公开(公告)号：US20080214648A1

公开(公告)日：2008-09-04

申请号：US10555712

申请日：2004-05-10

申请人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck ,  Jan Balzarini

发明人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck ,  Jan Balzarini

IPC分类号： A61K31/40 ,  C07D493/04 ,  C07D207/12 ,  A61P31/18 ,  A61K31/34

CPC分类号： C07D493/04 ,  A61K38/00 ,  A61K47/64 ,  C07H15/252 ,  C07K5/06052 ,  C07K5/06113 ,  C07K5/0808 ,  C07K5/1008 ,  C07K5/101 ,  C07K5/1019 ,  C07K5/1021 ,  C07K7/06 ,  C07K9/003

摘要： The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formula the stereoisomeric forms and salts thereof, wherein n is 1 to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R1 is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4alkyloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R2 is arylC1-4alkyl; R3 is C1-10alkyl, C2-6alkenyl or C3-7cycloalkylC1-4alkyl; R4 is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.

摘要翻译： 本发明提供了新的前体药物，其是治疗化合物和肽的缀合物，其中缀合物可被二肽基肽酶切割，更优选通过CD26，也称为DPPIV（二肽基氨基二肽酶IV））。 本发明的前药具有式的立体异构形式及其盐，其中n为1至5; Y是脯氨酸，丙氨酸，羟脯氨酸，二羟脯氨酸，噻唑烷羧酸（硫脯氨酸），脱氢脯氨酸，哌可酸（L-高脯氨酸），氮杂环丁烷羧酸，氮丙啶羧酸，甘氨酸，丝氨酸，缬氨酸，亮氨酸，异亮氨酸和苏氨酸; X选自D-或L-构型中的任何氨基酸; [Y-X]的每个重复中的X和Y彼此独立地独立地选自其它重复; Z是直接键或具有1至4个碳原子的二价直链或支链饱和烃基; R 1是芳基，杂芳基，芳氧基，杂芳氧基，芳氧基C 1-4烷基，杂环烷氧基，杂环烷基C 1-4烷氧基，杂芳氧基C 1-4烷基，杂芳基C 1-4烷氧基; R 2是芳基C 1-4烷基; R 3是C 1-10烷基，C 2-6链烯基或C 3-7环烷基C SUB 1-4烷基; R 4是氢或C 1-4烷基。 本发明还提供所述前体药物作为药物的用途以及制备所述前体药物的方法。

公开(公告)号：US20110160468A1

公开(公告)日：2011-06-30

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 ,  C07C213/08 ,  C07C271/20 ,  C07C215/28

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：US08557854B2

公开(公告)日：2013-10-15

申请号：US11911465

申请日：2006-04-14

申请人： Gerben Albert Van 'T Klooster ,  Piet Tom Bert Paul Wigerinck ,  Sandra De Meyer ,  Lieven Elvire Colette Baert ,  Herman Augustinus De Kock

发明人： Gerben Albert Van 'T Klooster ,  Piet Tom Bert Paul Wigerinck ,  Sandra De Meyer ,  Lieven Elvire Colette Baert ,  Herman Augustinus De Kock

IPC分类号： A61K31/423 ,  C07D277/24

CPC分类号： C07D417/12

摘要： A method for improving the pharmacokinetics of drugs, which are metabolized by cytochrome P450 monooxygenase is disclosed. More specifically it relates to a method for improving the pharmacokinetics of retroviral protease inhibitors and in particular for improving the pharmacokinetics of human immunodeficiency virus (HIV) protease inhibitors. A pharmaceutical composition and its use in the manufacture of a medicament for the inhibition or treatment of an HIV infection or AIDS in a human being are also part of the invention.

摘要翻译： 公开了一种改善由细胞色素P450单加氧酶代谢的药物的药代动力学的方法。 更具体地说，本发明涉及一种用于改善逆转录病毒蛋白酶抑制剂的药代动力学的方法，特别涉及改善人类免疫缺陷病毒（HIV）蛋白酶抑制剂的药代动力学。 药物组合物及其在制备用于抑制或治疗人体中的HIV感染或AIDS的药物中的用途也是本发明的一部分。

公开(公告)号：US20100121060A1

公开(公告)日：2010-05-13

申请号：US12690673

申请日：2010-01-20

申请人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck

发明人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck

IPC分类号： C07D239/48

CPC分类号： C07D239/48 ,  C07D405/12

摘要： HIV replication inhibitors of formula pharmaceutically acceptable addition salts; or stereochemically isomeric forms thereof, wherein R1 is halo; R2 and R3 each independently are C1-6alkyl; pharmaceutical compositions containing these compounds as active ingredient and processes for preparing these compounds and compositions.

摘要翻译： 式可复用的药学上可接受的加成盐的HIV复制抑制剂; 或其立体化学异构体形式，其中R 1为卤素; R2和R3各自独立地为C1-6烷基; 含有这些化合物作为活性成分的药物组合物和制备这些化合物和组合物的方法。

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：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。

公开(公告)号：US07803836B2

公开(公告)日：2010-09-28

申请号：US12094697

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： C07D405/02 ,  A61K31/4025

CPC分类号： C07D493/04

摘要： The present invention concerns substituted aminophenylsulfonamide compounds and derivatives, their use as protease inhibitors, in particular as broadspectrum 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 and derivatives 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及其衍生物，它们作为蛋白酶抑制剂的用途，特别是作为广谱的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和其衍生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。

公开(公告)号：US20080214588A1

公开(公告)日：2008-09-04

申请号：US11814982

申请日：2006-03-02

申请人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck

发明人： Herman Augustinus De Kock ,  Piet Tom Bert Paul Wigerinck

IPC分类号： A61K31/513 ,  C07D239/48 ,  A61P31/18

CPC分类号： C07D239/48 ,  C07D405/12

摘要： HIV replication inhibitors of formula (I) pharmaceutically acceptable addition salts; or stereochemically isomeric forms thereof, wherein R1 is halo; R2 and R3 each independently are C1-6alkyl; pharmaceutical compositions containing these compounds as active ingredient and processes for preparing these compounds and compositions.

摘要翻译： 式（I）的HIV复制抑制剂药学上可接受的加成盐; 或其立体化学异构体形式，其中R 1是卤素; R 2和R 3各自独立地为C 1-6烷基; 含有这些化合物作为活性成分的药物组合物和制备这些化合物和组合物的方法。

公开(公告)号：US08143421B2

公开(公告)日：2012-03-27

申请号：US12430547

申请日：2009-04-27

申请人： Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Marieke Christiane Johanna Diepenbeek Voets ,  Sandrine Marie Helene Vendeville ,  Herman Augustinus De Kock ,  Bernhard Joanna Bernard Vergouwen

发明人： Dominique Louis Nestor Ghislain Surleraux ,  Piet Tom Bert Paul Wigerinck ,  Marieke Christiane Johanna Diepenbeek Voets ,  Sandrine Marie Helene Vendeville ,  Herman Augustinus De Kock ,  Bernhard Joanna Bernard Vergouwen

IPC分类号： A61K31/4184 ,  C07D405/12

CPC分类号： C07D401/12 ,  A61K31/415 ,  C07D235/30 ,  C07D235/32 ,  C07D405/12 ,  C07D413/12 ,  C07D417/12 ,  C07D493/04

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 amino-C1-6alkyl; R6 is C1-6alkylO, Het1, Het1O, Het2, Het2O, aryl, arylO, C1-6alkyloxy-carbonylamino 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′ R12 is H, —NH2, —NR5AR6, —C1-6alkyl or alkyl-W—R14, wherein said alkyl is optionally substituted with halogen, hydroxy, aryl, heteroaryl, Het1, Het2, or amino wherein said amino is optionally mono- or di-substituted with C1-4alkyl and R13 is H, C1-6-alkyl, optionally substituted by aryl, Het1, Het2, hydroxy, halogen, amino whereby the amino group may be optionally be mono- or di-substituted with C1-4alkyl.