.06 mmol) was dissolved in dioxane (19 ml), and DCC (425 mg, 2.06 mmol) and iV-hydroxy-succinimde (237 mg, 2.06 mmol) were added. The reaction mixture was stirred at room temperature overnight. The precipitated DCHU was removed, the filtrate evaporated and shaked with ether, filtrated again and evaporated to give 540 mg (68 %) of the product. 1H NMR (CDCl3): 7.46-7.38 (5H, m, Ph), 6.33 (IH, d, J=7.48 Hz, NH*CH), 6.03 (1 H, d, J= 7.67 Hz, *CH), 2.79 (4 H, OSu), 2.27-2.21 (2H, m, CH2CO), 1.63 (2 H, m, CH2), 1.28-1,26 (10 H, m, 5x CH2), 0.87 (3 H, t, J=7.67 Hz, CH3).
13C NMR (CDCl3): 172.39, 168.31, 166.89 (3x CO), 134.71 (C81Om), 129.17, 129.13, 127.63 (CHarom), 54.45 (*CH), 36.16, 31.73, 29.18, 29.10, 29.04, 25.51, 25.34, 22.57 (CH2), 14.00 (CH3).
Example 2 — Gelation of Compounds in Water and Other Solvents
The gelation properties of some of the compounds of the invention were tested by adding them to water or organic solvents in the procedure described above and the results are shown in the Tables below. The results we have obtained show that for compounds of general formula (Ia) and (Ib) the best gel forming properties are obtained when R2 is pyridyl. It is also preferable that X is NH-CH2.
In order to compare the gelation properties of compounds composed of similar structural units, we also tested the gelation properties of Comparator Compounds IX5 XIV and XII and their hydrochloride salts in water and organic solvents. However, we were not able to form gels with the comparator compounds or their salts in any solvent.
Table 1. Hydrogelation of leucine monoamides and esters
Figure imgf000093_0001
Compound ra n hydrochloride
No. (10 mg) /water
VI 10 3 NG (crystals)
VII 10 3 NG (crystals)
VIII 10 3 NG (crystals)
Figure imgf000094_0001
NG = not gelating
Table 2. Hydrogelation of phenylglycine monoamides and esters
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000095_0001
Table 3. Hydrogelation of phenylalanine monoamides and esters
Figure imgf000095_0002
Compound m n R hydrochloride
No. (10 mg) / water
le)
Figure imgf000095_0003
Table 3a. Hydrogelation of other picolylamide gelators
Figure imgf000096_0001
Figure imgf000096_0002
Table 4. Gelation properties of some compounds (bases and hydrochlorides) in organic solvents (volume in μL gelated by 10 mg of tested compound)
Figure imgf000096_0003
Figure imgf000097_0001
NG = not gelating, ins. = insoluble
Example 3 - Near Infrared Spectrometry
Near infrared (NIR) spectrometry was used to study the process of gel formation. NIR spectra were recorded using a Bruker® NIR Systems spectrometer (Bruker Optik GmbH) with the fibre-optic probe situated below the flat-bottomed glass vial. Each NIR measurement was the mean of 32 scans over the wavelength range 1100 run - 2500 nm. AU of the gel forming compounds had similar spectra and a typical example is shown in Figure 1, which is NIR spectra of Compound 2 hydrochloride in water at concentrations of 5%, 1%, 0.5% and 0.33% wt./vol. together with the NIR spectrum of Compound 2 free base at 0.33% wt/vol.
For this compound, the four samples of the hydrochloride have formed gels but the free base is in the sol state.
Example 4 - Water Vapour Sorption/Desorption
Dynamic vapour sorption was performed to assess the ability of the gel forming compounds to interact with water molecules. The water vapour sorption isotherm was determined by measuring the mass changes of the sample at various humidity conditions. At equilibrium, the reaction between water content and equilibrium humidity of a material can be displayed graphically by a curve, the so called sorption isotherm. For each humidity value, a sorption isotherm indicates the corresponding water content value at a given, constant temperature. The sorption behaviour changes if the composition or quality of the material changes. Dynamic Vapour Sorption (DVS) is employed to measure the moisture sorption properties of hygroscopic gel forming compounds. The affinity of these materials for moisture is due to a degree of amorphous character present in the material. However, highly crystalline gelators may have very low affinities for moisture sorption due to the low surface energy of the particles formed during the crystallisation process. The gel forming compounds of the invention show classic sorption behaviour with a slight hysteresis between the sorption and desorption course.
Method
Gravimetric sorption/ desorption studies of particles of gel forming compounds were undertaken in a humidity-controlled microbalance (DVS Dynamic Vapour Sorption instrument, Surface Measurement Systems, UK). The DVS is based on a Cahn microbalance capable of measuring changes in sample mass lower than 1 part per million, placed in an incubator to control the temperature. Mixing dry and saturated vapour gas flows in the correct proportions using mass flow controllers generates the required humidity. The apparatus is computer controlled, allowing a preprogramming of the sorption and desorption isotherms. Samples of about 10 - 20 mg were loaded on one side of the pan balance and the program set to isothermal measurements at 25 0C in a two cycles: sorption from 0 %RH up to 90 % RH, and then desorption from 90 % RH to 0 %RH, all in 10 %RH steps.
Figure 2 is water vapour sorption/desorption plot for Compound 2 hydrochloride at a temperature of 250C.
The instrument was equipped with a optional microscopy assembly that allows video tracking of sorption/desorption processes and Figure 3 illustrates Compound 10 hydrochloride particles at both 0% relative humidity (in the dry state) and at 90% relative humidity with 27% adsorbed water.
The maximal water vapour sorption (at 90% relative humidity, 250C) was measured for several of the compounds of the present invention and the results are presented in Table 5. A maximal water vapour sorption of 5% or less indicates that the compounds are poor at forming hydrogels.
Table 5 - Maximal Water Vapour Sorption
Compound Water vapour sorption (at 90% RH) (%)
16 hydrochloride 31.97
2 hydrochloride 12.3
10 hydrochloride 27.01
11 hydrochloride 16.08 15 hydrochloride 15.2
From the table, it can be seen that all of the hydrochloride salts tested will form hydrogels when mixed with water. Example 5 - Formation of Gels in Various Solvents and Determination of Minimal Gelation Concentration
Attempts were made to form gels using a selection of the compounds of the invention in the following solvents: Water
Buffer pH 1.658 (potassium tetraoxalate 50 mmol/L)
Buffer pH 4 (potassium hydrogen phthalate 50 mmol/L)
Buffer pH 7 (disodium hydrogen phosphate 27.5 mmol/L + potassium dihydrogen phosphate 20 mmol/L) Buffer pH 10 (sodium hydrogen carbonate 25mmol/L + sodium carbonate 25 mmol/L)
Aqueous sodium chloride solution
Aqueous acetic acid solution
Octyldodecanol Cetiol® LC
Paraffin oil
Propylene glycol
Polyethylene glycol
Glycerine Oleic acid
The results for the selected compounds in some of the aqueous solvents are shown in Table 6.
Table 6 shows that all of the compounds are capable of forming gels but that gel formation is dependent upon various factors including the nature of the solvent (i.e. pure water, aqueous sodium chloride solution or aqueous acetic acid), the pH, and the salt concentration, with the different gel forming requiring different conditions for gelation. Table 6 - Gel Formation in Various Solvents
Solvent Compound Compound Compound Compound Compound
16.HCI 2.HCI 10.HC1 11.HC1 15.HC1
Water no; yes, with fast gelling after and slow prolonged cooling; staying at room gel point temperature (2- concentration 1
3 weeks) % wt./vol.
(partial, soft gel at 0.5%wt./vol.)
Buffer pH yes yes
1.658
Buffer pH 10 not gelled not gelled
NaCl+water - Gel (0.5M) ; Gel (0.5- 1.2 Sol (0.5 M- Gel (0.5M) ;
Sol (1 M- 3M) M-) ; Sol (2- 3M) Sol (1 M- 3M)
3M)
Acetic - Gel Gel gel at pH 1.74; Gel acid+water (in pH range (in pH range sol (in pH range from 1.74 to from 1.95 to (in pH range from 1.74 to
3.8) 3.8); sol at pH from 1.95 to 3.8) transparent
1.74 3.8) gel at pH 1.74, opaque gel at pH 3.8
The minimal gelation concentration was then determined for a selection of compounds in the solvents listed above.
Method
The gel forming compounds (from 10 mg up to 50 mg) were dissolved in water (or buffers or pharmaceutical oil; from 1 up to 5 mL) to make up a concentration from 0.2 up to 5 % wt./voL. The glass container (vial) was heated until the gel forming compound dissolved completely, and it was then cooled to room temperature. Gelation was observed, and the minimal gelation concentration (MGC) was determined visually by the vial-inversion method. The sample vials were put in an inverted position, and the concentration was taken as MGC at the point at which the gel started to flow. The gels were strong enough not to flow on inversion of the container and were found to be stable at room temperature for several months. They are pH-sensitive, forming around acidic and neutral pH but not at pH 10.0.
Dimethyl sulfoxide has also been shown to increase the rate and amount of transdermal diffusion (Y. Kalia, V. Merino, R. Guy; Dermatologic Clinics; 1998, 16, 289-299). The binary composition of water and DMSO has even better gelation properties than single components. For example, Compound 15 hydrochloride (10 mg) can gel 1.2 mL water, or 0.1 mL DMSO. However, it can gel mix of 18 mL DMSO and 6.4 mL water.
Table 7 shows the minimal gelation concentration of various compounds of the invention in water measured by the vial inversion method.
Tables 8 and 9 show the effect of pH and salt concentration on the gelation of various compounds of the invention at a concentration of 10 mg/mL.
Table 7 - Minimal Gelation Concentrations in Water Measured by Vial Inversion
Figure imgf000102_0001
Table 8 - Effect of acidity on Gelation; Gelation in (acetic acid + water)
Figure imgf000102_0002
Table 9 - Effect of Sodium Chloride on Gelation; Gelation in (water+NaCl)
Figure imgf000102_0003
It is clear from these results that salt concentration and pH have different effects on the different compounds. For example Compound 11 hydrochloride forms a gel at pH 1.74 but not at higher pH, whereas the other compounds tested form gels at higher pH but not at pH 1.74. This means that it is possible to select a gel forming compound for a desired use according to the gel forming properties of that particular compound.
Gelation in oils
Gelation of Compounds 2, 10, 15 and 11 (at lOmg/1 mL) in various pharmaceutical oils (glycerine, Oleic acid, octyldodecanol and Cetiol® LC) is shown in Table 10. Many transdermal and topical products show high incidences of adverse skin reactions such as scaling, pruritic erythema, and vesicobollous irritant and allergic contact dermatitis. The problem has also been approached by the additional inclusion of non-irritating ingredients such as glycerine. By gelation in glycerine the skin irritation caused by the drug-gel formulations can be completely avoided.
Oleic acid (cis-9-octadecenoic acid) is a monounsaturated fatty acid and has the ability of oleic acid to lessen the irritation caused by other penetration enhancing agents and/or other formulation components to a greater extent than oleyl alcohol has been described previously (United States Patent 6,319,913 Penetration enhancing and irritation reducing systems). The gelled combination of oleic acid with a gelling agent (supramolecular hydrogelator), such as referred here, and/or other irritation reducing agents, can result in drug formulations that produce markedly reduced levels of skin irritation.
Table 10 - Formation of Gels in Oils
Figure imgf000103_0001
The results presented in Table 10 demonstrate that the compounds of the invention are capable of forming gels in oils as well as in aqueous solvents.
Example 6 - Textural Analysis (Probe tack; adhesion to steel)
The interaction of solvent with the gel forming compounds and its distribution within the gel system are critical for the gel's mechanical strength, and also its ability to control drug release. Desirable gels for bioadhesive systems would be those that exhibited high values of the work of adhesion and high mechanical strength. The ability of the adhesive to form a bond to the skin is directly related to the probe tack of the adhesive. Tack is the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas excessive tack may leave adhesive residue on removal or cause dermal irritation. If the probe tack value of gel is less than 0.25 N, then the skin adhesiveness of gel becomes insufficient, so that it is likely to peel off even upon a little movement. Adhesives with a very high tack could form strong initial bonds with the skin upon application and thus may be difficult to remove. If the probes tack value of gel exceeds the 1.2 N value, the skin irritation increases so much that rashes in the skin and pains upon peeling are likely to occur.
Method In a tack test an adhesive covered substrate is pressed against a flat (steel) punch for a short time at a fixed pressure and then the joint is pulled apart. The force and energy involved in the detachment process are measured. As the two surfaces are moved apart the force increases rapidly to a maximum and then, for strong adhesion, tends to drop to a nearly constant value where it remains until final detachment. For weaker adhesion the force decreases rapidly to zero (detachment) after the maximum, hi the strong adhesion case the adhesive forms voids and then fibrillates during the stress plateau with much energy dissipated in drawing out the fibrils. Measurements of probe tack were based on the method described in ASTM D2979- 01 Standard Test Method for Pressure-Sensitive Tack of Adhesives Using an Inverted Probe Machine using an inverted probe machine (Texture Analyzer TA- XTPlus, Stable Micro Systems). Namely, by using the probe tack tester defined in ASTM D 2979-01, after one bottom face of a cylinder (probe) made of steel having a diameter of 12.5 mm and a gel layer surface are brought into contact with each other at a contact load of 4.9 ± 0.01 N for a contact time of 10.0 ± 0.01 seconds, the probe is separated from the adhesive layer surface in the perpendicular direction of the latter at a separating speed of 0.5 ± 0.1 mm/s. The probe tack value refers to the force [N] required at the time of separation. In this test, conducted at room temperature, the approach pre-test speed was 1 mm/second and the dwell time was 10 second, with the applied force of 4.9 N and contact area of 122.7 mm2; test speed 0.5 mm/second. Figure 4 shows a typical curve of tack probe measurement: force (in g) vs. distance (or displacement in mm). Probe tack (or Adhesive Peak Force) is the maximum force (point 2 in Figure 4) required to break adhesive bond; in g or Newton (or g/cm2 or N/mm2). The average force at maximum is average of 10 repeated measurements. Adhesion throughout the contact surface was achieved only for a short period of time, as indicated by the shape of the curve.The area under the curve of tack force vs. length (displacement or time) was integrated to determine the work of fracture of the adhesive bond (gel to steel)' Other parameters that can be derived from the probe tack measurements are: a) area of adhesive work (area between anchors 1 and 3); b) stringiness of the product (distance between anchors 1 and 3); c) cohesiveness of the product relative to the adhesiveness to the probe (area 2:3 over area 1:2); and, d) initial adhesive strength (gradient 1 :4).
Table 11 below shows the probe tack measurements of various compounds of the invention in water, and from the table we can determine where the minimal gelation concentration (MGC) is by up-slope of the tack force values.
The results presented in Table 11 show that when water is used as solvent many of the gels (marked in bold) have a tack force of greater than 0.25N and less than 1.2N, which makes them ideal candidates for use in bioadhesive systems. Table 11
Tack force, Fmaχ, ist (N) of Compounds + Water
Figure imgf000106_0001
Table 12 shows the effect on the tack force of adding a buffer (pH 1.658) to the solvent.
Table 12
Tack force, Fmax, ist (N) of compounds + buffer pH 1.658
Figure imgf000106_0002
Again, Table 12 shows that many of the compounds, when mixed an aqueous solvent having a pH of 1.658, form gels which have a tack force of greater than 0.25N and less than 1.2N, which makes them ideal candidates for use in bioadhesive systems. Table 13 shows the effect of acidity on the tack force by comparing the effect on the tack force of using as a solvent acetic acid of varying concentrations and therefore varying pH. The results from the table show that for all of the tested compounds, it is possible to select a pH value at which the tack force will make the gel suitable for use in bioadhesive systems.
Table 13
Tack force, F1113x, ist (N)
Figure imgf000107_0001
Table 14 illustrates the effect of sodium chloride in gels on probe tack and show that for some compounds it is possible to form a gel using a solvent which contains sodium chloride in which the gel has a tack value which makes it suitable for use in bioadhesive systems.
Table 14
Tack force, Fmaχ, ist (N) of Compound + sodium chloride solution
Figure imgf000107_0002
Adhesive work
The work of fracture decreased with decreasing concentration of gel forming compound (gelator). This observation is attributed to loss of adhesive linear gelator chains as crystallization occurs due to the slow incorporation of all the linear gelator chains in the crystalline structure formed. Thus, a gel produced with gelator concentration well above the minimal gelation concentration (MGC) contains relatively mobile, non-crystalline chains which exhibit strong adhesive behaviour either because of hydrogen bonding due to their hydroxyl groups or because of significant chain interpenetration or because of both. Contrary to this, for concentrations in the vicinity of MGC very few linear gelator chains are available for this interaction with (steel) substrate. It must be noted that samples produced with concentrations in the vicinity of MGC were not solid enough (although being able to be tested), rendering them useless.
The gels can be described as weakly adhering gels. The adhesive properties of the gels are dominated by the solvent (or water). Because aqueous solutions of the gel forming compounds are freely flowing liquids at elevated temperatures, these materials can readily be moulded into different shapes at temperatures above the gel point. When these solutions are cooled to room temperature, elastic solids are formed with very weak moduli, depending on the hydrogelator concentration in the gel. Adhesion of these gels has been studied using a rigid cylindrical indenter in contact with a thin layer of the gel. The experiments indicate that adhesion of the gel is dominated by the solvent, and can be viewed as a simple wetting process, Table 15. From the mechanical characterization, it was found that less the compressibility, less the cohesiveness, and that implies less of bio-adhesion. From results in Table 15, we can conclude that Compound 10.HC1 gels were the most flexible in that they hold on the probe continued for the longest distance. Table 15
Compound wt./vol. % water average (displacement(mm)*stress (MPa))
10.HC1 1 1.67E-03
1.5 2.02E-03
2 3.77E-03
2.5 1.03E-02
1 1.36E-03
0.5 6.27E-04
0.33 6.12E-04
0.25 5.48E-04
0.2 1.59E-04
11.HC1 1.00 3.97E-04
1.50 7.60E-04
2.00 7.55E-04
2.50 1.46E-03
1.00 4.59E-04
0.50 3.52E-04
0.33 3.70E-04
0.25 3.07E-04
0.20 2.28E-04
2.HC1 0.33
0.5 4.31E-04
0.5 3.47E-04
1 8.65E-04
1 6.10E-04
1.5 1.25E-03
2 1.48E-03
2.5 1.57E-03
5 5.28E-03
15.HC1 1.00 5.13E-04
0.50 2.64E-04
Effect of pharmaceutical oils; Gelation in oils
Hydrogelators 2, 10, 15 and 11 did not gel (at lOmg/1 mL) in paraffin oil, ethylene glycol, or propylene glycol. They gelation properties in other oils are given in Table 16, which show that some of the compounds form gels in some non-aqueous solvents which are suitable for use in bioadhesive systems. In particular, Compounds 2, 10 and 15 all form such gels in oleic acid and Compound 3 also forms a suitable gel with Cetiol® LC Table 16
Tack force, Fmax, 1st (N)
Figure imgf000110_0001
Example 13- Textural Analysis (Extnisional Force)
The quality of gels as usable objects was checked by measuring the gel texture using the viscosity values. Viscosity often determines the flow of products and controls the productivity. The flowability of the gel (e.g. the ability to be extruded through a syringe) is the ability of the gel to be applied onto and conform to sites on or in tissue, including tissue surfaces and defined cavities (intravertebral spaces, tissue). In particular, the gel flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula, when sprayed onto the delivery site, or the like. The threshold stresses are typically in the range of several kPa. The compositions, however, will remain generally immobile when subjected to stresses below the threshold level. A minimum pressure gradient is required to extrude a given gel through orifice. Once this minimum pressure gradient is exceeded, the pressure gradient during gel extrusion is insensitive to the flow rate.
Method
Measurements of extrusion were based on flow rate determination using a capillary extrusion viscosimeter with a plunger (tube length: 6, tube diameter 12.5 mm) that was attached to a texture analyzer machine (Texture Analyzer TA-XTPlus, Stable Micro Systems), and it consists of a cylindrical steel flow cell that has a steel bottom with a small size orifice (lmm in diameter). The pre-test speed was 1.5 mm/second, and test speed 2 mm/second. The trigger force was set at 0.00981 N. The force and stress required to extrude the gel through the orifice at the constant speed was measured and the results are shown in Table 17.
The force required to extrude the gel formulations is co-measurable to forces required to extrude from the collapsible tube. The low values (at concentrations in the vicinity of minimal gelation concentration (MGC)) reveal the easy of extrusion of such gels.
Table 17
Extrusional force/ stress
Compound wt./vol.% water Average i Force value (N) Average stress value
(kPa)
2.HC1 0.33 0.188 1.53
0.5 0.233 1.90
0.5 0.485 3.95
1 1.168 9.52
1 1.762 14.36
1.5 1.781 14.51
2 3.561 29.02
2.5 4.821 39.29
5 4.854 39.55
15.HC1 1 0.240 1.96
0.5 0.048 0.39
11.HC1 _ _ _
10. HCl 1.00 2.397 19.53
0.50 0.551 4.49
0.33 0.647 5.27
0.25 0.801 6.53
1.00 1.888 15.38
1.50 2.754 22.44
2.00 3.115 25.38
2.50 5.593 45.58
Example 14 - Diffusion imaging in gels
Method Diffusion System Here we examine the mass transfer of water and small molecular weight coloured penetrant (cresol) into the gels. To evaluate the permeability of the gels, a diffusional system was designed. The appropriate diffusion cell was constructed. The diffusion cell consists of two parts: the upper and lower PMMA sheet parts that are spaced by thin Teflon® spacers. The gels are placed at the bottom PMMA part as small drop. The whole construction is screwed and placed in a Petri dish filled with coloured (by cresol) standard buffer (pHl.658, pH 4, pH 7, and pHIO). The diffusion of coloured buffer into a gel was optically monitored and scanned with the flat-bet scanner. The gel front diffusivity or penetration depth is measured from the scanned images and diffusional constant calculated. Measurements collected from analyzing these images were fit to an equation of motion for a swelling gel and conventional diffusion models to characterize the transport characteristics of these materials. The mean-square displacement (MSD), and the time lag (tlag) yielded the expected linear relationship. Using the relation:
MSD = 4Diattiag, the cresol diffusional front penetration (as measure of model drug diffusion) is characterized by the lateral diffusion constant Diat in the range of 10-6 cm2/s. This value is in fair agreement with DM determined for other gel systems. The results are shown in Table 23. The experimentally determined diffusivity values are similar to those published for diffusion of unlinked PEG molecules in aqueous solution, where dilute solutions containing PEG 590 or 942 had diffusivities of 5.4 x 10"6 and 4.9 x 10"6 cm2/s. However, while increasing the water content had a pronounced effect upon the diffusion of small molecular weight analytes into the hydrogel (judging from the hydrogel diffusivity in the orders of magnitude as 10"6 cm2/s), it also resulted in decreasing hydrogel rigidity. Both the increased diffusivity and decreased rigidity are likely a direct result of decreased physical entanglements.
In the hydrogels system, absorption of water from the environment changes the dimensions and physicochemical properties of the system and thus the drug release kinetics. The diffusion of permeant (i.e., water in hydrogels) is determined by the relative rates of diffusion and network relaxation (T. Alfrey, E.F. Gurnee and W.G. Lloyd, Diffusion in glassy polymers, J. Polym. Sd. Part C 1966, 12, 249-261.). This effect of the diffusion of permeant can determine the drug release profiles from the swelling gel matrix. The release of water-soluble drug, entrapped in a hydrogels, occur only after water penetrates the networks to swell the polymer and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. The release of drug is closely related to the swelling characteristics of the hydrogels, which in turn, is a, key function of chemical architecture of the hydrogels. Drug release depends on two simultaneous rate processes, water migration into the device and drug diffusion through continuously swelling hydrogels. Diffusion coefficients were observed to be in order of 10~6 (cmVsec). Fick's first and second laws of diffusion adequately describe the most diffusion processes. For cylindrical shaped hydrogels the integral diffusion is given in simple equation (P.L. Ritger and N.A. Peppas, A simple equation for description of solute release. I. Fickian and non- Fickian release from non-swellable devices in the form of slabs, spheres cylinders or discs, J. Contr. Release 1987, 5, 23-36.; P.L. Ritger and N.A. Peppas, A Simple equation for description of solute release. I. Fickian and non-Fickian release from swellable devices, J. Contr. Release 1987, 5, 37-42.):
M1 = 4(JDt ,1/2
Mx πl 2 '
where (Mt/Mm) is the fractional release and Mt and M∞ is drug released at time lf and at equilibrium, respectively, D the diffusion coefficient and ■£ is the thickness of the sample.
Table 23
Compound Gelled % wtAoL Diffusion diffusion constant St. error with in buffer Diat(cm2/s)
2.HC1 water 1 pH4.6 - -
1.5 6.88 xlO"7 4.92 xlO"8
2 3.405 xlO"7 1.09 xlO"8
2.5 2.31 xlO"7 -
2.HC1 water 1 pH7 6.98 xlO"6 2.58 xlO"9
1.5 6.51 xlO"6 0.63 xlO"6
2 5.32 xlO"6 0.35 xlO"6
2.5 5.73 xlO"6 0.34 xlO"6
5 1.62 xlO"6 0.04 xlO"6
2.HC1 water 0.5 pHIO 41.78 xlO"6 3.17 xlO"6
1 8.03 xlO"6 1.26 xlO"6
1.5 3.00 xlO"6 1.33 xlO"6
2 12.06 xlO"6 0.76 xlO"6
2.5 7.45 xl 0"6 0.39 xlO"6
5 11.5 xlO"6 0.91 xlO"6
10.HC1 water 1.5 pH7 5.34 xlO"6 0.38 xlO"6
2 2.96 xlO"6 0.47 xlO"6
2.5 4.42 xlO"6 0.15 xlO"6
11.HC1 water 2.5 pHIO 10.5 xlO"6 0.81 xlO"6

Claims

1. A compound of general formula (Ia) or (Ib):
Figure imgf000115_0001
(Ia) (Ib)
wherein:
R1 is C1-6 alkyl, benzyl, phenyl, or indolylmethyl, any of which may be substituted with OH, 0(C1-6 alkyl) or S(C1-6 alkyl); each of X and Xa is independently -O-[CH2]P- or -NH-[CH2]r-; p is 1 to 4 except when:
R1 is C1-6 alkyl, and: n is < 6 in compounds of formula (Ia); or q is < 5 in compounds of formula (Ib); in which case, p is 2 to 4; r is 0 to 4; each of R2 and R2a is independently pyridyl; m is an integer of 4 to 12; n is an integer of 5 to 12; q is an integer of 4 to 11; or a salt thereof.
2. A compound as claimed in claim 1, wherein, in general formula (Ia) and (Ib), independently or in any combination: R1 is C1-6 alkyl, phenyl, benzyl, j?-hydroxybenzyl, indolylmethyl or methylthioethyl; m is 5 to 10; p is 0 to 3;
X is -NH-[CH2]r-; and each of R2 and R2a is 4-pyridyl.
3. A compound as claimed in claim 1 or claim 2 which is a compound of general formula (Ia) and wherein, independently or in any combination, m is 7 to 10, n is 8 to 10, X is -NH-CH2- and R2 is 4-pyridyl.
4. A compound as claimed in claim 1 or claim 2, which is a compound of general formula (Ib) and wherein , q is 1 to 3, X is -NH-CH2- and R2 is 4-pyridyl.
5. A compound as claimed in any one of claims 1 to 4 wherein R1 is isobutyl or phenyl.
6. A hydrochloride salt of a compound as claimed in any one of claims 1 to 5.
7. A compound as claimed in any one of claims 1 to 6 selected from: M-[(li-)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyl] decanamide;
M -(4-Pyridylmethyl)-l 1 -{ [(2J?)-(decanoylamino)-2-phenylethanoyl] amino}undecanamide;
3-(4-Pyridyl)propyl-l l-{[(2jS)-2-(dodecanoylamino)-3-phenylpropanoyl] amino} undecanoate;
M - { ( 15)-3 -Methyl- 1 - [( { 6-oxo-6- [4-pyridylmethyl)amino]hexyl} amino) carbonyl]butyl} dodecanamide;
M-{(l<S)-3-Methyl-l-[({l 1-oxo-l l-[(4-pyridylmethyl)amino]undecyl} amino)carbonyl]butyl} dodecanamide; 3-(4-Pyridylpropyl)-ll-{[(2S)-2-(dodecanoylamino)-4-methylpentanoyl] amino } undecanoate;
4-Pyridylmethyl- 11 - { [(2<S}-2-(dodecanoylamino)-4-methylpentanoyl]amino } undecanoate;
M-[(li?)-2-Oxo-2-({6-oxo-6-[(4-pyridylmethyl)amino]hexyl}amino)-l- phenylethyljdodecanamide;
4-Pyridylmethyl-6-{[(2i2)-2-(dodecanoylamino)-2-phenylethanoyl]amino} hexanoate; M -(4-Pyridylmethyl)- 11 - { [(2i?)-(heptanoylamino)-2-phenylethanoyl] amino} undecanamide;
M-(4-Pyridylmethyl)-ll-{[(2i?)-(nonanoylainino)-2-plienylethanoyl]amino} undecanamide; M -(4-Pyridylmethyl)- 12- { [(2i?)-(nonanoylamino)-2-phenylethanoyl] amino } dodecanamide;
M -(4-pyridylmethyl)- 12- { [(2i-)-(decanoylamino)-2-phenylethanoyl] amino } dodecanamide;
M -((li?)-2-Oxo-2- {[11 -oxo- 11 -(4-pyridylamino)undecyl] amino} - 1 -phenylethyl) dodecanamide;
M-[(li?)-2-oxo-2-({ll-oxo-ll-[4-pyridylmethyl)amino]undecyl}amino)-l- phenylethyl]dodecanamide;
M ,N5-di(4-pyridylmethyl)-(25)-2- { [(21S)-2-(dodecanoylamino)-4- methylpentanoyl]amino}pentanediamide; M ,N5-di(4-pyridylmethyl)-(2S)-2-{[(2i?)-2-(dodecanoylamino)-2- phenylethanoyl]amino}pentanediamide;
M -(pyridylmethyl)- 11 - { [(2,S)-(decanoylammo-4-methylpentanoyl] amino } undecanamide;
M -(4-Pyridylmethyl)- 11 - { [(2S)-2-(decanoylamino-3 - methylbutanoyl]amino}undecanamide;
M-[(lS)-l-Benzyl-2-oxo-2-({l 1-oxo-l l-[4- pyridylmethyl)amino]undecyl}amino)ethyl]dodecanamide;
M -(4-Pyridylmethyl)- 11 - { [(2S)-2-(decanoylamino)-3- phenylpropanoyl] amino } undecanamide; Nl-(4-Pyridylmethyl)-ll-{[(2i?,5)-(decanoylamino)-2-methylethanoyl]amino} undecanamide;
M -(4-Pyridylmethyl)- 11 - { [(2 S)-2-(nonanoylamino)-3 - phenylpropanoyl] amino } undecanamide;
M -(4-Pyridylmethyl)- 11 - { [(2R, 5)-2-(decanoylamino)-4-(methylsulfanyl) butanoyl] amino} undecanamide;
M-(4-pyridylmethyl)-ll-{[(25)-2-(decanoylamino)-3-(lH-3- indolyl)propanoyl]amino}undecanamide; M -(4-Pyridylmethyl)- 11 - { [(25)-2-(decanoylamino)-3 -(4- hydroxyphenyl)propanoyl]amino}undecanamide; and salts thereof.
8. A process for the preparation of a compound of general formula (Ia) as defined in claim 1 comprising: a) reacting a compound of general formula (II):
Figure imgf000118_0001
(H) wherein R1, m and n are as defined in claim 1 ; in a condensation reaction with acompound of general formula (III):
HX-R2 (III)
wherein X and R2 are as defined in claim 1 ; or
b) reacting a compound of general formula (V):
Figure imgf000118_0002
(V) wherein R1 and m are as defined in claim 1 ; with a compound of general formula (IX):
Figure imgf000118_0003
(IX) wherein R2 and n are as defined in claim 1; or
c) reacting a compound of general formula (XIII):
Figure imgf000119_0001
(XIII) wherein R1, R2, X and n are as defined in claim 1 ;
with a compound of general formula (VII) :
Figure imgf000119_0002
(VII) wherein m is as defined in claim 1.
9. A process for the preparation of a compound of general formula (Ib) as defined in claim 1, the process comprising: a) reacting a compound of general formula (V) as defined in claim 9 with a compound of general formula (XVIII):
Figure imgf000119_0003
(XVIII) wherein R2, R2a, X5 Xa and q are as defined in claim 1 ; or
b) reacting a compound of general formula (XX):
Figure imgf000119_0004
(XX) wherein R , m and q are as defined in claim 1 and R is C1-6 alkyl; with a compound of general formula (III):
HX-R2 (III)
wherein X and R are as defined in claim 1 in a condensation reaction.
10. A gel comprising a compound as claimed in any one of claims 1 to 7 mixed with a solvent.
11. A process for preparing a gel as claimed in claim 10, the process comprising:
a. mixing a compound as claimed in any one of claims 1 to 7 with a solvent; and b. heating and then cooling the solution.
12. A gel as claimed in claim 10 or a process as claimed in claim 11, wherein the solvent is a) an aqueous solvent such as water, sodium chloride solution or aqueous acetic acid or a physiological fluid such as stomach acid or saliva; b) a mixture of water with an organic solvent such as DMSO; c) an organic solvent such as DMSO, ethanol, rø-decanol, propylene glycol, polyethylene glycol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, p- xylene, or tetraline; or d) an oil such as glycerine, oleic acid, octyldodecanol and cocoyl caprylocaprate.
13. A process or a gel as claimed in any one of claims 10 to 12, wherein the solvent is an aqueous solvent and the compound of claims 1 to 7 is present in a concentration of at least 0.2 mg/mL.
14. A composition comprising: i. a compound as claimed in any one of claims 1 to 7; and ii. an active agent selected from a pharmaceutically or biologically active substance, a cosmetically acceptable compound or a dietary supplement.
15. A composition as claimed in claim 14, further comprising a solvent.
16. A composition as claimed in claim 14 or claim 15 which is intended for topical, transdermal, rectal, buccal or sublingual administration.
17. A composition as claimed in claim 16 which is a pharmaceutical composition in which the active agent is a pharmaceutically or biologically active substance.
18. A composition as claimed in claim 16 which is a cosmetic composition intended for topical administration and in which the active agent is a cosmetically acceptable compound, for example an enzyme or a vitamin.
19. A composition as claimed in any one of claims 15 to 18 wherein the solvent is either an aqueous solvent, a mixture of an aqueous and an organic solvent or a pharmaceutical oil such as glycerine, oleic acid, octyldodecanol or cocoyl caprylocaprate.
20. A composition as claimed in any one of claims 15 to 19 which is formulated as a patch which adheres to the skin.
21. A composition as claimed in claim 14 or claim 15 which is formulated for oral administration.
22. A composition as claimed in claim 21 which is a pharmaceutical composition and in which the active agent is a pharmaceutically or biologically active compound.
23. A compostion as claimed in claim 21 in which the active agent is a dietary supplement.
24. A composition as claimed in any one of claims 21 to 23, when dependent on claim 15, in which the solvent is an aqueous solvent, an organic solvent, a mixture of aqueous and organic solvents or an oil.
25. A composition as claimed in any one of claims 21 to 23 which does not comprise a solvent.
26. A composition as claimed in claim 17 or claim 22, wherein the pharmaceutically active substance is selected from anaesthetics (such as benoxinate, bupivacaine, dibucaine hydrochloride, dyclonine hydrochloride, etidocaine cocaine, hexylcaine, lidocaine, mepivacaine, naepaine, phenacaine hydrochloride, piperocaine, prilocaine, proparacaine hydrochloride, and tetracaine hydrochloride), analgesics (such as aspirin, acetaminophen and diflunisal), angiogenesis inhibitors, antiallergic agents, antibiotics (such as bacitracin, carbenicillin, cefazolin, cefoxitin, cephaloridine, chloramphenicol, chibrorifamycin, n-formamidoylthienamycin, gramicidin, neomycincolistin, penicillin G, polymyxin B, tetracyclines, vancomycin, and sulfonamides), anticancer, anticoagulants (such as heparin, bishydroxycoumarin, and warfarin), antidepressants (amitriptyline, chlordiazepoxide perphenazine, doxepin, imipramine and protriptyline), antidiabetic agents (such as acetohexamide, chlorpropamide insulin, tolazamide and tolbutamide), antiepileptic agents, antifungal (such as amphotericin B, miconazole, natamycin, nystatin and tlucytosine), antihypertensive agents (such as spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride and reserpine), anti-infective, anti-inflammatory (such as betamethasone, cortisone, dexamethasone sodium phosphate, fluorometholone, hydrocortisone, hydrocortisone acetate, dexamethasone, indomethacin, methylprednisolone, medrysone, prednisolone, preunisone, preunisolone sodium phosphate, triamcinolonesulindac, and its salts and analogs), antimicrobial, antipyretics, antiarrhythmic agents, antithrombotics, antituberculous agents, antitussive expectorants, antiulcer agents, antiviral (such as acyclovir, adenosine arabinoside (Ara-A), interferon, 5-iodo-2'- deoxyuridine and trifluorothymidine), bone resorption inhibitors, cholinergic or adrenergic agonists and antagonists, cardiotonics, cytostatic, haemostatics, fibrinolytics, muscle relaxants (such, as melphalan, danbrolene, cyclobenzoprine, methocarbamol and diazepam), narcotic antagonists, sedatives, thrombolytics and wound healing agents or buflomedil pyridoxalphosphate, diltiazem hydochloride, riboflavin sodium phosphate or a biologically active substance selected from proteins and their fragments, peptides and polynucleotides, growth factors, enzymes, vaccines and substances used in the treatment of diseases associated with genetic defects, for example angiotensins, adrenocorticotrophic hormone (ACTH), bacitracins, bombesin antagonists, bradykinin, calcitonin, colistins, growth hormone, growth hormone releasing factor, endomorphins, enkephalins, glucagon, gastrin, gramicidines, insulin, interferon, luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or antagonists, monoclonal antibodies, tetragastrin, pentagastrin, urogastrone, prolactin, renin, secretin, oxytocin, polymyzins, somatostatin, tyrocidin, transforming growth factor antagonists, soluble vaccines, and vasopressin.
27. A process for the preparation of a composition as claimed in any one of claims 14 to 26 comprising mixing a compound as claimed in any one of claims 1 to 7 with an active compound and optionally adding a solvent.
28. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of a gel.
29. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of a gel-forming composition, wherein the gel-forming composition comprises a compound as claimed in any one of claims 1 to 7 and an active agent selected from a pharmaceutically or biologically active substance, a cosmetically acceptable compound or a dietary supplement.
30. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound as claimed in any one of claims 1 to 7, and a pharmaceutically or biologically active agent.
31. The use of a compound as claimed in any one of claims 1 to 7 as a gastroprotective agent for an acid sensitive biologically active agent.
32. The use of a compound as claimed in any one of claims 1 to 7 for controlling the rate of release of an active agent from a composition.
33. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of a cosmetic composition, wherein the cosmetic composition comprises a cosmetically acceptable compound.
34. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of a dietary supplement.
35. A compound as claimed in any one of claims 1 to 7 for use as a gastroprotective agent for an acid sensitive biologically active agent.
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WO2024045158A1 (en) * 2022-09-02 2024-03-07 宁德时代新能源科技股份有限公司 Amide compound and preparation method therefor, electrode sheet, secondary battery, and electric device

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