5-substituted amino-4-hydroxy-pentanoic acid derivatives and their use

• US 4,851,387 A
• Filed: 10/13/1987
• Issued: 07/25/1989
• Est. Priority Date: 10/14/1986
• Status: Expired due to Fees

• Current Assignee: Banyu Pharmaceutical Company Limited (Merck & Co., Inc.)
• Original Assignee: Banyu Pharmaceutical Company Limited (Merck & Co., Inc.)
• Inventors: Nakano, Masato, Tanaka, Seiichi, Matsuyama, Kenji, Koike, Yutaka, Morishima, Hajime, Atsuumi, Shugo
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US07/106,804
• Time in Patent Office: 651 Days
• Field of Search: 530/330, 530/331, 530/323, 530/332, 514/17, 514/18, 514/19, 548/344, 560/159, 564/157, 564/158, 564/152, 564/153
• US Class Current: 514/15.8
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07D 263/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 263/06 with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• CPC Class Codes: C07K 5/0227 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10S 530/86 Renin inhibitors

Abstract

A 5-substituted amino-4-hydroxy-pentanoic acid derivative having the formula: ##STR1## wherein R¹ is a hydrogen atom or an N-protecting group, R², R³ and R⁵ may be any of a variety of groups including the side chains of amino acid residues, R⁴ is a hydrogen atom or a lower alkyl group, R⁶ is a group which is substituted by one or two hydroxyl groups, and R⁷ is any of a variety of groups, including a hydroxyl group, which compounds are renin inhibitors useful as hypotensive drugs, are disclosed.

Claims

1. A 5-substituted amino-4-hydroxy-pentanoic acid derivative having the formula:

##STR35## wherein R¹ is a hydrogen atom, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group or a lower alkanoyl group which is unsubstituted or substituted by from one to three substituents selected from the group consisting of an amino group, a hydroxyl group, a carbonyl group, an aryloxy group, an aralkyloxycarbonylamino group, a lower alkoxycarbonylamino group and a ##STR36## group wherein each of X¹ and X², which is the same or different, is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, or X¹ and X² together with the adjacent nitrogen atom from a 5- or 6-membered heterocyclic ring which contains no additional hetero atom or contains an additional hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and wherein said alkanoyl group is saturated or contains a double bond in the carbon chain thereof,

each of R², R³ and R⁵, which is the same or different, is a hydrogen atom, a lower alkyl group or a side chain of an acidic, neutral or basic amino acid selected from the group consisting of alanine, arginine, histidine, homoserine, leucine, naphthylalanine, norleucine, lysine, norvaline, ornithine, serine, threonine, throsine, valine, aspartic acid, glutamic acid, tryptophan, isoleucine, phenylalanine and cysteine,

R⁴ is a hydrogen atom or a lower alkyl group,

R⁶ is a lower alkyl, cycloalkyl, or cycloalkylalkyl which is substituted by one or two hydroxyl groups,

R⁷ is a hydroxyl group, a --OY group wherein Y is a lower alkyl group, an aryl group, an aralkyl group, a lower alkoxyalkyl group, a lower alkanoyloxyalkyl group, a lower alkoxycarbonyloxyalkyl group or a 1-phthalidyl group, or a ##STR37## group wherein each of Y¹ and Y², which may be the same or different, is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a cycloalkyl group, or Y¹ and Y² together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring which contains no additional hetero atoms or contains an additional hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and

each of n and m, which is the same or different, is 0 or 1.

2. The pentanoic acid derivative according to claim 1, which is (2RS,4S,5S)-5-(L-N-benzyloxycarbonylnaphthyl alanyl-L-norleucyl)amino-4-hydroxy-2-(3-hydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-N-benzyloxycarbonylnaphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxyethyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-N-benzyloxycarbonylnaphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(3-hydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxyethyl)7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2,3-dihydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-N-methylnaphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxypropyl)-7-methyl-octanoic acid isobutylamide, (2RS,4S,5S)-5-(L-N-benzyloxycarbonyl naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxyethyl)-7-methyl-octanoic acid methylamide, or (2RS,4S,5S)-5-(L-N-benzyloxycarbonyl naphthylalanyl-L-norleucyl)amino-4-hydroxy-2-(2-hydroxyethyl)-7-methyl-octanoic acid 4-picolylamide.

3. A hypotensive drug comprising an effective amount of a 5-substituted amino-4-hydroxy-pentanoic acid derivative of the formula I as defined in claim 1 and a pharmaceutically acceptable carrier.