C6-and C9-substituted chromeno[4,3-c]isoxazoline derivatives and their use as anti-depressants
    1.
    发明授权
    C6-and C9-substituted chromeno[4,3-c]isoxazoline derivatives and their use as anti-depressants 有权
    C6-和C9-取代的色烯并[4,3-c]异恶唑啉衍生物及其作为抗抑郁剂的用途

    公开(公告)号:US07462717B2

    公开(公告)日:2008-12-09

    申请号:US10524989

    申请日:2003-08-19

    CPC分类号: C07D498/04

    摘要: The invention concerns substituted tricyclic isoxazoline derivatives, more in particular tricyclic dihydrobenzopyranoisoxazoline, dihydroquinolinoisoxazoline, dihydronaphthalenoisoxazoline and dihydrobenzothiopyranoisoxazoline derivatives substituted on at least one of the C6- and C9-positions of the phenylpart of the tricyclic moiety with a selected radical, according to Formula (I) wherein X=CH2, N—R7, S or O, R1, R2, R14 and R15 are certain specific substituents, with the proviso that at least one of R14 and R15 is not hydrogen, Pir is preferably an optionally substituted piperidinyl or piperazinyl radical and R3 represents an optionally substituted aromatic homocyclic or heterocyclic ring system including a partially or completely hydrogenated hydrocarbon chain of maximum 6 atoms long with which the ring system is attached to the Pir radical and which may contain one or more heteroatoms selected from the group of O, N and S; a process for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for the treatment of depression, anxiety, movement disorders, psychosis, Parkinson's disease and body weight disorders. The compounds according to the invention have surprisingly been shown to have a serotonine (5-HT) reuptake inhibitor activity in combination with additional α2-adrenoceptor antagonist activity and show a strong anti-depressant activity without being sedative. The invention also relates to novel combination of isoxazoline derivatives according to the invention with one or more other compounds selected from the group of antidepressants, anxiolytics, anti-psychotics and anti-Parkinson's disease drugs to improve efficacy and/or onset of action.

    摘要翻译: 本发明涉及取代的三环异恶唑啉衍生物,更具体地是三环二氢苯并吡喃恶唑啉,二氢喹诺酮异恶唑啉,二氢萘硫基异恶唑啉和二氢苯并噻唑并恶唑啉衍生物,其被三选择基团的苯基部分的C 6 - 和C 9位中的至少一个与选定的基团取代, )其中X = CH 2,N-R 7,S或O,R 1,R 2,R 14和R 15是某些具体取代基,条件是R14和R15中的至少一个不是氢,Pir优选为任选取代的哌啶基或哌嗪基 基团和R 3表示任选取代的芳族双环或杂环系统,其包括最多6个原子长的部分或完全氢化的烃链,其中环系统连接到Pir基团,并且其可以含有一个或多个选自以下的杂原子: O,N和S; 其制备方法,包含它们的药物组合物及其作为药物的用途,特别是用于治疗抑郁症,焦虑症,运动障碍,精神病,帕金森病和体重障碍。 根据本发明的化合物令人惊奇地显示具有与另外的α2-肾上腺素受体拮抗剂活性组合的5-羟色胺(5-HT)再摄取抑制剂活性,并且在没有镇静作用的情况下表现出强烈的抗抑郁活性。 本发明还涉及根据本发明的异恶唑啉衍生物与一种或多种选自抗抑郁药,抗焦虑药,抗精神病药和抗帕金森病药物的其它化合物的新组合,以改善疗效和/或起效。

    4,5-dihydro-isoxazole derivatives and their pharmaceutical use
    4.
    发明授权
    4,5-dihydro-isoxazole derivatives and their pharmaceutical use 失效
    4,5-二氢异恶唑衍生物及其药物用途

    公开(公告)号:US06583141B1

    公开(公告)日:2003-06-24

    申请号:US09807149

    申请日:2001-04-06

    IPC分类号: C07D41304

    摘要: The present invention is concerned with the compounds of formula wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5; —A1═A2—A3═A4— is a pyridinylidene, pyridazinylidene, pyrimidinylidene, pyrazinylidene or phenylidene; B represents an amide, ketone or oxadiazole; D represents Ar or Het; Q represents a covalent direct bond or a ketone, —N—, —O—, —CR5R6—, amide ethenyl, imine, sulfonyl, sulfinyl, 3-oxobutenyl, pyrazole, isoxazole or thiazole; L represents Ar or Het; R1 represents hydrogen, halo, hydroxy, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, cyano, guanidine, nitro, NR17R18, an optionally substituted C(1-6)alkyl or C(1-6)alkyloxy; R2 and R3 each independently represent hydrogen, halo, C(1-6)alkyloxy or an optionally substituted C(1-6)alkyl; R5 and R6 each independently represent hydrogen, hydroxy, halo, an optionally substituted C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, cyano, (C═O)R25, (C═O)OR16, (SO2)R16, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar or Het; or R5 and R6 together with the carbon atom to which they are attached, form an Ar or Het; Ar represents an optionally substituted C(6-14)aryl; Het represents an optionally substituted C(1-14)heterocycle; or a N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof; the processes for their preparation and compositions comprising them. It further relates to their use as a medicine.

    摘要翻译: 本发明涉及糠醛的化合物m,n和p各自独立地为0或1,q为0,1,2,3,4或5; -A1 = A2-A3 = A4-是亚吡啶基,哒嗪亚基,亚嘧啶亚基,亚吡嗪基或亚苯基; B代表酰胺,酮或恶二唑; D表示Ar或Het; Q表示共价直接键或酮,-N-,-O-,-CR5R6-,酰胺乙烯基,亚胺,磺酰基,亚磺酰基,3-氧代丁烯基,吡唑,异恶唑或噻唑; L表示Ar或Het; R1表示氢,卤素,羟基,C(2-6)烯基,C(2-6)炔基,C(3-6)环烷基,C(3-6)环烯基,氰基,胍,硝基,NR17R18, 取代的C(1-6)烷基或C(1-6)烷氧基; R2和R3各自独立地表示氢,卤素,C(1-6)烷氧基或任选取代的C 1-6烷基; R 5和R 6各自独立地表示氢,羟基,卤素,任选取代的C 1-6烷基,C(2-6)烯基,C(2-6)炔基,C(3-6)环烷基,C(3) -6)环烯基,C(1-6)烷氧基,氰基,(C = O)R25,(C = O)OR16,(SO2)R16,氨基羰基氧基,氨基C(1-6)烷基,NR17R18,N3,Ar或 Het; 或R 5和R 6与它们所连接的碳原子一起形成Ar或Het; Ar表示任选取代的C(6-14)芳基; Het表示任选取代的C(1-14)杂环; 或N-氧化物,药学上可接受的加成盐,季胺或其立体化学异构体形式; 其制备方法和包含它们的组合物。 它还涉及它们作为药物的用途。

    PDE IV inhibiting pyridine derivatives
    5.
    发明授权
    PDE IV inhibiting pyridine derivatives 有权
    PDE IV抑制吡啶衍生物

    公开(公告)号:US06656959B1

    公开(公告)日:2003-12-02

    申请号:US09647668

    申请日:2000-09-29

    IPC分类号: A61K3144

    CPC分类号: C07D401/06

    摘要: The present invention concerns pyridine derivatives having the formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein L is hydrogen; C1-6alkyl; C1-6alkyl carbonyl; C1-6alkyloxycarbonyl; substituted C1-6alkyl; C3-6alkenyl; substituted C3-6alkenyl; piperidyl; substituted piperidyl; C1-6alkylsulfonyl or arylsulfonyl; —A—B— is —CR8═CR5— or—CHR4—CHR5—; D is O or NR6; R1 is a hydrogen or C1-4alkyl; R2 is hydrogen; halo; C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyl oxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or substituted C1-6alkyl; or R2 is —O—R9 or —NH—R10; R3 is hydrogen, halo, hydroxy, C1-6alkyl or C1-6alkyloxy; or R2 and R1, or R2 and R3 taken together may form a bivalent radical; Q is disubstituted pyridine; R7 and R8 each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cyclo alkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; having PDE IV and cytokine inhibiting activity. The invention also relates to processes for preparing the compounds of formula (I), pharmaceutical compositions thereof and their use as a medicament.

    摘要翻译: 本发明涉及具有N-氧化物形式的吡啶衍生物,其药学上可接受的加成盐和立体化学异构形式,其中L是氢; C 1-6烷基; C 1-6烷基羰基; C 1-6烷氧基羰基; 取代的C 1-6烷基; C 3-6烯基; 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; -A-B-是-CR 8 = CR 5 - 或-CHR 4 -CHR 5 - ; D是O或NR 6; R 1是氢或C 1-4烷基; R 2是氢; 光环; C 1-6烷基; 三氟甲基 C 3-6环烷基; 羧基; C 1-4烷氧基羰基; C 3-6环烷基氨基羰基; 芳基; Het <1>; 或取代的C 1-6烷基; 或R 2为-O-R 9或-NH-R 10; R 3是氢,卤素,羟基,C 1-6烷基或C 1-6烷氧基; 或R 2和R 1,或R 2和R 3一起可以形成二价基团; Q是二取代的吡啶; R 7和R 8各自独立地为氢; C 1-6烷基; 二氟甲基 三氟甲基 C 3-6环烷基; 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; 双茚满 6,7-二氢-5H-环戊吡啶基; 双环[2.2.1] -2-庚烯基; 双环[2.2.1]庚基; C 1-6烷基磺酰基; 芳基磺酰基; 或取代的C 1-10烷基; 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,其药物组合物及其作为药物的用途的方法。

    Vasoconstrictive substituted dihydropyranopyridines
    6.
    发明授权
    Vasoconstrictive substituted dihydropyranopyridines 失效
    血管收缩性取代二氢吡喃并吡啶

    公开(公告)号:US5691344A

    公开(公告)日:1997-11-25

    申请号:US586851

    申请日:1996-01-24

    CPC分类号: C07D491/04

    摘要: The present invention is concerned with compounds of formula ##STR1## the pharmaceutically acceptable acid addition salts thereof, the N-oxides thereof and the stereochemically isomeric forms thereof, wherein .dbd.a.sub.1 --a.sub.2 .dbd.a.sub.3 --a.sub.4 .dbd. is a bivalent radical of formula: .dbd.N--CH.dbd.CH--CH.dbd. (a), .dbd.CH--N.dbd.CH--CH.dbd. (b), .dbd.CH--CH.dbd.N--CH.dbd. (c), .dbd.CH--CH.dbd.CH--N.dbd. (d), wherein in said bivalent radicals one or two hydrogen atoms can be substituted by halo, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy; R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.2 is hydrogen or C.sub.1-6 alkyl; R.sup.3 is hydrogen or C.sub.1-6 alkyl; Alk.sup.1 is C.sub.1-5 alkanediyl; Alk.sup.2 is C.sub.2-15 alkanediyl; Q is a five- or six-membered heterocyclic ring containing at least one nitrogen atom or a radical of formula ##STR2## wherein R.sup.4 is hydrogen, cyano, aminocarbonyl or C.sub.1-6 alkyl; R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 alkynyl; R.sup.6 is hydrogen or C.sub.1-6 alkyl; or R.sup.5 and R.sup.6 taken together may form a bivalent radical of formula --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --. Pharmaceutical compositions, preparations and use as a medicine are described.

    摘要翻译: PCT No.PCT / EP94 / 02700 Sec。 371日期:1996年1月24日 102(e)日期1996年1月24日PCT 1994年8月12日PCT PCT。 公开号WO95 / 05381 日期:1995年2月23日本发明涉及式(I)化合物:其药学上可接受的酸加成盐,其+ E,非N + EE-氧化物及其立体化学异构形式,其中= a2 = a3-a4 =是式的二价基团:= N-CH = CH-CH =(a),= CH-N = CH-CH =(b),= CH-CH = N-CH = )= 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; R1是氢或C1-6烷基; R2是氢或C1-6烷基; R3是氢或C1-6烷基; Alk1是C1-5烷二基; Alk2是C2-15烷二基; Q是含有至少一个氮原子或式(aa)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; R5是氢,C1-6烷基,C3-6烯基或C3-6炔基; R6是氢或C1-6烷基; 或R 5和R 6一起形成式 - (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。

    Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines
    7.
    发明授权
    Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines 失效
    血管收缩性取代2,3-二氢-1,4-二恶英吡啶

    公开(公告)号:US5990123A

    公开(公告)日:1999-11-23

    申请号:US875835

    申请日:1997-08-06

    CPC分类号: C07D491/04

    摘要: The present invention is concerned with compounds of formula ##STR1## the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein .dbd.a.sub.1 --a.sub.2 .dbd.a.sub.3 --a.sub.4 .dbd. is a bivalent radical of formula .dbd.N--CH.dbd.CH--CH.dbd. (a), .dbd.CH--N.dbd.CH--CH.dbd. (b), .dbd.CH--CH.dbd.N--CH.dbd. (c), .dbd.CH--CH.dbd.CH--N.dbd. (d), wherein one or two hydrogen atoms can be substituted by halo, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy; R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.2 is hydrogen or C.sub.1-6 alkyl; R.sup.3 is hydrogen or C.sub.1-6 alkyl; Alk.sup.1 is C.sub.1-5 alkanediyl; Alk.sup.2 is C.sub.2-15 alkanediyl; Q is a five- or six-membered heterocyclic ring containing at least one nitrogen atom or a radical of formula --C(NR.sup.5 R.sup.6).dbd.C--R.sup.4 wherein R.sup.4 is hydrogen, cyano, aminocarbonyl or C.sub.1-6 alkyl; R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 alkynyl; R.sup.6 is hydrogen or C.sub.1-6 alkyl; or R.sup.5 and R.sup.6 taken together may form a bivalent radical of formula --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --.Pharmaceutical compositions, preparations and use as a medicine are described.

    摘要翻译: PCT No.PCT / EP96 / 00396 Sec。 371日期:1997年8月6日 102(e)日期1997年8月6日PCT 1996年1月30日PCT PCT。 公开号WO96 / 24596 日期:1996年8月15日本发明涉及N-氧化物形式的化合物,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= N-CH = CH-CH =(a),= CH-N = CH-CH =(b),= CH-CH = N-CH =(c),= CH-CH = CH-N =(d) 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; R1是氢或C1-6烷基; R2是氢或C1-6烷基; R3是氢或C1-6烷基; Alk1是C1-5烷二基; Alk2是C2-15烷二基; Q是含有至少一个氮原子或式-C(NR 5 R 6)= C-R 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; R5是氢,C1-6烷基,C3-6烯基或C3-6炔基; R6是氢或C1-6烷基; 或R 5和R 6一起形成式 - (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。