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    High affinity small molecule C5a receptor modulators
    1.
    发明授权
    High affinity small molecule C5a receptor modulators 失效
    高亲和力小分子C5a受体调节剂

    公开(公告)号：US06723743B1

    公开(公告)日：2004-04-20

    申请号：US09672071

    申请日：2000-09-28

    申请人： Andrew Thurkauf ,  Xiao-shu He ,  He Zhao ,  John Peterson ,  Xiaoyan Zhang ,  Robbin Brodbeck ,  James Krause ,  George Maynard ,  Alan Hutchison

    发明人： Andrew Thurkauf ,  Xiao-shu He ,  He Zhao ,  John Peterson ,  Xiaoyan Zhang ,  Robbin Brodbeck ,  James Krause ,  George Maynard ,  Alan Hutchison

    IPC分类号： A61K31415

    CPC分类号： C07D207/327 ,  C07C233/11 ,  C07C233/22 ,  C07C233/65 ,  C07C233/66 ,  C07C233/73 ,  C07C233/78 ,  C07C235/46 ,  C07C235/48 ,  C07C235/54 ,  C07C235/60 ,  C07C235/62 ,  C07C235/66 ,  C07C237/20 ,  C07C323/62 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/10 ,  C07C2603/18 ,  C07D213/38 ,  C07D213/82 ,  C07D215/12 ,  C07D217/04 ,  C07D217/06 ,  C07D217/14 ,  C07D217/16 ,  C07D231/12 ,  C07D233/64 ,  C07D233/68 ,  C07D235/02 ,  C07D235/14 ,  C07D235/18 ,  C07D317/58 ,  C07D333/24 ,  C07D333/28 ,  C07D333/54 ,  C07D401/06 ,  C07D401/12 ,  C07D403/12 ,  C07D405/06 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12 ,  C07D409/14 ,  C07D417/12 ,  C07D471/04

    摘要： This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a receptor ligands and also to such ligands that act as antagonists or inverse agonists of complement C5a receptors, preferably human C5a receptors, Preferred compounds of the invention possess one or more, and preferably two or more, three or more, four or more, or all of the following properties in that they are; 1) multi-aryl in structure (having a plurality of un-fused or fused aryl groups), 2) heteroaryl in structure, 3) orally available in vivo (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose can provide a detectable in vitro effect such as a reduction of C5a-induced neutropenia), 4) comprised of fewer than four, preferably fewer than three, or fewer than two, or no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations. Specifically exemplified representative compounds include, but are not limited to optionally substituted arylimidazoles, optionally substituted arylpyridyls, optionally substituted aryl-substituted cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines, and optionally substituted biaryl carboxamides. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

    摘要翻译： 本发明涉及作为哺乳动物补体C5a受体调节剂的低分子量，非肽，非拟肽，有机分子，优选用作高亲和力C5a受体配体的调节剂，还涉及作为拮抗剂或反向激动剂的这些配体 的补体C5a受体，优选人C5a受体。本发明的优选化合物具有一个或多个，优选两个或更多个，三个或更多个，四个或更多个或全部以下性质： 1）结构上的多芳基（具有多个未稠合或稠合芳基），2）结构上的杂芳基，3）在体内可口服（使得亚致死或优选药学上可接受的口服剂量可提供 可检测的体外效应，例如C5a诱导的中性粒细胞减少的减少），4）由少于4个，优选少于3个，或少于2个或不存在的酰胺键组成，以及5）能够以纳摩尔浓度抑制白细胞趋化性， 优选亚纳摩尔浓度。 具体示例的代表性化合物包括但不限于任选取代的芳基咪唑，任选取代的芳基吡啶基，任选取代的芳基取代的环烷基咪唑，任选取代的芳基吡唑，任选取代的苯并咪唑，任选取代的芳基取代的四氢异喹啉和任选取代的双芳基甲酰胺。 本发明还涉及包含这些化合物的药物组合物。 它还涉及这些化合物在治疗各种炎性和免疫系统疾病中的应用。 此外，本发明涉及使用这些化合物作为C5a受体定位的探针。

    Substituted imidazoles as selective modulators of Bradykinin B2 receptors
    7.
    发明授权
    Substituted imidazoles as selective modulators of Bradykinin B2 receptors 失效
    取代的咪唑作为缓激肽B2受体的选择性调节剂

    公开(公告)号：US06509366B2

    公开(公告)日：2003-01-21

    申请号：US09764805

    申请日：2001-01-17

    申请人： Stanislaw Rachwal ,  Alan Hutchison ,  Kenneth Shaw ,  George D. Maynard ,  Xiao-shu He ,  Robert DeSimone ,  Kevin Hodgetts

    发明人： Stanislaw Rachwal ,  Alan Hutchison ,  Kenneth Shaw ,  George D. Maynard ,  Xiao-shu He ,  Robert DeSimone ,  Kevin Hodgetts

    IPC分类号： A61K314174

    CPC分类号： C07D233/64 ,  C07D233/68 ,  C07D401/06

    摘要： Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein Y, R1, R2, R3, R4, R5, R6, R7 R7′ are variables defined herein, which compounds are modulators of Bradykinin B2 receptors. These compounds are therefore useful in the diagnosis and treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility, glaucoma, pain, asthma, and rhinitis, and for the increase of permeability of the blood-brain barrier or the blood-brain-tumor barrier.

    摘要翻译： 公开了下式的化合物或其药学上可接受的无毒盐，其中Y，R 1，R 2，R 3，R 4，R 5，R 6，R 7 R 7'是本文定义的变量，该化合物是缓激肽B2受体的调节剂。 因此，这些化合物可用于诊断和治疗肾脏疾病，心力衰竭，高血压，梅尼埃病，阴道炎症和疼痛，外周循环障碍，更年期障碍，视网膜循环障碍，心肌缺血，心肌梗死，心肌梗死后综合征，心绞痛 经皮腔内冠状动脉血管成形术，肝炎，肝硬化，胰腺炎，肠梗阻，糖尿病，糖尿病并发症，男性不育症，青光眼，疼痛，哮喘和鼻炎的再狭窄，以及增加血脑屏障或血液 - 脑肿瘤屏障。

    1-(N'-(arylalkylaminoalkyl)) aminoisoindoles; a new class of dopamine receptor subtype specific ligands
    8.
    发明授权
    1-(N'-(arylalkylaminoalkyl)) aminoisoindoles; a new class of dopamine receptor subtype specific ligands 失效
    1-（N' - （芳基烷基氨基烷基））氨基异吲哚; 一类新的多巴胺受体亚型特异性配体

    公开(公告)号：US5932729A

    公开(公告)日：1999-08-03

    申请号：US907402

    申请日：1997-08-07

    申请人： Xiao-shu He ,  Brian de Costa ,  Jan W. F. Wasley

    发明人： Xiao-shu He ,  Brian de Costa ,  Jan W. F. Wasley

    IPC分类号： C07D209/44 ,  C07D401/12 ,  C07D403/12 ,  C07D401/14 ,  C07D403/14

    CPC分类号： C07D401/12 ,  C07D209/44 ,  C07D403/12

    摘要： Disclosed are compounds of the formula ##STR1## or the pharmaceutically acceptable salts thereof wherein the 6-membered A ring may be optionally substituted with up to four groups independently selected from halogen, hydroxy, lower alkyl, or lower alkoxy;Ar represents optionally substituted aryl or heteroaryl;Z represents carbon or nitrogen provided thatwhere Z is carbon, R.sub.11 represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; andwhere Z is nitrogen, R.sub.11 represents an electron pair;R.sub.5 is hydrogen or lower alkyl;L and m represent integers;n is 0, or an integer;R.sub.12 and R.sub.13 independently represent lower alkyl; or together may together form an optionally substituted 5-11 membered ring with the nitrogen atoms to which they are bonded; CR'R" represents a methylene group optionally substituted with lower alkyl; andk is an integer of from 1 to 3,which compounds are useful in treating various neuropsychochological disorders including, for example, schizophrenia, dementia, depression, anxiety, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

    摘要翻译： 公开了下式的化合物或其药学上可接受的盐，其中6元环可以任选被至多四个独立地选自卤素，羟基，低级烷基或低级烷氧基的基团取代; Ar表示任选取代的芳基或杂芳基; Z表示碳或氮，条件是其中Z为碳，R11表示氢，卤素，羟基，低级烷基或低级烷氧基，或任选被一个或两个选自氢，卤素，羟基，低级烷基或低级烷氧基的基团取代的苯基 ; 并且其中Z是氮，R11表示电子对; R5是氢或低级烷基; L和m表示整数; n为0，或整数; R 12和R 13独立地表示低级烷基; 或者一起可以与它们所键合的氮原子一起形成任选取代的5-11元环; CR'R“表示任选被低级烷基取代的亚甲基; k为1〜3的整数，该化合物可用于治疗各种神经精神障碍，包括精神分裂症，痴呆，抑郁症，焦虑症，帕金森样运动障碍以及与使用精神抑制药有关的运动障碍。

    3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands
    10.
    发明授权
    3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands 失效
    3-氨基烷基氨基-2H-1,4-苯并恶嗪和3-氨基烷基氨基-2H-1,4-苯并噻嗪类：多巴胺受体亚型特异性配体

    公开(公告)号：US06432946B1

    公开(公告)日：2002-08-13

    申请号：US09633042

    申请日：2000-08-04

    申请人： Xiao-shu He

    发明人： Xiao-shu He

    IPC分类号： A61K3154

    CPC分类号： C07D413/12 ,  C07D265/36 ,  C07D417/12

    摘要： Disclosed are compounds of the formula: or the pharmaceutically acceptable acid addition salts thereof, wherein: Ar represents aryl or heteroaryl; R1 and R2 are the same or different and represent organic or inorganic substituents; R5 is hydrogen or C1-C6 alkyl; W represents CH or nitrogen; X is oxygen or sulfur; and A represents an alkylene group, which compounds bind selectively with high affinity to the dopamine D4 receptor subtype and are therefore of use in treatment of various neuropsychological disorders.

    摘要翻译： 公开了下式的化合物或其药学上可接受的酸加成盐，其中：Ar表示芳基或杂芳基; R 1和R 2相同或不同，表示有机或无机取代基; R 5表示氢或C 1 -C 6烷基; W表示 CH或氮; X为氧或硫; 并且A表示亚烷基，该化合物以高亲和力选择性结合多巴胺D4受体亚型，因此可用于治疗各种神经心理障碍。