Claims
- 1. A compound of the formula ##STR12## in which R.sup.1 is hydrogen or methyl, R.sup.2 is imidazol-4-yl, R.sup.3 is isobutyl, cyclohexylmethyl, or benzyl, R.sup.4 is phenyl, furyl, vinyl, ethyl, or 1,2-dihydroxyethyl and A is -Y-Z in which Y is a bivalent residue of optionally N- and/or .alpha.-methylated phenylglycine, cyclohexylglycine, phenylalanine, cyclohexylalanine, 4-fluorophenylalanine, 4-chlorophenyldamine, tyrosine, methionine, proline, .alpha.-napththylalanine, homophenylalanine, aspartic acid ethyl ester, or glutamic acid benzyl ester linked with Z at the N-terminal, and Z is hydrogen, a group of the formula ##STR13## or is the residue, linked with Y at the C-terminal, of optionally N- and/or .alpha.-methylated natural amino acid with the L-configuration which is optionally N-substituted with the group R.sup.b --CO-- or R.sup.a --O--CO-- or of an epimer of such an amino acid with the D-configuration or of a dipeptide from two such amino acids or a tripeptide from three such amino acids or the group R.sup.b --CO-- or R.sup.a --O--CO--, wherein R.sup.a is an optionally substituted residue selected from C.sub.1-18 alkyl; C.sub.2-8 alkenyl; C.sub.2-8 alkynyl; C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkenyl; C.sub.5-10 bicycloalkyl; C.sub.8 tricycloalkyl; C.sub.5-10 bicycloalkenyl; C.sub.3-8 cycloalkyl-C.sub.3-8 alkyl; C.sub.3-8 cycloalkenyl-C.sub.1-8 alkyl; C.sub.3-8 cycloalkyl-C.sub.2-8 alkenyl; C.sub.3-8 cycloalkenyl-C.sub.2-8 alkenyl; aryl selected from phenyl, naphthyl, and fluorenyl; a heteroaromatic residue, a heteroaromatic-C.sub.1-8 alkyl residue, an aryl C.sub.1-8 alkyl residue, or a heterocycle, wherein the heteroaromatic portion of the heteroaromatic and heteroaromatic-C.sub.1-8 -alkyl residues is selected from the group of moieties consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyramidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl and .beta.-carbolinyl, or a benz-fused derivative of the above moieties, said above moieties which contain a nitrogen atom can be substituted at said nitrogen atom with alkyl, phenyl or phenylalkyl, said above moieties also can be substituted on at least one of the carbon atoms with alkyl, phenyl, phenylalkyl, halogen, hydroxy, alkoxy, phenylalkoxy, and oxo, the aryl portion of the aryl-C.sub.1-8 -alkyl residue is selected from the group consisting of phenyl, .alpha.- or .beta.-naphthyl, indenyl and phenanthryl which can be substituted with at least one of alkyl, alkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino hydroxy, halogen trifluoromethyl and nitro, the heterocycle is selected from the group consisting of pyrrolidin-3-yl, 4-hydroxypyrrolidin-2-yl, 5-oxo-pyrrolidin-2-yl, piperidin-2yl, piperdin-3-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-2yl, morpholin-3yl, thiomorpholin-2yl, thiomorpholin-3yl, 1,4-dimethylpiperazin-2-yl, 2-indolinyl, 3-indolinyl, 1,2,3,4-tetrahydroquinol-2-, -3 or -4-yl, 1,2,3,4-tetrahydroisoquinol-1-, -3- or -4-yl, 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl, tertiary butoxy-carbonyl piperidin-2-yl, thiazolidin-4-yl, hexahydro-8a-methyl-5-oxo-5H-thiazolo[3,2-a]pyrid-3-yl, and tetrahydro-7a-methyl-pyrrolo[2,1-b]thiazol-3-yl; and R.sup.b is R.sup.a or hydrogen, the compound being in the form of an optionally pure diastereomer, diastereomeric mixture, diastereomeric racemate of mixture of diastereomeric racemates; or a pharmaceutically acceptable usable salt of the compound.
- 2. The compound of claim 1 wherein Z is the residue, linked with Y at the C-terminal of the L-configuration or its epimer of optionally substituted proline, prolylproline, histidine, methionine, N-methylphenylalanine, histindinylproline, prolylprolylproline, the amino group in each case is optionally substituted with t-butoxycarbonyl, benzoxycarbonyl, isovaleryl or the group R.sup.b --CO--.
- 3. The compound of claim 2 wherein Z is Boc-D-Pro, D-Pro, 5-oxo-Pro, 4imidazolylproprionyl-Pro, 3-hydroxy-2-pyridylcarbonyl-Pro, dibenzylacetyl-Pro, isoalenylcarbonyl-Pro, Boc-Pro, Pro, t-butylcarbonyl-Pro, t-butylcarbonyl-Met, Boc-His, Boc-His(3Bom), 1-imidazolylproprioyl-D-Pro, Boc-D-Pro-Pro, Boc-Pro-Pro, isolalenyl-D-Pro-L-Pro, Boc-Pro-D-Pro, Boc-D-Pro-D-Pro, Boc-D-Pro-D-Pro-Pro, Boc-thiazolidin-4-ylcarbonyl-Pro, 2-(2-pyridyl)benzoyl-Pro, 2-(1-imidazolyl)-2,2-dimethylpropionyl-Pro-Pro, 1-imidazolylacetyl-D-Pro-Pro, benzyloxycarbonyl-Pro-Pro, D-Pro-Pro, 1-imidozolylpropioyl-D-Pro-Pro, or Boc-3-pyrrolin-2-yl-Pro.
- 4. The compound of claim 1 wherein Z is Boc, 3,3-dimethylbutyryl, isovaleryl, cyclopentylcarbonyl, Boc-aminovaleryl, aminoethylglycyl, 3-(4-hydroxyphenyl)propionyl, 3-pyridylcarbonyl, 4-pyridyloxylcarbonyl, 3-pyridyloxylcarbonyl, 4-imidazolylzylcarbonyl, 1,3,4,5-cyclohexyl-carbonyl, 2-quinolylcarbonyl, methylcarbonylethylcarbonyl, 3-pyridylmethylcarbonyl, 4-chlorophenylvinylcarbonyl, 4-nitrophenylvinylcarbonyl, ethoxycarbonylvinylcarbonyl, diphenylaminocarbonyl, isobutoxycarbonyl, Boc-aminoisobutyryl, fluorenylmethylcarbonyl-2-t-butoxyalkyl, fluorenylmethoxycarbonyl, adamatylmethylcarbonyl, phenoxycarbonyl, 2,2,2-trichloroethoxy, Boc-aminocyclohexycarbonyl, 2-t-butyoxyalanyl, aminovaleryl, ethoxycarbonylethoxycarbonly, adamatylacetyl, 3-pyrridylacetyl, fluorenylacetyl, ethoxycarbonyl, 4-aminophenypropionyl, acetylpropionyl, 4-hydroxyphenylpropionyl, 3-pyridiylpropionyl, 4-imidozalylpropionyl, Boc-aminoisobutyl, 1-amino-2-hydroxyproprioyl, dibenzyaminoacarbonyl, morpholinecarbonyl, 4-biphenyloxyethylaminocarbonyl, N-Boc-2-azetidinecarbonyl, hexahydro-8a-methyl-5-oxo-5H-thiazole[3,2-a]pyridyl-3-carbonyl, tetrahydro-7a-methylpyrrolo[2,1-b]thiazolyl-3-carbonyl, Boc-aminovalerylaminoproprionyl, phentylacetyl, 2-pyridylcarbonyl, 2-(2-pyridyl)benzoyl, Boc-phenylalycyl, boc-2-piperidinylcarbonyl, or Boc-thiazolidin-4-ylcarbonyl.
- 5. A compound in accordance with claim 2, wherein Y is phenylalanine and Z is the residue, linked with Y at the C-terminal, of a N- and/or .alpha.-methylated natural amino acid with the L-configuration which is optionally N-substituted with the group R.sup.b --CO-- or R.sup.a --O--CO-- or of an epimer of such an amino acid with the D-configuration or of a dipeptide from two such amino acids or the group R.sup.b --CO-- or R.sup.a --O--CO--, wherein R.sup.4 is an optionally substituted, saturated or unsaturated aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydrocarbon residue having from 1 to 18 carbon atoms, an optionally substututed aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon residue having from 1 to 18 carbon atoms or an optionally substituted, saturated 5- or 6-membered heterocycle and R.sup.b is hydrogen or has the same meaning as R.sup.a the residue, linked with Y at the C-terminal, of proline, prolyproline or histidinylproline, whereby the amino group in each case is substituted t-butoxy-carbonyl, benzoxycarbonyl, isovaleryl or the group R.sup.b --CO-- in which R.sup.b is a heteroaromatic-aliphatic hydrocarbon residue having from 1 to 10 carbon atoms or a saturated 5- or 6-membered heterocycle.
- 6. A compound in accordance with claim 1 which is t-butyl(R)-2-[[(S)-.alpha.-]](S)-1-[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropylhexyl]-2-imidazol-4-ylethyl]carbamoyl]phenethy]carbamoyl]-1-pyrrolidinecarboxylate.
- 7. A compound in accordance with claim 2 which is (2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol
- 8. A compound in accordance with claim 1 which is (2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol.
- 9. A compound in accordance with claim 1 which is N-(S)-[(1S,2S,4S)-1-(Cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-.alpha.-3-methylbutyramido]imidazole-4-propionamide.
- 10. A compound in accordance with claim 1 which is t-butyl [(S)-.alpha.-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate.
- 11. A compound in accordance with claim 1 which is t-butyl [(S)-.alpha.-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate.
Priority Claims (1)
Number |
Date |
Country |
Kind |
3903/87 |
Oct 1987 |
CHX |
|
Parent Case Info
This application is a continuation of application Ser. No. 07/254,003, filed Oct. 5, 1988, now abandoned.
US Referenced Citations (8)
Foreign Referenced Citations (3)
Number |
Date |
Country |
172346 |
Feb 1986 |
EPX |
229667 |
Jul 1987 |
EPX |
8805050 |
Jul 1988 |
WOX |
Non-Patent Literature Citations (4)
Entry |
Szelke, et al. Chemical Abstracts, vol. 101, 1984, Abstract 86219s. |
Biochemical Soc. Trans. 10, 164 (1982). |
Science, 217, 121 (1982). |
Biochem. & Biophys. Res. Commun. 146(3), 959 (1987). |
Continuations (1)
|
Number |
Date |
Country |
Parent |
254003 |
Oct 1988 |
|