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1. 发明申请

WO1996031486A1 1,3-DIHYDRO-1-(PHENYLALKENYL)-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDE IV AND CYTOKINE INHIBITING ACTIVITY 审中-公开
标题翻译：具有PDE IV和细胞因子抑制活性的1,3-二氢-1-（苯乙烯基）-2H-咪唑-2-酮衍生物
公开(公告)号：WO1996031486A1
公开(公告)日：1996-10-10
申请号：PCT/EP1996001395
申请日：1996-03-28
申请人： JANSSEN PHARMACEUTICA N.V. , FREYNE, Eddy, Jean, Edgard , DIELS, Gaston, Stanislas, Marcella , ANDRES-GIL, José Ignacio , FERNANDEZ-GADEA, Francisco Javier
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D233/32
CPC分类号： C07D233/32 , C07D233/70
摘要： The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceuticlaly acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein R and R each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; R is hydrogen, halo or C1-6alkyloxy; R is hydrogen; cyano; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl or aryl; R is hydrogen; cyano; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl or aryl; Y is a direct bond or C1-3alkanediyl; -A-B- is a bivalent radical of formula -CR =CR - or -CHR -CHR -; L is hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het is morpholinyl or optionally substituted piperidinyl, -piperazinyl, -pyridinyl; -furanyl or -thienyl; having PDE IV and cytokine inhibiting acitivity. Further, pharmaceutical compositions, preparations and use as a medicine are described.
摘要翻译：本发明涉及式（I）化合物，N-氧化物形式，药学上可接受的酸或碱加成盐及其立体化学异构形式，其中R 1和R 2各自独立地为氢; C1-6烷基; 二氟; 三氟甲基; 3-6环; 含有一个或两个选自氧，硫或氮的杂原子的饱和的5-，6-或7-元杂环; 二氢化茚基; 二环[2.2.1] -2-庚烯基; 二环[2.2.1]庚烷基; C1-6alkylsulfonyl; 芳基磺酰基; 或取代的C 1-10烷基; R 3是氢，卤素或C 1-6烷氧基; R 4是氢; 氰基; 任选取代的C 1-6烷基; C 1-6烷氧基羰基或芳基; R 5是氢; 氰基; 任选取代的C 1-6烷基; C 1-6烷氧基羰基或芳基; Y是直接键或C1-3烷二基; -A-B-是式-CR 6 = CR 7 - 或-CHR 6 -CHR 7 - 的二价基团; L是氢; 任选取代的C 1-6烷基; C1-6烷基; C1-6alkyloxycarbonyl; C 1-6烷基磺酰基或芳基磺酰基; 芳基是任选取代的苯基; Het是吗啉基或任选取代的哌啶基，哌嗪基， - 吡啶基; - 呋喃基或 - 噻吩基; 具有PDE IV和细胞因子抑制活性。此外，描述了作为药物的药物组合物，制剂和用途。

2. 发明申请

WO1995005381A1 VASOCONSTRICTIVE SUBSTITUTED DIHYDROPYRANOPYRIDINES 审中-公开
标题翻译：血管内取代二氢吡啶类药物
公开(公告)号：WO1995005381A1
公开(公告)日：1995-02-23
申请号：PCT/EP1994002700
申请日：1994-08-12
申请人： JANSSEN PHARMACEUTICA N.V. , VAN LOMMEN, Guy, Rosalia, Eugène , FERNANDEZ-GADEA, Francisco Javier , ANDRES-GIL, José Ignacio , MATESANZ-BALLESTEROS, Maria Encarnacion
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D491/04
CPC分类号： C07D491/04
摘要： The present invention is concerned with compounds of formula (I), the pharmaceutically acceptable acid addition salts thereof, the N &cir& _-oxides thereof and the stereochemically isomeric forms thereof, wherein =a1-a2=a3-a4= is a bivalent radical of formula: =N-CH=CH-CH= (a); =CH-N=CH-CH= (b); =CH-CH=N-CH= (c); =CH-CH=CH-N= (d), wherein in said bivalent radicals one or two hydrogen atoms can be substituted by halo, hydroxy, C1-6 alkyl or C1-6 alkyloxy; R is hydrogen or C1-6 alkyl; R is hydrogen or C1-6 alkyl; R is hydrogen or C1-6 alkyl; Alk is C1-5 alkanediyl; Alk is C2-15 alkanediyl; Q is a five- or six-membered heterocyclic ring containing at least one nitrogen atom or a radical of formula (aa), wherein R is hydrogen, cyano, aminocarbonyl or C1-6 alkyl; R is hydrogen, C1-6 alkyl, C3-6 alkenyl or C3-6 alkynyl; R is hydrogen or C1-6 alkyl; or R and R taken together may form a bivalent radical of formula -(CH2)4- or -(CH2)5-. Pharmaceutical compositions, preparations and use as medicine are described.
摘要翻译：本发明涉及式（I）化合物，其药学上可接受的酸加成盐，其N-氧化物及其立体化学异构形式，其中= a1-a2 = a3-a4 =是式：= N-CH = CH-CH =（a）; = CH-N = CH-CH =（b）; = CH-CH = N-CH =（c）; = CH-CH = CH-N =（d），其中在所述二价基团中，一个或两个氢原子可以被卤素，羟基，C 1-6烷基或C 1-6烷氧基取代; R 1是氢或C 1-6烷基; R 2是氢或C 1-6烷基; R 3是氢或C 1-6烷基; Alk 1是C 1-5烷二基; Alk 2是C 2-15烷二基; Q是含有至少一个氮原子或式（aa）基团的五元或六元杂环，其中R 4是氢，氰基，氨基羰基或C 1-6烷基; R 5是氢，C 1-6烷基，C 3-6烯基或C 3-6炔基; R 6是氢或C 1-6烷基; 或R 5和R 6一起可以形成式 - （CH 2）4 - 或 - （CH 2）5 - 的二价基团。描述了作为药物的药物组合物，制剂和用途。

3. 发明申请

WO1996014321A1 SUBSTITUTED TETRACYCLIC OXAZEPINE AND THIAZEPINE DERIVATIVES WITH 5-HT2 RECEPTOR AFFINITY 审中-公开
标题翻译：具有5-HT2受体亲和力的取代的四环氧化物和噻唑衍生物
公开(公告)号：WO1996014321A1
公开(公告)日：1996-05-17
申请号：PCT/EP1995004197
申请日：1995-10-25
申请人： JANSSEN PHARMACEUTICA N.V. , FERNANDEZ-GADEA, Francisco Javier , SIPIDO, Victor, Karel , ANDRES-GIL, José Ignacio , MEERT, Theo, Frans
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D498/04
CPC分类号： C07D513/04
摘要： This invention concerns the compounds of Formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof, and also the N-oxide forms thereof. In said formula, R and R each independently are hydrogen; C1-6 alkyl; C1-6 alkylcarbonyl; trihalomethylcarbonyl; C1-6 alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6 alkylcarbonyloxy, C1-6 alkyloxycarbonyl or aryl; or R and R taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; R to R each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluormethoxy, carboxyl, nitro, amino, mono-or di(C1-6alkyl)amino, C1-6 alkylcarbonylamino, aminosulfonyl, mono-or di(C1-6alkyl)- aminosulfonyl, C1-6 alkyl, C1-6 alkyloxy, C1-6alkylcarbonyl, C1-6 alkyloxycarbonyl; R is hydrogen, C1-6alkyl, or trifluoromethyl; R is hydrogen, C1-6 alkyl, cyano, or trifluorotmethyl; n is zero to 6; and X is O, S, S(=O) or S(=O)2. The compounds of formula (I)may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.
摘要翻译：本发明涉及式（I）的化合物，其药学上可接受的盐和立体异构形式，以及它们的N-氧化物形式。在所述式中，R 1和R 2各自独立地为氢; C 1-6烷基; C 1-6烷基羰基; trihalomethylcarbonyl; 被羟基，C 1-6烷氧基，羧基，C 1-6烷基羰氧基，C 1-6烷氧羰基或芳基取代的C 1-6烷基; 或R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; R 3至R 10各自独立地为氢，卤素，氰基，羟基，三氟甲基，三氟甲氧基，羧基，硝基，氨基，单 - 或二（C 1-6烷基）氨基，C 1-6烷基羰基氨基，氨基磺酰基，或二（C 1-6烷基） - 氨基磺酰基，C 1-6烷基，C 1-6烷氧基，C 1-6烷基羰基，C 1-6烷氧基羰基; R 11是氢，C 1-6烷基或三氟甲基; R 12是氢，C 1-6烷基，氰基或三氟甲基; n为0〜6; X为O，S，S（= O）或S（= O）2）。式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

4. 发明申请

WO1996024596A1 VASOCONSTRICTIVE SUBSTITUTED 2,3-DIHYDRO-1,4-DIOXINOPYRIDINES 审中-公开
标题翻译：血管造影取代2,3-二氢-1,4-二氧杂环丙啶
公开(公告)号：WO1996024596A1
公开(公告)日：1996-08-15
申请号：PCT/EP1996000396
申请日：1996-01-30
申请人： JANSSEN PHARMACEUTICA N.V. , VAN LOMMEN, Guy, Rosalia, Eugène , ANDRES-GIL, José Ignacio , FERNANDEZ-GADEA, Francisco Javier , MATESANZ-BALLESTEROS, Maria Encarnacion
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D491/04
CPC分类号： C07D491/04
摘要： The present invention is concerned with compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein =a1-a2=a3-a4= is a bivalent radical of formula (a): =N-CH=CH-CH=, (b): =CH-N=CH-CH=, (c): =CH-CH=N-CH=, (d): =CH-CH=CH-N=, wherein one or two hydrogen atoms can be substituted by halo, hydroxy, C1-6 alkyl or C1-6 alkyloxy; R is hydrogen or C1-6 alkyl; R is hydrogen or C1-6 alkyl; R is hydrogen or C1-6 alkyl; Alk is C1-5 alkanediyl; Alk is C2-15 alkanediyl; Q is a five- or six-membered heterocyclic ring containing at least one nitrogen atom or a radical of formula -C(NR R )=C-R wherein R is hydrogen, cyano, aminocarbonyl or C1-6 alkyl; R is hydrogen, C1-6 alkyl, C3-6 alkenyl or C3-6 alkynyl; R is hydrogen or C1-6 alkyl; or R and R taken together may form a bivalent radical of formula -(CH2)4- or -(CH2)5-. Pharmaceutical compositions, preparations and use as a medicine are described.
摘要翻译：本发明涉及式（I）化合物，N-氧化物形式，其药学上可接受的酸加成盐及其立体化学异构形式，其中= a1-a2 = a3-a4 =是式（a ）：= N-CH = CH-CH =，（b）：= CH-N = CH-CH =，（c）：= CH-CH = N-CH =，（d）：= CH-CH = CH -N =，其中一个或两个氢原子可以被卤素，羟基，C 1-6烷基或C 1-6烷氧基取代; R 1是氢或C 1-6烷基; R 2是氢或C 1-6烷基; R 3是氢或C 1-6烷基; Alk 1是C 1-5烷二基; Alk 2是C 2-15烷二基; Q是含有至少一个氮原子或式-C（NR 5 R 6）= CR 4的基团的五元或六元杂环，其中R 4是氢，氰基，氨基羰基或C 1-6烷基; R 5是氢，C 1-6烷基，C 3-6烯基或C 3-6炔基; R 6是氢或C 1-6烷基; 或R 5和R 6一起可以形成式 - （CH 2）4 - 或 - （CH 2）5 - 的二价基团。描述了作为药物的药物组合物，制剂和用途。

5. 发明申请

WO1996031485A1 1,3-DIHYDRO-1-(PHENYLALKYL)-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDEIV AND CYTOKINE ACTIVITY 审中-公开
标题翻译：具有PDEIV和细胞因子活性的1,3-二氢-1-（苯甲醇）-2H-咪唑烷-2-酮衍生物
公开(公告)号：WO1996031485A1
公开(公告)日：1996-10-10
申请号：PCT/EP1996001394
申请日：1996-03-28
申请人： JANSSEN PHARMACEUTICA N.V. , FREYNE, Eddy, Jean, Edgard , DIELS, Gaston, Stanislas, Marcella , ANDRES GIL, José Ignacio , FERNANDEZ GADEA, Francisco Javier
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D233/32
CPC分类号： C07D401/06 , C07D233/36 , C07D233/38 , C07D233/70
摘要： The present invention describes the use of compounds for the manufacture of a medicament for treating warm-blooded animals suffering from desease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, said compounds having formula (I), the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein R and R each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7- membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; R is hydrogen, halo or C1-6alkyloxy; R is hydrogen; halo; optionally substituted C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het ; or R is a radical of the formula: -O-R ; or -NH-R ; R is hydrogen, halo, hydroxy or C1-6alkyl; or R and R taken together may form a bivalent radical of the formula: -(CH2)n-; -CH2-CH2-O-CH2-CH2-; -CH2-CH2-N(R )-CH2-CH2-; or -CH2-CH=CH-CH2-; Y is a direct bond, haloC1-4alkanediyl or C1-4alkanediyl; -A-B- is a bivalent radical of the formula: -CR =CR -; or -CHR -CHR -; and L is hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; optionally substituted C3-6alkenyl; optionally substituted piperidinyl; C1-6alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het is morpholinyl or optionally substituted pirydinyl, -furanyl, -thienyl, -hydroxypyridinyl, -imidazolyl, -thiazolyl, -oxazolyl, -isoquinolinyl, -quinolinonyl, -piperidinyl, or -piperazinyl; Het is morpholinyl or optionally substituted piperidinyl; -piperazinyl, -pyridinyl, -furanyl or -thienyl. The present invention also relates to new compounds having PDE IV and cytokine inhibiting activity, processes for their preparation and compositions comprising said new compounds.
摘要翻译：本发明描述了化合物在制备用于治疗患有与磷酸二酯酶IV（PDE IV）的异常酶促或催化活性相关的疾病状态的温血动物和/或与生理有害的疾病相关的温血动物的药物中的用途所述具有式（I）的化合物，N-氧化物形式，其药学上可接受的酸或碱加成盐及其立体化学异构形式，其中R 1和R 2各自独立地为氢， 2>各自独立地为氢; C1-6烷基; 二氟; 三氟甲基; 3-6环; 含有一个或两个选自氧，硫或氮的杂原子的饱和的5-，6-或7-元杂环; 二氢化茚基; 二环[2.2.1] -2-庚烯基; 二环[2.2.1]庚烷基; C1-6alkylsulfonyl; 芳基磺酰基; 或取代的C 1-10烷基; R 3是氢，卤素或C 1-6烷氧基; R 4是氢; 光环; 任选取代的C 1-6烷基; 三氟甲基; 3-6环; 羧基; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; 芳基; 杂<1>; 或R 4是下式的基团：-O-R 6; 或-NH-R 7; R 5是氢，卤素，羟基或C 1-6烷基; 或R 4和R 5一起可以形成下式的二价基团： - （CH 2）n - ; -CH2-CH2-O-CH2-CH2-; -CH2-CH2-N（R <8>） - CH2-CH2-; 或-CH 2 -CH = CH-CH 2 - ; Y是直接键，卤代C 1-4烷二基或C 1-4烷二基; -A-B-是下式的二价基团：-CR 9 = CR 10 - ; 或-CHR 9 -CHR 10 - ; L是氢; 任选取代的C 1-6烷基; C1-6烷基; C1-6alkyloxycarbonyl; 任选取代的C 3-6烯基; 任选取代的哌啶基; C 1-6烷基磺酰基或芳基磺酰基; 芳基是任选取代的苯基; - Het 1是吗啉基或任选取代的吡啶基， - 呋喃基， - 噻吩基， - 羟基吡啶基， - 咪唑基， - 噻唑基， - 恶唑基， - 异喹啉基， - 喹啉基， - 哌啶基或哌嗪基。 Het 2是吗啉基或任选取代的哌啶基; - 哌嗪基， - 吡啶基， - 呋喃基或 - 噻吩基。本发明还涉及具有PDE IV和细胞因子抑制活性的新化合物，其制备方法和包含所述新化合物的组合物。

6. 发明申请

WO1998014432A1 PDE IV INHIBITING 2-CYANOIMINOIMIDAZOLE DERIVATIVES 审中-公开
标题翻译： PDE IV抑制2-氰基氨基咪唑衍生物
公开(公告)号：WO1998014432A1
公开(公告)日：1998-04-09
申请号：PCT/EP1997005322
申请日：1997-09-24
申请人： JANSSEN PHARMACEUTICA N.V. , FREYNE, Eddy, Jean, Edgard , FERNANDEZ-GADEA, Francisco Javier , ANDRES-GIL, José Ignacio
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D233/44
CPC分类号： C07D405/12 , C07D233/48 , C07D233/88
摘要： The present invention concerns 2-cyanoiminoimidazole derivatives having formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R and R each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridinyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; R is hydrogen, halo or C1-6alkyloxy; R is hydrogen; halo; C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het ; or substituted C1-6alkyl; or R is -O-R or -NH-R ; R is hydrogen, halo, hydroxy, C1-6alkyl or C1-6alkyloxy; R is a hydrogen or C1-4alkyl; or R and R , or R and R taken together may form a bivalent radical; -A-B- is -CR =CR - or -CHR -CHR -; L is hydrogen; C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; substituted C1-6alkyl; C3-6alkenyl; substituted C3-6alkenyl; piperidinyl; substituted piperidinyl; C1-6alkylsulfonyl or arylsulfonyl; having PDE IV and cytokine inhibiting activity. The invention also relates to processes for preparing the compounds of formula (I) and pharmaceutical compositions thereof.
摘要翻译：本发明涉及具有式（I）的N-氧化物形式的2-氰基亚氨基咪唑衍生物，其药学上可接受的加成盐和立体化学异构形式，其中R 1和R 2各自独立地为氢; C1-6烷基; 二氟; 三氟甲基; 3-6环; 含有一个或两个选自氧，硫或氮的杂原子的饱和的5-，6-或7-元杂环; 二氢化茚基; 6,7-二氢-5H-cyclopentapyridinyl; 二环[2.2.1] -2-庚烯基; 二环[2.2.1]庚烷基; C1-6alkylsulfonyl; 芳基磺酰基; 或取代的C 1-10烷基; R 3是氢，卤素或C 1-6烷氧基; R 4是氢; 光环; C1-6烷基; 三氟甲基; 3-6环; 羧基; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; 芳基; 杂<1>; 或取代的C 1-6烷基; 或R 4为-O-R 7或-NH-R 8; R 5是氢，卤素，羟基，C 1-6烷基或C 1-6烷氧基; R 6是氢或C 1-4烷基; 或R 4和R 6，或R 4和R 5一起可以形成二价基团; -A-B-是-CR 10 = CR 11 - 或-CHR 10 -CHR 11 - ; L是氢; C1-6烷基; C1-6烷基; C1-6alkyloxycarbonyl; 取代的C 1-6烷基; C3-6alkenyl; 取代的C 3-6烯基; 哌啶基; 取代的哌啶基; C 1-6烷基磺酰基或芳基磺酰基; 具有PDE IV和细胞因子抑制活性。本发明还涉及制备式（I）化合物及其药物组合物的方法。

7. 发明申请

WO1996031487A1 1,3-DIHYDRO-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDE IV AND CYTOKININ INHIBITING ACTIVITY 审中-公开
标题翻译：具有PDE IV和细胞因子抑制活性的1,3-二氢-2H-咪唑-2-酮衍生物
公开(公告)号：WO1996031487A1
公开(公告)日：1996-10-10
申请号：PCT/EP1996001393
申请日：1996-03-28
申请人： JANSSEN PHARMACEUTICA N.V. , FREYNE, Eddy, Jean, Edgard , DIELS, Gaston, Stanislas, Marcella , ANDRES-GIL, José, Ignacio , FERNANDEZ-GADEA, Francisco, Javier
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D233/70
CPC分类号： C07D405/04 , C07D233/32 , C07D233/70
摘要： The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein R and R each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; R is hydrogen, halo or C1-6alkyloxy; =C=X is a bivalent radical of formula =C=O; =C=CH-R ; =C=N-O-R ; or formula (a-4); Alk is C1-4alkanediyl; -A-B- is a bivalent radical of formula: -CR =CR - or -CHR -CHR -; L is hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; optionally substituted C3-6alkenyl; optionally substituted piperidinyl; C1-6alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het is morpholinyl or optionally substituted pyridinyl, -furanyl, -thienyl, -hydroxypyridinyl, -imidazolyl, -thiazolyl, -oxazolyl, -isoquinolinyl, -quinolinonyl, -piperidinyl, -piperazinyl; and Het is morpholinyl or optionally substituted piperidinyl, -piperazinyl, -pyridinyl, -furanyl or -thienyl; having PDE IV and cytokine inhibiting activity. The invention also relates to processes for preparing the compounds of formula (I) and pharmaceutical compositions thereof.
摘要翻译：本发明涉及式（I）化合物，N-氧化物形式，其药学上可接受的酸或碱加成盐及其立体化学异构形式，其中R 1和R 2各自独立地为氢; C1-6烷基; 二氟; 三氟甲基; 3-6环; 含有一个或两个选自氧，硫或氮的杂原子的饱和的5-，6-或7-元杂环; 二氢化茚基; 二环[2.2.1] -2-庚烯基; 二环[2.2.1]庚烷基; C1-6alkylsulfonyl; 芳基磺酰基; 或取代的C 1-10烷基; R 3是氢，卤素或C 1-6烷氧基; = C = X是式= C = O的二价基团; = C = CH-R <4>; = C = N-O-R <5>; 或式（a-4）; Alk是C1-4烷二基; -A-B-是下式的二价基团：-CR 6 = CR 7 - 或-CHR 6 -CHR 7 - ; L是氢; 任选取代的C 1-6烷基; C1-6烷基; C1-6alkyloxycarbonyl; 任选取代的C 3-6烯基; 任选取代的哌啶基; C 1-6烷基磺酰基或芳基磺酰基; 芳基是任选取代的苯基; - Het 1是吗啉基或任选取代的吡啶基， - 呋喃基， - 噻吩基， - 羟基吡啶基， - 咪唑基， - 噻唑基， - 恶唑基， - 异喹啉基， - 喹啉酮基， - 哌啶基 - 和Het 2是吗啉基或任选取代的哌啶基，哌嗪基， - 吡啶基， - 呋喃基或 - 噻吩基; 具有PDE IV和细胞因子抑制活性。本发明还涉及制备式（I）化合物及其药物组合物的方法。

8. 发明申请

WO1996014320A1 SUBSTITUTED TETRACYCLIC AZEPINE DERIVATIVES WHICH HAVE AFFINITY FOR 5-HT2 RECEPTORS 审中-公开
标题翻译：具有5-HT2受体亲和力的取代的四环唑衍生物
公开(公告)号：WO1996014320A1
公开(公告)日：1996-05-17
申请号：PCT/EP1995004196
申请日：1995-10-25
申请人： JANSSEN PHARMACEUTICA N.V. , SIPIDO, Victor, Karel , FERNANDEZ-GADEA, Francisco Javier , ANDRES-GIL, José Ignacio , MEERT, Theo, Frans , GIL-LOPETEGUI, Pilar
发明人： JANSSEN PHARMACEUTICA N.V.
IPC分类号： C07D498/04
CPC分类号： C07D223/20
摘要： This invention concerns the compounds of formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof, and also the N-oxide forms thereof. In formula (I) R and R each independently are hydrogen; C1-6alkyl; C1-6alkylcarbonyl; trihalomethylcarbonyl; C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl; or R and R taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substitued heterocycle; R , R , R , R , R , R , R or R each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C1-6alkyl)-amino, C1-6alkylcarbonylamino, aminosulfonyl, mono- or di(C1-6alkyl)-aminosulfonyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxy-carbonyl; R and R are each independently hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy or R and R taken together may form mono- or di(cyano)methylene, or together with the carbon atom to which they are attached form a carbonyl or a spiro substituent; or R and R taken together may form methylene; R is hydrogen, C1-6alkyl, or trifluoromethyl; R is hydrogen, C1-6alkyl, cyano, or trifluoromethyl; n is zero to 6. These compounds were tested as mCPP-antagonists in rats. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.
摘要翻译：本发明涉及式（I）化合物，其药学上可接受的盐和立体异构形式，以及它们的N-氧化物形式。在式（I）中，R 1和R 2各自独立地为氢; C1-6烷基; C1-6烷基; trihalomethylcarbonyl; 被羟基，C 1-6烷氧基，羧基，C 1-6烷基羰基氧基，C 1-6烷氧基羰基或芳基取代的C 1-6烷基; 或R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; R 3，R 4，R 5，R 6，R 9，R 10，R 11或R 12各自独立地是氢，卤素，氰基，羟基，三氟甲基，三氟甲氧基，羧基，硝基，氨基，单或二（C 1-6烷基） - 氨基，C 1-6烷基羰基氨基，氨基磺酰基，单 - 或二（C 1-6烷基） - 氨基磺酰基，C 1-6烷基，C 1-6烷氧基， C 1-6烷基羰基，C 1-6烷氧基羰基; R 7和R 8各自独立地为氢，羟基，C 1-6烷基，C 1-6烷氧基或R 7和R 8一起可以形成一或二（氰基）亚甲基，或与它们所连接的碳原子形成羰基或螺环取代基; 或R 7和R 8一起可以形成亚甲基; R 13是氢，C 1-6烷基或三氟甲基; R 14是氢，C 1-6烷基，氰基或三氟甲基; n为0至6.这些化合物在大鼠中作为mCPP拮抗剂测试。式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

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