公开(公告)号：AU2005201198B8

公开(公告)日：2011-03-10

申请号：AU2005201198

申请日：2005-03-18

Applicant: SERVIER LAB

Inventor： RUPIN ALAIN ,  PAMENTIER JEAN-GILES ,  VERBEUREN TONY ,  GLOANEC PHILLIPPE ,  BENOIST ALAIN ,  VALLEZ MARIE-ODILE ,  NANTEUIL GUILLAUME DE

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

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：AU2005201198B2

公开(公告)日：2010-11-11

申请号：AU2005201198

申请日：2005-03-18

Applicant: SERVIER LAB

Inventor： RUPIN ALAIN ,  PAMENTIER JEAN-GILES ,  VERBEUREN TONY ,  GLOANEC PHILLIPPE ,  BENOIST ALAIN ,  VALLEZ MARIE-ODILE ,  NANTEUIL GUILLAUME DE

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

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：AU2005201198A1

公开(公告)日：2005-10-06

申请号：AU2005201198

申请日：2005-03-18

Applicant: SERVIER LAB

Inventor： RUPIN ALAIN ,  PAMENTIER JEAN-GILES ,  VERBEUREN TONY ,  GLOANEC PHILLIPPE ,  BENOIST ALAIN ,  VALLEZ MARIE-ODILE ,  NANTEUIL GUILLAUME DE

IPC: A61K31/519 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P43/00 ,  C07D487/04 ,  A61K31/4196 ,  A61K31/381 ,  A61K31/395 ,  A61K31/00

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：CY1107157T1

公开(公告)日：2012-10-24

申请号：CY081100096

申请日：2008-01-28

Applicant: SERVIER LAB

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

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

Abstract: Ένωσητουτύπου (Ι):

公开(公告)号：AU2006201326A1

公开(公告)日：2006-10-19

申请号：AU2006201326

申请日：2006-03-30

Applicant: SERVIER LAB

Inventor： ORTUNO JEAN-CLAUDE ,  GLOANEC PHILLIPPE ,  NANTEUIL GUILLAUME DE ,  COUR CLOTILDE MANNOURY LA ,  MILLAN MARK ,  GOBERT ALAIN ,  PORTEVIN BERNARD

IPC: C07D295/092 ,  A61K31/495 ,  A61P25/18 ,  A61P25/24 ,  C07D295/104 ,  C07D401/12 ,  C07D419/12

Abstract: Indanyl-piperazine derivatives (I) are new. Indanyl-piperazine derivatives of formula (I) and their optical isomers, salts, enantiomers or diastereoisomers are new. R 3 = H and R 1+R 2 = benzene, naphthalene or quinoline (optionally substituted by H, halo or 1-6C alkyl (optionally substituted by halo)); or R 1 = H; and R 2+R 3 = benzene, naphthalene or quinoline (optionally substituted by H, halo or 1-6C alkyl (optionally substituted by halo)); n = 1-2; X = (CH 2) m-OT, (CH 2) m-NR 4T, C(O)NR 4T or (CH 2) mNR 4C(O); m = 1-6; T = 1-6C alkyl optionally substituted by OH; R 4 = H or 1-6C alkyl; A = (hetero)aryl; aryl = phenyl, biphenyl or naphthyl (optionally substituted by halo, 1-6C alkyl, 1-6C alkoxy, OH, CN or 1-6C trihaloalkyl); and heteroaryl = 5-12 membered aromatic mono- or bicyclic rings containing O, N or S heteroatoms and optionally substituted by halo, 1-6C alkyl, 1-6C alkoxy, OH or 1-6C trihaloalkyl. An independent claim is also included for preparation of (I). [Image] ACTIVITY : Antidepressant; Tranquilizer; Anorectic; Analgesic; Antiinflammatory; Neuroleptic; Antiemetic; Gastrointestinal-Gen. MECHANISM OF ACTION : Serotonin receptor inhibitor; Neurokinin-1 antagonist. The ability of (1RS)-1-[1-(3,5-difluorobenzyloxymethyl)indan-1-yl]piperazine dihydrochloride to inhibit serotonin receptor in rats was tested using biological assays. The result showed that (1RS)-1-[1-(3,5-difluoro-benzyloxymethyl)-indan-1-yl]-piperazine dichlorhydrate exhibits a pK i (negative log of inhibitory constant) value of 8.49.