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    • 1. 发明申请
    • 1,3-DIHYDRO-1-(PHENYLALKENYL)-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDE IV AND CYTOKINE INHIBITING ACTIVITY
    • 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
    • WO1996031486A1
    • 1996-10-10
    • PCT/EP1996001395
    • 1996-03-28
    • JANSSEN PHARMACEUTICA N.V.FREYNE, Eddy, Jean, EdgardDIELS, Gaston, Stanislas, MarcellaANDRES-GIL, José IgnacioFERNANDEZ-GADEA, Francisco Javier
    • JANSSEN PHARMACEUTICA N.V.
    • C07D233/32
    • C07D233/32C07D233/70
    • 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.
    • 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
    • VASOCONSTRICTIVE SUBSTITUTED DIHYDROPYRANOPYRIDINES
    • 血管内取代二氢吡啶类药物
    • WO1995005381A1
    • 1995-02-23
    • PCT/EP1994002700
    • 1994-08-12
    • JANSSEN PHARMACEUTICA N.V.VAN LOMMEN, Guy, Rosalia, EugèneFERNANDEZ-GADEA, Francisco JavierANDRES-GIL, José IgnacioMATESANZ-BALLESTEROS, Maria Encarnacion
    • JANSSEN PHARMACEUTICA N.V.
    • C07D491/04
    • C07D491/04
    • 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.
    • 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
    • SUBSTITUTED TETRACYCLIC OXAZEPINE AND THIAZEPINE DERIVATIVES WITH 5-HT2 RECEPTOR AFFINITY
    • 具有5-HT2受体亲和力的取代的四环氧化物和噻唑衍生物
    • WO1996014321A1
    • 1996-05-17
    • PCT/EP1995004197
    • 1995-10-25
    • JANSSEN PHARMACEUTICA N.V.FERNANDEZ-GADEA, Francisco JavierSIPIDO, Victor, KarelANDRES-GIL, José IgnacioMEERT, Theo, Frans
    • JANSSEN PHARMACEUTICA N.V.
    • C07D498/04
    • C07D513/04
    • 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.
    • 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
    • VASOCONSTRICTIVE SUBSTITUTED 2,3-DIHYDRO-1,4-DIOXINOPYRIDINES
    • 血管造影取代2,3-二氢-1,4-二氧杂环丙啶
    • WO1996024596A1
    • 1996-08-15
    • PCT/EP1996000396
    • 1996-01-30
    • JANSSEN PHARMACEUTICA N.V.VAN LOMMEN, Guy, Rosalia, EugèneANDRES-GIL, José IgnacioFERNANDEZ-GADEA, Francisco JavierMATESANZ-BALLESTEROS, Maria Encarnacion
    • JANSSEN PHARMACEUTICA N.V.
    • C07D491/04
    • C07D491/04
    • 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.
    • 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
    • 1,3-DIHYDRO-1-(PHENYLALKYL)-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDEIV AND CYTOKINE ACTIVITY
    • 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
    • WO1996031485A1
    • 1996-10-10
    • PCT/EP1996001394
    • 1996-03-28
    • JANSSEN PHARMACEUTICA N.V.FREYNE, Eddy, Jean, EdgardDIELS, Gaston, Stanislas, MarcellaANDRES GIL, José IgnacioFERNANDEZ GADEA, Francisco Javier
    • JANSSEN PHARMACEUTICA N.V.
    • C07D233/32
    • C07D401/06C07D233/36C07D233/38C07D233/70
    • 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.
    • 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
    • PDE IV INHIBITING 2-CYANOIMINOIMIDAZOLE DERIVATIVES
    • PDE IV抑制2-氰基氨基咪唑衍生物
    • WO1998014432A1
    • 1998-04-09
    • PCT/EP1997005322
    • 1997-09-24
    • JANSSEN PHARMACEUTICA N.V.FREYNE, Eddy, Jean, EdgardFERNANDEZ-GADEA, Francisco JavierANDRES-GIL, José Ignacio
    • JANSSEN PHARMACEUTICA N.V.
    • C07D233/44
    • C07D405/12C07D233/48C07D233/88
    • 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.
    • 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
    • 1,3-DIHYDRO-2H-IMIDAZOL-2-ONE DERIVATIVES HAVING PDE IV AND CYTOKININ INHIBITING ACTIVITY
    • 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
    • WO1996031487A1
    • 1996-10-10
    • PCT/EP1996001393
    • 1996-03-28
    • JANSSEN PHARMACEUTICA N.V.FREYNE, Eddy, Jean, EdgardDIELS, Gaston, Stanislas, MarcellaANDRES-GIL, José, IgnacioFERNANDEZ-GADEA, Francisco, Javier
    • JANSSEN PHARMACEUTICA N.V.
    • C07D233/70
    • C07D405/04C07D233/32C07D233/70
    • 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.
    • 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
    • SUBSTITUTED TETRACYCLIC AZEPINE DERIVATIVES WHICH HAVE AFFINITY FOR 5-HT2 RECEPTORS
    • 具有5-HT2受体亲和力的取代的四环唑衍生物
    • WO1996014320A1
    • 1996-05-17
    • PCT/EP1995004196
    • 1995-10-25
    • JANSSEN PHARMACEUTICA N.V.SIPIDO, Victor, KarelFERNANDEZ-GADEA, Francisco JavierANDRES-GIL, José IgnacioMEERT, Theo, FransGIL-LOPETEGUI, Pilar
    • JANSSEN PHARMACEUTICA N.V.
    • C07D498/04
    • C07D223/20
    • 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.
    • 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。