公开(公告)号：US06197772B1

公开(公告)日：2001-03-06

申请号：US09054963

申请日：1998-04-03

申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

IPC分类号： A61K31496

CPC分类号： C07D401/12 ,  C07D211/58 ,  C07D405/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04 ,  Y02P20/55

摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐和立体异构形式作为物质-P拮抗剂; 其制剂，含有它们的组合物及其作为药物的用途。

公开(公告)号：US06521621B1

公开(公告)日：2003-02-18

申请号：US09745513

申请日：2000-12-22

申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

IPC分类号： A61K31496

CPC分类号： C07D401/12 ,  C07D211/58 ,  C07D405/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04 ,  Y02P20/55

摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 1 or 2; ═Q is ═O or ═NR3; X is a covalent bond or a bivalent radical of formula —O—, —S—, —NR3—; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent; R2 is Ar2, Ar2C1-6alkyl, Het1 or Het1C1-6alkyl; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substituents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2; C3-6alkenyl; Ar3C3-6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula (a-1), (a-2), (a-3), (a-4) or (a-5); Ar1, Ar2 and Ar3 are each phenyl or substituted phenyl; Het1 and Het2 are each monocyclic or a bicyclic heterocycles; as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐和立体异构形式，其中n为0,1或2; m为1或2，条件是如果m为2，则n为1; p为1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R 1是Ar 1，Ar 1 C 1-6烷基或二（Ar 1）C 1-6烷基，其中每个C 1-6烷基任选被羟基，C 1-4烷氧基，氧代或缩酮化的取代基取代; R2是Ar2，Ar2C1-6烷基，Het1或Het1C1-6烷基; R3是氢或C1-6烷基; L是氢; Ar3; C 1-6烷基; 被1或2个选自羟基，C 1-6烷氧基，Ar 3，Ar 3 C 1-6烷氧基和Het 2的取代基取代的C 1-6烷基; C 3-6烯基; Ar3C3-6烯基; 二（Ar 3）C 3-6烯基或式（a-1），（a-2），（a-3），（a-4）或（a-5）的基团。 Ar 1，Ar 2和Ar 3分别为苯基或取代的苯基; Het1和Het2分别是单环或双环杂环; 作为物质-P拮抗剂; 其制剂，含有它们的组合物及其作为药物的用途。

公开(公告)号：US06169097A

公开(公告)日：2001-01-02

申请号：US09102295

申请日：1998-06-22

申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Yves Emiel Maria Van Roosbroeck

发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Yves Emiel Maria Van Roosbroeck

IPC分类号： A61K31445

CPC分类号： C07D401/06 ,  C07D211/44 ,  C07D211/46 ,  C07D211/52 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14 ,  C07D471/10 ,  C07D491/10

摘要： The present invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 0, 1 or 2; ═Q is ═O or ═NR3; X is a covalent bond or a bivalent radical of formula —O—, —S—, —NR3—; R1 is Ar1; Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent of formula —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—; R2 is Ar2; Ar2C1-6alkyl; Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; R4 is hydrogen; C1-4alkyl; C1-4aklyloxyC1-4alkyl; hydroxyC1-4alkyl; carboxyl; C1-4aklyloxycarbonyl or Ar3; R5 is hydrogen; hydroxy; Ar3; Ar3C1-6alkyloxy; di(Ar3)C1-6alkyloxy; Ar3C1-6alkylthio; di(Ar3)C1-6alkylthio; Ar3C1-6alkylsulfoxy; di(Ar3)C1-6alkylsulfoxy; Ar3C1-6alkylsulfonyl; di(Ar3)C1-6alkylsulfonyl; —NR7R8; C1-6alkyl substituted with —NR7R8; or a radical of formula (a-1) or (a-2); R4 and R5 may also be taken together; R6 is hydrogen; hydroxy; C1-6alkyloxy; C1-6alkyl or Ar3C1-6alkyl; Ar1, Ar2 and Ar3 are phenyl or substituted phenyl; Ar2 is also naphtalenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; as substance P antagonists; their preparation, compositions containing them and their use as a medicine.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构形式，其中n为0,1或2; m为1或2，条件是如果m为2，则n为1; p为0,1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R1是Ar1; Ar 1 C 1-6烷基或二（Ar 1）C 1-6烷基，其中每个C 1-6烷基任选被羟基，C 1-4烷氧基，氧代或式-O-CH 2 -CH 2 -O-或-O-CH 2 -CH2-CH2-O-; R2是Ar2; Ar2C1-6烷基; Het或HetC 1-6烷基; R3是氢或C1-6烷基; R4是氢; C 1-4烷基; C 1-4烷氧基C 1-4烷基; 羟基C 1-4烷基; 羧基; C 1-4烷氧基羰基或Ar 3; R5是氢; 羟基; Ar3; Ar 3 C 1-6烷氧基; 二（Ar 3）C 1-6烷氧基; Ar 3 C 1-6烷硫基; 二（Ar 3）C 1-6烷硫基; Ar3C1-6烷基磺酰基; 二（Ar 3）C 1-6烷基亚磺酰基; Ar 3 C 1-6烷基磺酰基; 二（Ar 3）C 1-6烷基磺酰基; -NR7R8; 被-NR 7 R 8取代的C 1-6烷基; 或式（a-1）或（a-2）的基团; R4和R5也可以一起使用; R6是氢; 羟基; C 1-6烷氧基; C 1-6烷基或Ar 3 C 1-6烷基; Ar1，Ar2和Ar3是苯基或

公开(公告)号：US06346540B1

公开(公告)日：2002-02-12

申请号：US09615523

申请日：2000-07-13

申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Yves Emiel Maria Van Roosbroeck

发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Yves Emiel Maria Van Roosbroeck

IPC分类号： A61K31454

CPC分类号： C07D401/06 ,  C07D211/44 ,  C07D211/46 ,  C07D211/52 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14 ,  C07D471/10 ,  C07D491/10

摘要： The present invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 0, 1 or 2; ═Q is ═O or ═NR3; X is a covalent bond or a bivalent radical of formula —O—, —S—, —NR3—; R1 is Ar1; Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent of formula —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—; R2 is Ar2; Ar2C1-6alkyl; Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; R4 is hydrogen; C1-4alkyl; C1-4alkyloxyC1-4alkyl; hydroxyC1-4alkyl; carboxyl; C1-4alkyloxycarbonyl or Ar3; R5 is hydrogen; hydroxy; Ar3; Ar3C1-6alkyloxy; di(Ar3)C1-6alkyloxy; Ar3C1-6alkylthio; di(Ar3)C1-6alkylthio; Ar3C1-6alkylsulfoxy; di(Ar3)C1-6alkylsulfoxy; Ar3C1-6alkylsulfonyl; di(Ar3)C1-6alkylsulfonyl; —NR7R8; C1-6alkyl substituted with —NR7R8; or a radical of formula (a-1) or (a-2); R4 and R5 may also be taken together; R6 is hydroxy; C1-6alkyloxy; C1-6alkyl or Ar3C1-6alkyl; Ar1, Ar2 and Ar3 are phenyl or substituted phenyl; Ar2 is also naphtalenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; as substance P antagonists; their preparation, compositions containing them and their use as a medicine.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构形式，其中n为0,1或2; m为1或2，条件是如果m为2，则n为1; p为0,1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R1是Ar1; Ar 1 C 1-6烷基或二（Ar 1）C 1-6烷基，其中每个C 1-6烷基任选被羟基，C 1-4烷氧基，氧代或式-O-CH 2 -CH 2 -O-或-O-CH 2 -CH2-CH2-O-; R2是Ar2; Ar2C1-6烷基; Het或HetC 1-6烷基; R3是氢或C1-6烷基; R4是氢; C 1-4烷基; C 1-4烷氧基C 1-4烷基; 羟基C 1-4烷基; 羧基; C 1-4烷氧基羰基或Ar 3; R5是氢; 羟基; Ar3; Ar 3 C 1-6烷氧基; 二（Ar 3）C 1-6烷氧基; Ar 3 C 1-6烷硫基; 二（Ar 3）C 1-6烷硫基; Ar3C1-6烷基磺酰基; 二（Ar 3）C 1-6烷基亚磺酰基; Ar 3 C 1-6烷基磺酰基; 二（Ar 3）C 1-6烷基磺酰基; -NR7R8; 被-NR 7 R 8取代的C 1-6烷基; 或式（a-1）或（a-2）的基团; R4和R5也可以一起使用; R6是羟基; C 1-6烷氧基; C 1-6烷基或Ar 3 C 1-6烷基; Ar1，Ar2和Ar3是苯基或取代基

公开(公告)号：US06218381B1

公开(公告)日：2001-04-17

申请号：US09142932

申请日：1998-09-17

申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

IPC分类号： A61K31435

CPC分类号： C07D487/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14

摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dotted line is an optional bond; n is 1 or 2; R1 is hydrogen; halo; formyl; C1-4alkyl optionally substituted with hydroxy, C1-4alkyloxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula —X—COOR5, —X—CONR6R7 or —X—COR10 wherein —X— is a direct bond, C1-4alkanediyl or C2-6alkenediyl; R5 is hydrogen, C1-12alkyl, Ar, Het, C1-6alkyl substituted with C1-4alkyloxy, aryl or heteroaryl; R6 and R7 each independently are hydrogen or C1-4alkyl; R2 is hydrogen, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl; R3 is hydrogen, C1-4alkyl or C1-4alkyloxy; R4 is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Z is —CH2—, —CH2—CH2—, —CH═CH—, —CHOH—CH2—, —O—CH2—, —C(═O)—CH2— or —C(═NOH)—CH2—; —A—B— is a bivalent radical; A1 is a direct bond, optionally substituted C1-6alkanediyl, C1-6alkanediyl-oxy-C1-6alkanediyl, carbonyl, C1-6alkanediylcarbonyl, optionally substituted C1-6alkanediyloxy; A2 is a direct bond or C1-6alkanediyl; and Q is aryl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for inhibiting or reversing the effects of multidrug resistance.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐及其立体化学异构形式，其中虚线是任选的键; n为1或2; R1是氢; 光环; 甲酰基 任选被羟基，C 1-4烷氧基，C 1-4烷基羰基氧基，咪唑基，噻唑基或恶唑基取代的C 1-4烷基; 或式-X-COOR5，-X-CONR6R7或-X-COR10基团，其中-X-是直接键，C1-4烷二基或C2-6亚烯基; R 5是氢，C 1-12烷基，Ar，Het，被C 1-4烷氧基，芳基或杂芳基取代的C 1-6烷基; R6和R7各自独立地为氢或C1-4烷基; R 2是氢，卤素，C 1-4烷基，羟基C 1-4烷基，C 1-4烷氧基羰基，羧基，甲酰基或苯基; R3是氢，C1-4烷基或C1-4烷氧基; R 4是氢，卤素，C 1-4烷基，C 1-4烷氧基或卤代C 1-4烷基; Z是-CH 2 - ， - CH 2 -CH 2 - ， - CH = CH-，-CHOH-CH 2 - ， - O-CH 2 - ， - C（= O）-CH 2 - 或-C（= NOH） -A-B-是二价基团; A1是直接键，任选取代的C 1-6烷二基，C 1-6烷二基 - 氧基-C 1-6烷二基，羰基，C 1-6烷二基羰基，任选取代的C 1-6烷二基氧基; A2是直接键或C1-6烷二基; Q为芳基。 公开了用于制备所述产品的方法，包含所述产品的制剂及其作为药物的用途，特别是用于抑制或逆转多药耐药性的作用。

公开(公告)号：US06476018B1

公开(公告)日：2002-11-05

申请号：US09775524

申请日：2001-02-02

申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francois Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francois Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

IPC分类号： A61K31437

CPC分类号： C07D487/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14

摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dotted line is an optional bond; n is 1 or 2; R1 is hydrogen; halo; formyl; C1-4alkyl optionally substituted with hydroxy, C1-4alkyloxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula —X—COOR5, —X—CONR6R7 or —X—COR10 wherein —X— is a direct bond, C1-4alkanediyl or C2-6alkenediyl; R5 is hydrogen, C1-12alkyl, Ar, Het, C1-6alkyl substituted with C1-4alkyloxy, aryl or heteroaryl; R6 and R7 each independently are hydrogen or C1-4alkyl; R2 is hydrogen, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl; R3 is hydrogen, C1-4alkyl or C1-4alkyloxy; R4 is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Z is —CH2—, —CH2—CH2—, —CH═CH—, —CHOH—CH2—, —O—CH2—, —C(═O)—CH2— or —C(═NOH)—CH2—; —A—B— is a bivalent radical; A1 is a direct bond, optionally substituted C1-6alkanediyl, C1-6alkanediyl-oxy-C1-6alkanediyl, carbonyl, C1-6alkanediylcarbonyl, optionally substituted C1-6alkanediyloxy; A2 is a direct bond or C1-6alkanediyl; and Q is aryl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for inhibiting or reversing the effects of multidrug resistance.

摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐及其立体化学异构形式，其中虚线是任选的键; n为1或2; R1是氢; 光环; 甲酰基 任选被羟基，C 1-4烷氧基，C 1-4烷基羰基氧基，咪唑基，噻唑基或恶唑基取代的C 1-4烷基; 或式-X-COOR5，-X-CONR6R7或-X-COR10基团，其中-X-是直接键，C1-4烷二基或C2-6亚烯基; R 5是氢，C 1-12烷基，Ar，Het，被C 1-4烷氧基，芳基或杂芳基取代的C 1-6烷基; R6和R7各自独立地为氢或C1-4烷基; R 2是氢，卤素，C 1-4烷基，羟基C 1-4烷基，C 1-4烷氧基羰基，羧基，甲酰基或苯基; R3是氢，C1-4烷基或C1-4烷氧基; R 4是氢，卤素，C 1-4烷基，C 1-4烷氧基或卤代C 1-4烷基; Z是-CH 2 - ， - CH 2 -CH 2 - ， - CH = CH-，-CHOH-CH 2 - ， - O-CH 2 - ， - C（= O）-CH 2 - 或-C（= NOH） -A-B-是二价基团; A1是直接键，任选取代的C 1-6烷二基，C 1-6烷二基 - 氧基-C 1-6烷二基，羰基，C 1-6烷二基羰基，任选取代的C 1-6烷二基氧基; A2是直接键或C1-6烷二基; Q为芳基。 公开了用于制备所述产品的方法，包含所述产品的制剂及其作为药物的用途，特别是用于抑制或逆转多药耐药性的作用。