RENIN INHIBITORS CONTAINING A CYCLOPROPYL AMINO ACID AND/OR A CYCLOALKYL TRANSITION-STATE ANALOGUE

Abstract: The present invention provides novel renin-inhibiting peptides having non-cleavable transition state inserts corresponding to the 10,11-position of a renin substrate (angiotensinogen) and having at least one cyclopropyl amino acid in place of an amino acid residue corresponding to position 6, 8, 9, 12, 13 or 14 of the renin substrate; and/or a cycloalkyl amino acid non-cleavable transition state insert in place of an amino acid residue corresponding to position 10 and 11 of the renin substrate. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension and other related deseases.

Description: Renin inhibitors containing a cyclopropyl amino acid and/o a cycloal yl transition-state analogue. DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More partic larly, the present invention provides novel renin-inhibiting pepti analogs. Most particularly, the present invention provides reni inhibitory compounds having non-cleavable transition state inserts a having at least one cyclopropyl amino acid and/or a cycloalkyl no cleavable transition state insert. The renin inhibitors provid herein are useful for the diagnosis and control of renin-depende hypertension and other related diseases. Renin is an endopeptidase which specifically cleaves a particul peptide bond of its substrate (angiotensinogen) , of which the N-te minal sequence in equine substrate is for example: Renin 4. As -Arg-Val-Tyr-lie-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser- IA 1 2 3 4 . 5 6 7 8 9 10 11 12 13 14 as found by L.T. Skeggs et al, J. Exper. Med. 106, 439 (1957). Hum renin subsrrate has a different sequence as recently discovered b D.A. Tewkesbury et al, Biochem. Biophys. Res. Comm. 99, 1311 (1981) It may be represented as follows: Renin I -Val-Ile-His- 11 12 13 IB and having the sequence to the left of the arrow (4-) being as desig nated in formula IA above. Renin cleaves angiotensinogen to produce angiotensin I, which i converted to the potent pressor angiotensin II. A number of an giotensin I converting enzyme inhibitors are known to be useful in th treatment of 'hypertension. Inhibitors of renin are also useful in th treatment of hypertension. A number of renin-inhibitory peptides have been disclosed. Thus U.S. Patent 4,424,207; European published applications .45,665; 104,041 and 156,322; and U.S. patent application, Serial No. 825,250, filed February 1986; disclose certain peptides with the .dipeptide at th 10,11-ρosition containing an isostere bond. A number of statine deriv atives stated to be renin inhibitors have been disclosed, see, e.g. European published applications 77,028; 81,783; 114,993; 156,319; a 156,321; and U.S. patents 4,478,826; 4,470,971; 4,479,941; a 4,485,099. Terminal disulfide cycles have also been disclosed in reni inhibiting peptides; see, e.g., U.S. patents 4,477,440 and 4,477,441 Aromatic and aliphatic amino acid residues at the 10,11 position of t renin substrate are disclosed in U.S. patents 4,478,827 and 4,455,303 C- terminal amide cycles are disclosed In U.S. patent 4,485,099 a European published applications 156,320 and 156,318. Certain tetrape tides are disclosed In European publications 111,266 and 77,02 Further, European published application No. 118,223 discloses certa renin inhibiting peptide analogs where the 10-11 peptide link replaced by a one to four atom carbon or carbon- itrogen lin Additionally, Holladay et al. , in "Synthesis of Hydroxyethylene a Ketomethylene Dipeptide Isostεres" , Tetrahedron Letters, Vol. 2 No. 41, pp. 4401-4404, 1983 disclose various intermediates in a proce to prepare stereo -direc- ted "ketomethylene" and "hydroxyethylen dipeptide isosteric functional gro'ups disclosed in the above not U.S. Patent No. 4,424,207. Evans, et al., J. Org. Chem. , 50, 46 (1985) discloses the synthesis of Hydroxyethylene Dipeptide Isostere See also, published European patent application 163,237, which di closes certain renin inhibiting peptides. Additionally, published European Applications 45,161 and 53,0 disclose amide derivatives useful as inhibitors of angiotensin conve ting enzymes . Certain dipeptide and tripeptides are disclosed in U.S. paten 4,514,332; 4,510,085; and 4,548,926 as well as in European publish applications 128,762; 152,255; and 181,110. Pepstatin derived ren inhibitors have been disclosed in U.S. patent 4,481,192. Retroinver bond modifications at positions 10-11 have been disclosed in U. patent 4,560,505 and in European published applications 127,234 a 127,235. Derivatives of isosteric bond replacements at positions 10- have been disclosed in European published applications 143,746 a 144,290; and U.S. patent application, Serial No. 904,149, filed September 1986. Isosteric bond modifications at positions 11-12 a 12-13 have been disclosed in European published application 179,35 Certain peptides containing 2 -substituted statine analogues have be disclosed in European published application 157,409, Certain peptid containing 3-aminodeoxystatine have been disclosed in European pu lished application 161,588. Certain peptides containing l-amino- hydroxybutane derivatives at positions 10-11 have been disclosed European published application 172,346. Certain peptides containing amino-2-hydroxypropane derivatives at positions 10-11 have be disclosed in European published application 172,347. Certain peptid containing N- erminal amide cycles have been disclosed in U.S. pate application, Serial No. 844,716, filed 27 March 1986. Certain peptid containing dihalostatine have been disclosed in PCT application, Seri No. 000,713, filed 7 April 1986. Certain peptides containing terminus truncated epoxy or azido or cyano groups or containing position 10-11 diol and a position 11-12 retro bond have been disclos in U.S. patent application, Serial No. 945-,340, filed 22 December 198 European published applications 156,322; 114,993; and 118,223; a PCT patent application, Serial No. 002,227, filed 21 November 198 U.S. patent application, Serial No. 825,250, filed 3 February 198 U.S. patent application, Serial No. 904,149, filed 5 September 198 and U.S. patent application, Serial No. 844,716, filed 27 March 198 disclose hydroxamic acids or esters at the C-terminus. E.P. 189,203 discloses new N-dihydroxyalkyl peptide derivativ which are useful as inhibitors of renin for treating hypertension. E.P. 184,855 discloses new hydroxy substituted-statine pepti derivatives which are useful as inhibitors of renin for treati hypertension. Derivatives of isosteric bond replacements at positions 10-11 dihydroxy ethylene isosteres have been disclosed in U.S. pate application, Serial No. 904,149, filed 5 September 1986. The following references disclose additional substituents at t 10, 11-position: A. Spaltenstein, P. Carpino, F. Miyake and P.B Hyskins, Tetrahedron Letters, 27:2095 (1986); D.H. Rich and M.S Bernatowicz, J. Med. Chem. , 25:791 (1982); Roger, J. Med. Che . 28:1062 (1985); D.M. Glick et al. , Biochemistry, 21:3746 (1982); D.H Rich, Biochemistry, 24:3165 (1985); R.L. Johnson, J. Med. Chem., 25:60 (1982); R.L. Johnson and K. Verschovor, J. Med. Chem., 26:1457 (1983) R.L. Johnson, J. Med. Chem., 27:1351 (1984); P.A. Bartlett and W.B Kezer et al. , J. Am. Chem. Soc. , 106:4282 (1984); Peptides: Synthesis Structure and Function (V.J. Hruby; D.H. Rich, eds.) Proc. 8th America Peptide Sym. , Pierce Chemical Company, Rockford, 111., pp. 511-20; 587- 590 (1983). INFORMATION DISCLOSURE Certain peptides having cleavable bonds corresponding to the 10,11-position of the renin substrate and containing cyclopropylamino acids are disclosed in U.S. Patent 4,629,784 (1986) Stammer; PCT Application WO 85/00809 Stammer. Different peptides are shown to have different uses such as food additives, analgetics, CNS regulators, renin inhibitors, and an ihypertensive agents. The synthesis of cyclopropylphenylalanine and the preparation o stabilized peptides are disclosed in Ki ura, Biochem. and Biophy. Research Commun. 115:112 (1983). The synthesis of enkephalin analogues containing cyclopropane amino acids is disclosed in CH. Stammer, Pept. Struct. Funct. , Proc. Am. Pept. Sym . , 287 (1983). The synthesis of peptides containing cyclopropane amino acids is disclosed in F.H.C. Stewart, Austrian J. of Chemistry, 34:2431 (1981). Phenylcyclopropane carboxylic acids and esters as hypotensiv agents are disclosed in U.S. Patent 4,293,760 (1967) Kaiser; U.S. Patent 3,068,283 (1962) Kaiser; U.S. Patent 3,313,842 (1967) Smith- Kline. An improved preparation of 1-aminocyclopropane-l-carboxylic aci and its use for plant growth regulation are disclosed in U.S. Paten 4,298,760. General syntheses of 2-substituted cyclopropane amino acids ar found in the following references: J.E. Baldwin, Tetrahedron Letters, 481, 485 (1985); M. Bernabe, Synthesis, 773 (1985); M. Bernabe, J. Heterocyclic Chem., 20:607 (1983); CH. Stammer, J. Org. Chem., 48:244 (1983); CH. Stammer, Tetrahedron Letters, 24:3839 (1983); CH. Stammer, J. Org. Chem., 47:3270 (1982); M. Bernabe, Eur. J. Med. Chem. Chimica Therapeutics, 14:33 (1979); M. Bernabe, Synthesis, 191 (1977); CH. Stammer, J. Org. Chem., 41:1466 (1976); M. Bernabe, Anales d Quimica, 68:1005 (1972); and W.I. Awad, Tetrahedron, 20:891 (1967). The synthesis of cyclopropyl thyronine is disclosed in A. Burge and R.A. Pages, J. Med. Chem., 10:435 (1967). The synthesis of cyclopropyl-3-chloroalanine is disclosed in CH. Stammer, J. Org. Chem., 49:1534 (1984). The synthesis of l-ammo-2-(4-imldazolyl)cyclopropane carboxyli acid is disclosed in A. Burger, J. Med. Chem., 9:766 (1966); f related work see A. Burger, J. Med. Chem., 10:435 (1967); C.L. Zirkl J. Med. Phar . Chem., 5:1265 (1962); and C Kaiser, Belgian Pate 648,020 (1964). The synthesis of spirocyclopropane amino acids is disclosed Liebigs Ann. Chem., 611 (1973), U. Schollkopf. The synthesis of phenethylamine cyclopropane carboxylic acid disclosed in A. Burger, J. Am. Chem. Soc, 70:2198 (1948); and R. Tedeschi, Proc. Soc. Exp. Biol. Med., 102:380 (1959). SUMMARY OF THE INVENTION The present invention particularly provides: A renin inhibitory peptide having a non-cleavable transition sta insert corresponding to the 10,11-position of a renin substra (angiotensinogen) and having: (a) at least one cyclopropyl amino acid of the formula XL2b place of an amino acid residue corresponding to position 6, 8, 9, 12 13 or 14 of the renin substrate: and/or (b) a cycloalkyl amino acid non-cleavable transition state inser of the formula L2 C in place of an amino acid residue corresponding t position 10 and 11 of the renin substrate; wherein R5 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rg Q and Rg ] _ are the same or different and are (a) hydrogen, (c) - (CH 2 ) p - aryl , (d) - (CH 2 ) p -Het , (e) - (CH 2 ) p -C 3 -C 7 cycloalkyl, or ( f) 1 - or 2 - adamantyl ; or wherein RgQ and Rg^ taken together form a spirocycle of the formul II wherein R70 is (a) -CHR 80 , (b) -0-, (c) -S-, (d) -SO-, (e) -S0 2 -, or (f) -NR 81 ; wherein Rgn and Rg^ are the same or different and are (a) hydrogen, (b) Ci-Csalk l, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg is (a) hydrogen, or (b) C 1 -C 5 alkyl; wherein Rioo - s (a) hydrogen, (b) C 1 -C 5 alkyl, (c) aryl, (d) C β -Cycycloalkyl, (e) -Het, (f) C -C3alko y, or (g) C-L-€ β alk lthio; wherein χ o ^ s (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein χι is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein p is zero to two, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, Inclusive; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: (a) C^-C β alkyl, (b ) hydroxy, (c ) C -C alkox , <d ) halo, (e ) amino, (g ) -CHO, (b ) -COOH, (i ) COOR 2 6, (j ) CONHR 26 , (k ) nitro, (1 ) mercapto, (m ) C_-C3alkylthio, (n ) C -C3alkylsulfinyl, (o ) C -C3alkylsulfonyl, <p: ) -N(R 4 )-C 1 -C 3 alkylsulfonyl, (q ' ) S0 3 H, (r) ) S0 2 NH 2 , (s) -CN, or ( -CH 2 NH 2 ; wherein -Het is a 5- or 6-membered saturated or unsaturated rin containing from one to three heteroatoms selected from the grou consisting of nitrogen, oxygen, and sulfur; and including any bicycli group in which any of the above heterocyclic rings is fused to benzene ring, which heterocyclic moiety is substituted with zero to of the following: (i) Ci-Cgalkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C^-C lkoxy, (v) halo, (vi) aryl, (vii) aryl C_-C alkyl-, (viii) amino, (ix) mono- or di- (0 -Chalky1)amino, and (x) C^-C5al anoyl; wherein R at each occurrence is the.same or different and is (a) hydrogen, (b) C C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R 2 g is (a) hydrogen, (b) C 1 -C3alk l, or (c) phenyl-C 1 -C3alkyl. In a renin inhibitory peptide having a non-cleavable transitio state insert corresponding to the 10 , 11-position of a renin substrat (angiotensinogen) , the improvement which comprises inclusion in th renin inhibitory peptide of: (a) at least one cyclopropyl amino acid of the formula XL 2 ^ i place of an amino acid residue corresponding to position 6 , 8 , 9 , 12 13 or 14 of the renin substrate ; and/or (b) a cycloalkyl amino acid non-cleavable transition state inser of the formula XL 2c in place of an amino acid residue corresponding t position 10 and 11 of the renin substrate ; wherein 50 is (a) hydrogen, (b) C -Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgn and g ] _ are the same or different and are (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -ar l, (d) -(CH 2 ) p -He , (e) -(CH 2 )p-C3-C cycloalkyl, or (f) 1- or 2-adamantyl; or wherein Rgg aι *d Rgi taken together form a spirocycle of the formul II wherein R u is (a) -CHR 80 , (b) -0-, (c) -S-, (d) -SO-, (e) -S0 2 -, or (f) -NR 81 ; wherein Rgg and Rg ] _ are the same or different and are (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R90 is (a) hydrogen, or (b) Cx-Csalk l; wherein R]_00 is (a) hydrogen, (b) C 1 - C 5 alkyl , (c) aryl , (d) C3 -C 7 cycloalkyl , (e) -Het , (f) C -C3alkox , or (g) C _ -C3alkylthio ; wherein no I s (a) hydrogen , (b) C 1 -C 5 alkyl , (c) -(CH 2 )p-aryl, or (d) halogen; wherein Rm is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein p is zero to two, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to three the following: (a) C 1 -C 3 alkyl, (b) hydroxy , (c) C _-C3alkoxy, (d) halo , (e) amino , (f) mono- or di-C^^alkylamino, (g) -CHO, (h) -COOH, (i) C00R 26 , (j) C0NHR 26 , (k) nitro, (1) mercapto, (m) C -C3 lkylthio, (n) C -C3alkylsulfinyl, (o) C -C3alkylsulfonyl, (p) -N(R )-C 1 -C 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; wherein -Het Is a 5- or 6-membered saturated or unsaturated rin containing from one to three heteroatoms selected from the grou consisting of nitrogen, oxygen, and sulfur; and including any bicycli group in which any of the above heterocyclic rings is fused to benzene ring, which heterocyclic moiety is substituted with zero t three of the following: (i) Cx-Cgalkyl, (ϋ) hydroxy r (ill) trifluoro ethyl, (iv) C -C alko , (v) halo, ( i) aryl, (vll) aryl Ci^alkyl- , (viii) amino, (ix) mono- or di-(C_-C4alkyl)amino, and (x) C -C5alkanoyl; wherein R at each occurrence is the same or different and is (a, hydi • ogen, (b) Cx-Cs lkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R g is (a) hydrogen, (b) C^^alkyl, or (c) phenyl-C_-C3alkyl. Examples of renin inhibitors of the present invention of formula I ar wherein X is (a) hydrogen, (b) Cx-Cs lkyl, (c) R 5 -0-CH 2 -C(0)-, (d) R 5 -CH 2 -0-C(0)-, (e) R 5 -0-C(0)-, (f) R 5 -(CH 2 ) n -C(0)-, (g) R 4 N(R4)-(CH 2 ) ri -C(0), (h) R 5 -S0 2 -(CH 2 ) q -C(0)-, (i) R 5 -SO 2 -(CH 2 ) q -0-C(0)-, or (j) R 6 -(CH 2 ) i -C(0)-; wherein Ag is absent or a divalent moiety of the formula XL ] _, XL XL 2a , or XL 2b ; wherein B 7 is absent or a divalent moiety of the formula XL b ; wherein Cg is absent or a divalent moiety of the formula XL ] _, XL 2 XL 2a , or XL 2b ; wherein Do . is absent or a divalent moiety of the formula XL3 XL 2a , or XL 2b ; or wherein Cg-Dg is XL 7 , XL 7a , or when X, Ag and B 7 are absent XL 7b! wherein E ] _ Q "F ] _ is a divalent moiety of the formula XL , XLg a XLg b , XL 6c , XLg d , XLg e , XLg f , or XL 6g ; wherein * indicates an asymmetric center which is either in the or S configuration; wherein G is absent or a divalent moiety of the formula XL4 L a , or XL 2 b '< wherein H 3 is absent or a divalent moiety of the formula XL4 o XL 2b ; wherein I ] _4 is absent or a divalent moiety of the formula XL5 o L 2 b; wherein 2 is (a) -0-R 10 , (b) -N(R 4 ) 1 4, or (c) C -C c clic amino; wherein R Is (a) isopropyl, (b) isobutyl, (c) phenylmethyl, or (d) C3-C 7 cycloalkyl; wherein R ] _ is (a) hydrogen, (b) C -C 5 lkyl, (c) aryl, (d) C3-C 7 cycloalkyl, (e) -Het, (f) C -C3alko y, or -(g) C -C3alkylthio; wherein R is (a) hydrogen, or (b) -CH(R 3 )R 4 ; wherein R3 is (a) hydrogen, (b) hydroxy, (c) C -C5alk l, (d) C3-C cycloalkyl, (e) aryl, (f) -Het, (g) C -C3 l o y, or 00 C -C3 lkylthio; wherein R at each occurrence is the same or different and is (a) hydrogen, (b) Ci-Cs lkyl, (c) -(CH 2 )p-aryl, (d) -(CH 2 )p-Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R-, is (a) C - C alkyl , (b) C3-C 7 cycloalkyl, (c) aryl, (d) -Het, or (e) 5-oxo-2-ρyrrolidinyl; wherein Rg is (a) hydrogen, (b) Ci-Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R 7 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) hydroxy, (d) amino C ] _-C4alkyl- , (e) guanidinyl C -C3alkyl-, (f) aryl, (g) -Het, (h) methylthio, (i) -(CH 2 ) p -C3-C 7 cycloalkyl, or (j) amino; wherein Rg is (a) hydrogen, (b) C^-C5al l, (c) hydroxy, (d) aryl, (e) -Het, (f) guanidinyl C -C3alkyl-, or (g) -(CH 2 ) p -C 3 -C 7 cycloalkyl; wherein R9 is (a) hydrogen, (b) hydroxy, (c) amino Cχ-C alkyl- , or (d) guanidinyl C^-C3alkyl-; wherein R^ is (a) hydrogen, (b) C -C 5 alkyl, (c) -(CH 2 ) n R 16 , (d) -(CH 2 ) n R 17 , (e) C3-C 7 cycloalkyl, (f) a pharmaceutically acceptable cation, (g) -CH(R 25 )-CH 2 -R 15 , or 00 -CH 2 -CH(R 12 )-R 15 ; wherein R^ is -R or -R 2 ; wherein ' l 12 is -(CH 2 ) n -R 13 ; wherein Il 13 is (a) aryl, (b) amino, (c) mono-, di or tri-C^-C3alkylamlno, (d) -Het, (e) C 1 -C5alkyl (f) C3-C 7 cycloalkyl, (g) C -C5alkenyl, 00 C3-C 7 cycloalkenyl, (1) hydroxy, (j) C;L-C3alkoxy, 00 C 1-C3alkano 1ox , (1) mercapto, (m) C^-C3 lk l hio, 00 -C00H, (o) -CO-O-C^Cgalkyl, (P) -CO-0-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl) 2 , (q) -C0-NR 22 R 26 ; (r) C -C c clic amino, (s) C4-C cycloalkylamino, (t) guanidyl, (u) cyano, (v) N-c anoguanidyl, (w) cyanoamino, (x) (hydroxy C 2 -C alkyl)amino, or ( y ) di-(hydroxyC -C4alk )amino; wherein R 14 Is (a) hydrogen, (b) L-Cxoalkyl, (c) -(CH 2 ) n -R I8 , (d) -(CH 2 ) n -R 19 , (e) -CH(R 25 )-CH 2 -R 15 , (f) -CH 2 -CH(R 12 )-R 15 , (g) (hydroxy C^Cgalkyl) , or (h) (C 1 .C 3 alkoxy)C 1 -Cgalkyl; wherein R 5 is (a) hydroxy, (b) C3-C 7 cycloalkyl, (c) aryl, (d) amino, (e) mono-, di- , or tri- C ] _-C3al l mi o , (f) mono- or di- (hydroxy C -C4 lkyl) amino , (g) -Het, (h) C 1 -C 3 alkoxy-, (i) C- ] _-C3alkanoyloxy- , ( j ) mercapto, (k) C 1 -C 3 alkylthio- , (1) Cx-Csalkyl, (m) C4-C 7 cyclic amino, (n) C4-C cycloalkylamino, (o) C ] _-C5alkenylo , (p) C3-C cycloalkenyl; wherein R ] _g is (a) aryl, (b) amino, (c) mono- or di- (C^-C alkyl)amino, (d) hydroxy, (e) C3-C cycloalkyl, (f) C4-C 7 cyclic amino, or (g) Cι-C3alk noylox ; wherein R^ is (a) -Het, (b) C -C5alkenyl " , (c) C3-C 7 cycloalkenyl, (d) C^^ lko y, (e) mercapto, (f) C 1 -C 3 alkylthio, (g) -COOH, (h) -CO-0-C 1 -C 6 alkyl, (i) -C0-0-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C3alkyl) 2 , (j) -C0-NR 22 R 26 , (k) tri-C 1 -C3alkylamino, (1) guanidyl, (m) cyano, (n) N-cyanoguanidyl, (o) (hydroxy C 2 -C4alkyl)amino, (p) di-(hydroxy C 2 -C lkyl amino, or (q) cyanoamino; wherein R ] _g is (a) amino, (b) mono-, or di- C^-C3alkyl)amino, (c) C4-C 7 cyclic amino; or (d) C4-C 7 cycloalkylamlno; wherein R ] _g is (a) aryl r (b) -Het, (c) tri-C j _-C3alkylamino, (d) C3-C 7 cycloalkyl, (e) C^_-C5alke l, (f) C -C 7 cycloalkenyl, (g) hydroxy, 00 C ] _-C3 lkox , (i) C ] _-C3alkanoylox , (j) mercapto, 00 C L -C3alkylthio, (1) -COOH, On) -C0-0-C 1 -C 6 alkyl, (n) -CO-0-CH 2 -(C 1 -C3alkyl)-N(C 1 -C 3 alkyl)2, (o) -CO-NR 22 R 26 , (P) guanidyl, (q) cyano, (r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy C 2 -C aly1)amino, O di-(hydroxy C 2 -C alkyl) mino; or (v) -S0 3 H; wherein R 2 o is (a) hydrogen, (b) C ] _-C5al l, or (c) aryl-C 1 -C 5 alkyl; wherein R 2 is (a) -NH 2 , or (b) -OH; wherein R 22 is (a) hydrogen, or (b) C 1 -C 3 alkyl; wherein R 2 3 is (a) -(CH 2 ) n -0H, (b) -(CH 2 ) n -NH 2 , (c) aryl, or (d) C 1 -C 3 alkyl; wherein R 4 is (a) -Rx, (b) -(CH 2 ) n -0H, or (c) -(CH 2 ) n -NH 2 ; wherein R 2 5 is (a) hydrogen, (b) CiL-C3alkyl, or (c) phenyl -C -C alkyl; wherein R g is (a) hydrogen, (b) C -C3alkyl, or (c) phenyl -C -C3alkyl; wherein R50 is (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgo and R 61 are the same or different and are (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; erein Rgg and R 61 taken together form a spirocycle of the formula wherein R Q is (a) -CHR 80 , (b) -0-, (c) -S-, (d) -SO-, (e) -S0 2 -, or (f) -NR 81 ; wherein Rgn and ^ are the same or different and are (a) hydrogen, (b) t^-Chalky!, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein RQQ is (a) hydrogen, or . (b) Ci-Cgal yl; wherein R]_oo ^ s (a) hydrogen, (b) C -Csal yl, (c) aryl, (d) C3-C 7 cycloalkyl, (e) -Het, (f) C 1 -C 3 alkoxy, or (g) C 1 -C 3 alkylthio; wherein χιo i (a) hydrogen, (b) C 1 -C 5 alkyl, (c) - (CH 2 ) p -aryl , or (d) halogen; wherein m is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d halogen; wherein i is zero to five, inclusive; wherein m is one or two; wherein for each occurrence n is independently an integer of ze to five, inclusive; wherein p is zero to two, inclusive; wherein q is one to five, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, inclusive; wherein Q is (a) -CH 2 -, (b) -CH(OH)-, (c) -0-, or (d) -S-; and wherein M is (a) -CO-, or (b) -CH 2 -; wherein aryl is phenyl or naphthyl substituted by zero to three the following: (a) C 1 -C 3 alkyl, (b) hydroxy, (c) C ] _-C3alkoxy, (d) halo, (e) amino, (f) mono- or di-C- j _-C3alkylamino, (g) -CHO, (h) -COOH, (i) C00R 26 , (j) C0NHR 26 , (k) nitro, (1) mercapto, (m) C 1 -C3alkylthio, (n) C 1 -C3alkylsulfinyl, (o) C 1 -C3alkylsulfonyl, (p) -N(R 4 )-C 1 -C 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; 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 blcyclic 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: (i) C C alkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C^^alko y, (v) halo, (vi) aryl, (vil) aryl C- j _-C4alkyl- , (viii) amino, (ix) mono- or di-(C- j _-C al yl)amino, and (x) C^-C5alkanoyl; with the overall provisos that: (1) at least one cyclopropyl amino acid of the formula XL 2b or cycloalkyl amino acid non-cleavable transition state insert of the formula XL 2c is present; (2) ] _ or R^g is hydroxy, mercapto, or amino, or a mono-sub- stituted nitrogen containing group bonded through the nitrogen only when n is not one; (3) R]_ 2 is and R 5 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen; (4) R- j _ or R^α is -COOH only when n for that moiety is other than zero; (5) R ] _ or R is an amino-containing substituent, hydroxy, mercapto, or -Het bonded through the hetero atom only when n for. that substituent Is an integer from two to five, inclusive; (6) when R]_ 2 is -(CH 2 ) n -R ] _3 and n is zero, then ^_ and R-^5 cannot both be -COOH; and (7) R^ or 9 is -Het, only when -Het is other than -cyclic amino; or a carboxy- , amino- , or other reactive group-protected thereof; or a pharmaceutically acceptable acid addition salt thereof. In formula XL 2c , both R^Q an d Rm are attached to the carbon atom of the cycloalkyl ring. By "renin inhibitory peptide" is meant a compound capable inhibiting the renin enzyme in mammalian metabolism and having thre more amino acid residues linked by peptidic or pseudo-peptidic bond By "a non-cleavable transition state insert" is meant a transi state insert which is not cleavable by ' a hydrolytic enzyme in mamma metabolism. A variety of such transition state inserts, correspon to the 10,11-position of the renin substrate, are known in the including those disclosed in the following references, which are he incorporated by reference: U.S. Patent 4,424,207 (Szelke); European Patent 104041A (Szel European Patent Application 144.290A (Ciba Geigy AG) ; European Pa 0,156,322 (Merck); European Patent 161-588A (Merck); European Pa 0,172,347 (Abbott); European Patent 172-346-A (Abbott); European Pa 156-318 (Merck); European Patent 157-409 (Merck); European Patent 255 (Sankyo); and U.S. Patent 4,548,926 (Sankyo) ; and U.S. patent application, Serial No. 904,149, filed 5 Septe 1986; U.S. patent application, Serial No. 844,716, filed 27 March 19 PCT application, Serial No. 000,713, filed 7 April 1986; U.S. pat application, Serial No. 945,340, filed 22 December 1986; and U patent application, Serial No. 825,250, filed 3 February 1986; and A. Spaltenstein, P. Carpino, F. Miyake and P.B. Hyskins, Tet hedron Letters, 27:2095 (1986); D.H. Rich and M.S. Bernatowicz, J. M Chem., 25:791 (1982); Roger, J. Med. Chem., 28:1062 (1985); D.M. Gl et al., Biochemistry, 21:3746 (1982); D.H. Rich, Biochemistry, 24:3 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982); R.L. Johnson and Verschovor, J. Med. Chem., 26:1457 (1983); R.L. Johnson, J. Med. Che 27:1351 (1984); P.A. Bartlett et al., J. Am. Chem. Soc, 106:4 (1984); arid Peptides: Synthesis, Structure and Function (V.J. Hru D.H. Rich, eάs.) Proc. 8th American Peptide Sy . , Pierce Chemi Company, Rockford, 111., pp. 511-20; 587-590 (1983). As is apparent to those of ordinary skill in the art, the re inhibitory l -peptides of the present invention can occur in seve Isomeric forms, depending on the configuration around the asymmetric carbon atoms. All such isomeric forms are included within the scope of the present invention. The E isomer of the cyclopropyl amino acids is preferred. The trans isomer of the cycloalkyl transition state inserts is preferred. Preferably, the stereochemistry of the other amino acids corresponds to that of the naturally-occurring amino acids. Renin inhibitory peptides commonly have protecting groups at the N- erminus and the C-terminus. These protecting groups are known In the polypeptide art. Examples of these protecting groups are given below. Any of these protecting groups are suitable for the renin inhibitory peptides of the present invention. Furthermore, the cyclopropyl amino acid of the formula XL 2b of the present Invention may occur at the N-terminus of the renin inhibitory peptide and, as such, will, when coupled with a suitable protecting group, assume * the ending position. These compounds are shown in relation to the human renin substrate as follows: 6 7 8 9 10 11 12 13 -His Pro Phe His Leu Val He His- X Ag B 7 Cg D 9 E 10 F U G 12 H 13 I 1 Z, The present invention provides peptide inhibitors of renin which contain at least one cyclopropane amino acid and have transition state inserts. Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesul- fonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, hep anoate, hexanoate, hydrochloride, hydrobro ide, hydrσiodide, 2-hydroxyethane- sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nlcotinate, oxalate, palmoate, pectinate, persulf te, 3-phenylpropio- nate, plcrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. The carbon atom ccntent of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix indicates a moiety of the integer "I" to the integer π j" carbon atoms, inclusive. Thus (C1-C alkyl refers 1 " to 'alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C4-C 7 c cl amino indicates a monocyclic group containing one nitrogen and 4 to carbon atoms. Examples of (C -C o) c y cloallc y 1 which include alkyl-substitut cycloalkyl containing a total of up to 10 total carbon atoms, a cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcycloρropyl, 2,3-diethy cyclopropyl, 2-butylcycloproρyl, cyclobutyl, 2-methylcyclobutyl, propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexy cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric for thereof. Examples of aryl include phenyl, naphthyl, (o- , m- , p-)tolyl, (o- m- , p-)ethylphenyl, 2-ethyl- olyl, 4-ethyl-o-tolyl, 5-ethyl-m-toly (o- , m- , or p-)propylphenyl, 2-propyl- (o- , m- , or p-)tolyl, 4-isopr pyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-) trimethylphenyl, (o- , m- , or p-)fluorophenyl, (o- , m- , or p-trifluor methyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)d fluorophenyl, (o-, m- , or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4- 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlor phenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o- m- , or p-)trifluoro-methylphenyl, (o-, m- , or p-)ethoxyphenyl, (4- 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro(5- or 6-)methylphenyl, a the like. Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl indolyl, N in -formyl-indolyl, N in -C 1 -C 5 alkyl-C(0)-indolyl, [1,2,4] triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, quinolinyl isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl thienyl, and benzothienyl. Each of these moieties may be substitute as noted above. As would be generally recognized by those skilled in the art o organic chemistry, a heterocycle as defined herein for -Het would no be bonded through oxygen or sulfur or through nitrogen which is withi a ring and part of a double bond. Halo is halogen (fluoro, chloro, bromo, or iodo) or trifluoro methyl. Examples of pharmaceutically acceptable cations include: pharm¬ acologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations. Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationlc forms of other metals, e.g., aluminum, zinc, and iron are also within the scope of this invention. Pharmacologi¬ cally acceptable amine cations are those derived from primary, secon¬ dary, or tertiary amines. The novel peptides herein contain both natural and synthetic amino acid residues. These residues are depicted using standard amino acid abbreviations (see, e.g., Eur. J. Biochem. , 138, 9 (1984)) unless otherwise indicated. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the Invention are effective In the treatment of humans. The renin inhibitors of this Invention are useful for treating any medical condition for which it is beneficial to reduce the levels of active circulating renin. Examples of such conditions include renin- associated hypertension and hyperaldosteronism, hypertension, hyperten¬ sion under treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, angina, and post-myocardial infarc¬ tion. The renin-anglotension system may play a role in maintenance of intracellular homeostasis: see Clinical and Experimental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discussion. Further, the renin inhibitors of this invention may be useful In the treatment of cerebrovascular disorders and disorders of intracel¬ lular homeotasis. The possible role of the renln-angiotensin system in the maintenance of intracellular homeostasis is disclosed in Clinical and Experimental Hypertension, 86:1739-1742 (1984). Additionally, the renin inhibitors of this invention potentiate the antithrombotic activity of a thromboxane antagonist (U.S. patent 4,558,037). The antihypertensive effect of the renin inhibitors of this invention are potentiated by combination with a thromboxane synthetase inhibitor. The compounds of the present invention are preferably orally administered to humans to effect renin inhibition for the purpose of favorably affecting blood pressure. For this purpose, the compounds are administered from 0.1 mg to 1000 mg per kg per dose, administered from 1 to 4 times daily. The compounds of the present invention a preferably orally administered in the form of pharmacological acceptable acid addition salts. Preferred pharmacologically acceptab salts for oral administration include the citrate and aspartate salt although any pharmacologically acceptable salt is useful in th invention, including those listed above. These salts may be hydrated or solvated form. Other routes of administration include parenteral, by inhalati spray, or rectally in dosage unit formulations containing convention non-toxic pharmaceutically acceptable carriers, adjuvants and vehicle The term parenteral as used herein includes subcutaneous injection intravenous, intramuscular, intrasternal injection or infusion tec niques. The pharmaceutical compositions may be in the form of a steri injectable preparation, for example as a sterile injectable aqueous oleagenous suspension. This suspension may be formulated according the known art using suitable dispersing or wetting agents and suspen ing agents. The sterile injectable preparation may also be a steri injectable solution or suspension in a non-toxic parenterally-acce table diluent or solvent, for example as a solution in 1,3-butanedio Among the acceptable vehicles and solvents that may be employed a water, Ringer's solution and isotonic sodium chloride solution. addition, sterile, fixed oils are conventionally employed as a solve or suspending medium. For this purpose any bland fixed oil may employed including synthetic mono- or diglycerides. In addition, fat acids such as oleic acid find use in the preparation of injectibles. Equivalent dosages for such other routes of administration a thus employed. The exact dose depends on the age, weight, and cond tion of the patient and on the frequency and route of administratio Such variations are within the skill of the practitioner or can readi be determined. The compounds of the present invention may be in the form pharmaceutically acceptable salts both those which can be produced fr the free bases by methods well known in the art and those with whi acids have pharmacologically acceptable conjugate bases. Conventional forms and means for administering renin-inhibiti compounds may be employed and are described, e.g., in U.S. Pate No. 4,424,207 which is incorporated by reference herein. Likewise, t amounts disclosed In the U.S. Patent No. 4,424,207 are examples appli¬ cable to the compounds of the present invention. The renin-inhibiting compounds of this invention may be adminis¬ tered in combination with other agents used in antihypertenslve therapy such as diuretics, or and/or / 3-adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described, for example, in published European patent application 156 318. For example, the compounds of this invention can be given in combination with such compounds or salts or other derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benz- thiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethlazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respec¬ tively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolactone; ticrynaten; trimaterene; trichlormethlazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxy- benzamine; prazosin; tolazoline; ^-Adrenergic Blocking Agents: atenolol; m toprolol; nadolol; propranolol; timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furananilide) (an- carolol) ; (2-acetyl-7- (2-hydroxy-3-isopropylaminoproρoxy)benzofuran HCl) (befun- olol) ; ( (±) -1- (isopropyla ino) - 3 - (p - (2-cyclopropylmethoxyethyl) -phenoxy) -2- propranol HCl) (betaxolol) ; (1- [ (3 ,4- dime thoxyphenethyl) mino] -3- (m-tolyloxy) -2-propanol HCl) (be- vantolol) ; ( ( (±) - 1 - (4 - ( (2 - isopropoxyethoxy)methyl)phenoxy) -3- isopropylamino-2- propanol)fumarate) (blsoprolol) ; (4- (2 -hydroxy- 3- [4- (phenoxymethyl)-piperidino] -p opoxy) -indole) ; (carbazolyl-4-oxy-5 , 2- (2-me hoxyphenoxy) -ethylamino- 2-propanol) ; (l- ((l, l-dimethylethyl)amino) -3-((2-methyl Η-indol-4-yl)oxy) -2-pro¬ panol benzoate) (bopindolol) ; ( l- ( 2-exob icyclo^2.2.1] -hept-2-ylphenoxy) -3- [ (l-mathylethyl) -amino] -2- propanol HCl) (bornaprolol) ; ( o - [ 2 - hydroxy - 3 - [ ( 2 - indo 1 - 3 - y 1 - 1 , 1 - dime thyle thyl) - amino ] propoxy ] be zonitrile HCl) (bucindolol) ; ( α - [ ( t ert.butylamino)methyl] -7-ethyl-2-benzofuranmethanol) (bufur-al 1); (3- [ 3 -acetyl-4- [3- ( tert . butylamino) - 2-hydroxypropyl ] -phenyl] -1, diethylurea HCl) (celiprolol) ; ((±)-2-[2-[3-[ (1,1-dimethyle thyl) amino] -2-hydroxyρropoxy]phenoxy] - methylacetamide HCl) (cetamolol) ; (2-benzimidazolyl-phenyl(2-isoρropylaminopropanol)) ; ((±) -3' -acetyl-4' - (2-hydroxy-3-isoρropylaminopropoxy) -acetanilide HC (diacetolol) ; (methyl-4- [2-hydroxy-3- [ (l-methylethyl)aminopropoxyl] ] -benzene-propa oate HCl) (esmolol) ; (erythro-DL-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol) ; (1- (tert. butylamino) -3- [0- (2-propynyloxy)phenoxy] -2-propanol (parg lol); (1- (tert.butylamino) -3- [o- (6-hydr.azino-3-pyridazinyl)phenoxy] -2 propanol diHCl) (prizidilol) ; ( (-)-2-hydroxy-5- [ (R) -1-hydroxy-2- [ (R) - (1-methyl-3-phenylpropyl) amino]ethyl]benzamide) ; (4-hydroxy-9- [2-hydroxy-3- (isopropylamino) -propoxy] -7 -methyl-5H furo[3,2-g] [1] -benzopyran-5-one) (iprocrolol) ; ((-)-5-(tert .butylamino) -2-hydroxypropoxy] -3,4-dihydro-l-(2H)-nap thalenone HCl) (levobunolol) ; (4- (2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole HCl) ; (4- [3-(tert.butylamino) -2-hydroxypropoxy] -N-methylisocarbostyril HCl) ; ((±)-N-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N' -isopro pylurea) (pafenolol) ; (3- [ [(2-trifluoroacetamido)ethyl]amino] -l-phenoxyproρan-2-ol) ; (N- (3- (o-chlorophenoxy)-2-hydroxypropyl) -N' -(4' -chloro-2,3-dihydro-3 oxo-5-pyridazinyl)ethylenediamine) ; ( (±) -N- [3-acetyl-4- [2-hydroxy-3- [(1-methylethyl)amino]propoxyphenyl] butanamide) (acebutolol) ; ((±)-4'-[3- (tert-butylamino)-2-hydroxypropoxy]spiro[cyclohexane-l,2' indan] -1' -one) (spirendolol) ; (7- [3- [ [2-hydroxy-3- [(2-methylindol-4-yl)oxylpropyl]amino]butyl]thio phylline) (teoprolol); (( ± ) -l- t er t .bu t ylamino-3-(thiochroman-8-yloxy) -2-propanol) (tertato- lol) ; (( ± ) -l- t er t .butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol) ; (8- [3- (tert. butylamino) -2 -hydroxypropoxy] -5-methylcoumarin) (bucumo-1- ol) (2-(3-(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HCl) (bunitro- lol); ( (±) - 2 ' - [ 3 - (tert -butylamino) -2 -hydroxypropoxy -5 ' -fluorobutyrophenone) (butof ilolol) ; (1- (carbazol-4-yloxy) -3- (isopropylamino) -2-propanol) (carazolol) ; (5- (3- tert. butylamino -2-hydroxy) propoxy- 3 ,4-dihydrocarbotyril HCl) (carteolol) ; (1-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-proρanol) (clorano- lol) ; • (l-(inden-4(or 7)-yloxy)-3-(isopropylamino) -2-propanol HCl) (indeno- lol) ; (1- isopropylamino- 3- [ (2-methylindol-4-yl)oxy] -2-propanol) (mepindo- lol) ; (1- (4-acetoxy-2, 3 , 5- trimethylphenoxy) -3- isoprop laminopropan-2-ol) (metipranolol) ; (1- (isopropylamino) -3- (o-methoxyphenoxy) -3- [ (1-me thyle th l.) amino] -2- propanol) (moprolol) ; ((1-tert .butylamino) -3-[(5 r 6,7, 8- tetrahydro-cis -6 , 7-dihydroxy-l- naphthyl)oxy] -2-propanol) (nadolol) ; ((S)-l- (2-cyclopentylphenoxy) -3- [ (1,1 -dime th le th l) amino] -2-propanol sulf te (2:1)) (penbutolol) ; (4' - [l-hydroxy-2- (amino)ethyl]methanesulfonanilIde) (sotalol) ; (2-methyl-3- [4- (2-hydroxy-3-tert .butylaminopropoxy) phenyl] -7-aethoxy- isoquinolin-1- (2H) -one) ; (1- (4- (2- (4-fluorophenyloxy)ethoxy)phenoxy) -3 -isopropylamino- 2-ρroρanol HCDΓ ((-)-p-[3-[(3 ,4-dlmethoxyphenethyl)amino] -2-hydroxypropoxy] -^-methyl- cinnamonltrile) (pacrlnolol) ; ((±) -2-(3' -tert.butylamino-2' -hydroxypropylthio)-4-(5' -carbamoyl-2' - thienyl)thiazole HCl) (arotinolol) ; ((±)-l-[p-[2-(cyclopropyl ethoxy)ethoxy]phenoxy] -3-(isopropylamino)-2- propancl) (cicloprolol); ((±) -1-[ (3-chloro-2-methylindol-4-yl)oxy] -3-[(2-phenoxye hyl)amino] -2- propanol) (indopanolol) ; ( (±) -6- [ [2- [ [3- (p-butoxyphenoxy) -2-hydroxypropyl]amino]ethyl]amino 1,3-dimethyluracil) (pirepolol) ; (4- (cyclohexylamino) -1-(1-naphtholenyloxy)-2-butanol) ; (1-phenyl-3- [2- [3- (2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hyda toin HCl) ; (3 ,4-dihydro-8- (2-hydroxy-3-isopropylaminopropoxy) -3-nitroxy-2H- benzopyran) (nipradolol) ; Angiotensin I Converting Enzyme Inhibitors: 1- (3-mercapto-2-methyl-l-oxoproρyl)÷-L-proline (captopril) ; (1- (4-ethoxycarbonyl-2 ,4(R,R) -dimethylbutanoyl)indoline-2(S) -ca boxylic acid) ; (2- [2- [(l-(ethoxycarbonyl)-3-phenyl-propyl]amino] -1-oxopropyl] -1,2,3, tetrahydro-3-isoquinoline carboxylic acid); ((S)-l-[2-[(l- (ethoxycarbonyl) -3-phenylpropyl]amino] -1-oxoρropyl]o tahydro-lH-indole-2-carboxylic acid HCl); (N-cyclopentyl-N- (3- (2, 2-dimethyl-1-oxopropyl)thiol-2-me hyl-1-ox propyl)glycine) (pivalopril) ; ( (2R.4R) -2- (2-hydroxyphenyl) -3-(3-mercaptopropionyl)-4-thiazolidin carboxylic acid) ; (1-(N- [1(S) -ethoxycarbonyl-3-phenylpropyl] -(S)-alanyl) -cis,syn-oct hydroindol-2(S)-carboxylic acid HCl); ((-)-(S)-l-[(S) -3-mereapto-2-methyl-1-oxopropyl]indoline-2-carboxyl acid) ; ( [1(S) ,4S] -1- [3- (benzoylthio) -2-methyl-1-oxoρropyl] -4-ρhenylthio- proline; (3- ( [1-ethoxycarbonyl-3-phenyl- (IS)-propyl]amino)-2,3,4,5-tetrahydr 2-oxo-l-(3S)-benzazepine-1-acetic acid HCl); (N- (2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-meth analogue; (N-(1(S) -ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleat (enalapril) ; N- [1-(S)-carboxy-3-phenylpropyl] -L-alanyl-1-proline; N - [1- (S)-carboxy-3-phenylpropyl] -L-lysyl-L-proline (lysinopr-j.1) ; Other Antihypertensive Agents: a inophylline; cryptenami acetates and tannates; deserpidine; mere ethoxylline procaine; pa gyline; tri-methaphan camsylate; and the like, as well as admixtur and combinations thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Coadministration is most readily accomplished by combining the active ingredients into a suitable unit dosage form containing the proper dosages of each. Other methods of coadministra¬ tion are, of course, possible. The compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Exam- pies. In the charts, Ph is used to represent the phenyl ring. Chart A The synthesis of both (Z) and (E) cyclopropylphenylalanine derivatives is reported in the literature and is outlined in Chart A. The (Z) benzyldineoxazoline A-2 is prepared from hippuric acid A-l via an Org. Syn. procedure, J.S. Buck and W.S. Ide, Org. Syn., Coll. Vol. II, 55 (1943). A standard means of isomerizing (Z) arylidineoxazolones is with saturated hydrobromic acid, Y.S. Rao, Synthesis, 1975:749 (1975). Treatment of the (Z) isomer A-2 suspended in hydrobromic acid saturated with hydrogen bromide at 0 β C in the light overnight affords the (E) isomer A-3. Various literature reports describe the addition of diazomethane to the benzilidineoxazolones. S.W. King, J.M. Riordan, E.M. Holt, and CH. Stammer, J. Org. Chem., 47:3270 (1982). Also see CH. Stammer, CA 103(25) 215811w. I. Arenal, M. Bernabe, E. Fernandez-Alvarez, M.L. Izquierdo, and S. Penades, J. Heterocyclic Chem., 20:607, 1983; and I. Arenal, M. Bernabe, E. Fernandez-Alvarez, and S. Penades, Synthesis, 1985:773, 1985. Using the procedure of Stammer, excess diazomethane in ether is added to the pure (Z) Isomer A-2 in methylene chloride and stirred at ambient temperature overnight. This reaction affords (Z)-2- phenyl-4-(l-methylbenzylidene)-5(4H)-oxazolone A-4, (Z)-l,5-diphenyl-6- oxa-4-azaspiro(2.4) hept-4-en-7-one A-6 as the major product, and, in some cases, (E)-1,5-diphenyl-6-oxa-4-azaspiro(2.4)hept-4-en-7-one A-7. Each of these products is separated by silica gel chroma ography using toluene as the eluent. The diazomethane addition to (E) benzilidine oxazolone A-3 affords the (E) cyclopropyl product A-7 as the major product, (E)-2-phenyl-4- (l-methylbenzylidene)-S(4H)-oxazolone A-5, and, in some cases, the (Z) cyclopropyl product A-6. Charts B and C In Chart B, the A-6 compound of Chart A is employed as the B starting material. In Chart C, the A-7 compound of Chart A is employ as the C-l starting material. For both stereoisomers, the oxazolone B-l or C-l is opened with dimethylaminopyridine in methanol to afford the compounds B-2 or C- This is followed by removal of the benzoyl group with freshly prepar Meerwein's salt via the procedure of Stammer (S.W. King, J.M. Riorda E.M. Holt, and CH. Stammer, J. Org. Chem., 47:3270, 1982; also s CH. Stammer, CA, 103(25) :215811w) to afford the compounds B-3 or C- The amine is protected with a Boc group and the ester saponified afford the compounds B-4 or C-4. The cyclopropyl amino acids B-4 or C-4 are incorporated into peptide using standard coupling procedures. Should the peptide exi in a protected form, the protecting groups are removed prior coupling. For example, a Boc group is removed from an N-terminus wi trifluoroacetic acid in methylene chloride and then the cycloprop amino acid is introduced. After coupling, any remaining protecti groups are removed under standard conditions. For example a tos group is removed from histidine using 1-hydroxybenzotriazole dimethylformamide. Chart D The phenylalaninol of formula D-l is commercially availabl Treatment of phenylalaninol of formula D-l with Boc anhydride tetrahydrofuran at room temperature affords the compound of formula D as a white crystalline solid. Hydrogenation of the phenyl ring affected with 5% Rh/Al in ethanol under 50 PSI for two days and affor the compound of formula D-3. Sulfur trioxide (3 equivalents) in DM is added to a solution of the alcohol of formula D-3 and triethylami (TEA) (3 equivalents) in DMSO maintaining the reaction temperature 25°C to afford the aldehyde of formula D-4. This aldehyde is worked cold, the solvent evaporated at 30°C, and is quickly used in the ne step. When the crude aldehyde of formula D-4 is added to the Grigna reagent [of l-bromo-2-methylproρene at -10°C, the allylic alcohol o formula D-5 is obtained after column chromatography. This material b H-NMR and ^C-NMR is a 6/1 threo/erythio mixture of diastereomers The allylic alcohol of formula D-5 is protected as its acetonide o formula D-6 by standard procedures. Cyclopropanation by adding 5 equivalents of ethyl diazoacetate to the neat olefin of formula D-6 and anhydrous copper or palladium catalyst at 90"C affords five diastereomeric cyclopropane products. These cyclopropanes are separated into 3 fractions via chromatography, which are referred to as fractions A, B and C from least to most polar. Fraction A is a single diastereomer. This material is a waxy solid with a melting point of 50-64°C Fraction B is a 5/2 mixture of two diastereo ers designated b- j _ and b 2 . Fraction G which is also a solid is a 7/5 mixture of two diastereomers designated c^_ and c 2 . All of these fractions have M+l molecular ions in their FAB mass spectra with the theoretical high resolution mass. Their IR and ■ '-H-NMR look practically identical. The separate diastereomers can be observed in the -"C-NMR. The two major diastereomeric cyclopropane products are formula D-7a and D-7bl, with the more polar one being preferred for the further reactions described below. Any of these diastereomeric cyclopropane products can be utilize in the following reaction steps to achieve the peptides of this invention. The trans diastereomeric cyclopropane products are pre- ferred. Fraction B Is treated with catalytic tosic acid in methanol a 60°C to remove the acetonide and to afford the alcohol of formula D-8. The compound of formula D-8 Is saponified using 50% methanol/2N LiO (aq) at 40°C to afford the acid of formula D-9. The D-9 acid and isoleucyl-2-pyridyl-methylamide are coupled i dimethylformamide (DMF) using diethylcyanophosphonate and triethylamin (TEA) to afford the D-10 compound. The D-10 compound is dissolved i me hylene chloride/trifluoroacetic acid (TFA) at -20°C and stirred fo 19 h. Work-up with saturated sodium bicarbonate yields the amin intermediate of formula D-11 which is coupled to Boc-His(Tos) in DMF i the presence of diethylcyanophosphonate and TEA to yield the compoun of formula D-12. Deprotection of the compound of formula D-12 is conducted in th same manner as described above for the compound of formula D-10 and th resulting amine of formula D-13 is coupled to Boc-Phe, In the sam manner as described above for the compound of formula D-11, to yiel the compound of formula D-14. The Tos group is removed from the compound of formula D-14 b treatment with 1-hydroxybenzotriazole in methanol to yield the fin product of formula D-15. Chart E Chart E describes the preparation of peptides of this inventi containing two cyclopropyl amino acid groups. The intermediate of formula E-l, prepared in Chart D as t compound of formula D-13, is coupled to (Z) -2-phenyl-l- (Boc)aminocycl ρropane-1-carboxylic acid in the presence of diethylcyanophosphona and diisopropylethylamine in methylene chloride to yield two maj isomers of the compound of formula E-2. (Both R and S are present The more polar isomer is treated with 1-hydroxybenzotriazole methanol to effect removal of the Tos group to yield the compound formula E-3. Chart F The synthesis of the cyclobutane transition state inserts orig nates with the olefin of formula F-1, prepared as the compound formula D-5 in Chart D. Conversion of the compound of formula F-1 the allylic ester of formula F-2 is accomplished in straightforwar fashion via esterification. The compound of formula F-2 is submitted t a photochemical 2+2 cycloaddition. M. Tanaka et al. , Tetrahedro Letters (1985) 3035. Both the compounds of formula F-3a and F-3b ar formed in 'the cycloadditon reaction and are separable by chromato graphic me ns. Treatment of the compound of formula F-3a with hy droxide first opens the lactone and secondly results in the epimeriza tion of the acid group to give the desired product of formula F-4a (sy isomer) . Treatment of the crude reaction with anhydrous acid the effects lactonization of any cis hydroxy acid that may be present an thus provides a means of separating isomers. The acid of formula F-4 is then ready for further C-terminal coupling. Treatment of th compound of formula F-3b under identical conditions leads to th compound of formula F-4b (anti isomer) . Following procedures analogou to those described in Chart D starting withi, the compound of formula D 9, the compounds of formula F-4a and F-4b can be converted to th peptides of the present invention. Chart G Chart G illustrates an additional method for the synthesis of th cyclobutane transition state inserts. The trans olefin of formula G- is generated via a Wittig reaction, i.e., reaction of the compound o formula G-l, prepared as the compound of formula D-4 in Chart D, with Ph3P-C(CH 2 )3C0 2 R. Epoxidation of the compound of formula G-2, using the directing influence of the protected nitrogen, provides the desired epoxide of formula G-3. Deprotonation of the compound of formula G-3 effects an intramolecular cyclization giving rise to the desired target "compound of formula G-4. Following procedures analogous to those described in Chart D starting with the compound of formula D-9, the compound of formula G-4 (wherein R is hydrogen) can be converted to the peptides of the present invention. Also, following procedures analo- gous to those described in Charts G and D, peptides of the present invention containing cyclopentyl and cyclohexyl transition state inserts may be prepared. Chart H Chart H illustrates another method for the synthesis of the cyclobutane transition state inserts. Addition of ylid P(Ph)3=CCH2C≡C to the compound of formula H-l, prepared as the compound of formula D-4 In Chart D, affords the enyne of formula H-2. Carbomethoxylation o the compound of formula H-2 gives the compound of formula H-3 whic upon addition of lithium dimethyl cuprate, and then a higher order cuprate, B.H. Lipshutz et al. , Tetrahedron (1984) 40, 5005 and refer¬ ences therein, for the introduction of the second methyl group, yields the compound of formula H-4. Direct epoxidation of the olefin o formula H-4, or epoxide introduction via iodocarbamatlon, M. Hirama e al., Tetrahedron Letters (1984) 4963, to give an intermediate such as the compound of formula H-5, provides the desired epoxide of formula H- 6 with the correct stereochemistry. Cyclization of the compound o formula H-6 then affords the final product of formula H-7. Followin procedures analogous to those described In Chart D starting with th compound of • formula D-9, the compound of formula H-7 (wherein R is hydrogen) can be converted to the peptides of the present invention. Charts G and H described above provide entry to the syn series. To approach the anti series, the cis olefins corresponding to formul G-2 and H-2 must be used. In the cyclopropane, cyclobutane, cyclopentane, and cyclohexan cases, these transition state inserts can readily be coupled to amin acids to build the desired peptides through the use of standar procedures. Generally, the renin Inhibiting polypeptides may be prepared b either polymer assisted or solution phase peptide synthetic procedure analogous to those described hereinafter or to those methods known i the art. For example, the carboxylic moiety of N 01 -t-butyloxycarbony (Boc) -substituted amino acid derivatives having suitable side chai protecting groups, if necessary, may be condensed with the amino func tionality of a suitably protected amino acid, peptide or polymer-boun peptide using a conventional coupling protocol such as dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethyl phosphoryl cyanide (DEPC) and triethylamine (E 3N) in methylen chloride or dimethylformamide. The synthetic procedures used to in corporate the novel moieties herein are analgous to those described for example, in U.S. patents 4,424,207; 4,470,971; 4,477,440 4,477,441; 4,478,826; 4,478,827; 4,479,941; and 4,485,099, and copend ing application Serial No. 753,198, filed 9 July 1985, and copendin application Serial No. 825,250, filed 3 February 1986, all of which ar expressly incorporated by reference herein. See, also, publishe European patent applications 45,161; 45,665; 53,017; 77,028; 77,029 81,783; 104,041; 111,266; 114,993; and 118,223. Following coupling reaction completion, the Ϊ^-Boc moiety may b selectively removed with 45% trifluoroacetlc acid with or without 2 anisole (v/v) in methylene chloride. Neutralization of the resultan trifluoroacetate salt may be accomplished with 10% diisopropylethyl amine or sodium bicarbonate in methylene chloride. In the case o polymer-assisted peptide synthesis, this stepwise, coupling strateg may be partially or completely automated to provide the desire peptide-polymer intermediates. Anhydrous hydrofluoric acid treatmen of the peptide-polymer intermediate may then be used to effect simul taneous protecting group removal and cleavage of the peptide from it polymeric support. A notable exception to this includes N ιn -formyl Indolyl-substituted peptides in which the N xn -formyl-indolyl moiety i stable to TFA or HF but may be removed by NH3 or NaOH. Because FTrp i somewhat unstable to base in synthetic procedures, possibly causin lower yields, it may be desirable in solution phase synthesis t introduce the FTrp-containing moiety late in " the synthetic sequence s that it is not exposed to such conditions. The incorporation of N ιn -formyl-Trp into compounds of the present invention is easily accomplished because of the commercial availability of N α -Boc-N :ι - n -formyl-Trp-OH. However, the N ln -formyl moiety may be introduced into indolyl-substituted amino acid derivatives or relate compounds by reaction with HCl-formic acid as reported in the litera ture, see A. Previero et al, Biochim. Biophys. Acta 147, 453 (1967); Y.C.S- Yang et al, Int. J. Peptide Protein Res. 15, 130 (1980). Generally, methods of alkylation useful in alkylating histidin for use in the present invention are found in Cheung, S.T. et al, Can. J. Chem., Vol 55, pp. 906-910 (1977). However it is now foun that in Cheung, S. T. et al, methods it is critical that the reactio conditions for the alkylation of histidine be anhydrous. Further, i is now found also that during work-up instead of adding water directl to the reaction mixture, It Is preferred that a buffered aqueou solution be added to the reaction mixture, for example, aqueous sodiu or potassium hydrogen sulfate. Variations in the above description for starting materials reactants, reaction conditions and required protecting groups to obtai other such N-alkylated compounds are known to an ordinarily skille chemist or are readily available in the literature. These peptides may also be prepared by the standard solid phas techniques of Merrifleld. Appropriate protecting groups, reagents, an solvents for both the solution and solid phase methods can be found i "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5 eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983. The compounds of the present invention may be in either free for or In protected form at one or more of the remaining (not previousl protected) peptide, carboxyl, amino, hydroxy, or other reactiv groups. The protecting groups may be any of those known in th polypeptide art. Examples of nitrogen and oxygen protection groups ar set forth in T.W. Greene, Protecting Groups in Organic Synthesis Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups i Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin Organic Synthesis, Verlag Chemie (1983). Included among the nitroge protective groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like. DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Preparations and Examples illustrate the presen invention. In the Preparations and Examples below and --throughout thi document: Ac is acetyl; AMP is 2-(aminomethyl)pyridinyl; BOC is t-butoxycarbonyl; BOM is benzyloxymethyl; Bz is benzyl; C is centigrade; Celite is a filter aid; CVDA is "Cha-Val diol" where Cha is 3-cyclohexylalanyl, i.e. t moiety of the formula XLg wherein R^ is cyclohexyl and R ] _ isopropyl and the configuration at each carbon atom with a is (R); DCC is dicyclohexylcarbodiimide; DMF is dimethylformamide; EtOAc is ethyl acetate; g. is grams; GEA is 2-(quanidylethyl)amino; GMPMA is (3-(guanidylmethyl)phenyl)methylamino; HPLC is high performance liquid chromatography; 12 is iodine; IR is infra red spectra; A Lindlar catalyst is a modified 5% palladium on calcium carbonate catalyst obtained from Engelhard Industries and used for reduction; LVDA is "Leu-Val diol," i.e., the moiety of the formula XL wherein R and R ] _ are isopropyl and the configuration a each carbon atom with a * is (R) ; M or mol is mole; MBA is 2-methylbutylamino (racemic or optically active) ; MBAS is 2S-methylbutylamino; Me is methyl; min. is minute; ml is milliliter; MS is mass spectroscopy; NMHis is N -methyl-L-histidine; NMR is nuclear magnetic resonance; NOAl is (l-naphthyloxy)acetyl; p-TSA salt is para-toluene sulfonic acid salt; Ph is phenyl; POA is phenoxyacetyl; RIP means a compound having the formula H-Pro-His-Phe-His-Phe- Phe-Val-Tyr-Lys-0H.2(CH 3 C(0)0H) .XH2O which is a known renin- inhibiting peptide. Skellysolve B is as defined in the Merck Index, 10th edition; TBDMS is t-butyldimethylsilyl; TFA is trifluoroacetic acid; THF Is tetrahydrofuran; TLC is thin layer chromatography; Tos is p-toluenesulfonyl; Tr is trityl (triphenylmethyl) ; 2HPA Is (±) - (2-hydroxypropyl)amino; and UV is ultraviolet. The wedge-shape line indicates a bond which extends above th plane of the paper relative to the plane of the compoun thereon. The dotted line indicates a bond which extends below the plane o the paper relative to the plane of the compound thereon. Preparation 1 (Z) 2-Phenyl-4-benzylidene-5(4H)-oxazolone (Formula A- 2) Refer to Chart A. Benzaldehyde (51 g) , hlppuric acid (96 g) , and sodium acetat (arih. 40 g) are suspended in acetic anhydride (140 ml) in a 1 Ehrlenmeyer flask. This is heated on a hot plate with shaking. Afte becoming a solid mass, it begins liquifying. Once all of the materia is a yellow liquid, the flask is maintained at 100°C for 2 hours. Ethanol (200 ml) is added at 0°C. After sitting overnight, th crystals are collected and washed two times with 50 ml of cold ethano and boiling water to afford 88.25 g of crude material. This yellow solid is dissolved in hot benzene (600 ml) an filtered through sodium sulfate. After sitting at 4 β C, 64.5 g o yellow crystalline title product is collected. Physical characteristics are as follows: Mp: 163-166°C Silica gel TLC: Rf-0.5 in benzene. IR (cm "1 , mull): 2954, 2926, 2855, 1797, 1655, 1492, 1450, 1329, 1297, 1169, 869, 768, 699, 687. ^-NMR (δ , CDCI3): 8.25-8.11, 7.53-7.41, 7.23. UV (λ maχ ): 223, 240, 246, 261, 292, 330, 348, 362, 381. Mass spectrum found: 249.0793; (ions at m/e) : 250, 249, 11 106, 105, 89, 77, 51, 38. Anal, found: C, 76.58; H, 4.55; N, 5.54. Preparation 2 (E) 2-Phenyl-4-benzylidene-5(4H) -oxazolone (Formula 3) Refer to Chart A. Hydrobromic acid (167 ml) is added to the (Z)-oxazolone Preparation 1 (10 g) at 0°C Anhydrous hydrogen bromide is bubbl through this suspension for 30 min. After standing at 4°C under lig overnight, the reaction suspension is poured over ice, filtered and t yellow solid washed with ice water. The solid is dissolved in eth acetate and dried over magnesium sulfate to afford 9.2 g of the tit product. Physical characteristics are as follows: Mp: 145-147°C Silica gel TLC: Rf=0.4 in benzene. IR (cm "1 , mull): 2954, 2926, 2870, 2855, 1799, 1772, 1647, 145 1369, 1326, 1296, 1227, 1156, 1118, 1008, 899, 777, 760, 700, 685, 63 X H-NMR (δ, CDC1 3 ): 8.21-8.02, 7.56-7.25. UV (λ maχ ): 225, 239, 246, 261, 292, 348, 362, 380. Mass spectrum (ions at m/e): 249, 116, 106, 105, 89, 77, 76, 6 51, 50. Anal found: C, 76.25; H, 4.56; N, 5.53. Preparation 3 (Z) -2-Phenyl-4- (1-methylbenzylidene)-5(4H) -oxazolon (Z) -1, 5-Diρhenyl-6-oxa-4-azaspiro(2.4)hept-4-en-7-on and (E)-l,5-Diphenyl-6-oxa-4-azaspiro(2.4)hept-4-en-7 one (Formulas A-4, A-6 and A-7) Refer to Chart A. Diazomethane (formed from 30 g of N-methyl-N' -nitro-N-nitroso guanidine over 160 ml 45% potassium hydroxide in 400 ml ether and drie over potassium hydroxide pellets) is added to a solution of the titl product of Preparation 1 (12 g) in methylene chloride (200 ml) a ambient temperature. Nitrogen evolution is immediate. After stirrin overnight, excess diazomethane is destroyed by adding solid calciu chloride. Filtration and evaporation of the filtrate affords 19.8 g o crude product. Flash chromatography over silica gel (1.2 kg, toluene) afford 1.24 g of a mixture of starting material and the first title product Further elution affords 2.59 g of the first title product. An analyti cal sample is prepared by recrystallization from methylene chloride t give yellow crystals. Physical characteristics are as follows: Mp: 101-104°C Silica gel TLC: R j -0.45 in benzene. IR (cm *1 , mull): 2954, 2926, 2869, 2856, 1784, 1761, 1649, 163 1452, 1329, 1299, 1194, 971, 768, 701. l-H-NMR (δ, CDC1 3 ): 8.12-8.09, 8.05-8.00, 7.52-7.19, 2.79. UV (λ maχ ): 242sh, 247, 255, 334sh, 345. Mass spectrum found: 263.0953; (ions at m/e): 263, 106, 10 103, 78, 77, 76, 63, 51, 50. Anal, found: C, 77.21; H, 4.89; N, 5.26. Further elution affords 5.36 g of the second title product. analytical sample is prepared by recrystallization from methyle chloride/hexane to give the crystalline form. Physical characteristics are as follows: Mp: 145-146°C Silica gel TLC: Rf-0.4 in benzene. IR (cm , mull).: 2954, 2925, 2855, 1805, 1635, 1453, 1322, 125 1017, 994, 985, 877, 710, 696, 689. T-H- R (δ, CDCI3): 7.98-7.85, 7.47-7.30, 3.22, 2.36, 2.25. UV (λ maχ ): 205, 236, 264, 270. Mass spectrum (ions at m/e): 263, 219, 218, 130, 115, 106, 10 78, 77, 51. Anal, found: C, 77.14; H, 4.99; N, 5.32. Further elution affords 1.90 g of the third title product. analytical sample is prepared by recrystallization from methyle chloride/hexane to give the crystalline form. Physical characteristics are as follows: Mp: 119-120°C Silica gel TLC: Rf=0.25 in benzene. IR (cm "1 , mull): 2954, 2925, 2855, 1805, 1797, 1636, 1451, 132 1303, 1036, 1016, 1001, 981, 874, 776, 720, 692. ^-N R (δ, CDCI3): 8.04-7.92, 7.53-7.45, 7.32, 3.53, 2.44, 2.32 UV (λ maχ ): 270. Mass spectrum (ions at m/e): 263, 219, 130, 115, 106, 105, 10 78, 77, 51. Anal, found: C, 77.21; H, 5.13; N, 5.24. Preparation 4 (E) -2-Phenyl-4- (1-methyϊbenzylidene)-5(4H)-oxazolon and (E) -l,5-Diphenyl-6-oxa-4-azaspiro(2.4)hept-4-en- one (Formulas A-5 and A-7) Refer to Chart A. Diazomethane (formed from 30 g of N-methyl-N' -nitro-N-nitros guanidine over 160 ml 45% potassium hydroxide in 400 ml ether and dri over potassium hydroxide pellets) is added to a solution of the tit product of Preparation 2 (12 g) in methylene chloride (200 ml) ambient temperature. Nitrogen evolution is immediate. After stirri overnight, excess diazomethane is destroyed by adding solid calci chloride. Filtration and evaporation of the filtrate affords 15.1 g crude product. Flash chromatography over silica gel (800 g, toluene) affords 0. g of the first title product. An analytical sample is prepared recrystallization from methylene chloride/hexane to give the crysta line form. Physical characteristics are as follows: Mp: 114-115°C Silica gel TLC: Rf=0.4 in benzene. IR (cm' 1 , mull): 2954, 2925, 2869, 2855, 1790, 1653, 1450, 144 1290, 1202, 1059, 883, 763, 695, 685. T-H-NMR (δ, CDC1 3 ): 8.16-8.04, 7.59-7.35, 2.66. UV (λ maχ ): 239, 245, 341. Mass spectrum (ions at m/e): 264, 263, 106", 105, 103, 78, 77, 7 51, 50. Anal, found: C, 77.17; H, 5.17; N, 5.35. Further elution affords 8.05 g of the second title product. Preparation 5 Methyl (Z)-2-phenyl-1-benzamidocyclopropane-1-carbox late (Formula B-2) Refer to Chart B. 4-Dimethylaminopyridine (5.32 g) is added to a solution of th second title product of Preparation 3 (11.2 g) in absolute methano (300 ml) . After stirring at ambient temperature until everything is i solution (110 min) , the solution is evaporated in vacuo. The residu is transferred in methylene chloride to a separatαry funnel containin 5% citric acid. Extracting two times with methylene chloride an filtering the combined organic layers through sodium sulfate afford 13.0 g of crude product after evaporation of the solvent. Recrystallization from methylene chloride/hexane affords 10.68 of the title product. Flash column chromatography of the mothe liquors (200 g 'silica gel, ether) affords an additional 0.73 g. Physical characteristics are as follows: Mp: 164-166.5°C Silica gel TLC: Rf-0.5 in ether. IR (cm" 1 , mull): 3275, 2950, 2923, 2867, 2855, 1716, 1667, 1648, 1552, 1455, 1437, 1338, 1274, 1162, 713, 696. -H-NMR (δ, CDC1 3 ): 7.40-7.25, 5. ' 96, 3.76, 3.05, 2.33, 1.86. UV (λ maχ ): 224, 271sl sh. Mass spectrum (ions at m/e): 295, 263, 191, 190, 130, 106, 105, 104, 103, 78, 77, 51. Anal, found: C, 72.74; H, 5.76; N, 4.72. Preparation 6 Methyl (E)-2-ρhenyl-l-benzamidocyclopropane-l-carboxy late (Formula C-2) Refer to Chart C 4-DimethylamInoρyridine (6.33 g) Is added to a solution of th second title product of Preparation 4 (13.3 g) in absolute methano (360 ml) . After stirring at ambient temperature until everything is i solution (130 min) , the solution is evaporated in vacuo. The residu is transferred in methylene chloride to a separatory funnel containin 5% citric acid. Extracting two times with methylene chloride an filtering the combined organic layers through sodium sulfate afford 14.8 g of crude product after evaporation of the solvent. Recrystallization from methylene chloride/hexane affords 12.44 of the title product. Flash column chromatography of the mothe liquors (200 g silica gel, ether) followed by recrystallization of th fractions containing the title product affords an additional 0.26 g. Physical characteristics are as follows: Mp: 194-197°C Silica gel TLC: in ether. IR (cm '1 , mull).: 3326, 2957, 2924, 2870, 2855, 1734, 1636, 1580, 1529, 1489, 1438, 1350, 1220, 1196, 1163, 1154, 730, 718, 701. ^- MR (δ, CDCI3): 7.90-7.77, 7.50-7.21, 6.94, 3.35, 2.98, 2.32, 1.73. UV (λ maχ ): 224. Mass spectrum (ions at m/e): 295, 191, 190, 130, 106, 105, 104, 103, 78, 77, 51. Anal, found: C, 72.80; H, 5.92; N, 4.63. Preparation 7 Methyl (Z)-2-phenyl-l-aminocyclopropane-l-carboxylate, hydrochloride (Formula B-3) Refer to Chart B. A solution of triethyloxonium tetrafluoroborate (Meerwein's salt freshly prepared and stored under ether at -15°C, 8.86 g) in methyle chloride (26 ml) is placed in a flame dried flask under nitrogen. this solution is added a suspension of the title product of Preparati 5 ('3.79 g) in methylene chloride (36 ml). After refluxing for 19 under nitrogen, the reaction solution is transferred to a separato funnel containing 0,93 M potassium dihydrogen phosphate (27 ml Extracting with methylene chloride and drying over magnesium sulfa affords 4.42 g of crude amine product after evaporation of the solven This is dissolved in ether (27 ml) and cooled to -25°C before addi hvdrochloride saturated ether (20 ml) and 1 N hydrochloric acid ( ml). After stirring at room temperature for 10 min, the aqueous lay is extracted twice with ether and lypholized to afford 2.79 g of cru product. Recrystallization from acetonitrile/ether affords 2.00 g the title product. Physical characteristics are as follows: Mp: 186-188°C IR (cm "1 , mull): 2954, 2920, 2869, 2855, 2820, 2680, 1734, 156 1461, 1440, 1312, 1211, 770, 722. ^-N R (δ, CDC1 3 ): 7.59, 3.84, 3.11, 2.19, 2.00. UV (λ maχ ): 218, 252, 259, 264. Mass spectrum (ions at m/e): 191, 159, 132, 131, 130, 117, 11 104, 103, 91, 77. Anal, found: C, 57.92; H, 6.06; N, 6.21. Preparation 8 Methyl (E) -2-phenyl-1-aminocyclopropane-1-carboxylat hydrochloride (Formula C-3) Refer to Chart C A solution of triethyloxonium tetrafluoroborate (Meerwein's sal freshly prepared and stored under ether at -15 0 C, 8.6 g) in methyle chloride (25 ml) is placed in a flame dried flask under nitrogen. this solution is added a suspension of the title product of Preparati 6 (3.68 g) in methylene chloride (35 al) . After refluxing for 23 under nitrogen, the reaction solution is transferred to a separato funnel containing 0.93 M potassium dihydrogen phosphate (27 ml) Extracting with methylene chloride and drying over magnesium sulfat affords 4.59 g of crude amine product after evaporation of the solvent This is dissolved in ether (27 ml) and cooled to -25°C before addin hydrochloride saturated ether (20 ml) and 1 N hydrochloric acid (5 ml). After stirring at room temperature for 1 h, the aqueous layer i extracted twice with ether and lypholized to afford" 2.60 g of crud product. Recrystallization from isopropanol/ether affords 2.35 g of the title product. Physical characteristics are as follows: Mp: 185-188 β C. IR (cm' 1 , mull): 2953, 2924, 2867, 2855, 1754, 1458, 1447, 1370, 1248, 1200, 1170, 773. ^-NM (δ, CDC1 3 ): 7.27, 3.39, 3.42, 2.27, 2.15, 1.72. UV (λ maχ ): 247, 254, 260, 266. Mass spectrum (ions at m/e): 191, 159, 132, 131, 130, 115, 104, 103, 91, 77, 51. Anal, found: C, 57.81; H, 6.32; N, 6.25. Preparation 9 (Z)-2-Phenyl-l-(tert-butyloxycarbonyl)aminocyclopropane- 1-carboxylic acid (Formula B-4) Refer to Chart B. A solution of the title product of Preparation 7 (3.47 g) in dioxane (106 ml) and water (45 ml) is adjusted to pH 8.0 with 2N sodium hydroxide. Di-t-butyl dicarbonate (6.62 g) is added portionwise over 1.5 h maintaining the pH at 8.0-8.5 with 2N sodium hydroxide as necessary. After stirring at ambient temperature for 22 h, the solution is cooled to 0°C and extracted two times with ether. Washing the combined organic layers with brine and filtering through sodium sulfate affords 6.46 g of crude boc methyl ester after evaporation of the solvent. Physical characteristics are as follows: X H-NMR (δ, CDCI3): 7.26, 4.56, 3.75, 2.94, 2.04, 1.65, 1.33. The crude methyl ester is dissolved in methanol (38 ml) and 2N sodium hydroxide (38 ml) . After stirring at ambient temperature for 21 h, the reaction solution is reduced to half volume in vacuo and the residue transferred to a separatory funnel with ethyl acetate/water. Acidification with 2N hydrochloric acid to pH 5, extracting with ethyl acetate, washing the combined organic layers with brine, and filtering through sodium sulfate affords 3.14 g of the title product after evaporation of the solvent. Physical characteristics are as follows: Mp: 200-203 β C IR (cm "1 , mull): 3345, 2954, 2926, 2870, 2855, 1691, 1657, 1649, 1460, 1453, 1444, 1410, 1367, 1270, 1170, 704. ^-NM (δ, CDCI3): 7.25, 4.68, 3.03, 2.13, 1.73, 1.32. UV (λ maχ ): 224, 259, 266, 273. Mass spectrum (ions at m/e): 221, 203, 159, 132, 131, 130, 104 103, 57, 41. Anal, found: C, 64.88; H, 6.88; N, 4.85. Preparation 10 (E)-2-Phenyl-l- (tert-butyloxycarbonyl)aminocyclopropane 1-carboxylic acid (Formula C-4) Refer to Chart C A solution of the title product of Preparation 8 (0.60 g) i dioxane (18 ml) and water (7.8 ml) is adjusted to pH 8.0 with 2N sodiu hydroxide. Di-t-butyl dicarbonate (1.14 g) is added portionwise over h maintaining the pH at 8.0-8.5 with 2N sodium hydroxide as necessary. After stirring at ambient temperature for 21 h, the solution is coole to 0°C and extracted two times with ether. Washing the combine organic layers with brine and filtering through sodium sulfate afford 1.01 g of crude boc methyl ester after evaporation of the solvent. Physical characteristics are as follows: ^-H-NMR (δ, CDC1 3 ): 7.26, 5.29, 3.69, 2.83, 2.17, 1.61, 1.48. The crude methyl ester is dissolved in methanol (6.5 ml) and 2 sodium hydroxide (6.5 ml). After stirring at ambient temperature fo 23 h, the reaction solution is reduced to half volume in vacuo and th residue transferred ■ to a separatory funnel with ethyl acetate/water. Acidification with 2N hydrochloric acid to pH 5, extracting with ethy acetate, washing the combined organic layers with brine, and filterin through sodium sulfate affords 0.60 g of the title product afte evaporation of the solvent. An analytical sample is prepared b recrystallization from ethyl acetate/hexane. Physical characteristics are as follows: M : 163-173°C decomposed. IR (cm '1 , mull): 3373, 2954, 2925, 2869, 2855, 1694, 1512, 1457, 1453,. 1310, 1252, 1164, 700. ^-NM (δ, CDCI3): 7.25, 3.30, 2.78, 2.15, 1.65, 1.48. UV (λ maχ ): 221, 258sh, 266, 273. Mass spectrum (ions at m/e): 221, 203, 159, 132, 131, 130, 77, 59, 57, 41. Anal, found: C, 64.96; H, 6.96; N, 5.30. Example 1 N α - [ (2S ,4S , 5S) -5- [N- [N 0 - [ (E) -2-Phenyl-l- (tert-butoxy- carbonylamino) cyclopropane-1-carbonyl] -L-histidyl] - amino] -4 -hydroxy- 2 -isopropyl -7 -methyl -1-oxooctyl] -N- (2- pyridinylmethyl) -L-isoleucinamide (Isomers A and B) 1. A solution of N-tert-butyloxycarbonyl-N lm -tosyl-L-histidyl- 5S-amino-2S-isopropy1-7-methyl-4S-tert-butyldiaethylsilyloxyoctanoyl- L-isoleucyl-2-pyridylmethylamide (see EP 0173.481A2, p. 100, C81) (0.068 g) in methylene chloride (0.5 ml), under a nitrogen atmosphere, is cooled in an ice bath and treated dropwise with trifluoroacetic acid (0.5 ml) . The mixture Is allowed to warm to room temperature and stirred for 1 hr, 5 mln; it is then concentrated in vacuo. The residue is dissolved in methylene chloride, washed with aqueous sodium bicar¬ bonate, dried over magnesium sulfate and concentrated to give 0.047 g of a gummy residue, N im -tosyl-L-histidyl-5S-amino-4S-hydroxy-2S- Isoproρyl-7-methyloctanoyl-L-isoleucyl-2-pyrIdylmethylamide, which is pure by TLC on silica gel with 5% methanol-0.5% ammonium hydroxide- methylene chloride. 2. A solution of the product prepared in paragraph 1 (0.047 g) in methylene chloride (6.5 ml) under a nitrogen atmosphere is treated with 0.025 g of d,l-(E) -2-phenyl-l-(tert-butoxycarbonyl)aminocyclopropane-l- carboxylic acid (prepared in Preparation 10) and then successively with triethylamlne (0.013 ml) and diethylcyanophosphonate (0.015 ml). The mixture is stirred at room temperature for 3 hr, 45 in, diluted with methylene chloride, washed with aqueous sodium bicarbonate, dried with magnesium sulfate and concentrated to give 0.075 g of a gummy residue. This material, is chromato raphed on silica gel (50 g) with 3.5% m thanol-0.35% ammonium hydroxide-methylene chloride; 4.7 ml fractions are collected. Isomer A is eluted from the column first in fractions 100-144 and amounts to 0.018 g. The high resolution FAB mass spectrum has [M + H] + at m/z 985. Theory for C 52 H 73 Ng0 9 S: 985.5221. Measured: 985.5243. Isomer B is eluted from the column in fractions 145-250 and amounts to 0.020 g. The high resolution FAB mass spectrum has [M + H] + at m/z 985. Theory for C 5 2H 7 3N 0 9 S: 985.5221.- Measured: 985.5195. 3. A solution of the product (Isomer A) prepared In paragraph 2 (0.018 g) in dimethylformamide (0.21 ml) and tetrahydrofuran (1.2 ml) under a nitrogen atmosphere is treated with 1-hydroxybenzotriazole (0.025 g) and stirred at room temperature for 20 hr. The mixture is concentrated in vacuo and the residue is chromatographed on silica gel (25 g) with 5% methanol-0.5% ammonium hydroxide-raethylene chloride; 5.4 ml fractions are collected. The titled product (Isomer A) is eluted in fractions 78-118 and amounts to 0.014 g. The high resolution FAB mass spectrum has [M + H] + at m/z 831. Theory for C 5 Hg 7 N g 0 7 : 831.5132. Measured: 831. 5112. 4. A solution of the product (Isomer B) prepared in paragrap (0.020 g) in dimethylforma ide (0.24 ml) and tetrahydrofuran (1.4 under a nitrogen atmosphere is treated with 1-hydroxybenzotriaz (0.028 g) and stirred at room temperature for 21. 5 hr . The mixture concentrated in vacuo to give a gummy residue (0.051 g) which chromatographed on silica gel (25 g) with 5% methanol-0. 5% ammon hydroxide-methylene chloride ; 5.4 ml fractions are collected. titled product (Isomer B) is eluted in fractions 104-146 and amounts 0.010 g . The high resolution FAB mass spectrum has [M + H] + at 831. Theory for C45H 7 N g 0 7 : 831.5132. Measured: 831.5112. Example 2 N α - [ (2S , 4S , 5S) -5- [N- [N°- [ (Z) - 2 -Phenyl-1- (tert-butoxy- carbonylamino) cyclopropane - 1 - carbonyl ] -L-histidyl amino ] -4 -hydroxy- 2 - isopropyl -7 -methyl - 1-oxooctyl] -N- ( pyridinylmethyl) -L- isoleucinamide (Isomers A and B) 1. A solution of N-tert-butyloxycarbonyl-N lm - tosyl-L-histid 5S - amino - 2S - isopropyl-7 -methyl-4S- tert-butyldimethylsilyloxyoctano L- isoleucyl-2-pyridylmethylamide (see EP 0173.481A2 , p . 100 , C8 (0.068 g) in methylene chloride (0. 5 ml) , under a nitrogen atmospher is cooled in an ice bath and treated dropwise with trifluoroacetic ac (0. 5 ml) . The mixture is allowed to warm to room temperature a stirred for 1 hr , 5 min; it is then concentrated in vacuo . The resid is dissolved in methylene chloride , washed with aqueous sodium bica bonate , dried over magnesium sulfate and concentrated to give 0.039 of a gummy residue , N lm -tosyl-L-histidyl- 5S-amino-4S-hydroxy-2 isopropyl-7-methyloctanoyl-L- isoleucyl-2-pyridylmethylamide , which pure by TLC on silica gel with 5% methanol-0.5% ammonium hydroxid methylene chloride . 2. A solution of the product prepared in paragraph 1 (0.039 g) methylene chloride (6.5 ml) under a nitrogen atmosphere is treated wi 0.025 g of d, 1- (Z) -2-phenyl-l- (tert-butyloxycarbonyl) aminocyclopropan 1-carboxylic acid (prepared in Preparation 9) and then successive with triethylamine (0.013 ml) and diethylcyanophosphonate (0.015 ml The mixture is stirred at room temperature for 2 hr , 20 min, dilut with methylene chloride , washed with aqueous sodium bicarbonate , dri over magnesium sulfate and concentrated to give 0.066 g of a gum residue . This material is chromatographed on silica gel (50 g) wi 3.5% methanol-0. 35% ammonium hydroxide-methylene chloride ; 5 fractions are collected. Isomer A is eluted in fractions 106-184 and amounts to 0.011 g. Isomer B Is eluted in fractions 198-330 and also amounts to 0.011 5- 3. A solution of the product (Isomer A) prepared in paragraph 2 (0.011 g) in dimeth lformamide (0.13 ml) and tetrahydrofuran (0.72 ml) under a nitrogen atmosphere is treated with 1-hydroxybenzotriazole (0.015 g) and stirred at room temperature for 17.5 hr. The mixture is concentrated and chromatographed on silica gel (25 g) with 5% methanol- 0.5% ammonium hydroxide-methylene chloride; 5 ml fractions are col¬ lected. The titled product (Isomer A) is eluted in fractions 69-100 and amounts to 0.009 g. The high resolution FAB mass spectrum has [M + H] + at m/z 831. Theory for C 5 Hg 7 N 0 7 : 831.5132. Measured: 831.5112. 4. A solution of the product (Isomer B) prepared in paragraph 2 (0.011 g) in dlmethylformamdie (0.13 ml) and tetrahydrofuran (0.72 ml) under a nitrogen atmosphere is treated with 1-hydroxybenzotriazole (0.015 g) and stirred at room temperature for 19 hr. The mixture is concentrated in vacuo to give 0.029 g of a residue which is chromato- graphed on silica gel (25 g) with 7% methanol-0.5% ammonium hydroxide- methylene chloride; 5.2 ml fractions are collected. The titled product (Isomer B) is eluted In fractions 64-95 and amounts to 0.008 g. The high resolution FAB mass spectrum has [M + H] + at m/z 831. Theory for C 5 Hg 7 Ng0 7 : 831.5132. Measured: 831.5151. Preparation 11 (S) -β-[((l,l-Dimethylethoxy)carbonyl)amino]phenylpro- panol (Formula D-2) Refer to Chart D. Phenylalaninol (40 g) in tetrahydrofuran (665 ml) is stirred under nitrogen at 0°C In an oven dried 3-neck 3 1 round bottom flask equipped with an addition funnel. Di-t-butyl dicarbonate (63.7 g) In tetrahy- drofuran (250 ml) is added over 30 min, after which the ice bath is removed. After stirring 4.25 h, the solvent Is removed in vacuo. Recrystallization from carbon tetrachloride/Skevfely B affords 59.3 g of the title product as white crystals. Physical characteristics are as follows: Mp: 96-98°C IR (cm '1 , mull): 3357, 3319, 2958, 2925, 2870, 2855, 1687, 1670, 1528 τ 1454, 1444, 1366, 1315-, 1270, 1253, 1185, 1170, 1007, 701. ^-H-NMR (CDC1 3 , δ): 7.32, 4.77, 3.82, 3.60, 2.77, 2.32, 1.40. UV λ maχ ( : 207, 238sl sh, 243sl sh, 248, 253, 258, 261sl s 264, 268. Mass spectrum: ions at m/e (relative intensity): 251, 164, 16 120, 104, 92, 91, 60, 59, 57, 40. Rotation: ( ) D - -24° (0.822, CHC1 3 ) . Anal. Found: C, 66.88; H, 8.34; N, 5.73. Preparation 12 (S) -β- [ ((1,l-Dimethylethoxy)carbonyl)amino]cyclohexane propanol (Formula D-3) Refer to Chart D. 5% Rhodium on alumina (6.57 g) is added to a solution of the tit product of Preparation 11 (57.8 g) in absolute ethanol (79 ml, heati necessary to obtain solution) . After this suspension is shaken und 50 lbs hydrogen for 4 days, it is filtered through Celite rinsing wi 600 ml ethanol. The filtrate is evaporated in vacuo to afford 61.25 of the title product. An analytical sample is prepared by Kugelro distillation (70-105°C at 1.8 mm Hg) . Physical characteristics are as follows: Silica gel TLC: Rf-0.25 in 25% EtOAc/SSB (ninhydrin spray). IR (cm '1 , mull): 3435, 3386, 2930, 2926, 2854, 1692, 1507, 1450 1393, 1367, 1265, 1247, 1172, 1077, 1061, 1050, 1030, 740, 705. iH- MR (CDCI3, δ): 4.63, 3.80-3.32, 2.40, 1.90-0.70, 1.46. UV λ maχ (ε) end absorption. Mass spectrum Found: 257.2001; ions at m/e (relative intensity) 170, 126, 86, 60, 57, 55, 44, 43, 40, 38. Rotation (α) D - 26° (.698, CHCI3) . Anal. Found: C, 65.02; H, 10.75; N, 5.23. Preparation 13 (S) - β-(((1 ; 1-Dimethylethoxy)carbonyl)amino)cyclo- hexanepropanal (Formula D-4) Refer to Chart D. A 2 1 3-neck round bottom flask equipped with an addition funnel nitrogen inlet, and a thermometer is flame dried and then charged wit the title product of Preparation 12 (33.68 g) in DMSO (366 ml) an triethylamine (55 ml). Sulfur trioxide pyridinium complex (62.64 g) i DMSO (366 ml) is added slowly over 70 min, using a cold water bath a necessary to maintain the reaction temperature at 25°C + 2°C Afte stirring 45 min, the reaction solution is poured over 600 ml of ice an then transferred to a separatory funnel. Extracting once with ethe and 2 times with ethyl acetate, washing the combined organic layers times with 10% citric acid, saturated sodium bicarbonate, and brine and drying over magnesium sulfate affords --32.62 g of crude titl product after evaporation of the solvent at 26-30°C This material is used within 3 h without further purification in subsequent steps. Physical characteristics are as follows: Silica gel TLC: Rf-0.35 In 15% ethyl acetate/SSB. ^-NMR (δ, CDC1 3 ): 9.68, 4.93, 4.23, 1.86-0.70, 1.45. Preparation 14 (S- (R*,R*) ) -(1-(Cyclohexylmethyl-2-hydroxy-4-methyl-3- pentenyl)-carbamic acid, 1,1-dimethyleth l ester (Formula D-5) Refer to Chart D. l-Bromo-2-methylpropene (17.7 g) is added dropwise to a refluxing mixture of Mg (turnings, 3.05 g) , 1,2-dibromo-ethane (.25 ml), and iodine (0.1 g) in tetrahydrofuran (135 ml). After refluxing until all of the magnesium is in solution (3.8 h) , the Grignard reagent is cooled to -10°C The title product of Preparation 13 (13.34 g) in tetrahydro¬ furan (70 ml) Is then slowly added over 55 min. After maintaining the reaction at -10°C for 40 min, the reaction mixture is poured into cold stirring saturated ammonium chloride. After stirring for 20 min, the reaction solution is transferred to a separatory funnel containing ether. Extracting with ether, washing the combined organic layers with saturated sodium bicarbonate and brine, and drying over magnesium sulfate affords 16.7 g of crude title product af er evaporation of the solvent. This material is used In the next step without further purification. An analytical sample Is prepared by adding a tenth of the crude title product to silica gel (150 g, 15% ethyl acetate/SSB, 35 ml fractions) to afford 0.96 g of the title product. Physical characteristics are as follows: Silica gel TLC: Rf=0.15 in 5% ethyl acetate/SSB. IR (mull, cm "1 ): 3440, 2977, 2923, 2853, 1717, 1695, 1502, 1449, 1392, 1366, 1248, 1173, 1044, 1022. X H-NMR (δ, CDCl 3 ):5.28 t 4.52, 4.28, 3.70, 1.90-0.70, 1.75, 1.70, 1.45. Mass spectrum (FAB) found: 312.2555 ; ions at m/e: 312, 239 , 238 , 194, 170 , 126 , 95 , 81 , 57 , 55 , 41. Rotation ( ) D *» -24° (0.751, chloroform) . Anal . Found: C , 69 . 17 ; H, 10.43 ; N, 4.41. Preparation 15 (4S - Trans ) -4- (cyclohexylmethyl) -2 , 2 -dimethyl- 5- (2 - methyl - 1 -propenyl) - 3 - oxazolidinecarboxylic acid , 1 , 1- dimethylethyl ester (Formula D-6) Refer to Chart D. 2-Methoxypropene (30.2 g) is added to a stirring solution of the- title product of Preparation 14 (13.36 g) in methylene chloride (8 ml). Pyridinium-p- oluene sulfonate (0.53 g) is added and the reactio stirred at ambient temperature for 7.5 h. The reaction is quenche with solid sodium bicarbonate. After filtering, the filtrate i evaporated to afford 18.7 g containing the crude title product. Flash chromatography over silica gel (800 g, 0-2% ethyl ace tate/SSB) affords 6.50 g of the title product. Physical characteristics are as follows: Silica gel TLC: Rf=0.5 in 5% ethyl acetate/SSB. IR (mull, cm "1 ): 2978, 2926, 2853, 1700, 1449, 1387, 1375, 1365 1255, 1206, 1178, 1144, 1108, 1087, 1080, 1046, 770. X H-NMR (δ, CDC1 3 )(2 diastereomers 85/15): 5.31, 4.72, 4.50, 3.67 1.8-0.7, 1.77, 1.76, 1.57, 1.50. UV λ max (ε): 228, 236 si sh. Mass spectrum ions at m/e: 351, 336, 280, 267, 236, 194, 166 126, 111, 57, 55, 41. Mass spectrum (FAB) ions at m/e: 353, 352, 297, 296, 238. Rotation (α) D = -2° (0.716, chloroform). Anal. Found: C, 71.79; H, 10.68; N, 3.89. Preparation 16 (4S-(4a, 5b(lS*,3R*))) 4-(Cyclohexylmethyl) -5-(3-(ethoxy carbonyl) -2 ,2 -dimethylcyclopropyl) -2 , 2-dimethyl-3 oxazolidinecarboxylic acid, 1,1-dimethylethyl este (Formula D-7a); (4S- (4a,5b(lR*))) 4- (Cyclohexyl-methyl) 5- (3- (ethoxycarbonyl) -2, 2-dimethylcyclopropyl) -2,2 dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethy ester (Formula D-7b); and (4S-(4a,5a)) 4-(Cyclohexyl¬ methyl) -5- (3- (ethoxycarbonyl-2,2-dimethylcyclopropyl) - 2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethyl¬ ethyl ester (Formula D-7c) Refer to Chart D. The title product of Preparation 15 (13.6 g) and anhydrous copper sulfate (kept in drying oven at 110°C, 78 mg) is stirred at 90°C under vacuum for 40 min. The reaction is then placed under nitrogen and ethyl diazoacetate (20.33 ml) is slowly added over 2 hours with the reaction temperature maintained at 90°C. This material is then allowed to cool to ambient temperature and added to a column. Flash chromatography over silica gel (800 g, 1.5% EtOAc/SSB, 300 ml fractions) affords 0.98 g of starting material (fractions 23-27). Further elution affords 7.37 g of starting material and cis-diethyl- maleonate (fractions 28-46). Further elution affords 1.96 g of the title product D-7a (fractions 86-95). Physical characteristics are as follows: Mp: 50-64°C Silica gel TLC: Rf-0.3 in 5% EtOAc/SSB. IR (cm" 1 , mull): 2976, 2952, 2926, 2855, 1729, 1715, 1698, 1456, 1447, 1389, 1377, 1363, 1202, 1185, 1172, 1095, 1055, 769. ^-H-NMR (CDC1 3> δ): 4.25, 3.5, 3.20, 1.9-1.0, 1.45, 1.28, 1.25, 1.21. 13 C-NMR (CDC1 3 , pp ): 171.08, 151.22, 93, 80.5, 79.1, 60.4, 59.8, 41.1, 37.0, 35.1, 33.8, 31.9, 31.6, 28.0, 26.0, 25.9, 25.6, 21.4, 20.0, 13.8. UV λ maχ (ε): 276 sh. Mass spectrum (FAB) found: 438.3189; ions at m/e: 438, 392, 380, 338, 324, 196, 95, 81, 58, 57, 55, 41, 29. Rotation (c-) n - 0 (0.95, chloroform). Anal. Found: C, 68.95; H, 10.14; N, 3.04. Further elution affords 10.86 g of a mixture of the title products of formulas D-7a and D-7b, and trans-dlethyl maleonate (fractions 96- 142). Further elution affords 1.20 g of the title. roduct of formula D-7c (fractions 146-159), m.p. 110-124°C Physical characteristics are as follows: Silica gel TLC: Rf=0.25 in 5% ethyl acetate/SSB. IR (mull, cm "1 ): 2983, 2955, 2926, 2916, 2867, 2854, 1723, 1686, 1463, 1456, 1395, 1389, 1378, 1373, 1366, 1253, 1180, 1175, 1157, 1116, 1089, 1022, 844, 770. ^-N R (δ, CDCI3): 4.15, 3.95, 3.60, 2.2-0.7, 1.50. 13 C-NMR (CDCI3, ppm) (2 compounds): (Major diastereomer) : 171.02, 151.2, 91.71, 79.01, 76.90, 59.84, 56.25, 38.1, 33.62, 32.94, 31.88, 30.48, 28.0.8, 27.65, 26.73, 26.07, 25.94, 25.17, 23.21, 21.52, 20.23, 13.84; (Minor diastereomer) : 171.02, 51.6, 91.2, 79.11, 76.76, 59.85, 56.25, 37.6, 33.62, 32.94, 31.88, 30.48, 28.08, 27.65, 26.73, 26.07, 25.94, 25.17, 23.21, 21.52, 20.23, 13.84. Mass spectrum (FAB) M+l Found: 438.3231; Ions at m/e: 438, 380, 338, 324, 280, 95, 83, 73, 58, 57, 43, 41, 29. Rotation ( ) D = +4° (0.983, chloroform). Flash chromatography of the 10.86 g of mixed fractions over silica gel (800 g, 2% acetone/SSB, 300 ml fractions) affords 6.43 g of mixed title products of formulas D-7a and D-7b (fractions 18-21) and 0.32 of title product of formula D-7b (fractions 22-24). Physical characteristics are as follows: Silica gel TLC: R f =0.27 in 5% ethyl acetate/SSB. IR (mull, cm -1 ): 2927, 1726, 1700, 1449, 1387, 1366, 1256, 1251 1203, 1179, 1176, 1149, 1117, 1097, 1077, 854, 849, 769. 1 H-NMR ( 5 , CDC1 3 ): 4.09, 3.95, 3.55, 1.90-0.07, 1.47. 13 C-NMR (CDCI3, ppm) (2 compounds): (Major diastereomer): 170.89 150.95, 92.7, 78.8, 78.0, 60.96, 59.44, 40.1, 36.77, 34.72, 33.82 31.47, 30.82, 27.80, 27.38, 25.76, 25.51, 20.84, 20.09, 13.69; (Mino diastereomer): 170.43, 150.95, 92.7, 78.8, 78.0, 60.77, 59.13, 40.1 36.77, 34.46, 33.82, 31.47, 30.82, 27.80, 27.38, 25.76, 25.51, 20.84 20.09, 13.32. UV λ maχ (ε): 280 si sh. Mass spectrum (FAB) M+l Found: 438.3231; ions at m/e: 438, 422 380, 338, 324, 196, 95, 73, 58, 57, 55, 41, 29. Rotation (α) D - -19° (0.522, chloroform). Preparation 17 (lR-(lα,20 (1R*,2R*))) 3-(3-Cyclohexyl-2- (((1,1-dimeth ylethoxy) carbonyl)amino)-1-hydroxypropyl) -2,2-dimethyl- ' cyclopropanecarboxylic acid, ethyl ester (Formula D-8) Refer to Chart D. Tosic acid (0.2 g) is added to a stirring solution of the titl product of formula D-7b of Preparation 16 (218 mg) in methanol, 6.7 m at 60°C After 1 h, the reaction is quenched with solid sodiu bicarbonate. After evaporation the residue is added to a column. Flash chromatography over silica gel (15 g, 15% ethyl acetate/SSB) affords 58 mg of the title product. Physical characteristics are as follows: Silica gel TLC: Rf-0.3 in 25% ethyl acetate/SSB. ^-N R (δ, CDCI3): 4.83, , 4.01, 3.64, 3.13, 1.80-0.60, 1.32, 1.15, 1.11, 1.06. 13 C-NMR (CDCI3, ppm): 172.37, 155.80, 78.83, 73.40, 60.24, 51.49, 39.68, 36.10, 34.00, 33.60, 32.61, 31.74, 28.15, 27.17, 26.32, 26.12, 25.93, 21.46, 20.25, 14.06. Mass spectrum (FAB) M+l Found: 398.2912; ions at m/e: (relative intensity) 398, 298, 280, 170, 126, 95, 83, 57, 55, 41, 29. Anal. Found: C, 66.22; H, 10.09; N, 3.40. Preparation 18 (IR- ( la,20(IR*,2R*)))3-(3-Cyclohexyl-2-(((1,1-dimethyl- ethoxy) carbonyl) amino ) - 1 -hydroxypropyl) - 2 , 2 -dImethyl- cyclopropanecarboxylic acid, ethyl ester (Formula D-8) Refer to Chart D . Tosic acid (0.2 g) Is added to a stirring solution of the title product of formula D- 7b of Preparation 16 (218 mg) in methanol (6 . 7 ml) at ambient temperature . After 4.5 h, the reaction is quenched with solid sodium bicarbonate . After evaporation, the residue Is added to a column. Flash chromatography over silica gel (15 g, 15% ethyl acetate/SSB) affords 75 mg of the title product which is Identical by silica gel TLC, -kϊ-NMR, and 1 C-NMR to previously prepared material. Further elution affords 31 mg of the title product containing a small amount of a second diastereomeric ethyl ester. Physical characteristics are as follows: Silica gel TLC for the second diastereomer: Rf-0.27 in 25% ethyl acetate/SSB. ^-NMR (CDCI3, δ) looks similar to that of the title product. 13 C-NMR (CDCI3, ppm): 172.37, 155.80, 78.83, 73.40, 60.24, 51.49, 39.68, 36.70, 34.00, 33.60, 32.61, 31.74, 28.15, 27.17_, 26.32, 26.12, 25.93, 21.61, 20.48, 14.06. Preparation 19 (IR- (lα,20(lS*,2S*)))3-(3-Cyclohexyl-2-(((l,1-dlmethyl- ethoxy)carbonyl)amino) -1-hydroxypropyl)-2,2-dlmethyl- cyclopropanecarboxylic acid, ethyl ester. Refer to Chart D. Tosic acid (0.2 g) is added to a stirring solution of the title product of formula D-7a of Preparation 16 (1.09 g) in methanol (33 ml). After 7 h, the reaction Is quenched with solid sodium bicarbonate. After evaporation, the residue is added to a column. Flash chromatography over silica gel (80 g, 15% ethyl acetate/SSB) affords 0.65 g of the title product. Physical characteristics are as follows: Silica gel TLC: Rf-0.3 in 25% ethyl acetate/SSB. ^-NMR (CDCI3, δ): 4.64, 4.12, 3.70, 3.25, 2.58, 1.90-0.70, 1.44, 1.38, 1.26, 1.27, 1.25. 13 C-NMR (CDCI3, ppm): 171.54, 156.38, 79.43, 74.53, 60.33, 52.71, 39.20, 35.64, 34.17, 34.10, 32.54, 31.95, 28.35, 27.42, 26.52, 26.32, 26.09, 21.60, 20.89, 14.39. Mass spectrum (FAB) M+l Found: 398.2910; ions at m/e (relative intensity) 398, 342, 324, 298, 170, 126, 95, 83, 81, 57, 55, 41, 29. Anal. Found: C, 66.47; H, 10.09; N, 3.47. Preparation 20 (1S- (1020))3-(3-Cyclohexyl-2- (((1,1-dimethylethoxy)car bonyl)amino)-1-hydroxypropyl)-2,2-dimethylcyclopropane carboxylic acid, ethyl ester. Refer to Chart D. Tosic acid (25 mg) is added to a stirring solution of the titl product of formula D-7c of Preparation 16 (0.14 g) in methanol (4. ml). After 5 h, the reaction is quenched with solid sodium bicar bonate. After evaporation, the residue is added to a column. Flash chromatography over silica gel (15 g, 15% ethyl acetate/SSB affords 50 mg of the title product. Physical characteristics are as follows: Silica gel TLC: Rf-0.3 in 25% ethyl acetate/SSB. iH-NMR (CDC1 3 , δ): 4.75, 4.12, 3.75, 3.40, 2.80, 2.00-0.60, 1.60 1.48. Preparation 21 [IS- [lα,20(lR*,2R*)] ]3[3-Cyclohexyl-2- [ [(1,1-dimethyl- ethoxy)carbonyl] amino] -1-hydroxypropyl] -2,2-dimethyl cyclopropanecarboxylic acid (Formula D-9) Refer to Char . D. Lithium hydroxide (2N, 9 ml) is added to a solution of the titl product of Preparation 17 (0.23 g) in methanol (9 ml). After stirrin at 40°C for 6 h, the reaction solution is transferred to a separator funnel with 2N hydrochloric acid/ether. Extracting 3 times with ether washing the combined organic layers with brine, and drying ove magnesium sulfate affords 0.18 g of the title product after evaporatio of the solvent. Physical characteristics are as follows: Silica gel TLC: Rf-0.25 in 2% acetic acid, 50% ethyl acetate/SSB. ^H-NMR (δ, CDCI3): 7.3, 5.60, 5.02, 3.75, 3.63, 3.25, 1.90-0.80, 1.44. 13 C-NMR (CDCI3, ppm): 177.3, 156.1, 79.1, 73.8, 51.8, 39.9, 37.3, 34.2, 33.9, 32.9, 32.0, 28.4, 26.6, 26.3, 26.2, 21.8, 20.6. Mass spectrum ions at m/e: 226, 170, 126, 97, 83, 81, 69, 67, 59, 57, 55. Preparation 22 [IR- [l ,20(lS*.2S*)] ]3[3-Cyclohexyl-2- [ [(1,1-dimethyl- ethoxy)carbonyl]amino] -1-hydroxypropyl] -2,2-dimethyl- cyclopropanecarboxylic acid. Refer to Chart D. Lithium hydroxide (2N, 16 ml) is added to a solution of the title product of Preparation 19 (0.4 g) in methanol (16 ml). After stirring at 40°C for 5 h and at ambient temperature for 17 h, the reaction solution is transferred to a separatory funnel with 2N hydrochloric acid/ether. Extracting three times with ether, washing the combined organic layers with brine, and drying over magnesium sulfate afford 0.32 g of the title product after evaporation of the solvent. Physical characteristics are as follows: Silica gel TLC: Rf-0.45 in 0.5% acetic acid, 50% ethyl acetate/- SSB. IR (cm' 1 , mull): 3311, 2956, 2916, 2868, 2855, 1723, 1695, 1460, 1456, 1378, 1366, 1171. l-H-NMR (CDC1 3 , δ): 6.8, 3.75, 3.2, 1.90-0,70, 1.40. 13 C-NMR (CDCI3, ppm): 176.1, 82.8, 74.1, 56.2, 43.0, 35.4, 34.2, 33.2, 32.8, 32.4, 31.6, 28.2, 26.2, 26.0, 25.9, 21.4, 20.2. Mass spectrum (FAB) Found: 370.2578; ions at m/e (relative intensity) 370, 314, 296, 270, 250, 170, 154, 126, 55, 41. Preparation 23 [IS- [lα,20(1R*,2R*)]]3[3-Cyclohexyl-2- [[(1,1-dimethyl- ethoxy)carbonyl]amino]-1-hydroxy-propyl]-2,2-dimethyl- cyclopropanecarboxylic acid, L-isoleucyl-2-pyridyl- methylamide (Formula D-10) Refer to Chart D. The title product of Preparation 21 (185 mg) , isoleucyl-2-pyridyl- methylamide (110.6 mg) , and dlethyl cyanophosphonate (95 mg) are dissolved in dim thylformamide (4 ml) at 0°C. Triethylamine (55.3 mg) is added and the ice bath removed. After 2.5 h, the reaction solution is diluted with 60 ml of 2/1 ethyl acetate/benzene and transferred to a separatory funnel. Washing with water, saturated sodium bicarbonate, and brine, and drying over magnesium sulfate affords 303 mg of crude title product after evaporation of the solvent. Flash chromatography over silica gel (30 g, 1-3% ^ methanol/ethyl acetate, 5 ml fractions) affords 209 mg of the title product (fractions 51-67). Physical characteristics are as follows: Silica gel TLC: Rf-0.5 in 5% methanol/ethyl acetate. HPLC: 28.2% RT-11.65 min and 67.6% RT-14.6 min. [Synchrom RP-18, 1.5 ml/min, 17% B 2 min., linear gradient 17% to 100% B; A - 10% CH3CN- H 0, 0.2% TFA; B - 70% CH 3 CN-H 2 0, 0.29. TFA.] IR (mull, cm "1 ): 3284, 2967, 2862, 2850, 1715, 1668, 1636, 1537, 1501, 1462, 1377, 1365, 1173. X H-NMR (δ, CDCI3): 8.46, 8.18, 7.58, 7.28, 7.15, 5.12, 4.6-4. 3.71, 3.14, 1.9-0.81, 1.40. 13 C-NMR (CDCI3, ppm): 172.4, 171.6, 157.1, 155.9, 148.8, 137. 122.7, 122.5, 78.7, 73.4, 58.1, 51.8, 44.6, 40.3, 37.3, 36.4, 34. 34.0, 33.9, 32.9, 28.4, 26.6, 26.2, 25.9, 24.9, 21.7, 20.6, 15.5, 11. Mass spectrum (FAB) Found: 573.4044; ions at m/e: 574, 573, 51 499, 473, 409, 248, 109, 95, 93, 86, 57, 55. Preparation 24 [IR- [ la,20(IS*,2S*) ] ]3[3-Cyclohexyl-2- [ [ (1, 1-dimethyl- ethoxy)carbonyl] amino] -1-hydroxypropyl] -2,2-dimethy cyclopropanecarboxylic acid, L-isoleucyl-2-pyridy methyla ide. Refer to Chart D. The title product of Preparation 22 (95 mg) , isoleucyl-2-pyridyl methylamide (56.8 mg) , and diethyl cyanophosphonate (48.8 mg) ar dissolved in dimethylformamide (2 ml) at 0°C Triethylamine (28.4 mg .039 ml) is added and the ice bath removed. After 2.5 h, the reactio solution is diluted with 30 ml of 2/1 ethyl acetate/benzene an transferred to a separatory funnel. Washing with water, saturate sodium bicarbonate, and brine, and drying over magnesium sulfat affords 177 mg of crude title product after evaporation of the solvent Flash chromatography over silica gel (18 g, 1-3% methanol/ethy acetate, 5 ml fractions) affords 92.8 mg of the title product (frac tions 16-25) . Physical characteristics are as follows: Mp 92-98°C. Silica gel TLC: Rf-0.5 in 5% methanol/ethyl acetate. HPLC: 28.2% RT 11.65 min and 67.6% RT 14.6 min [synchorm RP-18 1.5 ml/min, 17% B 2 min., linear gradient 17% to 100% B (A - 10% CH3CN H 0, 0.2% TFA; B - 70% CH 3 CN-H 2 0, 0.2% TFA)]. IR (KBr, cm "1 ): 3298, 2965, 2926, 1745, 1681, 1646, 1529, 1391 1380, 1366, 1242, 1172. ^-N (CDCI3, δ): 8.51, 7.63, 7.30-7.00, 4.9, 4.55, 4.42, 3.76, 3.2, 2.0-0.7, 1.42. 13 C-NMR (CDCI3, ppm): 171.8, 170.5 and 169.7, 156.9, 156.3, 149.0, 136.8 and 136.7, 122.4 and 122.2, 121.8 and 121.6, 83.0 an 74.9, 79.5, 58.2 and 58.0, 56.3 and 53.8, 44.5 and 43.4, 39.2, 37.4 an 36.7, 34.2, 33.8 and 33.6, 32.8 and 32.7,- 28.4, 26.5, 25.1, 24.7, 21.5, 20.1, 15.6 and 14.2, 11.2 and 11.0. Mass spectrum (FAB) Found: 573.4017; ions at m/e (relativ intensity) 573, 517, 499, 473, 409, 248, 109, 95, 93, 86, 69, 57, 55, 41. Preparation 25 [IS- [lα,20(1R*,2R*) ]]3[3-Cyclohexyl-2- [ (amino) -1- hydroxypropyl] -2,2-dime hylcyclopropanecarboxylic acid, L-isoleucyl-2-pyridylmethylamide (Formula D-11) Refer to Chart D. A solution of the title product of Preparation 23 (0.2 g) in methylene chloride (8 ml) and trifluoroacetlc acid (8 ml), is placed at -20°C After 19 h, the reaction solution is transferred to a separa- tory funnel containing saturated sodium bicarbonate. Extracting 2 times with methylene chloride and drying over magnesium sulfate affords 139.2 mg of the title product. Physical characteristics are as follows: ^-N R (δ, CDC1 3 ): 8.49, 8.34, 7.78, 7.62, 7.27, 7.15, 5.23, 4.45, 3.16, 3.00, 1.91, 1.80-0.70. 13 C-NMR (CDCI3, ppm): 172.7, 172.1, 157.2, 148.8, 137.0, 122.4, 122.1, 72.4, 58.4, 54.4, 44.6, 39.1, 37.0, 35.5, 34.1, 33.6, 32.7, 32.5, 27.2, 26.4, 26.1, 25.9, 24.9, 22.5, 21.0, 20.6, 15.6, 11.2. Preparation 26 [IS-[lα,20(lR*,2R*) ] ]3[3-Cyclohexyl-2- [ [L-Boc-His(Ts) (a- mino) -1-hydroxypropyl] -2,2-dimethylcycloproρanecar- boxylic acid, -L-isdleucyl-2-pyr.idylmethylamide (Formula D-12) Refer to Chart D. The title product of Preparation 25 (139 mg) , boc-his(ts) (153.7 mg) , and diethyl cyanophosphonate. (77.3 mg) are dissolved in dimeth- ylformamide (1.2 ml) at 0°C Triethylamine (61.8 mg) is added and the ice bath removed. After 18.5 h, the reaction solution is diluted with 35 ml of 2/1 ethyl acetate/benzene and transferred to a separatory funnel. Washing with water, saturated sodium bicarbonate, and brine, and drying over magnesium sulfate affords 234 mg of crude title product after evaporation of the solvent. Flash chromatography over silica gel (25 g, 5% methanol/ethyl acetate, 2 ml fractions) affords 159.2 mg of the title product (frac¬ tions 33-40) . Physical characteristics are as follows: Silica gel TLC: Rf-0.15 in 5% methanol/methylene chloride. ^-N R (δ, CDCI3): 8.48, 8.10, 8.01, 7.79, 7.66, 7.54, 7.29, 7.30, 7.18, 7.13, 5.48, 4.53, 3.95, 3.14, 2.96, 2.77, 2.41, 2.05-0.70, 1.38. 13 C-NMR (CDCI3, ppm): 172.7, 171.9, 171.5, 156.3, 155.5, 148. 146.0, 140.8, 137.0, 136.7, 135.0, 130.3, 127.4, 122.5, 122.3, 114. 79.3, 73.2, 58.4, 54.0, 53.5, 50.4, 44.5, 39.7, 37.0, 34.2, 34.0, 33. 32.6, 31.8, 28.3, 26.6, 26.2, 26.0, 25.5, 24.8, 21.8, 21.7, 20.6, 15. 11.0. Preparation 27 [IS- [lα,23(1R*.2R*) ] ]3[3-Cyclohexyl-2- [ [L-His(Ts) (a- mino) -1-hydroxypropyl] -2,2-dimeth leyclopropaneca boxylic acid, -L-isoleucyl-2-pyridylmethylamide (Formu D-13) Refer to Chart D. A solution of the title product of Preparation 26 (159.2 g) methylene chloride (4 ml) and trifluoroacetic acid (4 ml) is placed -20°C After 3 h, the reaction solution is transferred to a separato funnel containing saturated sodium bicarbonate. Extracting 2 tim with methylene chloride and drying over magnesium sulfate affords 133. mg of the title product. Physical characteristics are as follows: l-H-NMR (δ, CDCI3): 8.47, 8.04, 7.94, 7.79, 7.64, 7.55, 7.3 7.28, 7.18, 7.15, 4.55-4.40, 3.96, 3.70, 3.12, 2.42, 2.0-0.80. 13 C-NMR (CDCI3, ppm): 173.4, 172.4, 171.9, 156.4, 148.9, 146.2 141.8, 137.0, 136.4, 135.0, 130.4, 127.4, 122.4, 122.2, 114.8, 72.5 58.3, 55.1, 53.5, 50.6, 44.5, 39.5, 37.1, 34.3, 33.9, 33.6, 32.8, 30.9 26.5, 26.2, 26.1, 25.8, 25.7, 24.8, 21.7, 20.7, 15.6, 11.0. Preparation 28 [IS- [lα,20(1R*,2R*) ] ]3[3-Cyclohexyl-2- [L-Boc-Phe-L- HIs(Ts) (amino) -1-hydroxypropyl] -2,2-dimethylcyclopro panecarboxylic acid, -L-isoleucyl-2-pyridylmethylamid (Formula D-14) Refer to Chart D. The title product of Preparation 27 (65 mg) , L-boc-phe (29.3 mg) and diethyl cyanophosphonate (22.4 mg) are dissolved in methylen chloride (0.35 ml) at 0°C under nitrogen. N,N-diisopropylamine (22. mg) is added and the ice bath removed. After 16.5 h, the reactio solution is evaporated in vacuo to afford crude title product. Flash chromatography over silica gel (10 g, 3% methanol/meth len chloride, 1 ml fractions) affords 71.6 mg of the title product (frac tions 35-84) . Physical characteristics are as follows: Silica gel TLC: Rf-0.40 in 5% methanol/methylene chloride. ^-NMR (δ, CDCI3): 8.49, 7.96, 7.79, 7.65, 7.30-7.11, 4.60-4.30, 3.93, 3.09, 2.89, 2.39, 1.60-0.83, 1.37. 13 C-NMR (CDCI3, ppm): 172.23, 171.55, 171.47, 170.12, 156.88, 148.90, 146.26, 140.27, 137.02, 136.45, 134.93, 134.78, 130.39, 129.24, 128.65, 127.46, 127.01, 122.37, 115.08, 80.43, 79.35, 58.29, 56.28, 53.25, 51.78, 44.57, 39.65, 39.15, 37.98, 37.26, 33.89, 32.65, 29.68, 28.29, 26.55, 25.99, 24.88, 21.67, 20.70, 15.65, 11.21. Preparation 29 [IS- [lα,20(1R*,2R*) ] ]3[3-Cyclohexyl-2-[(Z)-(2-phenyl-l- (Boc)aminocyclopropane-l-carboxyl)-L-His(Ts)(amino)-1- hydroxypropyl] -2,2-dlmethylcyclopropanecarboxyllc acid, -L-Isoleucyl-2-pyrldylmethylamide (Formula E-2) Refer to Chart E. The title product of Preparation 27 (65 mg) , (Z)-2-phenyl-1- (boc)amino-cyclopropane-l-carboxylic acid (30.7 mg) , and diethyl cyanophosphonate (22.4 mg) are dissolved in methylene chloride (0.35 ml) at 0°C under nitrogen. N,N-diisopropylamine (22.5 mg) is added and the ice bath removed. After 19.5 h, the reaction solution is evapor¬ ated in vacuo to afford crude title product. Flash chromatography over silica gel (10 g, 3% methanol/methylene chloride, 2 ml fractions) affords 42.3 mg of the title product (first diastereomer) (fractions 20-38). Physical characteristics are as follows: Silica gel TLC: Rf-0.35 in 5% methanol/methylene chloride. X H-NMR (δ, CDCI3): 8.47, 7.98-7.61, 7.37-6.90, 5.62, 4.75, 4.54- 4.44, 3.96, 3.25-2.80, 2.41, 1.91, 1.60-0.80. 13 C-NMR (CDCI3, ppm): 172.11, 171.74, 171.3, 170.8, 156.2, 148.94, 146, 140.69, 136.91, 134.79, 130.42, 128.60, 127.47, 122.31, 115, 80, 73.20, 5.51, 37.01, 34.32, 33.92, 32.67, 28.29, 26.58, 26.00, 24.84, 21 ' .85, 21.72, 15.61, 11.25. Further . elution affords 22. 9 mg of the title product (second diastereomer) (fractions 42- 60) . Physical characteristics are as follows : Silica gel TLC : Rf-0.30 In 5% methanol/methylene -.chloride . ^-N R (δ , CDCI3) : 8.47 , 7 .90-7.61 , 7. 37 -7.00 , 6 . 62, 5.05 , 4.75 - 4.08 , 4.00 , 3 .40-3.10 , 2.43 , 1.91 , 1.60-0. 80. Example 3 [ IS - [ lα , 20(lR* , 2R*) ] ] 3 [3 -Cyclohexyl- 2- [ [L-Boc-Phe-L- His (amino ) - 1 -hydr oxypropyl ] - 2 , 2 - dimethylcyclopropanecar - boxylic acid, -L-isoleucyl-2-pyridylmethylamide (Formula D-15) Refer to Chart D . A solution of the the title product of Preparation 28 (71.6 mg) and 1-hydroxybenzotriazole (70 mg) in methanol (2.5 ml) is stirred ambient temperature. After 17.5 h, the solution is evaporated in vac and the residue is submitted to flash chromatography over silica g (12 g, 5% methanol (saturated with ammonia/aethylene chloride, 3 fractions) to afford 26.7 mg of the title product (fractions 51-57). Physical characteristics are as follows: Silica gel TLC: Rf=0.5 in 10% methanol (ammonia)/methylene chlo ide. Mass spectrum (FAB) Found: 857.5289; ions at m/e: 858, 857, 12 110, 109, 95, 83, 57, 55, 41. Example 4 [IS- [lα,20(1R*, 2R*) ] ]3[3-Cyclohexyl-2- [ [ (Z)- (2-phenyl- (boc) aminocyclopropane-1-carboxyl) -L-His(amino) - hydroxypropyl] -2,2-dimethylcyclopropanecarboxylic aci -L-isoleucyl-2-pyridylmethylamide (Formula E-3) Refer Chart E. A solution of the title product of Preparation 29 (the more pol epimer, 22.9 mg) and 1-hydroxybenzotriazole (22 mg) in methanol (0. ml) is stirred at ambient temperature. After 22 h, the solution evaporated in vacuo and the residue is submitted to flash chrom tography over silica gel (2.5 g, 5% methanol (saturated with a monia/methylene chloride, 3 ml fractions) to afford 2.7 mg of the titl product (fractions 18-25) . Physical characteristics are as follows: Silica gel TLC: Rf-0.4 in 10% methanol (ammonia)/methylene chlor ide. Mass spectrum (FAB) Found: 869.5255; ions at m/e: 869, 110, 109 95, 83, 82, 69, 57, 55, 41. FORMULA CHART X-A 6 -B 7 -Cg-D9-E 10 -F 11 -G 12 -H 1 3-I 1 4-Z FORMULA CHART (Continued) R, ^ 8 V CH" 15 XL 4 -N CH C- FORMULA CHART (Continued) FORMULA CHART (Continued) CHART A P A-l A-2 A-3 i 4 A-4 A- 5 A-6 A-6 A-7 A-7 CHART B 4 B-2 y B-3 B-4 CHART C C-2 C-3 I CHART D H 2 N ,0H H BocN. OH BocN \-/"\0H D-4 CHART D (Continued) CHART D (Continued) OH OH CHART D (Continued) CHART E Ile-AMP E-3 CHART F CHART G CHART H BocHN HO H-1 (D-4) B H-4 CHART H (Continued)

Claims: CLAIMS 1. A renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) and having: (a) at least one cyclopropyl amino acid of the formula L^ in place of an amino acid residue corresponding to position 6, 8, 9, 12, 13 or 14 of the renin substrate; and/or (b) a cycloalkyl amino acid non-cleavable transition state insert of the formula XL 2c in place of an amino acid residue corresponding to position 10 and 11 of the renin substrate; wherein gn is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg and Rg- j _ are the same or different and are (a) hydrogen, (b) Chalk !, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; or wherein Rg Q and R ^ taken together form a spirocycle of the formula II wherein R 7 g is (a) -CHR 80 , (b) -0-, (c) -S-, (d) -SO-, (e) -S0 2 -, or (f) - R 81 ; wherein R30 and Rg_ are the same or different and are (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rαø is (a) hydrogen, or (b) C 1 -C 5 alkyl; wherein 100 ^- s (a) hydrogen, (b) C -Csalkyl, (c) aryl, (d) C3-C cycloalkyl, (e) -Het, (f) C^-C3alko , or (g) C 1 -C3alkylthio; wherein Rno I s (a) hydrogen, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein m is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein p is zero to two, inclusive; wherein r Is zero to three, inclusive; wherein t is zero to three, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: . (a) C 1 -C3al yl, (b) hydroxy, (c) C ] _-C3alkoxy, (d) halo, (e) amino, (f) mono- or di-C ] _-C3alkylamlno, (g) -CHO, (h) -COOH, (I) C00R 2 g, (j) CONHR 26 , (k) nitro, (1) mercapto, (m) C 1 -C3al lthio, (n) C- j _-C3alkylsulfinyl, (o) C- ] _-C3alkylsulfonyl, (p) -N(R4)-C 1 -C 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; 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 bicycllc 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: (i) C 1 -Cgalkyl, (II) hydroxy, (ill) trifluoromethyl, (Iv) C^-C alkox , (v) halo, (vi) aryl, (vii) aryl C ] _-C al yl-, (viii) amino, (ix) mono- or di- (C j _-C4alkyl) mino , and (x) C]_-C5alkano l; wherein R4 at each occurrence is the same or different and is (a) hydrogen, (b) C L -C 5 alkyl, (c) -<CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C cycloalkyl, or (f) 1- or 2-adamantyl; wherein R 2 g is (a) hydrogen, (b) C^-C al yl, or (c) phenyl-C_-C3 lk l. 2. In a renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) , the improvement which comprises inclusion in the renin inhibitory peptide of: (a) at least one cyclopropyl amino acid of the formula XL 2b in place of an amino acid residue corresponding to position 6, 8, 9, 12, 13 or 14 of the renin substrate; and/or (b) a cycloalkyl amino acid non-cleavable transition state insert of the formula XL 2c in place of an amino acid residue corresponding to position 10 and 11 of the renin substrate; wherein R50 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg and R ^_ are the same or different and are (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH ) p -C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; erein Rgg and Rg^_ taken together form a spirocycle of the formula wherein R 7Q is (a -CHR 80 (b) -0-, (c) -s-, (d) -SO-, (e) -so 2 -, or wherein R 8 Q and R - j _ are the same or different and are (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) - CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg is (a) hydrogen, or (b) C-L-Csal yl; wherein Rio is (a) hydrogen, (b) Cx-Csal yl, (c) aryl, (d) C3-C cycloalkyl, (e) -Het, (f) C 1 -C3alkoxy, or (g) C 1 -C alkylthio; wherein R o is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein R ] _n is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein p is zero to two, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to three o the following: (a) C 1 -C 3 alkyl, (b) hydroxy, (c) Cι-C 3 alkoxy, (d) halo, (e) amino, (f) mono- or di-C 1 -C3alkylamino, (g) -CHO, (h) -COOH, (i) COOR 26 , (j) C0NHR 26 , (k) nitro, . (1) mercapto, (m) C ] _-C 3 alkylthio, (n) C 1 -C 3 alkylsulfinyl, (o) C^-C3alkylsulfonyl, (p) -N(R4)-C 1 -C 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; wherein -Het is a 5 - or 6-membered saturated or unsaturated ring con t aining 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: (1) C 1 -Cgalkyl, (li) hydroxy, (iii) trifluorom thyl, (iv) C ] _-C4al ox , • (v) halo, (vi) aryl, (vii) aryl C 1 -C4 l l- , (viii) amino, (ix) mono- or di-(C^-C4al yl)amino, and (x) C ] _-C 5 alkanoyl; wherein R4 at each occurrence is the same or different and is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R g is (a) hydrogen, (b) C L -C 3 alkyl, or (c) phenyl-C^^alkyl. 3. The renin inhibitory peptide of claim 1 wherein the cyclopropyl amino acid of the formula XL b Is at the N- terminus of the peptide. 4. The renin inhibitory peptide of claim 2 wherein the cyclopropyl amino acid of the formula XL b is at the N- erminus of the peptide. 5. The renin inhibitory peptide of claim 1 of the formula I X-Ag-B 7 -C 8 -D 9 -E 1 o-F 11 -G 12 -H 13 -I 14 -Z I wherein X is (a) hydrogen, (b) Ci-Csalkyl, (c) R 5 -0-CH 2 -C(0)-, (d) R 5 -CH 2 -0-C(0)-, (e) R 5 -0-C(0)-, (f) R 5 -(CH 2 ) n -C(0)-, (g) R 4 N(R 4 )-(CH 2 ) n -C(0), (h) R 5 -SO 2 -(CH 2 ) q -C(0)-, (i) R 5 -SO 2 -(CH 2 ) q -0-C(0)-, or (j) Rg-(CH 2 ) i -C(0)-; wherein Ag is absent or a divalent moiety of the formula XL^, XL , XL 2a , or XL 2b ; XL 2b wherein B 7 is absent or a divalent moiety of the formula XL b ; wherein C 8 is absent or a divalent moiety of the formula XL ] _, XL 2 , XL 2a , or XL 2b ; XL 2b wherein Dg is absent or a divalent moiety of the formula XL , XL a . or XL 2b ! XL 2b or wherein Cg-Dg Is XL 7 , XL 7a , or when X, Ag and B 7 are absent, XL 7b ; XL 7 XL 7a X^7b wherein E^g-F^ is a divalent moiety of the formula XLg, XLg a , XL 6b , XL 6c , XL 6d , XL 6e , XLg f , or XLg g ; XLδb XL c ' XLge wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G^_ 2 is absent or a divalent moiety of the formula XL4, XL 4a , or XL 2b ; XL4 XL 4a XL b wherein H^_3 is absent or a divalent moiety of the formula XL4 or XL 2b> XL 4 XL b wherein 1^4 is absent or a divalent moiety of the formula XL5 or XL 2b ; XL5 XL 2b wherein Z is (a) -0-R 10 , (b) -N(R 4 )R 14 , or (c) C _-C 8 cyclic amino; wherein R is (a) isopropyl, (b) isobutyl, (c) phenylmethy1, or (d) C3-C 7 cycloalkyl; wherein ^_ is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) aryl, (d) C3-C 7 cycloalkyl, (e) -Het, (f) C ] _-C3alkoxy, or (g) C 1 -C 3 alkylthio; wherein R 2 is (a) hydrogen, or (b) -CH(R 3 )R 4 ; wherein R3 is (a) hydrogen, (b) hydroxy, (c) Ci-Cgalkyl, (d) C3-C 7 cycloalkyl, (e) aryl, (f) -Het, (g) C 1 -C 3 alkoxy, or (h) C ] _-C3alk lthio; wherein R4 at each occurrence is the same or different and is (a) hydrogen, (b) Cx-Csalk l, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R5 is (a) C 1 -Cgalkyl, (b) C3-C 7 cycloalkyl, (c) aryl, (d) -Het, or (e) 5-oxo-2-pyrrolidInyl; wherein Rg is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R 7 is (a) hydrogen, (b) Cx-Csalkyl, (c) hydroxy, (d) amino C -C4 lkyl- , (e) guanidinyl C -C3alkyl- , (f) aryl, (g) -Het, (b) methylthio , (i) -(CH 2 )p-C 3 -C 7 cycloalkyl, or (j) amino; wherein B : 8 is (a) hydrogen, (b) C ] _-C5alkyl, (c) hydroxy, (d) aryl, (e) -Het, (f) guanidinyl C -C3alkyl- , or (g) ' -(CH 2 ) p -C3-C 7 cycloalkyl; wherein Rg is (a) hydrogen, (b) hydrox , (c) amino C -C4alk l-, or (d) guanidinyl C -C alkyl-; wherein R^g is (a) hydrogen, (b) C -C5alkyl, (c) -(CH 2 ) n R 15 , (d) -(CH 2 ) n R 17 , (e) C3-C 7 cycloalkyl, (f) a pharmaceutically acceptable cation, (s ) -CH(R 25 )-CH 2 -R 15 , or (h) -CH 2 -CH(R 12 )-R 15 ; wherein R]_χ is -R or -R 2 ; wherein Rχ 2 is - (CH 2 ) n -R 3; wherein R 3 is (a) aryl, (b) amino, (c) mono-, di or tri-C -C3alkylamino, (d) -Het, (e) C -C 5 alkyl (f) C3-C 7 cycloalkyl, (ε) C 2 -C5alken l, (h) C3-C cycloalkenyl, (1) hydrox , ϋ) Cχ-C3alkox , (k) 0 -C3alkanoyloxy, (1) mercapto, (m) C -C3alkylthlo, (n) -COOH, o) -CO-0-C -Cgalkyl, (P) -CO-0-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl) 2 , (q) -C0-NR 22 R 2 g; (r) C4-C 7 cyclic amino, (s) C4-C cycloalkylamino, (t) guanidyl, ( ) cyano, (v) N-cyanoguanidyl, (w) cyanoamino, . ( x (hydroxy C 2 -C alkyl)amino, or ( y ) di-(hydroxyC -C4alkyl)amino; wherein R 4 is (a) hydrogen, (b) C -C galk l, (o) -(CH 2 ) n -R 18 , (d) -(CH 2 ) n -R 19 , (e) -CH(R 25 )-CH 2 -R 15l (f) -CH 2 -CH(R 12 )-R 15 , ( s ) (hydroxy C -C 8 alkyl) , or (h) C .C3alko )C >C 8 alkyl; wherein R 5 is (a) hydroxy, (b) C3-C 7 cycloalkyl, (c) aryl, (d) amino, (e) mono-, di- , or tri- C ] _-C3alkylanino, (f) mono- or di-(hydroxy C 2 -C4alkyl)amino, (g) -Het, (h) C -C 3 alkoxy- , (i) Cχ-C3alkanoyloxy- , (j) mercapto, (k) Cχ-C3alkylthio-, (1) Ci-Csalkyl, (m) C -C 7 c clic amino, (n) C4-C cycloalkylamino, (0) C -C5 lkenyloxy, (p) C3-C 7 cycloalkenyl; wherein R^ is (a) aryl, (b) amino, (c) mono- or di- (C -C3alkyl)amino, (d) hydroxy, (e) C3-C 7 cycloalkyl, (f) C4-C 7 cyclic amino, or (g) C -C3alk o lo y; wherein R 7 is (a) -Het, (b) C -C5al enyl, (c) C3-C 7 cycloalkenyl, (d) C -C3alkoxy, (e) mercapto, (f) C 1 -C 3 alkylthio, (g) -COOH, (h) -CO-0-Cχ-Cgalkyl, (i) -CO-0-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl) 2> (j) -C0-NR 22 R 2 , (k) tri-C -C β alkylamino, ■ (1) guanidyl, (m) cyano, (n) N-cyanoguanidyl, (0) (hydroxy C 2 -C4alkyl)amino, (p) di-(hydroxy C 2 -C alkyl)amino, or (q) cyanoamino; wherein R 8 is (a) amino, (b) mono-, or di- (C -C3alkyl)amino, (c) C4-C cyclic amino; or (d) C4-C 7 cycloalkylamino; wherein R o. is (a) aryl, (b) -Het, (c) tri-C -C3 lkylamino, (d) C3-C 7 cycloalkyl, (e) C -C5alke yl, (f) C3-C 7 cycloalkenyl, (g) hydroxy, (h) C -C3 lko y, (1) C -C3alkanoyloxy, (j) mercapto, * (k) C 1 -C 3 alkylthio, (1) -COOH, (m) -CO-0-C -C alkyl, (n) -CO-0-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C3alkyl) 2 , (o) -CO-NR 22 R 2 g, (p) guanidyl, (q) cyano, (r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy C -C4al yl)amino, (u) di-(hydroxy C 2 -C alkyl)amino; or (v) -S0 3 H; wherein R 2 g is (a) hydrogen, (b) Cχ-C5alk l, or (c) ar l-C -Cs l l; wherein R 2 is " (a) -NH 2 , or (b) -OH; wherein R 2 is (a) hydrogen, or (b) C 1 -C 3 alkyl; wherein R 2 3 is (a) -(CH 2 ) n -0H, (b) -(CH 2 ) n -NH 2 , (c) aryl, or (d) C -C β alkyl; wherein R 2 4 is (a) -R χ , (b) ' -(CH 2 ) n -0H, or (c) -(CH 2 ) n -NH 2 ; wherein R 2 5 is (a) hydrogen, (b) C 1 -C 3 alkyl, or (c) phenyl-Cχ-C 3 alkyl; wherein R 2 g is (a) hydrogen, (b) C -C3alkyl, or (c) phenyl-C -C 3 'alkyl; wherein R5g is (a) hydrogen, (b) C -Csalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg and R are the same or different and are (a) hydrogen, (b) C -C 5 alkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH ) p -C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; erein Rgg and Rgx taken together form a spirocycle of the formul II wherein R g is (a) -CHRgg, (b) -0-, (c) -s-, (d) -SO-, (e) -S0 -, or (f) - Rgi; wherein R 8 g and R 8 χ are the same or different and are (a) hydrogen, (b) Cχ-C 5 alkyl, . (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 )p-C3-C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein Rgg Is (a) hydrogen, or (b) Cχ-C 5 alkyl; wherein g is (a) hydrogen, GO C -C5alkyl, (c) aryl, (d) C3-C 7 cycloalkyl, (e) -Het, (f) C -C alkox , or (s) C -C3alk lthlo; wherein Rχιg is (a) hydrogen, (b) Cχ-C5al l, ..(c) -(CH 2 ) p -aryl, or (d) halogen; wherein m is (a) hydrogen, (b) C -C5alkyl, (c) -(CH 2 ) p -aryl, or (d) halogen; wherein : I Is zero to five, inclusive; wherein ιa Is one or two; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein p is zero to two, inclusive; wherein q is one to five, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, inclusive; wherein Q is (a) -CH 2 -, (b) -CH(OH)-, (c) -0-, or (d) -S-; and wherein M is (a) -CO-, or (b) -CH 2 -; wherein aryl is phenyl or naphthyl substituted by zero to three o the following: (a) C -C3al yl, (b) hydroxy, (c) C -C3alkoxy, (d) halo, . (e) amino, (f) mono- or di-Cχ-C3alkylamino, (g) -CHO, (h) -COOH, (i) COOR 26 , (j) CONHR 26 , (k) nitro, (1) mercapto, (m). Cχ-C3alkylthio, (n) Cχ-C3alkylsulfinyl, (o) Cχ-C3alkylsulfonyl, (p) -N(R4)-Cχ-C 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; 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: (i) Cx-Cgalkyl, (ϋ) hydroxy, (iii) trifluoromethyl, (iv) C -C4 lkox , (v) halo, (vl) aryl, (vii) aryl Cχ-C alkyl- , (vlii) amino, (ix) mono- or di-(C -C4alk l)amino, and (x) Cx-Cgalkanoyl; with the overall provisos that: (1) at least one cyclopropyl amino acid of the formula XL 2b or cycloalkyl amino acid non-cleavable transition state insert of the formula XL 2c Is present; (2) Rχ 8 or R g is hydroxy, mercapto, or amino, or a mono-sub¬ stituted nitrogen containing group bonded through the nitrogen only when n is not one; (3) Rχ 2 is -(CH 2 ) n -Rχ3 and n is zero and both 3 and R 5 are oxygen- , nitrogen- , or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen; (4) Rχ or R is -COOH only when n for that moiety is other than zero; (5) R g or Rχ 7 is an amino-containing substituent, hydroxy, mercapto, or -Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive; (6) when Rχ is -(CH 2 ) n -Rχ3 and n is zero, then R 3 and Rχ5 cannot both be -COOH; and (7) Rχ 7 or Rx Is -Het, only when -Het is other than cyclic amino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof. 6. The renin inhibitory peptide of claim 5 wherein X is R 5 -0-C(0)-; wherein Ag is absent; wherein B 7 is absent; wherein C 8 is XL 2b ; wherein Dg is XL3; wherein Eχg-Fχχ is XLg; wherein Gχ 2 is XL4 a ; wherein H 3 is absent; wherein I 4 is absent; wherein Z is - (R4)R ; wherein R is C -C5alkyl; wherein R 2 is -CH(R 3 )R4,- wherein R3 is hydrogen; wherein R4 is (a) hydrogen, or (b) Cχ-C 5 alkyl; wherein R5 is Cχ-Cgalkyl; wherein R 7 is -Het; wherein Rxx is isopropyl; wherein χ 4 is - (CH 2 ) n -Rχg ; wherein Rxg is -Het; wherein R^g is hydrogen; wherein Rgg and gx are the same or different and are (a) hydrogen, or (b) -(CH 2 ) p -aryl. 7. N α - [ (2S ,4S , 5S) -5- [N- [ϊf°- [ (E) -2-Phenyl-l- (tert-butoxycarbonyl- amino)cyclopropane-l-carbonyl] -L-histidyl] amino] -4-hydroxy- 2- isopropyl - 7 -methyl -1-oxooctyl] -N- (2-pyridinylmethyl) -L-isoleucinamide , a compound of claim 6. 8. N α - [ (2S ,4S , 5S) -5- [N- [N 0 - [ (Z) -2-Phenyl-l- (tert-butoxycarbonyl- amino ) cyclopropane - 1 - carbonyl ] - L-his tidyl ] amino ] -4 -hydroxy- 2 - isopropyl - 7 -methyl -1-oxooctyl] -N- (2-pyridinylmethyl) -L-isoleucinamide , a compound of claim 6. 9. The renin inhibitory peptide of claim 5 having the cycloalkyl non- cleavable transition state insert of the formula XL 2c . 10. [lS-[l ,2 r 3(lR*,2R*)]]3[3-Cyclohexyl-2-[[L-Boc-Phe-L-His(amino)-l- hydroxypropyl]-2,2-dimethylcycloρropanecarboxylic acid, -L-isoleucyl-2- pyrldylmethylamide, a compound of claim 9. 11. The renin inhibitory peptide of claim 5 having the cyclopropyl amino acid of the formula XL 2 and the cycloalkyl amino acid non- cleavable transition state insert of the formula XL^. 12. [lS-[lα,2yS(lR*,2R*)]]3[3-Cyclohexyl-2-[[(Z)-(2-phenyl-l-(boc)a- mino cyclopropane- 1-carboxyl) -L-His (amino) -1-hydroxypropyl] -2, 2-dimeth- ylc clopropanecarboxyllc acid, -L- isoleucyl-2 -pyrldylmethylamide, a compound of claim 11.

Inventors: GAMMILL RONALD B, HESTER JACKSON B JR, GAMMILL, RONALD, B., HESTER, JACKSON, B., JR.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1988
Main classification: C07K5
IPC codes: A61K38, A61P9, C07C237, C07D233, C07D401, C07K5, C07K14, C12N9