公开(公告)号：US06235787B1

公开(公告)日：2001-05-22

申请号：US09098235

申请日：1998-06-16

申请人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

发明人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

IPC分类号： A61K3115

CPC分类号： C07D207/325 ,  C07C243/28 ,  C07C243/32 ,  C07C259/06 ,  C07C311/49 ,  C07C2601/02 ,  C07C2601/04 ,  C07C2601/08 ,  C07C2601/14 ,  C07D209/14 ,  C07D209/48 ,  C07D211/38 ,  C07D211/58 ,  C07D213/42 ,  C07D213/56 ,  C07D213/77 ,  C07D215/38 ,  C07D231/12 ,  C07D233/56 ,  C07D233/76 ,  C07D239/26 ,  C07D239/42 ,  C07D249/08 ,  C07D263/22 ,  C07D275/02 ,  C07D277/30 ,  C07D277/56 ,  C07D277/82 ,  C07D279/02 ,  C07D305/06 ,  C07D307/52 ,  C07D307/68 ,  C07D307/81 ,  C07D309/06 ,  C07D309/14 ,  C07D309/30 ,  C07D317/28 ,  C07D333/34 ,  C07D333/38 ,  C07D335/02 ,  Y10S514/837 ,  Y10S514/861 ,  Y10S514/863 ,  Y10S514/885 ,  Y10S514/903

摘要： Hydrazine derivatives of the formula wherein Y is CO or SO2; R1 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R2 is lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y is SO2 and is lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-lower alkoxy or NR5R6 when Y is CO; and R3 is hydrogen, lower alkyl optionally substituted by cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or R2 and R3 together form the residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulphonamide or cyclic urethane group; R4 is lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the formula X-aryl, X-heteroaryl or —(CH2)1-2—CH═CR7R8; X is a spacer group; R5 and R6 each individually are hydrogen, lower alkyl or aryl-lower alkyl; and R7 and R8 together represent a lower alkylene group in which one methylene group is optionally replaced by a hetero atom; and their pharmaceutically acceptable salts inhibit not only the release of tumour necrosis factor (TNF-&agr;) and transforming growth factor (TGF-&agr;) from cells, but also keratinocyte proliferation. They are useful as medicaments, especially for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.

摘要翻译： 甲酰亚胺Y的肼衍生物是CO或SO 2; 低级烷基，低级烯基，低级环烷基，低级环烷基 - 低级烷基，芳基或芳基 - 低级烷基; 当Y为SO 2时，R 2为低级烷基，卤代低级烷基，芳基 - 低级烷基，芳基 - 低级烯基或芳基，为低级烷基，卤代低级烷基，低级烷氧基，低级烷氧基羰基，酰基，低级环烷基，芳基， 当Y为CO时，低级烷基，芳基 - 低级烷氧基或NR5R6; 低级烷基，低级烷基，低级环烷基，低级环烷基 - 低级烷基，芳基 - 低级烷基，芳基 - 低级烷基，芳基 - 低级烷基，低级烷氧基，低级烷氧基， ，芳基或杂环基; 或R 2和R 3一起形成5-，6-或7-元环酰胺，环状酰亚胺，环状磺酰胺或环状氨基甲酸酯基团的残基; R4是低级烷基，羟基 - 低级烷基，低级烯基，低级环烷基，低级环烷基 - 低级烷基或式X-芳基，X-杂芳基或 - （CH2）1-2-CH = CR7R8基团; X是间隔基; R5和R6各自独立地为氢，低级烷基或芳基 - 低级烷基; 并且R 7和R 8一起表示低级亚烷基，其中一个亚甲基任选被杂原子取代; 并且其药学上可接受的盐不仅抑制来自细胞的肿瘤坏死因子（TNF-α）和转化生长因子（TGF-α）的释放，还抑制角质形成细胞增殖。 它们可用作药物，特别是用于治疗炎症，发烧，出血，败血症，类风湿性关节炎，骨关节炎，多发性硬化或银屑病。

公开(公告)号：US4044017A

公开(公告)日：1977-08-23

申请号：US740894

申请日：1976-11-11

申请人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

发明人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

IPC分类号： A61K38/00 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06 ,  C07K5/065 ,  C07K5/068 ,  C07K5/072 ,  C07K5/078 ,  C07D249/06

CPC分类号： C07K5/06191 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06026 ,  C07K5/06034 ,  C07K5/06043 ,  C07K5/06078 ,  C07K5/06086 ,  C07K5/06095 ,  C07K5/06104 ,  C07K5/06165 ,  A61K38/00 ,  Y10S514/906

摘要： This invention is directed toward pharmacologically active compounds of the formula ##STR1## wherein A represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, di(C.sub.1-4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together represent a grouping of the formula ##STR2## in which R.sup.a represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C-R.sup.b wherein R.sup.b represents a hydrogen atom or a lower alkyl or hydroxymethyl group; R represents a halogen atom or a nitro or trifluoromethyl group; R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R.sup.3 represents a phenyl, halophenyl or 2-pyridyl groupAnd acid addition salts thereof.Also provided are methods for their preparation and intermediates thereof, These compounds exhibit activity as anticonvulsants, muscle relaxants and sedatives.

摘要翻译： 本发明涉及下式的药理学活性化合物，其中A表示可被甲基，环丙基甲基，二（C 1-4烷基）氨基乙基，甲氧基甲基或羟乙基取代的氮原子，B表示羰基或A 和B一起表示其中R a表示氢原子或低级烷基或羟甲基并且X表示氮原子的式“IMAGE”或其中R b表示氢原子或低级烷基或羟甲基的C-R b的基团; R表示卤素原子或硝基或三氟甲基; R1表示氢原子或低级烷基; R 2表示衍生自天然存在的氨基酸的酰基（所有这些基团含有具有L或D，L构型的不对称碳原子），R 3表示苯基，卤代苯基或2-吡啶基。其酸加成盐 。

公开(公告)号：US06265446B1

公开(公告)日：2001-07-24

申请号：US09444861

申请日：1999-11-22

申请人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

发明人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

IPC分类号： A61K3118

CPC分类号： C07D295/088 ,  C07C311/49 ,  C07D213/34 ,  Y10S514/824 ,  Y10S514/863

摘要： Hydrazine derivatives of the formula wherein R1 represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl, R2 represents heterocyclyl or NR5R6, R3 represents hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl or aryl-lower alkyl, R4 represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula -Z-aryl, -Z-heterocyclyl or —(CH2)n—, CH═CR7R8, R5 and R6 each independently represent hydrogen or lower alkyl, R7 and R8 each independently represent hydrogen or lower alkyl or R7 and R8 together represent lower alkylene in which one CH2 group is optionally replaced by a hetero atom, X and Z each represent a spacer group, and n stands for 0, 1 or 2, and their pharmaceutically acceptable salts thereof, inhibit the release of tumor necrosis factor alpha (TNF-&agr;) from cells. They can be used as medicaments, especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, haemorrhage and sepsis.

摘要翻译： 式中R 1的肼衍生物代表低级烷基，低级链烯基，低级环烷基，低级环烷基 - 低级烷基，芳基或芳基 - 低级烷基，R2代表杂环基或NR5R6，R3代表氢，低级烷基，卤代低级烷基，氰基低级 烷基，羟基 - 低级烷基，氨基 - 低级烷基，低级烷氧基 - 低级烷基，低级烷氧基羰基 - 低级烷基，低级环烷基 - 低级烷基，芳基 - 低级烷基，杂环基 - 低级烷基，杂环基羰基 - 低级烷基，低级烯基， ，低级环烷基，芳基，杂芳基或芳基 - 低级烷基，R4代表低级烷基，低级烯基，低级环烷基，低级环烷基 - 低级烷基或式-Z-芳基，-Z-杂环基或 - （CH2）n - ，CH = CR 7 R 8，R 5和R 6各自独立地表示氢或低级烷基，R 7和R 8各自独立地表示氢或低级烷基，或者R 7和R 8一起表示低级亚烷基，其中一个CH 2基团任选地被杂原子X， Z各自表示间隔物 并且n代表0,1或2及其药学上可接受的盐，从细胞中抑制肿瘤坏死因子α（TNF-α）的释放。 它们可以用作药物，特别是用于治疗炎性和自身免疫性疾病，骨关节炎，呼吸系统疾病，肿瘤，恶病质，心血管疾病，发烧，出血和败血症。

公开(公告)号：US5731441A

公开(公告)日：1998-03-24

申请号：US741158

申请日：1996-10-29

申请人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

发明人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

IPC分类号： C07D401/06 ,  A61K20060101 ,  A61K31/16 ,  A61K31/40 ,  A61K31/41 ,  A61K31/415 ,  A61K31/4178 ,  A61K31/42 ,  A61K31/425 ,  A61K31/435 ,  A61K31/4427 ,  A61K31/445 ,  A61K31/454 ,  A61K31/535 ,  A61K31/5377 ,  A61K31/54 ,  A61K31/55 ,  A61P9/10 ,  A61P19/02 ,  A61P29/00 ,  A61P35/00 ,  A61P37/00 ,  A61P43/00 ,  C07C20060101 ,  C07C259/04 ,  C07C259/06 ,  C07D207/36 ,  C07D209/48 ,  C07D233/72 ,  C07D233/74 ,  C07D249/12 ,  C07D263/30 ,  C07D263/44 ,  C07D271/07 ,  C07D291/06 ,  C07D403/06 ,  C07D413/06 ,  C07D417/06 ,  C07D487/04 ,  C07D491/113 ,  C07D285/10 ,  C07D209/32 ,  C07D211/36 ,  C07D265/26

CPC分类号： C07D209/48 ,  A61K31/4178 ,  A61K31/454 ,  A61K31/5377 ,  C07D233/74 ,  C07D263/44 ,  C07D401/06 ,  C07D403/06 ,  C07D417/06 ,  C07D487/04 ,  Y02P20/55

摘要： The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

摘要翻译： 本发明提供通式为（I）的异羟肟酸衍生物，其中R 1表示环丙基，环丁基，环戊基或环己基; R2表示饱和的5-至8-元单环或桥连的N-杂环，N-杂环通过N原子连接，当其为单环时，任选地含有作为环成员的NR4，O，S，SO或SO2 羟基，低级烷基，低级烷氧基，氧代，缩酮化的氧代，氨基，单（低级烷基）氨基，二（低级烷基）氨基，羧基，低级烷氧基羰基，羟基 - 甲基 ，低级烷氧基甲基，氨基甲酰基，单（低级烷基） - 氨基甲酰基，二（低级烷基）氨基甲酰基或羟基亚氨基; （a）经由N原子连接的5-或6-元N-杂环，（b）任选地含有N，O和/或S，SO或SO 2作为另外的环成员，（c）是 在与连接的N原子相邻的一个或两个C原子上被氧代取代，（d）任选地被苯并稠合或任选地在一个或多个其它C原子上被低级烷基或氧代和/或任何另外的N原子取代， 由低级烷基或芳基取代; R4表示氢，低级烷基，芳基，芳烷基或保护基; m代表1或2，n代表1-4，其药学上可接受的盐，制备中使用的中间体及其用途。 式I化合物是可用于控制或预防变性关节疾病如类风湿性关节炎和骨关节炎或用于治疗浸润性肿瘤，动脉粥样硬化或多发性硬化的胶原酶抑制剂。

公开(公告)号：US4007219A

公开(公告)日：1977-02-08

申请号：US605580

申请日：1975-08-18

申请人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

发明人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

IPC分类号： A61K38/00 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06 ,  C07K5/065 ,  C07K5/068 ,  C07K5/072 ,  C07K5/078 ,  C07C103/28 ,  A61K31/165 ,  C07C103/127 ,  C07C103/30

CPC分类号： C07K5/06191 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06026 ,  C07K5/06034 ,  C07K5/06043 ,  C07K5/06078 ,  C07K5/06086 ,  C07K5/06095 ,  C07K5/06104 ,  C07K5/06165 ,  A61K38/00 ,  Y10S514/906

摘要： This invention is directed toward pharmacologically active compounds of the formula ##STR1## wherein A represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, di(C.sub.1-4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together represent a grouping of the formula ##STR2## in which R.sup.a represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C--R.sup.b wherein R.sup.b represents a hydrogen atom or a lower alkyl or hydroxymethyl group; R represents a halogen atom or a nitro or trifluoromethyl group; R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R.sup.3 represents a phenyl, halophenyl or 2-pyridyl groupAnd acid addition salts thereof.Also provided are methods for their preparation and intermediates thereof. These compounds exhibit activity as anticonvulsants, muscle relaxants and sedatives.

摘要翻译： 本发明涉及下式的药理学活性化合物，其中A表示可被甲基，环丙基甲基，二（C 1-4烷基）氨基乙基，甲氧基甲基或羟乙基取代的氮原子，B表示羰基或A 和B一起表示其中R a表示氢原子或低级烷基或羟甲基并且X表示氮原子的式“IMAGE”或其中R b表示氢原子或低级烷基或羟甲基的C-R b的基团; R表示卤素原子或硝基或三氟甲基; R1表示氢原子或低级烷基; R 2表示衍生自天然存在的氨基酸的酰基（所有这些基团含有具有L或D，L构型的不对称碳原子），R 3表示苯基，卤代苯基或2-吡啶基。其酸加成盐 。

公开(公告)号：US06281363B1

公开(公告)日：2001-08-28

申请号：US09457798

申请日：1999-12-09

申请人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

发明人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

IPC分类号： C07D23340

CPC分类号： C07D235/02 ,  C07D233/34 ,  C07D233/80 ,  C07D233/84 ,  C07D233/96 ,  C07D239/54 ,  C07D239/96 ,  C07D241/08 ,  C07D249/12 ,  C07D251/34 ,  C07D285/10 ,  C07D285/18 ,  C07D401/06 ,  C07D471/10 ,  C07D487/04 ,  C07D495/04

摘要： Hydrazine derivatives and their pharmaceutically acceptable salts useful for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular disease, fever, hemorrhage, and sepsis.

摘要翻译： 肼衍生物及其药学上可接受的盐可用于治疗炎性和自身免疫疾病，骨关节炎，呼吸系统疾病，肿瘤，恶病质，心血管疾病，发热，出血和败血症。

公开(公告)号：US06239151B1

公开(公告)日：2001-05-29

申请号：US09332809

申请日：1999-06-14

申请人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

发明人： Michael John Broadhurst ,  William Henry Johnson ,  Daryl Simon Walter

IPC分类号： A61K31445

CPC分类号： C07D207/327 ,  C07C259/06 ,  C07C317/44 ,  C07C323/60 ,  C07C2601/02 ,  C07C2601/04 ,  C07C2601/08 ,  C07C2601/14 ,  C07D205/04 ,  C07D207/16 ,  C07D207/28 ,  C07D207/34 ,  C07D209/18 ,  C07D209/48 ,  C07D211/34 ,  C07D211/60 ,  C07D211/62 ,  C07D213/54 ,  C07D213/86 ,  C07D213/87 ,  C07D231/04 ,  C07D231/12 ,  C07D233/46 ,  C07D233/56 ,  C07D233/64 ,  C07D239/54 ,  C07D249/04 ,  C07D249/08 ,  C07D257/04 ,  C07D277/36 ,  C07D285/06 ,  C07D295/15 ,  C07D295/215 ,  C07D307/24 ,  C07D307/68 ,  C07D309/04 ,  C07D309/08 ,  C07D309/12 ,  C07D309/14 ,  C07D333/24 ,  C07D333/38 ,  C07D335/02 ,  C07D405/12 ,  C07D407/12 ,  C07D409/12 ,  C07D417/12

摘要： The invention provides hydrazine derivatives of the formula wherein R1 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R2 is an acyl group derived from an &agr;-, &bgr;-, &ggr;- or &dgr;-(amino, hydroxy or thiol)carboxylic acid in which the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, sulphonylated or amidated and in which any functional group present in a side-chain is optionally protected, or a group of the formula Het(CH2)mCO; R3 is hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl or heterocyclyl; R4 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula X-aryl, X-heteroaryl or —(CH2)n—CH═CR5R6; R5 and R6 together are lower alkylene in which one CH2 group is optionally replaced by a hetero atom; Het is heterocyclyl; X is a spacer group; m is 0, 1, 2, 3 or 4; and n is 1 or 2; and their pharmaceutically acceptable salts inhibit the release of tumour necrosis factor alpha (TNF-&agr;) from cells. They can be used as medicaments, especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumours, cachexia, cardiovascular diseases, fever, haemorrhage and sepsis.

摘要翻译： 本发明提供了糠醛的肼衍生物，R1是低级烷基，低级烯基，低级环烷基，低级环烷基 - 低级烷基，芳基或芳基 - 低级烷基; R2是衍生自α-，β-，γ-或δ-（氨基，羟基或硫醇）羧酸的酰基，其中氨基，羟基或硫醇基任选被低级烷基化或氨基任选地被酰化，磺酰化 或酰胺化，并且其中存在于侧链中的任何官能团任选被保护，或式Het（CH 2）mCO的基团; R3是氢，低级烷基，卤代低级烷基，氰基 - 低级烷基，氨基 - 低级烷基，羟基 - 低级烷基，低级烷氧基 - 低级烷基，低级烷氧基羰基 - 低级烷基，低级环烷基 - 低级烷基，芳基 - 低级烷基， 杂环基 - 低级烷基，杂环基羰基 - 低级烷基，低级烯基，低级炔基，低级环烷基，芳基 - 低级烯基，芳基或杂环基; R4是低级烷基，低级烯基，低级环烷基，低级环烷基 - 低级烷基或式X-芳基，X-杂芳基或 - （CH2）n-CH = CR5R6的基团; R5和R6一起是其中一个CH 2基任选被杂原子取代的低级亚烷基; Het是杂环基; X是间隔基; m为0,1,2,3或4; n为1或2; 及其药学上可接受的盐抑制肿瘤坏死因子α（TNF-α）从细胞释放。 它们可以用作药物，特别是用于治疗炎性和自身免疫疾病，骨关节炎，呼吸系统疾病，肿瘤，恶病质，心血管疾病，发烧，出血和败血症。

公开(公告)号：US6066662A

公开(公告)日：2000-05-23

申请号：US737947

申请日：1996-11-20

申请人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

发明人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

IPC分类号： C07D233/72 ,  A61K31/16 ,  A61K31/165 ,  A61K31/415 ,  A61K31/4166 ,  A61P9/10 ,  A61P35/00 ,  A61P37/06 ,  A61P43/00 ,  C07C237/22 ,  C07C239/18 ,  C07C259/06 ,  C07D233/74 ,  C07D233/78

CPC分类号： C07D233/78 ,  C07C237/22 ,  C07C239/18 ,  C07C259/06 ,  C07C2101/02 ,  C07C2101/04 ,  C07C2101/08

摘要： The invention provides hydroxylamine derivatives of formula (I) wherein A, R.sup.1, R.sup.2 and R.sup.3 have the significance given in the description, which are matrix metalloproteinase inhibitors and which also prevent TNF release. They are therefore useful for the control or prevention of degenerative joints diseases such as rheumatoid arthritis and osteoarthritis or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured according to generally known methods. ##STR1##

摘要翻译： PCT No.PCT / EP95 / 01955 Sec。 371日期：1996年11月2日 102（e）1996年11月2日PCT PCT 1995年5月23日PCT公布。 公开号WO95 / 33709 日期1995年12月14日本发明提供式（I）的羟胺衍生物，其中A，R1，R2和R3具有在描述中给出的含义，其是基质金属蛋白酶抑制剂，并且还可以防止TNF释放。 因此，它们可用于控制或预防变性关节疾病如类风湿性关节炎和骨关节炎，或用于治疗侵袭性肿瘤，动脉粥样硬化或多发性硬化。 它们可以根据通常已知的方法制造。

公开(公告)号：US5710167A

公开(公告)日：1998-01-20

申请号：US741153

申请日：1996-10-29

申请人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

发明人： Michael John Broadhurst ,  Paul Anthony Brown ,  William Henry Johnson

IPC分类号： C07D401/06 ,  A61K20060101 ,  A61K31/16 ,  A61K31/40 ,  A61K31/41 ,  A61K31/415 ,  A61K31/4178 ,  A61K31/42 ,  A61K31/425 ,  A61K31/435 ,  A61K31/4427 ,  A61K31/445 ,  A61K31/454 ,  A61K31/535 ,  A61K31/5377 ,  A61K31/54 ,  A61K31/55 ,  A61P9/10 ,  A61P19/02 ,  A61P29/00 ,  A61P35/00 ,  A61P37/00 ,  A61P43/00 ,  C07C20060101 ,  C07C259/04 ,  C07C259/06 ,  C07D207/36 ,  C07D209/48 ,  C07D233/72 ,  C07D233/74 ,  C07D249/12 ,  C07D263/30 ,  C07D263/44 ,  C07D271/07 ,  C07D291/06 ,  C07D403/06 ,  C07D413/06 ,  C07D417/06 ,  C07D487/04 ,  C07D491/113 ,  C07D401/08

CPC分类号： C07D209/48 ,  A61K31/4178 ,  A61K31/454 ,  A61K31/5377 ,  C07D233/74 ,  C07D263/44 ,  C07D401/06 ,  C07D403/06 ,  C07D417/06 ,  C07D487/04 ,  Y02P20/55

摘要： The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxy-imino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

摘要翻译： 本发明提供通式为（I）的异羟肟酸衍生物，其中R 1表示环丙基，环丁基，环戊基或环己基; R2表示饱和的5-至8-元单环或桥连的N-杂环，N-杂环通过N原子连接，当其为单环时，任选地含有作为环成员的NR4，O，S，SO或SO2 羟基，低级烷基，低级烷氧基，氧代，缩酮化的氧代，氨基，单（低级烷基）氨基，二（低级烷基）氨基，羧基，低级烷氧基羰基，羟基 - 甲基 ，低级烷氧基甲基，氨基甲酰基，单（低级烷基） - 氨基甲酰基，二（低级烷基）氨基甲酰基或羟基亚氨基; （a）经由N原子连接的5-或6-元N-杂环，（b）任选地含有N，O和/或S，SO或SO 2作为另外的环成员，（c）是 在与连接的N原子相邻的一个或两个C原子上被氧代取代，（d）任选地被苯并稠合或任选地在一个或多个其它C原子上被低级烷基或氧代和/或任何另外的N原子取代， 由低级烷基或芳基取代; R4表示氢，低级烷基，芳基，芳烷基或保护基; m代表1或2，n代表1-4，其药学上可接受的盐，制备中使用的中间体及其用途。 式I化合物是可用于控制或预防变性关节疾病如类风湿性关节炎和骨关节炎或用于治疗浸润性肿瘤，动脉粥样硬化或多发性硬化的胶原酶抑制剂。

公开(公告)号：US4069229A

公开(公告)日：1978-01-17

申请号：US740701

申请日：1976-11-11

申请人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

发明人： Cedric Herbert Hassall ,  William Henry Johnson ,  Antonin Krohn ,  Carey Ernest Smithen ,  William Anthony Thomas

IPC分类号： A61K38/00 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06 ,  C07K5/065 ,  C07K5/068 ,  C07K5/072 ,  C07K5/078

CPC分类号： C07K5/06191 ,  C07D213/50 ,  C07D243/24 ,  C07D249/08 ,  C07K5/06026 ,  C07K5/06034 ,  C07K5/06043 ,  C07K5/06078 ,  C07K5/06086 ,  C07K5/06095 ,  C07K5/06104 ,  C07K5/06165 ,  A61K38/00 ,  Y10S514/906

摘要： This invention is directed toward pharmacologically active compounds of the formula ##STR1## wherein A represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, di(C.sub.1-4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together represent a grouping of the formula ##STR2## in which R.sup.a represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C-R.sup.b wherein R.sup.b represents a hydrogen atom or a lower alkyl or hydroxymethyl group; R represents a halogen atom or a nitro or trifluoromethyl group; R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R.sup.3 represents a phenyl, halophenyl or 2-pyridyl groupAnd acid addition salts thereof.Also provided are methods for their preparation and intermediates thereof. These compounds exhibit activity as anticonvulsants, muscle relaxants and sedatives.

摘要翻译： 本发明涉及下式的药理学活性化合物，其中A代表可被甲基，环丙基甲基，二（C 1-4烷基）氨基乙基，甲氧基甲基或羟乙基取代的氮原子，B代表羰基或 A和B一起表示式为“IMAGE”的分组，其中Ra表示氢原子或低级烷基或羟甲基，X表示氮原子或C-Rb，其中Rb表示氢原子或低级烷基或羟甲基 ; R表示卤素原子或硝基或三氟甲基; R1表示氢原子或低级烷基; R 2表示衍生自天然存在的氨基酸的酰基（所有这些基团含有具有L或D，L构型的不对称碳原子），R 3表示苯基，卤代苯基或2-吡啶基。其酸加成盐 。