METHOD FOR TREATING VASCULAR DISEASES

Abstract: The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treating, inhibiting, relieving or reversing vascular diseases including those vascular diseases associated with functional and/or biochemical abnormalities, and in particular peripheral vascular diseases and microvascular diseases associated with diabetes, especially diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

Description: -1 - METHOD FOR TREATING VASCULAR DISEASES This is a continuation-in-part of U.S. Patent Application Serial No. 275,151, filed November 21, 1988. Technical Field The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treating, inhibiting, relieving or reversing vascular diseases with respect to functional and/or anatomical abnormalities, and in particular peripheral vascular diseases and microvascular diseases associated with diabetes, especially diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. Background Art Vascular diseases are often the result of decreased perfusion in the vascular system or physical or biochemical injury to the blood vessel. One disease in which vascular diseases and their complications are very common is diabetes mellitus. Diabetes mellitus causes a variety of physiological and anatomical irregularities, the most prominent of which is the inability of the body to utilize glucose normally, which results in hyperglycemia. Chronic diabetes can lead to complications of the vascular system which include atherosclerosis, abnormalities involving large and medium size blood vessels (macroangiopathy) and abnormalities involving small blood vessels (microangiopathy) such as arterioles and capillaries. The thickening and leakage of capillaries caused by diabetes primarily affect the eyes (retinopathy) and kidneys (nephropathy). The thickening and leakage of capillaries caused by diabetes are also associated with skin disorders and disorders of the nervous system (neuropathy) . The eye diseases associated with diabetes are nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic aculopathy, glaucoma and cataracts. It is estimated that up to 50% of diabetics will develop diabetic nephropathy, and ultimately renal failure, between 10 and 30 years from the time of onset of the diabetes. Associations between diabetic microvascular complications and the renin-angiotensin-aldosterone system (RAAS) have been observed. Elevated plasma levels of inactive renin (prorenin) have been found in patients with incipient nephropathy, frank nephropathy, retinopathy and neuropathy. (See Luetscher, et al., Arch. Intern. Med. 148 937 (1988); Luetscher, et al., New Eng. J. Med. 312 1412 (1985); Shionoiri, et al., Curr. Therapeutics Res. 43_ 857 (1988); and Nakamura, et al., Acta Endocrinologica 104 216 (1983)). Chronic diabetic rats also have been found to exhibit elevated plasma prorenin. (See Ubeda, et al., Hypertension ] . 339 (1988)). Some diabetic patients have been reported to have lower than normal plasma renin activity. (See Shionoiri, et al. , Curr. Therapeutics 43 857 (1988); Perez, et al., Arch. Interux. Med. 137 852 (1977); Christlieb, et al. , Diabetes 23 835 (1974); and Campbell, et al. , Eur. J. Clin. Invest. 6 381 (1976)). Studies in diabetic rats which also have low plasma renin activity have shown enhanced activity of the local tissue RAAS in blood vessels and the adrenal gland. (See Ubeda, et al. , Hypertension 1Λ 339 (1988)). Suppressed plasma renin activity has not been, however, a consistent finding. Elevated plasma renin activity has been observed in diabetic patients with retinopathy and hypertension. (See Drury, et al. , Clin. Endo. 1_6 453 (1982) and Drury, et al. , Hypertension, 7 (Suppl. II) 11-84 (1985)). Hypertension, if not adequately treated, will increase the incidence, severity, and rate of microvascular disease. It is thought that high pressures in isolated vascular beds (e.g. ocular, renal) caused by localized increases in activity of the RAAS may be needed for the expression of microangiopathy. Thus an inhibitor of the renin-angiotensin-aldosterone system would be a useful therapeutic agent for diabetic microangiopathy. Prorenin may be converted to the proteolytic enzyme renin by renal proteases or may change conformation to reveal the active proteolytic site and thus function as active renin. Renin is a highly specific enzyme which acts on only one naturally occurring substrate, angiotensinogen, which is a circulating protein. Renin acts on angiotensinogen to cleave out a fragment called angiotensin I (Al). Al itself has only slight pharmacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE) , forms the potent molecule angiotensin II (All) . The major pharmacological effects of All are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention. Vasoconstriction and sodium retention, which cause blood volume to increase, lead to hypertension. All is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to All, is a less potent vasoconstrictor but a more potent inducer of aldosterone release. Recently, an angiotensin converting enzyme (ACE) inhibitor has been shown to be effective in reducing albuminuria and lowering glomerular hypertension in patients with diabetic nephropathy (see Ho mel, et al., Brit. Med. J. 293 467 (1986)) and, thus, it appears that inhibiting the renin-angiotensin— aldosterone system is useful for reversing or halting the progression of microangiopathy in the diabetic kidney and possibly other diabetic microvascular diseases. In addition, it has recently been shown (Science 245 186 (1989)) that ACE inhibitors have a protective and corrective effect on adverse histologic effects on blood vessels following balloon angioplasty and, therefore, inhibiting the renin-angiotensin- aldosterone system may be useful for preventing and/or reversing biochemical or physical injury to blood vessels. However, ACE acts on several substrates other than angiotensin I (Al), most notably the kinins which cause such undesirable side effects as pain, "leaky" capillaries, prostaglandin release and a variety of behavorial and neurologic effects. Further, ACE inhibition leads to the accumulation of Al . Although Al has much less vasoconstrictor activity than All, its presence may negate some of the hypotensive effects of the blockade of All synthesis. Renin inhibitors have been disclosed as agents for treating systemic hypertension and there are no known side effects which result when renin is inhibited from acting on its substrate. Disclosure of the Invention It has now been discovered that renin inhibitors are useful for the prevention, treatment, inhibition or reversal of vascular diseases including those vascular diseases associated with functional and/or anatomical abnormalities, and in particular peripheral vascular diseases and microvascular diseases associated with diabetes, especially diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. Examples of renin inhibitors and the methods for preparing the renin inhibitors include, but are not limited to, those disclosed in the following references, which are hereby incorporated by reference. References Disclosing Renin Inhibiting Compounds 1. Luly, et al. , U.S. Patent No. 4,652,551, issued March 24, 1987. 2. Luly, et al. , U.S. Patent No. 4,645,759, issued February 24, 1987. 3. Luly, et al., U.S. Patent No. 4,680,284, issued July 14, 1987. 4. Luly, et al. , U.S. Patent No. 4,725,583, issued February 16, 1988. 5. Luly, et al., U.S. Patent No. 4,725,584, issued February 16, 1988. 6. Riniker, et al., U.S. Patent No. 4,595,677 issued June 17, 1986. 7. Fuhrer, et al., U.S. Patent No. 4,613,676, issued September 23, 1986. 8. Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988. 9. Buhlmayer, et al. , U.S. Patent No. 4,758,584, issued July 19, 1988. 10. Iizuka, et al., U.S. Patent No. 4,656,269, issued April 7, 1987. 11. Iizuka, et al. , U.S. Patent No. 4,711,958, issued December 8, 1987. 12. Veber, et al., U.S. Patent No. 4,384,994, issued May 24, 1983. 13. Boger, et al., U.S. Patent No. 4,470,971, issued September 11, 1984. 14. Boger, et al., U.S. Patent No. 4,477,440, issued October 16, 1984. 15. Boger, et al., U.S. Patent No. 4,477,441, issued October 16, 1984. 16. Veber, et al. r U.S. Patent No. 4,479,941, issued October 30, 1984. 17. Boger, et al., U.S. Patent No. 4,485,099, issued November 27, 1984. 18. Boger, et al. , U.S. Patent No. 4,668,663, issued May 26, 1987. * 19. Boger, et al., U.S. Patent No. 4,665,052, issued May 12, 1987. 20. Bock, et al., U.S. Patent No. 4,636,491, issued November 3, 1987. 21. Boger, et al., U.S. Patent No. 4,661,473, issued April 28, 1987. 22. Bock, et al. , U.S. Patent No. 4,663,310, issued May 5, 1987. 23. Evans, et al. , U.S. Patent No. 4,609,641, issued September 2, 1986. 24. Evans, et al. , U.S. Patent No. 4,665,055, issued May 12, 1987. 25. Boger, et al., U.S. Patent No. 4,668,770, issued May 26, 1987. 26. Boger, U.S. Patent No. 4,743,584, issued May 10, 1988. 27. Raddatz, et al., U.S. Patent No. 4,666,888, issued May 19, 1987. 28. Holzemann, et al. , U.S. Patent No. 4,709,010, issued November 24, 1987. 29. Raddatz, et al. , U.S. Patent No. 4,721,776, issued January 26, 1988. 30. Raddatz, et al. , U.S. Patent No. 4,755,592, issued July 5, 1988. 31. Hoover, U.S. Patent No. 4,599,198, issued July 8, 1986. 32. Bindra, et al . , U.S. Patent No. 4,729,985, issued March 8, 1988. 33. Hoover, U.S. Patent No. 4,668,769, issued May 26, 1987. 34. Bindra, et al. , U.S. Patent No. 4,749,687, issued June 7, 1988. 35. Matsueda, et al. , U.S. Patent No. 4,548,926, issued October 22, 1985. 36. Matsueda, et al. , U.S. Patent No. 4,698,329, issued October 6, 1987. 37. Cazaubon, et al. , U.S. Patent No. 4,481,192, issued November 6, 1984. 38. agnon, et al . , U.S. Patent No. 4,725,580, issued February 16, 1988. m „_, 90/05531 -8- 39. Hansen, et al. , U.S. Patent No. 4,510,085, issued April 9, 1985. 40. Hansen, et al. , U.S. Patent No. 4,514,332, issued April 30, 1985. 41. Baran, et al., U.S. Patent No. 4,657,931, issued April 14, 1987. 42. Hansen, et al., U.S. Patent No. 4,722,922, issued February 2, 1988. 43. Ryono, et al., U.S. Patent No. 4,616,088, issued October 7, 1986. 44. Ryono, et al., U.S. Patent No. 4,665,193, issued May 12, 1987. 45. Ryono, et al. , U.S. Patent No. 4,629,724, issued December 16, 1986. 46. Natarajan, et al., U.S. Patent No. 4 r 757,050, issued July 12, 1988. 47. Gordon, U.S. Patent No. 4,749,781, issued June 7, 1988. 48. Szelke, et al., U.S. Patent No. 4,609,643, issued September 2, 1986. 49. Szelke, et al. , U.S. Patent No. 4,650,661, issued March 17, 1987. 50. Szelke, et al., U.S. Patent No. 4,713,445, issued December 15, 1987. 51. Thaisrivongs, U.S. Patent No. 4,705,846, issued November 10, 1987. 52. Hudspeth, et al., U.S. Patent No. 4,735,933, issued April 5, 1988. - 53. Hudspeth, et al. , U.S. Patent No. 4,743,585, issued May 10, 1988. 54. Sham, U.S. Patent No. 4,826,958, issued May 2, 1989. 55. Rosenberg, et al., U.S. Patent No. 4,857,507, issued August 15, 1989. 56. Luly, et al., U.S. Patent No. 4,826,815, issued May 2, 1989. 57. Rosenberg, et al. , U.S. Patent No. 4,837,204, issued June 6, 1989. 58. Luly, et al., U.S. Patent No. 4,845,079, issued July 4, 1989. 59. Bender, et al. , U.S. Patent No. 4,818,748, issued April 4, 1989. 60. Kleinman, et al. , U.S. Patent No. 4,729,985, issued March 8, 1988. 61. Hoover, et al. , U.S. Patent No. 4,814,342, issued March 21, 1989. 62. Wagnon, et al. , U.S. Patent No. 4,746,648, issued May 24, 1988. 63. Natarajan, et al., U.S. Patent No. 4,757,050, issued July 12, 1988. 64. Patel, U.S. Patent No. 4,820,691, issued April 11, 1989. 65. Kaltenbronn, et al. , U.S. Patent No. 4,804,743, issued February 14, 1989. 66. Pinori, et al. , U.S. Patent No. 4,560,505, issued December 24, 1985. 67. Yamato, et al. , U.S. Patent No. 4,683,220, issued July 28, 1987. 68. Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989. 69. Patchett, et al., U.S. Patent No. 4,839,357, issued June 13, 1989. * 70. Boger, et al. , U.S. Patent No. 4,812,442, issued March 14, 1989. 71. Veber, et al. , U.S. Patent No. 4,478,826, issued October 23, 1984. 72. Raddatz, et al. , U.S. Patent No. 4,812,555, issued March 14, 1989. 90/05531 -10- 73. Wagnon, et al., U.S. Patent No. 4,840,935, issued June 20, 1989. 74. Iizuka, et al. , U.S Patent No. 4,841,067, issued June 20, 1989. 75. Raddatz, et al., U.S. Patent No. 4,829,053, issued May 9, 1989. Preferred renin inhibitors and methods for making them include those disclosed in U.S. Patent No. 4,826,815, issued May 2, 1989; U.S. Patent No. 4,857,507, issued August, 15, 1989; U.S. Patent No. 4,826,958, issued May 2, 1989; U.S. Patent No. 4,837,204, issued June 6, 1989; U.S. Patent No. 4,845,079 issued July 4, 1989, which are hereby incorporated by reference. Preferred renin inhibitors and methods for making them also include those disclosed in copending U.S. patent applications, USSN 403,906, filed September 1, 1989; USSN 231,869, filed August 16, 1988 (EP0307837, published March 22, 1989); USSN 132,356, filed December 18, 1987 (WO88/05050, published July 14, 1988); PCT/US89/04385, filed October 3, 1989; and PCT/US89/04649, filed October 18, 1989, which are hereby incorporated by reference. The preferred renin inhibiting compounds of this invention are selected from the group consisting of compounds of the formula: (1) wherein A is hydrogen, loweralkyl, arylalkyl, -0 2Q wherein R 2Q is hydrogen, or loweralkyl, -NR„ R wherein R-. and R_ 2 are independently selected from hydrogen and loweralkyl; or A is wherein B is NH, 0, CH_ or NHCH 2 ; and _ 3 is loweralkyl, alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkoxycarbonyalkyl, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic; W is C=0, CH 2 or CHOH; U is CH- or NR 2 , wherein R 2 is hydrogen or loweralkyl, provided that when W is CHOH then U is CH 2 ; 1 is loweralkyl, eyeloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthy1)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R 1 is phenoxy, thiophenoxy or anilino, then B is CH 2 or A is hydrogen; « is loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; 5 is hydrogen or loweralkyl; - is loweralkyl, cycloalkylmethyl, or benzyl; R_, R Q and R g are hydrogen or loweralkyl -12- and may be the same or different; V is NH, O, S, SO, SO 2' or CH 2' R _ is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or V and R, Q taken together are N 3 ; with the proviso that R, 0 may be an N—protecting group only when V is NH; (2) wherein A, is hydrogen, loweralkyl, arylalkyl; OR__, or SR 2Q , wherein R 20h -~ S hydrogen, loweralkyl or aminoalkyl, N - R 21b' R 22b wn erein R ib an( ^ R 22b are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A, is wherein B, is NH, alkylamino, S, 0, CH 2 , or CHOH; and E. 2 3h is -*- owera -*-- s Y 1 ' cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) mino, -13- (dihydroxyalkyl) (alkyl) mino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic; W fa is C=0 or CHOH; U , is CH, or N*R 2 b' wh s rein R 2 b is hydrogen or loweralkyl, provided that when , is CHOH lb is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R.,, is phenoxy, thiophenoxy or anilino, then B is CH 2 or CHOH or A, is hydrogen; R 3b is loweralkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl; j .. is hydrogen or loweralkyl; g , is loweralkyl, cycloalkylmethyl, or benzyl; R ι θb *^ s ■*- owera **-kyl' cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or L, and -R 10b taken together can be N_, with the proviso that when is NH then R 10b is an N-protecting group; R 13b is CH0H or 0; R 14b is CH 2' CF 2 or F wit - tl tlιe Proviso that when R 13b is CO then R 14t) s CF 2 ; R 15b is CH 2' CHR 25b wherein R 2 5b iS loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or . 90/05531 -14- arylalkyl, or R T4h and --■ -_ ] . taken together can be • C C— I I F H with the proviso that when R χ4 is CF 2 then 15 is L b is 0, S, SO, S0 2 , R 26b wherein R 2gb is hydrogen or loweralkyl, or NR 2 _ b C(0) wherein R 27b is hydrogen or loweralkyl; (3) wherein A is wherein B is NH, or CH 2 ; and -R 23c is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic; U is -~~- 2c ' wherein R 2 is hydrogen or loweralkyl; R χ is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alph )-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl; R-_r is loweralkyl, benzyl or heterocyclic ring substituted methyl; R j . is hydrogen or loweralkyl; R fi is loweralkyl, cycloalkylmethyl, benzyl, or CH 2 R 24 , where R 24c is selected from l,3-dioxan-2-yl; 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl; R,16,„c is CH2_, CF2_ or CHR6,.3.-.c where -._6.3_c„ is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl; R-_ is hydrogen or loweralkyl; R lfi is loweralkyl or lipophilic or aromatic amino acid side chain; D is hydrogen, loweralkyl or ~CH 2 OR 28c' wherein R„ R is hydrogen, loweralkyl or arylalkyl; (4) wherein A, is hydrogen, loweralkyl, arylalkyl, ~OR 20d or ~SR 20d wherein 20d is h y dro ? en ' loweralkyl or aminoalkyl, ~NR 2 1 d R 22d wherein R id and R* 22d are i n dependently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A, is wherein B, is NH, alkylamino, S, 0, CH 2 , or NHCH 2 , and -R* 23d is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl) (alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic; U d is CH 2 or NR 2 , r wherein R 2 , is hydrogen or loweralkyl, provided that when W, is CHOH then U, is CH 2 ; R ld is CHR,., wherein R- 24c = is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, (alpha, alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl, or -j is C=CHR 25 , wherein R 25d is aryl; R 3d is loweralkyl, alkenyl, benzyl or heterocyclic ring substituted methyl; 5 , is hydrogen or loweralkyl; ■ 17- Εd is loweralkyl, cycloalkylmethyl, or benzyl; R -_. , is hydrogen or hydroxy; n is 0 or 1; when n is 0 then , is alkylidene or alkylidene oxide; and when n is l then Z-, is hydrogen or hydroxy and T, is loweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl; R 1 2d ^ s hydrogen, loweralkyl, cycloalkylalkyl, arylalkyl, aminoalkyl, or dialkylaminoalkyl; ( 5 ) wherein A is hydrogen, loweralkyl, arylalkyl, -OR 20e or -SR 20e wherein R 20e iε h y dro< 3 en ' loweralkyl or aminoalkyl, _NR 2l e R 22e wtιerein R 2 i e and R 2 e are i nde P endentl y selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; wherein B is NH, alkylamino, S, 0, CH,, or CHOH; e ■" and R 23 is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl) (alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic; e is C=0; U is NK* 2 e' w ^ ere i n R 2 o ^ s n y3 *ro< 3 en or loweralkyl; R, is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthy1)methyl, (2-naphthy1)methyl, ( -imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when R, is phenoxy, thiophenoxy or anilino, then B is CH 2 or CHOH or is hydrogen; R_ is loweralkyl, benzyl or heterocyclic ring substituted methyl; R 5 is hydrogen or loweralkyl; R g is loweralkyl, cycloalkylmethyl, or benzyl; M is 0, NH or S; R 10e is h y <iro '? en ' loweralkyl , cycloalkyl , (cycloalkyl) alkyl , aryl , arylalkyl or an N-protecting group ; -19- ( 6 ) wherein A is hydrogen, loweralkyl, arylalkyl. -ORlOf or " SR ιof where: *- n R ιo s hydrogen, loweralkyl or aminoalkyl, -NR ι1 f R 1 f wherein R 1]L £ and ~- 12f are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, (amino)carboxyalkyl, ( (N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkyl, (dialkylamino)carboxyalkyl, (amino)alkoxycarbonylalkyl, ((N-protected)amino)alkoxycarbonylalkyl, (alkyamino)alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonylalkyl and (dialkylamino)alkoxycarbonylalkyl; or A is wherein B f is NH, alkylamino, S, 0, CH 2 or CHOH and R- 3f is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, ,„ 90/05 -20- dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-p otected- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyl, carboxyalkyl, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino, (amino)carboxyalkyl, (amino)carboxyalkylamino, ((N-protected)amino)carboxyalkyl, ((N-protected) mino)- carboxyalkyamino, (alkylamino)carboxyalkyl, ( lkylamino)carboxyalkylamino, ((N-protected)alkylamino)- carboxyalkyl, ((N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl, (amino)alkoxycarbonylalkylammo, ((N-protected)amino)alkoxycarbonylalkyl, ((N-protected)amino)- alkoxycarbonylalkylammo, (alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylammo, ((N-protected)alkylamino)- alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonyl- alkylamino, (dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylammo, ammocycloalkyl, aminoalkylamino, dialkylaminoalkyl(alkyl)amino, arylalkylamino, arylalkyl(alkyl)amino, alkoxyalkyl(alkyl)amino, (polyalkyoxy)- alky1(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy, (polyalkoxy)alkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyclics may be unsubstituted. monoεubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; W f is C=0 or CHOH; U f is CH 2 or NR_, provided that when W f is CHOH then U f is CH 2 ; R lf is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alph )-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R f iε phenoxy, thiophenoxy or anilino, then B £ iε CH 2 or CHOH or A f is hydrogen; R 2f is hydrogen or loweralkyl; RJ- £ __. is loweralkyl, loweralkenyl, ( (alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R c bi~. is loweralkyl, cycloalkylmethyl or benzyl; R - is vinyl, for yl, hydroxymethyl or hydrogen; R, f is hydrogen or loweralkyl; R b f anc ^ R ef are i nde P enden't ly selected from OH and NH 2 ; and R , is hydrogen, loweralkyl, vinyl or arylalkyl; -22- ( 7) . Rig O R 4 g wherein A is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substituted phenyl)alkyl wherein the phenyl ring is substituted with one, two or three subεtituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, naphthylalkyl, (subεtituted naphthyl)alkyl wherein the naphthyl ring is εubεtituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, substituted or unsubstituted heterocyclic, where saturated heterocyclics may be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyhaloalkyl; -unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweraklyl, haloalkyl or polyhaloalkyl, or A is ( ■ unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A is -OR., or g 'y -SR_/g wherein R_/g iε hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy) (alkyl)aminoalkyl, phenylalkyl, (substituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein the substituted naphthyl is as defined above, substituted or unsubεtituted heterocyclic aε defined above, (unεubεtituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, (unsubstituted heterocyclic)C(O)- or (substituted heterocyclic)C(O)- wherein unsubεtituted or substituted heterocyclic is as defined above ; or A iε -NR 8 σ R 9σ wnerein R 8 σ and R g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or iε wherein B is NH, alkylamino, S, O, CH 2 , NHCH 2 or CH(OR 52 ) wherein R 52σ is hydrogen, loweralkyl or loweralkylcarbonyl, and *R* 10σ is hydrogen, loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl-, substituted naphthyl as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxy wherein substituted phenyl is as defined above, naphthylalkoxy, (substituted naphthyl)alkoxy wherein substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl) lkoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalkyl, (substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein subεtituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, a substituted or unsubstituted heterocyclic as defined above, ammocycloalkyl, aminoalkylamino, (dialkylaminoalkyl)(alkyl)amino, phenylalkylamino, (substituted phenyl)alkylamino wherein substituted phenyl is as defined above, naphthylalkylamino, (substituted naphthyl)alkylamino wherein substituted naphthyl is as defined above, (phenylalkyl)(alkyl)amino, ((substituted phenyl)alkyl)(alkyl)amino wherein substituted phenyl is as defined above, (naphthylalkyl)(alkyl)amino, ((substituted naphthyl)alkyl)(alkyl)amino wherein substituted naphthyl is as defined above, alkoxyalkyl(alkyl)amino, (polyalkoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, ((heterocyclic)alkyl) (alkyl)amino, ( (heterocyclic)alkyl)amino, (heterocyclic) (alkyl)amino, (alkylaminoalkyl) (alkyl)amino, (dialkylaminoalkyl) (alkyl)amino, ((alkoxy)(alkyl)aminoalkyl) (alkyl)amino, ( (alkoxy)aminoalkyl)(alkyl)amino, polyalkoxy or (polyalkoxy)alkyl; or A is R 4 CH(OH)CH 2 ~ or R CH(OH)CH(OH)- wherein R 4 is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, phenylalkyl, (subεtituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein subεtituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl)alkoxyalkyl wherein substituted phenyl iε aε defined above, naphthylalkoxyalkyl, (substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylεulfinylalkyl, loweralkylεulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, heterocyclicalkyl, a substituted or unsubεtituted heterocyclic as defined above, ammocycloalkyl or (polyalkoxy)alkyl; W is C=0, CHOH or NR_ wherein R is hydrogen or loweralkyl; U is C=0, CH 2 or NR- wherein R 2 is hydrogen or loweralkyl, with the proviso that when W is CHOH then U is CH 2 and with the proviso that U is C=0 V is CH, C(OH) or C(halogen) with the proviso that Vg„ is CH when Ug is NR 0 2g: R, is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthy1)methyl, (unεubεtituted heterocyclic)methyl, (εubstituted heterocyclic)methyl wherein unsubstituted or subεtituted heterocyclic iε as defined above, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B is CH 2 or CHOH or A is hydrogen when R., is phenoxy, thiophenoxy or anilino; R 3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy) lkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, di lkylaminoalkyl, (alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzyl or heterocyclic ring substituted methyl; R. is loweralkyl, cycloalkylmethyl or benzyl; -27- Z g is wherein is 0, S or NH, T is C=0, C=S, S, S(O), S(0) Δ or CH___,, E_g_ is 0, S, N ,o.„ wherein R,.„ is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E is CR 6σ R 2σ wherein R, is as defined above and *R 42σ is hydrogen or loweralkyl or E is c=CR 4 3 σ R 44σ wherein R 43σ and R 44 σ are i nde endent --Y selected from hydrogen and loweralkyl, G is absent, CH 2# or NR llσ wherein R li σ ^ s hydrogen or loweralkyl, with the proviso that when Gg„ is NRl,l_.g „ then R6-.g„ is loweralky -l or hydroxyalkyl, Q g is C 45g R 4gg wherein R 45g and R 46 are independently selected from hydrogen and loweralkyl or Q is c=CR 7σ R 4 oσ wherein *R 47σ and R 48 σ are independently selected from hydrogen and loweralkyl, and R 49σ is -CH 2 OH, carboxy, alkoxycarbonyl or - ~CONR 50σ R 5 i σ w herein R 50σ is hydrogen or loweralkyl and R 51σ is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl; 90/055 -28- ( 8 ) wherein A, is hydrogen, loweralkyl, arylalkyl, ~OR 2 0 h or _SR 20 h w herein *R 2Q -_ is hydrogen, loweralkyl or aminoalkyl, -NR 2l h* 22 h wherein *R 21 -_ and R 22tl are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A, is wherein B, is NH, alkylamino, S, O, CH 2 , NHCH 2 or CHOH; and E* 23tl is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic; W h is C=0 or CHOH; ^ is CH 2 or NR 2h , wherein 2 , is hydrogen or loweralkyl, provided that when W, is CHOH then U. iε CH 2 ; R lh iε loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthy1)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when R,, is phenoxy, thiophenoxy or anilino, then B, is CH 2 or CHOH or A, is hydrogen; R-. is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; 5h is hydrogen or loweralkyl; R gh is loweralkyl, cycloalkylmethyl, or benzyl; /05531 -3 0 - wherein Ai is (I) R 5i C (0) - (CH 2 ) w „- wherein 1) " is 0 to 4 and 2 ) R 5 i is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino; (II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl; (III) aryl, arylalkyl, heterocyclic or (heterocyclic)alkyl; or (IV) R 90i ~ or R 9Qi NHC(0)- wherein R goi is a C. to C. straight or branched carbon chain substituted by a substituent selected from 1) carboxy r 2) alkoxycarbonyl, 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6) heterocyclic or 7) (heterocyclic) sulfonyl) ; (I) hydrogen. (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (VIIII) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a C. to C, straight or branched carbon chain substituted by a substituent selected from 1) alkoxy, 2) thioalkoxy, . 3) aryl and 6) heterocyclic; is (I) CH 2 , (II) CHOH, (III) C(O), (IV) NH, (V) 0, (VI) S, (VII) S(0), (VIII) so 2 , (IX) N(0) or (X) -P(0)0-; ι is (I) loweralkyl, (II) haloalkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy) alkyl, (IX) hydroxyalkyl, (X) -(CH 2 ) ee NHR 12i wherein 1) ee is 1 to 3 and 2) R 12i is i) hydrogen, ii) loweralkyl or iii) an N-protecting group; (XI) arylalkyl or (XII) (heterocyclic) alkyl; and Ti is wherein R.. is 4x (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and -33- s wherein R 73i s loweralkyl, v) NR lgi wherein R 18i is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and 4) Gi is i) absent, ii) CH 2 or iii) NR.1,-9x. wherein R-1 Q 9x. is hydrogen or loweralkyl, with the proviso that when Gi is NR_. „. , then R-. R • is loweralkyl or hydroxyalkyl; (III) -(CH 2 ) v ..-C(0)-N R 21I wherein 1) v" is 0 or 1 and 2) R 21i is i) NH, ii) 0, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; and (10) wherein X j is (I) N, (II) 0 or (III) CH; xs ^ij (I) absent, (II) hydrogen, (III) an N-protecting group, (IV) aryl, (V) heterocyclic, or (VI) R-.-Qj- wherein 1) R c . is i) loweralkyl, ii) amino, iii) alkylamino, iv) dialkylamino, v) (alkoxyalkyl) (alkyl) amino, vi) (alkoxyalkoxyalkyl) (alkyl)amino, vii) aryl, viii) arylalkyl, ix) aminoalkyl, x) (N-protected) minoalkyl, -36- xi) alkoxy, xii) substituted, loweralkyl wherein the substituent is selected from. alkoxy, thioalkoxy, halogen, alkylamino, (N-protected) (alkyl) amino and dialkylamino, xiii) wherein m* ' ' is 1 to 5 and R_ . is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or dialkylamino; or xiv) wherein R8 D j. is 0, S, S02, 0=C or R n 9j.N wherein R g . is hydrogen, loweralkyl or an N-protecting group; and 2) Q j is i) C=0 or ii) CH 2 , with the proviso that X j is N when R... is an N-protecting group; (VII) R 5 - .S(0) 2 - wherein R 5 - . is 1) amino, 2) alkylamino, 3) dialkylamino, 4) loweralkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl, 8) heterocyclic or (VIII) (R_ c .) P(0)- wherein R__ . is 3D] _! D O 1) alkoxy, 2) alkylamino or 3) dialkylamino; Aj and Lj are independently selected from .(I) absent, (ID C=0, (III) S0 2 and (IV) CH 2 ; Dj is (I) C=0, (II) S0 2 or (III) CH 2 ; Yj is (I) N or (II) CH; xs ^2j (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, (IV) -CH 2 -R 1Q ,-(CH 2 ) t l l -R n , wherein 1) q » • ' is 0, 1 or 2, -38 - 2) - 0 . is absent or - Q . is O, NH or S only when q' l ' is 1 or 2, and 3) R ι;Lj is i) aryl or ii) heterocyclic; xs (I) hydrogen or ( II ) -R 2 8j C(0)R 29j' "R 28jS ( 0 ) 2 R29j or -R 2 8jC(S)R29j wherein 1) R 28j is i) NH, ii) -N(R200j) _ wherein R20OJ is loweralkyl or benzyl or iii) CH 2 and 2) R 29 . is i) alkoxy, ii) benzyloxy, iii) alk lamino, iv) dialkylamino, v) aryl or vi) heterocyclic; R-, . is 3D (I) hydrogen, (II)* loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIIII) (alkoxyalkoxy) alkyl, (IX) (polyalkoxy) alkyl, (X) arylalkyl or (XI) (heterocyclic)alkyl; n 1 ' ' is 0 or 1; and wherein R.. is 4D (I) loweralkyl, (II) cycloalkylalkyl or (III) arylalkyl; and R c . is wherein R__ . is loweralkyl, wherein 1) M j is i) 0, ii) S or iii) NH; 2) Qj is i) O or ii) S; 3) Ej is i) 0, ii) S, iii) CHR 6,-1j . wherein R 6,-1j . is loweralkyl, iv) C=CH 2 or v) R lg . wherein R lg . xs a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) aIk 1amino; and 4) G j is i) absent, ii) CH 2 or iii) NR.1.9 -3 , wherein R-1 Q 9j. is hydrogen or loweralkyl, with the proviso that when G j is NR, Λ .. then R- 0 . is loweralkyl or 13 183 hydroxyalkyl; (III) -(CH 2 ) v ....C(0)—N R 21j wherein 1) v 1 ' ' is 0 or 1 and 2) R 21j is i) NH, ii) 0, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof. The term "loweralkyl" as used herein referε to εtraight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methyl-pentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl and the like. the term "loweralkenyl" as used herein refers to a straight or branched chain loweralky radical which contains at least one carbon-carbon double bond. The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl residue appended to a loweralkyl radical and includes but is not limited to cyclohexylmethyl and cyclopentylmethyl. The term "cycloalkenyl" as used herein refers to an aliphatic ring having 3-7 carbon atoms and also having at least one carbon-carbon double bond including, but not limited to, cyclohexenyl and the like. The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical including, but not limited to, cyclohexenylmethyl, cylcopentenylethyl and the like. The term "arylalkyl" as used herein refers to an aryl group as defined herein appended to a loweralkyl radical including but not limited to benzyl, 1- and 2-naphthylmethyl, halobenzyl, and alkoxybenzyl. The term "phenylalkyl" as used herein refers to a phenyl group appended to a loweralkyl radical, including, but not limited to benzyl, phenethyl and the like. The term "(substituted phenyl)alkyl" as used herein refers to a subεtituted phenyl group appended to a loweralkyl radical wherein the phenyl ring is substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halobenzyl, alkoxybenzyl and the like. The term "naphthylalkyl" as used herein refers to a naphthyl group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethyl, 2-naphthyimethyl and the like. The term "(substituted naphthyl)alkyl" as used herein refers to a substituted naphthyl group appended to a loweralkyl radical wherein the naphthyl ring is substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthyImethyl, alkoxynaphthyImethyl and the like. The term "(heterocyclic)alkyl" as used herein refers to an unsubstituted or substituted heterocyclic ring as defined below appended to a loweralkyl radical, including, but not limited to imidazolyImethyl, thiazolyImethyl and the like. The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical. The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical. The term "arylalkoxyalkyl" as used herein refers to an arylalkoxy appended to a loweralkyl radical _. ,_. * _ _ 0/05 -44- The term "phenylalkoxyalkyl" aε uεed herein referε to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to phenylmethoxymethyl and the like. The term "(εubεtituted phenyl)alkoxyalkyl" as used herein refers to a (substituted phenyl)alkoxy group appended to a loweralkyl radical, including, but not limited to 4-chlorophenylmethoxymethyl. The term "naphthylalkoxyalkyl" as used herein refers to a naphthylalkoxy group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethoxymethyl and the like. The term "(subεtituted naphthyl)alkoxyalkyl" as uεed herein refers to a (substituted naphthyl)alkoxy group appended to a loweralky radical, including, but not limited to halonaphthylmethoxymethyl and the like. The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group appended to a loweralkyl radical. The term "((alkoxy)alkoxy)alkyl" aε used herein refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical, including, but not limited to methoxymethoxymethyl and the like. The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residue appended to a loweralkyl radical, including, but not limited to methoxyethoxymethoxymethyl and the like. The term "aminoalkyl" aε used herein refers to -NH 2 appended to a loweralkyl radical. The term "alkylaminoalkyl" as used herein refers to -NHR_ Q appended to a loweralkyl radical, wherein R_ 0 is a loweralkyl radical. The term "dialkylaminoalkyl" as used herein refers to a dialkylamino appended to a loweralkyl radical . The term "ammocycloalkyl" as used herein refers to an -NH 2 appended to a cycloalkyl radical. The term "N-protected aminoalkyl" as used herein refers to -NHR-, appended to a loweralkyl group, wherein R-. is an N-protecting group. The term "(N-protected)(alkyl)amino alkyl" as used herein referε to NR 71 R 72 which is appended to a loweralkyl radical, wherein 71 iε defined aε above and R 72 is a loweralkyl group. The term "alkoxycarbonylalkyl" as used herein refers to R 73 C0R 74 -, wherein R 73 is an alkoxy group and R ? . is a loweralkyl radical. The term "carboxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical. The term "cyanoalkyl" as used herein refers to -CN appended to a loweralkyl radical. The term "azidoalkyl" as used herein refers to -N 3 appended to a loweralkyl radical. The term "(alkoxy)aminoalkyl" as used herein refers to an alkoxy group appended to an amino group which in turn is appended to a loweralkyl radical. The term "(alkoxy)(alkyl)aminoalkyl" as used herein refers to an -N _ 5 R 7g group appended to a loweralkyl radical wherein R 75 is an alkoxy group and R 76 is a.loweralkyl group. The term "loweralkylsulfinylalkyl" as used herein refers to a R ?7 S(0)- group appended to a loweralkyl radical wherein R 77 is a loweralkyl group. The term "loweralkylsulfonylalkyl" aε used herein refers to a R 7g S(0) 2 - group appended to a loweralkyl radical wherein R 7g is a loweralkyl group. The term "phenylthioalkyl" as used herein refers to a R 7g S- group appended to a loweralkyl radical wherein R ?g is a phenyl group. The term "(substituted phenyl)thioalkyl" as used herein refers to a *R* 80 S- group appended to a loweralkyl radical wherein R g _ is a substituted phenyl group. The term "naphthyl thioalkyl" as used herein refers to a Ro 0 ,S- group appended to a loweralkyl radical wherein R gl is a naphthyl group. The term "(substituted naphthyl)thioalkyl" as used herein refers to a R g2 S- group appended to a loweralkyl radical wherein R g2 is a substituted naphthyl group. The term "phenylεulfonylalkyl" aε used herein refers to a R g3 S(0) 2 ~ group appended to a loweralkyl radical wherein R g3 is a phenyl group. The term "(substituted phenyl)sulfonylalkyl" as used herein refers to a R g4 S(0) 2 ~ group appended to a loweralkyl radical wherein R g . is a substituted phenyl group. The term "naphthylsulfonylalkyl" as used herein refers to a R g5 S(0) 2 - group appended to a loweralkyl group wherein R g5 is a naphthyl group. The term "(substituted naphthyl)sulfonylalkyl" as used herein refers to a R gg S(0) 2 - group appended to a loweralkyl group wherein R gg is a substituted naphthyl group. The term "carboxyalkoxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to an alkoxy group which iε appended to a loweralkyl radical. The term "alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R g7 C0- wherein R g _ is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical. The term "(amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-C00H) and an amino group (-NH 2 ). The term "( (N-protected)amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR gg wherein R gg is an N-protecting group. The term "(alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an alkylamino group. The term "( (N-protected)alkylamino)- carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR gg R go wherein R gg is as defined above and R gQ is a loweralkyl group. The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-C00H) and -NR gι R g2 wherein R g . and R g2 are independently selected from loweralkyl. The term "(amino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended.an alkoxycarbonyl group as defined above and an amino group (-NH-). The term "((N-protected)amino)alkoxy¬ carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR g3 wherein R g3 is as defined above. The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above. The term "((N-protected)alkylamino)- alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR g4 R g5 wherein R g4 is an N-protecting group and R g5 is a loweralkyl group. The term "(dialkylamino)alkoxycarbonyalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR g R g7 wherein R gg and R g? are independently selected from loweralkyl. The term "carboxyalkylamino" as used herein refers to -NHR gg wherein R gg is a carboxyalkyl group. The term "alkoxycarbonylalkylammo" as used herein refers to -NHR gg wherein R gg is an alkoxycarbonylakyl group. The term "(amino)carboxyalkylamino" as used herein refers to -NHR 1Q0 wherein *R 100 is an (amino)carboxyalkyl group. The term-"((N-protected)amino)carboxy¬ alkylamino" as used herein refers to -NHR- Q1 wherein R lθ i ^ s an ( N ~P rotecte ^)- a no)carl30χ y alk yi group. The term"(alkylamino)carboxyalkylamino" as used herein refers to -NHR- 02 wherein R 102 is an (alkylamino)carboxyalkyl group. The term "((N-protected)alkylamino)- carboxyalkylamino" as used herein refers to -NHR 1Q3 wherein *R 103 is an ( (N-protected) alkylamino ) - carboxyalkyl group . The term " ( dialkylamino ) carboxyalkylamino" as used herein refers to -NHR η 1 n 04. wherein R, 1 n 04. is a (dialkylamino)carboxyalkyl group. The term"(amino)alkoxycarbonylalkylammo" as used herein refers to -NHR 1Q5 wherein ~ - 1 Q 5 is an (amino)alkoxycarbonylalkyl group. The term "((N-protected)amino)alkoxy- carbonylalkylamino" as used herein refers to -NHR 1Qg wherein R 10g is an ((N-protected)amino)- alkoxycarbonylalkyl group. The term "(alkylamino)alkoxycarbonylalkylammo" aε used herein refers to -NHR- Q7 wherein *R 1Q7 is an (alkylamino)alkoxycarbonylalkyl group. The term "( (N-protected)alkylamino)alkoxy¬ carbonylalkylammo" as used herein refers to -NHR 1Qg wherein R, 08 is an ((N-protected)alkylamino)- alkoxycarbonylalkyl group. The term "(dialkylamino)alkoxycarbonyl¬ alkylammo" as used herein refers to -NHR 1Qg wherein R log is a (dialkylamino)alkoxycarbonylalkyl group. The term "alkylidene" as used herein refers to a straight or branched chain alkyl radical which is attached via a carbon-carbon double bond and includes but is not limited to methylidene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 2-propylidene, 2-butylidene, 2-pentylidene, 3-pentylidene, 3-hexylidene, 3-heptylidene and 4-heptylidene. The term "alkylidene oxide" as used herein refers to an epoxide moiety which is derived from an alkylidene group. -50- The term "amino" as used herein refers to an —NH„ substituent. The term "alkylamino" as used herein refers to -NHR - 0 , wherein ~ - 11 Q is a loweralkyl group. The term "dialkylamino" as used herein refers to -NR 11 ι R 112 ' wherein -R*,*,*, and R,, 2 are independently selected from loweralkyl groups. The term "arylalkylamino" as used herein refers to R _NH-, wherein ■£-,-,■■■ > is an arylalkyl residue. The term "arylalkyl(alkyl)amino" as used herein refers to R 114 R 115 N- '- wherein ---, -, , is an arylalkyl residue and -R 115 is a loweralkyl residue. The term "phenylalkylamino" as used herein refers to a phenylalkyl group appended to an amino radiόal, including, but not limited to benzylamino and the like. The term "(subεtituted phenyl)alkylamino" aε uεed herein refers to a (substituted phenyl)alkyl group appended to an amino radical, including, but not limited to 4-chlorobenzylamino and the like. The term "napthylalkylamino" as used herein refers to a naphthylalkyl group appended to an amino radical, including, but not limited to 1-naphthyImethylamino and the like. The term "(substituted naphthyl)alkylamino" as used herein refers to a (substituted naphthyl)alkyl group appended to an amino radical. The term "(phenylalkyl)(alkyl)amino" as used herein refers to R llg R 117 N-, wherein R llg iε a phenylalkyl residue and R 117 is a loweralkyl residue. The term "((substituted phenyl)alkyl)- ( lkyl)amino" as used herein refers to R_.._R,,_N- wherein -R- 118 is a (substituted phenyl)alkyl group and R H9 ^ Ξ a i°weralkyl group. The term "(naphthylalkyl)(alkyl)amino" as used herein referε to R ι n R 1 ι N ~ wherein ~- 12 Q ^ S a naphthylalkyl group and R 12 *ι is a loweralkyl group. The term "((substituted naphthyl)alkyl)- (alkyl) mino" as used herein refers to R i22 R i23 N ~ wherein R* 122 is a (substituted naphthyl)alkyl group and ~- 123 i a loweralkyl group. The term "aminoalkylamino" as used herein referε to R 12 .NH- where *R 124 is an aminoalkyl reεidue. The term "dialkylamino(alkyl)amino" as used herein refers to R 125 R i26 N_ ' wn erein *R 125 is a dialkylamino residue appended to a loweralkyl residue and ~- 12 r is a loweralkyl residue. The term "((dialkylamino)alkyl)(alkyl)amino" as used herein refers to -NR 127 R i28 wherein R 127 is a dialkylamino residue appended to a loweralkyl residue and R... is a loweralkyl residue. The term "(hydroxyalkyl)(alkyl) mino" as used herein refers to _NR 129 R i30 wherein R 12g is a hydroxyalkyl group and R 130 is a loweralkyl group. The term "(di-hydroxyalkyl)(alkyl)amino" aε uεed herein refers to a loweralkyl group which is disubstituted with -OH radicals appended to an amino group, which amino group also has appended another loweralkyl group. - The term "di-(hydroxyalkyl)amino" as used herein refers to R i3 i R *i 32 N ~' wherein R 131 and R 132 are*hydroxyalkyl residues. The term "alkoxyalkyl(alkyl) mino" as used herein refers to R i 3 3 R i 3 4 N ~' wherein R 133 is a loweralkyl group and is an alkoxyalkyl group. The term "di-(alkoxyalkyl)amino" as used herein refers to R. 1.3_5 C R.13_ _6.N- , wherein R,13, c 5 and R,13- c 6 are alkoxy reεidueε appended to loweralkyl residues. The term "di-(polyalkoxyalkyl)amino" as used herein refers to R 137 R 13g N-, wherein R 137 and R i38 are P°ly a -i- 5 o χ residueε appended to loweralkyl residues. The term "((polyalkoxy)alkyl)(alkyl)amino" as used herein refers to R *- q R ;ι 4 n N- ' wherein R* 13g is a polyalkoxy residue appended to a loweralkyl radical and ~- 1AQ is a loweralkyl residue. The term "((heterocyclic)alkyl)(alkyl)amino" as used herein refers to -NR. 14.1.R.14.2 wherein R,14.,1 iε a heterocyclicalkyl group and R* 142 is a loweralkyl group. The term "(heterocyclicalkyl)amino" as used herein refers to -NHR. 1.4.3- wherein R,14._3 is a heterocyclic alkyl group. The term "(heterocyclic)(alkyl)amino" as used herein refers to -NR. 1.4.4.R,14. c 5 wherein R.14.4. is a substituted or unsubstituted heterocyclic group and R 45 is a loweralkyl group. The term "(alkylaminoalkyl)(alkyl)amino" as used herein refers to -NR η 14.6..R.1.4._7 wherein R.14.6.. is an alkylaminoalkyl group and R 147 is a loweralkyl group. The term "(dialkylaminoalkyl)(alkyl)amino" as used herein refers to -NR T 14. Q 8R η 14. Q 9 wherein R,14.8 0 is a dialkylaminoalkyl group and R 149 is a loweralkyl group. The term "((alkoxy)(alkyl)aminoalkyl)- (alkyl)amino" as used herein refers to -NR.l,_oU_R,15__1 wherein R 150 is - 152 R_ 53 appended to a loweralkyl radical wherein R* 152 is an alkoxy group and R χς _ is a loweralkyl group and -- 151 is a loweralkyl group. The term "( (alkoxy)aminoalkyl)(alkyl)amino" as used herein refers to _NR i54 R i55 wherein R 154 is -NHR- 1. C 5b / . appended to a loweralkyl group and wherein R 15g is an alkoxy group and *R 155 is a loweralkyl group. The term "(alkoxyalkoxyalkyl)(alkyl)amino" as used herein refers to -NR 305 R 3Qg wherein R 3Q5 is an alkoxyalkoxyalkyl group and R 30g is a loweralkyl group. The term "di(alkoxyalkoxyalkyl)amino" as used herein refers to -N 307 R 3Qg wherein *R 307 and R 3Qg are alkoxyalkoxyalkyl groups. The term "alkylsulfonylamino" aε used herein refers to R 30g NH- wherein *R 30g is an alkylsulfonyl gorup. The term "arylsulfonylamino" as used herein refers to R 31Q H- wherein R 310 is an arylsulfonyl group. The term "alkylaminocarbonylamino" as used herein refers to R 3 C(0)NH- wherein R 311 is an alkylamino group. The term "alkylammocarbonyloxy" as used herein refers to R 312 C(0)0- wherein 312 is an alkylamino group. The term "alkoxycarbonyloxy" as used herein refers to R 313 C(0)0- wherein -E^-*^ is an alkoxy group. The term "loweralkylcarbonyl" as used herein refers to R 15 _C(0)- wherein R 157 is a loweralkyl group, including, but not limited to acetyl, propionyl and the like. The terms "alkoxy" and "thioalkoxy" as used herein refer to R 15g O- and R 15g S-, respectively, wherein *R 158 is a loweralkyl group. The term "alkoxyalkoxy" as used herein refers to an alkoxy group appended to an alkoxy radical including, but not limited to, methoxymethoxy and the like. The term "aryloxyalkyl" as used herein refers to an aryloxy group (R 3 ø 3 0 ~ wherein R3 Q 3 is an aryl group) appended to a loweralkyl radical. The term "thioaryloxyalkyl" as used herein refers to a thioaryloxy group (R 30 s- wherein R 304 is an aryl group) appended to a loweralkyl radical. The terms "arylalkoxy" and "arylthioalkoxy" as used herein refer to an aryl group appended to an alkoxy radical or a thioalkoxy radical, respectively, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like. The terms "arylalkoxyalkyl" and "arylthioalkoxyalkyl" as used herein refer to an arylalkoxy group or an arylthioalkoxy group, respectively, appended to a loweralkyl radical. The term "alkenyloxy" as used herein refers to R 15g O-, wherein R 15g is an alkyl group of 1 to 7 carbon atoms which contains at least one carbon-carbon double bond. The term "hydroxyalkoxy" as used herein refers to -OH appended to an alkoxy radical. The term "dihydroxyalkoxy" as used herein refers to an alkoxy radical which is disubstituted with -OH radicals. The term "arylalkoxy" as used herein refers to an aryl group appended to an alkoxy radical. The term "alkylaryloxy" as used herein refers to R lgo 0- wherein *R lg0 is an alkylaryl group. The term "phenylalkoxy" as used herein refers to a phenyl group appended to an alkoxy radical, including, but not limited to benzyloxy and the like. The term "(subεtituted phenyl)alkoxy" aε uεed herein referε to a substituted phenyl group appended to an alkoxy radical, including, but not limited to 4-chlorobenzyloxy and the like. The term "naphthylalkoxy" as used herein refers to a naphthyl group appended to an alkoxy radical. The term "(subεtituted naphthyl)alkoxy" as used herein refers to a subεtituted naphthyl group appended to an alkoxy radical. The term "polyalkoxy" as used herein refers to R 161 0-, wherein R 161 is a straight or branched chain containing J 1-5, C -O-Cm. linkag J es where m and m' are independently 1 to 3. The terms "halo" or "halogen" as used herein refer to Cl, Br, F or I subεtituentε. The term "haloalkyl" aε used herein refers to a loweralkyl radical in which one or more hydrogen atomsare replaced by halogen including, but not limited to fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and the like. The term "polyhaloalkyl" as used herein refers to a loweralkyl radical substituted with two or more halogens, including, but not limited to trifluoromethyl, 2,2-dichloroethyl and the like. The term "halobenzyl" as used herein refers to a halo substituent appended to the phenyl ring of a benzyl radical. The term "halophenyl" as used herein refers to a halo substituent appended to a phenyl radical. The term "alkylsulfonyl" as use dherein refers to R 30 _s(o) 2 - wherein R 300 is a loweralkyl group. Λ „„, ««« O 90/05531 -56- The term " (aryl)sulfonyl" as used herein referε to R 301 S(0) 2 - werein R 301 is an aryl group. The term "(heterocyclic)sulfonyl" as used herein refers to R 302 S(0) 2 ~ wherein R 3Q2 is a heterocyclic group. The term "arylsulfonylalkyl" as used herein refers to an arylsulfonyl group appended to a loweralkyl radical. The term "aryl" as used herein refers to a monocylic or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; or "aryl" refers to a heterocyclic aromatic ring as defined herein. Aryl groups can be unsubεtituted or εubεtituted with one, two or three εubstituents independently εelcted from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. The term "εubεtituted phenyl" aε used herein refers to a phenyl ring substituted with one, two or three subεtituentε choεen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halophenyl, lowe alkylphenyl, alkoxyphenyl and the like. The term "εubεtituted naphthyl" as used herein refers to a naphthyl ring substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthyl, alkoxynaphthyl and the like. -57- The term "alkylaryl" aε uεed herein refers to a loweralkyl group appended to an aryl radical. The term "heterocylcic group" or "heterocyclic" as used herein referε to any 3- or 4-membered ring containing a heteroatom εelected from oxygen, sulfur and nitrogen, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0 to 2 double bonds and the 6-membered ring has 0 to 3 double bonds; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, wherein the nitrogen heteroatom may optionally be guaternized, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocyclics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, iεoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, guinolinyl, iεoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl. Heterocyclicε can be unsubεtituted or monoεubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=0), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, haloalkyl or cycloalkyl. The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, thiazolyl, thienyl, triazolyl and the following: wherein k is 1 or 2 and X is N, NH, 0, or S, provided that X is the point of connection only when X is N, wherein Y is NH, N-loweralkyl, 0, S, or S0 2 , or wherein the symbols (i), (ii) and (iii) represent 5-membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z. is N, 0, or S and not the point of connection and Z iε N when it iε the point of connection and NH, 0 or S when it is not the point of connection; with the proviso that when Z 2 is the point of connection, then Z., is N. The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidaseε on the compoundε or to increase the solubility of the compounds and includes but is not limited to sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz), benzoyl or an L- or D- aminoacyl residue, which may itself be N-protected similarly. The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes but is not limited to substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenyImethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates. - 60 - The term "substituted amino" as used herein refers to: I) alkylamino, II) dialkylamino, III) (hydroxyalkyl) (alkyl) amino, IV) (dihydroxyalkyl) (alkyl) amino, V) alkoxycarbonylalkylamino, VI) carboxyalkylamino, VII) (amino) carboxyalkylamino, VIII) ( (N-protected) amino) carboxyalkylamino, IX) (alkylamino) carboxyalkylamino, X) ( (N-protected) alkylamino) carboxyalkylamino, XI) (dialkylamino) caboxyalkylamino, XII) (amino) alkoxycarbonylalkylamino, XIII) ( (N-protected) amino) alkoxycarbonylalkyl¬ amino, XIV) (alkylamino) alkoxycarbonylalkylamino, XV) ( (N-protected) alkylamino) alkoxycarbonyl¬ alkylamino, XVI) (dialkylamino)alkoxycarbonylalkylamino, XVII) (alkoxyalkyl) (alkyl) amino, XVIII) (alkoxyalkoxyalkyl) (alkyl) mino, XIX) di-(alkoxyalkyl)amino , XX) di-(alkoxyalkoxyalkyl) amino, XXI) di-(hydroxyalkyl) amino, XXII) ((unsubstituted heterocyclic) alkyl) (alkyl) - amino, XXIII) ((substituted heterocyclic) alkyl) (alkyl) - amino, -61- ndependently selecte from 1) hydrogen, 2) hydroxy, 3) alkoxy, 4) thioalkoxy,. 5) alkoxyalkoxy, 6) carboxy, 7) alkoxycarbonyl, 8) halogen, 9) amino, 10) alkylamino, 11) dialkylamino, 12) alkylsulfonylamino, 13) arylsulfonylamino, 14) alkylaminocarbonylamino, 15) alkylaminocarbonyloxy, 16) alkoxycarbonyloxy, wherein dd' is 1 to 5, and 18) R R -Z - wherein Z q is 0, S or NH and R g is a C. to Cβ 05531 - 62 - straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic; wherein R Λ 9q is wherein R_, _ is lOq 1) hydrogen, 2) loweralkyl, 3) an N-protecting group or 4) R, . -C(O)- wherein R. , is llq llq aminoalkyl, (N-protected)aminoalkyl, 1- amino-2-phenylethyl or 1-(N- . protected)amino-2- phenylethyl. The term "substituted methylene group" as used herein refers to: ( I ) ~ CHR 1 3 C τ R i4σ wherein 1) R-13_q is - 63 - i) hydrogen or ii) hydroxy and 2) R 14q is i) hydrogen, ii) loweralkyl, iii) hydroxy, iv) hydroxyalkyl, v) alkoxy, vi)alkoxyalkyl, vii) azido, viii) azidoalkyl, ix) amino, x) (N-protected) amino, xi) aminoalkyl, xii) (N-protected) aminoalkyl, xiii) alkylamino, xiv) (N-protected) (alkyl) amino, xv) alkylaminoalkyl, xvi) (N-protected) (alkyl) - aminoalkyl, xvii) dialkylamino, xviii) dialkylaminoalkyl, xix) carboxyalkyl, xx) thioalkoxy, * xxi) thioalkoxyalkyl, xxii) alkylsulfonyl, xxiii) alkylsulfonylalkyl, xxiv) thioaryloxy, xxv) thioaryloxyalkyl, xxvi) arylsulfonyl, xxvii) arylsulfonylalkyl, xxviii) (unsubstituted heterocyclic)alkyl or xxvix) (substituted heterocyclic) alkyl such that when R_._ is hydroxy then R- . is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected)amino, (N-protected) (alkyl)amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R- , is hydrogen then R.. is not hydrogen or loweralkyl; (II) -C(=CH 2 )C(0)NHR ; (III) -C(OH) (R 16 )C(0)NHR 15q or (IV) -CH(R.l,.q) C(O)NHR,lo_q wherein 1 ] R 15q ±S i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl, v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl, viii) heterocyclic or ix) (heterocyclic)alkyl and 2) R 16q ±S - i) hydrogen, ii) loweralkyl, iii) hydroxyalkyl, iv) haloalkyl or v) azidoalkyl; -65- wherein 1) t 1 is 0 to 3, 2) R 2Qq is i) CH 2 or ii) N and 3) R 21q is i) NH, ii) 0, iii) S or iv) S0 2 , such that when t' is 0 then R -».O_q is CH2,, and when t' is 1 to 3 then R 2Q is N, (VI) -CH 2 CH(R 22 )C(0)NHR 23 wherein 1) R 22q is i) loweralkyl or ii) cycloalkylalkyl and 2) R 23q is i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl, v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl, viii) arylalkyl ix) heterocyclic. - 66- x) (heterocyclic)alkyl or xi) "(CH 2 ) U ' R 2q , R 25q wherein a) u' is 0 to 3, b) R 24 is CH 2 or N and c) R 25 is NH, O, S or so 2 , such that when u* is 0 then R_4.q is CH 2„. and when u' is 1 to 3 then R 2-4.q is N; wherein 1) R 2„_„_2q is as defined above and ogen, ii) loweralkyl, iii) an N-protecting group or iv) R_75 c q-C(0)- wherein R_,/5 c q is aminoalkyl or (N-protected) - aminoalkyl; -67- wherein 1) R s 26q i) loweralkyl or ii) cycloalkylalkyl and ■ 2) R 2?q is i) loweralkyl or ii) cycloalkylalkyl; (IX) -CH 2 CH(R gl )NHC(0)R 82 or -CH 2 CH(R 81 )NHS(0) 2 R 82 wherein 1 R 81q is i) loweralkyl or ii) cycloalkylalkyl and 2) R 82q iS i) loweralkyl, ii) alkoxy, iii) alkylamino, iv) dialkylamino, v) -OR* wherein R* is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or (heterocyclic) alkyl or wherein R2iq is as defined above; (X) -CH2NHC(0)Rs2q or -CH2NHS (0)2 R 82q wherein R 8 2q is as defined above; or (XI) -CF 2 CH(OH)R g3 wherein R g3 is loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyenylalkyl, aryl, aryalkyl, heterocyclic or (heterocyclic)alkyl. The terms "lipophilic or aromatic amino acid side chains" aε uεed herein refer to amino acid side chains selected from the group isobutyl, isopropyl, sec-butyl, benzyl, p-methoxybenzyl, imidazole-4-yl-methyl, p-hydroxybenzyl, 1- and 2-naphthyImethyl, (pyrazolyl)methyl, (thiazolyl)methyl, cyclohexyImethyl, (3-indolyl)methyl, CH 3 SCH 2 ~ and the like. General references to amino acid side chains in both the description and claims herein is to be taken as reference to such, whether naturally occurring in proteins or not, and to both D- and L- forms. The terms "Ala", "His", "Leu", "Phe", "Tyr", "Cys", "Gly", "Lys", "Sar", "Pro", "HomoPhe" and "norLeu" as used herein refer to alanine, histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine, sarcosine, proline, homophenylalanine and norleucine, reεpectively. In general, the amino acid abbreviationε follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem. 1984, 158, 9-31). The chiral centers of the novel renin inhibiting compounds of the invention may have either the "R", "S" or "R,S" configuration. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. - 6 9 - Renin inhibitors having the general structure shown in group (9) can be prepared as shown in Schemes IA-XXIIIA. The syntheses of segments containing substituents D are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al. , J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al. , U.S. Patent No. 4,727,060; Morisawa, et al., European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. O87/02986) . In particular, the process shown in Scheme IA discloses the preparation of compounds of the invention having the general structure (1) wherein A is carboxy or alkoxycarbonyl and X is NH. As illustrated in Scheme IA, reductive a ina ion of an amino acid ester (I) with an alpha-keto ester (II, R=loweralkyl) provides a diastereomeric mixture which is separated. Each of the diastereomers is hydrolyzed and coupled to the amine (VI) using standard peptide coupling reagents such as N- methylmorpholine (NMM) , 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide (EDAC) to give the desired compound (VII) . Compound (VII) can also be prepared using the following method. After reductive amination of (II) with (I) , the diastereomeric mixture is hydrolyzed to give (III) and then coupled to amine (VI) as described above. The mixture of diastereomers is then separated, providing two separate isomers. Compound (VII) may be further hydrolyzed to the acid (VIII) . The assignment of R or S configuration to the carbon bearing the R 3 substituent in compound (VIII) is based on the fact that the compound derived from the L- the L-isomer is generally a more potent renin inhibitor than the compound derived from the corresponding D-isomer. The stereochemistry at the chiral carbons of (VIII) can also be established by using chiral starting materials. As illustrated in Scheme HA, chiral amino acid ester (XV, R=loweralkyl) is reacted with chiral D-trifluorosulfonyloxy ester (XVI) to give the single isomer (XVII) which is then hydrolyzed and coupled to (VI) to obtain the desired compound (XVIII) . Alternatively, Scheme IIIA illustrates the preparation of compounds (XI) . Reductive amination of (IX, R =loweralkyl) by (X) provides a mixture of diastereomers which can be separated. A further alternative illustrated by Scheme IIIA involves reductive amination of (IX, R 2 =-loweralkyl) by (XII) followed by separation of the diastereomers (XIII) . Each of the diastereomers is then debenzylated and coupled to (VI) as previously described. The methods of Scheme III provide compound (XI) having unknown stereochemistry at the carbon bearing the R- substituent. The process of Scheme IVA discloses the preparation of compounds of the general structure (1) wherein A is a carboxy derivative R,_CO- wherein R- is an amine and X is NH. Selective hydroysis of one of the diastereomers (IV) gives the acid derivative (XIX) . The acid (XIX) is coupled to the amine R c ~H' and the resulting amide-ester is hydrolyzed to give (XXI) . The acid (XXI) is coupled to amine (VI) to give (XXII) . Alternatively, compound (VIII) can be coupled to amine (VI) to provide (XXII) . The process in Scheme VA discloses the preparation of compounds of the general structure (XXV) wherein R 2 ~ is a C. to C. straight or branched carbon chain substituted by a substituent selected from carboxy, alkoxycarbonyl, alkylsulfonyl or a substituted or unsubstituted heterocylic. A reaction sequence similar to that used in Scheme I is followed except that compound (XXIII) is employed instead of the amino acid ester (I) . The process in Scheme VIA discloses the preparation of compounds of general structure (XXIX) wherein A is alkoxycarbonyl or R-CO- wherein R- is a substituted amine and X is 0 or S. The reaction of an alcohol or thiol (XXVI) with the bromo-acid (XXVII) provides a single diastereomer (XXVIII) which is then coupled to the amine (VI) using standard peptide coupling conditions to give the desired product (XXIX) . If the racemic form of the bromo- acid (XXVII) is used, diastereomer separation can take place with compound (XXVIII) or (XXIX) . Scheme VIIA discloses the preparation of compounds of σeneral structure (1) wherein X is CH,, and A is R c CO- -i 5 wherein R_ is hydroxy, alkoxy, thioalkoxy or an amine. Compound (XXX) (J. Med. Chem. 2£ 1277 (1983)) is coupled to amine (VI) to provide the amide ester (XXXI) which is hydrolyzed to give the carboxylic acid (XXXII) . Coupling to the appropriate amine provides (XXXIII) wherein R_ is a substituted amine-. The process in Scheme VIIIA discloses the preparation of compounds of the general structure (1) wherein X is CHOH. Aldol condensation of an aldehyde (XXXIV) (J. Am. Chem. Soc. 103 2876 (1981)) with the chiral oxazolidinone imide (XXXV) (J. Am. Chem. Soc. 103 2127 (1981)) provides (XXXVI) . After protection of the secondary alcohol, the benzyl group is removed and the primary alcohol oxidized to the carboxylic acid (XXXVII) . The acid is coupled to the appropriate amine R---H, the imide is hydrolyzed, the resulting acid is coupled to the amine (VI) and the alcohol is deprotected providing the desired compound (XXXVIII) . Schemes IXA-XIIIA disclose the preparation of intermediates used in Schemes IA, VA and VIA, respectively. In Scheme XA, R is loweralkyl. In Scheme XIA, R is loweralkyl, Ts is p-toluenesulfonyl and P is an N- protecting group. In Scheme XIIA, R is loweralkyl, R^-H is an amine and X is O or S. In Scheme XIIIA, R 5 -H is an amine. The process in scheme XIVA describes the preparation of compounds of the general structure XLII wherein R 3 is a Ci to CQ straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, S, N or substituted by a substitutent selected from a heterocycle or substituted heterocycle. Ri is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl, alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. R5 is a cyclic amine, substituted amine, substituted cyclic amine, aryl, substituted aryl, heterocycle, substituted heterocycle. The synthesis of intermediate XL begins by the metalation of the sulfonyl derivative XXXIX with alkyl lithium reagents in THF or THF/HMPA at low temperature according to the procedure sited in European Patent Application No. EP0309841, published April 5, 1989. The subseguent anion is trapped with the appropriate 2-substituted-3-benzyloxypropyl - 7 3 - iodide (prepared from the alcohlol by the procedure of M. Holladay; J. Med. Chem. 1983, 26, 1277 ), p-toluenesulfonyl chloride and sodium iodide. The resulting diastereomeric sulfonyl ethers XL are deprotected ( H 2 Pd/C or PdOH) and oxidized to the corresponding carboxylic acids XLI using a variety of oxidants (KMnC* 4 , Jones, PDC, RUO , Pt/0 2 ) . Coupling of the acids with mimics of the Leu-Val cleavage site of angiotensinogen (T-H) using standard coupling procedures gives the diastereomeric amides XLII and XLIII which are separated to give optically active inhibitors. Scheme XVA outlines the synthesis of carboxylic acids of the general formula XLIX wherein Ri is a Ci to C_ straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, S, N. or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl, alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a Ci to Cβ straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by O, S, N. The synthesis begins by esterificaton followed by allylation of the 2S-hydroxyacid XLIV. Ester XLV is reduced with lithium aluminum hydride and the resulting alcohol is reacted with ozone. Reductive workup of the ozonide and Collins oxidation (Crθ3-2Pyr) gives the optically pure lactone XLVI. Reaction of the lactone with LiHMDS in THF or THF/HMPA followed by the addition of R l -I or Rχ-Br (i.e., an alkyl iodide or arylalkyl iodide or bromide) gives the disubstituted lactone XLVII. The lactone XLVII is reacted with the amino aluminum reagent which is prepared from the secondary amine and trimethylaluminum according to the procedure of einreb et. al. Org. Syn. 1980, 59, 49, to give the alcohol XLVIII. Oxidation of the alcohol using a variety of oxidants (KMnθ 4 , Jones, PDC, RUO , Pt/02) gives the acid XLIX which is ready for coupling to T-H using known methods. An alternative synthesis of the disubstituted lactone LIII and related lactone LVII is shown in scheme XVIA. The 2 (S) -hydroxyacid L is first converted to the ethyl ester by Fisher esterification. Trans esterification with the Z-allylic alcohol and titanium isopropoxide (using the procedure of Seebach et. al. Org. Syn. 1986, 65, 230) gives the hydroxy ester LI. Halo ( I 2 or NBS) or mercuric trifluoroacetate cyclization of the hydroxy olefin gives the disubstituted lactone LII. Reduction of LII with tributyltinhydride or sodium borohydride affords the reduced lactone intermediate LIII. Scheme XVIIA discloses an alternative synthesis of carboxylic acids LVIII and LIX wherin Ri is a Ci to C straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by O, S, N or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl, alkylaryl, alk lheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a Ci to C_ straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, S, N. The synthetic strategy is similar to that outlined in scheme XVA. The lactone LV is prepared from the corresponding amino alcohol LIV. Alkylation of LV with NaHMDS and alkyl iodide or bromide gives the disubstituted lactone LVI . The lactone LVI is hydrolyzed and esterified to hydroxy ester LVII which is converted to the acid LIX as shown in the scheme. Alternatively, LVI is transformed to the acid LVIII. Carboxylic acids LVIII and LIX are converted to final inhibitor compounds LVIIIa and LIXa as previously described. Scheme XVIIAa discloses a synthetic route to inhibitors containing esters of the general formula LVlb and LVIlb wherein R and Ri are the same as previously described for scheme XVIIA and R 2 is selected from C x to C_ straight or branched carbon chain. T is selected from a variety of mimics of the Leu-Val cleavage site of angiotensinogen. The five step seguence from LVI to LVlb prepares the key acid intermediate from permanganate oxidation which is coupled to give final products. The seven step sequence from LVI to LVIIb produces a similar final product with the R and Ri substituents reversed. The syntheses of hydroxyethylene dipeptide isosteres are depicted in Schemes XVIIIA and XIXA. The chirality of the valine-mimic isopropyl group is established via a highly diastereoselective aldol condensation. Scheme XVIIIA details the use of technology developed by D. A. Evans and coworkers (see D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127), in which the aldehyde X (synthesized in analogy to the isobutyl- substituted aldehyde described by S. Thaisrivongs, D. T. Pals, L. T. Kroll, S. R. Turner and F.-S. Han, J. Med. Chem. 1987, 30, 976) is condensed with the norephedrine- derived acyloxazolidinone to produce the aldol product LXI. Barton deoxygenation (D. H. R. Barton and S. . McCombie, J " . Chem . Soc , Perkin Trans . 1, 1975, 1574) provides the diprotected hydroxyethylene dipeptide isostere LXIII. Removal of the chiral auxiliary with basic peroxide (D. A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett . 1987, 28(49), 6141) affords the intermediate carboxylic acid LXIV, which is then coupled to the desired amines (RNH 2 ) to yield amides LXV. An alternative strategy is outlined in Scheme XIXA. - Employment of the cysteine-derived thiazolidinethione (C. N. Hsiao, L. Liu and M. J. Miller, J. Org-. Chem. 1987, 52, 2201) as chiral auxiliary allows the direct conversion of aldol adduct LXVII to the hydroxy amide LXVIII, thereby avoiding the hydrolysis step in Scheme XVIIIA. The secondary hydroxyl group is deoxygenated to produce the same protected amides LXV. The synthesis of P2 1 retro-inverted amine derivatives is described in Scheme XXA. The intermediate carboxylic acid LXIV is transformed into isocyanate LXX by the action of diphenylphosphorylazide, and the isocyanate is trapped with a range of nucleophiles, including, but not limited to primary and secondary amines, alcohols, thiols and organomagnesium halides. Scheme XXA illustrates the synthesis of retro-inverted amides LXXI f ureas LXXII and carbamates I.XXIII. These various hydroxyethylene dipeptide isosteres are then deprotected under the conditions listed in Scheme XXIA. The resulting free-base forms of the aminoalcohols LXXIV and LXXV are then available for standard peptide couplings. Scheme XXIIA outlines a method for producing analogs of P2 '-retro-inverted statine isosteres (an extension of the previous work of S. H. Rosenberg, J. J. Plattner, K. . Woods, H. H. Stein, P. A. Marcotte, J. Cohen and T. J. Perun, J. Med. Chem. 1987, 30, 1224), in which the protected amino-epoxide LXXVI (J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist and N. Yi, J. Org. Chem . 1987, HZ, 1487) is opened with a primary amine to provide aminoalcohols LXXVII. These compounds are then derivatized as sulfonamides, sulfamides, ureas, carbamates, amides or other amine derivatives. Scheme XXIIA details the example of a sulfonamide or sulfamide. The free aminoalcohol (LXXIX) is provided by simple deprotection of the Boc-group. Scheme XXIIIA depicts an alternative strategy for the production of the P2 1 retro-inverted amide derivatives. Intermediate aldehyde 1_∑ is condensed with a primary amine under standard reductive alkylation conditions, and the resulting amine LXXX is derivatized to the desired protected amine derivative LXXXII. This has been accomplished by the use of the appropriate sulfonyl or sulfa oyl chloride, to yield, respectively, the corresponding sulfonamide or sulfamide. In addition, the catechol sulfamate ester LXXXI can be employed to produce sulfamide derivatives. Deprotection produces aminoalcohols LXXXIII. available for coupling reactions. R 4 Hα a: NaOAc, NaCNBH 3 ; b: separate diastereomers; c: as a; d: LiOH, H 2 0, dioxane; e: (VI), NMM, HOBT, EDAC; f: as b; g: as d; h: as e; i; riinxanfi/HCl. -79- SCHEMEΠA (XVIII) a: 2 eq TEA, CH 2 C1 2 , 0-25°; b: selective hydrolysis; c: coupled to (VI). /05531 ■ 80- Xs (XI a ) a: NaOAc, NaCNBH 3 : b: separate diastereomers; c: II,, Pd/C; d: NMM, HOBT, EDAC S . CKEMET A (XXII) _ Diosane/HCl; b: R 5* H, HOBT.EDAC; H : J /C or L . OH/H : 0; iNMM.HOBTJΞDAC. SCHEMEVA (XXV h ) a: NaOAC, NaCNBH 3 ; b: separate diastereomers; c: H 2 , Pd/C; d: (VI), NMM.HOBT, EDAC. -83- SCHEMEVIA (XXVI) (XXVII) (XXIX) a: NaH, THF-, b:( VI ^NMM.HOBT.EDAC. SCHEMEVHA ( XXX II ) ( XXX III ) a: NMM, HOBT, EDAC; b: LiOH/H,0/dioxane; c: R s -H, HOBT, EDAC. -85- SCHEMEVIΠA (XXXVIII) a: CH 2 CI 2 , -72°C; b: protect; c: H 2 , Pd/C; d: Jones [Oj; e: R 5 -H, H03T, EDAC; f: LiOH/H 2 0; g: (VI). HOBT, EDAC; h: deprotect. /05531 -86- SCKΞMEKA H •_< SCHEME X A ONa R-σ CR R 3 DMF (ID 50° C SCHEME XI b) HBr Ri SCHEME XIII NH*, HOCC^ NH-Cbz Rc . H ^jT NH . Cbz / a. BH, 1, HOBT.EDΛC R 5 » κ_"^ * ϊ b. Pd/c. H, R l R, Ri -87- SCHEME XIVA 1. H Pd/C 2. Jones or PDC oxidation /05531 -88- SCHEME XV A 1.BOH, H 2 S0 4 1. LAH HO. C0 2 H : — * ^- -O. ^C0 2 Et R 2. allyl bromide, NaH R 2.0 3 XLIV XLV 3. Collins reagent XLVII -89- SCHEME XVI A NBS. I 2 or R CH 2 OH LI X = Br. I, HgTFAc LIII LII 531 -90- SCHEME XVII A H 2 N. ,CH 2 OH MPA L1V 3. TsOH,-H,0 LV reflux LVI LVll LVIII ux SCHEME XVII'A LVI 4. F ' LVII 1. Swern oxidation 2. KMn0 4 or Ag 2 0 3. R 2 CHN 2 or AgO, R 2 I LVlb LVIIb -93- SCHEME XX A SCHEME XXII ft. 1. TFA/CH 2 CI 2 /0 C OH H^^ ^NR ' SOsR 82 2. Na 2 C0 3 (LXXIX) R = H, loweralkyl SCHEME XXITI R (LXXX) (LXXXI) dioxane, reflux R = H, loweralkyl In the above schemes, optically active or racemic starting materials can be used to obtain products of known or mixed stereochemistry. Renin inhibitors having the general structure shown in group (10) can be made as shown in Schemes 1B-17B. The syntheses of segments containing substituents R- are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al . , J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al. , U.S. Patent No. 4,727,060; Morisawa, et al. , European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. O87/02986) . Scheme IB discloses a general method for the synthesis of compounds of the invention containing substituted piperazines . The process involves reaction of the appropriately substituted piperazine with an alph-halo ester. The ester 2. is hydrolyzed (LiOH/MeOH/H 2 0) and then coupled to the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl-3, 4-dihydroxy-6-methyl heptane) using a EDAC, l-(3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride, or other standard peptide coupling methods to provide the desired product __. Scheme 2B discloses a general method for the synthesis of compounds of the invention containing N-substituted benzyl piperazines. The dipeptide ϋ is synthesized using a mixed anhydride coupling method. The diketopiperazine £., which is formed by heating 5_ in refluxing xylene, is reduced (excess lithium aluminum hydride (LAH) in THF) to give 7.. Reaction of 2. with an alpha-bromo ester (in this case ethyl 2—brorαo hexanoate) gives &. The amine ____ is protected (Boc-anhydride in CH 2 C1 2 ) and then the ester is hydrolyzed (LiOH/MeOH/H 2 0) . The free acid _£ is then coupled to the hydrochloride salt of the appropriately functionalized amine ( in this case 2-amino-l-cyclohexyl- 3, 4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods to provide 10.. Scheme 3B discloses a general method for the synthesis of benzyl ketopiperazine containing compounds of the invention. The reduced dipeptide .11 is synthesized by oxidation of the precursor protected amino alcohol, followed by a reductive amination. The free amine of H is reacted with an alpha-bromo ester such as benzyl bromoacetate to give 12, which is deprotected by hydrogenolysis and then cyclized with EDAC-HOBT (hydroxybenzotriazole) or other peptide or lacta forming agents. The lactam-ester 13. is hydrolyzed (LiOH/dioxane/H 2 0) and then coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl-3, 4-dihydroxy-6-methyl heptane) using a standard peptide coupling method such as EDAC to give the desired product 14.. Scheme 4B discloses a method for synthesizing substituted ketopiperazines of the invention which are isomeric with those prepared in Scheme 3. The methyl ester of D-Phe is protected with Boc-anhydride and then allylated with allyl bromide. The intermediate lϋ is oxidized to aldehyde 1 . Aldehyde £ is coupled to an amino acid by reductive amination and then cyclized. The lactam-ester IS. is hydrolyzed (LiOH/water/dioxane) and then coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl-3, -dihydroxy-6- ethyl heptane) to give the desired product 20.. Scheme 5B discloses the synthesis of compounds of the invention containing substitued delta-lactams. Valerolactone is alkylated (in this case with a benzyl group) by lithiation at -78°C in THF followed by an alkyl halide (benzyl bromide) . The resulting lactone 21 is transesterified with benzyl alcohol. The primary alcohol 22 is oxidized using Swern conditions and then reductively aminated* with an amino acid ester such as L-norleucine methyl ester. The benzyl ester ___. is subjected to hydrogenolysis to remove the benzyl group and the amino acid is cyclized to give lactam 23. using EDAC or other standard peptide coupling or lactam forming methods. The lactam-ester is hydrolyzed and the acid is coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl—3, 4-dihydroxy-6- methyl heptane) to give the.desired product 23.. Scheme 6B discloses a general method for synthesizing compounds of the invention containing amino substituted gamma- and delta—lactams. Compound 22. (J. AM. Chem. Soc. 79 5736 (1957)) is deprotonated and alkylated with allyl bromide to provide 28.. Hydrolysis (aq. sodium hydroxide) followed by acidification provides the acid corresponding to 22., which is treated with excess ethereal diazomethane to provide 22.. Oxidation of 22. gives aldehyde 30a. Reductive amination of 30a with the methyl ester of the desired amino acid hydrochloride salt (in this case His- OMe) provides the amino ester _____., which is cyclized to the corresponding lactam 22. (n=l) . The lactam ester 22. is hydrolyzed to the corresponding acid. The acid is coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl- 3,4-dihydroxy-6-methyl heptane) through a standard solultion phase peptide coupling method using a water soluble carbodiimide to give the desired product wherein n=l. Hydroboration of 28. followed by oxidation gives the aldehyde 30b. Reductive amination of 30b with the methyl ester of the desired amino acid hydrochloride salt (in this case L-His-OMe) provides _____.. Lactam ester 22. (n=2) is produced by refluxing a methanolic solution of 31b with isopropyl amine. Ester hydrolysis, followed by coupling to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl-3, 4-dihydroxy-6- methyl heptane) using EDAC or other standard peptide coupling methods, provides the desired product wherein n=2. Scheme 7B discloses a general method for synthesizing compounds of the invention containing an oxa-lactam. For example, D-phenylalanine is converted to D-3-phenyllactic acid , which is esterified to produce 24.. The free hydroxy group is allylated with allyl bromide to provide ester 23., which is oxidized to the aldehyde 2£. The aldehyde __ϋ is reductively aminated with the appropriate amino acid ester (in this case L-His-OMe) to give amino ester 21, which is thermally cyclized to lactam 28.. Lactam ester 28. is hydrolyzed and the imidazole nitrogen is protected as the N-t-Boc derivative. The acid is then coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl- 3,4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods to produce the desired product 39. Scheme 8B discloses a method for the synthesis of compounds of the invention containing an N-terminal substituted gamma-lactam. A mixed diester 4.0. is converted to acids 4L or 42, which are reduced to alcohols 42 or 44, respectively. Alcohols .42 and AA are then oxidized to aldehydes A3 and AH- Reductive amination of with the appropriate amino acid ester (in this case L-His-OMe di-p- toluenesulfonic acid salt) provides amino ester 42. This compound is converted to the free acid, which is then cyclized to 42. Similarly, reductive amination of 42 leads directly to the cyclic derivative _\ _ . Protection of the imidazole nitrogen of 4 and 4.2 as the N-t-Boc derivative, followed by ester hydrolysis, leads to acids 20. and 21. Amide formation with the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l- cyclohexyl-3,4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods, followed by imidazole deprotection, affords 32. and 22, respectively. Scheme 9B discloses a method for the synthesis of compounds of the invention containing an unsubstituted N- terminal cyclic urea. For example, Boc-phenylalanol 24. is oxidized to the aldehyde and reductively aminated with the appropriate amino acid ester (in this case L-His-OMe di-p- toluenesulfonic acid salt) to give mono-protected diamine 55. Removal of the protecting group and cyclization affords cyclic urea 26.. Protection of the imidazole nitrogen and benzyl ester hydrogenolysis provides the acid 57. Amide formation with the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l- cyclohexyl-3,4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods, followed by imidazole deprotection, affords 28.. Scheme 10B discloses a method for the synthesis of compounds of the invention containing an N'-substituted N- terminal cyclic urea. For example, phenylalanine methyl ester hydrochloride salt is reductively alkylated with an aldehyde or ketone (in this case isobutanal) and the resulting amine is protected to provide ester 20.. The ester is reduced to the alcohol and the alcohol is oxidized to the aldehyde £1. Treatment of this aldehyde as described in Scheme 9 provides the desired compound 62. Scheme 11B discloses a general method for the synthesis of benzyl ketopiperazine containing compounds which are isomeric with the compounds of Scheme 3. Alkylation and protection of amino-alcohol 22 provides alcohol 24.. Oxidation and reductive amination of 24. gives diamine 22. Ring closure to 22, followed by coupling to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-l-cyclohexyl-3, 4-dihydroxy- 6-methyl heptane) using EDAC or other standard peptide coupling methods to provide £1- Scheme 12B discloses a general method for synthesizing compounds of the invention containing a sulfonyl substituted ketopiperazine. Compound 22 is sulfonylated, followed by ring formation, to give compounds such as 22 and 22. Deprotection and coupling of the resulting acid with the appropriately functionalized amine provides products such as 21 and 73. Scheme 13B discloses a general method for synthesizing compounds of the invention containing amino substiuted delta-lactams . Compound 22. (Scheme 6, n=2) is treated with H 2 and Pd/C in acetic acid, followed by treatment with toluenesulfonyl chloride, to produce di-tosylate 75. Treatment of 22 with LiOH, followed by ditertbutyldicarbonate, produces acid 22. Acid 23. is coupled to the appropriately functionalized amine using EDAC, or other standard peptide coupling methods, to provide the desired product wherein n=2. Scheme 14B discloses a general method for synthesizing compounds of the invention containing amino substituted delta-lactams which do not contain histidine residues. Compound 30b (Scheme 6, n=2) is reductively alkylated with the corresponding amino acid methyl ester and the resulting product is thermally cyclized to delta-lactam 22. Treatment of 22 with HBr/HOAc, followed by reaction with sulfonyl chlorides or sulfamoyl chlorides, produces the amino protected compound 22. Ester hydrolysis of 78, followed by coupling to the appropriately functionalized amine using EDAC or other standard peptide coupling methods, provides the desired product wherein n=2. Scheme 15B describes an improved synthesis for the amine in Example 139. The lactone 0 was reduced with LAH at room temperature in 5 min and then cyclized under Mitsonobu condition to give the tetrahydrofuran derivative 24. in high yield. The free amine 22 was obtained by deprotection of 84 under acidic condition followed by a basic work-up with saturated NaHCθ3. Scheme 16B discloses a general method for the synthesis of the compounds of the invention containing an N,N- disubstituted terminal amino group. Treatment of lactam ester 22 with various aldehydes and sodium cyanoborohydride in inert solvents produces the N-alkyl compound 22. Standard ester hydrolysis and coupling to various amines using standard peptide coupling methods produces the final inhibitors. Scheme 17B discloses an improved method for the synthesis of lactam intermediates such as 22 and 22 which are used in the synthesis of compounds of the invention. Compound OH (J. Chem. Soc. (c) , 329, 1971 ) is deprotonated and alkylated with allyl bromide to provide 22. Hydrolysis (aq. lithium hydroxide followed by acidification) affords the amino acid which is treated with CBZ-NOS and then paraformaldehyde to give chiral oxazolidinone 88. Hydroboration of 28 (9-BBN then NaOOH) and oxidation to the aldehyde (PCC) is followed by reductive alkylation with amino acid esters to provide the lactams. Scheme-1 B K 2 C0 3 , EtOH; b: LiOH, eOH-H 2 0; c: HOBT, EDAC, Amine.HCI 90/05 - 1 05 - Scheme-2 ' B Mixture a: Mixed anhydride coupling followed by HCI/Dioxane b: Heating in Xylene for 6 h c: LAH in THF, Reflux overnight d: Ethyl Bromohexanoate, K 2 C03, Dioxane . Reflux f or 2 h e: teoC-Anhydride, CH 2 CI 2 f: Hydrolysis followed by EDAC coupling of the amine /05531 •106- Sc eme-3 CCCMe -j 2 a: SOo-Pyricine b: or-Leu-Cr.e, NaCNBH 3 c: Benzyl bromoacetate, Na C03, Dioxane d: H 2 -Pd, eOH e: EDAC, H03T, DMF f:LiOH, H 2 0-Dioxane g: EDAC, HOBT. Amine.HCl, DMF -107- Sc eme-48 a: ^OC-Aπhydride, CH 2 CL 2 b: NaN(TMS) 2 , Allyl Bromide, DMF c: Ozone, CH 2 CI 2 d: nor-Leu-OMe, NaCNBH 3 e: Reflux in Xylene f: LiOH, H 2 0-Dioxane g: EDAC, HOBT, Amine.HCl, DMF 90/05531 - 10 8 - Scheme-5B a- LDA Benzyl Bromide, THF b: Methanol/Sulphuric Acid followed by Benzyl Alcohol/ TsOH ' Reflux c: Oxalyl Chloride. DMSO.TEA d: L-nor-Leu-O e, Sodium Cyano D orohydride IPA e:' Hydrogen; 10% Pd-C. MeOH f: EDAC. HOBT.TEA.DMF g: LiOH. Diox-Water h: HClΛmine. EDAC. HOBT, TEA, DMF -109- Scheme-6B a: KHMDS.THF, -7S°C,allyl bromide e: His-OMe.NaOΛc,N τ aCN τ BH b: aq. aOH; H + ; CH-,N 2 f: HOBT,Tolucne:DME.rctlux c: 0,,-78 u C,thenMe S g: 2 eq. isopropvlamine.MeOH d: 9- " BBN/THF, aO " OH;PCC h: aq.LiOII-EDΛCAminc Scheme-7B __2. SΛ g: L:OH, BocOBoc. amine, EDAC. HOAc • 111- SCHEME 8B a: CF 3 C0 2 H; b: H 2 , P 'C; c: EH THF; d: CICOCCCI. DMSO. TEA; e: H-His-03n * TsOH 2 , NaOAc, .\'aCNEH 3 ; f: CF 3 CO = H, then EDAC, HOST; g: Ecc-O-Ecc, then H 2 , Pd'C; h: EDAC, HG3T, Amine, then HOAc. SCHEME 9B a: CICOCOCl, DMSO, TEA; b: H-Hϊs-OBn sOH 2 , NaOAc, NaCN3H 3 ; c: CF 3 C0 2 H, then CDI; d: Ecc-O-Bcc, then H 2 , Pd/C; e: EDAC, HOST, Amine, then HOAc; f: (CH 3 ) 2 CHCHO, NaOAC, NaCNBH,, then Ecc-O-Eoc; g: Ca(EH ) 2 . - 1 1 3 - Scheme-11 a) Benzyl bromoacetate, TEA, THF b) BOC-Anhydride, Methylene Chloride c) Pyridine-S03 d) L-nor-Leu-OMe, NaCNBH 3 , IPA e) Reflux in Xylene f) NaOH, MeOH-H 2 0 g) Amine, EDAC, HOBT, DMF, TEA Scheme-12» -115- SCHEMEJ '6 a:H 2 , Pd/CHOAc e: Amine,EDAC, HOBT b:TsCI,NMM,DMAP,CH 2 Cl 2 f: HOAc,THF,H 2 0 c:LiOH,H 2 0 d:BocOBoc Scheme 14 B c.d e.f a: Thiazolvlalanine-OCH 3 , d: RSO l.DMAP. NMM, DMF NaCNBH j , NaOAc b: MeOH, NaOAc, Reflux e: LiOH,H 2 0 c: HBr / HO Ac f: AmincED AC. I IOBT -117- Srheme-15B 31 -118- SCHEMF 1RP. R = Tosyl or N-methylpipcrazinyl R' = Methyl. Ethyl, etc. a: R'CHO, NaCNBH 3 , CH 3 CN b: LiOH,H 2 0 c: Amine, EDAC, HOBT SCHEME 17 B 8.8 a: LiHMDS,DMPU,Allyl Bromide f: 9-BBN b: LiOH.H 2 0 g: NaOOH c: IN HC1 h: PCC d: Cbz-Nos i: Thiala-OCH,. NaCNBH, e: HCHO, TsOH j: NaOAc.MeOH.Reflux The following examples will serve to further illustrate preparation of the novel compounds of the invention. Example 1 ? (SI- f ~ l (S) - ( -- (Methoxymethoxylpiperidin-l-yl-) carbonyl- - phenyDethoxyhexanoic acid amide of 3-(4- morpholinyllpropyl 5 (Si) -amino-6-cyclohexyl-4 (Si) -hyriroxy- 2 (Si) -isopropvlhexanamide Example IA: 4 (S) -t-B-Qtyloxycarbonylamino-5-cyclohexyl- 3 (R,SI -hydroxy-1-pentene To a strired -78°C solution of Boc-cyclohexylalanine methyl ester (10.2 g, 35.8 mmol) in dry toluene (60 ml) was added diisobutylaluminum hydride (34 ml of a 1.5 M solution in toluene) . After 30 min, vinyl magnesium bromide (108 ml of 1 M solution in tetrahydrofuran (THF) ) was added. After stirring for 15 h at 0°C, the mixturte was carefully quenched with methanol, treated with Rochelle salts (22 ml of saturated aqueous solution in 140 ml H2O) , and filtered. After extracting the solids 5 times with ethyl acetate, the extracts and filtrate were combined and the organic phase was washed with brine, dried, filtered and evaporated to an oil (10.2 g) . Chromatography on silica gel eluting with hexane/ethyl acetate mixtures provided 6.1 g of the desired product. Anal, calcd. for C 1 6H29NO3 .1/4 H 2 0: C, 66.8; H, 10.3; N, 4.9. Found: C, 66.9; H, 10.2; N, 4.7. ■ 12 1 - Example IB: 3- (t-Butyloxycarbonyl) -4- (cvclohexylmethyl) - 2.7-di.mpt-.hy1-5-vinγloxazolidine . The procedure of S. Thaisrivong (J. Med. Chem. 1987, 30. 976) was employed. A solution of 40 g of the resultant compound of Example IA and 102 g of 2-methoxy- propene in 250 ml of dichloromethane was stirred at room temperature. Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated. Flash chromatography on silica gel gave 57 g of the desired compound. IR (CDCI 1690 (C=0 carbamate) cm -1 ; 1 H NMR (CDClg) δ 5.95 (m, 1H) , 5.32 (m,lH), 5.20 (dt,lH), 4.27 (dd, 1H) , 1.47 (s, 9H) . Anal. Calcd. for C 19 H 33 N0 3 : C, 70.55; H, 10.28; N, 4.33. Found: C, 70.47; H, 10.27; N, 4.09. Example 1C: 3- (t-Butyloxycarbonyl) -4- (cvclohexylmethyl) - 2,2- dimethyloxazolidine-5-carboxaldehyde. A solution of 10 g of the resultant compound of Example IB in 150 ml of 2:1 dichloromethane: methanol was cooled in an dry-ice acetone bath. Ozone was bubbled through the solution until a blue color persisted (1 h) . Dry nitrogen was then bubbled through the reaction mixture to remove excess dissolved ozone. The reaction mixture was cannulated into a suspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and 200 ml of methanol cooled to -45°C. After 5 min the bath was removed and the mixture allowed to warm to room temperature overnight . 100 ml of saturated sodium chloride was added and the Λ , Λ« „_. 90/05531 -122 - entire reaction mixture extracted with two 300 ml portions of dichloromethane. The combined dichloromethane extracts were decanted, dried (MgSO.), filtered, and evaporated. The crude aldehyde was purified by flash chromatography (1:4) ethyl acetate:hexane to give 9.7 g of the desired compound as a mixture of diastereomers (3:1 trans:cis) as judged by the integrated resonances of the two aldehyde protons. IR (CDC1 3 ) 1735 (C=0 aldehyde), 1690 (C=0 carbamate) cm -1 ; 1 H NMR (CDC1 3 ) δ 9.83 (s,lH,CH0), 9.73 (d, 1H,CH0 cis diastereomer), 4.14 ( , 1H) , 1.46 (s,9H) . Anal. Calcd. for C 18 H 31 0 4 : C, 66.43; H, 9.60; N, 4,30. Found: C, 65.27; H, 9.79; N, 4.20. Equ li ra ion of Aldehyde Isomers A suspension of 25 g of the above aldehyde in 300 ml of methanol and powdered potassium carbonate (10.7 g) was stirred at room temperature for 6 h. The reaction mixture was cooled in an ice-water bath and treated with 9.3 g of glacial acetic acid for 5 min. A solution of 0.5 M sodium dihydrogen phosphate (300 ml) was added to the mixture. After 30 min, the solution was concentrated to one-half the volume under reduced pressure and extracted with ether (600 ml) . The combined ether extracts were dried (MgSO.), filtered, and concentrated. The aldehyde was purified by flash chromatography using (1:4) ethyl acetatethexane to give 19.5 g of the desired compound as an 8:1 mixture of trans:cis diastereomers . Example ID: 3-f3 (Rl- (3-(tert-Bu vloxvcarbonvll -2.?- diτrtethyl-4 (S)- yclohexylme hγ1- (Rl -oxazolidiny] 1 -3-hγriroxγ-? CR )- isopropyl- 1-oxopropyl 1 -4 (R ) -me hvl-5 (S)-phenvl-2-oxazolidinonp. - 12 3 - The title compound was prepared in analogy to the procedure of S. Thaisrivongs, D. T. Pals, L. T. Kroll, S. R. Turner and F. S. Han, J. Med. Chem. 1987, 30, 976-82, from the resultant compound of Example 1C, in 63% yield. M. p. 97 °C. 1H NMR (CDCI3) δ 0.91 (d, 3H) , 1.06 (d, 3H) , 1.1 (d, 3H) , 1.48 (s, 9H) , 0.9-1.9 (several bm, 12 H total), 2.12 (bd, IH) , 2.3 (m, IH) , 3.81 (dd, IH) , 3.94 (td, IH) , 4.04 (bm, IH) , 4.22 (dd, IH) , 4.84 (dq, IH) , 5.61 (d, IH) , 7.31-7.45 (m, 5H) . High resolution mass spectrum. Calcd. for (M+H) + of C33H51N2O7: 587.3698. Found: 587.3696. Analysis. Calcd. for C33H50N2O7 : C, 67.55; H, 8.59; N, 4.77. Found: C, 67.41; H, 8.61; N, 4.77. Example IE: 3- (3 CR ) - (3- ( rt-Bπ yl oxv arbonγl ) -7 . 7- dimethyl-4 ( Si ) - cyclohexylmethyl-S( )-Qxazolidinyl)-3-( f1- i i dazolyl * )thionyloxy " ) -2 (R) -isopropyl-1-oxopropy1 ) -A (R ) - m thyl-5 (S)-phenyl-2-PxazQ__._Ltii.nQne. The resultant compound from Example ID (1.840 g, 3.136 mmol) and 1, 1 '-thiocarbonyldiimidazolide (1.128 g, 6.330 mmol) were refluxed in 8 mL dry 1,2-dichloroethane under a nitrogen atmosphere for 24 h. The mixture was concentrated and the residue purified by flash chromatography (2.5% MeOH-CH2Cl2) to afford 1.896 g (87%) of the title compound. λ R NMR (CDCI3) δ 0.93 (d, 3H) , 1.04 (d, 3H) , 1.08 (d, 3H) , 1.5 (bs, 9H) , 0.9-1.9 (several bm, 13H total), 2.05 (m, IH) , 4.13 (bm, IH) , 4.23 (dd, IH), 4.81 (dd, IH), 4.94 (dq, IH) , 5.70 (d, IH) , 6.33 (dd, IH) , 7.06 (bs, IH) , 7.3-7.5 (m, 5H) , 7.61 (bs, IH) , 8.40 (bs, IH) . High resolution mass spectrum. Calcd. for (M+H) + of C37H53N4O7S: 697.3635. Found: 697.3629. Analysis, Calcd. for C37H52N4O7S: C, 63.77; H, 7.52; N, 8.04. Found: C, 63.58; H, 7.44; N, 7.94. Eyam le IF: 3-(3- (3-( r -Bπ γloxγcarbonvl ) -7 . ?-dimethyl- 4 (Si )-cvclohexylmethyl -F> (Si) -oxazolidinvl)-2 (Rl -isopropyl-1- oxopropyl)-4 (R) -me yl-5 (Si) -phenγl-2-oxazolidinone. A solution of the resultant product from Example IE (6.50 g, 9.33 mmol) in 275 ml of dry toluene was degassed with argon for 30 min, then warmed to reflux (under argon) . A solution of tri-n-butyltin hydride (5.43 g, 18.6 mmol) in 75 ml of dry, degassed toluene was added dropwise over 15 min. After an additional 2 h of reflux, the reaction was cooled, concentrated and purified by flash chromatography (5% EtOAc-hexanes) to afford 4.82 g (90%) of the title compound as a white foam. 1H NMR (CDCI3) δ 0.90 (d, 3H) , 0.92 (d, 3H) , 0.9-1.1 (bm, 3H) , 1.06 (d, 3H) , 1.15-1.35 (bm, 3H) , 1.51 (s, 9H) , 1.57-2.14 (several bm, 16H total), 3.84 (m, IH) , 3.97 (m, IH) , 4.85 (dq, IH) , 5.68 (d, IH) , 7.3-7.46 (m, 5H) . Mass spectrum: (M+H) + = 571. Analysis. Calcd. for C33H50N2O6: C, 69.44; H, 8.83; N, 4.91. Found: C, 69.31; H, 8.82; N, 4.89. Example IK : 2. (Si) -( (3-ftert-Butvloxvcarbonvl-2.2-dimethvl- 4 (S)-cyr.lohexylmethyl-5 (S)-oxazolidinyl)methyl) -3- e hylbutanoic acid. Using the procedure of D, A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett . 1987, 28 {49) , 6141-44, the resultant product from Example IF (6.10 g, 10.7 mmol) was hydrolyzed with aq. LiOH and hydrogen peroxide in THF. The crude material was purified by flash chromatography (15% EtOAc-0.5% HOAc-hexanes) to provide 3.53 g (90%) of the title compound as a viscous colorless oil. --R NMR (CDCI3) δ 0.96 (d, 3H) , 1.00 (d, 3H) , 1.1-1.3 (bm, 5H) , 1.48 (s, 9H) , 1.5-1.9 (several bm, 15H total), 2.0 (m, IH) , 2.66 (m, IH) , 3.7 (bm, IH) , 3.90 (m, IH) . Mass spectrum: (M+H) + = 412. Analysis. Calcd. for C23H41NO5 -0.25 H2O: C, 66.39; H, 10.05; N, 3.37. Found: C, 66.46; H, 9.84; N, 3.36. Example IH: 3- ( -Mnrphnl inyl)PT-Q VI 2 (S - ( (3- (tert- bu vloxycarbonyl ) -2. -dimethyl-4 (S) -cvclohexvlmethvl-5 (S) - oxazo idinyl )methyl)-3-methvlbutanamide. The procedure of P. Buhlmayer, et . al. , J. Med . Chem . 1988, 32(9), 1839-46 is adapted. The resultant compound from Example 1G (75 mg, 0.182 mmol), HOBt (42.0 mg, 0.274 mmol) and N-methylmorpholine (55 mg, 0.55 mmol) were dissolved in 1.0 ml dry DMF, and the solution was cooled to -20 °C (under nitrogen) . EDAC (53 mg, 0.28 mmol) was added as a solid, and the resulting mixture was stirred at -20 to 0 °C for 1 h. The mixture was sealed, and allowed to react at 0 °C (in refrigerator) for 48 h. To the resulting solution was added 4-(3-aminopropyl)morpholine (0.23 mmol) . The resulting solution was stirred at 0 °C for 4 h, and for a further 20 h, allowing it to warm slowly to room temperature. The volatiles were removed by high vacuum distillation, and the residue was partitioned between CH2CI2 and aq. NaHC03. The aqueous phase was extracted 3X with CH2CI2 and the combined organic phases were washed with brine, dried (Na2≤θ ) and concentrated. Purification by flash chromatography (4% MeOH-CH2Cl2) provided the desired compound. NMR (CDCI3) δ 0.92 (d, 3H) , 0.95 (d, 3H) , 1.46 (s) and 1.48 (s, 12H total) , 1.57 (bs, 3H) , 0.8-1.8 (several bm, 18H total) , 2.01 (m, IH) , 2.46 (bm, 6H) , 3.37 ( , 2H) , 3.64 (bm, IH) , 3.75 (bm, 5H) , 6.80 (bt, IH) . High resolution mass spectrum. Calcd. for (M+H) + of C30H56N3O5: 538.4220. Found: 538.4220. Example IT: 1 (S)- (4-(Methoxymethoxyl)piperidin-1-γl- carbonyl) -2-phenylethanol. A solution of 176 g (1.3 mol) of 1- hydroxybenzotriazole (Aldrich) , 80 g (0.48 mol) of L-3- phenyllactic acid (prepared from L-phenylalanine) 76 g (0.52 mol) of 4-(methoxymethoxy)piperidine in 800 mL of DMF was cooled to -25 0°C (internal temperature) while 132 g EDC HC1 (Saber Labs) was added (mechanical stirring) . After addition the reaction was stirred to rt over 24 h. Excess DMF was removed under high vacuum and the residue dissolved into 1.5 L of ethyl acetate. The ethyl acetate solution was washed with 4 L of saturated sodium bicarbonate. The ethyl acetate layer was separated, dried (MgS04) and evaporated to give approximately 138 g of crude amide. The product was isolated by silica gel chromatography using ethyl acetate/hexane as eluant. Yield 120 g (79%) . NMR (CDCI3, TMS) δ 1.61 (m,2H), 1.81 (m,2H), 2.89 (m,2H), 3.38 (s,3H), 3.5 (m,2H) , 3.79 (m,2H) , 3.96 (m, IH) , 4.62 (t,lH) , 4.68 (s,2H) . Example 1.T: 2 (S) - M (S) - (4-(Methoxvmethoxv)piper riin-1-yl- rarbonyl)-2-phenylethoxy)hexanoic aπid. The resultant compound of Example II (1.45 g, 4.95 mmol) , in 10 ml THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0-5oC) . The suspension was stirred for 20 mins at 0-5oC and then warmed up to room temperature and stirred for additional 1 h. Solution of D-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooled suspension (0-5oC) at N„ atmosphere. It was then allowed to warm up to room temperature and stirred overnight. Quenched with cold H 2 0 and extracted with ethylacetate to remove undesired starting material. It was acidified with 1 M sodium hydrogen sulfate and extracted with chloroform. After filtration and evaporation, the crude product was purified on silica gel, eluted with CH 2 C1 2 : CH 3 0H: AcOH (19.4 = 0.3:0.3) to obtain 0.79 g of desired acid (43 % yield) . IH NMR (CDC1 3 , TMS) δ 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,lH), 4.6 (m, IH), 4.64 (s,2H), 7.38 (m, 5H) . Mass spectrum: (M+H) + = 408. Example IK: 2 (S)-(1 (S)-(4-(Methoxvmethoxv)pjperidin-l- yl) carbonyl-2-phenyl)ethoxyhexanoic acid amide of 3-(4- morpholinyDpropyl 5 (S)-amino-6-cyclohexγl-4 (S) -hydroxy- 2 (S) -isopropylhexanamide. The resultant compound from Example IH (0.161 mmol) was deprotected by dissolving in 1.0 ml dry CH2CI2, cooling the solution to -10 °C (under nitrogen) , and treating with 1.0 ml of trifluoroacetic acid. The resulting solution was stirred at -10 to 0 °C for 4 h. The solvents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolved in 1.0 ml THF and 0.3 ml water at 0 °C. The solution was allowed to warm slowly to ambient temperature over 18 h. The crude aminoalcohol was isolated by basifying the reaction with an excess of 1.0 M aq. Na2C03, saturating the solution with NaCl, and extracting with 5 x 10 ml of 5% EtOH-CHCl3. The combined organic phases were washed with brine, dried (Na2S04) , concentrated, and the residue placed under high vacuum overnight to yield 66.2 mg (>100%) of yellow viscous oil. Coupling was acheived by combining the resultant compound from Example 1J (72 mg, 0.177 mmol), the above aminoalcohol (0.168 mmol), HOBt (34 mg, 0.22 mmol) and N- methylmorpholine (25 mg, 0.25 mmol) in 1.0 ml dry DMF. The resulting solution was cooled to -20 °C (under argon) , and EDAC (45 mg, 0.23 mmol) was added. The reaction was allowed to slowly warm to room temperature as the ice bath melted, for a total of 24 h. The solvent was removed by high vacuum distillation, and the residue was partitioned between 15 ml CH2CI2, 9 ml sat. aq. NaHC03 and 1 ml H2O. The aqueous phase was further extracted (3 X 10 ml CH2CI2) , and the combined organic phases were washed with 10 ml brine, dried ( a2S0 ) and concentrated. Purification by flash chromatography yielded the title compound as a hygroscopic glassy solid, m.p. 49-51 °C. 1 H NMR (CDCI3) δ 0.90 (m) , 0.91 (d) and 0.92 (d, 9H total), 0.65-1.90 (several bm, approx. 28H total) , 2.02 (m, IH) , 2.45 (bm, 6H) , 2.95 (m, IH) , 3.05 (dd, IH) , 3.20 (bm, 2H) , 3.36 (s, 3H) , 3.45 (m, 2H) , 3.6-4.0 (several bm) and 3.71 (m, 10H total) , 4.48 (dd, IH) , 4.68 (s, 2H) , 5.80 (d) and 5.88 (d, IH total) , 6.87 (bt, IH) , 7.3 (bm, 5H) . Mass spectrum: (M+H) + - 787. Example 2 (2S)-( (3S)-( (N-methylpiperazinsul onyl ) amino-3-phenγlmethvl-2-oxo-l-piperidiπyl ) -3- (4-thiazolyl)propioni acid amide of (2S r 4S.1 'R.2 'S) -2- (2 '-am nn-3'-cγc1ohexγl- '-hydroxypropyl )-4- methyltetrahydmfuran Exa l 2Λ; (2S. S) -3-Benzv_1oxvcarbonyl-2-pheny1- 4-phenylme hyl-5-oxo-oxazoli ine Following the procedure of Karady, Tett . Lett . 23. 4337 (1984), N-Cbz-L-phenylalanine (25 g, 83.5 mmol), benzaldehyde (18 g, 170 mmol) and p-toluenesulfonic acid (11.2 g, 58 mmol) were suspended in 1, 1, 1-trichloroethane (300 ml) . The solution was refluxed for 18 hr and the water was removed by azeotropic distillation using a Dean- Stark trap for liquids heavier than water. After cooling, the reaction was washed with saturated aqueous NaHC03 (3x50 ml) , water (1x50 ml) , dried over sodium sulfate and concentrated in vacuo to produce an orange oil. After about 1 hr, a solid crystallized from the oil and it was collected by vacuum filtration. The orange solid was recrystallized from ethyl acetate/hexane to produce colorless crystals (4.0 g, 12%); mp 120-122°C. MS (CI) : 405 (M+NH ) + , 388 (M+H) + . Example 2B; (2S, 4S)-3-Benzy3oxyπarbQnyl-2-phenyl-4- pheny1methyl-4-(l-(2-propenvl) ) -5-oxo- nxazolidine A 250 ml round-bottom flask was charged with the resultant compound from Example 2A (3.75 g, 9.7 mmol), THF (100 ml) and a magnetic stir bar. While under a nitrogen atmosphere, the flask was cooled to -78°C and via a syringe potassium hexamethyldisilylamide (25 ml, 12.5 mmol, 0.5 M solution in toluene) was added dropwise. After 15 min at -78°C, allyl bromide (1.76 g, 14.6 mmol, passed through neutral alumina prior to addition) was added over 1 min. . After 1.5 h, the reaction was quenched with saturated aqueous NH 4 CI (100 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3x100 ml) and the combined oraginc extracts were washed with saturated aqueous NaCl (2x50 ml) , dried over a 2 Sθ 4 and concentrated in vacuo to afford a light yellow oil (4.4 g) . Flash chromatography (100 g silica gel, 20% ethyl acetate/hexane, 8 ml fractions) afforded the desired product. mp 102-104°C. MS (DCI) : 445 (M+NH 4 ) + , 428 (M+H) + . Ex 2C; f2S.4Si-3-Bftn7-γ1oxγr.arhonγl-2-phenγ1-4- phenγlmethγ1-4-π-(3-hγdmxγpropγ1 ) -5- oxo-oxazolidine The resultant compound of Example 2B (3 g, 7 mmol) was dissoved in dry THF (100 ml) and then treated with 9- BBN (0.5 M in THF, 21 ml, 10.5 mmol) . After stirring overnight at room temperature, excess 9-BBN was quenched by the dropwise addition of water (1 ml) . The reactoin flask was then immersed in a room temperture water bath, followed by the concurrent and dropwise addition of 3 E NaOH (23 ml, 69 mmol) and 30% H 2 O 2 (23 ml) . Stirring was continued for 10 min after the addition was completed, after which the solution was staurated with solid NaCl. The layers were separated and the aqueous layer was - 13 1 - extracted with ether (3x50 ml) . The combined organic extracts were washed with saturated aqueous NaHCθ 3 (2x50 ml) , dried over Na2Sθ 4 and concentrated in vacuo to afford a colorless solid. Flash chromatography (100 g silica gel, 40% ethyl acetate/hexane) afforded the title compound as a colorless solid. Recrystallization from methylene chloride/hexane provided the title compound as colorless crystals, mp 130-131°C. MS (DCI) : 463 (M+NH 4 ) + , 446 (M+H) + . Example 2D: (2?, 4S)-3-Benzylpχycarbpnyl-2-phenyl-4- phenvlmethvl-4- ( 2- (e hvlcarboxaldehvde) ) - 5-QXQ-pχazplidine The resultant compound from Example 2C (860 mg, 1.9 mmol) was dissoved in methylene chloride (10 ml) and added to a vigorously stirred mixture of PCC (1.0 g, 4.9 mmol) and 4 A molecular sieves (4 g) in methylene chloride (100 ml) . Additional portions of PCC (0.5 g, 2.5 mmol) were added after 30 min and 45 min. After 1 h total reaction time, the mixture was poured into moist ether (200 ml) . The reaction flask was rinsed with ether (4x50 ml) and the combined organic solutions were filtered through celite and concentrated in vacuo to afford a dark semisolid. The crude product was dissoved in methylene chloride and fltered through a 4 inch column of florisil. The filtrate (200 ml) was concentrated in vacuo to afford the title compound as a light yellow oil (450 mg, 52%) . MS (DCI) : 461 (M+NH 4 ) + , 444 (M+H)+. ,„„„„ 0/05531 - 132 - Evaπiple ?F.: (2S) -MethvT-( (3S) -( (Benzyloxycarbonyl ) amino-3-phenγlrπethvl-2-oxo-l-piperidinγ1 )- 3-( -thiazolyl)propionate To the resulting aldehyde of Example 2D (1 g, 2.2 mmol) in isopropanol (40 ml) as added the bis hydrochloride salt of (L) -(4-thiazolyl)alanine (620 mg, 2.4 mmol), anhydrous sodium acetate (6.3 mmol) and sodium cyanoborohydride (3.18 mmol) . After 80 h at room temperature, the mixture was poured into sturated NaHCθ3 solution and extracted wilth ethyl acetate which was dried over Na 2 Sθ 4 and evaporated. The resulting compound was treated with anhydrous sodium acetate (22 mmol) and glacial acetic acid (5 drops). in dry MeOH (30 ml) . After heating for 72 h at 110°C in a sealed tube, the solution was concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and saturated NaHC03. The aqueous layer was further extracted with ethyl acetate and the combined organic extracts were dried over Na 2 Sθ and concentrated. Flash chromatography with ethyl acetate/hexane mixtures provided the desired compound as a light yellow semi- solid. MS (FAB) : 508 (M+H) + . Example ?F: (2S) -Methyl-( (3S)-( (amino-3-phenvlmethyl-?- oxo-1-piperidinyl) -3- (4-thiazolyl)propionat . The resultant compound from Example 2E (2.5 g, 4.9 mmol) was dissolved in glacial acetic acid (10 ml) and then treated with HBr/HOAc (10 ml) . After stirring for 45 min, the orange solution was concentrated in vacuo. The residue was dissolved in 50 ml H2O and washed with CCI4 (4X) . Solid NaHCθ3 was added to the aqueous layer to bring the pH to 9 and the aqueous layer was extracted with CH2CI2 (2X) and ethyl acetate (2X) . The combined organic extracts were dried (Na2Sθ4) and concentrated in vacuo to afford a yellow oil (1.8 g) . MS (DCI) : 374 (M+H) + . Example 2G: (2S) -Methy -( (3S) -( (N-methylpiperazinsulfonvl) amino-3-phenylmethyl-2-oxo-l-piperidinyl) -3- (4-thiazolyl)propionate. The resultant compound from Example 2F (250 mg, 0.67 mmol) was dissolved in 5 ml dry dimethylformamide. To this solution was added N-methylmorpholine (407 mg, 4 mmol), N,N-dimethylaminopyridine (42 mg, 0.34 mmol) and N- methylpiperidinesulfamoyl chloride (470 mg, 2 mmol) . After stirring for 18 hr, the solution was diluted with ethyl acetate (150 ml) and washed with saturated brine (3X) , dried (Na2S04) and concentrated in vacuo to afford a yellow oil. Flash chromatography with methanol/chloroform mixtures provided the title compound as a colorless foam (180 mg, 50%) . MS(CI) : 536(M+H) + . Example 2H: (?S)- ( ( )-( N-methvlpiperazinsul ony ) amino-3-phenγlmethγl-2-oxo-l-piperidinvl)-3- (4-thiazolyl)propionic acid amide of (2S.4S.1 'R.2 ■ ) -?- (7 '-amino- '-cvclohexvl- '-hydroxvpropyl) -4- methyltetrahydrofuran. The resultant compound from Example 2G (500 mg, 0.93 mmol) was dissolved in dioxane (9 ml) and cooled to 0°C under a 2 atmosphere. A solution of LiOH (98 mg, 2.3 mmol) in water (3 ml) was added dropwise and the solution was stirred for 15 min at 0°C and at 1 hr at 25°C. The reaction was neutralized with HCl/dioxane (500 μl, 2.3 mmol) and the solution was concentrated in vacuo and dried overnight on the Hl-vac. The resultant colorless acid, the amine hydrochloride resulting from HCl/dioxane treatment of (4S,5R, 2 'S,4 *S)-3-(t- butyloxycarbonyl) -4-(cyclohexyImethyl)-2,2-dimethyl-5-(4- methyltetrahydrofuran-2-yl)oxazolidine (European Patent Application No. EP0307837, published March 22, 1989) (0.93 mmol), HOBT (377 mg, 2.8 mmol), and N-methylmorpholine (104 mg, 1.02 mmol) were dissolved in dry DMF and cooled to -23°C. To this solution was added EDAC (178 mg, 0.93 mmol) in one portion. The reaction was stirred "for 3 h at -23°C, warmed to 25°C, and stirred overnight. The reaction was poured into saturated aqueous NaHC03 (50 ml) and extracted with ethyl acetate (4X) . The combined organic extracts were washed with saturated aqueous NaCl (2X) dried over Na2Sθ and concentrated in vacuo to afford a yellow foam. Flash chromatography with methanol/methylene chloride mixtures afforded the product as a colorless powder.Mp 85-89°C. MS(DCI) : 746 (M+H) + . Example 3 (2S) - ( (3S) - ( (N-methylpipera nsu l fonvl ) -ami πn-3- phenylmethyl-2-oxo-l-piperidinyl) -3- (4-thiazol yl ) propi onic acid amide of (2S. 3R. 4S) -2-amino-l-cγc.l ohexyl - 3 r 4-dihydroxy-6-methylheptan . The resultant compound from Example 2G ( 500 mg, 0 . 93 mmol) was dissolved in dioxane ( 9 ml) and cooled to 0°C under a N2 atmosphere . A solution of LiOH (98 mg, 2 .3 mmol) in water (3 ml) was added dropwise and the solution was stirred for 15 min at 0°C and at 1 hr at - 13 5 - 25°C. The reaction was neutralized with HCl/dioxane (500 μl, 2.3 mmol) and the solution was concentrated in vacuo and dried overnight on the Hl-vac. The resultant colorless acid, 2 (S) -Amino-l-cyclohexyl-3 (R) , (S) - dihydroxy-6-methylheptane (U.S. Patent No. 4,845,079, issued July 4, 1989) (226 mg, 0.93 mmol), HOBT (377 mg, 2.8 mmol), and N-methylmorpholine (104 mg, 1.02 mmol) were dissolved in dry DMF and cooled to -23°C. To this solution was added EDAC (178 mg, 0.93 mmol) in one portion. The reaction was stirred for 3 h at -23°C, warmed to 25°C, and stirred overnight. The reaction was poured into saturated aqueous NaHC03 (50 ml) and extracted with ethyl acetate (4X) . The combined organic extracts were washed with saturated aqueous NaCl (2X) dried over a2Sθ4 and concentrated in vacuo to afford a yellow oil. Flash chromatography with methanol/methylene chloride mixtures afforded the product as a colorless powder (110 mg, 16%) . Mp 93-97°C. MS (DCI) : 747 (M+H) + . MS(Hi-Res) : Calcd. Mass for C37H5gN6θ6S2=747.3937 Measured Mass=747.3929. Example 4 3-(3-Th azolyl) -2-(3R-benzvl-4-N-(N-methvlpipera7.γ1 ) - snl fnnyl- -kflt.n-DJPfirazin-l-vl -propionic acid Amide nf Butyl (S) -amino-6-cvclohexvl-4 (S) -hvdroxγ-2 CR) - isopropy] exan-amide. This compound was synthesized following the same procedure as described in Scheme 4B. A minor change was made (see Scheme 10B) at the allyla ine stage ££. The intermediate <_&. was sulfonated with N-methylpiperazyl /05531 - 13 6- sulfonyl chloride (J. Med. Chem. IS, 538, 1972) to give ££ in moderate yield (40-65%) . The acid obtained following the hydrolysis of 70 with LiOH was coupled under standard EDAC condition with 5 (S)-amino-6-cyclohexy1-4 (S)-hydroxy- 2 (R)-isopropylhexanoic acid-n-butylamide (U.S. Patent No. 4,727,060, issued February 23, 1988) to give the final product 71. DCI-NH3-MS, m/e. 816 (MH + , 60%), 798 (10%), 750 (3%) and 327 (100%); --R NMR (300 MHz, CDCI3) δ:8.75 (d,J=2Hz,H), 7.35-7.20 (m,5H) , 7.12 (d,J=2Hz,H), 6.58 (d,J=9Hz,H) , 6.01 (t,J=5Hz,H) , 5.18 (6m,H), 4.26 (dd,J=9.4Hz) , 4.06 (m,H) , 3.90-3.00 (m) , 3.00-2.70 (m) , 2.20 (s,3H), 2.20- 1.05 (m) and 0.90 (m, 9H) ; Anal. (C44H65N7O6S2) C,H,N. -137- The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfate, glucoheptonate, glycerophosphate, hemislufate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, pie ate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds of the present invention can also be used in the form of prodrugs which include esters. Examples of such esters include a hydroxyl-substituted compound of the invention which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used. Other esters include the compounds of the invention wherein a carboxylic acid group has been esterified to provide esters which include, but are not limited to, methyl, ethyl or benzyl esters. These esters serve as prodrugs of the compounds of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract. The prodrugs are metabolically converted in vivo to parent compound of the invention. The preparation of the pro-drug esters is carried out by reacting a hydroxyl-substituted compound of the invention with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester. Prodrugs which are esters of carboxylic acid group containing compounds of the invention are prepared by methods known in the art. The novel method of this invention is directed to the use of a renin inhibitor for treating, inhibiting, relieving or reversing vascular diseases with respect to functional and/or anatomical abnormalities, especially peripheral vascular diseases and microvascular diseases associated with diabetes mellitus in mammals. These diseases may be, among others, diseases of the retina, diaseases of the skin, diseases of the general circulation, diseases of the kidney, or peripheral, central or autonomic nervous system. All of these diseases may occur as symptoms -139- associated with the acute or chronic complications of diabetes mellitus. In particular, this invention is directed to the use of a renin inhibitor for treating, inhibiting, relieving or reversing diabetic retinopathy, diabetic nephropathy or diabetic neuropathy. This invention is also directed to renin inhibitor compositions useful for treating, inhibiting, relieving or reversing microvascular diseases with respect to functional and/or anatomical abnormalities, and especially those diseases associated with diabetes mellitus in mammals. In particular, this invention is directed to renin inhibitor compositions useful for treating, inhibiting, relieving or reversing diabetic retinopathy, diabetic nephropathy or diabetic neuropathy. While not intending to be bound by any theoretical mechanisms of action, the method and composition of this invention is believed to prevent localized increases in microvascular blood pressure due to locally enhanced activity of the renin-angiotensin- aldosterone system in the microvascular tissues, thus preventing or minimizing leakage from the vascular wall into the extracellular space and thus preventing the damage to the vascular system which would otherwise be caused by such leakage. The method and composition of this invention are both therapeutic and preventative. The method and composition of this invention inhibit or minimize physically or biochemically caused damage to blood vessels, and in particular the development of serious complications of diabetes mellitus where symptoms are not yet detectable; and provide relief by reversing vascular damage already done or inhibiting or minimizing further vascular damage in chronic diabetes mellitus patients where microvascular complications have already developed. The ability of renin inhibitors to prevent, reverse or inhibit microvascular disease associated with diabetes can be demonstrated by comparing urinary protein excretion in control diabetic Wistar rats with urinary protein excretion in diabetic Wistar rats treated with a renin inhibitor. Wistar rats are made diabetic by streptozocin treatment. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The compounds of the present invention may be administered orally, parenterally, by inhalation spray, by nasal spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Topical -141- administration may also involve the use of ocular inserts. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniq es. Injectable preparations, for example, sterile i jectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable ' solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, dextrose solution, mannitol solution, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. While the renin inhibitors can be administered as the sole active pharmaceutical agent, they can also be used in combination with insulin and/or a hypoglycemic agent such as an aldose reductase inhibitor or an agent selected from tolbutamide, acetohexamide, tolazamide and chlorpropamide. The renin inhibitors can also be used in combination with vasodilators useful for the treatment of peripheral vascular diseases including, but not limited to, calcium antagonists, beta-blockers and agents such as pentoxifylline and buflomedil. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims: -143- CLAIMS What is claimed is: 1. A method comprising administering to a host in need thereof a therapeutically effective amount of a renin inhibitor for treating, inhibiting, relieving or reversing vascular abnormalities or diseases including peripheral vascular diseases. 2. The method of Claim 1 wherein the vascular disease is a microvascular disease associated with diabetes. 3. The method of Claim 2 wherein the microvascular disease is diabetic retinopathy, daibetic nephropathy or diabetic neuropathy. 4. The method of Claim 1 wherein the renin inhibitor is selected from the group consisting of compounds of the formula: wherein A f is hydrogen, loweralkyl, arylalkyl, ~OR 10f or ~SR 10f wherein R ιof is h y dr °ge h , loweralkyl or aminoalkyl, ~ NR nf R 1 2f therein R llf and ~ - 12f are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl , hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, (amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkyl, (dialkylamino)carboxyalkyl, (amino)alkoxycarbonylalkyl, ((N-protected)amino)alkoxycarbonylalkyl, (alkyamino)alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonylalkyl and (dialkylamino)alkoxycarbonylalkyl; or A f is wherein B f is NH, alkylamino, S, 0, CH 2 or CHOH and R l3 f ^" s ■ 1 - oweralk y 1 ' cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyl, carboxyalkyl, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino, (amino)carboxyalkyl, (amino)carboxyalkylamino, ((N-protected)amino)carboxyalkyl, ((N-protected)amino)- carboxyalkyamino, (alkylamino)carboxyalkyl, (alkylamino)carboxyalkylamino, ((N-protected)alkylamino)- carboxyalkyl, ( (N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl, (amino)alkoxycarbonylalkylamino, ((N-protected)amino)alkoxycarbonylalkyl, ((N-protected) mino)- alkoxycarbonylalkylamino, (alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylamino, ((N-protected)alkylamino)- alkoxycarbonylalkyl, ((N-protected)alkylamino) lkoxycarbonyl- alkylamino, (dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylamino, ammocycloalkyl, aminoalkylamino, dialkylaminoalkyl(alkyl)amino, arylalkylamino, arylalkyl(alkyl)amino, alkoxyalkyl(alkyl)amino, (polyalkyoxy)- alkyl( lkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy, (polyalkoxy)alkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyclics may be unsubstituted, monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; W f is C=0 or CHOH; ϋ f is CH 2 or NR 2 , provided that when W f is CHOH then U f is CH 2 ; R lf is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzy1, halobenzyl, (1—naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoly1)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R lf is phenoxy, thiophenoxy or anilino, then B f is CH 2 or CHOH or A f is hydrogen; 2f is hydrogen or loweralkyl; 3f is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; gf is loweralkyl, cycloalkylmethyl or benzyl; Rα_-. is vinyl, formyl, hydroxymethyl or hydrogen; R, f is hydrogen or loweralkyl; R b f selected from OH and H 2 ; and R f is hydrogen, loweralkyl, vinyl or arylalkyl; wherein A is hydrogen, loweralkyl, aminoalkyl, ( lkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substituted phenyl)alkyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, naphthylalkyl, (substituted naphthyl)alkyl wherein the naphthyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, substituted or unsubstituted heterocyclic, where saturated heterocyclics may be unsubstituted, monosubεituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyhaloalkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweraklyl, haloalkyl or polyhaloalkyl, or A is (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A is -OR- or -SR_ wherein R_ is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein the substituted naphthyl is as defined above, substituted or unsubstituted heterocyclic as defined above, (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, (unsubstituted heterocyclic)C(O)- or (substituted heterocyclic)C(0)- wherein -unsubstituted or substituted heterocyclic is as defined above; or is -NR g R_ wherein R g and R g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A is - wherein B is NH, alkylamino, S, 0, CH 2 , NHCH 2 or CH(OR 52 ) wherein 52σ is hydrogen, loweralkyl or loweralkylcarbonyl, and *R 10σ is hydrogen, loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxy wherein substituted phenyl is as defined above, naphthylalkoxy, (substituted naphthyl)alkoxy wherein substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl)alkoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalkyl, (substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, lowe alkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, a substituted or unsubstituted heterocyclic as defined above, ammocycloalkyl, aminoalkylamino, (dialkylaminoalkyl)(alkyl)amino, phenylalkylamino, (substituted phenyl)alkylamino wherein substituted phenyl is as defined above, naphthylalkylamino, (substituted naphthyl)alkylamino wherein substituted naphthyl is as defined above, (phenylalkyl)(alkyl)amino, ((substituted phenyl)alkyl)(alkyl) mino wherein substituted phenyl is as defined above, (naphthylalkyl)(alkyl)amino, ((substituted naphthyl)alkyl)(alkyl)amino wherein substituted naphthyl is as defined above, alkoxyalkyl(alkyl)amino, (polyalkoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, ( (heterocyclic)alkyl)(alkyl)amino, ((heterocyclic)alkyl)amino, (heterocyclic)(alkyl)amino, (alkylaminoalkyl)(alkyl)amino, (dialkylaminoalkyl)(alkyl)amino, ((alkoxy)(alkyl)aminoalkyl)(alkyl)amino, ((alkoxy)aminoalkyl)(alkyl)amino, polyalkoxy or (polyalkoxy)alkyl; or A is R 41 CH(OH)CH 2 - or R 41 CH(OH)CH(OH)- wherein 41σ is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, phenylalkyl, (substituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl)alkoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalky1, (substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsul onylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, heterocyclicalkyl, a substituted or unsubstituted heterocyclic as defined above, ammocycloalkyl or (polyalkoxy)alkyl W is C=0, CHOH or 2 wherein R 2 is hydrogen or loweralkyl; * U is C=0, CH 2 or NR 2 wherein R 2 is hydrogen or loweralkyl, with the proviso that when is CHOH then U is CH 2 and with the proviso that U is C=0 or CH 2 when W is N 2q .; V is CH, C(OH) or C(halogen) with the proviso that V is CH when U is N 2 ; R is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthy1)methyl, (unsubstituted heterocyclic)methyl, (substituted heterocyclic)methyl wherein unsubstituted or substituted heterocyclic is as defined above, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B is CH 2 or CHOH or A is hydrogen when R, is phenoxy, thiophenoxy or anilino; 3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, ( lkoxy)(alkyl) minoalkyl, (alkoxy)aminoalkyl, benzyl or heterocyclic ring substituted methyl; R. is loweralkyl, cycloalkylmethyl or benzyl; wherein M is 0, S or NH, is C=0, C=S, S, S(O), S(0) 2 or CH 2 , E is 0, S, NR g wherein R & is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E is CR 6q R 2 σ wtιere ih R is as defined above and R 42σ is hydrogen or loweralkyl or E is c=CR 43σ R 44σ wherein 43σ and R.. are independently selected from hydrogen and loweralkyl, G is absent, CH 2 , or NR llσ wherein R llcr is hydrogen or loweralkyl, with the proviso that when Gg„ is NRl..l..g,, then R6,,g„ is loweralky J l or hydroxyalkyl, Q g is CR 45g 46g wherein R 45g and 46 are independently selected from hydrogen and loweralkyl or Q is c=CR 47σ R 8σ where i n ^4 70 an< ^ R 48 are independently selected from hydrogen and loweralkyl, and " ~ -_, Qσ is -CH 2 0H, carboxy, alkoxycarbonyl or -C0NR 5 _ R 51 wherein R 50σ is hydrogen or loweralkyl and R 51 _ is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl; - 153 - wherein Ai is ( I) R 5 i C (0) - (CH 2 ) w „- wherein 1) w" is 0 to 4 and 2 ) R 5 i is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino; (II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl; (III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or (IV) R 90i ~ or R 9Qi NHC(0)- wherein 9Qi is a C- to C. straight or branched carbon chain substituted by a substituent selected from 1) carboxy, 2) alkoxycarbonyl, 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6) heterocyclic or 7) (heterocyclic) sulfonyl) ; R η . is li (I) hydrogen, (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (VIIII) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a C- to C, straight or branched carbon chain substituted by a substituent selected from 1) alkoxy, 2) thioalkoxy, 3) aryl and 6) heterocyclic; (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy)alkyl, (IX) hydroxyalkyl, (X) -(CH 2 ) ee NHR 12i wherein 1) ee is 1 to 3 and 2) R 12i is i) hydrogen, ii) loweralkyl or iii) an N-protecting group; (XI) arylalkyl or (XII) (heterocyclic) alkyl; and T-i is wherein R 4i 1S (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and - 15 6- O ' IS wherein R-,-*-,- is loweralkyl, wherein 1) Mi is i) 0, ii) S or iii) NH; 2) Qi is i) O or ϋ) S; 3) Ei is i) O, ii) S, iii) CHR--, . wherein R-,.,. is 73ι 73ι loweralkyl, iv) C=CH 2 or v) NR. Q . wherein R-g . is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and 4) Gi is i) absent, ii) CH 2 or iii) NR- n . wherein R. Q . is ιyι iyl hydrogen or loweralkyl, with the proviso that when Gi is NR_. q . , then R, 0 . is loweralkyl or ±ol hydroxyaIky1; (III) -(CH 2 ) v -.-C(0)-N R 21l wherein 1) v" is 0 or 1 and 2) R 21i is i) NH, ii) 0, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; and - 15 8 - wherein X j is ( I) N, (II) O or (III) CH; R lj is (I) absent, (II) hydrogen, (III) an N-protecting group, (IV) aryl, (V) heterocyclic, or (VI) R, .-Q-i- wherein 1) R 6j is i) loweralkyl, ii) amino, iii) alkylamino, iv) dialkyla ino, v) (alkoxyalkyl) (alkyl) amino, vi) (alkoxyalkoxyalkyl) (alkyl) amino, vii) aryl, viii) arylalkyl, ix) aminoalkyl, x) (N-protected) aminoalkyl, xi) alkoxy, xii) substituted loweralkyl wherein the substituent is selected from alkoxy, thioalkoxy, halogen, alkylamino, (N-protected) (alkyl) amino and dialkylamino, xiii) wherein m' * ' is 1 to 5 and R_ . is 73 hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or dialkylamino; or xiv) wherein R 0 . is 0, S, SO,,, 0=C or R n .N 8j 2 9j wherein R Q . is hydrogen, loweralkyl or an N-protecting group; and 2) Qj is i) C=0 or ii) CH 2 , with the proviso that Xj is N when R , is an N-protecting group; (VII) R 54 .S(0) 2 - wherein R 54 . is 1) amino, 2) alkylamino, 3) dialkylamino, - 1 60 - 4) loweralkyl, 5) haloalkyl, 6) v aryl, 7) p-biphenyl, 8) heterocyclic or (VIII) (R cc , ) -Ε (0) - wherein R__ . is bj O 1) alkoxy, 2) alkylamino or 3) dialkylamino; Aj and Lj are independently selected from (I) absent, (II) C=0, (III) S0 2 and (IV) CH 2 ; (I) C=0, ( (iIiI)) sSo0 22 or (I) N or (ID CH; R 2j is (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, (IV) -CH 2 -R 10j -(CH 2 ) qr ι ,-R 1;Lj wherein 1) q' « ' is 0, 1 or 2, 2) R. n . is absent or R. _ . is O, NH or S only when q" 1 is 1 or 2, and 3) R 1 ± . is i) aryl or ii) heterocyclic; Zj is (I) hydrogen or (II) -R 2 g ,C(0)R 29 ., -R28jS(0) 2 R29j or -R28jC(S)R29j wherein 1) 28j is i) NH, ii) -N(R200j)~ wherein R20OJ is loweralkyl or benzyl or iii) CH ? and 2) R 29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic; R-, . is 3D (I) hydrogen, (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIIII) (alkoxyalkoxy) alkyl, (IX) (polyalkoxy) alkyl, (X) arylalkyl or (XI) (heterocyclic) alkyl; n' ' ' is 0 or 1; and wherein R. , is 43 (I) loweralkyl, (II) cycloalkylalkyl or (III) arylalkyl; and R- . is 5D wherein R-^ . is loweralkyl, -163- i) 0, ii) S, iii) CHRg.. wherein R gl . i£ loweralkyl, iv) C=CH 2 or v) NR-I8„3. wherein R_I8_3. is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and 4) G j is i) absent, /05531 -164- ii) CH 2 or iii) NR1- n 93. wherein R.19 - * j . is hydrogen or loweralkyl, with the proviso that when G j is NR_._ ., then R- jo • is loweralkyl or hydroxyalkyl; wherein 1) v' * ■ is 0 or 1 and 2) R 21j is i) NH, ii) O, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof. 5. The method of Claim 4 wherein the renin inhibitor is selected from the group consisting of: H-( (bet ,beta-dimethyl)-beta-Ala)-(4-OCH 3 )Phe-His amide of 2(S)-amino-l-cyclohexyl-3(R) ,4(S)- dihydroxy-6-methylheptane; 2(S)-(l(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbony1-2- phenyl)ethoxyhexanoic acid amide of 3-(4-morpholinyl)propyl-5-(S)-amino-6-cyclohexyl-4(S)- hydroxy-2 ( S ) isopropylhexanamide ; 2(S )-( (3 (S )-( (N-methylpiperazinsulf onyl ) amino-3 -phenyl- methyl-2-oxo-l-piper idinyl)-3-( 4-thiazolyl )propionic acid amide of (2S,4S,1'R,2'S)-2-(2'-amino-3'-cylcohexyl-1'-hydroxy- propyl)-4-methyltetrahydrofur n; 2(S)-((3(S)-((N-methylpiperazinsulfonyl)amino-3-phenyl- methyl-2-oxo-l-piperidinyl)-3-(4-thiazolyl)propionic acid amide of (2S,3R,4S)-2-amino-l-cyclohexyl-3,4-dihydroxy-6- methylheptane; 3-(3-Thiazolyl)-2-(3R-benzyl-4-N-(N-methylpiperazinyl)- sulfonyl-2-keto-piperazin-l-yl)propionic aicd amide of Butyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(R)- isopropylhexanamide; and 2(R)-2-Benzyl-3-( (2-methoxyethoxymethoxyethyl)methylamino- carbonyl)propionyl-His amide of (2'S,1'R,5S)3-Ethyl-5-(1'-hdyroxy-2'-amino-3'cyclohexyl- propyl)oxazolidin-2-one; or a pharmaceutically acceptable salt, ester or prodrug thereof. 6. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a renin inhibitor for treating, inhibiting, relieving or reversing vascular abnormalities or diseases including peripheral vascular diseases. 7. The composition of Claim 10 wherein the vascular disease is a microvascular disease associated with diabetes. 8. The composition of Claim 11 wherein the microvascular disease is diabetic retinopathy, diabetic nephropathy or diabetic neuropathy. 9. The composition of Claim 6 wherein the renin inhibitor is selected from the group consisting of compounds of the formula: wherein A f is hydrogen, loweralkyl, arylalkyl, -OR 1Qf or -SR 10 £ wherein R 10f is hydrogen, loweralkyl or aminoalkyl, -NR ι if R i 2f wherein R llf and R 12 f are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, (amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkyl, (dialkylamino)carboxyalkyl, (amino)alkoxycarbonylalkyl, ((N-protected)amino)alkoxycarbonylalkyl, (alkyamino) lkoxycarbonylalkyl, ((N-protected) lkylamino)alkoxycarbonylalkyl and (dialkylamino)alkoxycarbonylalkyl; or A f is wherein B f is NH, alkylamino, S, 0, CH 2 or CHOH and R 13£ is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialky1amino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyl, carboxyalkyl, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino, (amino)carboxyalkyl, (amino)carboxyalkylamino, ((N-protected)amino)carboxyalkyl, ((N-protected)amino)- carboxyaIkyamino, (alkylamino)carboxyalkyl, (alkylamino)carboxyalkylamino, ((N-protected)alkylamino)- carboxyalkyl, ((N-protected) lkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino) lkoxycarbonylalkyl, (amino) lkoxycarbonylalkylamino, ((N-protected) mino)alkoxycarbonylalkyl, ((N-protected)amino)- alkoxycarbonylalkylamino, (alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylamino, ((N-protected)alkylamino)- alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonyl- alkylamino, (dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylamino, ammocycloalkyl, aminoalkylamino, dialkylaminoalkyl(alkyl)amino, arylalkylamino, arylalkyl(alkyl)amino, alkoxyalkyl(alkyl)amino, (polyalkyoxy)- alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy, (polyalkoxy)alkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyclics may be unsubstituted, monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; W f is C=0 or CHOH; U e is CH 2 or NR 2 , provided that when W-. is CHOH then U f is CH 2 ; R. f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzy1, (1-naphthyl)methyl, (2-naphthy1)methyl, ( -imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when lf is phenoxy, thiophenoxy or anilino, then B f is CH 2 or CHOH or A f is hydrogen; R_ £ is hydrogen or loweralkyl; R 3f is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R gf is loweralkyl, cycloalkylmethyl or benzyl; R - is vinyl, formyl, hydroxymethyl or hydrogen; -169- R , r is hydrogen or loweralkyl; R hf and R - are independently selected from OH and NH„; and is hydrogen, loweralkyl, vinyl or arylalkyl; wherein A iε hydrogen, loweralkyl, aminoalkyl, (alkyl) minoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substituted phenyl) lkyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, naphthylalkyl, (substituted naphthyl)alkyl wherein the naphthyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, substituted or unsubstituted heterocyclic, where saturated heterocyclics may be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyhaloalkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, lowe aklyl, haloalkyl or polyhaloalkyl, or A is (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A is _ 0 R 7σ o r -SR_ wherein R_ is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein the substituted naphthyl is as defined above, substituted or unsubstituted heterocyclic as defined above, (unsubstituted heterocyclic)alkyl or (substituted heterocyclic) lkyl wherein unsubstituted or substituted heterocyclic is aε defined above, (unsubεtituted heterocyclic)C(O)- or (substituted heterocyclic)C(O)- wherein unsubεtituted or substituted heterocyclic is as defined and R g are hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A is y wherein B is NH, alkylamino, S, O, CH 2 , NHCH 2 or CH(OR 52 ) wherein R 52q . is hydrogen, loweralkyl or 1oweralkylcarbony1, and ~- 1 Qq is hydrogen, loweralkyl, cycloalkyl, phenyl, subεtituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxy wherein substituted phenyl is as defined above, naphthylalkoxy, (substituted naphthyl)alkoxy wherein subεtituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl)alkoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalkyl, (substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (subεtituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl) mino, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)- aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, a substituted or unsubstituted heterocyclic as defined above, aminocycloalkyl, aminoalkylamino, (dialkylaminoalkyl)(alkyl)amino, phenylalkylammo, (subεtituted phenyl)alkylamino wherein substituted phenyl is as defined above, naphthylalkylamino, (subεtituted naphthyl)alkylamino wherein εubstituted naphthyl is as defined above, (phenylalkyl)(alkyl)amino, ((subεtituted phenyl)alkyl)(alkyl)amino wherein substituted phenyl is as defined above, (naphthylalkyl) (alkyl)amino, ((subεtituted naphthyl)alkyl)(alkyl)amino wherein substituted naphthyl is as defined above, alkoxyalkyl(alkyl)amino, (polyalkoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, ((heterocyclie)alkyl)(alkyl)amino, ((heterocyclic)alkyl)amino, (heterocyclic)(alkyl)amino, (alkylaminoalkyl)(alkyl)amino, (dialkylaminoalkyl)(alkyl)amino, ((alkoxy)(alkyl)aminoalkyl)(alkyl)amino, ( (alkoxy)aminoalkyl)(alkyl)amino, polyalkoxy or (polyalkoxy)alkyl; or A is R 41 CH(OH)CH 2 ~ or R CH(OH)CH(OH)- wherein R 4 is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, subεtituted naphthyl aε defined above, phenylalkyl, (εubεtituted phenyl)alkyl wherein εubεtituted phenyl iε aε defined above, naphthylalkyl, (substituted naphthyl)alkyl wherein subεtituted naphthyl is as defined above, phenylalkoxyalkyl, (εubεtituted phenyl)alkoxyalkyl wherein εubεtituted phenyl iε aε defined above, naphthylalkoxyalkyl, (εubstituted naphthyl) lkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein subεtituted phenyl iε as defined above, πaphthylsulfonylalkyl, (subεtituted -173- naphthyDεulfonylalkyl wherein substituted naphthyl is as defined above, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, (N-protected)aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, heterocyclicalkyl, a substituted or unsubstituted heterocyclic as defined above, ammocycloalkyl or (polyalkoxy)alkyl; W is C=0, CHOH or NR 2 wherein R 2 is hydrogen or loweralkyl; U is C=0, CH 2 or NR 2σ wherein 2 is hydrogen or loweralkyl, with the proviso that when W is CHOH then U is CH 2 and with the proviso that U is C=0 gen) with the proviso that R., is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthy1)methyl, (unsubstituted heterocyclic)methyl, (substituted heterocyclic)methyl wherein unsubstituted or substituted heterocyclic is as defined above, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that By is CH _ 2 _ or CHOH or Ay is hydrogen when R., is phenoxy, thiophenoxy or anilino; R 3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzyl or heterocyclic ring subεtituted methyl; 0/05531 -174- R is loweralkyl, cycloalkylmethyl or benzyl; is wherein M is 0, S or NH, T is C=0, C=S, S, S(O), S(0) 2 or CH 2 , E iε O, S, NRg σ wherein R g iε hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E iε CR g R 42 wherein R g iε aε defined above and R 42cr is hydrogen or loweralky J l or E„g iε C=CR4.3,gR4.4.g„ wherein R4.3,„g and R 44 σ are independently εelected from hydrogen and loweralkyl, G iε absent, CH 2 , or NR llσ wherein R llσ s hydrogen or loweralkyl, with the proviso t when G is NR llσ then R g is loweralkyl or hydroxyalkyl, Q is CR 45σ R 46σ wherein -R 45σ and R 46 are independently selected from hydrogen and loweralkyl or Q is C=CR 47 R 4g wherein R 47σ and R 48 are independently selected from hydrogen and loweralkyl, and 49σ is -CH 3H, carboxy, alkoxycarbonyl or -CONR 5Q R 5 - wherein R 50σ is hydrogen or loweralkyl and R 51σ is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl; i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino; (II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl; (III) aryl, arylalkyl, heterocyclic or (heterocyclic)alkyl; or (IV) R 90i - or R 90i NHC(O)- wherein R goi is a C. to C. straight or branched carbon chain substituted by a substituent selected from 1) carboxy, 2) alkoxycarbonyl, 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6) heterocyclic or 7) (heterocyclic) sulfonyl) ; R_, . is li (I) hydrogen, (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (VIIII) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a C- to C- straight or branched carbon chain substituted by a substituent selected from 1) alkoxy, 2) thioalkoxy, 3) aryl and 6) heterocyclic; Xi is (I) CH 2 , (II) CHOH, (III) C(O), (IV) NH, (V) 0, (VI) S, (VII) S(0), (VIII) so 2 , (IX) N(0) or (X) -P(0)0-; (I) loweralkyl, (II) haloalkyl, • (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy) alkyl, (IX) hydroxyalkyl, (X) -(CH 2 ) ee NHR 12i wherein 1) ee is 1 to 3 and 2) R 12± is i) hydrogen, ii) loweralkyl or iii) an N-protecting group; (XI) arylalkyl or (XII) (heterocyclic) alkyl; and i is wherein R 4i ±S (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and s wherein Rη -. - is loweralkyl, v) NR- 0 . wherein R. 0 . is 18ι 18ι a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f ) amino or g) alkylamino; and 4) Gi is i) absent, ii) CH 2 or iii) NR1 1 9 Λ ι. wherein R1.9 n ι. is hydrogen or loweralkyl, with the p r roviso that when Gi^ is NR.19_ι. ,' then R- D . is loweralkyl or hydroxyalkyl; (III) -(CH,) v ..-C(0)-N r ~ " *21l wherein 1) v" is 0 or 1 and 2) R 21i is i) NH, ii) 0, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; and - 18 0 - wherein X j is ( I) N, (II) O or (III) CH; R lj is (I) absent, (II) hydrogen, (III) an N-protecting group, (IV) aryl, (V) heterocyclic, or (VI) Rg,-Qj- wherein 1) R_- . is i) loweralkyl, ii) amino, iii) alkylamino, iv) dialkylamino, v) (alkoxyalkyl) (alkyl) amino, vi) (alkoxyalkoxyalkyl) (alkyl) amino, vii) aryl, viii) arylalkyl, ix) aminoalkyl, x) (N-protected) aminoalkyl. xi) alkoxy, xii) substituted loweralkyl wherein the substituent is selected from alkoxy, thioalkoxy, halogen, alkylamino, (N-protected) (alkyl) amino and dialkylamino, xiii) wherein m 1 ' ' is 1 to 5 and R_ . is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or dialkylamino; or xiv) wherein R» 0 3. is 0, S, S0 Δ, 0=C or R-y * j.N wherein R„ . is hydrogen, loweralkyl or an N-protecting group; and 2) Qj is i) C=0 or ii) CH 2 , with the proviso that X j is N when R . is an N-protecting group; (VII) R 54 .S(0) 2 - wherein is 1) amino, 2) alkylamino, 3) dialkylamino, 4) loweralkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl, 8) heterocyclic or (VIII) (R cc .)_P(0)- wherein R cc . is oo _ . > z> -_ 1) alkoxy, 2) alkylamino or 3) dialkylamino; Aj and Lj are independently selected from (I) absent, (II) C=0, (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, (IV) -CH 2 -R 10 .-(CH 2 ) ,-R 1;L . wherein 1) q' « ■ is 0, 1 or 2, - 1 8 3 - 2) , J is absent or R. Q . is O, NH or S only when q' * ' is 1 or 2, and 3) R., .. is i) aryl or ii) heterocyclic; Zj is (I) hydrogen or (II) -R 28 .C(0)R 29 ., -R28jS(0) 2 R29j or -R28jC(S)R29j wherein 1) R 28j is i) NH, ii) -N(R200j) _ wherein R20OJ is loweralkyl or benzyl or iii) CH 2 and 2) R 29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic; (I) hydrogen, (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIIII) (alkoxyalkoxy) alkyl, (IX) (polyalkoxy) alkyl, (X) arylalkyl or (XI) (heterocyclic) alkyl; n' is 0 or 1; and - H? rOH R5 ' wherein R.. is (I) loweralkyl, (II) cycloalkylalkyl or (III) arylalkyl; and R_- . is 5 wherein R__, . is loweralkyl, wherein 1) Mj is i) 0, ii) S or iii) NH; 2) Qj is i) 0 or ii) S; 3) Ej is i) 0, ii) S, iii) CHR,.. wherein R,. . is loweralkyl, iv) C=CH 2 or v) NR- 0 . wherein R, 0 . is lo 3 lo] a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and 4) Gj is i) absent, 0/05531 -186- ii) CH 2 or iii) NR.. n . wherein R. _ . is 19U 1 3 hydrogen or loweralkyl, with the proviso that when G j is NR. Q ., then R. 0 . is loweralkyl or hydroxyalkyl; (III) (CH 2 ) v ...-C(0)— R 21J wherein 1) v'" is 0 or 1 and 2) R 21 _ is i) NH, ϋ) O, iii) S or iv) S0 2 ; or (IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof.

Inventors: KLEINERT HOLLIS D, KLEINERT, HOLLIS, D.
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1989
Main classification: A61K37
IPC codes: A61K38, A61K45, A61P3, A61P13, A61P15, A61P27, C07D211, C07D417, C07K5