Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-12-11
1992-12-29
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549477, 549478, 544238, 544369, 544139, 548217, C07D26326
Patent
active
051752980
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention provides novel processes and intermediates for the synthesis of the hydroxyethylene isostere dipeptide leu-val and similar transition state moieties. These compounds are useful in the synthesis of a large number of renin inhibitory peptides having this moiety in the 10,11 position corresponding to the renin substrate. See, e.g., U.S. Pat. No. 4,880,781, which is incorporated by reference herein. The sequence may readily be modified for the preparation of a large variety of both the N-terminal and C-terminal variants. When hydroxy ethylene isosteres of this type are incorporated into a variety of peptides they have enhanced or altered biological activity which makes them useful for treatment of a variety of disease states, particularly the treatment of hypertension.
INFORMATION DISCLOSURE
The use of the hydroxyethylene isostere dipeptide leu-val to prepare renin inhibitors is known. D. Tourwe, Janssen Chim. Acta, 3, (1985) gives a very brief review of some of the earlier work on transistion state analogs of dipeptides. This review gives the background and utility of dipeptide isosteres.
M. W. Holladay, et al., J. Med. Chem., 30, 375 (1987) describes the synthesis of Leu-gly and Leu-ala dipeptide isosteres and gives some biological data on their effectiveness as inhibitors when incorporated into renin inhibitory peptides.
M. W. Holladay, et al., Tetrahedron Letters, 24 (1983) describes the synthesis of the Leu-ala dipeptide isostere.
B. E. Evans, et al., J. Org. Chem., 50, 4615 (1985) describes a synthesis of the Phe-Phe dipeptide isostere.
D. J. Kempf, J. Org. Chem., 51, 3921 (1986) describes the preparation of the following dipeptide isosteres: Phe-ala, Phe-(BnS)ala, Phe-leu, Phe-(allyl)ala and Phe-phe.
A. H. Fray, et al., J. Org. Chem., 51, 4828 (1986) describes the thesis of the dipeptide hydroxyethylene isosteres Leu-leu, leu-gly and Leu-(2-propenyl)ala.
U.S. Pat. No. 4,613,676 describes an in situ preparation of Leu-val hydroxyethylene dipeptide isostere.
M. Szelke, et al., (1983) Novel Transition State Analogs of Renin. In V. J. Hruby and D. H. Rich (Eds.), Peptides: Structure and Function, Pierce Chem. Co., Rockford, Ill., pp 583-586, describes a synthesis of the hydroxyethylene isostere, Leu-val.
European patent application 173,481, published on Mar. 5, 1986, discloses the incorporation of Leu-val in renin inhibitory peptides.
SUMMARY OF THE INVENTION
The present invention particularly provides: different and are
(a) C.sub.1 -C.sub.10 alkyl,
(b) C.sub.2 -C.sub.10 alkenyl,
(c) aryl,
(d) C.sub.1 -C.sub.10 alkoxy,
(e) C.sub.1 -C.sub.10 alkylthio,
(f) Het, or
(g) --O--CH.sub.2 -aryl;
(a) C.sub.1 -C.sub.10 alkyl,
(b) benzyl, or
(c) substituted benzyl;
(a) hydrogen,
(b) C.sub.1 -C.sub.10 alkyl, or
(c) aryl;
(a) hydrogen,
(b) C.sub.1 -C.sub.10 alkyl, or
(c) C.sub.2 -C.sub.10 alkenyl; following:
(a) C.sub.1 -C.sub.10 alkyl,
(b) hydroxy,
(c) C.sub.1 -C.sub.10 alkoxy,
(d) halo, or
(e) C.sub.1 -C.sub.10 alkylthio, or
(f) Het;
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 three of the following:
(a) C.sub.1 -C.sub.10 alkyl, or
(b) --CH.sub.2 -aryl;
(a) hydroxy,
(b) --N.sub.3,
(c) --NH.sub.2,
(d) --NH--C(O)--O--R.sub.10, or
(e) --O--SO.sub.2 R.sub.11 ;
(a) C.sub.1 -C.sub.10 alkyl, or
(b) (C.sub.1 -C.sub.4 alkyl)-aryl;
(a) tert-butyl,
(b) benzyl,
(c) C(CO.sub.3)CH.sub.2 --,
(d) methyoxy benzyl, or
(e) fluorenyl;
(a) C.sub.1 -C.sub.10 alkyl,
(b) (C.sub.1 -C.sub.4 alkyl)aryl, or
(c) C.sub.n F.sub.n+1 ; following:
(a) C.sub.1 -C.sub.10 alkyl,
(b) hydroxy,
(c) C.sub.1 -C.sub.10 alkoxy,
(d) halo, or
(e) C.sub.1 -C.sub.10 alkylthio, or
(f) Het;
wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisti
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Daus Donald G.
The Upjohn Company
Welch Lawrence T.
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