公开(公告)号：AT331705T

公开(公告)日：2006-07-15

申请号：AT02291192

申请日：2002-05-14

Applicant: SERVIER LAB

Inventor： DE NANTEUIL GUILLAUME ,  PORTEVIN BERNARD ,  BENOIST ALAIN ,  LEVENS NIGEL ,  NOSJEAN OLIVIER ,  HUSSON-ROBERT BERNADETTE ,  BOULANGER MICHELLE

IPC: C07D295/10 ,  A61K31/40 ,  A61K31/426 ,  A61P3/04 ,  A61P3/08 ,  A61P3/10 ,  C07D207/16 ,  C07D277/04 ,  C07D277/06 ,  C07D295/185 ,  C07K5/02 ,  C07D295/18

Abstract: Alpha amino acid derivatives (I), their optical isomers and addition salts, are new. Alpha amino acid derivatives of formula (I), their optical isomers and addition salts, are new: A = five-membered heterocycle, optionally substituted by a cyano group; Ak = 1-6C alkylene; X = single bond or phenylene; R1, R2, R4 = H or 1-6C alkyl; Y = NR4 or CH-NO2; R3 = NO2 or CN; and provided that: (i) when Y is CH-NO2, then R3 may further be 1-6C alkyl; and (ii) when A is unsubstituted, then Ak is propylene, X is a bond, Y is NH and R3 is NO2, are excluded.

公开(公告)号：FR2867780B1

公开(公告)日：2006-05-19

申请号：FR0402841

申请日：2004-03-19

Applicant: SERVIER LAB

Inventor： DE NANTEUIL GUILLAUME ,  GLOANEC PHILIPPE ,  PARMENTIER JEAN GILLES ,  BENOIST ALAIN ,  RUPIN ALAIN ,  VALLEZ MARIE ODILE ,  VERBEUREN TONY

IPC: C07D487/04 ,  A61K31/4985 ,  A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D207/12 ,  C07D241/08

Abstract: 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.

公开(公告)号：NZ540108A

公开(公告)日：2006-04-28

申请号：NZ54010805

申请日：2005-05-18

Applicant: SERVIER LAB

Inventor： DE NANTEUIL GUILLAUME ,  BENOIST ALAIN ,  COMBETTES MURIELLE ,  HARLEY ELIZABETH

IPC: C07D295/18 ,  A61K31/40 ,  A61K31/4025 ,  A61K31/426 ,  A61K31/427 ,  A61K31/438 ,  A61P3/10 ,  A61P43/00 ,  C07D207/06 ,  C07D207/10 ,  C07D207/16 ,  C07D277/06 ,  C07D277/12 ,  C07D295/185 ,  C07D311/96 ,  C07D401/12 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D417/12 ,  C07D277/04

Abstract: Pyrrolidine and thiazolidine compounds of formula (I), a process for their preparation, pharmaceutical compositions containing them and their use as inhibitors of dipeptidyl peptidase IV (DPP IV) is disclosed, wherein X1, X2, X3, Ak, R1, R2, R3, m1, m2, n1, n2 and p are as defined in the specification. These compounds are suitable for use in the treatment of glucose intolerance, type II diabetes and disorders associated with hyperglycaemia.

公开(公告)号：AR048277A1

公开(公告)日：2006-04-12

申请号：ARP050101066

申请日：2005-03-18

Applicant: SERVIER LAB

Inventor： NANTEUIL GUILLAUME ,  GLOANEC PHILIPPE ,  PARMENTIER JEAN-GILLES ,  BENOIST ALAIN ,  RUPIN ALAIN ,  VALLEZ MARIN-ODILE ,  VERBEUREN TONY

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  A61K31/498

Abstract: Reivindicacion 1: Compuesto de la formula (1) donde el resto de formula (2) representa un grupo 1-oxidopiridilo sustituido por el resto de la molécula en una cualquiera de las posiciones 2, 3 y 4; cada uno de m y n, que pueden ser idénticos o diferentes, representa un entero de 1 a 3; R1 representa un átomo de H o un grupo alquilo C1-6 lineal o ramificado; cada uno de R2 y R3, que pueden ser idénticos o diferentes, representa un átomo o un grupo seleccionado entre los átomos H y halogeno y los grupos alquilo C1-6 lineal o ramificado, hidroxi, aciloxi C1-6 lineal o ramificado y alcoxi C1-6 lineal o ramificado, o juntos forman, con el átomo de C que los lleva, un cicloalcano C3-6, cada uno de R4 y R5 representa un átomo de H, o son adyacentes y juntos forman, con los átomos de C que los llevan, un anillo benzo; Ar representa un grupo arilo o heteroarilo, a sus enantiomeros, y a sus sales de adicion con un ácido farmacéuticamente aceptable, se entiende que ôgrupo ariloö se refiere a fenilo, bifenililo o naftilo, sustituyéndose opcionalmente cada uno de esos grupos por uno o más grupos idénticos o diferentes seleccionados entre: halogeno, alquilo C1-6 lineal o ramificado opcionalmente sustituido por un grupo hidroxi, carboxi o carbamoilo, siendo el grupo carbamoilo propiamente dicho a su vez opcionalmente sustituido por uno o dos grupos alquilo C1-6 lineal o ramificado; alcoxi C1-6 lineal o ramificado, hidroxi, trihalo-alquilo C1-6 en el que la parte alquilo puede ser lineal o ramificada, amino opcionalmente sustituido por uno o dos grupos alquilo C1-6 lineal o ramificado, carboximetoxi, y carbamoilmetoxi opcionalmente N-sustituido por uno o dos grupos seleccionados entre alquilo C1-6 lineal o ramificado, hidroxialquilo C1-6 donde la parte alquilo puede ser lineal o ramificada, un grupo alcoxialquilo donde las partes alcoxi y alquilo son cada una C1-6 lineal o ramificada, y piridilalquilo donde la parte alquilo es C1-6 lineal o ramificada, se entiende por ôgrupo heteroariloö un grupo aromático mono- o bicíclico que posee entre 5 y 12 miembros de anillo y contiene 1, 2 o 3 heteroátomos seleccionados entre O, N y S, entendiéndose que el grupo heteroarilo puede ser opcionalmente sustituido por uno o más grupos idénticos o diferentes seleccionados entre: halogeno, alquilo C1-6 lineal o ramificado opcionalmente sustituido por un grupo hidroxi, carboxi o carbamoilo, siendo el grupo carbamoilo propiamente dicho a su vez opcionalmente sustituido por uno o dos grupos alquilo C1-6 lineal o ramificado; hidroxi, oxo, alcoxi C1-6 lineal o ramificado, trihaloalquilo C1-6 donde la parte alquilo puede ser lineal, o ramificada, amino opcionalmente N-sustituido por uno o dos grupos alquilo C1-6 lineal o ramificado, carboximetoxi, y carbamoilmetoxi opcionalmente N-sustituido por uno o dos grupos seleccionados entre alquilo C1-6 lineal o ramificado, hidroxialquilo C1-6 donde la parte alquilo puede ser lineal o ramificada, alcoxialquilo donde las partes alcoxi y alquilo son cada una C1-6 lineal, o ramificada, y piridilalquilo donde la parte alquilo es C1-6 lineal o ramificada.

公开(公告)号：AU783908B2

公开(公告)日：2005-12-22

申请号：AU9744201

申请日：2001-12-21

Applicant: SERVIER LAB

Inventor： NANTEUIL GUILLAUME DE ,  BENOIST ALAIN ,  PASTOUREAU PHILIPPE ,  SABATINI MASSIMO ,  HICKMAN JOHN ,  PIERRE ALAIN ,  TUCKER GORDON

IPC: C07D491/048 ,  A61K31/443 ,  A61K31/4433 ,  A61K31/4436 ,  A61K31/444 ,  A61K31/541 ,  A61P9/10 ,  A61P19/02 ,  A61P29/00 ,  A61P35/00 ,  A61P43/00 ,  C07D405/14 ,  C07D417/14 ,  C07D491/04

Abstract: 5-Sulfonyl-2-(4-pyridinyl)-benzofuran, benzothiophene or indole derivatives (I), containing a hydroxamic acid function, are new. Benzofuran, benzothiophene or indole derivatives of formula (I) and their isomers, N-oxides and acid or base addition salts are new. R1 = H, halo, 1-6C alkyl or 1-6C alkoxy; X = O, S or NR; R = H or 1-6C alkyl; A = N-hydroxy-carboxamido-substituted tetrahydrofuropyridine, thiomorpholine or tetrahydropyranylmethyl group of formula (i)-(iii); Ra = H, halo, 1-6C alkyl or 1-6C alkoxy; Rb, Rc = H or 1-6C alkyl; and n = 0-2. An Independent claim is also included for the preparation of (I).

公开(公告)号：BRPI0500889A

公开(公告)日：2005-11-01

申请号：BRPI0500889

申请日：2005-03-21

Applicant: SERVIER LAB

Inventor： NANTEUIL GUILLAUME DE ,  GLOANEC PHILIPPE ,  PARMENTIER JEAN-GILLES ,  BENOIST ALAIN ,  RUPIN ALAIN ,  VALLEZ MARIE-ODILE ,  VERBEUREN TONY

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  A61K31/407

Abstract: 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.

公开(公告)号：DE60105746T2

公开(公告)日：2005-10-06

申请号：DE60105746

申请日：2001-12-21

Applicant: SERVIER LAB

Inventor： DE NANTEUIL GUILLAUME ,  BENOIST ALAIN ,  PASTOUREAU PHILIPPE ,  SABATINI MASSIMO ,  HICKMAN JOHN ,  PIERRE ALAIN ,  TUCKER GORDON

IPC: C07D491/048 ,  A61K31/4433 ,  A61K31/444 ,  A61K31/541 ,  A61P9/10 ,  A61P19/02 ,  A61P29/00 ,  A61P35/00 ,  A61P43/00 ,  C07D405/14 ,  C07D417/14 ,  C07D491/04

Abstract: 5-Sulfonyl-2-(4-pyridinyl)-benzofuran, benzothiophene or indole derivatives (I), containing a hydroxamic acid function, are new. Benzofuran, benzothiophene or indole derivatives of formula (I) and their isomers, N-oxides and acid or base addition salts are new. R1 = H, halo, 1-6C alkyl or 1-6C alkoxy; X = O, S or NR; R = H or 1-6C alkyl; A = N-hydroxy-carboxamido-substituted tetrahydrofuropyridine, thiomorpholine or tetrahydropyranylmethyl group of formula (i)-(iii); Ra = H, halo, 1-6C alkyl or 1-6C alkoxy; Rb, Rc = H or 1-6C alkyl; and n = 0-2. An Independent claim is also included for the preparation of (I).

公开(公告)号：ZA200502316B

公开(公告)日：2005-10-03

申请号：ZA200502316

申请日：2005-03-18

Applicant: SERVIER LAB

Inventor： NANTEUIL GUILLAUME DE ,  GLOANEC PHILIPPE ,  PARMENTIER JEAN-GILLES ,  BENOIST ALAIN ,  RUPIN ALAIN ,  VALLEZ MARIE-ODILE ,  VERBEUREN TONY

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  A61K ,  C07C ,  C07D ,  A61P

Abstract: 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.

公开(公告)号：FR2867780A1

公开(公告)日：2005-09-23

申请号：FR0402841

申请日：2004-03-19

Applicant: SERVIER LAB

Inventor： DE NANTEUIL GUILLAUME ,  GLOANEC PHILIPPE ,  PARMENTIER JEAN GILLES ,  BENOIST ALAIN ,  RUPIN ALAIN ,  VALLEZ MARIE ODILE ,  VERBEUREN TONY

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  A61K31/4985

Abstract: 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.

公开(公告)号：NO20051367D0

公开(公告)日：2005-03-16

申请号：NO20051367

申请日：2005-03-16

Applicant: SERVIER LAB

Inventor： NANTEUIL GUILLAUME DE ,  VERBEUREN TONY ,  VALLEZ MARIE-ODILE ,  RUPIN ALAIN ,  BENOIST ALAIN ,  PARMENTIER JEAN-GILLES ,  GLOANEC PHILIPPE

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  C07D

Abstract: 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds (I) are new. 4-Oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds of formula (I) are new. A : 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4; m, n : 1 - 3; R 1H or linear or branched (1-6C)alkyl; R 2, R 3hydrogen, halogen, linear or branched (1-6C)alkyl, hydroxy, linear or branched (1-6C)acyloxy or linear or branched (1-6C)alkoxy; R 2+R 33-6C cycloalkane; R 4, R 5H; R 4+R 5benzo ring; Ar : phenyl, biphenylyl or naphthyl (optionally substituted by at least one of T 1) or 5 - 12-membered mono- or bi-cyclic aromatic group (containing 1 - 3 heteroatoms selected from O, N or S; and optionally substituted by at least one of T 1); and T 1halo, linear or branched (1-6C)alkyl (optionally substituted by hydroxy, carboxy or carbamoyl (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, linear or branched (1-6C)alkoxy, hydroxy, trihalo-(1-6C)alkyl (in which the alkyl moiety is linear or branched), amino (optionally mono- or di-substituted by linear or branched (1-6C)alkyl, carboxymethoxy or carbamoylmethoxy (optionally mono- or di-N-substituted by linear or branched (1-6C)alkyl, hydroxy-(1-6C)alkyl (in which the alkyl moiety is linear or branched), alkoxyalkyl (in which the alkoxy and alkyl moieties are each linear or branched 1-6C) or pyridylalkyl (in which the alkyl moiety is linear or branched 1-6C)))). The configuration of the asymmetric centre at the alpha position with respect to the amide is (S). [Image] ACTIVITY : Antianginal; Thrombolytic; Cardiant; Vasotropic; Cardiovascular-Gen.; Antiarteriosclerotic. MECHANISM OF ACTION : Thrombin inhibitors. The inhibitory activity of 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-4-oxo-N-[2-(2-oxo-2-{[2-(2-pyridyl)ethyl]amino}ethoxy)benzyl]-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide hydrochloride (A) was evaluated on human thrombin. The purified human fibrinogen (4 mM) was added to thrombin (0.7 nM) that had previously been incubated optionally with the inhibitor to be tested (20[deg]C, 10 minutes). Inhibitors, enzymes and substrates were diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing sodium chloride (0.12 M) and bovine serum albumin (0.05%)) and then distributed on a polystyrene microtitre plate in a volume of 50 mu l. The fibrin formed by the thrombin was measured using a spectrophotometer at 405 nm after 10 - 15 minutes reaction at 20[deg]C. The IC 50 value of (A) was found to be 1.4 nM.