Claims for Patent: 6,344,457

Summary for Patent: 6,344,457

Title:	Amino acid derivatives inhibiting extracellular matrix metalloproteinase and TNF alpha release
Abstract:	The invention concerns compounds of general formula (X) in which Y represents in particular --CONHOH, R.sub.1 represents in particular a C.sub.1 -C.sub.5 alkyl group, AA represents an amino acid, or an amino acid sequence, and R.sub.3 represents in particular a group of formula --NH--(CH.sub.2).sub.2 --SCH.sub.3. The invention also concerns the pharmaceutical compositions containing them, and the methods for obtaining them.
Inventor(s):	Jeanpetit; Christian (Bougival, FR), Prigent; Didier (Bures sur Yvette, FR), Settembre; Pierre-Andre (Houilles, FR), Trancart; Marie-Michele (Voisins le Bretonneux, FR)
Assignee:	Chiesi Farmaceutici S.p.A. (Parma, IT)
Application Number:	09/403,037
Patent Claims:	1. Compounds of the following general formula (X): ##STR124## in which: Y represents: --CONHOH, or --SH, or a group with the formula ##STR125## or a group with the formula ##STR126## in which: R.sub.4 represents --H, or a C.sub.1 to C.sub.6 alkyl group, or a phenylalkyl group in which the alkyl group is C.sub.1 to C.sub.6, R.sub.5 represents a group with the formula ##STR127## in which: R.sub.6 represents --H, or a C.sub.1 to C.sub.6 alkoxy group, or a benzyloxy group, R.sub.7 represents --H, or a halogen atom R.sub.1 represents: a C.sub.3 to C.sub.16 linear or branched, or C.sub.3 to C.sub.6 cyclized alkyl chain, said chain comprising a heteroatom, a phenoxyalkyl or phenylalkyl group, substituted or unsubstituted, or a heteroarylalkyl group, the alkyl group being C.sub.2 to C.sub.5, R.sub.2 represents: a hydrogen atom, or, a C.sub.1 to C.sub.5 alkyl or C.sub.2 to C.sub.5 alkylidene group, or a hydroxyl, a C.sub.1 to C.sub.6 alkoxy or a benzyloxy, provided that Y represents --CONHOH when R.sub.2 represents a hydroxyl, or a hydroxymethyl, or C.sub.1 to C.sub.6 alkoxymethyl group, or an arylalkyl group in which the alkyl portion is C.sub.1 to C.sub.6, an aryloxymethyl group, an arylthiomethyl group, a heteroarylthiomethyl group, in which aryl designates a substituted or unsubstituted phenyl remainder --OCH.sub.3, a linear or branched C.sub.1 to C.sub.3 alkyl group, a halogen, an amine group, or a phthalimide alkyl group in which the alkyl portion is C.sub.1 to C.sub.6, or an alkoxycarbonmethyl group, a benzyloxycarbonylmethyl, an acetylmethyl, provided that Y represents --SH in these three cases, AA represents an amino acid, or an amino acid chain a group with the formula ##STR128## R.sub.3 represents a group with the formula --NH--(R.sub.8).sub.n --R.sub.9 in which: n represents 0 or 1, R.sub.8 represents a linear or branched alkyl chain, with 1 to 8 carbon atoms unsubstituted or substituted one or several heteroatoms, R.sub.9 represents a hydrogen atom or a methyl, nitrile, morpholino, phenyl, methoxy, hydroxyl, thiomethyl group, or a group with the formula --CH(NH.sub.2).dbd.N--OH, or a --N(CH.sub.3).sub.2 group. 2. The compounds according to claim 1, having the following formula (Xa): ##STR129## in which: Y represents: --CONHOH, R.sub.1 represents: --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, or ##STR130## R.sub.2 represents: an alkyl group with 1 to 5 carbon atoms, a hydroxyl, or an alkoxy group with 1 to 5 carbon atoms, R represents: --C(CH.sub.3).sub.3, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR131## aromatic or nonaromatic, in which R.sub.a and R.sub.b, independently of one another, represent --H, --Cl, --Br, --I, --F, --OCH.sub.3, --NO.sub.2, --NH.sub.2, or a group with the formula ##STR132## R.sub.3 represents a --NH--(CH.sub.2).sub.n1 --R.sub.9 group in which: n.sub.1 represents 0, 1 or 2, R.sub.9 represents --CH.sub.3, --C.ident.N, --COOHCH.sub.3, --SCH.sub.3, --O--(CH.sub.2).sub.2 --OH, --O--(CH.sub.2).sub.2 --OCH.sub.3, --CH(NH.sub.2).dbd.N--OH, ##STR133## 3. The compounds according to claim 2, wherein the R.sub.1 and R.sub.2 substituents are positioned in anti orientation in relation to the succinic residue in accordance with the following formula (XI.1): ##STR134## 4. Compounds according to claim 1, wherein R represents a group with the formula ##STR135## in which R.sub.a and R.sub.b represent a halogen atom. 5. The compounds according to claim 1, wherein R.sub.3 represents a group with the formula 6. A mixture comprising compounds with the following formula (XI.1): ##STR136## in which Y, R.sub.1 and R.sub.2, AA and R.sub.3 are such as defined in claim 20, and compounds with the following formula (XI.2): ##STR137## in which Y, R.sub.1, R.sub.2, AA and R.sub.3 have the meaning indicated hereinabove, the proportion of the compounds (XI.1) and (XI.2) in the mixture being approximately 50% to approximately 99% for the compound of formula (XI.1) and approximately 50% to approximately 1% for the compound of formula (XI.2). 7. The compounds according to claim 1, selected from the group consisting of: ##STR138## ##STR139## 8. A pharmaceutical composition comprising, as an active principle at least one of the compounds of claim 2, in combination with an acceptable pharmaceutical vehicle. 9. The pharmaceutical composition according to claim 8, which is in a form which may be administered orally, parenterally or rectally. 10. The pharmaceutical composition according to claim 8, wherein the dosage of active principle is approximately 0.1 to approximately 500 mg/kg/day. 11. The pharmaceutical composition according to claim 8, which is in a form which may be administered orally, in a unit dosage of 1 mg to 250 mg of active principle per dose, at the rate of 1 to 4 doses per day. 12. The pharmaceutical composition according to claim 8, which is in a form which may be administered parenterally, in a unit dosage of 1 .mu.g to 50 mg of active principle per injection, at the rate of 1 to 2 injections per day. 13. A process for preparation of the compounds of claim 1, wherein Y represents --CONHOH (XV) comprising the following steps: wherein: ##STR140## step 1 comprises condensing .alpha.-hydroxysuccinic acid XII, wherein R.sub.8 is a protective group compatible with the various elements of the molecule with an AA-R.sub.3 residue where AA and R.sub.3 are such as defined in claim 21, by a method of coupling used in peptide synthesis, step 2 comprises hydrolyzing the ester XIII obtained in the preceding step into carboxylic acid XIV with trifluoroacetic acid, step 3 comprises forming hydroxamic acid XV by reacting hydroxylamine, protected O hydroxylamine or diprotected N,O hydroxylamine, with a coupling reagent DCC/HOBT or WSC/HOBT at room temperature in a solvent THF, CH.sub.2 Cl.sub.2, or DMF for 1 to 24 hours, wherein if R.sub.2 =OH, the alcohols are protected prior to said coupling; the (di)protected O or N--O hydroxylamines are deprotected according to the nature of the protective group. 14. The compounds according to claim 1, wherein R.sub.7 is Cl or Br. 15. The compounds according to claim 1, wherein R.sub.1 is a C.sub.3 to C.sub.16 linear or branched, or C.sub.3 to C.sub.6 cyclized alkyl chain comprising O, S, and/or N. 16. The compounds according to claim 1, wherein R.sub.2 is a phenyl substituted by OH. 17. The compounds according to claim 1, wherein R.sub.2 is a Cl or Br. 18. The compounds according to claim 1, wherein R.sub.2 is an amine group selected from the group consisting of NH.sub.2, NHCOCH.sub.3, CHCOOR.sub.10, wherein R.sub.10 is a linear or branched C.sub.1 to C.sub.3 alkyl group. 19. The compounds according to claim 1, wherein R.sub.2 is a methoxycarbonmethyl group or a ethoxycarbonmethyl group. 20. The compounds according to claim 1, wherein AA represents an amino acid in an absolute S configuration and which has the formula ##STR141## wherein R represents: a C.sub.1 to C.sub.4 linear or branched alkyl chain, a --CH.sub.2 --Y group in which Y represents a ring of 4 to 6 carbon atoms which may be substituted by one of several heteroatoms, said ring being aromatic or nonaromatic, substituted by one or several --OCH.sub.3, --NO.sub.2, --NH.sub.2 groups, or by one or several halogen atoms. 21. The compounds according to claim 20, wherein Y represents a ring of 4 to 6 carbon atoms which may be substituted by O, S and/or N, said ring being aromatic or nonaromatic and substituted by one or several halogen atoms. 22. The compounds according to claim 20, wherein Y represents a ring of 4 to 6 carbon atoms which may be substituted by one or several heteroatoms, said ring being aromatic or nonaromatic and substituted by Cl, --Br, --F and/or --I. 23. The compounds according to claim 1, wherein R.sub.8 is a linear or branched alkyl chain, with 1 to 8 carbon atoms substituted or unsubstituted by O and/or S. 24. The compounds according to claim 2, wherein R.sub.2 is a methyl or propyl. 25. The compounds according to claim 2, wherein R.sub.2 is a methoxy group. 26. The pharmaceutical composition according to claim 8, wherein the active principle is in a form which may be administered orally and is in a unit dosage of from 10 mg to 250 mg of active principle per dose. 27. The pharmaceutical composition according to claim 8, wherein the dosage of the active principle is from 1 to 300 mg/kg/day orally and rectally. 28. The pharmaceutical composition according to claim 8, wherein the dosage of the active principle is from 0.1 .mu.g/kg/day to 1 mg/kg/day parenterally. 29. A method of preparing a medicine comprising mixing at least one compound according to claim 1 with a pharmaceutically acceptable vehicle. 30. A method of inhibiting the action of a metalloproteinase involved in the breakdown of the extracellular matrix comprising administering at least one compound according to claim 1 to a patient in need thereof in an amount sufficient to inhibit said metalloproteinase. 31. The method according to claim 30, wherein said extracellular matrix is collagenase, gelatinase, or stromelysines. 32. The method according to claim 30, wherein said patient is an animal or human patient. 33. A method of treating a patient suffering from a disease linked to metalloproteinase breakdown of the extracellular matrix comprising administering to said patient an effective amount of at least one compound according to claim 1 in an amount sufficient to inhibit the metalloproteinase breakdown of the extracellular matrix, wherein said disease is at least one selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, corneal ulceration, periodontitis, gingivitis, tumorous invasions, metastatic proliferation, atherosclerosis, AIDS, chronic inflammatory diseases of the intestine, and neurodegenerative disease. 34. The method according to claim 33, wherein said neurodegenerative disease is Alzheimer's disease or plaque sclerosis. 35. A method of inhibiting the release of TNF.alpha. from its inactive precursor comprising administering at least one compound according to claim 1 to a patient in need thereof in an amount sufficient to inhibit said release. 36. A method of treating a patient suffering from a disease linked to the release of TNF.alpha. from its inactive precursor comprising administering to said patient an effective amount of at least one compound according to claim 1 in an amount sufficient to inhibit said release, wherein said disease is at least one selected from the group consisting of rheumatoid arthritis, Crohn's disease, plaque sclerosis, septic shock, cancer, and cachexia associated with an immunodeficiency. 37. A method of treating a patient suffering from a disease linked to the production of TNF.alpha. comprising administering to said patient an effective amount of at least one compound according to claim 1 in an amount sufficient to inhibit said production, wherein said disease is at least one selected from the group consisting of cancer, psoriasis, eczema, formation of keloids, diabetic retinopathy, atherosclerosis, and inflammatory diseases. 38. Process for preparation of the compounds of formula X such as defined in claim 1, in which Y represents --CONHOH (also designated hereinafter as compounds of formula XV), with the exception that R.sub.1 is not a heteroarylalkyl group and that R.sub.2 is not a heteroarylthiomethyl group, characterized in that it comprises: an aldolization reaction from a keto-ester XXVII and alkene XXVIII (in particular in the presence of a Lewis acid such as SnCl.sub.4 at -80.degree. C. in a solvent such as CH.sub.2 Cl.sub.2 for 5 minutes to 2 hours), or from a keto-acid (in the form of a sodium salt or triethylamine) XXX and an alkene XXXI (in particular at room temperature between 1 and 10 hours in a THF--H.sub.2 O mixture) according to the following diagram: ##STR142## in which: R.sub.1 and R.sub.2 have the meaning indicated hereinabove, R.sub.10 is a possibly branched C.sub.1 -C.sub.12 alkyl, a benzyl or an optically pure compound such as mandelic acid esterified with a linear or branched C.sub.1 -C.sub.3 alkyl, or a benzyl, R.sub.11 is a linear or branched C.sub.1 -C.sub.3 alkyl, or a chlorine, R.sub.12 is sodium or triethylamine, R.sub.13 is hydrogen, a linear or branched C.sub.1 -C.sub.3 alkyl; R.sub.13 also may represent a chain forming a ring with the boron atom such as, for example, di-isopropyltartrate, the reactions are diastereoselective and lead to stereochemistry derivatives XVI if the double bond is of Z geometry for the compounds XXVIII and E geometry for the compounds XXXI, the obtaining of the aforementioned compounds of formula XV then being accomplished according to the following reaction diagram: ##STR143## in which: steps 4 and 6 are performed as in steps 1 and 3 of the reaction diagram of claim 17 respectively, and starting from compounds XVI and XIV, which leads to the compounds of formula XVII and XV respectively, step 5 consists in oxidizing the double ethylene bond of the compound of formula XVII into acid, in particular by ozonolysis (for example at -60.degree. C. in CH.sub.2 Cl.sub.2 until obtaining a steady blue color), then oxidation (in particular at room temperature with NaClO.sub.2 and NaH.sub.2 PO.sub.4 in tBuOH--H.sub.2 O for 15 hours) or directly by KMnO.sub.4 /NalO.sub.4 (in particular at room temperature in a tBuOH--H.sub.2 O mixture for 1 to 10 hours), which leads to the compound of formula XIV. 39. Process for preparation of the compounds of formula X such as defined in claim 1, in which Y represents: --SH, or a group with the formula ##STR144## or a group with the formula ##STR145## in which R.sub.4 and R.sub.5 are such as defined in claim 1, said process being performed according to the following diagram: ##STR146## in which: step 44 consists in opening an epoxide of formula L in which R.sub.1 and R.sub.2 are such as defined in claim 1, and R.sub.9 is a carboxylic acid protective group, in particular a benzyl remainder sensitive to catalytic hydrogenolysis, this opening of the epoxide L being accomplished with a nucleophile, for example a thiol protected by an R.sub.18 group compatible with R.sub.9, for example a benzyl in methanol for 1 hour at 60.degree. C., step 47 consists in deprotecting the ester LI, for example with trifluoroacetic acid as before, step 48 is identical to step 1 of the reaction diagram of claim 17, and performed starting from compound LII obtained in the preceding step, step 49 consists in deprotecting the sulfur, for example with sodium in liquid ammonia, in particular at -60.degree. C. for 5 to 15 minutes, step 45 consists in opening the epoxide L with protected hydroxylamine such as defined in step 3 of the process according to claim 17 (with, for example, R.sub.19 =benzyl or THP), step 50 consists in deprotecting the ester LV by a method compatible with R.sub.19, step 51 is identical to step 48, and performed starting from the compound LVI obtained in the preceding step, step 52 consists in reacting the hydroxylamine LVII with formic acid and acetic anhydride, in particular at a temperature of at least 100.degree. C. for 1 to 15 hours, step 53 consists in cleaving R.sub.19 on the compound LVIII with, for example, H.sub.2 Pd/C or HCl 1N depending on the structure of R.sub.19 as before, step 46 consists in opening an epoxide L with hypophosphorous acid with the formula H.sub.3 PO.sub.2, then esterification with a coupling agent such as DCC and an R.sub.4 OH group in which R.sub.4 is such as defined in claim 1, in the presence, for example, of trimethylorthoformate and tetramethylguanidine at room temperature for 5 hours, step 54 consists in treating the compound LIX with a compound with the formula ##STR147## (prepared according to the methods described in the literature) in which R.sub.6 and R.sub.7 are such as defined hereinabove, in particular in CH.sub.2 Cl.sub.2 in the presence of bis trimethylsilyl acetamide at room temperature for 5 hours, which leads to the obtaining of the compound of formula LX in which R.sub.5 represents: ##STR148## step 55 consists in cleaving the R.sub.9 ester by a method compatible with R.sub.4 as previously, step 56 is identical to step 48, and performed starting from the compound LXI obtained in the preceding step, step 57 consists in cleaving the R.sub.4 group of the compound LXII obtained in the preceding step, for example with the aid of Nal in acetone under reflux for 15 hours.

Details for Patent 6,344,457

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2017-04-22