US4698329A
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New renin-inhibitory peptides and their use
Assignee: Sankyo Co Ltd
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Filing: 1985-01-30
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Granted: 1987-10-06
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Expires: 2005-01-30
Abstract
Abstract Compounds of formula R1CO-NH-CH(R2)-CONH-CH(R3)-X [wherein: R1 represents alkyl having an alpha -amino or protected alpha -amino substituent and an aryl, heterocyclic or heterocyclic-dithio substituent; R2 represents a variety of aliphatic and cycloaliphatic hydrocarbon groups, which may be substituted; R3 represents isobutyl, sec-butyl, benzyl or (C3-C8 cycloalkyl)methyl; and X represents a group of formula -CH(-A-R4)-Y (in which: A represents a single bond or an alkylene group; R4 represents a carboxy group; a protected carboxy group, a carbamoyl group, an N-substituted carbamoyl group, a carbazoyl group, an N-substituted carbazoyl group or an acyl group; and Y represents a hydroxy group, a mercapto group or a formyl group), or a group of formula -P(O) (R5)-OH (in which R5 represents a substituted alkyl group having at least one substituent selected from carboxy groups, protected carboxy groups, N-substituted carbamoyl groups, carbazoyl groups, N-substituted carbazoyl groups, C2-C7 aliphatic carboxylic acyl groups and aromatic carboxylic acyl groups)]; and their salts are renin inhibitors, which may be used in the treatment of angiotensin-induced hypertension.
Inventors
- 👤 Rei Matsueda
- 👤 Yuichiro Yabe
- 👤 Mitsuo Yamazaki
- 👤 Tatsuo Kokubu
- 👤 Kunio Hiwada
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 20:54
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/04; C07K5/06; C07K5/02; C07K5/0227; A; A61; A61P; A61P43/00; A61P9/00; A61P9/12; C07F; C07F9/00; C07F9/02; C07F9/28; C07F9/30; C07F9/301; Y; Y10; Y10S; Y10S530/00; Y10S530/86
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
231 words
A compound of the formula (I): R.sup.1 CO--NH--CH(R.sup.2)--CONH--CH(R.sup.3)--X (I) wherein: R 1 represents a group of formula R 13 --CH(NHR 12 )-- in which: R 12 represents a 2-(2-methoxyethoxy)ethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 4-phenylbutyryl or 3-(3-nitropyrid-2-yldithio)propionyl, R 13 represents a benzyl group, a benzyl group having at least one substituent selected from the group consisting of C 1 -C 4 alkyl groups and C 1 -C 4 alkoxy groups, a 1-naphthylmethyl group, a 3-indolylmethyl group, a 5-quinolymethyl group, a 4-quinolylmethyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group or a 4-pyridylmethyl group; R 2 represents a C 1 -C 10 alkyl group, an allyl group, a propargyl group, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a benzyl group, a 3-indolylmethyl group, a 2-thienylmethyl group, a 4-thiazolylmethyl group, a 2-thiazolylmethyl group, a 4-methyl-5-thiazolylmethyl group, a 2-, 3- and 4-pyridylmethyl group or a 4-imidazolylmethyl group; R 3 represents an isobutyl, sec-butyl, cyclopropylmethyl, cyclopentylmethyl, or cyclohexylmethyl group; X represents a group of --CH(A--R 4 )OH, in which: A represents a single bond or an alkylene group; R 4 represents a protected carboxy group, a carbamoyl group, an N-substituted carbamoyl group, a carbazoyl group, an N-substituted carbazoyl group or an acyl group; provided that, when A represents an alkylene group and when R 2 represents a 4-imidazolylmethyl group, R 4 does not represent a carbamoyl group or formyl group; and pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
231 words
A compound of the formula (I): R.sup.1 CO--NH--CH(R.sup.2)--CONH--CH(R.sup.3)--X (I) wherein: R 1 represents a group of formula R 13 --CH(NHR 12 )-- in which: R 12 represents a 2-(2-methoxyethoxy)ethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 4-phenylbutyryl or 3-(3-nitropyrid-2-yldithio)propionyl, R 13 represents a benzyl group, a benzyl group having at least one substituent selected from the group consisting of C 1 -C 4 alkyl groups and C 1 -C 4 alkoxy groups, a 1-naphthylmethyl group, a 3-indolylmethyl group, a 5-quinolymethyl group, a 4-quinolylmethyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group or a 4-pyridylmethyl group; R 2 represents a C 1 -C 10 alkyl group, an allyl group, a propargyl group, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a benzyl group, a 3-indolylmethyl group, a 2-thienylmethyl group, a 4-thiazolylmethyl group, a 2-thiazolylmethyl group, a 4-methyl-5-thiazolylmethyl group, a 2-, 3- and 4-pyridylmethyl group or a 4-imidazolylmethyl group; R 3 represents an isobutyl, sec-butyl, cyclopropylmethyl, cyclopentylmethyl, or cyclohexylmethyl group; X represents a group of --CH(A--R 4 )OH, in which: A represents a single bond or an alkylene group; R 4 represents a protected carboxy group, a carbamoyl group, an N-substituted carbamoyl group, a carbazoyl group, an N-substituted carbazoyl group or an acyl group; provided that, when A represents an alkylene group and when R 2 represents a 4-imidazolylmethyl group, R 4 does not represent a carbamoyl group or formyl group; and pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
53 words
A compound as claimed in claim 1, wherein: R 2 represents an imidazolylmethyl group and is attached to a carbon atom having the S-configuration; R 3 represents an isobutyl or sec-butyl group and; R 4 represents a carboxy, N-substituted carbamoyl, carbazoyl, N-substituted carbazoyl or carboxylic acyl group having at least 2 carbon atoms.
Claim 4
Dependent Claim
7 words
N-(2-methylbutyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 5
Dependent Claim
7 words
N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol of the formula of claim 1.
Claim 6
Dependent Claim
7 words
N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanyl]amino-3(S)-hydroxy-6-methyl-heptanoyl}-L-isoleucinol of the formula of claim 1.
Claim 7
Dependent Claim
7 words
N-(2-methylbutyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(1,3-thiazol-4-yl)-DL-alanyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 8
Dependent Claim
7 words
N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(1,3-thiazol-4-yl)-DL-alanyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol of the formula of claim 1.
Claim 9
Dependent Claim
7 words
4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(4-thiazolyl)-DL-alanyl]amino-3(S)-hydroxy-6-methyl-N-(2-morpholinoethyl)heptanamide of the formula of claim 1.
Claim 10
Dependent Claim
7 words
N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-pyridyl)-L-alanyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol of the formula of claim 1.
Claim 11
Dependent Claim
7 words
N-(2-methylbutyl)-4(S)-{N-[2-(2-methoxyethoxy)ethoxycarbonyl]-3-(1-naphthyl)-L-alanyl-L-histidyl}amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 12
Dependent Claim
7 words
N-ethyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 13
Dependent Claim
7 words
N-sec-butyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 14
Dependent Claim
7 words
N-isobutyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 15
Dependent Claim
7 words
4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methyl-N-(2-methylbutyl)heptanamide of the formula of claim 1.
Claim 16
Dependent Claim
7 words
N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol of the formula of claim 1.
Claim 17
Dependent Claim
7 words
1-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-leucinol of the formula of claim 1.
Claim 18
Dependent Claim
7 words
2-[2-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamido}ethyl]-1-methylpyrrolidine of the formula of claim 1.
Claim 19
Dependent Claim
7 words
3-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamido}-6-methylheptan-1,3-diol of the formula of claim 1.
Claim 20
Dependent Claim
7 words
N-(1-ethyl-2-pyrrolidinylmethyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide of the formula of claim 1.
Claim 21
Dependent Claim
46 words
A method of treating angiotensin-induced hypertension in a mammal by administering to said mammal an effective amount of a renin inhibitor, wherein said renin inhibitor is selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts thereof as defined in claim 1.
Claim 22
Dependent Claim
53 words
A method as claimed in claim 20, wherein: R 2 represents an imidazolylmethyl group and is attached to a carbon atom having the S-configuration; R 3 represents an isobutyl or sec-butyl group and; R 4 represents a carboxy, N-substituted carbamoyl, carbazoyl, N-substituted carbazoyl or carboxylic acyl group having at least 2 carbon atoms.
Claim 23
Dependent Claim
35 words
A method as claimed in claim 20, wherein said renin inhibitor is selected from the group consisting of: N-(2-methylbutyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucyl]amino-3(S)-hydroxy-6-methylheptanamide N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol N-(2-methylbutyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(1,3-thiazol-4-yl)-DL-alanyl]amino-3(S)-hydroxy-6-methylheptanamide N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(1,3-thiazol-4-yl)-DL-alanyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(4-thiazolyl)-DL-alanyl]amino-3(S)-hydroxy-6-methyl-N-(2-morpholinoethyl)heptanamide N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-pyridyl)-L-alanyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol N-(2-methylbutyl)-4(S)-{N-[2-(2-methoxyethoxy)ethoxycarbonyl]-3-(1-naphthyl)-L-alanyl-L-histidyl}amino-3(S)-hydroxy-6-methylheptanamide N-ethyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide N-sec-butyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide N-isobutyl-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methyl-N-(2-methylbutyl)heptanamide N-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-isoleucinol 1-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoyl}-L-leucinol 2-[2-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamido}ethyl]-1-methylpyrrolidine 3-{4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamido}-6-methylheptan-1,3-diol N-(1-ethyl-2-pyrrolidinylmethyl)-4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanamide.
Claim 24
Dependent Claim
12 words
A method as claimed in claim 20, wherein said mammal is human.
References Cited (Backward Citations)
US4548926A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1990-10-05 | 1991-04-06 | 1991-10-06 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-10-05 | 1995-04-06 | 1995-10-06 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-10-05 | 1999-04-06 | 1999-10-06 | $7700.00 | Window Closed / Lapsed |