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WO2008067270A1 - Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique - Google Patents

Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique Download PDF

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Publication number
WO2008067270A1
WO2008067270A1 PCT/US2007/085562 US2007085562W WO2008067270A1 WO 2008067270 A1 WO2008067270 A1 WO 2008067270A1 US 2007085562 W US2007085562 W US 2007085562W WO 2008067270 A1 WO2008067270 A1 WO 2008067270A1
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alkyl
compound
pharmaceutically acceptable
solvate
hydrate
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PCT/US2007/085562
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English (en)
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Jr. Terrence R. Burke
Fa Liu
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Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Publication of WO2008067270A1 publication Critical patent/WO2008067270A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Signal transduction is critical to normal cellular homeostasis and is the process of relaying extracellular messages, e.g., chemical messages in the form of growth factors, hormones and neurotransmitters, via receptors, e.g., cell-surface receptors, to the interior of the cell.
  • Protein-tyrosine kinases play a central role in this biological function. Among others, these enzymes catalyze the phosphorylation of specific tyrosine residues to form tyrosine phosphorylated residues.
  • Protein-tyrosine phosphorylation is known to be involved in modulating the activity of some target enzymes as well as in generating specific complex networks involved in signal transduction via various proteins containing a specific amino acid sequence called an Src homology region or SH2 domain (see, e.g., Proc. Natl. Acad. Sd. USA, 90, 5891 (1990)).
  • a malfunction in this protein-tyrosine phosphorylation through tyrosine kinase overexpression or deregulation is manifested by various oncogenic and (hyper-) proliferative disorders such as cancer, inflammation, autoimmune disease, hyper-proliferative skin disorders, such as psoriasis, and allergy/asthma.
  • SH2- and/or SH3- comprising proteins that play a role in cellular signaling and transformation include, but are not limited to, the following: Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, phosphoinositol-3 (PI-3) kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, Tyk2, especially Src, phospholipase c, phoshoinositol-3 (PI-3) kinase, Grb
  • the invention provides macrocyclic compounds that inhibit the binding of a phosphoprotein with a Grb2 SH2 domain-containing protein.
  • the invention provides macrocyclic compounds of formula (I):
  • R and R are the same and are hydrogen or aryl which is optionally substituted;
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
  • R 3 is hydrogen, azido, amino, oxalylamino, carboxy C 1 -Ce alkyl, Ci-C 6 alkoxycarbonyl Ci-C ⁇ alkyl, aminocarbonyl Cj-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted;
  • R 6 is a linker;
  • AA is an amino acid;
  • m is 1 to 6; and
  • n is 1 to 6; or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
  • the invention further provides pharmaceutical compositions and methods of use of such compounds, for example, in the treatment of cancer.
  • Figure 1 illustrates a method of preparing achiral alkenyl amines 9a and 9f, which are intermediates in the synthesis of compounds in accordance with an embodiment of the invention.
  • Reagents and conditions (i) CH 3 SO 2 Cl, NEt 3 , CH 2 Cl 2 , room temp, 3 h; then NaN 3 , DMF-H 2 O, 50 0 C, overnight; (ii) LiAlH 4 , Et 2 O, 0 0 C, 1 h then (Boc) 2 O, Et 2 O - H 2 O, room temp, overnight; (iii) CF 3 CO 2 H, Et 3 SiH, CH 2 Cl 2 , room temp, 2 h; (iv) NaH, DMF 0 0 C to room temp, overnight; (vii) LiAlH 4 , Et 2 O.
  • Figure 2 illustrates a method of preparing N-Boc protected asparagine alkenylamides 10a and 1Of, which are intermediates in the synthesis of compounds in accordance with an embodiment of the invention.
  • Reagents and conditions (i) 4- methylmorpholine, Z-BuOC(O)Cl, DMF, 0 0 C 10 min then (ii) ra-Boc-L-Asn(Trt), room temperature, overnight.
  • Figure 3 illustrates a method of preparing compound 18, which is an intermediate in the synthesis of compounds in accordance with an embodiment of the invention.
  • Reagents and conditions (i) AUyI bromide, K 2 CO 3 , DMF, room temp, 2 days; (ii) CF 3 CO 2 H, Et 3 Si, CH 2 Cl 2 , room temp, 2 h; (iii) HOAt, EDCI, NEt(Z-Pr) 2 , DMF, room temp, 2 days; (iv) Pd(PPh 3 ) 4 , morpholine, THF, room temp, 30 min.
  • Figure 4 illustrates a method of preparing compounds of formula (Ilia) and (HIb) (5a and 5b, respectively) in accordance with an embodiment of the invention.
  • Reagents and conditions (i) HOAt, EDCI, NEt(Z-Pr) 2 , DMF, room temp, 2 days; (ii) 1,2-dichloroethane, reflux, 2 days; (iii) CF 3 CO 2 H, Et 3 Si, CH 2 Cl 2 , room temp, 2 h.
  • the invention provides macrocyclic compounds of formula (I):
  • R 1 and R 1 are the same and are hydrogen or aryl which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy;
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
  • R 3 is hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, C]-C 6 alkyl, Ci-C 6 alkoxy
  • the macrocyclic compounds of formula (I) can be of a suitable ring size.
  • m is from 1 to 4, more preferably, m is 1 or 2, and in a particular embodiment, m is 1.
  • n is from 2 to 4, more preferably, n is 2 or 3, and in particularly, n is 2.
  • the amino acids of (AA) n are incorporated, to arrive at the compounds of formula I, such that the N- and C-termini of (AA) n form amide linkages.
  • n is 2 and the amino acids of AA are ⁇ -aminocyclohexane carboxylic acid and asparagine, wherein each of the amino and carboxyl groups of the N- and C-termini of AA have been reacted to form amide linkages.
  • the amino acid or amino acids of (AA) n can be any suitable amino acids, natural or synthetic.
  • the amino acids can be selected from the group consisting of glycine, alanine, valine, norvaline, leucine, iso-leucine, norleucine, ⁇ -amino n-decanoic acid, serine, homoserine, threonine, methionine, cysteine, S-acetylaminomethyl-cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, ⁇ -phenylserine, ⁇ -hydroxyphenylalanine, phenylglycine, ⁇ -naphthylalanine, cyclohexylalanine, cyclohe
  • R 1 and R 1 are the same and can be either hydrogen or aryl.
  • the carbon atom to which R 1 and R 1 are attached is achiral.
  • R 1 and R 1 can be introduced, to prepare compounds of the invention, using any suitable method such as, for example, using achiral alkenyl amines as depicted in Figures 1-4.
  • R and R of formula (I) can be any suitable aryl group.
  • Aryl groups are well-known to the skilled artisan and include, for example, phenyl, naphthyl, anthracenyl, fluorenyl, biphenyl, dihydronaphthyl, tetrahydronaphthyl, heteroaryl, and the like.
  • Heteroaryl groups are well-known to the skilled artisan and include, for example, pyrrolyl, furanyl, pyrenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, imidazolyl, pyradazinyl, pyrimidinyl, triazinyl, pyranyl, thiazolyl, isothiazolyl, pteridinyl, piperonyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, and the like.
  • aryl and heterocyclyl moieties may be fused, such as, e.g., indole, isoindole, benzimidazole, quinoline, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, carbazolyl, benzodioxolyl, and the like.
  • R 1 and R 1 are aryl, which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-Ce alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy.
  • halo refers to any suitable halogen atom, including, for example, fluoro, chloro, bromo, iodo, and any combinations thereof.
  • the substituent can be located at any suitable position which is available for substitution, for example, in phenyl, the phenyl ring can be substituted at, for example, the 2, 3, 4, and/or 5 positions.
  • the aryl groups may be substituted by more than one substituent as appropriate.
  • R 2 in formula (I), in combination with the phenyl ring is a phenylphosphate mimic group or protected phenylphosphate mimic group.
  • a phenylphosphate mimic group can be one that has the functional property of the phosphorylated side chain of tyrosine-phosphorylated sequences, e.g., it can replicate the interaction of phenylphosphate side chain with proteins. The interaction may involve any number of mechanisms, including geometry, size, and/or charge.
  • a protected phenylphosphate mimetic is a phenylphosphate mimic that contains a protecting group that releases the mimetic, e.g., in a biological environment, such as due to chemical or enzymatic hydrolysis.
  • the protecting groups can be esters or amides.
  • R 2 can be hydroxyl, carboxyl, formyl, carboxy Ci-C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy C]-C 6 alkyloxy, dicarboxyhalo Ci-C 6 alkyl, dicarboxyhalo Ci-C 6 alkyloxy, phosphono, phosphono Cj-C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, and phosphoryl Ci-C 6 alkoxy, carboxy Ci-C 6 alkylamino, oxalylamino, C 6 -Ci 4 aryl Ci-C 6 alkyl, phosphino Cj-C 6 alkyl, Ci-C 6 alkyl phosphino C]-C 6 alkyl, C 6 -Ci 4 aryl, or RSO 2 NH- wherein R can be
  • R 2 is dicarboxy Ci-C 6 alkyl, e.g., dicarboxymethyl.
  • R 2 is phosphono Ci-C 6 alkyl, e.g., phosphonomethyl.
  • R 3 of formula (I) can be hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • R 3 is carboxy Ci-C 6 alkyl, e.g., carboxy methyl.
  • the invention provides compounds of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
  • R 1 and R 1 are the same and are hydrogen or aryl which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy;
  • R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
  • R 3 is hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl C]-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Cj-C 6 alkyl, Ci-C
  • R and R independently, can be hydrogen, Ci-C 6 alkyl, C 4 -C 8 cycloalkyl, or heterocyclyl, or R 4 and R 5 together can form a C 4 -C 8 cycloalkyl or heterocyclyl.
  • heterocyclyl is heterocycloalkyl.
  • R and R together form a C 4 -C 8 cycloalkyl, e.g., a cyclohexyl group.
  • R 6 is a linker.
  • the linker R 6 connects the benzylic carbon of the phenylphosphate mimic or protected phenylphosphate mimic group (i.e., the carbon atom of the macrocycle to which the R 2 -phenyl group is attached) to the carbon atom bearing R 1 and R 1 .
  • the bond connecting the linker to the linking sites can have any suitable configuration (R, S, or R/S).
  • the linking site at R 1 and R 1 has a R/S configuration.
  • the linker R 6 can be a bond or a group having 1-6 carbon atoms and can be optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • R 6 is a C 2 -CO alkenylenyl or C 2 -C 6 alkynylenyl group, optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • R 6 is a C 2 -C 6 alkenylenyl.
  • R 6 is propenylenyl.
  • R 6 can be a C 2 -C 6 alkenylenyl or C 2 -C 6 alkynylenyl group, preferably C 3 alkenylenyl or C 3 alkynylenyl.
  • R 6 can be optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, C]-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • m can be 1 or 2.
  • R 6 can be C 3 alkenylenyl or
  • C 3 alkynylenyl optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Cj-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • R and R 1 are hydrogen and m is 2, R can be C 3 alkenylenyl or
  • C 3 alkynylenyl optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
  • the present invention provides compounds of formula (II), wherein R 1 and R 1 are hydrogen, R 2 is dicarboxymethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R is propenylenyl, and m is 1.
  • the present invention provides compounds of formula (II), wherein R 1 and R 1 are hydrogen, R 2 is phosphonomethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1.
  • the present invention provides compounds of formula (II), wherein R 1 and R 1 are phenyl, R 2 is dicarboxymethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1.
  • the present invention provides compounds of formula (II), wherein R 1 and R 1 are phenyl, R 2 is phosphonomethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1. [0036] In a specific embodiment, the invention provides a compound of formula (Ilia):
  • the invention provides a compound of formula (HIb):
  • the present invention also provides pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates of the inventive compounds, as appropriate, including alkali or amine salts.
  • Suitable pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates of the inventive compounds are known to the skilled artisan.
  • the acidic groups, e.g., carboxylic, phosphoric, or phosphonic groups, of the compound can be converted to salts known to those skilled in the art, for example, a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium salt.
  • an alkali metal e.g., sodium or potassium
  • alkaline earth metal e.g., calcium
  • ammonium salt e.g., sodium or potassium
  • compositions include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, />-toluenesulphonic acids, and arylsulphanic, for example.
  • Solvates and hydrates of the present invention can be prepared using any suitable technique known in the art, for example, by crystallizing compounds of the invention in the presence of a suitable solvent, using conditions such that a solvate is formed.
  • hydrates of the present invention can be prepared, for example, by crystallizing compounds of the invention in the presence of water using conditions such that a hydrate is formed.
  • the present invention further provides compositions comprising a pharmaceutically acceptable carrier and an effective (e.g., therapeutically or prophylactically effective) amount of at least one of the compounds described above.
  • the present invention further provides a method of inhibiting an SH2 domain from binding with a phosphoprotein comprising contacting a sample or substance containing an SH2 domain with a compound of the present invention.
  • the present invention discloses the use of above compounds in the manufacture of a medicament for the treatment of a condition that responds to the inhibition of phosphoprotein binding to an SH2 domain of a mammal.
  • the present invention further provides the use of the above compounds in medicine.
  • the compounds can find use as an SH2 domain binding inhibitor.
  • SH2 domain-containing proteins are Grb2, Shp2, and STAT3 proteins.
  • the pharmaceutically acceptable (e.g., pharmacologically acceptable) carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants. The quantity of surfactant in such formulations typically ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art; see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4 th ed., pages 622- 630 (1986).
  • the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the present invention provides for a wide range of responses.
  • the dosages range from about 0.001 to about 1000 mg/kg body weight of the animal being treated/day.
  • Preferred dosages range from about 0.01 to about 10 mg/kg body weight/day, and further preferred dosages range from about 0.01 to about 1 mg/kg body weight/day.
  • Embodiments of the compounds have the advantage that they are stable to or in presence of enzymes encountered during in vivo use.
  • Embodiments of the compounds can find use in in vitro and in vivo applications.
  • the compounds can find use as molecular probes as well as in assays to identify, isolate, and/or quantitate receptor or binding sites in a cell or tissue.
  • the compounds also can find use in vivo for studying the efficacy in the treatment of various diseases or conditions involving SH2 domains.
  • the present invention further provides a method of preventing or treating a disease, state, or condition in a mammal by the use of the compounds of the present invention.
  • the method involves preventing a disease, state, or condition.
  • the method involves treating an existing disease, state, or condition.
  • the method involves inhibition of SH2 domain binding with a phosphoprotein.
  • the SH2 domain may involve one or more of the following proteins: Shp2, STAT3, Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, PI-3 kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, and Tyk2, especially Grb2, Shp2, and STAT3.
  • GAP GTPase-activating protein
  • Grb2 is an adaptor protein with N- and C-terminal src homology 3 (SH3) domains and a central src homology 2 (SH2) domain.
  • SH3 domain can bind to phosphoTyr residues of receptors or other adaptor proteins, such as SHC.
  • the SH3 domains bind the Ras exchange factor SOS, but can also bind to other adaptor proteins such as GABl and GAB2.
  • Grb2 is involved in activation of Ras but can also play a role in other signaling pathways in mammalian cells.
  • Shp2 is a tyrosine phosphatase that is recruited into tyrosine kinase signaling pathways through binding of its two amino-terminal SH2 domains to specific phosphotyrosine motifs.
  • Shp2 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
  • Shp2 contains two tandem Src homology-2 domains, which function as phosphotyrosine binding domains and mediate the interaction with its substrates.
  • Shp2 is widely expressed in most tissues and plays a regulatory role in various cell-signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration.
  • STATs Signal Transducers and Activators of Transcription
  • JAK kinases transcription factors that are phosphorylated by JAK kinases in response to cytokine activation of a cell surface receptor tyrosine kinases.
  • the STATs dimerize and are localized to the nucleus where they activate transcription of cytokine-responsive genes.
  • Cytokines that activate STAT3 include growth hormone, IL-6 family cytokines, and G-CSF.
  • STAT3 induces progression through the cell cycle, prevents apoptosis and upregulates oncogenes, such as c-myc and bcl-X and may play a role in oncogenesis.
  • STAT3 has been shown to play a critical role in hematopoiesis. The importance of STAT3 is underscored by the failure of mice lacking STAT3 to survive embryogenesis.
  • Crosstalk from pathways other than JAK kinases also leads to phosphorylation and activation of STAT3 as indicated by a role of mTOR (mammalian target of rapamycin, or p70 S 6 kinase) and MAP kinase pathways in STAT3 activation and signaling.
  • the method of treatment or prevention of a diseases comprises administering to the mammal one or more compounds of the present invention.
  • the disease, state, condition can be a cancer, e.g., a breast cancer or an ovarian cancer, or a tumor such as a solid tumor, e.g., a brain tumor, a prostate tumor, and the like, leukemia including chronic myelocytic leukemia, lymphoma, an autoimmune disease, an inflammatory disease, a metabolic disease, diabetes, obesity, or cardiovascular disease.
  • the present invention further provides a method of enhancing the therapeutic effect of a treatment rendered to a mammal comprising administering a compound in conjunction with the treatment.
  • the inhibitor can be used in any suitable manner, for example, prior to, simultaneous with, or post- administration of the therapeutic agent. Synergistic effects are observed when the SH2 domain binding inhibitor is used in combination with other treatments known to those skilled in the art.
  • the inhibitor enhances the cytotoxicity of the chemotherapeutic treatments. Cancer treatment is particularly suitable for this combination treatment.
  • the cancer may involve any number of mechanisms.
  • a majority of human breast cancers are dependent upon activation of the Ras signaling pathways through activation of growth factor receptor as the means to achieve continuous cellular proliferation.
  • the cancer may involve overexpression of Her-2/neu.
  • the cancer can be mediated through BCR-AbI or the expression of erbB-2 receptor.
  • therapeutic agents affecting Grb2 function at its SH2 domain may interrupt the flow of signal transduction to the Ras pathway and thus result in reversal of the cancer phenotype.
  • the therapeutic treatment can include chemotherapy, radiation therapy, and/or a biological therapy.
  • chemotherapy include the use of cancer treatment agents such as alkylating agents, hormonal agents, antimetabolites, natural products, and miscellaneous agents.
  • cancer treatment agents include paclitaxel, 5- fluoruracil, and doxorubicin.
  • biological therapy include the use of a protein such as an antibody (monoclonal or polyclonal) or a recombinant protein.
  • An example of an antibody is herceptin, which is targeted for inhibiting the erbB-2 receptor.
  • the enhancement of the therapeutic effect comprises blocking of a cell survival factor in the mammal and/or triggering, e.g., enhancing or speeding up, of cell apoptosis.
  • the treatment can be carried out in vivo and/or in vitro.
  • the Grb2 SH2 binding inhibitors are effective in inhibiting the association or binding of Grb2 with activated receptor PTKs. Interaction of native Grb2 protein with phosphotyrosinylated proteins including receptor PTKs can be monitored by immunoprecipitating Grb2 and detecting the amount of phosphotyrosinylated proteins which are coprecipitated using anti-phosphotyrosine Western Blotting.
  • the compounds of the present invention can be prepared by any suitable method, for example, a method that advantageously utilizes achiral alkenyl amines in a synthesis involving ring closing metathesis (RCM) reaction of asparagine pentenylamides onto a ⁇ -vinyl-containing residue; see, e.g., Figures 1-4.
  • RCM ring closing metathesis
  • For examples of RCM reactions see, Gao et al., Org. Lett. 2001, 3, 1617-1620; Reichwein et al., Angew. Chem., Int. Ed. 1999, 38, 3684-3687, J. Org. Chem., 2000, 65, 6187-6195; andJ. Org.
  • the RCM reaction advantageously allows ring closure with retention of desired functional groups, e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
  • desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
  • desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
  • desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
  • the preparation of multiple analogues may be made possible through the use of solid-phase chemistries.
  • macrocyclic compounds of any suitable size can be prepared.
  • homologs of compounds 9a and 9f which have one or more additional methylene units between the amino group and the carbon atom bearing R 1 and R 1 (i.e., m is greater than 1), can be prepared using any suitable chemistry known in the art. These homologs can then be used to prepare macrocyclic compounds of the invention, wherein m is greater than 1, using similar chemistry as depicted in Figures 2-4.
  • Another exemplary approach is varying the number of amino acids of (AA) n .
  • analogs of compounds 10a, 1Of, and/or 18 can be prepared, which comprise one or more additional amino acids (i.e., n of (AA) n is greater than 2). These analogs can then be used to prepare macrocyclic compounds of the invention, wherein n is greater than 2, using similar chemistry as depicted in Figure 4. Both of these approaches can be used to vary the ring size while producing macrocyclic compounds of the invention. In accordance with the invention, one or both of these approaches can be used to prepare macrocyclic compounds of the invention with various ring sizes.
  • This example demonstrates a method of preparing compounds 5a and 5f in accordance with an embodiment of the invention.
  • HPLC separations are conducted using a Waters Prep LC4000 system with photodiode array detection and either a J-sphere ODS-H80 column (20 x 250 mm) with a solvent system consisting of 0.1% aqueous TFA (v/v, solvent A) / 0.1% TFA in MeCN (v/v, solvent B).
  • the reaction mixtue is diluted with water (200 mL) and extracted with ether (300 mL). The ether layer is washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The concentrated oil is dissolved in anhydrous ether (100 mL), LiAlH 4 (2.2 g, 58.1 mmol) is added in several portions at 0 0 C, and the suspension is stirred for 1 hour. Water (5.0 rnL) is carefully added to the reaction mixture at 0 0 C, which is stirred vigorously until white.
  • N-Boc protected asparagines alkenylamides are prepared as depicted in Figure 2.
  • ⁇ -Boc- ⁇ -aminocyclohexanecarboxylic acid 2-propenyl ester A mixture of ⁇ -Boc-l-aminocyclohexanecarboxylic acid (1.70 g, 7.00 mmol), allyl bromide (0.89 mL, 10.5 mmol) and Na 2 CO 3 (881 mg, 10.5 mmol) in DMF (20 mL) is stirred at room temperature (2 days). The reaction mixture is diluted with ethyl acetate (150 mL), washed with H 2 O (2 x 50 mL) and brine (50 mL), dried (Na 2 SO 4 ) and solvent evaporated.
  • Dipeptide acid 18 To a solution of dipeptide allyl ester 17 (540 mg, 0.82 mmol) in anhydrous THF (30 mL) which has been degassed under argon for 5 minutes is added Pd(PPh 3 ) 4 (93 mg, 0.080 mmol) and morpholine (0.70 mL, 8.00 mmol). The mixture is stirred at room temperature (30 minutes) then 0.1 N HCl (100 mL) is added, THF is removed in vacuuo and the remaining residue is extracted with ethyl acetate (3 x 50 mL).
  • Metathesis precursor 13a ⁇ -Boc-protected asparagine amide 10a (94 mg, 0.174 mmol) is treated with CF 3 CO 2 H (1.60 mL) and triethylsilane (0.30 mL) in CH 2 Cl 2 (1.0 mL) at room temperature (4 h). Volatiles are then removed in vaccuo and the residue is placed in vacuum (30 minutes) to yield the CF 3 CO 2 H amine salt 19a.
  • Metathesis precursor 13f Deprotection of ⁇ -Boc-protected asparagine amide 1Of yields the CF 3 CO 2 H amine salt 19f, which is coupled with dipeptide acid 18 as in 13a to provide 13f in 85% yield.
  • the steady state values are determined using a Biacore 2000 and S51 instruments using amine coupled surfaces as described in Oishi et al. ChemBioChem, 2005, 6, 668-674 and Oishi et al. Bioorg. Med. Chem., 2005, 13, 2431-2438.
  • the binding experiment directly measures the binding of 5a and 5f to biotinylated Grb2 SH2 domain protein immobilized onto a sensor chip. Immobilization of protein is achieved either by amine coupling or by streptavidin capturing of the biotin functionality.
  • the binding data is provided in Table 1.
  • 5a and 5f display binding affinities of 320 nM and 72 nM, respectively.

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Abstract

L'invention concerne des composés permettant d'inhiber la liaison d'une protéine contenant le domaine SH2, par exemple un composé représenté par la formule (I), dans laquelle R1 et R1'sont semblables et sont hydrogène ou aryle éventuellement substitué tel que dans la description, R2 en combinaison avec son cycle phényle est un groupe analogue phényle phosphate ou un groupe analogue phényle phosphate protégé, R3 est hydrogène, azido, amino, oxalylamino, carboxy C1-C6 alkyle, C1-C6 alkoxycarbonyle C1-C6 alkyle, aminocarbonyle C1-C6 alkyle, ou C1-C6 alkyle carbonylamino; la partie alkyle de R3 est éventuellement substituée telles que dans de la description, R6 est un lieur, AA est un acide aminé, m est compris entre 1 et 6 et n est comprise entre 1 et 6. L'invention concerne aussi un sel, un stéréoisomère, un solvate ou un hydrate de ces composés pharmaceutiquement acceptable. L'invention concerne aussi des compositions pharmaceutiques et des procédés d'utilisation de ces composés.
PCT/US2007/085562 2006-11-27 2007-11-27 Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique WO2008067270A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
US11485750B1 (en) 2019-04-05 2022-11-01 Kymera Therapeutics, Inc. STAT degraders and uses thereof

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WO2004003005A2 (fr) * 2002-06-28 2004-01-08 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de liaison au domaine sh2
WO2006039527A1 (fr) * 2004-09-30 2006-04-13 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de liaison de domaine sh2 macrocyclique

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WO2004003005A2 (fr) * 2002-06-28 2004-01-08 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de liaison au domaine sh2
WO2006039527A1 (fr) * 2004-09-30 2006-04-13 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de liaison de domaine sh2 macrocyclique

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LIU FA ET AL: "Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis.", ORGANIC & BIOMOLECULAR CHEMISTRY 21 JAN 2007, vol. 5, no. 2, 4 December 2006 (2006-12-04), pages 367 - 372, XP002472708, ISSN: 1477-0520 *
SHI Z D ET AL: "Synthesis of a C-terminally biotinylated macrocyclic peptide mimetic exhibiting high Grb2 SH2 domain-binding affinity", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 13, no. 13, 1 July 2005 (2005-07-01), pages 4200 - 4208, XP004913665, ISSN: 0968-0896 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
US11485750B1 (en) 2019-04-05 2022-11-01 Kymera Therapeutics, Inc. STAT degraders and uses thereof
US11746120B2 (en) 2019-04-05 2023-09-05 Kymera Therapeutics, Inc. Stat degraders and uses thereof
US12077555B2 (en) 2019-04-05 2024-09-03 Kymera Therapeutics, Inc. STAT degraders and uses thereof

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