Claims for Patent: 6,765,003

Summary for Patent: 6,765,003

Title:	3-Arylsulfonyl-2 (substituted methyl) propanoic acid derivatives as matrix metalloproteinase inhibitors
Abstract:	Compounds which are 3-arylsulfonyl-2-methyl propanoic acid derivatives of formula (I): wherein X is HO--NH-- or HO--, R1 is selected from phenyl, 4-chlorophenyl, 4-florophenyl, 4-cyanophenyl, benzamido (i.e., --NH--CO-Ph) and benzamido substituted on the terminal phenyl ring by C.sub.1 -C.sub.4 alkyl, fluoro, chloro, cyano or C.sub.1-4 alkoxy; R.sub.2 is selected from (a) --S--Ar or --S--CH.sub.2 --Ar wherein Ar is an aromatic moiety; (b) --O--Ar wherein Ar is as defined above; (c) --S-Het or --S--CH.sub.2 -Het wherein Het is a heterocyclic ring; and (d) 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolinyl; and the pharmaceutically acceptable salts thereof; have potent and selective inhibitory activity against matrix metalloproteinases (MMPs) and can thus be used in the treatment and prevention of diseases mediated by MMPs.
Inventor(s):	Mantegani; Sergio (Milan, IT), Abrate; Francesca (Milan, IT), Bissolino; Pierluigi (Pavia, IT), Cremonesi; Paolo (Milan, IT), Perrone; Ettore (Milan, IT), Jabes; Daniela (Milan, IT)
Assignee:	Pharmacia Italia, SpA (Milan, IT)
Application Number:	10/030,681
Patent Claims:	1. A compound which is a 3-arylsulfonyl-2-methyl propanoic acid derivative of formula (I): ##STR44## wherein X is HO--NH-- or HO--; R.sub.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, benzamido and benzamido substituted on the terminal phenyl ring by C.sub.1 -C.sub.4 alkyl, fluoro, chloro, cyano or C.sub.1 -C.sub.4 alkoxy; R.sub.2 is selected from: 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolidinyl, which may be optionally substituted at the carbon atom by one or two methyl, linear or branched C.sub.2 -C.sub.4 alkyl, phenyl, benzyl or hydroxymethyl groups, and at the nitrogen atom with C.sub.1 -C.sub.4 linear or branched alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 which is an isomer having the configuration depicted in formula (I'): ##STR45## wherein X, R.sub.1 and R.sub.2 are as defined in claim 1. 3. A compound according to claim 1 which is selected from: 3-[(1,1'-Biphenyl]-4-ylsulfaonyl)-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazoli dinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)methyl]propanoic acid; (2R)-3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3,4,4-trimethyl-2,5-di oxo-1-imidazolidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3,4,4-trimethyl-2 ,5-dioxo-1-imidazolidinyl)methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(4,4-dimethyl-2,5-dioxo-1-im idazolidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(4,4-dimethyl-2,5- dioxo-1-imidazolidinyl)methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(2,5-dioxo-1-imidazolidinyl) methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(2,5-dioxo-1-imida zolidinyl)-methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3-methyl-2,5-dioxo-1-imidaz olidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3-ethyl-2,5-dioxo-1-imidazo lidinyl)methyl]-propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3-butyl-2,5-dioxo-1-imidazo lidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,5-dioxo -1-imidazolidinyl)methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3-butyl-2,4-dioxo-1-imidazo lidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,4-dioxo -1-imidazolidinyl)methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(5-isopropyl-2,4-dioxo-1-imi dazolidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-2,4-dioxo-1 -imidazolidinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-3-methyl-2, 4-dioxo-1-imidazolidinyl)methyl]propanoic acid; 3-[(4'-Cyano[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(3-butyl-2,5-dioxo-1-imidazol idinyl)methyl]propanoic acid; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,5-dioxo -1-imidazolidinyl)methyl]propanamide; 3-[(4'-Chloro[1,1'-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-2,4-dioxo-1 -imidazolidinyl)methyl]propanoic acid; 3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-[(5-hydroxymethyl-2,4-diox o-1-imidazolidinyl)methyl]propanoic acid; the pharmaceutically acceptable salts thereof. 4. A process for producing a compound as defined in claim 1, starting from a compound of formula 4: ##STR46## wherein R is H or the residue of a carboxylic acid ester, R.sub.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, benzamido and benzamido substituted on the terminal phenyl ring by C.sub.1 -C.sub.4 alkyl, fluoro, chloro, cyano or C.sub.1 -C.sub.4 alkoxy; R.sub.2 is selected from: 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolidinyl, which may be optionally substituted at the carbon atom by one or two methyl, linear or branched C.sub.2 -C.sub.4 alkyl, phenyl, benzyl or hydroxymethyl groups, and at the nitrogen atom with C.sub.1 -C.sub.4 linear or branched alkyl; and n is 0 or 2, said process comprising: (A) hydrolysing a said compound of formula 4 in which R is the residue of a carboxylic and ester to give a compound of formula (I) in which X is HO--; or (B) hydrolysing and oxidising, in either order, a said compound of formula 4 in which n is 0 and R is the residue of a carboxylic acid ester, to give a compound of formula (I) in which X is HO--; or (C) activating a said compound of formula 4 wherein R is H and n is 2 to form an activated carboxy group, coupling the activated carboxy group with hydroxylamine or an O-protected derivative thereof and, if necessary, deprotecting the hydroxamic group to give a compound of formula (I) wherein X is --NHOH; or (D) submitting a said compound of formula 4 wherein R is H and n is zero to a sequence of reactions comprising oxidation at the sulphur atom, activation of the carboxy group, condensation of the activated carboxy group with hydroxylamine or an O-protected derivative thereof and, if necessary, deprotection of the hydroxamic group to form a compound of formula (I) wherein X is --NHOH, the oxidation step being conducted either before the activation step or after the condensation step; and/or (E) if desired, converting a resulting compound of formula (I) into another compound of formula (I); and/or converting a free compound into a pharmaceutically acceptable salt thereof; and/or converting a salt into a free compound. 5. A process according to claim 4 wherein the compound of formula 4 is obtained by (a) subjecting a compound of formula 2: ##STR47## wherein R is H or the residue of a carboxylic acid ester, R.sub.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, benzamido and benzamido substituted on the terminal phenyl ring by C.sub.1 -C.sub.4 alkyl, fluoro, chloro, cyano or C.sub.1 -C.sub.4 alkoxy; and n is 0 or 2 to conjugate addition by treatment with a compound of formula R.sub.2 H wherein R.sub.2 is selected from: 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolidinyl, which may be optionally substituted at the carbon atom by one or two methyl, linear or branched C.sub.2 -C.sub.4 alkyl, phenyl, benzyl or hydroxymethyl groups, and at the nitrogen atom with C.sub.1 -C.sub.4 linear or branched alkyl; (b) treating a compound of formula 3: ##STR48## wherein R and R.sub.2 are as defined as above, with a thiol of formula: ##STR49## to obtain a compound of formula 4 in which n is zero. 6. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active principle, the compound as defined in claim 1. 7. A method of treating a mammal, including a human, comprising administering the compound claimed in claim 1, to said mammal, including a human, in need thereof. 8. A method for treating a disease in a mammal, including a human, comprising administering an effective amount of the compound as claimed in claim 1, to said mammal, including a human, in need thereof, wherein said disease is a disease mediated by a matrix metalloproteinase. 9. The method as claimed in claim 8, wherein the matrix metalloproteinase is selected from the group consisting of gelatinase (MMP-2), a membrane MMP involved in gelatinase activation (MMP-14), a stromelysin (MMP-3 or MMP-10), collagenase (MMP-13) and neutrophyl collagenase (MMP-8). 10. A method for the prevention of a disease in a mammal, including a human, comprising administering the compound claimed in claim 1, to said mammal, including a human, in need thereof, wherein said disease is a disease mediated by a matrix metalloproteinase. 11. The method as claimed in claim 10, wherein the matrix metalloproteinase is selected from the group consisting of gelatinase (MMP-2), a membrane MMP involved in gelatinase activation (MMP-14), a stromelysin (MMP-3 or MMP-10), collagenase (MMP-13) and neutrophyl collagenase (MMP-8). 12. The method as claimed in claim 8, wherein the disease is selected from the group consisting of tumor growth, tumor metastasis, rheumatoid arthritis, oseoarthritis, ophthalmic disease, cardiovascular disease, periodontal disease, multiple sclerosis and Alzheimer's disease. 13. The method as claimed in claim 12, wherein the disease is selected from the group consisting of tumor growth, tumor metastasis, rheumatoid arthritis, oseoarthritis, ophthalmic disease, cardiovascular disease, periodontal disease, multiple sclerosis and Alzheimer's disease.

Details for Patent 6,765,003

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2019-07-14