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    Treatment of diseases caused by abnormal action of elastase
    1.
    发明授权
    Treatment of diseases caused by abnormal action of elastase 失效
    治疗由弹性蛋白酶异常作用引起的疾病

    公开(公告)号：US4975464A

    公开(公告)日：1990-12-04

    申请号：US337812

    申请日：1989-04-14

    申请人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    发明人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    IPC分类号： A61K31/255 ,  C07C279/18 ,  C07C309/63 ,  C07C309/65 ,  C07C309/66 ,  C07C311/00 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C327/16 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26 ,  C07D521/00 ,  A61K31/24

    CPC分类号： C07D213/75 ,  C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    摘要： Compounds presented by the general formula: ##STR1## wherein Y is oxygen, R.sup.2 is H, alkyl, alkoxy, alkoxymethyl, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --CH.dbd.CH--COOR.sup.3, halogen, --CF.sub.3, --COR.sup.4, --OCOR.sup.4, --CH.sub.2 OCOR.sup.4, --SO.sub.2 R.sup.4, --OSO.sub.2 R.sup.4, --CONR.sup.5 R.sup.6, --OCONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --COHN-- SO.sub.2 NR.sup.5 R.sup.6, --NHSO.sub.2 R.sup.7, --NO.sub.2, --OH, --CH.sub.2 OH, guanidino, benzyloxy, guanidinophenylthiomethyl, morpholinosulfonylphenoxymethyl, pyridyloxymethyl, or (1,1-dioxothiazol-3-yl)carbonyl, or when Y is sulfur, R.sup.2 is H, alkyl, alkoxy, halogen, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --NO.sub.2, or --SO.sub.2 NR.sup.5 R.sup.6, and n represents an integer of one to five, and when n represents more than two, each or R.sup.2 may be the same group or the different group and acid addition salts thereof have inhibitory effect on elastase, and, therefore, are useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

    摘要翻译： 由以下通式表示的化合物：其中Y是氧，R2是H，烷基，烷氧基，烷氧基甲基，-COOR3，-CH2COOR3，-CH = CH-COOR3，卤素，-CF3，-COR4， - OCOR4，-CH2OCOR4，-SO2R4，-OSO2R4，-CONR5R6，-OCONR5R6，-SO2NR5R6，-COHN-SO2NR5R6，-NHSO2R7，-NO2，-OH，-CH2OH，胍基，苄氧基，胍基苯硫基甲基，吗啉代磺酰基苯氧基甲基，吡啶氧基甲基或（1 ，1-二氧代噻唑-3-基）羰基，或当Y为硫时，R 2为H，烷基，烷氧基，卤素，-COOR 3，-CH 2 COOR 3，-NO 2或-SO 2 NR 5 R 6，n为1至5的整数， 当n表示2以上时，各个或R2可以是相同的基团，也可以是不同的基团，其酸加成盐对弹性蛋白酶具有抑制作用，因此可用于治疗和/或预防由异常增强引起的疾病 蛋白质如弹性蛋白等的降解，通过弹性蛋白酶在哺乳动物，特别是人类中的作用。

    Derivatives of p-guantidinobenzoic acid and pharmaceutical agents containing them as active ingredient
    2.
    发明授权
    Derivatives of p-guantidinobenzoic acid and pharmaceutical agents containing them as active ingredient 失效
    对胍丁基苯甲酸的衍生物和含有它们作为活性成分的药剂

    公开(公告)号：US4843094A

    公开(公告)日：1989-06-27

    申请号：US929317

    申请日：1986-11-12

    申请人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    发明人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    IPC分类号： C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    CPC分类号： C07D213/75 ,  C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    摘要： Compounds presented by the general formula: ##STR1## [wherein when Y is oxygen, R.sup.2 is H, alkyl, alkoxy, alkoxymethyl, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --CH.dbd.CH--COOR.sup.3, halogen, --CF.sub.3, --COR.sup.4, --OCOR.sup.4, --CH.sub.2 OCOR.sup.4, --SO.sub.2 R.sup.4, --OSO.sub.2 R.sup.4, --CONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --CONH--SO.sub.2 NR.sup.5 R.sup.6, --NHSO.sub.2 R.sup.7, --NO.sub.2, --OH, --CH.sub.2 OH, guanidino, benzyloxy, guanidinophenylthiomethyl, morpholinosulfonylphenoxymethyl, pyridyloxymethyl, or (1,1-dioxothiazol-3-yl)carbonyl, or when Y is sulfur, R.sup.2 is H, alkyl, alkoxy, halogen, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --NO.sub.2, or --SO.sub.2 NR.sup.5 R.sup.6, and n represents an integer of one to five, and when n represents more than two, each of R.sup.2 may be the same group or the different group.] and acid addition salts thereof have inhibitory effect on elastase, and, therefore, are useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

    摘要翻译： 由以下通式表示的化合物：其中当Y为氧时，R 2为H，烷基，烷氧基，烷氧基甲基，-COOR 3，-CH 2 COOR 3，-CH = CH-COOR 3，卤素，-CF 3，-COR 4 ，-OCOR4，-CH2OCOR4，-SO2R4，-OSO2R4，-CONR5R6，-SO2NR5R6，-CONH-SO2NR5R6，-NHSO2R7，-NO2，-OH，-CH2OH，胍基，苄氧基，胍基苯硫基甲基，吗啉代磺酰基苯氧基甲基，吡啶氧基甲基，或（1， 或者当Y为硫时，R 2为H，烷基，烷氧基，卤素，-COOR 3，-CH 2 COOR 3，-NO 2或-SO 2 NR 5 R 6，n为1〜5的整数， 当n表示两个以上时，R2各自可以是相同的基团或不同的基团。]及其酸加成盐对弹性蛋白酶具有抑制作用，因此可用于治疗和/或预防由异常引起的疾病 通过弹性蛋白酶在哺乳动物，特别是人类中的作用，增强蛋白质如弹性蛋白等的降解。

    Derivatives of p-guanidinobenzoic acid and pharmaceutical agents containing them as an active ingredient
    3.
    发明授权
    Derivatives of p-guanidinobenzoic acid and pharmaceutical agents containing them as an active ingredient 失效
    对胍基苯甲酸的衍生物和含有它们作为活性成分的药剂

    公开(公告)号：US5376655A

    公开(公告)日：1994-12-27

    申请号：US70683

    申请日：1993-06-02

    申请人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    发明人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    IPC分类号： C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26 ,  A61K31/535 ,  A61K31/21 ,  A61K31/44 ,  C07C327/16

    CPC分类号： C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    摘要： A derivative of p-guanidinobenzoic acid of the general formula (IA): ##STR1## wherein Y represents an oxygen atom or a sulfur atom and (a) when Y is an oxygen atom, (R.sup.1).sub.m is selected from the group consisting of: 5-(4-guanidinobenzoyloxy)-3-methoxymethyl, 3,5-dicarboxy, 3,5-bis(isopropoxycarbonyl), 3,5-bistrifluoromethyl, 3-acetyl, 3,5-bis(N-ethylcarbamoyl), and 3,5-bis(N-propylcarbamoyl);(b) when Y is a sulfur atom, (R.sup.1).sub.m is selected from the group consisting of: 2-methyl, 3-methyl, 4-fluoro, 2-chloro, 3-chloro, 2,5-dichloro 2,6-dichloro, 3,4-dichloro, 2-bromo, 2-methoxycarbonyl, and 4-(N,N-diethylaminosulfonyl);or an acid addition salt of said derivative. A method for the treatment or prevention of diseases induced by abnormal enhancing of degradation of proteins by the action of elastase in mammals subject to or suffering therefrom, including the step of administering an effective amount of a p-guanidinobenzoic acid as described herein, is also disclosed.

    摘要翻译： 通式（IA）的对胍基苯甲酸的衍生物：其中Y表示氧原子或硫原子，（a）当Y是氧原子时，（R1）m选自 由5-（4-胍基苯甲酰氧基）-3-甲氧基甲基，3,5-二羧基，3,5-双（异丙氧基羰基），3,5-双三氟甲基，3-乙酰基，3,5-双（N-乙基氨基甲酰基 ）和3,5-双（N-丙基氨基甲酰基）; （b）当Y是硫原子时，（R1）m选自：2-甲基，3-甲基，4-氟，2-氯，3-氯，2,5-二氯2,6 二氯，3,4-二氯，2-溴，2-甲氧基羰基和4-（N，N-二乙基氨基磺酰基）; 或所述衍生物的酸加成盐。 用于治疗或预防由于受到或遭受的哺乳动物中的弹性蛋白酶的作用的蛋白质降解异常增强引起的疾病的方法，包括施用有效量的如本文所述的对胍基苯甲酸的步骤也是 披露

    Derivatives of p-guanidinobenzoic acid
    4.
    发明授权
    Derivatives of p-guanidinobenzoic acid 失效
    对胍基苯甲酸的衍生物

    公开(公告)号：US5247084A

    公开(公告)日：1993-09-21

    申请号：US765749

    申请日：1991-09-26

    申请人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    发明人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Hiroyuki Ohno

    IPC分类号： C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    CPC分类号： C07C279/18 ,  C07C309/65 ,  C07C309/66 ,  C07C311/08 ,  C07C311/29 ,  C07C311/46 ,  C07C329/10 ,  C07D213/65 ,  C07D213/75 ,  C07D277/04 ,  C07D277/22 ,  C07D295/26

    摘要： Compounds presented by the general formula: ##STR1## [wherein when Y is oxygen, R.sup.2 is H, alkyl, alkoxy, alkoxymethyl, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --CH=CH--COOR.sup.3, halogen, --CF.sub.3, --COR.sup.4, --OCOR.sup.4, --CH.sub.2 OCOR.sup.4, --SO.sub.2 R.sup.4, --OSO.sub.2 R.sup.4, --CONR.sup.5 R.sup.6, --OCONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --CONH--SO.sub.2 NR.sup.5 R.sup.6, --NHSO.sub.2 R.sup.7, --NO.sub.2, --OH, --CH.sub.2 OH, guanidino, benzyloxy, guanidinophenylthiomethyl, morpholinosulfonylphenoxymethyl, pyridyloxymethyl, or (1,1-dioxothiazol-3-yl)carbonyl, or when Y is sulfur, R.sup.2 is H, alkyl, alkoxy, halogen, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --NO.sub.2, or --SO.sub.2 NR.sup.5 R.sup.6, and n represents an integer of one to five, and when n represents more than two, each of R.sup.2 may be the same group or the different group.] and acid addition salts thereof have inhibitory effect on elastase, and, therefore, are useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

    摘要翻译： 由以下通式表示的化合物：其中当Y为氧时，R 2为H，烷基，烷氧基，烷氧基甲基，-COOR 3，-CH 2 COOR 3，-CH = CH-COOR 3，卤素，-CF 3，-COR 4 ，-OCOR4，-CH2OCOR4，-SO2R4，-OSO2R4，-CONR5R6，-OCONR5R6，-SO2NR5R6，-CONH-SO2NR5R6，-NHSO2R7，-NO2，-OH，-CH2OH，胍基，苄氧基，胍基苯硫基甲基，吗啉代磺酰基苯氧基甲基，吡啶氧基甲基或 （1,1-二氧代噻唑-3-基）羰基，或者Y为硫时，R2为H，烷基，烷氧基，卤素，-COOR3，-CH2COOR3，-NO2或-SO2NR5R6，n表示1〜 5，当n表示2以上时，R2各自可以相同或不同。]及其酸加成盐对弹性蛋白酶具有抑制作用，因此可用于治疗和/或预防疾病 通过弹性蛋白酶在哺乳动物，特别是人类中的弹性蛋白酶的作用，由弹性蛋白等蛋白质的异常增强引起的。

    3-phenoxy (or phenylthia) cyclopentanecarbonylamino acid analogues
    6.
    发明授权
    3-phenoxy (or phenylthia) cyclopentanecarbonylamino acid analogues 失效
    3-苯氧基（或苯基硫）环戊烷羰基氨基酸类似物

    公开(公告)号：US4888351A

    公开(公告)日：1989-12-19

    申请号：US268623

    申请日：1988-11-07

    申请人： Katsuhiro Imaki ,  Tadao Okegawa ,  Yoshinobu Arai

    发明人： Katsuhiro Imaki ,  Tadao Okegawa ,  Yoshinobu Arai

    IPC分类号： A61K31/195 ,  A61K31/34 ,  A61K31/341 ,  A61K31/343 ,  A61K31/38 ,  A61K31/381 ,  A61P7/10 ,  A61P25/00 ,  C07C67/00 ,  C07C235/40 ,  C07C313/00 ,  C07C323/61 ,  C07D307/46 ,  C07D307/80 ,  C07D333/22

    CPC分类号： C07D333/22

    摘要： This invention relates to compounds presented by the general formula: ##STR1## [wherein R.sup.1 and R.sup.2 are: (i) R.sup.1, R.sup.2 and carbon atoms to which R.sup.1 and R.sup.2 are linked, together represent the group of the general formula: ##STR2## (wherein R.sup.5 and R.sup.6 represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, independently, with the proviso that R.sup.5 and R.sup.6 is not hydrogen atoms at the same time), or(ii) R.sup.1 represents hydrogen and R.sup.2 represents the group of the formula: --COR.sup.7 (wherein R.sup.7 represents the group of the formula: ##STR3## (wherein Y represents a single-bond, alkylene, alkenylene, W represents oxygen or sulfur, m represents 1 to 3, R.sup.8 represents hydrogen, halogen, nitro, hydroxy, alkyl or alkoxy, with the proviso that when m represents two or more, plural R.sup.8 s may be different each, and R.sup.9 represents hydrogen, alkyl or phenyl group, with the proviso that two of R.sup.9 may be different each)), R.sup.3 represents hydrogen, halogen, alkyl group or two of R.sup.3 and phenyl to which two of R.sup.3 are linked, together represent naphthyl of the formula: ##STR4## (wherein R.sup.10 represents hydrogen, halogen or alkyl), with the proviso that when R.sup.1 represents hydrogen, the atom may be replaced by R.sup.3, and n represents 1 to 3, with the proviso that when n represents two or more, plural R.sup.3 s may be different each, X represents oxygen or sulfur and R.sup.4 represents amino acid-residue], or a non-toxic salt thereof, and methods for their preparation and treating agents for cerebral edema containing them as active ingredients.

    Derivatives of p-substituted phenyl ester of pivalic acid
    8.
    发明授权
    Derivatives of p-substituted phenyl ester of pivalic acid 失效
    新戊酸对取代苯基酯的衍生物

    公开(公告)号：US5017610A

    公开(公告)日：1991-05-21

    申请号：US364994

    申请日：1989-06-12

    申请人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Tadao Okegawa

    发明人： Katsuhiro Imaki ,  Yoshinobu Arai ,  Tadao Okegawa

    IPC分类号： C07C235/56 ,  C07C235/64 ,  C07C311/29 ,  C07C323/59 ,  C07C323/63 ,  C07D207/16 ,  C07D209/20 ,  C07D211/62 ,  C07D211/96 ,  C07D213/42 ,  C07D213/75 ,  C07D213/76 ,  C07D295/26 ,  C07D319/20 ,  C07D521/00

    CPC分类号： C07D213/42 ,  C07C235/56 ,  C07C235/64 ,  C07C311/29 ,  C07C323/59 ,  C07C323/63 ,  C07D207/16 ,  C07D209/20 ,  C07D211/62 ,  C07D211/96 ,  C07D213/75 ,  C07D213/76 ,  C07D231/12 ,  C07D233/56 ,  C07D249/08 ,  C07D295/26 ,  C07D319/20

    摘要： A derivative of general formula: ##STR1## wherein Y is --SO.sub.2 -- or ##STR2## (i) R.sup.1 and R.sup.2, which may be the same or different, each represent, (1) --H, (2) C1-16 alkyl or (3) the formula: --X-- .circle.A --(R.sup.4).sub.n wherein X is a single-bond, --SO.sub.2 --, C1-4 alkylene, C1-4 alkylene substituted by ##STR3## -- .circle.A -- is carbocyclic or heterocyclic ring, n is 1.about.5, R.sup.4 is (1) --H or C1-8 alkyl, (2) C1-14 alkoxy, (3) C1-6 alkylthio, (4) --OH, halogen, --NO.sub.2 or trihalomethyl, (5) the formula: --NR.sup.41 R.sup.42 wherein R.sup.41 and R.sup.42 each represents halogen or C1-4 alkyl, (6) tetrazole, (7) --SO.sub.3 H or --CH.sub.2 OH, (8) the formula: --SO.sub.2 NR.sup.41 R.sup.42 (9) the formula: --Z.sup.41 --COOR.sup.43 wherein Z.sup.41 is single-bond, C1-4 alkylene or C2-4 alkenylene, R.sup.43 is --H, C1-4 alkyl or benzyl, (10) the formula: --CONR.sup.41 R.sup.42 (11) the formula: --COO--Z.sup.42 --COOR.sup.43 wherein Z.sup.42 is C1-4 alkylene, R.sup.43 is --H, C1-4 alkyl or benzyl, (12) the formula: --COO--Z.sup.42 --CONR.sup.41 R.sup.42 (13) the formula: --OCO--R.sup.45 wherein R.sup.45 is C1-8 alkyl or p-guanidinophenyl, (14) the formula: --CO--R.sup.46 wherein R.sup.46 is C1-4 alkyl, (15) the formula: --O--Z.sup.43 --COOR.sup.450 wherein Z.sup.43 is C1-6 alkylene, R.sup.450 represents a hydrogen, C1-8 alkyl or p-guanidinophenyl, (16) the formula: ##STR4## wherein ##STR5## is an amino acid residue, R.sup.47 is bond, C1-4 alkyl, R.sup.48 is --H or C1-4 alkyl, R.sup.49 is --OH, C1-4 alkoxy, --NH.sub.2, amino substituted by one or two C1-4 alkyl, carbamoylmethoxy or carbamoylmethoxy substituted by one or two C1-4 alkyl at N atom of carbamoyl, wherein ##STR6## is C3-6 heterocyclic ring, (ii) R.sup.1, R.sup.2 and N atom bonded to R.sup.1 and R.sup.2 together represents heterocyclic ring containing at least a N atom(s) and substituted by --COOH or unsubstituted heterocyclic ring containing at least a N atom(s), R.sup.3 is (1) --H, (2) --OH, (3) C1-6 alkyl, (4) halogen, (5) C1-4 alkoxy or (6) C2-5 acyloxy, m is 1-4.or non-toxic salt or an acid addition salt thereof possess inhibitory activity on elastase, and therefore is useful for treating and/or preventing agent for pulmonary emphysema, atherosclerosis and rheumatoid arthritis and the like.

    3-phenoxy (or phenylthio)--cyclopentanecarbonylamino acid analogues
    10.
    发明授权
    3-phenoxy (or phenylthio)--cyclopentanecarbonylamino acid analogues 失效
    3-苯氧基（或苯硫基） - 环戊烷羰基氨基酸类似物

    公开(公告)号：US4829078A

    公开(公告)日：1989-05-09

    申请号：US158457

    申请日：1988-02-22

    申请人： Katsuhiro Imaki ,  Tadao Okegawa ,  Yoshinobu Arai

    发明人： Katsuhiro Imaki ,  Tadao Okegawa ,  Yoshinobu Arai

    IPC分类号： A61K31/195 ,  A61K31/34 ,  A61K31/341 ,  A61K31/343 ,  A61K31/38 ,  A61K31/381 ,  A61P7/10 ,  A61P25/00 ,  C07C67/00 ,  C07C235/40 ,  C07C313/00 ,  C07C323/61 ,  C07D307/46 ,  C07D307/80 ,  C07D333/22

    CPC分类号： C07D333/22

    摘要： This invention relates to compounds presented by the general formula: ##STR1## [wherein R.sup.1 and R.sup.2 are: (i) R.sup.1, R.sup.2 and carbon atoms to which R.sup.1 and R.sup.2 are linked, together represent the group of the general formula: ##STR2## (wherein R.sup.5 and R.sup.6 represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, independently, with the proviso that R.sup.5 and R.sup.6 is not hydrogen atoms at the same time), or(ii) R.sup.1 represents hydrogen and R.sup.2 represents the group of the formula: --COR.sup.7 (wherein R.sup.7 represents the group of the formula: ##STR3## (wherein Y represents a single-bond, alkylene, alkenylene, W represents oxygen or sulfur, m represents 1 to 3, R.sup.8 represents hydrogen, halogen, nitro, hydroxy, alkyl or alkoxy, with the proviso that when m represents two or more, plural R.sup.8 s may be different each, and R.sup.9 represents hydrogen, alkyl or phenyl group, with the proviso that two of R.sup.9 may be different each)), R.sup.3 represents hydrogen, halogen, alkyl group or two of R.sup.3 and phenyl to which two of R.sup.3 are linked, together represent naphthyl of the formula: ##STR4## (wherein R.sup.10 represents hydrogen, halogen or alkyl), with the proviso that when R.sup.1 represents hydrogen, the atom may be replaced by R.sup.3, and n represents 1 to 3, with the proviso that when n represents two or more, plural R.sup.3 s may be different each, X represents oxygen or sulfur and R.sup.4 represents amino acid-residue], or a non-toxic salt thereof, and methods for their preparation and treating agents for cerebral edema containing them as active ingredients.