AU2003212307A1

AU2003212307A1 - Oxo-azabicyclic compounds

Info

Publication number: AU2003212307A1
Application number: AU2003212307A
Authority: AU
Inventors: Bernard Gaudilliere; Henry Jacobelli; Catherine Kostlan; Jack Li; Wen-Song Yue
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2002-03-08
Filing date: 2003-03-06
Publication date: 2003-09-22
Also published as: CO5601020A2; TNSN04169A1; WO2003076417A3; JP2005526070A; CN1738806A; CA2478706A1; EP1492775A2; AP2004003125A0; SV2003001495A; PA8568501A1; EA200401053A1; MXPA04008681A; AR039562A1; WO2003076417A2; OA12782A; NO20044041L; PL372622A1; BR0308280A; ECSP045278A; UY27700A1

Description

I PCT/EP 03/02277 A. CLASSIFICATION OF SUBJECT MATTER IPC 7 -C07D239/91 'CO7D471/04 -A61K31/5025 A61K31/505 -A61P29/0O 'CO7D401/06 -C07D401/10 , C07D401/12 //(C07D471/04,239:00, 221:00),(C07D401/06,239:00,233:OO Y, (C07D401/10,257:00,239:00), According to International Patent Classification (IPC) orto both national classification and IPC B. FIELDSSEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 7 CO7D A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X LIVERTON N J ET AL: "Nonpeptide 1,30-33 glycoprotein IIb/IIIa inhibitors: substituted quinazolinediones and quinazolinones as potent fibrinogen receptor antagonists" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 5, 3 March 1998 (1998-03-03), pages 483-486, XP004136889 ISSN: 0960-894X Compound 2, abstract MV Further documents are listed in the continuation of box C. j Patent family members are listed in annex. SSpecial categories of cited documents: "1 later document published after the international filing date or priority date and not in conflict with the application but A' document defining the general state ofr the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention "E' earlier document but published on or after the international X. document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to *L' document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another .Y. document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the "O' document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu other means ments, such combination being obvious to a person skilled P" document published prior to the international filing date but in the art. later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 21 May 2003 04/06/2003 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Tx. 31 651 epo ni, Fax: (+31-70) 340-3016 GSS, I Formn PCT/ISA/210 (second sheet) (July 1992)

Claims

1- A compound selected from those of formula (I): X I G 1 \ (R)m (Z 1 )~ N - R (I) G 2 3X O 0 wherein: 5 * X 1 , X 2 , and X 3 , independently of each other, represent a nitrogen atom or a group -CR 3 in which R 3 represents a group selected from hydrogen, (C 1 -C 6 )alkyl, amino, mono(Ci C 6 )alkylamino, di(CI-C 6 )alkylamino, hydroxy, (CI-C 6 )alkoxy, and halogen, with the proviso that not more than two of the groups XI, X 2 and X 3 simultaneously represent a nitrogen atom, 10 * G, represents a group selected from those of formulae (i/a) and (i/b): R4 R0, R4 N-, N 2 R 5 (i/a) (i/b) in which: - the carbon atom with number 2 is attached to the group N-Ri in the ring, - R 4 and R 5 , identical or different, independently of each other, represent a group 15 selected from hydrogen, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, cycloalkyl, cycloalkyl(Ci-C 6 )alkyl, heteroaryl, heteroaryl(C 1 I-C 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(CI 1 -C 6 )alkyl, - R 6 represents a group selected from: ,/ hydrogen, trifluoromethyl, OR 7 , NR 7 Rs, in which R 7 and Rs, identical or 20 different independently of each other, represent hydrogen or (C 1 -C 6 )alkyl, / (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(Ci-C 6 )alkyl, cycloalkyl(CI-Cs)alkyl, heteroaryl, heteroaryl(C 1 I-C 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(C 1 -C6)alkyl, these groups being optionally substituted by one or WO 03/076417 PCT/EP03/02277 65 more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(CI-C 6 )alkylamino, di(C 1 -C 6 )alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(Ci-C 6 )alkyl, (CI-C 6 )acyl, -C(=O)OR 7 , -OR 7 and -SR7, in which R 7 is as 5 defined hereinbefore, SG 2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)n in which nl represents an integer from 0 to 2 inclusive, and a group of formula (i/c): 2 (i/c) Y 1 10 in which the carbon atom with number I is attached to the bicycle of the compound of formula (I), Y, represents a group selected from oxygen, sulphur, -NH and -N(C 1 -C 6 )alkyl, and Y 2 represents a group selected from oxygen, sulphur, -NH and -N(C 1 I-C 6 )alkyl, * n represents an integer from 0 to 6 inclusive, * ZI represents -CR 9 RIo, wherein R 9 and Ro 10 , identical or different independently of each 15 other, represent a group selected from hydrogen, (C 1 -C 6 )alkyl, trihalogeno(Cl-C6)alkyl, halogen, -OR 7 , -SR 7 , and -C(=O)OR 7 , in which R 7 is as defined hereinbefore, amino, mono(CI-C 6 )alkylamino, di(Ci-C 6 )alkylamino in which each alkyl moiety is identical or different independently of each other, and - wherein when n is greater than or equal to 2, the hydrocarbon chain ZI optionally 20 contains one to two isolated or conjugated multiple bonds, -and/or wherein when n is greater than or equal to 2, one of said -CR 9 Ro may optionally be replaced with a group selected from oxygen, S(O)ni in which ni is as defined hereinbefore, -NH and -N(C 1 -C 6 )alkyl, * A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, 25 these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6 membered monocycle, WO 03/076417 PCT/EP03/02277 66 * R 1 represents a group selected from: - hydrogen, - (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, these groups may be optionally 5 substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(CI-C6)alkyl, cycloalkyl, -C(=O)NR 7 Rs, -C(=O)ORs, ORs, SRs, in which R 7 and Rs, which may be identical or different independently of each other, represent hydrogen or (C 1 C 6 )alkyl, 10 - and the group of formula (i/d): (G )q aB- (Z 2 (i/d) / in which p is an integer from 0 to 8 inclusive, , Z 2 represents -CR IRI 2 wherein R 1 and R 12 , identical or different independently of each other, represent a group selected from hydrogen, (C 1 -C 6 )alkyl, phenyl, 15 trihalogeno(CI-C6)alkyl, halogen, amino, OR 7 , SR 7 and -C(=O)OR 7 in which R 7 represents hydrogen or (CI-C 6 )alkyl, and - wherein when p is greater than or equal to 2, the hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds, - and/or wherein n is greater than or equal to 2, one of said -CRIlR 12 may optionally 20 be replaced with a group selected from oxygen, S(O)ni in which ni is as defined hereinbefore, -NH, -N(Cl-C 6 )alkyl, and carbonyl, / B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle, 25 / q is an integer from 0 to 7 inclusive, WO 03/076417 PCT/EPO3/02277 67 V the group(s) G 3 , which may be identical or different independently of each other, is (are) selected from (C 1 -C 6 )alkyl, halogen, CN, NO 2 , CF 3 , OCF 3 , -(CH 2 )kNRI 3 RI 4 , -N(R 13 )C(=O)R 14 , -N(R 13 )C(=O)OR 14 , -N(Ri 3 )SO 2 RI 4 , -N(SO 2 RI3)2, -OR 13 , -S(O)kRI 3 , -SO 2 -N(R 1 3 )-(CH 2 )k2-NR 14 RI 5 , -(CH 2 )kSO 2 NRI 3 R 14 , 5 -X 4 (CH 2 )kC(=O)OR 1 3 , -(CH 2 )kC(=O)OR 3 , -C(=O)O-(CH 2 )k 2 -NR 13 R 4 , -C(=O)O-(CH 2 )k 2 -C(=O)OR6, -X 4 (CH 2 )kC(=O)NR1 3 R 1 4 , -(CH 2 )kC(=O)NRI 3 R 14 , -R 1 7 -C(=O)OR 1 3 , -Xs-R 1 s, and -C(=O)-R, 9 -NR13RI 4 in which: - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a 10 hydrogen atom or a (CI-C 6 )alkyl group, - k is an integer from 0 to 3 inclusive, - kl I is an integer from 0 to 2 inclusive, - k2 is an integer from I to 4 inclusive, - R 13 , R 1 4 and R 1 5 , which may be identical or different independently of each 15 other, are selected from hydrogen and (CI -C 6 )alkyl, - R 1 6 represents a group selected from (CI-C 6 )alkyl, -R 1 9 -NR 1 3 Rl 4 , -RI 9 -NR 1 3 -C(=O)-R 19 -NRI 4 R 15 , and -C(=O)O-RI 9 -NR 1 3 R 1 4 in which Rt 9 represents a linear or branched (CI-C 6 )alkylene group, and R 13 , R 14 and R 15 are as defined hereinbefore, 20 - R 17 represents a (C 3 -C 6 )cycloalkyl group, - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C 1 -C 6 )alkyl group, - R 1 8 represents a group selected from : WO 03/076417 PCT/EP03/02277 68 o 5- or 6-menbered monocycle aryl, heteroaryl, which is optionally substituted by one or more groups, which may be identical or different, selected from (CI C 6 )alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR 7 wherein R 7 represents hydrogen or (Cl-C 6 )alkyl, 5 o and 5- or 6-menbered monocycle cycloalkyl, heterocycloalkyl, which is optionally substituted by one or more groups, which may be identical or different, selected from (Cl-C 6 )alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR 7 wherein R 7 represents hydrogen or (C1 -C 6 )alkyl, 10 * m is an integer from 0 to 7 inclusive, * the group(s) R 2 , which may be identical or different independently of each other, is (are) selected from (CI-C 6 )alkyl, halogen, -CN, NO 2 , SCF 3 , -CF 3 , -OCF 3 , -NR 7 R 8 , -OR 8 , SR 8 , -SORs, -S0 2 R 8 , -(CH 2 )kSO 2 NR 7 Rs, -X 7 (CH 2 )kC(=O)OR8, -(CH 2 )kC(=O)ORs, -X 7 (CH 2 )kC(=O0)NR7Rs, -(CH 2 )kC(=O)NR 7 Rg, and -X 8 -R 2 0 in which: 15 - X 7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (CI-C 6 )alkyl, - k is an integer from 0 to 3 inclusive, - R 7 and R 8 , which may be identical or different independently of each other, are selected from hydrogen and (Cz-C 6 )alkyl, 20 - X 8 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (CI-C 6 )alkyl group, - R 2 0 represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may 25 be identical or different, selected from (C 1 -C 6 )alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, WO 03/076417 PCT/EPO3/02277 69 optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof, it being understood that when no specification are described: - an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated, - a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, 10 - a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character, - and a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, 15 sulfur, and nitrogen.

2- A compound according to claim 1 characterized in that: SG 2 represents a group selected from C=O, C=S, S(O)ni in which nI represents an integer from 0 to 2 inclusive, or a group of formula (i/c): Y2 (i/c) Y1 20 in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y 1 represents a group selected from oxygen, sulphur, -NH and -N(CI-C 6 )alkyl, and Y 2 represents a group selected from oxygen, sulphur, -NiH and -N(C 1 -C 6 )alkyl, * Xi, X 2 , X 3 , G 1 , n, Z 1 , A, R 1 , m and R 2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the 25 pharmaceutically acceptable salts thereof.

3- A compound according to Claim 1 characterized in that: * G 2 represents a carbon-carbon triple bond, WO 03/076417 PCT/EP03/02277 70 * n represents an integer from 1 to 6 inclusive, * Xt, X 2 , X 3 , G 1 , ZI, A, RI, m and R 2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof. 5

4- A compound according to claim 1 characterized in that: * G 2 represents a carbon-carbon triple bond, * n is zero, * Z 1 is absent, * A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these 10 groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle, * X, X 2 , X 3 , GI, R 1 , m and R 2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof. 15

5-A compound according to claim 1 characterized in that: * G 2 represents a carbon-carbon triple bond, * n is zero, * Z 1 is absent, * A represents a phenyl group, 20 * R, represents a hydrogen atom or a group of formula (i/d): (GB (Z _)_ (i/d) ( 3 )q ( 2 )p, / in which p is an integer from 0 to 8 inclusive, / Z 2 represents -CR 1 R 1 2 wherein R 1 1 and R 12 , identical or different independently of each other, represent a group selected from hydrogen, (CI-C 6 )alkyl, phenyl, 25 trihalogeno(Ci-C6)alkyl, halogen, amino, OR 7 , SR 7 and -C(=O)OR 7 in which R 7 represents hydrogen or (C 1 -C 6 )alkyl, and - wherein when p is greater than or equal to 2, the hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds, WO 03/076417 PCT/EP03/02277 71 - and/or wherein n is greater than or equal to 2, one of said -CR 1 R 12 may optionally be replaced with a group selected from oxygen, S(O)n in which nl is as defined hereinbefore, -NH, -N(CI-C 6 )alkyl, and carbonyl, / B represents a phenyl group, 5 V/ q is an integer from 1 to 7 inclusive, N the group(s) G 3 , which may be identical or different independently of each other, is (are) selected from -(CH 2 )kNR1 3 RI4, -N(R 13 )C(=0)OR 14 , -N(R13)SO2RI4, -N(SO 2 RI3)2, -S(O)klRI3, -S0O 2 -N(RI 3 )-(CH 2 )k2-NR14RI5, -(CH 2 )kSO 2 NRI 3 R l 4 , -X 4 (CH 2 )kC(=O)OR13, -(CH 2 )kC(=O)ORI3, -C(=O)O-(CH 2 )k 2 -NR13R4, 10 -C(=O)O-(CH 2 )k 2 -C(=O)ORI6, -X 4 (CH 2 )kC(=O)NRjI 3 RI 4 , -(CH 2 )kC(=O)NRI 3 R 14 , -R 1 7 -C(=O)OR13, -Xs-Rs, -C(=O)-R 9 -NR 1 3 R 1 4 and -X 6 -R 2 1 in which: - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C 1 -C 6 )alkyl group, 15 - k is an integer from 0 to 3 inclusive, - kl is an integer from 1 to 2 inclusive, - k2 is an integer from 1 to 4 inclusive, - R 1 3 , R 14 and Rs 15 , which may be identical or different independently of each other, are selected from hydrogen and (C 1 -C 6 )alkyl, 20 - R 16 represents a group selected from (CI-C 6 )alkyl, -R 1 9 -NRI 3 R 4 , -R,9-NR 13 -C(=O)-Rl9-NR14Rts, and -C(=0)O-R 9 -NR 13 R 1 4 in which R 19 represents a linear or branched (C 1 -C 6 )alkylene group, and R 13 , R 14 and R 15 are as defined hereinbefore, - R 17 represents a (C 3 -C 6 )cycloalkyl group, 25 - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C 1 -C 6 )alkyl group, - Rig represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 30 6- membered monocycle, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from WO 03/076417 PCT/EP03/02277 72 (CI-C 6 )alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR 7 wherein R 7 represents hydrogen or (C -C 6 )alkyl, - X 6 represents a group selected from -CH 2 -, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or 5 (CI-C 6 )alkyl group, - R 21 represents a phenyl group which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (Cl-C 6 )alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR 7 wherein R7 represents hydrogen or (C 1 -C 6 )alkyl, 10 - X 1 , X 2 , X 3 , G 1 , m and R2 are as defined in formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

6- A compound according to Claim 1 characterized in that: R, represent a group of formula (i/d): 15 (G,) B (Z (ild) wherein Z 2 , p, B, G 3 and q are as defined in the compound of formula (I), optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

7- A compound according to Claim 6 characterized in that Z 2 represents a group -CR 1 R 1 2 20 in which Rl and R12 represents an hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

8- A compound according to claim 6 characterized in that p is one, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the 25 pharmaceutically acceptable salts thereof. WO 03/076417 PCT/EPO3/02277 73

9- A compound according to claim 6 characterized in that B represents a phenyl group, q is equal to 0 or 1, and G 3 , when it is present, represents a group selected from OR 13 , halogen, S(O)klR13 and (CH 2 )kC(=O)OR 13 in which R 13 represents an hydrogen atom or a (Cl C 6 )alkyl group, k is zero, and ki is two, 5 optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

10- A compound according to claim 1 characterized in that G 1 represent a group of formula (i/a) in which R 4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which R 4 and Rs, identical, represent each a hydrogen atom or a methyl group, and R 6 10 represents a hydrogen atom or a methyl group, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof

11 - A compound according to claim I characterized in that X 1 represents a group -CR 3 in which R 3 represents a hydrogen atom, X 2 represents a nitrogen atom or a group -CR 3 in 15 which R 3 represents a hydrogen atom, and X 3 represents a group -CR 3 in which R 3 represents a hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

12- A compound according to claim 1 characterized in that G 2 represent a carbon-carbon 20 triple bond or a group of formula (i/c) in which Y 1 represents an oxygen atom, and Y 2 represents a group -NH, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.

13- A compound according to claim 1 characterized in that ZI represents -CR 9 Ro 0 in which 25 R 9 and R 0 io represent each a hydrogen atom, and n is one, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof WO 03/076417 PCT/EPO3/02277 74

14- A compound according to claim 1 characterized in that A represents a group selected from phenyl and pyridyl, m is equal to zero or one, and R 2 represents a (C 1 I-C 6 )alkoxy group or a hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the 5 pharmaceutically acceptable salts thereof.

15- A compound according to claim 1, which is selected from: - 3-(4-methoxy-benzyl)-4-oxo- 3 ,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy benzylamide - 3-(4-methoxy-benzyl)-2-methyl- 4 -oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4 10 methoxy-benzylamide, hydrochloride - 3-(4-methoxy-benzyl)- 1 -methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 3-(4-methoxy-benzyl)-1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinazoline- 6 carboxylic acid 4-methoxy-benzylamide 15 - 4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo-l1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid - 4-[6-(4-methoxy-benzylcarbamoyl)- 1 -methyl-4-oxo-1,4-dihydro-2H-quinazolin- 3 ylmethyl]-benzoic acid methyl ester 4-[6-(4-methoxy-benzylcarbamoyl)- 1 -methyl-4-oxo-1,4-dihydro-2H-quinazolin- 3 20 ylmethyl]-benzoic acid, 3-(4-fluoro-benzyl)- 4 -oxo- 3 ,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy benzylamide 3-(4-methanesulfonyl-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4 methoxy-benzylamide 25 4-Oxo-3-[4-(pyrrolidine-1-sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid, - 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy pyridin-4-ylmethyl)-amide, 30 - 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[ 3 ,4-d]pyrimidine-6-carboxylic acid 3 methoxy-benzylamide, WO 03/076417 PCT/EP03102277 75 -3 -(3-fluoro-benzyl)-4-oxo-3 ,4-dihydro-pyridol3 ,4-d]pyrimidine-6-carboxylic acid 4 methoxy-benzylamnide -3-(3,4-Difluoro-benzyl)-4-oxo-3 ,4-dihyclro-quinazoline-6-carboxylic acid (2-methoxy pyridin-4-ylmethyl)-amide and 5 - 3 -(3 ,4-Difluoro-benzyl)-4-oxo-3 ,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy benzylamide.

16- A compound according to claim 1, which is selected from: - 3-(4-fluorobenzyl)-6-(3 -phenyl-pro- 1-ynyl)-3 H-quinazolin-4-one, - methyl 4-[4-oxo-6-(3 -phenyl-prop- 1 yny1)-4H-quinazolin-3-ylmethy1II-beflzoate, 10 - 4-[4-oxo-6-(3-phenyl-prop- 1-ynyl)-4H-quinazolin-3-ylmethyl] -benzoic acid, - 3-(4-fluorobenzyl)-6-( 3 -phenyl-prop- 1 yny1)-3H-pyridoI3 ,4-d]pyrimidin-4-one, - methyl 4-[6-(3-phenyl-prop- 1-ynyl)-4-oxo-4H-pyrido [3,4-dI~pyrimidin-3-ylmethyl] benzoate, - 4-[6-(3-phenyl-prop-1 -ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidifl3 -ylmethyl]-benzoic 15 acid, - 4-[4-oxo-6-(3 -phenyl-prop- 1 ynyl)-4H-quinazoline-3-ylmethyl]-belzoic acid, - 4- {6-[3-(4-methoxy-pheny1)-prop-1I-ynyll-4-oxo-4H-quinazolifle- 3 -ylmcthyl} -benzoic acid, - 4-[4-oxo-6-(3 -phenyl-prop- 1-yy)4-unaoie3ymthl-ezm 20 - 3-[(3 ,5-difluoro-4-hydroxy)-benzy1F&{-3phel-lprop-1-ynyl)-3H-quinazolin- 4 -one - 4-[6-(3-Imidazol- 1-yl-prop- 1-yy)4oo4-qiaoi--lmtil-ez acid - 4- [4-Oxo-6-(3 -phenyl-prop- 1 ynyl)-4H-quinazolin-3-ylmethyl1 -benzenesulfonamide - 4-[4-Oxo-6-(3 -phenyl-prop-1-l) Hqiaoi--lmty]bnoirl - 3-(-hoobezl--4-hnlbt1 -ynyl)-3H-quinazolifl- 4 -ofle 25 - 3 -(3-Chloro-benzyl)-6-( 3 -phcnyl-prop-1 -yny1)-3H-quinazolifl- 4 - ofle - 4-[4-Oxo-6-(3-pyrazol-1I y-prop-1-ynyl)-4H-quinazolifl 3 -ylmethyl]-benzoic acid - 6-(3-Phenyl-prop-1I-ynyl)- 3 -[4-(1 ttao--l)bny]3-uiaoi--n - 3 -(3,4-Difluoro-benzyl)6-[3(pyrdin4-yloxy)prop-1-ynyl] -3L1-quinazolin-4-ofle - 3 -( 3 ,4-Difluoro-bezlZ)63(4-methoxy-phenyl)prop-1-ynyl]-3H-quiflazolinA4ofle 30 - N-14[ xo6(-pey po--ynyl)-4H-quinazolil- 3 -ylmnethyll -phenyl} -acetamide - 3 -(3,4-Difluoro-benzyl)6-(3phenylprop-1-yny1)-3H-quinazolifl- 4 -ofle WO 03/076417 PCT/EP03/02277 76 - 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop- 1 -ynyl]-3H-quinazolin-4-one - 6-(3-Phenyl-prop-1-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one and - 6-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-3-pyridin-4-ylmethyl-3H-quinazolin- 4 -one. 5

17- A compound according to claim 1, which is selected from: - Methyl 4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl] benzoate - 4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid - 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl] benzoic acid - 4- {6-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-4-oxo-4H-quinazoline-3-yhnethyl} -benzoic 10 acid - 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6 carboxylic acid 3 methoxy-benzylamide - 3-(3-Fluoro-benzyl)-4-oxo- 3 ,4-dihydro-pyrido[3,4-d]pyrimidine-6 carboxylic acid 4 methoxy-benzylamide 15 - 4-[6-(3-Imidazol-1-yl-prop-1-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid - 4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide - 4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile - 6-(3-Phenyl-prop-1-ynyl)-3-[4-(1H-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one - 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-1-ynyl]-3H-quinazolin-4-one 20 - 3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-3H-quinazolin-4-one - N-{4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazoin-3-ylmethyl]-phenyl}-acetamide - 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-3H-quinazolin- 4 -one - 6-(3-Phenyl-prop-1-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one and - 6-[3-(4-Methoxy-phenyl)-prop-1-ynyl]- 3 -pyridin-4-ylmethyl-3H-quinazolin-4-one. 25

18- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (II): ,,X I NH2 HO X OT xY O y 1 0 WO 03/076417 PCT/EP03/02277 77 in which X 1 , X 2 , X 3 , and Y 1 have the same definitions as the compound of formula (I) in claim 1, and T represents a group (Ci-C 6 )alkyl, compound of formula (II) which is treated with a compound of formula (III): (R 2 )m A (Z1,)(iI) 5~Y2H in which Z 1 , Y 2 , R2, A, n and m have the same definitions as the compound of formula (I), by activating the acid function with an activator, in the presence of diisopropylethylamine and a solvent, to yield the compound of formula (IV) : < ;Xl NH 2 x 2 (IV) Y O (R-)m- A- (Z 1 ) 2 r 3 y 1 0 10 in which X 1 , X 2 , X 3 , Y 1 , T, Z 1 , Y 2 , R2, A, n and m are as defined hereinbefore, compound of formula (IV) in which the ester group is hydrolyzed and the subsequently compound obtained is then treated with an activator in the presence of a base and a primary amine with the general formula Ri-NH 2 in which R, is as defined in the compound of formula (I), 15 to yield the compound of formula (V): X2 H (V) (R2)m (ZX)n/X,NR Y1 O in which X 1 , X 2 , X 3 , Y 1 , Y 2 , Z 1 , R2, R 1 , A, n and m are as defined hereinbefore, which compound of formula (V) is treated: * either with triethyl orthoformate under heating condition, to yield the compound of 20 formula (1/a), which is a particular case of the compound of formula (I): WO 03/076417 PCT/EP03/02277 78 XI N X (I/a) (R 2 ). A (Z,)n-/ 2 X3 NR, Yi O in which Xi, X 2 , X 3 , YI, Y 2 , ZI, R 2 , RI, A, n and m are as defined hereinbefore, * or under heating condition in the presence of acid, with a compound of formula (VI): R4) R4 (VI) 0 0 5 in which R 4 has the same definition as the compound of formula (I), to yield the compound of formula (Ib), which is a particular case of the compound of formula (I): X21 N R 4 (1/b) xX N' (I/b) -(ZI)n-, Y2 \X3 , R, 1Y O (R2)mD Al y1 0 in which X 1 , X 2 , X 3 , Y 1 , Y 2 , ZI, R 2 , R 1 , R 4 , A, n and m are as defined hereinbefore, 10 * or with a compound of formula (VII) in basic condition: R4" R s (VII) O in which R 4 and R 5 have the same definition as the compound of formula (I), to yield the compound of formula (I/c), which is a particular case of the compound of formula (I): H X 2R 5 (I/c) (R 2 )m (Zl)n/ 2 1Y O 15 in which X 1 , X 2 , X 3 , Y 1 , Y 2 , Z 1 , R2, R 1 , R4, R 5 , A, n and m are as defined hereinbefore, WO 03/076417 PCT/EP03/02277 79 which compound of formula (I/c) is optionally treated with a hydride, in the presence of a compound of formula (VIII): R 6 -Hal (VIII) in which R 6 has the same definition as the compound of formula (I), 5 to yield the compound of formula (I/d), which is a particular case of the compound of formula (I): R 16 X N R 4 2 IR (I/d) (- Z Y 2 - N '- 5 . Y (R 2 )m (Z 1 )n/~ 2 X R 1 in which X 1 , X 2 , X 3 , Y 1 , Y 2 , Z 1 , R 2 , Ri, R 4 , Rs, R 6 , A, n and m are as defined hereinbefore, compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of the 10 invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof. 15

19- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (X): x 1 N H (X) Hal X 0 in which X 1 , X 2 , and X 3 have the same definitions as the compound of formula (I), and Hal represents a halogen atom, 20 which compound of formula (X) is treated in a first step with a derivate of phosgene to yield the compound of formula (XI): WO 03/076417 PCT/EP03/02277 80 H ,-I N 0 2 (XI) Hal Xz 0 in which X 1 , X 2 , X 3 and Hal are as defined hereinbefore, which compound of formula (XI) is treated in basic medium with a primary amine of 5 general formula Ri-NH 2 in which R 1 has the same definition as in the compound of formula (I), to yield the compound of formula (XII): X-1 11NH2 X -H (Xi) Hal X 3 R, O 0 in which X1, X 2 , X 3 , RI and Hal are as defined hereinbefore, 10 which compound of formula (XII) is treated: * either with triethyl orthofonrmate under heating condition, to yield the compound of formula (XIII/a) : 2 (XIII/a) \Ns Hal X 3 R, O 0 in which Xi, X 2 , X 3 , Ri and Hal are as defined hereinbefore, 15 * or under heating conditions in the presence of an acid, with a compound of formula (VI): R4 ) R 4 (VI) 0 0 in which R 4 has the same definition as the compound of formula (I), to yield the compound of formula (XIII/b) : WO 03/076417 PCT/EPO3/02277 81 X N R4 X2 (XIII/b) Hal X3 RI O in which X 1 , X 2 , X 3 , Hal, RI, and R 4 are as defined hereinbefore, * or with a compound of formula (VII) in basic conditions: R4" R5 (VII) O 5 in which R 4 and R 5 have the same definition as the compound of formula (I), to yield the compound of formula (XIII/c) : H xXj N- R4 2 R 5 (XIII/c) Ns Hal X " R 1 O 0 in which X 1 , X 2 , X 3 , Hal, R 1 , R4, and R 5 are as defined hereinbefore, which compound of formula (XIII/c) is optionally treated with a hydride, in the presence of 10 a compound of formula (VIII): R 6 -Hal (VIII) in which R 6 has the same definition as the compound of formula (I), and Hal is a halogen atom, to yield the compound of formula (XIII/d), which is a particular case of the compound of 15 formula (I): R '16 I N R4 X2 Y R5 (XIII/d) Hal 3 R O in which X0, X2, X3, Hal, R, R4, R and R are as defined hereinbefore, in which X 1 , X 2 , X 3 , Hal, RI, R 4 , Rs and R 6 are as defined hereinbefore, WO 03/076417 PCT/EP03/02277 82 all compounds of formulae (XIII/a), (XIII/b), (XIII/c) and (XIII/d) constitute the compound of formula (XIII/e): x-X G 1 2 'N-RI (XIII/e) Hal /X3 " O in which X 1 , X 2 , X 3 , Hal, R 1 and G 1 are as defined in the compound of formula (I), 5 compound of formula (XIII/e) which is treated under conditions of palladium-catalyzed alkynylation with a compound of formula (XIV): (R 2 )m (Z SnBu(XIV) SnBu 3 in which Z 1 , R 2 , A, n and m have the same definitions as the compound of formula (I), to yield the compound of formula (I/e), which is a particular case of the compound of 10 formula (I): xXl G 1 2 N-R x 1 (I/e) (R2)mXA (Z 0 in which XI, X 2 , X 3 , RI, G 1 , Z 1 , R 2 , A, n and m have the same definitions as the compound of formula (I), compounds of formula (I/e) constitute some compounds of the invention, which are 15 purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.

20- A process for the preparation of compounds according to claim 1 wherein it is used as 20 starting material a compound of formula (XIII/e) WO 03/076417 PCT/EPO3/02277 83 1-X 1 G 1 2 'N-R, (XIII/e) Hal- O 0 in which X 1 , X 2 , X 3 , R 1 and G 1 are as defined in the compound of formula (I), and Hal is a halogen atom, compound of formula (XIII/e) which is condensed, in the presence of 5 dichlorobis(triphenylphosphine)palladium, cupper iodide and N,N'-diisopropylethylamine in dimethylfornamide, on a compound of formula (XV) : (R 2 ) (Z H(XV) in which ZI, R 2 , A, n and m have the same definitions as the compound of formula (I), to yield the compound of formula (I/e), which is a particular case of the compound of 10 formula (I): N-Re .x 3 (R)m A (Z 1 0 in which X 1 , X 2 , X 3 , R 1 , G 1 , Z 1 , R 2 , A, n and min have the same definitions as the compound of formula (I).

21 - A process for the preparation of compounds according to claim 1, which uses as 15 starting material a compound of formula (XIII/e): X-X -. GI 2Qz i 'GN-RI (XIII/e) Hal x3 O 0 in which X 1 , X 2 , X 3 , R 1 and GI are as defined in the compound of formula (I), and Hal is a halogen atom, WO 03/076417 PCT/EPO3/02277 84 compound of formula (XIII/e) which is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent and a catalytic amount of palladium, to yield the compound of formula (XVI): 71G X N-R (XVI) MeO X 3 O O 5 in which X 1 , X 2 , X 3 , R, and G 1 are as defined in the compound of formula (I), compound of formula (XVI) which is hydrolyzed under basic medium to yield the compound of formula (XVII): -X G HO , N-R, (XVII) HO" X 3 O 0 10 in which X 1 , X 2 , X 3 , RI and Gi are as defined in the compound of formula (I), compound of formula (XVII) which is condensed under basic medium in the presence of a Mukayama reagent, on the compound of formula (XVIII): (R 2 )m A (Z 1 ,2W 15 in which ZI, R 2 , A, n and m have the same definitions as the compound of formula (I), to yield the compound of formula (I/f), which is a particular case of the compound of formula (I): X X IN ' A - ~n-'X r 0 0 20 in which X 1 , X 2 , X 3 , ZI, R 2 , R 1 , A, n and m are as defined hereinbefore, compounds of formula (/f) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional WO 03/076417 PCT/EPO3/02277 85 separation technique, and which are converted, where appropriate, into addition salts thereof with a pharnmaceutically-acceptable acid or base, or into N-oxide thereof.

22 - A process for the preparation of compounds according to claim 1, which uses as starting material a compound of formula (XIX) : NH2 5 Hal2 (XIX) Hal C2H in which Hal represents a halogen atom, compound of formula (XIX) which is heated in the presence of formamidine acetate in a polar solvent, to yield compound of formula (XX): O N N (XX) 10 Hal N in which Hal is as defined hereinbefore, compound of formula (XX) which is treated in basic medium with a compound of formula R 1 -Hal, in which R 1 is as defined in the compound of formula (I) and Hal represents a 15 halogen atom, to yield the compound of formula (XXI): O N N, RI Hal Ne (XX )) in which Hal and R 1 are as defined hereinbefore, compound of formula (XXI) which is reacted with carbon monoxide under basic medium 20 in the presence of an alcoholic solvent and a catalytic amount of palladium, to yield the compound of formula (XXII): WO 03/076417 PCT/EPO3/02277 86 O N NRI MeO (XXII) MeO\ N O in which R 1 is as defined hereinbefore, compound of formula (XXII) which is condensed, in the presence of trimethylaluminium, 5 with a compound of formula (XVIII): (R)m (Z) in which Zi, R 2 , A, n and m have the same definitions as the compound of formula (I), to yield the compound of formula (I/g), which is a particular case of the compound of 10 formula (I): N H (1/g) HN~ (R 2 ) (Z 1 )n N \RI O O in which ZI, R 2 , RI, A, n and m are as defined hereinbefore, compounds of formula (I/g) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are 15 separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.

23- A method for treating a living body afflicted with a disease where the inhibition of type -13 matrix metalloprotease is involved, comprising the step of administering to the living 20 body an amount of a compound of claim 1 which is effective for alleviation of said conditions.

24- A method for treating a living body afflicted with a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel WO 03/076417 PCT/EP03/02277 87 disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration, and cancers, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for alleviation of said conditions. 5

25- A pharmaceutical composition comprising as active ingredient an effective amount of a compound as claimed in claim 1, alone or in combination with one or more pharmaceutically-acceptable excipients or carriers.

26- A pharmaceutical composition useful in the method of Claim 23 comprising as active ingredient an effective amount of a compound as claimed in claim 1, together with one or 10 more pharmaceutically-acceptable excipients or carriers.

27- A pharmaceutical composition useful in the method of Claim 23 comprising as active ingredient an effective amount of a compound as claimed in claim 16, together with one or more pharmaceutically-acceptable excipients or carriers.

28- A pharmaceutical composition useful in the method of Claim 23 comprising as active 15 ingredient an effective amount of a compound as claimed in claim 17, together with one or more pharmaceutically-acceptable excipients or carriers.

29- Use of a compound according to Claim 1, for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of type-13 matrix metalloproteases. 20

30- Use according to Claim 29, characterized in that the disease is arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration, and cancers.

31- Use according to Claim 30, characterized in that the disease is arthritis. WO 03/076417 PCT/EPO3/02277 88

32- Use according to Claim 30, characterized in that the disease is osteoarthritis.

33- Use according to Claim 30, characterized in that the disease is rheumatoid arthritis.