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公开(公告)号：US4443435A
公开(公告)日：1984-04-17
申请号：US320264
申请日：1981-11-12
IPC分类号： A61K31/095 , A61K31/10 , A61K31/16 , A61K31/165 , A61K31/195 , A61K31/215 , A61K31/22 , A61K31/365 , A61K31/40 , A61K31/415 , A61K31/505 , A61K31/52 , A61K31/70 , A61K31/7042 , A61K31/7052 , A61K31/7076 , A61P5/12 , A61P9/12 , A61P25/04 , A61P31/04 , A61P35/00 , A61P39/02 , C07C67/00 , C07C313/00 , C07C323/12 , C07C323/52 , C07C323/59 , C07C323/60 , C07C325/00 , C07C327/22 , C07C327/24 , C07C327/26 , C07D207/16 , C07D233/84 , C07D239/38 , C07D239/42 , C07D239/56 , C07D307/88 , C07D473/38 , C07H19/16 , C07H19/167 , C07K1/00 , C07K1/113 , C07D473/24
CPC分类号： C07D239/42 , C07D207/16 , C07D233/84 , C07D239/38 , C07D307/88 , C07D473/38 , C07H19/16 , Y02P20/55 , Y10S514/863
摘要： Novel, transient prodrug forms of biologically active agents containing mercapto groups have (i) the structural formula (I): ##STR1## wherein X is O, S, or NR.sup.5 ;R.sup.1 S is the residue of any biologically active agent R.sup.1 SH;R.sup.2 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweralkanoyloxyalkyl, carboxyalkyl, and lower alkanoyloxyalkyl wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, either directly bonded to the carbonyl function or linked thereto via an alkylene bridge, containing from 1 to 3 of any one or more of the heteroatoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8- membered; and mono- or polysubstituted derivatives of the above, each of said substituents being selected from the group consisting of lower akyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, carbethoxy, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR2## wherein R.sup.4 is hydrogen or alkyl having from 1 to 10 carbons;R.sup.3 is hydrogen, R.sup.2, lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH.sub.2 ONO.sub.2 and --CH.sub.2 OCOR.sup.2 ;R.sup.5 is hydrogen or lower alkyl; and further whereinR.sup.2 and R.sup.3 may be taken together to form a cyclizing moiety selected from the group consisting of ##STR3## with the proviso that when R.sup.1 S is the residue of a sulfur containing amino acid, then X cannot be NR.sup.5 ;(ii) the structural formula (I) wherein ##STR4## is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N,N-lower dialkyl of C.sub.4 -C.sub.7 cycloalkylamino acid; and(iii) the non-toxic, pharmaceutically acceptable salts thereof.
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2.发明授权
公开(公告)号：US4279900A
公开(公告)日：1981-07-21
申请号：US61177
申请日：1979-07-27
CPC分类号： C07J33/005 , C07J71/0031 , Y10S514/887
摘要： Novel 3,2'-spiro(1',3'-thiazolidine) compounds which are transient prodrug forms of known 6- and/or 9-haloglucocorticosteroids are described. The subject prodrugs provide improved delivery of the prior art steroids for therapeutic purposes, particularly in alleviating inflammation, and can be prepared by known methods, for example, by reacting the corresponding 3-keto steroids with a thiazolidine forming reagent such as an L-cysteine alkyl ester.
摘要翻译： 描述了已知的6-和/或9-卤素糖皮质激素的瞬时前药形式的新型3,2'-螺（1'，3'-噻唑烷）化合物。 本发明的前药提供了用于治疗目的的现有技术类固醇的改进递送，特别是在减轻炎症中，并且可以通过已知方法制备，例如通过使相应的3-酮类固醇与形成噻唑烷的试剂例如L-半胱氨酸 烷基酯。
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公开(公告)号：US4169147A
公开(公告)日：1979-09-25
申请号：US840291
申请日：1977-10-07
IPC分类号： C07D231/34 , A61K31/44 , A61K31/415 , A61K31/455
CPC分类号： C07D231/34 , Y02P20/55 , Y10S514/87
摘要： There is provided, novel, transient, pro-drug forms of phenylbutazone and oxyphenbutazone having the following formula: ##STR1## wherein R represents a member selected from the group consisting of a C.sub.1 -C.sub.2 O-alkylsulfonyl group, an aryl(phenyl, p-tolyl, naphthyl)sulfonyl group, a nicotinoyl group, an iso-nicotinoyl group, a picolinoyl group, an N-protected naturally occurring amino acid residue, wherein the protective group on the amino group of the amino acid residue is removable via hydrogenolysis or hydrolysis, and an amino acid residue containing a C.sub.1 -C.sub.2 N,N-dialkylamino or a C.sub.4 -C.sub.6 cycloalkylamino group. ##STR2## wherein X and Y each represent a member selected from the group consisting of a hydrogen atom and a --OR.sub.1 group, with the proviso that either X or Y is a hydrogen atom and that R.sub.2 is a member selected from the same or different groups represented by R.sub.1 ; and wherein R.sub.1 represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.2 O-alkylsulfonyl group, an aryl(phenyl, p-tolyl, naphthyl)sulfonyl group, a --CH.sub.2 COOM group, wherein M represents an alkali or alkaline earth metal (Na, K, Ca, Mg), a --CO-R.sub.3 group, wherein R.sub.3 represents a member selected from the group consisting of a straight or branched C.sub.1 -C.sub.5 alkyl group, a C.sub.1 -C.sub.2 alkoxy group, a phenyl group, a substituted phenyl group, whose substituents are selected from the group consisting of a 2,3, or 4-hydroxy group, a 2,3, or 4-acetyloxy group, and a 2,3, or 4-acetylamino group, a 2,3, or 4-pyridyl group, a 1,2, or 5-imidazolyl group, a residue of an N-protected naturally occurring amino acid, wherein the protective group on the amino group of the amino acid is removable via hydrogenolysis or hydrolysis, and an amino acid residue containing a C.sub.1 -C.sub.2 N, N-dialkylamino or C.sub.4 -C.sub.5 cycloalkylamino group. ##STR3## wherein X or Y represents a member selected from the group consisting of a hydrogen atom and a -OR.sub.1 group, wherein R.sub.1 is as defined above with the proviso that either X or Y is a hydrogen atom, wherein R.sub.4 represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group, an aryl group (phenyl, styryl), a 2,3, or 4-methoxyphenyl group, and a -CH.dbd.CH.sub.2 group; and wherein R.sub.5 represents a member selected from the group consisting of a --OOC- R.sub.6 group, a ##STR4## group, and a -COOM group, wherein M represents an alkali or alkaline earth metal (Na, K, Ca, Mg), wherein R.sub.6 represents a member selected from the group consisting of R.sub.4 as defined above, with the proviso that R.sub.6 cannot be a hydrogen atom, and wherein R.sub.7 and R.sub.8 each represent a C.sub.1 -C.sub.3 alkyl group.The above-identified compounds exhibit anti-inflammatory activity in warm-blooded animals. Upon administration to warm-blooded animals, these compounds pass through the gastrointestinal tract and "cleave" in the bloodstream, thus releasing phenylbutazone or oxyphenbutazone in an anti-inflammatory effective amount at their therapeutic site or sites of activity.
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公开(公告)号：US4340603A
公开(公告)日：1982-07-20
申请号：US177824
申请日：1980-08-13
IPC分类号： A61K31/265 , C07C69/74 , C07C69/76 , C09F5/08
CPC分类号： C07C211/27 , C07C229/24 , C07C327/30
摘要： Novel, transient inotropic prodrug forms of the N-(2-phenylethyl)-.omega.-phenylalkylamines, notably of dobutamine, have (i) the structural formula (I): ##STR1## with the proviso that at least one R.sup.1, R.sup.2 or OR.sup.1, when R.sup.7 and/or R.sup.10 is OR.sup.1, must be R.sup.3 COXCH(R.sup.4)-- or R.sup.3 COXCH(R.sup.4)O--, respectively.
摘要翻译： 新颖的N-（2-苯基乙基） - ω-苯基烷基胺，特别是多巴酚丁胺的瞬时变性前体药物形式具有（i）结构式（I）：条件是至少一个R 1， R2或OR1，当R7和/或R10为OR1时，必须分别为R3COXCH（R4） - 或R3COXCH（R4）O-。
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公开(公告)号：US4311706A
公开(公告)日：1982-01-19
申请号：US114205
申请日：1980-01-22
IPC分类号： A61K31/165 , A61K31/22 , A61K31/235 , A61K31/245 , A61K31/25 , A61K31/26 , A61K31/265 , C07C67/02 , C07C69/00 , C07C69/74 , C07C69/76 , C09F5/08 , C07C79/46 , C07C97/16 , C07C101/20 , C07C101/44 , C07C101/72 , C07C102/00 , C07C103/20 , C07C153/00
CPC分类号： C07C233/18 , C07C217/60 , C07C229/36 , C07C327/28 , Y02P20/55
摘要： Novel, transient prodrug forms of dopa and dopamine have (i) the structural formula (I): ##STR1## wherein each R is independently selected from the group consisting of hydrogen, R.sup.3 -CO- and ##STR2## wherein X is O, S or NR.sup.6 ; R.sup.1 is hydrogen or --COOR.sup.8 ; R.sup.2 is hydrogen or OR; R.sup.3 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the hetero atom N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono- or poly-substituted derivatives of the above, each of said substituents being selected from the group consisting of lower alkyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, lower alkoxycarbonyl, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR3## wherein R.sup.5 is hydrogen or alkyl having from 1 to 10 carbons; R.sup.4 is hydrogen, R.sup.3, lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH.sub.2 ONO.sub.2 and --CH.sub.2 OCOR.sup.3 ; R.sup.6 is hydrogen or lower alkyl; R.sup.7 is hydrogen, lower alkyl, COCF.sub.3, COOC(CH.sub.3).sub.3, COOCH.sub.2 C.sub.6 H.sub.5, or other N-protective group conventional to amino acid acid chemistry; R.sup.8 is hydrogen, benzyl, or other conventional, cleavable carboxyl protective group; with the proviso that at least one R must be R.sup.3 COXCH(R.sup.4)--; (ii) the structural formula (I) wherein at least one R.sup.3 CO- moiety comprising at least one R group is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N,N-lower dialkyl or C.sub.4 -C.sub.7 cycloalkylamino acid; and (ii) the non-toxic, pharmaceutically acceptable salts thereof.
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6.发明授权Transient pro-drug forms of xanthine derivatives and their use as topical anti-inflammatory agents 失效黄嘌呤衍生物的瞬时前药形式及其作为局部抗炎药的用途
公开(公告)号：US4275064A
公开(公告)日：1981-06-23
申请号：US34630
申请日：1979-04-30
IPC分类号： C07D473/06 , C07D473/08 , A61K31/52
CPC分类号： C07D473/08 , C07D473/06
摘要： Compounds of the formula: ##STR1## useful in treating dermal inflammation in warm-blooded animals are provided.
摘要翻译： 提供了用于治疗温血动物皮肤炎症的下式的化合物：（I）。
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公开(公告)号：US4221787A
公开(公告)日：1980-09-09
申请号：US059380
申请日：1979-07-20
CPC分类号： C07D295/185 , C07J41/005 , C07J43/003
摘要： Transient, C-21 and/or C-17 esteramide prodrugs of the anti-inflammatory corticosteroids, prepared by esterification of hydroxy steroids, are disclosed.
摘要翻译： 公开了通过羟基类固醇的酯化制备的抗炎皮质类固醇的瞬时，C-21和/或C-17酯酰胺前体药物。
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8.发明授权Prodrugs for improved bioavailability of certain .DELTA..sup.4 -3-ketosteroidal sex hormones 失效用于改善某些DELTA 4-3-酮甾体性激素的生物利用度的前药
公开(公告)号：US4268441A
公开(公告)日：1981-05-19
申请号：US57324
申请日：1979-07-13
CPC分类号： C07J31/006 , C07J33/005
摘要： Transient, orally active thiazolidine type prodrug forms of conventional, natural and synthetic ketosteroidal sex hormones, e.g., of progesterone, testosterone, and the like, are disclosed. The subject compounds can be prepared by known methods, for example, by reacting the corresponding 3-keto or 3,20-diketo steroids with a thiazolidine-forming reagent such as an L-cysteine alkyl ester.
摘要翻译： 公开了常规的，天然的和合成的酮甾体性激素例如孕酮，睾丸激素等的瞬时口服活性噻唑烷型前药形式。 本发明化合物可以通过已知方法制备，例如通过使相应的3-酮基或3,20-二酮类固醇与形成噻唑烷的试剂如L-半胱氨酸烷基酯反应。
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9.发明授权Thiazolidine prodrugs for the improved delivery of anti-inflammatory corticosteroids 失效噻唑烷前药用于改善抗炎皮质类固醇的输送
公开(公告)号：US4239757A
公开(公告)日：1980-12-16
申请号：US60220
申请日：1979-07-24
CPC分类号： C07J43/006
摘要： Novel 3,2'-spiro(1',3'-thiazolidine) compounds which are transient prodrug forms of known anti-inflammatory corticosteroids are disclosed. The subject compounds can be prepared by known methods, for example, by reacting the corresponding 3-keto steroids with a thiazolidine forming reagent such as an L-cysteine alkyl ester. Preferred compounds are derived from such known anti-inflammatory corticosteroids as cortisone acetate, hydrocortisone, prednisone, prednisolone and the like.
摘要翻译： 公开了作为已知抗炎皮质类固醇的瞬时前药形式的新型3,2'-螺（1'，3'-噻唑烷）化合物。 本发明化合物可以通过已知方法制备，例如通过使相应的3-酮类固醇与形成噻唑烷的试剂如L-半胱氨酸烷基酯反应。 优选的化合物衍生自已知的抗炎皮质类固醇，如醋酸可的松，氢化可的松，泼尼松，泼尼松龙等。
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公开(公告)号：US4313956A
公开(公告)日：1982-02-02
申请号：US108055
申请日：1979-12-28
IPC分类号： C07C233/16 , C07C149/40 , A61K31/165 , A61K31/22 , A61K31/235 , A61K31/245 , A61K31/25 , A61K31/265 , C07C67/02 , C07C69/00 , C07C69/74 , C07C69/76 , C07C79/46 , C07C97/16 , C07C101/20 , C07C101/44 , C07C101/72 , C07C102/00 , C07C103/20 , C07C153/00 , C09F5/08
CPC分类号： C07C233/16 , Y02P20/55
摘要： Novel, transient prodrug forms of the phenolic dihydroxy sympathomimetic amines have (i) the structural formula (I): ##STR1## wherein X is O, S or NR.sup.5 ; n is 1 or 2; R.sup.1 is the monodehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine when n is 1, and the didehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine when n is 2; R.sup.2 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the hetero atoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono-or poly-substituted derivatives of the above, each of said substituents being selected from the group consisting of lower alkyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, carbethoxy, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR2## wherein R.sup.4 is hydrogen or alkyl having from 1 to 10 carbons; R.sup.3 is hydrogen, R.sup.2, lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH.sub.2 ONO.sub.2 and --CH.sub.2 OCOR.sup.2 ; R.sup.5 is hydrogen or lower alkyl; (ii) the structural formula (II): ##STR3## wherein X, R.sup.2 and R.sup.3 are as defined above and R.sup.1 is the didehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine; (iii) either of the structural formulae (I) or (II) wherein ##STR4## is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N, N-lower dialkyl or C.sub.4 -C.sub.7 cycloalkylamino acid; and (iv) the non-toxic, pharmaceutically acceptable salts thereof.
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