公开(公告)号：EP1751165A1

公开(公告)日：2007-02-14

申请号：EP05752659.2

申请日：2005-05-17

申请人： Tibotec Pharmaceuticals Ltd.

发明人： KESTELEYN, Bart, Rudolf, Romanie ,  VAN DE VREKEN, Wim ,  SURLERAUX, Dominique, Louis, Nestor, Ghislain ,  VENDEVILLE, Sandrine, Marie, Helene ,  RABOISSON, Pierre, Jean-Marie, Bernard ,  WIGERINCK, Piet, Tom, Bert, Paul ,  PEETERS, Annick, Ann

IPC分类号： C07D491/04 ,  C07D491/14 ,  C07D471/04 ,  A61K31/4355 ,  A61K31/437 ,  A61K31/4353 ,  A61P31/18 ,  C07D307/00 ,  C07D221/00

CPC分类号： C07D471/04 ,  C07D491/04 ,  C07D491/14

摘要： 4-substituted 1,5-dihydro-pyrido[3,2-b]indol-2-ones of formula (I): the N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein n is 1, 2 or 3; R1 is hydrogen, cyano, halo, substituted carbonyl, methanimidamidyl, N-hydroxymethanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, Het1 or Het2; X is NR 2, O, S, SO, SO2; R2 is hydrogen, C 1-10alkyl, C2-10alkenyl, C 3-7cycloalkyl, which are optionally substituted; R2 is aryl substituted with -COOR4 ; or R2 is: (b-1); (b-2); -CpH2p-CH(OR14 )-CqH 2q-R15(b-3); -CH2-CH2-(O-CH2-CH2)m-OR14 (b-4); -CH2-CH2-(O-CH2-CH2)m-NR5aR5b(b-5); -a1=a2-a3=a4- is -CH=CH-CH=CH-; -N=CH-CH=CH-; -CH=N-CH=CH-; -CH=CH-N=CH-; -CH=CH-CH=N-; wherein hydrogen atoms in (c-1) - (c-5) may be replaced by certain radicals; R3 is obtionally substituted phenyl or a monocyclic or bicyclic aromatic heterocyclic ring system that can be substituted; R21 is halo, hydroxy, amino, carboxyl, C1-6alkyl, C3-7cycloalkyl, arylC1-6alkyl, formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylo xy, -C(=O)-NR13R14; C1-6alkyloxy, arylC1-6alkyloxy, polyhaloC1-6alkyloxy, amino, mono or di(C1-6alkyl)amino, formylamino, C1-6alkylcarbonylamino, C1-6alkylsulfo nylamino, mercapto, C1-6alkylthio, arylthio, aryloxy, arylC1-6alkylthio, C1-6alkylsulfynyl, C1-6alkylsulfo nyl, aryl, arylamino, Het1, Het2.

公开(公告)号：EP1594870B1

公开(公告)日：2011-05-11

申请号：EP03811395.7

申请日：2003-11-14

申请人： Tibotec Pharmaceuticals

发明人： KESTELEYN, Bart, Rudolf, Romanie ,  VAN DE VREKEN, Wim ,  KINDERMANS, Natalie, Maria, Francisca ,  CANARD, Maxime, Francis, Jean-Marie, Ghislain ,  HERTOGS, Kurt ,  BETTENS, Eva ,  DE VROEY, Veronique, Corine, Paul ,  JOCHMANS, Dirk, Edward, Désiré ,  WIGERINCK, Piet Tom Bert Paul ,  TAHRI, Abdellah ,  WANG, Jing ,  SURLERAUX, Dominique Louis Nestor Ghislain

IPC分类号： A61K31/437 ,  A61P31/12 ,  C07D471/04

CPC分类号： C07D471/04

摘要： The present invention concerns the compounds of formula (1) (R3)n P(I) N O R1 R2 their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, wherein n is 1, 2 or 3; R1 is H, CN, halo, aminoC(=O), C(=O)OH, C1-4-alkyloxyC(=O), C1-4alkylC(='O), mono- or di(C1-4alkyl)aminoC(=O), arylaminoC(=O), N-(aryl)-N-(C1-4alkyl)aminoC(=O), methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, Het1 or Het2; R2 is H, C1-10alkyl, C2-10allkenyl, C3-7cycloalkyl, wherein said C1-10alkyl,C2-10alkenyl and C3-7cycloalkyl may be optionally substituted; R3 is nitro, cyano, amino, halo, hydroxy,C1-4alkyloxy, hydroxyC(=O), aminoC(=O), C1-4alkyloxyC(=O), mono- or di(C1-4-alkyl)aminoC(=O), C1-4alkylC(=O), methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy methanimidamidyl or Het1; for use as a medicine. The invention further relates to a novel subgroup of the compounds of formula (I), and to compositions comprising compounds of formula (I).

公开(公告)号：EP1913015A1

公开(公告)日：2008-04-23

申请号：EP06764266.0

申请日：2006-07-28

申请人： Tibotec Pharmaceuticals Ltd.

发明人： RABOISSON, Pierre, Jean-Marie, Bernard ,  DE KOCK, Herman, Augustinus ,  VAN DE VREKEN, Wim ,  SURLERAUX, Dominique, Louis, Nestor, Ghislain ,  SIMMEN, Kenneth, Alan

IPC分类号： C07K5/078 ,  A61K38/05 ,  C07D403/04 ,  A61K31/41 ,  A61P31/14

CPC分类号： C07D487/04 ,  C07D403/04

摘要： Inhibitors of HCV replication of formula (I), wherein W is a heterocycle of formula (II), (II), (IV), or (V); and the remaining variables are as defined in the specification.

摘要翻译： 其中W是式（II），（II），（IV）或（V）的杂环的式（I）的HCV复制抑制剂; 其余变量如说明书中所定义。

公开(公告)号：EP1912995B1

公开(公告)日：2011-07-27

申请号：EP06764264.5

申请日：2006-07-28

申请人： Tibotec Pharmaceuticals

发明人： RABOISSON, Pierre, Jean-Marie, Bernard ,  DE KOCK, Herman, Augustinus ,  VENDEVILLE, Sandrine, Marie, Helene ,  HU, Lili ,  VAN DE VREKEN, Wim ,  MC GOWAN, David, Craig ,  TAHRI, Abdellah ,  SURLERAUX, Dominique, Louis, Nestor, Ghislain ,  SIMMEN, Kenneth, Alan

IPC分类号： C07D487/04 ,  C07K5/078 ,  A61K38/05 ,  A61P31/14 ,  C07K5/06

CPC分类号： C07D487/04 ,  C07K5/06165

摘要： Inhibitors of HCV of formula (I), and the N-oxides, salts, and stereochemically isomeric forms thereof, wherein R1 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 8 to 12 membered bicyclic heterocyclic ring system containing one nitrogen, and optionally one to three oxygen, sulfur or nitrogen, wherein said ring system may be optionally substituted; L is a direct bond, -O-. -O-C1-4alkanediyl-, -O-CO-, -O-C(=O)-NR5a- or -O-C(=O)-NR5a-C1-4alkanediyl-; R2 is hydrogen, -OR6, -C(O)OR6, -C(=O)R7, -C(=O)NR5aR5b, -C(=O)NHR5c, -NR5aR5b, -NHR5c, -NHSOpNR5aR5b, -NR5aSOpR8, or -B(OR6)2; R3 and R4 are hydrogen or C1-6alkyl; or R3 and R4 taken together may form a C3-7cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted ; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

公开(公告)号：EP1838709A2

公开(公告)日：2007-10-03

申请号：EP06707683.6

申请日：2006-01-10

申请人： Tibotec Pharmaceuticals Ltd.

发明人： KESTELEYN, Bart Rudolf Romanie ,  RABOISSON, Pierre Jean-Marie ,  VAN DE VREKEN, Wim ,  CANARD, Maxime Francis Jean-Marie Ghislain

IPC分类号： C07D471/16

CPC分类号： C07D471/16 ,  C07D498/16

摘要： HIV inhibitory compounds of formula: (I) salts and stereoiso mers thereof, wherein R1 and R2 are hydrogen or optionally substituted C1-10alkyl; R3 is: (a) n is 1, 2 or 3; R3a is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonyl, methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het; or 3 R is a monocyclic or bicyclic aromatic heterocyclic ring system, wherein one, two, three or four ring members are nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and wherein each of said heterocyclic ring systems may optionally be substituted; X is -NR7-, -O- or -S-; pharmaceutical compositions containing these compounds, methods for preparing these compounds and compositions.

公开(公告)号：EP1751154A1

公开(公告)日：2007-02-14

申请号：EP05742818.7

申请日：2005-05-17

申请人： Tibotec Pharmaceuticals Ltd.

发明人： KESTELEYN, Bart Rudolf Romanie ,  CANARD, Maxime Francis Jean-Marie Ghislain ,  VAN DE VREKEN, Wim ,  RABOISSON, Pierre Jean-Marie Bernard ,  SURLERAUX, Dominique, Louis, Nestor, Ghislain ,  WIGERINCK, Piet, Tom, Bert, Paul

IPC分类号： C07D471/04 ,  A61K31/437 ,  A61P31/12

CPC分类号： C07D471/04

摘要： Compounds of formula (I) the N-oxides, salts, stereoisomeric forms, prodrugs, esters and metabolites thereof, wherein X is NR2, O, S, SO, SO2; R1 is hydrogen, cyano, halo, a carbonyl derivative, methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)- methanimidamidyl, Het1 or Het2; n is 1, 2 or 3; R2 is (i) aryl substituted with a radical -COOR4; (ii) C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, substituted with aryl which is substituted with a radical -COOR4; (iii) C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, substituted with -NR5a-C(=NR5b)-NR5cR5d, -O-NR5a-C(=NR5b)-NR 5cR5d, -sulfonyl-R6, -NR7R8, -NR9R10, a radical (a-1), (a-2), (a-3), (a-4), (a-5); or (iv) a radical of formula: (a-6), (b-2), -CpH2p-CH(OR14)-CqH2q-R15; -CH2-CH2-(O-CH2-CH2)m-OR14; -CH2-CH2-(O- CH2-CH2)m-NR17aR 17b; R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, a carbonyl derivative, methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1.

公开(公告)号：EP1838709B1

公开(公告)日：2011-12-21

申请号：EP06707683.6

申请日：2006-01-10

申请人： Tibotec Pharmaceuticals

发明人： KESTELEYN, Bart Rudolf Romanie ,  RABOISSON, Pierre Jean-Marie ,  VAN DE VREKEN, Wim ,  CANARD, Maxime Francis Jean-Marie Ghislain

IPC分类号： C07D471/16 ,  A61P31/18 ,  A61K31/4985

CPC分类号： C07D471/16 ,  C07D498/16

摘要： HIV inhibitory compounds of formula: (I) salts and stereoiso mers thereof, wherein R1 and R2 are hydrogen or optionally substituted C1-10alkyl; R3 is: (a) n is 1, 2 or 3; R3a is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonyl, methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het; or 3 R is a monocyclic or bicyclic aromatic heterocyclic ring system, wherein one, two, three or four ring members are nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and wherein each of said heterocyclic ring systems may optionally be substituted; X is -NR7-, -O- or -S-; pharmaceutical compositions containing these compounds, methods for preparing these compounds and compositions.

摘要翻译： 下式的HIV抑制化合物：（I）其盐和立体异构体，其中R 1和R 2是氢或任选取代的C 1-10烷基; R3是：（a）n是1,2或3; （C1-4烷基）氨基羰基，C1-4烷基羰基，甲脒基，单或二（C1-4烷基）氨基羰基， 甲脒基，N-羟基 - 甲脒基或Het; 或3R是单环或双环芳族杂环系统，其中1,2,3或4个环成员是氮，氧和硫，并且其中剩余的环成员是碳原子; 并且其中所述杂环系统中的每一个可以任选被取代; X是-NR 7 - ， - O-或-S-; 含这些化合物的药物组合物，制备这些化合物和组合物的方法。

公开(公告)号：EP2097402A1

公开(公告)日：2009-09-09

申请号：EP07822656.0

申请日：2007-11-16

申请人： Tibotec Pharmaceuticals Ltd.

发明人： RABOISSON, Pierre Jean-Marie Bernard ,  DE KOCK, Herman Augustinus ,  MC GOWAN, David Craig ,  VAN DE VREKEN, Wim ,  HU, Lili ,  TAHRI, Abdellah ,  VENDEVILLE, Sandrine Marie Helene

IPC分类号： C07D401/12 ,  C07D491/04 ,  A61K31/4709 ,  A61K31/4741 ,  A61P31/14

CPC分类号： C07D491/056 ,  A61K31/427 ,  A61K31/4741 ,  C07D401/12 ,  C07D491/04 ,  C07D491/048 ,  Y02A50/385 ,  Y02A50/387 ,  Y02A50/389 ,  Y02A50/393 ,  A61K2300/00

摘要： Inhibitors of HCV replication of formula (I) and the salts and stereoisomers thereof, wherein each dashed line (represented by represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is -OR7, -NH-SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; n is 3, 4, 5, or 6; R4 is C1-6alkyl or C3-7cycloalkyl; R5 is hydrogen, halo, C1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkyl; R6 is hydrogen, C1-6alkoxy, mono- or diC1-6alkylamino; or R5 and R6 may form a 5- or 6-membered unsaturated or partially unsaturated ring, optionally comprising one or two selected from O, N and S; R7 is hydrogen; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl; R8 is C3-7cycloalkyl optionally substituted with C1-6alkyl; C1-6alkyl optionally substituted with C3-7cycloalkyl; or -NR8aR8b; R8a and R8b are C1-6alkyl, or both may form a 5- or 6-membered saturated heterocyclic ring; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I).

公开(公告)号：EP1919904A1

公开(公告)日：2008-05-14

申请号：EP06778068.4

申请日：2006-07-28

申请人： Tibotec Pharmaceuticals Ltd. ,  MEDIVIR AB

发明人： RABOISSON, Pierre Jean-Marie Bernard ,  DE KOCK, Herman Augustinus ,  DORANGE, Ismet ,  VENDEVILLE, Sandrine Marie Helene ,  SURLERAUX, Dominique Louis Nestor Ghislain ,  TAHRI, Abdellah ,  SIMONNET, Yvan ,  VAN DE VREKEN, Wim ,  HU, Lili ,  SIMMEN, Kenneth Alan ,  NILSSON, Karl Magnus ,  SAMUELSSON, Bengt Bertil ,  ROSENQUIST, Åsa Annica Kristina ,  WALLBERG, Hans Kristian

IPC分类号： C07D401/14 ,  C07K5/078 ,  A61K31/4725 ,  A61P31/14

CPC分类号： C07D401/14 ,  C07D401/12 ,  C07D417/14 ,  C07D487/04 ,  C07K5/06191

摘要： Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers thereof, wherein X is N, CH and where X bears a double bond it is C; R1 is -OR5, -NH-SO2R6; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, or C3-7cycloalkyl; R4 is isoquinolinyl optionally substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, hydroxy, halo, polyhalo- C1-6alkyl, polyhaloC1-6alkoxy, amino, mono- or diC1-6alkylamino, mono- or DiC1-6alkylaminocarbonyl, C1-6alkylcarbonyl-amino, aryl, and Het; n is 3, 4, 5, or 6; each dashed line (represented by ) represents an optional double bond; R5 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R6 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; each aryl is phenyl optionally substituted with one, two or three substituents; and each Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

公开(公告)号：EP1912995A1

公开(公告)日：2008-04-23

申请号：EP06764264.5

申请日：2006-07-28

申请人： Tibotec Pharmaceuticals Ltd.

发明人： RABOISSON, Pierre, Jean-Marie, Bernard ,  DE KOCK, Herman, Augustinus ,  VENDEVILLE, Sandrine, Marie, Helene ,  HU, Lili ,  VAN DE VREKEN, Wim ,  MC GOWAN, David, Craig ,  TAHRI, Abdellah ,  SURLERAUX, Dominique, Louis, Nestor, Ghislain ,  SIMMEN, Kenneth, Alan

IPC分类号： C07D487/04 ,  C07K5/078 ,  A61K38/05 ,  A61P31/14 ,  C07K5/06

CPC分类号： C07D487/04 ,  C07K5/06165

摘要： Inhibitors of HCV of formula (I), and the N-oxides, salts, and stereochemically isomeric forms thereof, wherein R1 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 8 to 12 membered bicyclic heterocyclic ring system containing one nitrogen, and optionally one to three oxygen, sulfur or nitrogen, wherein said ring system may be optionally substituted; L is a direct bond, -O-. -O-C1-4alkanediyl-, -O-CO-, -O-C(=O)-NR5a- or -O-C(=O)-NR5a-C1-4alkanediyl-; R2 is hydrogen, -OR6, -C(O)OR6, -C(=O)R7, -C(=O)NR5aR5b, -C(=O)NHR5c, -NR5aR5b, -NHR5c, -NHSOpNR5aR5b, -NR5aSOpR8, or -B(OR6)2; R3 and R4 are hydrogen or C1-6alkyl; or R3 and R4 taken together may form a C3-7cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted ; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

摘要翻译： 式（I）的HCV抑制剂及其N-氧化物，盐和立体化学异构体形式，其中R1为芳基或饱和的，部分不饱和或完全不饱和的5或6元单环或8-12元双环杂环 含有一个氮和任选1-3个氧，硫或氮的体系，其中所述环体系可以任选被取代; L是直接键，-O-。 -O-C（= O）-NR5a-或-O-C（= O）-NR5a-C1-4烷二基 - （= O）R7，-C（= O）NR5aR5b，-C（= O）NHR5c，-NR5aR5b，-NHR5c，-NHSOpNR5aR5b，-NR5aSOpR8， 或-B（OR 6）2; R3和R4是氢或C1-6烷基; 或者R3和R4一起形成C3-7环烷基环; n是3,4,5或6; p是1或2; 芳基是苯基，萘基，2,3-二氢化茚基或1,2,3,4-四氢萘基，它们中的每一个可以任选地被取代.Het是5或6元饱和，部分不饱和或完全不饱和的含有1至4个各自独立选择的杂原子的杂环 由氮，氧和硫任选地与苯环稠合，并且其中基团Het作为整体可以任选被取代; 含有化合物（I）的药物组合物和用于制备化合物（I）的方法。 还提供了式（I）的HCV抑制剂与利托那韦的生物可用组合。