Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 8 to 10 amino acid residues in defined sequence
Patent
1987-06-29
1990-01-16
Phillips, Delbert R.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
8 to 10 amino acid residues in defined sequence
530329, 530330, 530331, 530800, 560 39, C07K 706, A61K 3743, C07C10130
Patent
active
048944378
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention provides novel compounds. More particularly, the present invention provides novel renin-inhibiting peptide analogs. Most particularly, the present invention provides renin-inhibitory compounds having S-aryl-D- or L- or DL-cysteinyl, 3-(arylthio)lactic acid or 3-(arylthio)alkyl moieties at the 8 position (as compared to the renin substrate described below). The renin inhibitors provided herein are useful for the diagnosis and control of renin-dependent hypertension.
Renin is an endopeptidase which specifically cleaves a particular peptide bond of its substrate (angiotensinogen), of which the N-terminal sequence in equine substrate is for example: ##STR1## as found by L. T. Skeggs et al, J. Exper. Med. 106, 439 (1957). Human renin substrate has a different sequence as recently discovered by D. A. Tewkesbury et al, Biochem. Biophys. Res. Comm. 99, 1311 (1981). It may be represented as follows: ##STR2## and having the sequence to the left of the arrow (.dwnarw.) being as designated in formula IA above.
Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of angiotensin I converting enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin are also useful in the treatment of hypertension.
INFORMATION DISCLOSURE
A number of renin-inhibitory peptides have been disclosed. Thus, U.S. Pat. No. 4,424,207, and European published applications 45,665 and 104,041 disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; and 114,993; and U.S. Pat. Nos. 4,478,826; 4,470,971 and 4,479,941. Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. Pat. Nos. 4,477,440 and 4,477,441. Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S. Pat. No. 4,478,827. C-terminal amide cycles are disclosed in U.S. Pat. No. 4,485,099. Certain tetrapeptides are disclosd in European publications 111,266 and 77,027. Further, European published application No. 118,223 discloses certain renin inhibiting peptide analogs where the 10-11 peptide link is replaced by a one to four atom carbon or carbon-nitrogen link. Additionally, Holladay et al., in "Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isosteres", Tetrahedron Letters, Vol. 24, No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-directed "ketomethylene" and "hydroxyethylene" dipeptide isosteric functional groups disclosed in the above noted U.S. Pat. No. 4,424,207.
Additonally, published European Applications 45,161 and 53,017 disclose amide derivatives useful as inhibitors of angiotensin converting enzymes.
SUMMARY OF THE INVENTION
The present invention particularly provides a renin inhibitory peptide of the formula X-A.sub.6 -B.sub.7 -C.sub.8 -D.sub.9 -E.sub.10 -F.sub.11 -G.sub.12 -H.sub.13 -I.sub.14 -Z, XL.sub.2, or XL.sub.2a XL.sub.2, XL.sub.2a, XL.sub.6a, XL.sub.6b, XL.sub.6c, XL.sub.6d, or XL.sub.6e, configuration; XL.sub.4a alkyl).sub.2, alkyl).sub.2, alkyl).sub.2, inclusive; following:
wherein --Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: C.sub.8 are absent; mono-substituted nitrogen containing group bonded through the nitrogen only when n is not one; R.sub.13 and R.sub.15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen; R.sub.13 is other than a primary or secondary nitrogen-containing group hydroxy or mercapto g
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Phillips Delbert R.
The Upjohn Company
Welch Lawrence T.
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