Patent DE-10104597-A1 (DE)
Title: New (hetero)aryl-substituted amide or amine derivatives, are thrombin and factor Xa inhibitors useful as antithrombotic agents, e.g. for treating deep vein thrombosis or preventing reocclusion after angioplasty
Inventor: RIES UWE
IPC: C07C257/18
Filed: 2001-02-02
Abstract: N-(Aryl, heteroaryl, aralkyl or heteroaralkyl)-substituted benzamide, phenylacetamide, aniline, benzylamine or phenethylamine derivatives (I), their stereoisomers and salts, are new. N-(Aryl, heteroaryl, aralkyl or heteroaralkyl)-substituted benzamide, phenylacetamide, aniline, benzylamine or phenethylamine derivatives of formula (I), their stereoisomers and salts, are new. formula [Image] m : 0 - 2; n : 0 or 1; A : direct bond or 1-3C n-alkenylene (optionally substituted (os) by 1 or 2 alkyl or by one -(CH 2) p-R f); p : 0 - 3; R fCOOH, alkoxycarbonyl, CONH 2, mono-, di- or cyclo-alkylaminocarbonyl, N-(alkoxycarbonylmethyl)-N-alkyl-aminocarbonyl, N-(carboxymethyl)-N-alkyl-aminocarbonyl or 4-7 membered cycloalkyleneiminocarbonyl; R 1NH 2, 1-5C alkylamino, cycloalkylamino or phenylalkylamino (all os on N by phenylcarbonyl or phenylsulfonyl or by alkyl or alkylcarbonyl (both os by COOH, a group convertible into COOH in vivo, NH 2or mono- or dialkylamino)); di-(1-5C alkyl)-amino or N-cycloalkyl-N-(1-5C alkyl)-amino, where the alkyl moieties are os (but not in the 1-position) by OH, alkoxy, NH 2or mono- or dialkylamino; 4-7 membered cycloalkyleneimino-carbonyl or -sulfonyl, both os by alkyl, aminoalkyl, mono- or dialkylaminoalkyl, CONH 2or mono- or dialkylaminocarbonyl; 2,5-dihydropyrrol-1-ylcarbonyl; SO 2NH 2(os by 1 or 2 alkyl); cycloalkylcarbonyl, where the CH 2in the 3- or 4-position is optionally replaced by NQ; phenylcarbonyl or heteroarylcarbonyl; or alkyl (os by one of NH 2, mono- or dialkylamino, OH, phenyl or 4-7 membered cycloalkyleneimino; or terminally disubstituted by phenyl and OH; where phenyl substituents are themselves os by amidino (os by 1 or 2 alkyl), F, Cl, Br, alkyl or alkoxy); Q : H, alkyl(carbonyl), phenylcarbonyl or phenylsulfonyl; R 2H, F, Cl, Br, alkyl (os by one or more F), OH, alkoxy or OCF 3; R 3H or alkyl; R 4H or alkyl (os by COOH or a group convertible into COOH in vivo); Ar : phenyl or naphthyl, both substituted by R 5, R 6and R 7; or thienyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, all os on C by alkyl; R 5CN, amidino, mono- or dialkylamidino, aminoalkyl or mono- or dialkylaminoalkyl; R 6H, F, Cl, Br, CF 3, alkyl, OH, hydroxyalkyl, alkoxy(alkyl), COOH, carboxyalkyl, carboxyalkoxy, 1-4C alkoxycarbonylalkoxy, phenylalkoxy, NH 2or mono- or dialkylamino; R 7H, F, Cl, Br or alkyl; heteroaryl : C- or N-bonded 5-membered heteroaryl in which the heteroatoms are one NH, N(Q'), N(COQ'), O or S, one NH, N(Q'), O or S plus one N or one NH, NQ', O or S plus two N; 6-membered heteroaryl in which the heteroatoms are one or two N; or a ring is fused with phenyl and bonded via the heterocyclic or carbocyclic ring; Q' : 1-4C alkyl; and provided that: (a) when m is 0, n is 1, then A is 1-3C n-alkenylene (optionally substituted (os) by 1 or 2 alkyl or by one -(CH 2) p-R f); (b) when m and n are 1, then A is a direct bond; (c) when m is 0 or 1, n is 0, then A is 1-3C n-alkenylene (os by 1 or 2 alkyl); and (d) when m is 2, n is 0, then A is a direct bond. Phenyl or heteroaryl moieties are os (or additionally os in monosubstituted phenyl) on C by F, Cl, Br, CF 3, alkoxy or alkoxycarbonyl; all COOH groups are optionally replaced by a group convertible into COOH in vivo or a group which is negatively charged under physiological conditions; amino or imino moieties are os by a group cleavable in vivo; and alkyl moieties have 1-3C and cycloalkyl moieties 3-7C unless specified otherwise. An independent claim is also included for the preparation of (I). ACTIVITY : Thrombolytic; Anticoagulant; Vasotropic; Cerebroprotective; Cardiant; Cytostatic; Antiinflammatory; Antirheumatic; Antiarthritic; Vulnerary. MECHANISM OF ACTION : Serine protease inhibitor; Thrombin inhibitor; Factor VIIa, IX, Xa, XI, XII inhibitors; Trypsin inhibitor; Urokinase inhibitor. N-(5-Carbamimidoyl-2-hydroxybenzyl)-3-chloro-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-benzamide (Ia) had IC 500.01 MicroM for inhibition of Factor Xa.