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    Diamino acid derivatives as antihypertensives
    32.
    发明授权
    Diamino acid derivatives as antihypertensives 失效
    二氨基酸衍生物作为抗高血压药

    公开(公告)号：US5298492A

    公开(公告)日：1994-03-29

    申请号：US925338

    申请日：1992-08-04

    申请人： Bernard R. Neustadt ,  Elizabeth M. Smith ,  Deen Tulshian

    发明人： Bernard R. Neustadt ,  Elizabeth M. Smith ,  Deen Tulshian

    IPC分类号： A61K38/55 ,  A61K38/00 ,  A61P9/00 ,  A61P9/12 ,  A61P13/02 ,  A61P15/00 ,  A61P43/00 ,  C07D209/20 ,  C07K1/113 ,  C07K5/02 ,  C07K5/062 ,  C07K5/065 ,  C07K5/078 ,  C07K14/81 ,  A61K31/17

    CPC分类号： C07K5/022 ,  C07D209/20 ,  A61K38/00

    摘要： Novel diamino acid derivative dual inhibitors of neutral endopeptidase and angiotensin converting enzyme of the formula ##STR1## wherein: Z is amino, lower alkylamino, di-(lower alkyl)amino R.sup.9 C(O)NH-- or an optionally substituted guanidino group;R.sup.1 is hydrogen or R.sup.7 R.sup.8 N--;R.sup.2 is hydrogen, lower alkyl, cyclolower alkyl, aryllower alkyl or heteroaryllower alkyl; and R.sup.3 is hydrogen, lower alkyl or cyclolower alkyl; or R.sup.2 and R.sup.3, together with the carbon to which they are attached, comprise a 3-7 membered carboxyclic ring;R.sup.4 is hydrogen, lower alkyl, aryl lower alkyl or heteroaryllower alkyl;R.sup.5 and R.sup.6 are independently hydroxy, lower alkoxy, amino, aryllower alkoxy, lower alkylamino and di-(lower alkyl)amino;R.sup.7 is R.sup.9 C(O)-- or R.sup.10 SO.sub.2 --; and R.sup.8 is hydrogen, lower alkyl, aryllower alkyl or aryl; or R.sup.7 and R.sup.8, together with the nitrogen to which they are attached, comprise a 5-7 membered ring;R.sup.9 is lower alkyl, aryllower alkyl, aryl, heteroaryllower alkyl, heteroaryl, lower alkoxy, aryllower alkoxy, amino, alkylamino or dialkylamino;R.sup.10 is lower alkyl, aryl lower alkyl, aryl, heteroaryl lower alkyl, amino, lower alkylamino, di-(lower alkyl)amino or heteroaryl;n is 1, 2, 3, 4 or 5; and m is 1, 2, 3, 4 or 5;or a pharmaceutically acceptable addition salt thereof, useful in the treatment of cardiovascular disorders, are disclosed.

    摘要翻译： 新型二氨基酸衍生物双中性内肽酶抑制剂和式（*化学结构*）的血管紧张素转换酶其中：Z为氨基，低级烷基氨基，二 - （低级烷基）氨基R9C（O）NH-或任选取代的胍基 ; R1是氢或R7R8N-; R2是氢，低级烷基，环状烷基，芳基低级烷基或杂芳基低级烷基; 并且R 3是氢，低级烷基或环己烷基; 或R 2和R 3与它们所连接的碳一起包含3-7元羧基环; R4是氢，低级烷基，芳基低级烷基或杂芳基低级烷基; R5和R6独立地是羟基，低级烷氧基，氨基，芳基低级烷氧基，低级烷基氨基和二（低级烷基）氨基; R7是R9C（O） - 或R10SO2-; R8是氢，低级烷基，芳基低级烷基或芳基; 或R 7和R 8与它们所连接的氮一起包含5-7元环; R 9是低级烷基，芳基低级烷基，芳基，杂芳基低级烷基，杂芳基，低级烷氧基，芳基低级烷氧基，氨基，烷基氨基或二烷基氨基; R 10是低级烷基，芳基低级烷基，芳基，杂芳基低级烷基，氨基，低级烷基氨基，二 - （低级烷基）氨基或杂芳基; n为1,2,3,4或5; m为1,2,3,4或5; 或其药学上可接受的加成盐，其可用于治疗心血管疾病。

    Derivatives of aminobenzoic and aminobiphenylcarboxylic acids useful as anti-cancer agents
    34.
    发明授权
    Derivatives of aminobenzoic and aminobiphenylcarboxylic acids useful as anti-cancer agents 失效
    用作抗癌剂的氨基苯甲酸和氨基联苯羧酸的衍生物

    公开(公告)号：US06228985B1

    公开(公告)日：2001-05-08

    申请号：US09082787

    申请日：1998-05-21

    申请人： Christine H. Blood ,  Bernard R. Neustadt ,  Elizabeth M. Smith

    发明人： Christine H. Blood ,  Bernard R. Neustadt ,  Elizabeth M. Smith

    IPC分类号： C07K200

    CPC分类号： C07C229/38 ,  A61K38/00 ,  C07C237/36 ,  C07D209/18 ,  C07D209/20

    摘要： The present invention provides compounds having the formula: wherein n is 0 or 1; R is —NH2 or wherein R1 and R2 are independently selected from the group consisting of H, alkyl, aralkyl, heteroaralkyl, carboxy, carboxyalkyl, and carbamoyl; Q is R3C(O)— or wherein R5 is selected from the group consisting of H, alkyl, aralkyl, heteroaralkyl, and carbamoylalkyl, and R3 and R4 are selected from the group consisting of H, alkyl, alkoxy, arylalkoxy, aralkyl, heteroaralkyl, and carbamoylalkyl; the Q—NH—(CH2)n— and the —C(O)R substituents of the compound of formula I are independently positioned ortho, meta, orpara relative to the carbon atoms that form the bond between the two phenyl groups to which said substituents are bound, with the proviso that said substituents are not both positioned ortho; and the Q—NH—(CH2)n and the —C(O)R substituents of the compound of formula II are positioned meta orpara to each other; or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof. The compounds are useful for treating uPA- or uPAR-mediated disorders, e.g., tumor metastasis, tumor angiogenesis, restenosis, chronic inflammation, or corneal angiogenesis.

    摘要翻译： 本发明提供具有下式的化合物：其中n为0或1; R为-NH 2，其中R1和R2独立地选自H，烷基，芳烷基，杂芳烷基，羧基，羧基烷基和氨基甲酰基; Q为R3C （O） - 或其中R 5选自H，烷基，芳烷基，杂芳烷基和氨基甲酰基烷基，R 3和R 4选自H，烷基，烷氧基，芳基烷氧基，芳烷基，杂芳烷基和氨基甲酰基烷基; 式I化合物的Q-NH-（CH 2）n - 和-C（O）R取代基相对于形成所述取代基的两个苯基之间的键的碳原子独立地位于邻位，间位或对位 条件是所述取代基不都位于邻位; 和式II化合物的Q-NH-（CH 2）n和-C（O）R取代基彼此定位在间或其生物不稳定酯或其药学上可接受的盐中。 该化合物可用于治疗uPA或uPAR介导的病症，例如肿瘤转移，肿瘤血管发生，再狭窄，慢性炎症或角膜血管生成。

    Carboxyalkylcarbonyl aminoacid endopeptidase inhibitors
    39.
    发明授权
    Carboxyalkylcarbonyl aminoacid endopeptidase inhibitors 失效
    羧基烷基羰基氨基酸内肽酶抑制剂

    公开(公告)号：US5389610A

    公开(公告)日：1995-02-14

    申请号：US849036

    申请日：1992-04-21

    申请人： Bernard R. Neustadt ,  Elizabeth M. Smith ,  Martin F. Haslanger

    发明人： Bernard R. Neustadt ,  Elizabeth M. Smith ,  Martin F. Haslanger

    IPC分类号： A61K31/34 ,  A61K31/341 ,  A61K31/343 ,  A61K31/38 ,  A61K31/381 ,  A61K31/40 ,  A61K31/403 ,  A61K31/404 ,  A61K38/22 ,  A61K38/55 ,  A61P3/00 ,  A61P9/00 ,  A61P9/12 ,  C07C233/47 ,  C07C233/63 ,  C07C235/40 ,  C07C237/12 ,  C07C237/24 ,  C07C319/20 ,  C07C323/59 ,  C07C323/60 ,  C07C323/64 ,  C07D207/325 ,  C07D209/14 ,  C07D209/18 ,  C07D217/26 ,  C07D307/68 ,  C07D307/79 ,  C07D333/38 ,  C07K5/08 ,  A61K39/02

    CPC分类号： C07C323/59 ,  C07C233/63 ,  C07C235/40 ,  C07C2101/08

    摘要： Carboxyalkylcarbonyl aminoacid inhibitors of endopeptidases of the formula: ##STR1## or pharmaceutically acceptable salt thereof, wherein R.sup.1 is H, alkyl, arylalkyl, aryl or aryloxyalkyl; R.sup.2 is alkyl, alkenyl, alkynyl, alkoxy or alkylthio, wherein the alkyl portion is substituted with 0-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkylthio, aryl, alkoxyalkylthio, arylalkoxy and arylalkylthio; R.sup.3 and R.sup.4 are independently alkyl or arylalkyl; or R.sup.3 and R.sup.4 together with the carbon to which they are attached form an optionally substituted 5-, 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen; R.sup.5 is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl; R.sup.6 is H, hydroxy, alkoxy, alkyl, arylalkoxy, alkoxyalkyl, alkylthioalkyl, arylalkoxyalkyl, arylalkylthioalkyl, aryl or heteroaryl; R.sup.7 is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino; m is 0 or 1; and n is 0, 1, 2 or 3, use of the compounds, alone or in combination with an ACE inhibitor or an ANF, in the treatment of cardiovascular disorders such as hypertension, congestive heart failure, edema and renal insufficiency, use of the compounds in the treatment of nephrotoxicity and pain conditions, and pharmaceutical compositions containing said compounds are disclosed.

    摘要翻译： PCT No.PCT / US90 / 06655 Sec。 一九九二年四月二十一日 102（e）日期1992年4月21日PCT 1990年11月20日PCT PCT。 出版物WO91 / 07386 1991年5月30日。具有下式的内肽酶的羧基烷基羰基氨基酸抑制剂或其药学上可接受的盐，其中R 1是H，烷基，芳基烷基，芳基或芳氧基烷基; R2是烷基，烯基，炔基，烷氧基或烷硫基，其中烷基部分被独立选自羟基，烷氧基，烷氧基烷氧基，烷硫基，芳基，烷氧基烷硫基，芳基烷氧基和芳基烷硫基的0-3个取代基取代。 R3和R4独立地是烷基或芳基烷基; 或R 3和R 4与它们所连接的碳一起形成任选取代的5-，6-或7-元环，其中所述环包含0至1个选自硫和氧的杂原子; R 5是H，烷基，烷氧基烷基，烷硫基烷基，芳基，芳基烷基，杂芳基，杂芳基烷基，芳基烷氧基烷基或芳基烷硫基烷基; R6是H，羟基，烷氧基，烷基，芳基烷氧基，烷氧基烷基，烷基硫代烷基，芳基烷氧基烷基，芳基烷硫基烷基，芳基或杂芳基; R7是羟基，烷氧基，芳氧基，芳基烷氧基，氨基，烷基氨基或二烷基氨基; m为0或1; 和n为0,1,2或3，单独使用或与ACE抑制剂或ANF组合使用化合物治疗心血管疾病如高血压，充血性心力衰竭，水肿和肾功能不全的用途 公开了治疗肾毒性和疼痛病症的化合物和含有所述化合物的药物组合物。

    Mercapto-acylamino acids
    40.
    发明授权
    Mercapto-acylamino acids 失效
    巯基 - 酰氨基酸

    公开(公告)号：US5219886A

    公开(公告)日：1993-06-15

    申请号：US768647

    申请日：1991-10-01

    申请人： Elizabeth M. Smith ,  Philip M. DeCapite ,  Bernard R. Neustadt

    发明人： Elizabeth M. Smith ,  Philip M. DeCapite ,  Bernard R. Neustadt

    IPC分类号： A61K38/22 ,  A61K31/16 ,  A61K31/195 ,  A61K31/215 ,  A61K31/265 ,  A61K31/38 ,  A61K31/40 ,  A61K31/47 ,  A61K31/55 ,  A61K31/675 ,  A61K38/55 ,  A61K45/06 ,  A61P3/00 ,  A61P9/00 ,  A61P9/12 ,  A61P13/02 ,  A61P15/00 ,  A61P43/00 ,  C07C319/12 ,  C07C323/00 ,  C07C323/56 ,  C07C323/60 ,  C07C327/06 ,  C07C327/32

    CPC分类号： C07C327/32 ,  A61K38/2242 ,  A61K38/556 ,  C07C323/60

    摘要： Novel mercapto-acylamino acids of the formula ##STR1## wherein Q is hydrogen or R.sup.7 CO--;R.sup.1 is lower alkyl, cyclolower alkyl, aryl or heteroaryl;R.sup.2 is hydrogen; lower alkyl; cyclolower alkyl; lower alkyl substituted with hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl; aryl; or heteroaryl;R.sup.3 is --OR.sup.5 or --NR.sup.5 R.sup.6 ;R.sup.4 and R.sup.9 are independently --(CH.sub.2).sub.q R.sup.8, provided that when R.sup.4 and R.sup.9 are both hydrogen, R.sup.2 is biphenylyl, phenoxyphenyl, phenylthiophenyl, naphthyl, heteroaryl, or lower alkyl substituted with hydroxy, lower alkoxy, mercapto or lower alkylthio;R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl and aryl lower alkyl, or R.sup.5 and R.sup.6 together with the nitrogen to which they are attached form a 5-7 membered ring;R.sup.7 is hydrogen, lower alkyl or aryl;R.sup.8 is hydrogen, hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl;n is 1 or 2;p is 0 or 1;q is 0, 1 or 2; andt is 0 or 1; and the pharmaceutically acceptable salts thereof useful in the treatment of cardiovascular disorders and pain conditions and combinations of mercapto-acrylamino acids and atrial natriuretic factors or angiotensin converting enzyme inhibitors useful for treating cardiovascular disorders are disclosed.

    摘要翻译： PCT No.PCT / US90 / 01787 Sec。 371日期1991年10月1日 102（e）1991年10月1日授权PCT 1990年4月6日提交。式IMA的新型巯基酰基氨基酸其中Q为氢或R7CO-; R 1是低级烷基，环己烷基，芳基或杂芳基; R2是氢; 低级烷基 环状烷基; 被羟基，低级烷氧基，巯基，低级烷硫基，芳基或杂芳基取代的低级烷基; 芳基; 或杂芳基; R3为-OR5或-NR5R6; R 4和R 9独立地为 - （CH 2）q R 8，条件是当R 4和R 9均为氢时，R 2为联苯基，苯氧基苯基，苯硫基苯基，萘基，杂芳基或被羟基，低级烷氧基，巯基或低级烷硫基取代的低级烷基; R 5和R 6独立地选自氢，低级烷基，羟基低级烷基，低级烷氧基低级烷基和芳基低级烷基，或者R 5和R 6与它们所连接的氮一起形成5-7元环; R7是氢，低级烷基或芳基; R8是氢，羟基，低级烷氧基，巯基，低级烷硫基，芳基或杂芳基; n为1或2; p为0或1; q是0,1或2; t为0或1; 和其可用于治疗心血管疾病和疼痛病症的药学上可接受的盐，以及用于治疗心血管疾病的巯基丙烯酰胺酸和心房利钠因子或血管紧张素转换酶抑制剂的组合。