Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Patent
1986-11-28
1989-11-21
Phillips, Delbert R.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
530331, C07K 508, C07K 510, C07K 706
Patent
active
048824208
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention provides novel renin-inhibiting peptides and intermediates for their preparation. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension.
INFORMATION DISCLOSURE
The preparation and use of certain renin-inhibiting peptides is found in U.S. Pat. No. 4,424,207 which is incorporated herein by reference. Further, EP publication No. 0 118 223 filed Feb. 6, 1984 having U.S. priority application Ser. No. 469,540 and Great Britain Application No. 8,322,414 filed Aug. 19, 1983 also disclose renin inhibiting peptide analogs. 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. Holladay et al., first synthesized an acid which is then incorporated into peptides as disclosed by the references cited therein including EP application 45665. U.S. Pat. No. 4,424,207 in the U.S. patent corresponding to this EP document. See also EP publication Nos. 77028, 77029, 81783, 104041, 111266 and 114993 and U.S. Pat. Nos. 4,470,971 and 4,478,826.
Additionally, European Applications 0 045 161 and 0 053 017 disclose amide derivatives useful as inhibitors of angiotensin converting enzymes. Hallinan, et al., in Tetrahedron Letters, 25:2301-2302 (1984) discloses the preparation of 2,2-difluoro-3-hydroxy esters by the Reformatskii reaction. Brandange, et al., J. Am. Chem. Soc., 103, 4452 (1981) discloses the preparation of 2-fluoro-3-hydroxy esters. Castro, et al., Bull. Soc. Chim. Fr., 3521 (1969) discloses the preparation of 2,2-dichloro-3-hydroxy esters.
SUMMARY OF THE INVENTION
The present invention provides: a renin inhibitory peptide of the formula II: X--A--B--C--D--E--F--G--H--Z, --(CH.sub.2).sub.1-6 --CO--, tri--C.sub.1 --C.sub.5 alkyl)amino, that --(CH.sub.2).sub.1-6 --CO--, simultaneously; hydrogen, V.sub.x1 is other than oxygen for (CH.sub.2).sub.0, or
Formula III depicts the moieties A--H when present.
The present invention further relates to a novel intermediate of formula XXX simultaneously;
When a variable occurs two or more times in a molecule, each occurrence is independently selected from the set of definitions for that variable. The term alkyl means alkyl of the indicated number of carbon atoms, inclusive, and includes straight-chain and branched chain forms thereof. The number of carbon atoms is indicated by the prefix to each carbon containing substituent. Thus, for example, C.sub.1 -C.sub.3 indicates a carbon containing moiety of from 1 to 3 carbon atoms. The term cycloalkyl means cycloalkyl of the indicated number of carbon atoms, inclusive, and additionally includes (1) cycloalkyl substituted by alkyl and (2) alkyl substituted by cycloalkyl such that the total number of carbon atoms is in the indicated range. The term aryl means phenyl or naphthyl optionally substituted by one or more --halogen (F, Cl, Br, I), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, --OR.sup.x5, --aryl.sub.1, --heterocycle, --SOCH.sub.3, --SO.sub.2 CH.sub.3, --NHSO.sub.2 CH.sub.3, --NHSO.sub.3 Na, --NHSO.sub.3 K, --CO.sub.2 R.sub.x5, --CON(R.sub.x5)R.sub.x5, --CHO, --NHSO.sub.2 N(R.sub.x5)R.sub.x5, --S--(C.sub.1 -C.sub.3 alkyl). The term aryl.sub.1 is defined as for aryl except that it cannot contain aryl.sub.1 as a substituent. The term heterocycle is defined as a substituent which is any 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; being fully unsaturated, partially saturated, or fully saturated; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, including (*indicates a preferred group) 2-, 3-, or 4-pyridinyl*, N-formylindolyl*, imidazolyl*, 1,2,4-triazolyl*, thienyl, pyrimidinyl*, furanyl, benzo[b]-thienyl-inc
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S. Thaisrivongs et al., "Difluorostatine-and difluorostatone-containing peptides as potent and specific renin inhibitors", J. Med. Chem., vol. 28, No. 11, Nov. 1985, pp. 1553-1555.
Phillips Delbert R.
The Upjohn Company
Welch Lawrence T.
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