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WO2006056182A1 - Nouveaux principes actifs pour assurer le traitement, le diagnostic et la prophylaxie de la degenerescence maculaire - Google Patents

Nouveaux principes actifs pour assurer le traitement, le diagnostic et la prophylaxie de la degenerescence maculaire Download PDF

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WO2006056182A1
WO2006056182A1 PCT/DE2005/002106 DE2005002106W WO2006056182A1 WO 2006056182 A1 WO2006056182 A1 WO 2006056182A1 DE 2005002106 W DE2005002106 W DE 2005002106W WO 2006056182 A1 WO2006056182 A1 WO 2006056182A1
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alkyl
carbon atoms
radical
group
empirical formula
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German (de)
English (en)
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Thomas Schrader
Frank-Gerrit KLÄRNER
Michael Fokkens
Reza Zadmard
Jolanta Polkowska
Frank Bastkowski
Christian Jasper
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Philipps-Universität Marburg
Universität Duisburg-Essen
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Publication of WO2006056182A1 publication Critical patent/WO2006056182A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4021—Esters of aromatic acids (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds

Definitions

  • the present invention relates to the fields of chemistry, biology, biochemistry, pharmacology, toxicology and human and veterinary medicine.
  • the present invention relates in particular to new active compounds which interact with the lipophilic cation A2E (N-retinyl-N-retinylidene-ethanolamine) of the retina and are suitable for therapy, diagnostics and prophylaxis of dry age-related macular degeneration.
  • A2E N-retinyl-N-retinylidene-ethanolamine
  • Age-related macular degeneration affects about one-fifth of the population over the age of 65 and is a major cause of severe visual impairment among the elderly in developed countries. This will be apparent to those skilled in the art from, for example, S Ben-Shabat, CA Parish, M Hashimoto, J Liu, K Nakanishi, JR Sparrow, Bioorg. Med. Chem. Lett. 2001, 11, 1533-1540; G Wolf, Nutrition Rev. 2003, 61, 342-346 and CN Keilhauer, BHF Weber, Biospektrum 2003, 9, 1-3.
  • the AMD is evolving over many decades. Estimates suggest that the number of people affected by AMD will nearly double over the next 25 years.
  • the disease is associated with damage to the photoreceptors in the macula.
  • AMD dry and wet AMD.
  • drusen In dry AMD, deposits on the macula, the so-called drusen, form in the early stages of the disease. If these drusen exist for a long time, macular atrophy occurs and the function of the light receptors can no longer be fulfilled. Those affected notice the disease by the appearance of vacancies within their central visual area.
  • wet AMD is caused by abnormal blood vessels that proliferate through the macula and under the retina. These blood vessels tend to secrete cell fluid and blood into the surrounding cell tissue of the retina, which leads to scarring of the macula and loss of vision.
  • the destruction of the macula due to wet AMD causes the center of an image to be imaged as if by a gray disc, and only the edge of the image is sharply and clearly perceived.
  • the cells in the retina contain two unusual retinoids, namely the lipophilic cations A2E (N-retinyl-N-retinylidene-ethanolamine) and its isoform with a cis double bond in a position adjacent to the pyridine ring.
  • A2E N-retinyl-N-retinylidene-ethanolamine
  • This is for example in S De, TP Sakmar, J Gen. Physiol. 2002, 120, 147-157; M Suter, C Reme, C Grimm, A Wenzel, M Jä helpfultela, P Esser, N Kociok, M Leist, C Richter, J Biol. Chem.
  • the terpene-substituted N-alkylpyridinium derivative A2E is highly responsible for AMD, as described, for example, in H Shaban, C Richter, Biol. Chem. 2002, 383, 537-545.
  • A2E forms a complex with cytochrome C oxidase and thereby induces apoptotic cell death.
  • A2E prevents the binding of cytochrome C to cytochrome oxidase and thus blocks the flow of electrons along the respiratory chain. As a result, more oxygen radicals are formed and oxidative stress increases.
  • A2E is toxic in the dark for many cells, including RPE, and increases the sensitivity of cells to blue light. The irradiation leads to permanent modifications of the cytochrome oxidase after complex formation with A2E.
  • A2E For example, H Shaban, C Borras, J Vina, C Richter, Exp. Eye Res. 2002, 75, 99-108 discloses that phosphatidylglycerol effectively protects human RPE cells from A2E-induced apoptosis.
  • the A2E mirror is CA Parish, M Hashimoto, K Nakanishi, J Dillon, J Sparrow, Proc. Natl. Acad.
  • USA 1998, 95, 14609-14613 is still about 10 times higher in the elderly (65 years) compared to younger (25 years).
  • DPG 1,3-diphosphatidylglycerol
  • phosphatidylglycerol ie
  • the levels of negatively charged phospholipids that protect against oxidative stress decrease with increasing age, as understood, for example, by those skilled in the art from BN Arnes, Mk Shigenaga, TM Hagen, Biochim. Biophys. Acta 1995, 1271, 165-170.
  • DPG 1,3-diphosphatidylglycerol
  • phosphatidylglycerol ie
  • the levels of negatively charged phospholipids that protect against oxidative stress decrease with increasing age, as understood, for example, by those skilled in the art from BN Arnes, Mk Shigenaga, TM Hagen, Biochim. Biophys. Acta 1995, 1271, 165-170.
  • therapeutic approaches exist for the related wet form of AMD the prior art has not known any drug for the treatment of dry AMD. Worldwide, about 25 to 30 million people suffer from this disease, so there is a great need
  • Boese Molecular tweezers as synthetic reeeptors: molecular recognition of neutral and cationic aromatic substrates. A comparision between the supramolecular structures in crystal and solution. Journal of Physical Organic Chemistry 2000, 13, 604-611 describes clips and tweezers that complex organic ammonium cations. The complex formation preferably takes place in apolar aprotic solvents, and the binding affinity of the substrate to the host molecule decreases significantly with increasing degree of substitution of the pyridine ring.
  • calixarenes for example calix [4] arene phosphonates, which complex metal and ammonium cations, and the formation of cage-like associates from oppositely charged calix [4] arene derivatives in aqueous solution.
  • calixarenes for example, T. Schrader, T. Grawe, M. Gurrath, A. Kraft, F. Osterod: Self-organization of Spheroidal Molecular Assemblies in Polar Solvents. Org. Lett. 2000, 2, 29-32; R. Zadmard, T. Schrader, T. Grawe, A. Kraft: Self-Assembly of Molecular Capsules in Polar Solvents, Org. Lett.
  • 25,26,27,28-tetrabutoxycalixarenes 3 can be prepared, for example, by condensation of formaldehyde with p- / t-butyl) -phenol in the presence of sodium hydroxide after Gutsche, subsequent debutylation with AICI 3 / phenol and subsequent reaction with butyl bromide:
  • 7,16-dihydroxy-6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene 19 is accessible as follows: First, 1 equivalent of benzoquinone 11 and 2 equivalents of cyclopentadiene 12 are subjected to consecutive reactions - Diels- Alder reaction, oxidation of the (1: 1) Diels-Alder adduct and again Diels-Alder reaction - reacted to diketone 13, then the diketone 13 is basic isomerized to hydroquinone 14.
  • the hydroquinone 14 is acetylated twice and 1 equivalent of the resulting bisacetic acid ester 15 with 2 equivalents of tetraboron-o-xylene 16 in Diels-Alder reactions to the unisolated Bisadduct 17 implemented.
  • the elimination of HBr under the reaction conditions gives 18,17,16-diacetyl-6,8,15,174-tetrahydro-6,17: 8,15-dimethanoheptacene;
  • Hydrolysis of the acetic acid ester leads to the hydroquinone 7,16-dihydroxy-6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene 19.
  • the object of the present invention is to provide novel active ingredients for therapy, diagnostics and prophylaxis of dry macular degeneration as well as processes for their preparation.
  • the active compounds according to the invention bind A2E and thus prevent the A2E-induced apoptosis of RPE cells.
  • the active compounds according to the invention are calixarene derivatives or clips.
  • Calixarene derivatives according to the invention are understood to mean those calixarenes which contain four to eight arene rings, each arene ring carrying a phosphate or phosphonate substituent in the exo position and an oxo or thio substituent in the endo position.
  • a clip according to the invention is understood to mean a compound which has a linear condensed ring system, wherein
  • the two terminal rings of the fused ring system are aromatic, each consisting of (4n + 2) carbon atoms and n is a natural number from 1 to 3, ⁇ one of the three aromatic rings does not represent a terminal ring of the linear fused ring system, this ring consisting of six carbon atoms and hereinafter referred to as the "central aromatic",
  • the central aromatic has two mutually para-substituents which are independently selected from the group of phosphate and phosphonate.
  • the calixarene derivatives according to the invention have the following general structural formula:
  • A no atom or -CH 2 -;
  • R1 H; alkyl; wherein alkyl is a group of 4 to 20 carbon atoms which is linear or branched; Heteroalkyl, wherein heteroalkyl is a radical having 4 to 20
  • R2 and R3 independently represent H or OH
  • R 4 H, linear alkyl having 1 to 20 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
  • R5 O " , alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-
  • Cycloheteroalkyl wherein -alkyl represents a group having 1 to 10 carbon atoms, which is linear or branched, preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl,
  • (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl are a mono- or polyunsaturated group having 2 to 10 carbon atoms
  • -cycloalkyl is a group having 3 to 20 carbon atoms
  • alkyl groups are linear or branched, an isoprene radical of the empirical formula C 5 H 9 , a terpene radical of the general empirical formula C 10 Hi 9 , C 10 H 19 O, Ci 0 Hi 7 , Ci 0 Hi 7 O, Ci 0 Hi 5 , a sesquiterpene radical of the general empirical formula C 15 H 29 , C 15 H 29 O, C 15 H 27 , C 15 H 27 O,
  • M Li + , Na + , K + , NH 4 + , 41 N (C 1 -C 4 alkyl) 1 where the alkyl groups are identical or different,
  • R 2 represents an oxygen atom and R 2
  • R 3 and R 4 represent hydrogen atoms, excluding compounds in which R 1 is an n-butyl group, R 5 is an ethyl group and M + is a Li + ion.
  • the clips according to the invention have the following general structural formula:
  • R5 O ' , alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group having 1 to 10 carbon atoms which are linear or is preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl for a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl is a group having 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus , -Aryl is an aromatic radical having 5 to 20 carbon atoms
  • M Li + , Na + , K + , NH 4 + , + N (C r C 4 alkyl), wherein the alkyl groups are identical or different, and
  • Y and Z are independently selected from the group
  • R6 is selected from H, OH, Cl, Br, O- (C r C 4 -alkyl), N- (C 1 -C 4 -alkyl), wherein the alkyl groups are identical or different, or an isoprene radical of the empirical formula C 5 H 9 , a terpene radical of the general empirical formula C 10 Hi 9 , Ci 0 Hi 9 O, C 10 Hi 7 , C 10 Hi 7 O, Ci 0 Hi 5 , a Sesquiterpenrest the general empirical formula C 15 H 29, C 5 H 29 O, C 5 H 27, C 5 H 27 O,
  • the bis-alkylphosphonate clips according to the invention are prepared by means of the process according to the invention shown below:
  • the bis-alkylphosphonate clips according to the invention are prepared by reacting POCl 3 with one equivalent of an auxiliary base, for example triethylamine, and one equivalent of an alkyl or terpene alcohol, in a polar aprotic solvent to give the alkyl or terpenephosphonic acid chloride.
  • the resulting Phosphor Acidesterdichlorid is reacted in situ with the addition of another equivalent of auxiliary base directly with the hydroquinone precursor 10 (0.37 equivalents).
  • the reaction is terminated after 1 to 2 hours by addition of 2% to 5% aqueous acid.
  • the reaction mixture is then mixed with a nonpolar aprotic solvent and stirred for 10 to 15 hours at room temperature. Thereafter, the organic phase is separated, optionally washed with 2% to 5% aqueous acid and the organic solvents removed by distillation. After drying the distillation residue, the corresponding bis-alkylphosphonate clip is obtained.
  • auxiliary base is meant a tertiary amine, for example triethylamine, diisopropylamine, pyridine.
  • the polar aprotic solvent is selected from the group tetrahydrofuran (THF), diethyl ether, diisopropyl ether, pyridine.
  • the non-polar aprotic solvent is selected from the group of alkanes having 5 to 8 carbon atoms, these alkanes being linear, cyclic and / or branched, for example, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopentane, methylcyclohexane, methylcycloheptane.
  • the alkyl alcohols are primary alcohols having 1 to 20 carbon atoms, the alkyl chain being linear, cyclic and / or branched, for example n-butanol, i-butanol, sec-butanol, tert-butanol, n-pentanol, Cyclopentanol, cyclohexanol.
  • the terpene alcohols are alcohols of a mono-, di- or sesquiterpene with the general empirical formulas C 10 H 2 O, Ci 0 H 18 O, Ci 0 H 16 O, Ci ⁇ H 3 0 O, C15H28O, C 1 SHa 4 O, C2oH 4 oO, C20H38O, C2 H36 ⁇ 0, C2 0 H3 O 4, C20H32O,
  • Clip 22a is a potent, non-toxic dry AMD inhibitor [50% inhibition of apoptosis at 15 ⁇ M
  • calixarene derivatives according to the invention are non-toxic up to high doses of about 60 ⁇ M.
  • Studies on the immune response to calixarenes have shown that they produce substantially no immune response and their cellular cytotoxicity is sufficiently low that the use of the calixarenes of the invention for the preparation of pharmaceutical compositions is pharmaceutically acceptable.
  • the calixarenes and clips according to the invention can therefore be used as medicaments for patients for the therapy, diagnosis and prophylaxis of diseases in which a pathological concentration of the terpene-substituted N-alkylpyridinium derivative A2E occurs.
  • diseases are, for example, the age-related dry macular degeneration AMD.
  • R 1, R 2, R 3, R 4, R 5, A and M + are as defined above and the compound wherein A is not an atom, X represents an oxygen atom, R 1 is an n-butyl group, R 2, R 3 and R 4 are hydrogen atoms , R5 represents an ethyl group and M + represents a Li + ion, since its use is used for the preparation of a medicament for patients for the therapy, diagnosis and prophylaxis of diseases involving a pathological concentration of the terpene-substituted N-alkylpyridinium derivative A2E, as is the case for example with the age-related dry macular degeneration, is new and thus inventive.
  • R5, M +, Y and Z have the meanings given above and the compound in which Y and Z each form a naphthalene ring with one of the two bicyclo [2.2.1] hept-2-ene groups, R5 represents a methyl group and M + is a lithium ion or a tetra-n-butylammonium ion, since its use for the manufacture of a medicament for patients for the therapy, diagnosis and prophylaxis of Diseases are used in which a pathological concentration of the terpene-substituted N-alkylpyridinium derivative A2E, as is the case for example in the age-related dry macular degeneration, is new and thus inventive.
  • the term patient refers equally to humans and vertebrates.
  • the drugs can be used in human and veterinary medicine.
  • Pharmaceutically acceptable compositions of compounds according to the claims and their salts, esters, or amides can be used, provided they do not cause excessive toxicity, irritation or allergic reactions on the patient after reliable medical assessment.
  • the therapeutically active compounds of the present invention may be administered to the patient as part of a pharmaceutically acceptable composition either orally, rectally, parenterally, intravenously, intramuscularly, subcutaneously, intracisternally, intravaginally, intraperitoneally, intravascularly, intrathecally, intravesically, topically, locally (powder, ointment or drops) or in spray form (aerosol).
  • a pharmaceutically acceptable composition either orally, rectally, parenterally, intravenously, intramuscularly, subcutaneously, intracisternally, intravaginally, intraperitoneally, intravascularly, intrathecally, intravesically, topically, locally (powder, ointment or drops) or in spray form (aerosol).
  • the intravenous, subcutaneous, intraperitoneal or intrathecal administration can be carried out continuously by means of a pump or metering unit.
  • Dosage forms for the topical administration of the compounds according to the invention include ointments
  • a solution of 0.83 mmol (0.7 g) P (OEt) 3 in 2 mL of benzonitrile is within xy minutes under argon atmosphere at 180 0 C to a solution of 0.5 mmol (0.52 g) 25,26 , 27 J 28-tetrabutoxy-5,11, 17,23-tetrabromocalix [4] arene 4 and 0.25 mmol (0.03 g) of NiCl 2 in 3 mL of benzonitrile and stirred for one hour at 180 0 C after completion of the addition , The reaction mixture is cooled to room temperature and poured into 100 ml of toluene, washed 5 times with 5% aqueous NH 3 solution, dried over Na 2 SO 4 and the solvent removed on a rotary evaporator (40 0 C / 60 mbar).
  • A2E 1.525 equivalent, corresponding to substance 1
  • the resulting solution of A2E is added in an increasing amount from 0 to 5.0 equivalents to the ten solutions of substance 6.
  • changes in volume and concentration are taken into account.
  • no chemical shifts are observed, which is why no binding constants can be calculated.
  • a NIMA 601 BAM film balance (trough dimensions 700 x 100 mm 2) with a Wilhelmy plate for the measurement of the surface pressure as a function of the molecular surface at 25 0 C.
  • Pure water purified by ELGA Purelab UHQ,> 18M ⁇
  • aqueous solutions of the alkylpyridinium salts 100 ⁇ M
  • the A2E 100 nM or 10 nM
  • none of these solutions show any measurable surface pressure in the areas studied.
  • 50 ⁇ L of a 3.5 mM stearic acid solution in chloroform to the subphase, a lipid monolayer is obtained.
  • ⁇ -A isothermal cycles carrier speed: 50 cm 2 / min
  • carrier speed 50 cm 2 / min
  • Compound 6 is incorporated by dropping 5 .mu.l a 4.6 mM receptor solution in chloroform / methanol (1: 1 v / v) to the subphase at a surface pressure of 15 mN / m in the lipid monolayer.
  • Time-dependent ⁇ -A isothermal cycles are recorded until the measurement results of 2 consecutive measurements are substantially constant.
  • Host molecule here is the calix [4] arene tetraphosphonate 6.
  • Force field calculations are first performed as Molecular Mechanics (MM Calculations) calculations in water.
  • MM Calculations Molecular Mechanics
  • Monte Carlo simulations are then performed in water (MacroModel 7.0, Schrödinger Inc., 2000. Force field: OPLS-AA).
  • OPLS-AA Force field: OPLS-AA
  • a Monte Carlo simulation consisting of 3,000 steps is performed. All low-energy structures have essentially identical energy values and conformations ( ⁇ E ⁇ 5 kJ / mol).
  • the production of the clips 22 takes place according to a modular strategy.
  • the deprotonated hydroquinone precursor 10 is reacted with an alkyl or aryl phosphonic acid dichloride. Subsequently, the remaining chlorine substituent is hydrolyzed.
  • the then obtained mono-acid 21 is then deprotonated with tetrabutylammonium or lithium hydroxide to 22.
  • the reaction mixture is stirred for 2 h at room temperature, then the solvent is removed on a rotary evaporator to dryness.
  • the residue is taken up in 2 ml of methanol, then filtered with a syringe filter (pore size 0.2 ⁇ m) and concentrated again to dryness on a rotary evaporator.
  • the degree of conversion is monitored by means of NMR: If the NMR analysis of the crude product indicates an excess of tetrabutylammonium hydroxide, the crude product is redissolved in 5 ml of methanol and 10 mg of the respective phosphonic acid precursor (16.8 ⁇ mol) are added with vigorous stirring.
  • the binding constant K a is determined by nonlinear regression.
  • the film scale experiments are carried out as described under 3.
  • the concentration of A2E in the aqueous subphase is 10 M to 7 M. No additional shift is observed when A2E is sub-injected into the aqueous subphase and compound 22a is embedded in the monolayer.
  • Host molecule is here compound 22a.
  • hydroquinone precursor 19 430 mg (0.981 mmol) of hydroquinone precursor 19 are dissolved under argon in 45 mL of anhydrous THF and cooled to 0 0 C. It will be 0:36 ml (3.96 mmol) POCl 3 and 0:34 mL of anhydrous triethylamine was added and stirred for 2.5 h at 0 0 C. It precipitates a white, consisting mainly of triethylammonium existing solid. The still cold reaction mixture is filtered off by means of a D4 frit in vacuo. The filtrate is mixed with aqueous 2.5% HCl solution and stirred for 2 d.
  • V A2E volume of A2E stock solution in CD3OD / D2O (3: 1, V: V)
  • V 25 volume of host stock 25 in CD3OD / D2O (3: 1, V: V)
  • V tot total volume of the sample
  • Ratio host / guest 1.516 (calculated from the A2E concentration and the integral ratio from the 1 H-NMR spectrum)
  • the and the association constant K 3 of the protons 13 'and 15 ' could be determined by nonlinear regression.
  • FIG. 1 Schematic representation of pressure-area isotherms for different concentrations of A2E on the Langmuir film scale. 0.13 equivalents of the receptor 6 are embedded in the stearic acid monolayer. The A-range is widened compared to FIG. 1: It is 38 A 2 in FIG. 3 compared to 32 A 2 in FIG. 2.
  • NMR titration curve for the complex formation between clips 22a and A2E upfield shift of the proton ortho to the pyridinium N atom.

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Abstract

L'invention concerne de nouveaux principes actifs, qui interagissent avec le cation lipophile A2E (N-rétinyl-N-étinylidène-éthanolamine) de la rétine et s'utilisent pour assurer le traitement, le diagnostic et la prophylaxie de la dégénérescence maculaire sèche liée à l'âge. Les principes actifs selon l'invention sont des dérivés de calixarène substitués par phosphate ou phosphonate et ce qu'il est convenu d'appeler des clips. Les clips sont des combinaisons cycliques condensées, dans lesquelles des combinaisons cycliques aromatiques sont interconnectées par l'intermédiaire de groupes bicyclo-[2.2.1]-hept-2-ène, de sorte que l'ensemble de la molécule décrive un 'U' et forme une cavité.
PCT/DE2005/002106 2004-11-24 2005-11-23 Nouveaux principes actifs pour assurer le traitement, le diagnostic et la prophylaxie de la degenerescence maculaire WO2006056182A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004056822A DE102004056822A1 (de) 2004-11-24 2004-11-24 Neue Wirkstoffe zu Therapie, Diagnostik und Prophylaxe der Makula-Degeneration
DE102004056822.7 2004-11-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008148168A1 (fr) * 2007-06-07 2008-12-11 The University Of Western Australia Procédés de préparation de dérivés de calixarènes
WO2010102248A3 (fr) * 2009-03-05 2010-11-04 The Regents Of The University Of California Pince moléculaire pour le traitement d'amyloses
CN101987894B (zh) * 2009-07-30 2012-11-07 沁阳市双屿防腐设备有限公司 热塑性塑料制备无卤阻燃纳米复合材料的方法
US10918657B2 (en) 2013-11-08 2021-02-16 The Regents Of The University Of California Treatment of spinal cord injury or traumatic brain injury by inhibition of synuclein protein aggregation
US12076330B2 (en) 2018-04-27 2024-09-03 The Regents Of The University Of California Inhibition of lipofuscin aggregation by molecular tweezers
US12076332B2 (en) 2018-04-27 2024-09-03 The Regents Of The University Of California Treatment of lysosomal storage disorders

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003164A1 (fr) * 1992-08-06 1994-02-17 Genelabs Technologies, Inc. Inhibition et traitement de l'infection par un virus a enveloppe avec des composes de calix(n) arene
US5409959A (en) * 1991-01-29 1995-04-25 Genelabs Incorporated Antithrombotic treatment with calix(n)arene compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5409959A (en) * 1991-01-29 1995-04-25 Genelabs Incorporated Antithrombotic treatment with calix(n)arene compounds
WO1994003164A1 (fr) * 1992-08-06 1994-02-17 Genelabs Technologies, Inc. Inhibition et traitement de l'infection par un virus a enveloppe avec des composes de calix(n) arene

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHRISTIAN JASPER;THOMAS SCHRADER;JENS PANITZKY; FRANK-GERRIT KLÄRNER: "Selective Complexation of N-Alkylpyridinium Salts: Recognition of NAD+ in Water", ANGEW. CHEM. INT. ED, vol. 41, no. 8, 2002, pages 1355 - 1358, XP002368744 *
DARIUSZ WITT, JOANNA DZIEMIDOWICZ, JANUSZ RACHON: "Calix[4]arene Phosphonates - Recognition of Amino Alcohols in Water", HETEROATOM CHEMISTRY, vol. 15, no. 2, 23 March 2004 (2004-03-23), pages 155 - 161, XP008060328 *
FRANK-GERRIT KLÄRNER; BJÖRN KAHLERT: "Molecular Tweezers and Clips as Synthetic Receptors. Molecular Recognition and Dynamics in Receptor-Subtrate Complexes", ACC. CHEM. RES., vol. 36, 2003, pages 919 - 932, XP002368745 *
ZADMARD, REZA; JUNKERS, MATTHIAS; SCHRADER, THOMAS; GRAWE, THOMAS; KRAFT, ARNO: "Capsule-like Assemblies in Polar Solvents", JOURNAL OF ORGANIC CHEMISTRY, vol. 68, no. 17, 2003, pages 6511 - 6521, XP002368699 *
ZADMARD, REZA; SCHRADER, THOMAS; GRAWE, THOMAS; KRAFT, ARNO: "Self-Assembly of Molecular Capsules in Polar Solvents", ORGANIC LETTERS, vol. 4, no. 10, 2002, pages 1687 - 1690, XP002368700 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008148168A1 (fr) * 2007-06-07 2008-12-11 The University Of Western Australia Procédés de préparation de dérivés de calixarènes
US8252954B2 (en) 2007-06-07 2012-08-28 The Curators Of The University Of Missouri Processes for the preparation of calixarene derivatives
WO2010102248A3 (fr) * 2009-03-05 2010-11-04 The Regents Of The University Of California Pince moléculaire pour le traitement d'amyloses
US8791092B2 (en) 2009-03-05 2014-07-29 The Regents Of The University Of California Molecular tweezers for the treatment of amyloid-related diseases
CN101987894B (zh) * 2009-07-30 2012-11-07 沁阳市双屿防腐设备有限公司 热塑性塑料制备无卤阻燃纳米复合材料的方法
US10918657B2 (en) 2013-11-08 2021-02-16 The Regents Of The University Of California Treatment of spinal cord injury or traumatic brain injury by inhibition of synuclein protein aggregation
US12076330B2 (en) 2018-04-27 2024-09-03 The Regents Of The University Of California Inhibition of lipofuscin aggregation by molecular tweezers
US12076332B2 (en) 2018-04-27 2024-09-03 The Regents Of The University Of California Treatment of lysosomal storage disorders

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