公开(公告)号：EP1077929A1

公开(公告)日：2001-02-28

申请号：EP99924158.1

申请日：1999-05-10

申请人： AMERICAN HOME PRODUCTS CORPORATION

发明人： BUTERA, John, Anthony ,  CAUFIELD, Craig, Eugene ,  GRACEFFA, Russell, Francis ,  GREENFIELD, Alexander ,  GUNDERSEN, Eric, Gould ,  HAVRAN, Lisa, Marie ,  KATZ, Alan, Howard ,  LENNOX, Joseph, Richard ,  MAYER, Scott, Christian ,  McDEVITT, Robert, Emmett

IPC分类号： C07C235/44 ,  C07C59/70 ,  C07D307/80 ,  C07F9/38 ,  C07F9/40 ,  A61K31/165 ,  A61K31/19

CPC分类号： C07F9/4006 ,  C07B2200/07 ,  C07C17/16 ,  C07C45/68 ,  C07C45/71 ,  C07C47/575 ,  C07C205/35 ,  C07C205/37 ,  C07C225/20 ,  C07C233/43 ,  C07C235/46 ,  C07C235/48 ,  C07C235/52 ,  C07C237/30 ,  C07C255/54 ,  C07C271/12 ,  C07C271/16 ,  C07C271/28 ,  C07C271/30 ,  C07C309/77 ,  C07C2601/02 ,  C07C2601/04 ,  C07C2601/08 ,  C07C2601/14 ,  C07D209/08 ,  C07D213/40 ,  C07D233/54 ,  C07D263/58 ,  C07D295/088 ,  C07D295/13 ,  C07D307/58 ,  C07D307/80 ,  C07D307/81 ,  C07D317/54 ,  C07D333/74 ,  C07D413/12 ,  C07C22/04

摘要： This invention provides compounds of Formula (I) having structure (I) wherein: B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen; R1 is hydrogen, alkyl of 1-6 carbon atoms, -SO¿2?Ph(OH)(CO2H), -CH(R?2¿)W, -CH¿2?CH2Y, or -CH2CH2CH2Y; R?2¿ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, -CH¿2?(1H-imidazol-4-yl), -CH2(3-1H-indolyl), -CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or -CH2(3-pyridyl); W is -CO2R?3¿, -CONHOH, -CN, -CONHR3, aryl, heteroaryl, -CHO, -CH=NOR3, or -CH=NHNHR3; Y is -W, -OCH¿2CO2R?3, aryl, heteroaryl, -C(=NOH)NH¿2, -OR?3, -O(C=O)NR?4R5, -NR3(C=O)OR3, -NR3(C=O)NR4R5¿, or -NR4R5; R3 is hydrogen or alkyl of 1-6 carbon atoms; R?4 and R5¿ are each, independently, hydrogen, or alkyl of 1-6 carbon atoms or R?4 and R5¿ are, together, -(CH¿2?)n-, or -CH2CH2XCH2CH2-; X is O, S, SO, SO2, NR?3¿, or CH¿2?; n is 2 to 5; C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, -CONR?6R7, -NR3CONR6R7, -NR3COR6, -OR6, -O¿2CNR?6R7, -NR3CO¿2R6, -O2CR6, -CH2OR?6, -NR6R7, -CR3=CR3R8¿, -CPh¿3?, -CH2NR?6R7¿, or Formula (1); R?6 and R7¿ are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloalkyl of 3-10 carbon atoms, -(CH¿2?CH2O)nCH3, -(CH2)mA or R?6 and R7¿ are, together, -(CH¿2?)p-, -(CH2)2N(CH3)(CH2)4-, -(CH2)2N(R?8)(CH¿2)2-, or -(CH2)2CH(R8)-(CH2)2-; R8 is hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, cycloakyl or 3-10 carbon atoms, -(CH¿2?CH2O)nCH3, -(CH2CH2CH2O)nCH3, or -(CH2)mA; A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, -CHF2, -CH2F, -CF3, -(CH2CH2O)nCH3, -(CH2CH2CH2O)nCH3, -CO2R?3¿, -O(C=O)NR6R7, aralkyloxy, or heteroaralkyloxy; m is 2 to 16; p is 2 to 12; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

摘要翻译： 本发明提供具有结构的式I化合物，其中B，C，D和R 1如本说明书中所定义，或其药学上可接受的盐，其可用于治疗与胰岛素抵抗或高血糖相关的代谢紊乱。

公开(公告)号：EP0549727A1

公开(公告)日：1993-07-07

申请号：EP91919248.0

申请日：1991-09-19

申请人： AMERICAN HOME PRODUCTS CORPORATION

发明人： CAUFIELD, Craig, Eugene ,  FAILLI, Amedeo, Arturo ,  STEFFAN, Robert, John

IPC分类号： A61K31 ,  A61P9 ,  A61P29 ,  A61P31 ,  C07D498 ,  C07H19 ,  C07K5 ,  A61K38

CPC分类号： C07D498/18 ,  A61K38/00 ,  C07H19/01 ,  C07K5/06026

摘要： L'invention se rapporte à un composé représenté par la structure (I); où: R1, R2 et R3 représentent chacun séparément hydrogène ou R4; R4 représente (a), (b) ou (c); R5 représente hydrogène, alkyle, aralkyle, -(CH2)qCO2R8, -(CH2)rNR9CO2R10, carbamylalkyle, aminoalkyle, hydroxyalkyle, guanylalkyle, mercaptoalkyle, alkylthioalkyle, indolylméthyle, hydroxyphénylméthyle, imidazoylméthyle, ou phényle, éventuellement monosubstitué, disubstitué ou trisubstitué par un substituant choisi parmi alkyle, alkoxy, hydroxy, cyano, halo, nitro, carbalkoxy, trifluorométhyle, amino ou un acide carboxylique, R6 et R9 représentent chacun séparément hydrogène, alkyle ou aralkyle; R7, R8 et R10 représente chacun séparément alkyle, aralkyle, fluorénylméthyle ou phényle, éventuellement monosubstitué, disubstitué ou trisubstitué; R11 et R12 représentent chacun séparément alkyle, aralkyle ou phényle, éventuellement monosubstitué, disubstitué ou trisubstitué; X représente (d), O ou S; R13 et R14 représentent chacun séparément hydrogène ou alkyle; Y représente C, H ou N;; m est compris entre 0 et 4; n est compris entre 0 et 4; p est compris entre 1 et 2; q est compris entre 0 et 4; r est compris entre 0 et 4; t est compris entre 0 et 4; et u est compris entre 0 et 4; R5, R6, m et n étant indépendants dans chacune des sous-unités (e), lorsque p est égal à 2; ou à un sel pharmaceutiquement acceptable du composé de la structure (I), à condition que R1, R2 et R3 ne représentent pas tous hydrogène, à condition que R1, R2 et R3 ne représentent pas tous (a), et à condition en outre que t et u ne soient pas tous deux égaux à 0, lorsque X représente O ou S. Grâce à son action immunosuppressive, un tel composé est utile dans le traitement des phénomènes de rejet de la greffe, dans les affections dues aux réactions de l'hôte contre le greffon, dans les maladies auto-immunes et dans les maladies inflammatoires et grâce à son action fongicide, un tel composé est utile dans le traitement des mycoses.

公开(公告)号：EP0927182A2

公开(公告)日：1999-07-07

申请号：EP97939749.0

申请日：1997-09-03

申请人： AMERICAN HOME PRODUCTS CORPORATION

发明人： HU, David, Cheng ,  GRINFIELD, Alexander, Aleksey ,  CAGGIANO, Thomas, Joseph ,  CAUFIELD, Craig, Eugene

IPC分类号： A61K31 ,  A61P11 ,  A61P29 ,  A61P31 ,  A61P35 ,  A61P37 ,  C07D498

CPC分类号： C07D498/18

摘要： This invention relates to compounds which possess immunosuppressive and/or anti tumor and/or antiinflammatory activity in vivo and/or inhibit thymocyte proliferation in vitro. These compounds are therefore useful in the treatment of transplantation rejection, autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, multiple sclerosis and in the treatment of Candida albicans infections and also in treatment of diseases of inflammation. These compounds are represented by formula (I), wherein W and Y are OR1 and X and Z together form a bond or W and X are OR2 and Y and Z together form a bond, wherein: R1 is selected from -(CH¿2?)n-Ar where Ar is not phenyl, -(CH2CH2O)nCH3 where n is not 1, -CH2CH2CH2O(CH2CH2O)m-CH3, -(CH2)n-CH2CH(OR?3)CH¿2OR4 where R?3 and R4¿ are H, C¿1?-C10 alkyl, or R?3 and R4¿ together are ethylene, methylene or dimethylmethylene; -CH¿2?(CH2)n-OR?3¿ where R3 is not H, C¿1?-C10 alkyl, or C(O)C1-C10 alkyl; and -CH2(CH2)n-X where X is F, Cl, Br or I; R?2¿ is selected from H, C¿1?-C10 alkyl, Ar(CH2)n-, C3-C10 alkenyl, -(CH2CH2O)nCH3, -CH2CH2CH2O(CH2CH2O)m-CH3, -CH2(CH2)n-OR?3, -CH¿2(CH2)n-X where X is F, Cl, Br or I; and -(CH2)nCH2CH(OR5)CH2OR6 where R?5 and R6¿ are selected independently from H, C¿1?-C10 alkyl, -(CH2)n-Ar, -CONH(CH2)n-Ar or COC(CH3)2-(CH2)n-Ar, -COR?7¿ and -CO¿2R?7, where R7 is C1-C6 alkyl, C2-C6 alkenyl, or Ar; n = 1-10 independently; m = 1-5 independently; and Ar is selected independently from phenyl, pyridinyl, quinolinyl, indolyl, furanyl; 1,2,3-triazolyl and tetrazolyl, and a pharmaceutically acceptable acid addition salt where one can be formed.

公开(公告)号：EP0923552A1

公开(公告)日：1999-06-23

申请号：EP97938009.0

申请日：1997-07-22

申请人： AMERICAN HOME PRODUCTS CORPORATION

发明人： KREFT, Anthony, Frank, III ,  CAUFIELD, Craig, Eugene ,  FAILLI, Amedeo, Arturo ,  CAGGIANO, Thomas, Joseph ,  GREENFIELD, Alexander, Aleksey ,  KUBRAK, Dennis, Michael

IPC分类号： A61K31 ,  A61P19 ,  A61P25 ,  A61P35 ,  C07D209 ,  C07D491

CPC分类号： C07D491/04 ,  A61K31/403 ,  A61K31/407 ,  C07D209/88

摘要： This invention provides compounds of formula (I) wherein R1, R2, R3 and R4 are, each, independently, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aralkoxy, trifluoroalkoxy, alkanoyloxy, hydroxy, halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino, alkanamido, or alkanesulfonamido; R5 is hydrogen, alkyl, alkenyl, alkoxyalkyl or alkylcycloalkyl; R6 is hydrogen, alkyl or alkenyl; X is oxygen or carbon; A is oxygen or NZ; Z is hydroxyl, alkoxy, aryloxy, carboxyalkyloxy of 2-7 carbon atoms, arylamino, or alkylsulfonylamino of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in the treatment of arthritic disorders, colorectal cancer, and Alzheimer's disease.

摘要翻译： 本发明提供了其中R 1，R 2，R 3和R 4各自独立地为氢，烷基，烯基，炔基，烷氧基，芳烷氧基，三氟烷氧基，烷酰氧基，羟基，卤素，三氟甲基，氰基，氨基，单 - 或二烷基氨基，烷酰胺基或烷磺酰胺基; R5是氢，烷基，烯基，烷氧基烷基或烷基环烷基; R6是氢，烷基或链烯基; X是氧或碳; A是氧或NZ; Z是羟基，烷氧基，芳氧基，2-7个碳原子的羧基烷氧基，芳基氨基或1-6个碳原子的烷基磺酰基氨基; 或其药学上可接受的盐，其可用于治疗关节炎疾病，结肠直肠癌和阿尔茨海默氏病。