公开(公告)号：US08518987B2

公开(公告)日：2013-08-27

申请号：US12536807

申请日：2009-08-06

申请人： Hans Wim Pieter Vermeersch ,  Daniel Joseph Christiaan Thone ,  Luc Donne Marie-Louise Janssens ,  Piet Tom Bert Paul Wigerinck

发明人： Hans Wim Pieter Vermeersch ,  Daniel Joseph Christiaan Thone ,  Luc Donne Marie-Louise Janssens ,  Piet Tom Bert Paul Wigerinck

IPC分类号： A61K31/353

CPC分类号： C07D493/04

摘要： New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate and processes for producing them are disclosed.

摘要翻译： （3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基]（异丁基）氨基] -1- 公开了苄基-2-羟丙基氨基甲酸酯及其制备方法。

公开(公告)号：US08383608B2

公开(公告)日：2013-02-26

申请号：US13167682

申请日：2011-06-23

申请人： François Nique ,  Catherine Jagerschmidt ,  Florence Sylvie Namour ,  Roland Blanqué ,  Jean-Michel Lefrançois ,  Christophe Peixoto ,  Pierre Deprez ,  Nicolas Triballeau ,  Piet Tom Bert Paul Wigerinck

发明人： François Nique ,  Catherine Jagerschmidt ,  Florence Sylvie Namour ,  Roland Blanqué ,  Jean-Michel Lefrançois ,  Christophe Peixoto ,  Pierre Deprez ,  Nicolas Triballeau ,  Piet Tom Bert Paul Wigerinck

IPC分类号： A61K31/4166 ,  A61K31/675 ,  A61P15/00

CPC分类号： C07D233/60 ,  C07D233/66

摘要： Novel compounds are disclosed that have a Formula represented by the following: wherein X, R1, R2a, R2b, R2c, R3a R3b, R4a, R4b, R4c, and m1 are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction.

摘要翻译： 公开了具有由下式表示的式的新化合物：其中X，R1，R2a，R2b，R2c，R3a R3b，R4a，R4b，R4c和m1如本文所述。 化合物可以制备成药物组合物，并且可以用于预防和治疗包括人在内的哺乳动物中的各种病症，包括非限制性实例，恶病质，骨质疏松症，肌肉减少症，性欲下降和/或 性功能障碍。

公开(公告)号：US07772411B2

公开(公告)日：2010-08-10

申请号：US10596732

申请日：2004-12-23

申请人： Nicolaas Martha Felix Goyvaerts ,  Piet Tom Bert Paul Wigerinck ,  Hartmut Burghard Zinser ,  Birgit M. Ebert

发明人： Nicolaas Martha Felix Goyvaerts ,  Piet Tom Bert Paul Wigerinck ,  Hartmut Burghard Zinser ,  Birgit M. Ebert

IPC分类号： C07D493/04

CPC分类号： C07D493/02 ,  C07D493/04

摘要： The present invention relates to a process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate as well as intermediates for use in said process. More in particular the invention relates to processes for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate which make use of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene sulfonamide intermediate, and to processes amenable to industrial scaling up. (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate is particularly useful as HIV protease inhibitors.

摘要翻译： 本发明涉及制备（3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基] 异丁基）氨基] -1-苄基-2-羟基丙基氨基甲酸酯以及用于所述方法的中间体。 更具体地，本发明涉及制备（3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基] 使用4-氨基-N - （（2R，3S）-3-氨基-2-羟基-4-苯基丁基）-N-（异丁基）苯磺酰胺的（异丁基）氨基] -1-苄基-2-羟基丙基氨基甲酸叔丁酯 中间和适用于工业规模化的流程。 （3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基]（异丁基）氨基] -1-苄基-2- 羟丙基氨基甲酸酯特别可用作HIV蛋白酶抑制剂。

公开(公告)号：US07659404B2

公开(公告)日：2010-02-09

申请号：US10467609

申请日：2002-02-14

申请人： Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Daniel Getman ,  Wim Gaston Verschueren ,  Sandrine Vendeville ,  Marie-Pierre De Bethune ,  Jan Octaaf Antoon De Kerpel ,  Samuel Leo Christiaan Moors ,  Herman Augustinus De Kock ,  Marieke Christiane Johanna Voets

发明人： Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Daniel Getman ,  Wim Gaston Verschueren ,  Sandrine Vendeville ,  Marie-Pierre De Bethune ,  Jan Octaaf Antoon De Kerpel ,  Samuel Leo Christiaan Moors ,  Herman Augustinus De Kock ,  Marieke Christiane Johanna Voets

IPC分类号： A61K31/428 ,  C07D417/12

CPC分类号： C07D417/12 ,  C07D277/82

摘要： The present invention concerns the compounds having the formula N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R1 and R8 each are H, optionally substituted C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl, Het1, Het2; R1 may also be a radical of formula (R11aR11b)NC(R10aR10b)CR9—; t is 0, 1 or 2; R2 is H or C1-6alkyl; L is —C(═O)—, —O—C(═O)—, —NR8—C(═O)—, —O—C1-6alkanediyl-C(═O)—, —NR8—C1-6alkanediyl-C(═O)—, —S(═O)2—, —O—S(═O)2—, —NR8—S(═O)2; R3 is C1-6alkyl, aryl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or arylC1-4alkyl; R4 is H, C1-4alkylOC(═O), carboxyl, aminoC(═O), mono- or di(C1-4alkyl)aminoC(═O), C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or optionally substituted C1-6alkyl; A is C1-6alkanediyl, —C(═O)—, —C(═S)—, —S(═O)2—, C1-6alkanediyl-C(═O)—, C1-6alkanediyl-C(═S)— or C1-6alkanediyl-S(═O)2—; R5 is H, OH, C1-6alkyl, Het1C1-6alkyl, Het2C1-6alkyl, optionally substituted aminoC1-6alkyl; R6 is C1-6alkylO, Het1, Het1O, Het2, Het2O, aryl, arylO, C1-6alkyloxycarbonylamino or amino; and in case —A— is other than C1-6alkanediyl then R6 may also be C1-6alkyl, Het1C1-4alkyl, Het1OC1-4alkyl, Het2C1-4alkyl, Het2OC1-4alkyl, arylC1-4alkyl, arylOC1-4alkyl or aminoC1-4alkyl; whereby each of the amino groups in the definition of R6 may optionally be substituted; R5 and —A—R6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2. It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.

公开(公告)号：US20090203742A1

公开(公告)日：2009-08-13

申请号：US12426730

申请日：2009-04-20

申请人： Dominique Lois Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Daniel P. Getman

发明人： Dominique Lois Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Daniel P. Getman

IPC分类号： A61K31/428 ,  A61K31/4439 ,  A61P31/18

CPC分类号： C07D417/12 ,  A61K31/425 ,  C07D277/82 ,  C07D493/04

摘要： The present invention relates to the use of 2-amino-benzothiazoles, having the formula wherein R1 is hexahydrofuro[2,3-b]furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substituted with one or more substituents independently selected from C1-6alkyl, hydroxy, amino, halogen, aminoC1-4alkyl and mono- or di(C1-4alkyl)amino; R2 is hydrogen or C1-6alkyl; L is a direct bond, —O—, C1-6alkanediyl-O— or —O—C1-6alkanediyl; R3 is phenylC1-4alkyl; R4 is C1-6alkyl; R5 is hydrogen or C1-6alkyl; R6 is hydrogen or C1-6allyl; in the manufacture of a medicament useful for inhibiting mutant HIV protease in a mammal infected with said mutant HIV protease. It also relates to novel compounds of formula (I).

摘要翻译： 本发明涉及2-氨基 - 苯并噻唑的用途，其具有下式：其中R 1是六氢呋喃并[2,3-b]呋喃基，四氢呋喃基，恶唑基，噻唑基，吡啶基或任选地被一个或多个独立地选自 C 1-6烷基，羟基，氨基，卤素，氨基C 1-4烷基和单或二（C 1-4烷基）氨基; R2是氢或C1-6烷基; L是直接键，-O-，C 1-6烷二基-O-或-O-C 1-6烷二基; R3是苯基C 1-4烷基; R4是C1-6烷基; R5是氢或C1-6烷基; R6是氢或C1-6烯丙基; 在制备用于抑制感染了所述突变HIV蛋白酶的哺乳动物中的突变HIV蛋白酶的药物中。 它还涉及新的式（I）化合物。

公开(公告)号：US20090012046A1

公开(公告)日：2009-01-08

申请号：US12160115

申请日：2007-02-05

申请人： Dirk Edward Desire Jochmans ,  Piet Tom Bert Paul Wigerinck

发明人： Dirk Edward Desire Jochmans ,  Piet Tom Bert Paul Wigerinck

IPC分类号： C07D487/04 ,  A61K31/437 ,  A61K31/675 ,  A61P31/18

CPC分类号： A61K31/437

摘要： Nucleotide-competing reverse transcriptase inhibitors (NcRTI) bind to the active site of HIV reverse transcriptase (RT) in competition with the next incoming nucleotide. To further investigate the impact of RT inhibitor resistance mutations on the activity of NcRTIs, the susceptibility of >6000 recent clinical isolates for a prototype compound, NcRTI-1, was determined. Over 80% of the profiled clinical isolates remained susceptible for NcRTI-1 (FC 1700 of these viruses showed that the combination of active site mutations M184V+Y115F correlated most with resistance to NcRTI-1 (FC=75). Analysis also indicated that the K65R mutation is associated with hypersusceptibility to NcRTI-1 and that it reverses the reduced susceptibility caused by M184V. These findings were confirmed in SDM strains. This reciprocity between the K65R and M184V mutation is unparalleled among RT inhibitors. When replicating wild-type HIV-1 in the presence of NcRTI-1, M184V+Y115F were selected. In the presence of both NcRTI-1 and tenofovir, NcRTI-1 prevents the selection of K65R.

摘要翻译： 核苷酸竞争性逆转录酶抑制剂（NcRTI）与HIV逆转录酶（RT）的活性位点结合，与下一个进入的核苷酸竞争。 为了进一步研究RT抑制剂抗性突变对NcRTIs活性的影响，确定了原始化合物NcRTI-1的> 6000个近临床分离株的敏感性。 超过80％的异型临床分离物对NcRTI-1仍然敏感（FC <4）。 NcRTI-1和目前使用的RT抑制剂之间没有观察到交叉耐药性，除了3TC / FTC的有限交叉耐药性外。 对这些病毒> 1700的基因型的分析表明，活性位点突变M184V + Y115F的组合与NcRTI-1的抗性最相关（FC = 75）。 分析也表明，K65R突变与NcRTI-1的过度敏感性相关，并且反转了由M184V引起的降低的易感性。 这些发现在SDM菌株中得到证实。 K65R和M184V突变之间的这种互惠性在RT抑制剂中是无与伦比的。 在NcRTI-1存在下复制野生型HIV-1时，选择M184V + Y115F。 在NcRTI-1和替诺福韦两者的存在下，NcRTI-1阻止K65R的选择。

公开(公告)号：US07465727B2

公开(公告)日：2008-12-16

申请号：US11909747

申请日：2006-04-11

申请人： Abdellah Tahri ,  Lili Hu ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

发明人： Abdellah Tahri ,  Lili Hu ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

IPC分类号： C07D498/04 ,  A61K31/5365

CPC分类号： C07D498/04

摘要： The present invention relates to 5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenyl methanone derivatives as inhibitors of the viral replication of the HIV virus, processes for their preparation as well as pharmaceutical compositions, their use as medicines, and diagnostic kits comprising them. The present invention also concerns combinations of the present HIV inhibitors with other anti-retroviral agents. It further relates to their use in assays as reference compounds or as reagents. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.

摘要翻译： 本发明涉及作为HIV病毒的病毒复制的抑制剂的5H-吡唑并[1,5-c] [1,3]苯并恶嗪-5-基）苯基甲酮衍生物，其制备方法以及药物组合物， 它们用作药物，以及包括它们的诊断试剂盒。 本发明还涉及本发明的HIV抑制剂与其它抗逆转录病毒剂的组合。 它还涉及它们在测定中作为参考化合物或作为试剂的用途。 本发明的化合物可用于预防或治疗HIV感染和治疗AIDS。

公开(公告)号：US20080214534A1

公开(公告)日：2008-09-04

申请号：US11909747

申请日：2006-04-11

申请人： Abdellah Tahri ,  Lili Hu ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

发明人： Abdellah Tahri ,  Lili Hu ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

IPC分类号： A61K31/5383 ,  C07D498/04 ,  A61P31/18

CPC分类号： C07D498/04

摘要： The present invention relates to 5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenyl methanone derivatives as inhibitors of the viral replication of the HIV virus, processes for their preparation as well as pharmaceutical compositions, their use as medicines, and diagnostic kits comprising them. The present invention also concerns combinations of the present HIV inhibitors with other anti-retroviral agents. It further relates to their use in assays as reference compounds or as reagents. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.

摘要翻译： 本发明涉及作为HIV病毒的病毒复制的抑制剂的5H-吡唑并[1,5-c] [1,3]苯并恶嗪-5-基）苯基甲酮衍生物，其制备方法以及药物组合物， 它们用作药物，以及包括它们的诊断试剂盒。 本发明还涉及本发明的HIV抑制剂与其它抗逆转录病毒剂的组合。 它还涉及它们在测定中作为参考化合物或作为试剂的用途。 本发明的化合物可用于预防或治疗HIV感染和治疗AIDS。

公开(公告)号：US08580981B2

公开(公告)日：2013-11-12

申请号：US13060942

申请日：2009-09-01

申请人： Piet Tom Bert Paul Wigerinck ,  Dominique Louis Nestor Ghislain Surleraux ,  Wim Gaston Verschueren ,  Herman Augustinus De Kock ,  Wim Albert Alex Aelterman

发明人： Piet Tom Bert Paul Wigerinck ,  Dominique Louis Nestor Ghislain Surleraux ,  Wim Gaston Verschueren ,  Herman Augustinus De Kock ,  Wim Albert Alex Aelterman

IPC分类号： C07D493/04

CPC分类号： C07D493/04

摘要： The present invention relates to a process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate as well as novel intermediates for use in said process. (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate is particularly useful as an HIV protease inhibitor.

摘要翻译： 本发明涉及制备（3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基] 异丁基）氨基] -1-苄基-2-羟基丙基氨基甲酸酯以及用于所述方法的新型中间体。 （3R，3aS，6aR） - 六氢呋喃并[2,3-b]呋喃-3-基（1S，2R）-3 - [[（4-氨基苯基）磺酰基]（异丁基）氨基] -1-苄基-2- 羟丙基氨基甲酸酯特别可用作HIV蛋白酶抑制剂。

公开(公告)号：US08084494B2

公开(公告)日：2011-12-27

申请号：US12094799

申请日：2006-11-28

申请人： Herman Augustinus De Kock ,  Tim Hugo Maria Jonckers ,  Stefaan Julien Last ,  Paul Jozef Gabriel Maria Boonants ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

发明人： Herman Augustinus De Kock ,  Tim Hugo Maria Jonckers ,  Stefaan Julien Last ,  Paul Jozef Gabriel Maria Boonants ,  Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck

IPC分类号： A61K31/343 ,  C07D493/04

CPC分类号： C07D493/04

摘要： The present invention concerns substituted aminophenylsulfonamide compounds, their use as protease inhibitors, in particular as broad-spectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present substituted aminophenylsulfonamide compounds with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents.

摘要翻译： 本发明涉及取代的氨基苯基磺酰胺化合物，它们作为蛋白酶抑制剂的用途，特别是广谱的HIV蛋白酶抑制剂，其制备方法以及包含它们的药物组合物和诊断试剂盒。 本发明还涉及本发明的取代氨基苯基磺酰胺化合物与另一种抗逆转录病毒剂的组合。 它还涉及它们在测定中作为参考化合物或作为试剂的用途。