KR880009041A - Peptide derivatives, their preparation and use - Google Patents

Peptide derivatives, their preparation and use Download PDF

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KR880009041A
KR880009041A KR1019880000498A KR880000498A KR880009041A KR 880009041 A KR880009041 A KR 880009041A KR 1019880000498 A KR1019880000498 A KR 1019880000498A KR 880000498 A KR880000498 A KR 880000498A KR 880009041 A KR880009041 A KR 880009041A
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cyclohexyl
formula
hydroxy
boc
amido
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KR1019880000498A
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Korean (ko)
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하겐바흐 알렉산더
메터니흐 라이너
펜닌거 에밀
바이드만 비트
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예안 크라메르, 한스 루돌프 하우스
산도즈 리미티드
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

내용 없음.No content.

Description

펩티드유도체, 이것의 제조방법 및 사용방법Peptide derivatives, their preparation and use

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is a trivial issue, I did not include the contents of the text.

Claims (9)

하기 구조식 (I)의 화합물The compound of formula (I) 식중, A는 구조식의 아실기인데, 식중 R6은 (C1-5) 알콕시 또는 (C6-10)아릴옥시로 임의치환 가능한 직쇄 또는 측쇄의 (C1-10) 알킬 라디칼 ; (C3-7) 시클로알킬 라디칼, (C3-10)-시클로알킬-(C1-5) 알킬라디칼, (C6-10)아릴라디칼, 1 또는 2개의 질소원자, 산소 또는 황원자 또는 1개의 질소원자와 하나의 산소원자 및/또는 하나의 황원자를 함유하는 5- 또는 6원 헤테로 아릴 라디칼 ; 헤테로 아릴부가 5- 또는 6원으로서 1 또는 2개의 질소원자, 산소 또는 황원자 또는 하나의 질소원자와 하나의 산소원자 및/또는 하나의 황원자를 함유하는 헤테로 아릴-(C1-5)-알킬라디칼 ; 직쇄 또는 측쇄의 (C1-5) 알콕시라디칼 또는 (C6-10)아릴-(C1-5)-알콕시라디칼 또는 R10이 직쇄 또는 측쇄의 (C1-5)알킬 라디칼이고, n이 1 내지 20의 정수이고, m이 1 내지 5의 정수인 구조식 R10O(CH2CH2O)n(CH2)m-의 기, 또는 구조식의 기인데, 식중 R은 수소 또는 아세틸이고, 또는 A는 하기 구조식의 기인데식중, R7은 직쇄 또는 측쇄의 (C1-5) 알킬 라디칼 또는 (C6-10) 아릴라디칼이고, R8및 R9는 각각 수소, 직쇄 또는 측쇄의 (C1-5)-알킬라디칼 또는 (C6-10)아릴 라디칼이고, R1은 수소 또는 직쇄 또는 측쇄의 (C1-5)-알킬라디칼이고, B 및 C는 동일 또는 상이한 것으로서, 결합 또는 하기식의 기이고,식중, R1은 상기 정의와 동일하고 R11은 친수성 또는 친액성 아미노산 측쇄이고, B 및 C는 동시에 결합일 수 없고, D는 결합 또는 -O-,또는(식중, R1은 상기 정의와 동일하다)이고, R2는 직쇄 또는 측쇄의 (C1-10)알킬라디칼, 시클로 알킬부가 임의 치환된 (C3-10) 시클로알킬(C1-5) 알킬라디칼, (C6-10)아릴-(C1-5) 알킬라디칼, 또는 헤테로 아릴부가 5- 또는 6원으로서 1 또는 2개의 질소원자, 산소 또는 황원자 또는 하나의 질소원자와 하나의 산소원자 및/또는 하나의 황원자를 함유하는 헤테로 아릴-(C1-5)-알킬라디칼, 또는 하기식의 기로서,, 식중, R15는 수소, (C1-4)알킬 또는 벤질이고, S는 O 또는 1이고 P는 1 또는 2이고, R3은 수소, 히드록실기, 아미노기 또는 R2가 상기 정의와 같은 구조식 -OCOR2의 기이고, R4및 R5는 동일 또는 상이하며, 각각 수소, 직쇄 또는 측쇄의 (C1-5)알킬라디칼, (C6-10)-아릴-(C1-5)-알킬, 또는 헤테로 아릴부가 5- 또는 6-원으로서 1 또는 2개의 질소원자, 산소 또는 황원자 또는 하나의 질소원자와 하나의 질소원자 및/또는 하나의 황원자를 함유하는 헤테로 아릴-(C1-5)-알킬라디칼, 또는 하기 구조식의 기로서,식중, R12는 직쇄 또는 측쇄의 (C1-5)-알킬라디칼 또는 직쇄 또는 측쇄의 (C1-5)-히드록시알킬라디칼이고, R13은 히드록시 알킬, 직쇄 또는 측쇄의 (C1-5)알콕시기, 아미노기 또는 (C1-5) 알킬아미노기이고, 이때 알킬 라디칼은 직쇄 또는 측쇄의 아미노메틸 피리딜기 또는 벤질기, 또는 라디칼은 하기 구조식의 기로서,식중, R14는 수소, (C1-5)-알킬, 벤질 또는 R16이 (C1-4)알킬 또는 (C1-4) 알콕시 (OC2H2)q-CH2(식중, q는 2 내지 5의 정수이다)이고, Y는 R4및 R5가 상기 정의와 동일한 하기식의 기이다.또는.In the formula, A represents the formula Wherein R 6 is a straight or branched (C 1-10 ) alkyl radical optionally substituted with (C 1-5 ) alkoxy or (C 6-10 ) aryloxy; (C 3-7 ) cycloalkyl radical, (C 3-10 ) -cycloalkyl- (C 1-5 ) alkyl radical, (C 6-10 ) aryl radical, one or two nitrogen atoms, oxygen or sulfur atom or 1 A 5- or 6-membered heteroaryl radical containing one nitrogen atom and one oxygen atom and / or one sulfur atom; Heteroaryl- (C 1-5 ) -alkyl radical containing one or two nitrogen atoms, oxygen or sulfur atoms or one nitrogen atom and one oxygen atom and / or one sulfur atom as the 5- or 6-membered heteroaryl moiety ; Straight or branched (C 1-5) alkoxy radical or a (C 6-10) aryl - (C 1-5) - alkoxy radicals, or R 10 is a straight chain or (C 1-5) alkyl radical of the side chain, n is A group of the formula R 10 O (CH 2 CH 2 O) n (CH 2 ) m- wherein m is an integer from 1 to 20 and m is an integer from 1 to 5, Wherein R is hydrogen or acetyl, or A is a group of the formula Wherein R 7 is a straight or branched (C 1-5 ) alkyl radical or a (C 6-10 ) aryl radical and R 8 and R 9 are each hydrogen, straight or branched (C 1-5 ) -alkyl radical Or a (C 6-10 ) aryl radical, R 1 is hydrogen or a straight or branched (C 1-5 ) -alkyl radical, B and C are the same or different and are a bond or a group of formula: Wherein R 1 is as defined above and R 11 is a hydrophilic or lyotropic amino acid side chain, B and C can not be simultaneously bonded, D is a bond or -O-, or (Wherein, R 1 is as defined above), and, R 2 is a straight or branched (C 1-10) alkyl radical, a cycloalkyl add an optionally substituted (C 3-10) cycloalkyl (C 1-5) An alkyl radical, a (C 6-10 ) aryl- (C 1-5 ) alkyl radical, or a heteroaryl group as a 5- or 6-membered nitrogen atom, oxygen or sulfur atom or one nitrogen atom and one oxygen atom And / or a heteroaryl- (C 1-5 ) -alkyl radical containing one sulfur atom, or a group of the formula: , Wherein R 15 is hydrogen, (C 1-4 ) alkyl or benzyl, S is O or 1 and P is 1 or 2 and R 3 is hydrogen, hydroxyl, amino or R 2 is as defined above a group of the formula -OCOR 2, R 4 and R 5 are the same or different and are each hydrogen, linear or branched (C 1-5) alkyl radical, (C 6-10) - aryl - (C 1-5) -Alkyl, or heteroaryl-containing heteroaryl- (C 1 -C 6 -alkyl) which contains 1 or 2 nitrogen atoms, oxygen or sulfur atoms as a 5- or 6-membered ring or one nitrogen atom and one nitrogen atom and / 5 ) -alkyl radical, or a group of the formula: Wherein, R 12 is a straight or branched (C 1-5) - alkyl radical or a linear or branched (C 1-5) - hydroxy and hydroxy alkyl radicals, R 13 is a hydroxyalkyl, linear or branched (C 1 -5 ) alkoxy group, an amino group or a (C 1-5 ) alkylamino group, wherein the alkyl radical is a linear or branched aminomethylpyridyl group or a benzyl group, or a radical Is a group of the following structural formula, Wherein R 14 is hydrogen, (C 1-5 ) -alkyl, benzyl or R 16 is (C 1-4 ) alkyl or (C 1-4 ) alkoxy (OC 2 H 2 ) q-CH 2 Is an integer of 2 to 5, and Y is a group of the formula: wherein R 4 and R 5 are as defined above. or . 제항에 있어서, 하기구조식 (Iy)를 가지는 것을 특징으로 하는 화합물.A compound according to claim 1, which has the following structural formula (Iy). 식중, Ay는 t-부틸옥시카르보닐, 파발로일, 비스(1-나프틸메틸) 아세틸, 벤조일 또는 1-아다만틸 카르보닐이고, By는 결합, 페닐아닐린 또는 β-시클로헥실 아닐린이고, Cy는 히스티딘, 노르로이신, 페닐알라닌 또는 로이신이고, Yy는기이고, R1 y는 수소 또는 메틸이고, R2 y는 이소부틸, 벤질, 시클로헥실메틸 또는 1-아다만틸메틸이고, R3 y는 히드록시, 아미노 또는 구조식 OCOCH3또는 OCOC(CH3)3의 기이고, R4 y는 수소, 메틸, i-프로필, i-부틸 또는 n-부틸이고, R5 y는 메틸, i-프로필, i-부틸 또는 n-부틸, 또는 기 -N R4 yR5 y이 피롤리디닐-, 피페리디닐 또는 모르폴리닐기이고, Dy는 NH, N-i-프로필, CH2또는 CH-i-프로필기이다.Wherein A y is t-butyloxycarbonyl, pavaloyl, bis (1-naphthylmethyl) acetyl, benzoyl or 1-adamantylcarbonyl and B y is a bond, a phenylaniline or a? -Cyclohexyl aniline C y is histidine, norleucine, phenylalanine or leucine, Y y is Group and, R 1 y is hydrogen or methyl, R y 2 is isobutyl, benzyl, cyclohexyl-methyl or 1-adamantyl-methyl, R 3 y is hydroxy, amino or the following structural formula, or OCOCH 3 OCOC (CH 3 ) and the third group of, R 4 y is hydrogen, methyl, i- propyl, i- butyl or n- butyl, R 5 y is methyl, i- propyl, i- butyl or n- butyl, or a group -NR 4 y R 5 y is a pyrrolidinyl-, piperidinyl- or morpholinyl group and D y is NH, Ni-propyl, CH 2 or CH-i-propyl. 제1항에 있어서, 하기 구조식 (Iz)를 가지는 것을 특징으로 하는 화합물A compound according to claim 1, which has the following structure (Iz): 식중, Az는 t-부틸옥시카르보닐 또는 비스(1-나프틸메틸)-아세틸이고, Bz는 결합, 페닐알라닌일 또는 β-시클로헥실알라닌일이고, Cz는 히스티딘, 로이신 또는 노르로이신이고, Yz는또는 C=O 기이고, R1 z는 수소이고, R2 z는 시클로헥실메틸 또는 1-아다만틸메틸이고, R3 z는 히드록시 또는 아미노이고, R4 z는 수소 또는 메틸이고, R5 z는 수소, 이소프로필 또는 이소부틸 ; 또는 -N R4 zR5 z는 피롤리디닐-, 피페리디닐 또는 모르폴리닐기이고, Dz는 NH- - 또는 CH-이소프로필- 또는 CH2-기이다.Wherein A z is t-butyloxycarbonyl or bis (1-naphthylmethyl) -acetyl, B z is a bond, phenylalanine yl or beta -cyclohexylalanine, C z is histidine, leucine or norleucine, , Y z is Or C = O group, R 1 z is hydrogen, R 2 z is cyclohexylmethyl or 1-adamantylmethyl, R 3 z is hydroxy or amino, R 4 z is hydrogen or methyl, R 5 z is hydrogen, isopropyl or isobutyl; Or -NR 4 z R 5 z is a pyrrolidinyl-, piperidinyl- or morpholinyl group and D z is NH- or CH- isopropyl- or CH 2 - group. 제1항에 있어서, 하기에서 선택되는 것을 특징으로 하는 화합물(2S,3S)-3-(N-BOC-페닐알리닌일-히스티딜)아미도-1-(n-부틸카르바모일-아미노)-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-히스티딜)아미도-1-(n-부틸카르바모일-아미노)-4-시클로헥실-2-부탄올, (2S,3S)-3-(n-BOC-페닐알라닌일-노르로이실)아미도-1-(이소-프로필카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-[N-(3-시클로헥실프로피오닐)-노르로이실]아미도-1-(이소프로필카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-노르노이실)아미도-1-[비스-(디메틸-아미노)]포스포릴아미도-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-노르로이실)-1-(N-벤질-4-피페리디노카프바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알리닌일-노르로이실)아미도-1-(4-피페리디노카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-노르로이실)아미도-1-(디메틸-카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-노르로이실)아미도-1-(이소프로필-카르바모일)이소프로필아미노-4-시클로헥실-2-부탄올, (2S,3S)-3[N-(1-아다만틸-프로피오닐)-노르로이실 ]-1-(이소프로필 카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(N-BOC-노르로이실)-아미도-1-(이소프로필 카르바모일)아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(노르로이실)아미노-1-(이소프로필 카르바모일)아미노-4-시클로헥실-2-부탄올, 히드로클로라이드, (2S,3S)-3-N-[1-벤조일-아미노-2-(1-나프틸)프로페노일-노르로이실]아미노-4-시클로헥실-1-(이소프로필아미노 카르바모일)아미노-2-부탄올, (2S,3S)-3-[N-(비스(1-나프틸-메틸)아세틸)-노르로이실]-아미노-4-시클로헥실-1-(이소프로필카르바모일)아미노-2-부탄올, (2S,3S)-3-(N-시클로펜틸-카르보닐-페닐알라닌일-노르로이실)아미노-4-시클로헥실-1-(이소프로필-카르바모일)아미노-2-부탄올, (2S,3S)-3-(N-BOC-페닐알라닌일-히스티딜)아미도-1-(이소프로필-카르바모일)아미노-4-시클로헥실-2-부탄올, (2R,3S)-3-(t-부틸옥시카르보닐아미노)-4-시클로헥실 -2-히드록시부탄술폰산 디메틸아미드, (2R,3S)-3-(t-부틸옥시카르보닐아미노)-4-(1,4-디옥사스피로[4,5]운데스-8-일)-2-히드록시부탄-술폰산 디메틸아미드, (2R,3S)-3-(t-부틸옥시카르보닐아미노)-4-시클로헥실-2-아지도-부탄-술폰산 디메틸아미드, (2R,3S)-3-(t-부틸옥시카르보닐아미노)-2-히드록시-4-(2-나프틸)-부탄-술폰산 디메틸아미드, (2R,3S)-3-(t-부틸옥시카르보닐 아미노)-2-히드록시-5-메틸-헥산-술폰산 디메틸아미드, (3S,4S)-4-(t-부틸옥시카르보닐아미노)-5-시클로헥실-3-히드록시-펜탄-술폰산 디메틸아미드, (1S,3S,4S)-4-(t-부틸옥시카르보닐아미노)-5-시클로헥실-3-히드록시-1-이소프로필-펜탄-술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-페닐알라닐)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (SR,3S)-3-(N-BOC-β-시클로헥실알라닐-β-시클로헥실알라닐)아미도-4-시클로헥실-2-히드록시-부탄술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-β-시클로헥실알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-히스티딜)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-[N-BIS(1-나프틸메틸)아세틸)노르로이실]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-2-아미노-4-시클로헥실-부탄 술폰산 디메틸아미드, (2R,2S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-(1,4-디옥사스피로[4,5]운덱-8-일)-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실) 아미도-4-(4′-옥소시클로-헥실)-2-히드록-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-(4′-히드록시-시클로헥실)-2-히드록시-부탄 술폰산 디메틸아미드, (3S,4S)-3-(N-BOC-페닐알라 닐-노르로이실)아미도-5-시클로헥실)-3-히드록시-펜탄 술폰산 디메틸아미드, (1R,3S,4S)-4-(N-BOC-페닐알라닐-노르로이실)아미도-5-시클로헥실-3-히드록시-이소프로필-펜탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-2-히드록시-4-(2-나프틸)-부탄 술폰산 디메틸아미도, (2R,3S)-3-[N-(BIS-(1-나프틸메틸)아세틸)-노르로이실]아미도-2-히드록시-5-메틸-헥산 술폰산 디메틸아미드, (2S,2S)-및 (2R,3S)-3-(BOC-페닐알라닐-노르로이실)-아미도-4-시클로헥실-1-이소부틸-술파모일아미노-2-부탄올, (2S ,3S)-3-(BOC-페닐알라닌일-노르로이실)아미도-4-시클로헥실-1-디메틸술파모일아미노-2-부탄올, (2R,3S)-3-(N-벤조일-디히드로페닐알라닌일-노르로이실) -아미도-1-디메틸술파모일-아미노-5-메틸-2-헥산올 N-(3-시클로헥실프로피오닐)-노르노이신 (2S,3S)-3-(3-시클로헥실-프로피오닐-노르로이실)아미도-1-Cbz-아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(3-시클로헥실-프로피오닐, 노르로이실)아미도-1-아미노-4-시클로헥실-2-부탄올, (2S,3S)-3-(3-시클로헥실-프로피오닐-노르로이실)아미도-4-시클로헥실-1-디메틸술파모일아미노-2-부탄올, (2R,3S)-3-[N(1-아다만틸)프로피오닐)노르로이실]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-[N-BOC-β-시클로헥실알라닐히스티딜]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-[N-(BIS-(1-나프틸메틸)아세틸)히스티딜]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-[N-BOC-β-(2,1,3-벤즈옥사디아졸-4-일)알라닐-노르로이실]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-((N[2-메톡시-폴리(2-에톡시)아세틸]페닐 알라닐-노르로이실))아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-[N(BIS-(1-나프틸메틸)아세틸)메티오닐]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3[N(BIS-(1-나프틸메틸)아세틸)메티온(D,L-S-옥시드)일]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-(1-아다만틸)-2-히드록시-부탄 술폰산 디메틸 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-5,5-디메틸-2-히드록시-헥산 술폰산 디메틸 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 피롤리딘 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 피페리딘 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 피페리딘 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-(4-벤질)피페라진아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산 피페라진아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-(4-아세틸)피페라진아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-[4-(2,5,8,11-테트라옥사도데카닐)카르보닐]-피페라진아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-4-메틸)피페라진 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-모르폴린 아미드, (2R,3S)-3-(N-BOC-페닐알라닐-히스티딜)아미도-4-시클로헥실-2-히드록시-부탄 술폰산-피페리딘아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로아실)아미도-2-히드록시-5-메틸-메르캅토-펜탄 술폰산 디메틸아미드, (2R,3S)-3-(N-BOC-페닐알라닐-노르로이실)아미도-2-히드록시-5-메틸-술피닐-펜탄 술폰산 디메틸아미드, (2R,3R)-3-(N-BOCP페닐알라닐-노르로이실)아미도-2-히드록시-4-벤질-메르캅토-부탄 술폰산 디메틸 아미드, (2R,3R)-3-(N-BOC-페닐알라닐-노르로이실)아미도-2-히드록시-4-메르캅토-부탄 술폰산 디메틸 아미드, (2R,3R)-3-(N-BOC-페닐알라닐-노르로이실)아미도 -2-히드록시-4-에틸-메르캅토-부탄 술폰산 디메틸 아미드, (2R,3S)-3-[N-(2,3,4,6-테트라-O-아세틸-β-D-글루코실-1-O)-이소부티릴-페닐알라닐-노르로이실]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸 아미드, (2R,3S)-3-[N-(β-D-글루코실-1-O)-이소부티릴-페닐알라닐-노르로이실]아미도-4-시클로헥실-2-히드록시-부탄 술폰산 디메틸 아미드.(2S, 3S) -3- (N-BOC-phenylalaninium-histidyl) amido-1- (n-butylcarbamoylamino) (N-butylcarbamoyl-amino) -4-cyclohexyl-2-butanol, (2S, 3S) -3- 2-butanol, (2S, 3S) -3- (n-BOC-phenylalaninyl-norroisyl) amido-1- (iso-propylcarbamoyl) amino- (2S, 3S) -3- [N- (3-cyclohexylpropionyl) -nonloxyl] amido-1- (isopropylcarbamoyl) amino- (2S, 3S) -3 (N-BOC-phenylalanine-nornoyl) amido-1- [bis- (dimethyl- amino)] phospholylamido-4-cyclohexyl- Amino-4-cyclohexyl-2-butanol, (2S, 3S) -3- ( N-BOC-phenylalaninil-norroisyl) amido-1- (4-piperidinocarboxylic acid (Dimethyl-carbamoyl) amino-4-cyclohexyl-2-butanol, (2S, 3S) -3- (N-BOC- phenylalaninyl- Cyclohexyl-2-butanol, (2S, 3S) -3- (N-BOC-phenylalaninyl-norroisyl) amido-1- (isopropylcarbamoyl) isopropylamino- Butanol, (2S, 3S) -3 [N- (1-adamantyl-propionyl) -nonloxyl] -1- (isopropylcarbamoyl) amino-4-cyclohexyl- Cyclohexyl-2-butanol, (2S, 3S) -3- (nor (2S, 3S) -3- (N-BOC-norloisyl) Amino-2- (1- (4-fluoro-phenyl) -1H-pyrazol-3- Amino-2-butanol, (2S, 3S) -3- [N- (bis (1- (isopropylamino) Naphthyl-methyl) acetyl) -nonloisyl] -amino-4-cycl Amino-2-butanol, (2S, 3S) -3- (N-cyclopentyl-carbonyl- phenylalanineyl) amino-4-cyclohexyl- (Isopropylcarbamoyl) amino-2-butanol, (2S, 3S) -3- (N-BOC- phenylalanineyl-histidyl) amido- (2R, 3S) -3- (t-butyloxycarbonylamino) -4-cyclohexyl-2-hydroxybutane sulfonic acid dimethylamide, (2R, 3S) -3- (t-butyloxycarbonylamino) -4- (1,4-dioxaspiro [4,5] undec-8-yl) -2-hydroxybutane-sulfonic acid dimethylamide, (2R, 3S) -3- (t-butyloxycarbonylamino) -2-hydroxy-4- ( (2S, 4S) -3- (t-butyloxycarbonylamino) -2-hydroxy-5-methyl-hexane-sulfonic acid dimethylamide, -4- (t-butyloxycar 5-cyclohexyl-3-hydroxy-pentanoic acid dimethylamide, (1S, (2R, 3S) -3- (N-BOC-phenylalanyl-phenylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2S, 3S) -3- (N-BOC-? -Cyclohexylalanyl-? -Cyclohexylalanyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, Cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- (N-BOC-β-cyclopentylamino) Cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- (N-BOC-phenylalanyl-histidyl) amido-4 Cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- [N-BIS (1-naphthylmethyl) Amino-4-cyclohexyl-butanesulfonic acid dimethylamide, (2R, 2S) -3- (N-BOC-phenylalanyl- (1,4-dioxaspiro [4,5] undec-8-yl) -2-hydroxy-butanesulfonic acid dimethylamide (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) amido-4- (4'-oxocyclohexyl) -2-hydroxabutanesulfonic acid dimethylamide, (3S, 4S) - (4-hydroxy-cyclohexyl) -2-hydroxy-butanesulfonic acid dimethylamide, (1R, 3S, 4S) -4- (N-BOC-phenyl) -3-hydroxy-pentanesulfonic acid dimethylamide (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) amide-5-cyclohexyl-3-hydroxy-isopropyl-pentanesulfonic acid dimethylamide Dihydroxy-4- (2-naphthyl) -butanesulfonic acid 2-hydroxy-5-methyl-hexanesulfonic acid dimethylamide, ((2R, 3S) -3- [N- Amino-4-cyclohexyl-1-isobutyl-sulfamoylamino-2-butanol, (2S, 2S) - and (2R, 3S) -3- (BOC- phenylalanyl- (2R, 3S) -3- (N-benzoyl-dihydrophenylalanine (2S) -3- Amino-5-methyl-2-hexanol N- (3-Cyclohexylpropionyl) -nornoic acid (2S, 3S) -3- (2S, 3S) -3- (3-cyclohexyl-propionyl, norloisyl) amido-1-Cbz-amino-4-cyclohexyl- Amino-4-cyclohexyl-2-butanol, (2S, 3S) -3- (3-cyclohexyl-propionyl- Amino-2-butanol, (2R, 3S) -3- [N (1- ) Propionyl) norroisyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- [N-BOC- beta -cyclohexylalanylhistidyl] amido Cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- [N- (BIS- (1- (2R, 3S) -3- [N-BOC-? - (2,1,3-benzoxadiazol-4-yl) alanyl-norroisyl] amido Cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3 - ((N- [2- methoxy-poly (2- ethoxy) acetyl] phenylalanyl- ) Amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- [N- (BIS- Hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3 [N (BIS- (1-naphthylmethyl) acetyl) methionine (D, LS- Cyclohexyl-2-hydroxy-butanesulfonic acid di (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) amido-4- (1-adamantyl) -2-hydroxy-butanesulfonic acid dimethylamide, (2R, 3S) -3- (N-BOC-phenyl) -hexane sulfonic acid dimethylamide, Cyclohexyl-2-hydroxy-butanesulfonic acid pyrrolidinamide, (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) amido-4- Cyclohexyl-2-hydroxy-butanesulfonic acid piperidinamide, (2R, 3S) -3- (N-BOC- Hydroxy-butanesulfonic acid piperidine amide, (2R, 3S) -3- (N-BOC-phenylalanyl-norroisyl) amido-4-cyclohexyl- (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid piperazineamide, ) -3- (N-BOC-phenylalanyl-norloisyl) (4-acetyl) piperazinamide, (2R, 3S) -3- (N-BOC-phenylalanyl-norloisyl) (2R, 3S) -3- (N-BOC-2-hydroxy-butanesulfonic acid- [4- (2,5,8,11-tetraoxadodecanyl) carbonyl] -piperazinamide, (2R, 3S) -3- (N-BOC-phenylalanyl-nor) phenylalanine-norroisyl) amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid Cyclohexyl-2-hydroxy-butanesulfonic acid-morpholinamide, (2R, 3S) -3- (N-BOC- phenylalanyl-histidyl) amido-4-cyclohexyl (2R, 3S) -3- (N-BOC-phenylalanyl-noroacyl) amido-2-hydroxy-5-methyl-mercapto- (2R, 3R) -3- (N-BOC-phenylalanyl-norroisyl) amido-2-hydroxy-5-methyl-sulfanyl-pentanesulfonic acid dimethylamide, ) -3- (N-BOCP phenylalanyl-norloisyl) amino Hydroxy-4-benzyl-mercapto-butanesulfonic acid dimethylamide, (2R, 3R) -3- (N-BOC-phenylalanyl- (2R, 3R) -3- (N-BOC-phenylalanyl-norroisyl) amido-2-hydroxy-4-ethyl-mercapto-butanesulfonic acid dimethylamide, 2R, 3S) -3- [N- (2,3,4,6-tetra-O-acetyl -? - D-glucosyl-1-O) -isobutyryl-phenylalanyl- (2R, 3S) -3- [N- (beta -D-glucosyl-1-O) -isobutyryl-phenylalanyl-nor Roxyl] amido-4-cyclohexyl-2-hydroxy-butanesulfonic acid dimethylamide. 하기와 같이 행하는 것을 특징으로 하는 제1항 내지 제4항의 구조식 (I)의 화합물의 제조방법. a) 하기 구조식 (Ia)의 화합물은 하기 구조식 (II)의 화합물을 하기 구조식 (III)의 화합물과 반응시켜서 제조할 수 있다.A process for producing a compound of formula (I) according to any one of claims 1 to 4, wherein the process is carried out as follows. a) a compound of formula (Ia) below can be prepared by reacting a compound of formula (II) below with a compound of formula (III) 식중, A,B,C,D,Y,R1,R2,R4및 R5는 제1항의 정의와 동일하고 R3′, 는 수소, 히드록실 또는 구조식 -OCOR2의 라디칼이다. b) 하기 구조식 (Ib)의 화합물은 하기 구조식 (IV)의 화합물을 환원시켜서 제조할 수 있다.R 1 , R 2 , R 4 and R 5 are as defined in claim 1 and R 3 'is hydrogen, hydroxyl or a radical of the formula -OCOR 2 , in which A, B, C, D, Y, b) Compounds of formula (Ib) below may be prepared by reduction of compounds of formula (IV). 식중, A,B,C,D,Y,R1,R2,R4및 R5는 상기 정의와 동일하다. c) 하기 구조식 (Ic)의 화합물은 하기 구조식 (V)의 화합물을 하기 구조식 (VI)의 화합물과 반응시켜서 제조할 수 있다.In the formula, A, B, C, D, Y, R 1 , R 2 , R 4 and R 5 are as defined above. c) Compounds of formula (Ic) below can be prepared by reacting a compound of formula (V) with a compound of formula (VI) 식중, A,B,C,Y,R1,R2,R3′,R4및 R5는 상기 정의와 동일하고, D′는 -O- 또는이고, X는 할로겐, 특히 염소이다. d) 하기 구조식 (Id)의 화합물을 구조식 (Ie)의 화합물을 산화시켜서 제조할 수 있다.In the formula, A, B, C, Y, R 1 , R 2 , R 3 ', R 4 and R 5 are as defined above, D' And X is halogen, especially chlorine. d) oxidizing the compound of formula (Id) below with a compound of formula (Ie). 식중, A,B,C,D,Y,R1,R3′,R4,R5,R15및 p는 상기 정의와 동일하고, s′는 1이다. e) 하기 구조식 (If)의 화합물은 하기 구조식 (Ig)의 화합물의 벤질기를 분리하여 제조할 수 있다.In the formula, A, B, C, D, Y, R 1 , R 3 ', R 4 , R 5 , R 15 and p are as defined above and s' e) Compounds of formula (If) below can be prepared by isolating benzyl groups of compounds of formula (Ig). 식중, A,B,C,D,Y,R1,R3,R4,R5및 p는 상기 정의와 동일하다. f) 하기 구조식 (Ih)는 상기 구조식 (If)의 화합물에 알킬기를 첨가하여 제조할 수 있다.In the formula, A, B, C, D, Y, R 1 , R 3 , R 4 , R 5 and p are as defined above. f) The following structural formula (Ih) can be prepared by adding an alkyl group to the compound of the structural formula (If). 식중, A,B,C,D,Y,R1,R3,R4,R5및 p는 상기 정의와 동일하다. g) 하기 구조식 (Ii)의 화합물은 하기 구조식 (Ij)의 화합물에서 벤질기를 촉매적으로 분리하여 얻을 수 있다.In the formula, A, B, C, D, Y, R 1 , R 3 , R 4 , R 5 and p are as defined above. g) Compounds of formula (Ii) below can be obtained by catalytically separating benzyl groups from compounds of formula (Ij). 식중, A,B,C,D,Y,R1,R2및 R3는 상기 정의와 동일하다. h) 하기 구조식 (Ik)의 화합물은 하기 구조식 (Ix)의 화합물을 하기 구조식 (X)의 화합물과 반응시키고, 제조된 구조식 (I)의 화합물의 전구체를 구조식 (I)의 화합물로 임의 변형시켜서 제조할 수 있다.Wherein A, B, C, D, Y, R 1 , R 2 and R 3 are as defined above. h) reacting a compound of formula (Ik) below with a compound of formula (X) and optionally modifying the precursor of the compound of formula (I) with a compound of formula (I) Can be manufactured. 식중, C,D,Y,R1내지 R5및 R7내지 R9는 상기 정의와 동일하다.In the formula, C, D, Y, R 1 to R 5 and R 7 to R 9 are the same as defined above. 제1항 내지 제4항중 어느 한항에 의한 약학적 허용 형태의 화합물과 약학적 담체 또는 희석제를 함유하는 약학 조성물.A pharmaceutical composition comprising a pharmaceutically acceptable form of a compound according to any one of claims 1 to 4 and a pharmaceutical carrier or diluent. 고혈압 및 충혈성 심장질환의 치료용 약제 제조시의 제6항에 의한 약학 조성물의 사용방법.Use of a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of hypertension and congestive heart disease. 치료를 요하는 동물에 치료적 유효량의 제1항의 화합물을 투여하는 것을 특징으로 하는 고혈압 또는 충혈성 심장질환의 예방 또는 치료방법.A method for the prophylaxis or treatment of hypertension or congestive heart disease, which comprises administering a therapeutically effective amount of the compound of claim 1 to an animal in need of treatment. 약학용인 것을 특징으로 하는 제1항 내지 제4항중 어느 한항에 의한 화합물.A compound according to any one of claims 1 to 4, characterized in that it is for pharmaceutical use. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: It is disclosed by the contents of the first application.
KR1019880000498A 1987-01-21 1988-01-20 Peptide derivatives, their preparation and use KR880009041A (en)

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