WO1990005531A1 - Method for treating vascular diseases - Google Patents

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

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 maculopathy, 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 11 339 (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 11 339 (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. 16 453 (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 maj or 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 Hommel, 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., 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. Wagnon, et al., U.S. Patent No.

4,725,580, issued February 16, 1988. 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.

4,757,050, 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. 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:

wherein A is hydrogen, loweralkyl, arylalkyl, -OR₂₀ wherein R₂₀ is hydrogen, or loweralkyl, -NR₂₁R₂₂ wherein R₂₁ and R₂₂ are independently selected from hydrogen and loweralkyl;

or A is

wherein B is NH, O, CH₂ or NHCH₂; and R₂₃ 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=O, CH₂ or CHOH;

U is CH₂ or NR₂, wherein R₂ is hydrogen or loweralkyl, provided that when W is CHOH then U is CH₂;

R₁ 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 R₁ is phenoxy, thiophenoxy or anilino, then B is CH₂ or A is hydrogen;

R₃ is loweralkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl;

R₅ is hydrogen or loweralkyl;

R₆ is loweralkyl, cycloalkylmethyl, or benzyl;

R₇, R₈ and R₉ are hydrogen or loweralkyl and may be the same or different;

V is NH, O, S, SO, SO₂' or CH₂;

R₁₀ is loweralkyl, cycloalkyl,

(cycloalkyl) alkyl, aryl, arylalkyl or an N-protecting group, or V and R₁₀ taken together are N₃; with the proviso that R₁₀ may be an N-protecting group only when V is NH;

(2)

wherein A_b is hydrogen, loweralkyl, arylalkyl; OR_20b or SR_20b wherein R_20b iS hydrogen, loweralkyl or aminoalkyl, NR_21bR_22b wnerein R_21b and R_22b are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;

or A_b is

wherein B_b is NH, alkylamino, S, O, CH₂, or CHOH; and E_23b 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;

W_b is C=O or CHOH;

U_b is CH₂ or NR_2b, wherein R_2b is

hydrogen or loweralkyl, provided that when W_b is CHOH then U_b is CH₂;

R_1b 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_1b is phenoxy,

thiophenoxy or anilino, then B_b is CH₂ or CHOH or

A, is hydrogen;

R_3b is loweralkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl;

R_5b is hydrogen or loweralkyl;

R_6b is loweralkyl, cycloalkylmethyl, or benzyl;

R_10b is loweralkyl, cycloalkyl,

(cycloalkyl) alkyl, aryl, arylalkyl or an N-protecting group, or L_b and R_10b taken together can be N₃,

with the proviso that when L_b is NH then R_10b is an N-protecting group;

R_13b is CHOH or CO;

R_14b is CH₂, CF₂ or CF with the Proviso that when R_13b is CO then R_14b is CF₂;

R_15b is CH₂, CHR_25b wherein R_25b is

loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or R_14b and R_{1 5 b} taken together can be

with the proviso that when R₁₄ is CF₂ then R₁₅ is

CH ₂;

L_b is O, S, SO, SO₂, NR_26b wherein R_26b

is hydrogen or loweralkyl, or NR_27bC(O) wherein R_27b is hydrogen or loweralkyl;

wherein Ac is

wherein B is NH, or CH₂; and -R_23c is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;

W_c is C=O;

U_c is NR _2c , wherein R_2c is hydrogen or

loweralkyl; R_1c is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,

(1-naphthyl)methyl, (2-naphthyl)methyl,

(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl;

R_3c is loweralkyl, benzyl or heterocyclic ring substituted methyl;

R_5c is hydrogen or loweralkyl;

R_6c is loweralkyl, cycloalkylmethyl, benzyl, or CH₂R₂₄ , where R_24c is selected from

1,3-dioxan-2-yl; 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl;

R_16c is CH₂, CF₂ or CHR_63c where R _63c is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl;

R_17c is hydrogen or loweralkyl;

R_18c is loweralkyl or lipophilic or aromatic amino acid side chain;

D_c is hydrogen, loweralkyl or -CH₂OR_28c, wherein R_28c is hydrogen, loweralkyl or arylalkyl;

(4)

wherein A_d is hydrogen, loweralkyl, arylalkyl,

-OR_20d or -SR_20d wherein R_20d is hydrogen,

loweralkyl or aminoalkyl, -NR_21dR_22d wherein R_21d and R_22d are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;

or A, is

wherein B_d is NH, alkylamino, S, O, CH₂, or NHCH₂, 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;

Wa, is C=O or CHOH;

U_d is CH₂ or NR_2d, wherein R_2d is

hydrogen or loweralkyl, provided that when W_d is CHOH then U, is CH₂;

R_1d is CHR_24d wherein R_24d 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 R_1d is C=CHR_25d wherein R_25d is aryl;

R_3d is loweralkyl, alkenyl, benzyl or heterocyclic ring substituted methyl;

R_5d is hydrogen or loweralkyl; Ε_6d is loweralkyl, cycloalkylmethyl, or benzyl;

R_{11 d} is hydrogen or hydroxy;

n is 0 or 1; when n is 0 then T_d is alkylidene or alkylidene oxide; and when n is 1 then Z_d is hydrogen or hydroxy and T_d is loweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl;

R_12d is hydrogen, loweralkyl,

cycloalkylalkyl, aryla l, aminoalkyl, or

dialkylaminoalkyl;

( 5 ) .

wherein A_e is hydrogen, loweralkyl, arylalkyl,

-OR_20e or -SR_20e wherein R_20e is hydrogen,

loweralkyl or aminoalkyl, -NR_21eR_22e wtιerein R_21e and R_22e are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A_e is

wherein B_e is NH, alkylamino, S, O, CH₂, or CHOH; and R_23e 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;

W_e is C=O;

U_e is NK_2e, wherein R_2e is hydrogen or loweralkyl;

R_1e is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,

(1-naphthy1)methyl, (2-naphthy1)methyl,

(4-imidazolyl)methyl, (alpha, alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when R_1e is phenoxy,

thiophenoxy or anilino, then B_e is CH₂ or CHOH or

A_e is hydrogen;

R_3e is loweralkyl, benzyl or heterocyclic ring substituted methyl;

R_5e is hydrogen or loweralkyl;

R_6e is loweralkyl, cycloalkylmethyl, or benzyl;

M_e is O, NH or S;

R_10e is hydrogen, loweralkyl , cycloalkyl , (cycloalkyl) alkyl , aryl , arylalkyl or an N-protecting group; ( 6 )

wherein A_f is hydrogen, loweralkyl, arylalkyl.

-ORlOf or -SR_10f wherein R_10f is hydrogen,

loweralkyl or aminoalkyl, -NR_11fR_12f wherein R_11f and R _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, O, CH₂ or CHOH and R_13f 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,

(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)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)- 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=O or CHOH;

U_f is CH₂ or NR₂, provided that when W_f is CHOH then U_f is CH₂;

R_1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl,

(2-naphthyl)methyl, ( 4-imidazolyl)methyl,

( alpha, alpha)-dimethylbenzyl, 1-benzyloxyethyl,

phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_1f is phenoxy, thiophenoxy or anilino, then B_f is CH₂ or CHOH or A_f is hydrogen;

R_2f is hydrogen or loweralkyl;

R_3f is loweralkyl, loweralkenyl,

( (alkoxy) alkoxy) loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;

R_6f is loweralkyl, cycloalkylmethyl or benzyl;

R_af is vinyl, formyl, hydroxymethyl or hydrogen;

R_df is hydrogen or loweralkyl;

R_bf and R_ef are independently selected from OH and NH₂; and

R_cf is hydrogen, loweralkyl, vinyl or arylalkyl;

wherein A_g 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 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,

loweraklyl, haloalkyl or polyhaloalkyl, or A_g is

(unsubstituted heterocyclic) alkyl or (substituted heterocyclic) alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A_g is -OR_7g or

-SR_7g wherein R_7g 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(O)- wherein unsubstituted or substituted heterocyclic is as defined above; or A_g is -NR_8gR_9g wnerein R_8g and

R_9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and

hydroxyalkyl; or A_g is

wherein B_g is NH, alkylamino, S, O, CH₂, NHCH₂ or

CH(OR_52g) wherein R_52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R_10g 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, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl)thioalkyl wherein substituted phenyl is as defined above,

naphthylthioalkyl, (substitutednaphthyl)thioalkylwherein 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)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) (alayl) amino,

((alkoxy) (alkyl) aminoalkyl) ( alkyl) amino,

((alkoxy) aminoalkyl) (alkyl) amino, polyalkoxy or

(polyalkoxy) alkyl; or A_g is R_41gCH(OH)CH₂- or

R_41gCH(OH)CH(OH)- wherein R_41g 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 phenylis 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 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=O, CHOH or NR_2g wherein R_2g is hydrogen or loweralkyl;

U_g is C=O, CH₂ or NR_2g wherein R_2g is hydrogen

or loweralkyl, with the proviso that when W is CHOH then U_g is CH₂ and with the proviso that U_g is C=O or CH₂ when W is NR_2g;

V_g is CH, C(OH) or C(halogen) with the proviso that

V_g is CH when U_g is NR_2g:

R_1g is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, ( 1-naphthyl)methyl, (2-naphthyl)methyl, (unsubstituted heterocyclic)methyl, (substituted

heterocyclic)methyl wherein unsubstituted or substituted heterocyclicis as defined above, phenethyl,

1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B_g is CH₂ or CHOH or A is hydrogen when R₁₉ is phenoxy, thiophenoxy or anilino;

R_3g is loweralkyl, loweralkenyl,

((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl) aminoalkyl,

dialkylaminoalkyl, (alkoxy) (alkyl)aminoalkyl,

(alkoxy)aminoalkyl, benzyl or heterocyclic ring

substituted methyl;

R_4g is loweralkyl, cycloalkylmethyl or benzyl; R_5g is OH or NH₂; and

Z_g is

wherein M_g is O, S or NH, T_g is C=O, C=S, S, S(O),

S(O)₂ or CH₂, Eg is O, S, NR_6g wherein R_6g is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E_g is CR_6gR_42g wherein

R_6g is as defined above and R_42g is hydrogen or loweralkyl or E is C=CR_43gR_44g wherein R_43g and

R_44g are independently selected from hydrogen and loweralkyl, G is absent, CH₂, or NR_11g wherein

R_11g is hydrogen or loweralkyl , with the proviso that when G_g is NR_11g then R_6g is loweralkyl or

hydroxyalkyl, Q_g is CR_45gR_46g wherein R_45g and

R₄₆ are independently selected from hydrogen and loweralkyl or Q is c=CR_47gR_48g wherein R_47g and R_48g are independently selected from hydrogen and loweralkyl, and R_49g is -CH₂OH, carboxy,

alkoxycarbonyl or -CONR_50gR_51g wherein R_50g is hydrogen or loweralkyl and R_51g is hydrogen,

loweralkyl, aminoalkyl, alkylaminoalkyl,

dialkylaminoalkyl or alkoxyalkyl;

wherein A_h is hydrogen, loweralkyl, arylalkyl,

-OR_20h or -SR_20h wherein R₂₀h is hydrogen,

loweralkyl or aminoalkyl, -NR_21hR_22h wherein R_21h and R_22h are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A_h is

wherein B_h is NH, alkylamino, S, O, CH₂, NHCH₂ or

CHOH; and R_23h 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=O or CHOH;

U_h is CH₂ or NR_2h, wherein R_2h is

hydrogen or loweralkyl, provided that when W_h is CHOH then U_h is CH₂;

R_1h is 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_1h is phenoxy,

thiophenoxy or anilino, then B, is CH₂ or CHOH or

A_h is hydrogen;

R_3h is loweralkyl, loweralkenyl,

((alkoxy)alkoxy) alkyl, carboxyalkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl;

R_5h is hydrogen or loweralkyl;

R_6h is loweralkyl, cycloalkylmethyl, or benzyl;

( 9) .

wherein A_i is

(I) R_5iC (O) - (CH₂ ) _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_90iNHC(O)- wherein R_90i is a C₁ to C₄ 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_1i is

(I) hydrogen, (II) loweralkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl,

(VI) aryloxyalkyl,

(VII) thioaryloxyalkyl,

(VIIII) arylalkoxyalkyl,

(IX) arylthioalkoxyalkyl or

(X) a C₁ to C₃ straight or branched

carbon chain substituted by a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl and

6) heterocyclic;

X_i is

(I) CH₂,

(II) CHOH,

(III) C(O),

(IV) NH,

(V) O,

(VI) S,

(VII) S(O),

(VIII) SO₂,

(IX) N(O) or

(X) -P(O)O-;

R_3i is

(I) loweralkyl,

(II) haloalkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl, (V) cycloalkenylalkyl,

(VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl,

(X) -(CH₂)_eeNHR_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_{4 i} is

4x

(I) loweralkyl,

(II) cycloalkylalkyl

(III) cycloalkenylalkyl or (III) arylalkyl; and

D_i is

wh _73i oweralkyl,

(II)

wherein

1) M_i is

i) O,

ii) S or

iii) NH;

2) Q_i is

i) O or

ii) S;

3) Ei is

i) O,

ii) S,

iii) CHR_73i wherein R_73i is loweralkyl, iv) C=CH₂ or v) NR_18i wherein R_18i is a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl, d) hydroxy,

e) alkoxy, f) amino or

g) alkylamino;

and

4) G_i is

i) absent,

ii) CH₂ or

iii) NR_19i wherein R_19i is

hydrogen or loweralkyl,

with the proviso that when G_i is NR_19i , then R_18i is loweralkyl or

hydroxyalkyl;

(III)

wherein

1) v" is 0 or 1 and

2) R_21i is

i) NH,

ii) 0,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group; and

(10)

wherein X_j is

(I) N,

(II) O or

(III) CH; is

R_1j

(I) absent,

(II) hydrogen,

(III) an N-protecting group,

(IV) aryl,

(V) heterocyclic, or

(VI) R_{6 j}-Q_j- wherein

1) R_{6 j} 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''' is 1 to 5 and R_{7 j} is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or

dialkylamino; or

xiv)

wherein R_8j is O, S, SO₂, O=C or R_9jN wherein R_9j is hydrogen, loweralkyl or an N-protecting group; and

2) Q_j is

i) C=O or

ii) CH₂,

with the proviso that X_j is N when R_{1 j} is an N-protecting group;

(VII) R_{54 j}S(O)₂- wherein R_{54 j} is

1) amino,

2) alkylamino,

3) dialkylamino, 4) loweralkyl,

5) haloalkyl,

6) aryl,

7) p-biphenyl,

8) heterocyclic or

(VIII) (R_{55 j})₂P(O)- wherein R_{55 j} is

1) alkoxy,

2) alkylamino or

3) dialkylamino;

A_j and L_j are independently selected from (I) absent,

(II) C=O,

(III) SO₂ and

(IV) CH₂;

D_j is

(I) C=O,

(II) SO₂ or

(III) CH₂;

Y_j is

(I) N or

(II) CH; is

R_2j

(I) hydrogen,

(II) loweralkyl,

(III) cycloalkylalkyl,

(IV) -CH₂-R_{10 j}-(CH₂) q_{' ' '}-R_11j wherein 1) q''' is 0, 1 or 2, 2) R_10j is absent or R_10j is O, NH or S only when q' ' ' is 1 or 2, and

3) R_{11 j} is

i) aryl or

ii) heterocyclic; Z_j is

(I) hydrogen or

(II) -R_28jC(O)R_29j, "R_28jS (O) ₂R_29j or -_R28jC(S)R_29j wherein

1) R_28j is

i) NH,

ii) -N(R_200j)^_ wherein R_200j is loweralkyl or benzyl or

iii) CH₂ and

2) R_29j is

i) alkoxy,

ii) benzyloxy,

iii) alkylamino,

iv) dialkylamino,

v) aryl or

vi) heterocyclic;

R_3j is

(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_{4 j} is

(I) loweralkyl,

(II) cycloalkylalkyl or

(III) arylalkyl; and

R_{5 j} is

(I)

wherein R_{73 j} is loweralkyl,

wherein

1) M_j is

i) O,

ii) S or

iii) NH;

2) Q_j is

i) O or

ii) S;

3) E_j is

i) O,

ii) S,

iii) CHR_{61 j} wherein R_{61 j} is loweralkyl, iv) C=CH₂ or

v) NR_18j wherein R_18j is a) hydrogen,

b) loweralkyl, c) hydroxyalkyl, d) hydroxy,

e) alkoxy,

f) amino or

g) aIkylamino; and

4) G_j is

i) absent, ii) CH₂ or

iii) NR_19j wherein R_19j is

hydrogen or loweralkyl,

with the proviso that when G_j is

NR_19j, then R_{18 j} is loweralkyl or hydroxyalkyl;

(III)

wherein

1) v''' is 0 or 1 and

2) R_21j is

i) NH,

ii) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof.

The term "loweralkyl" as used herein refers to straight 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 substituted 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. The term "phenylalkoxyalkyl" as used herein refers to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to

phenylmethoxymethyl and the like.

The term "(substituted 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 "(substituted naphthyl) alkoxyalkyl" as used 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" as 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" as used herein refers to -NH₂ appended to a loweralkyl radical.

The term "alkylaminoalkyl" as used herein refers to -NHR₇₀ appended to a loweralkyl radical, wherein R₇₀ 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 -NH₂ appended to a cycloalkyl radical.

The term "N-protected aminoalkyl" as used herein refers to -NHR-, appended to a loweralkyl group, wherein R₇₁ is an N-protecting group.

The term "(N-protected) (alkyl) amino alkyl" as used herein refers to NR₇₁R₇₂ which is appended to a loweralkyl radical, wherein R₇₁is defined as above and R₇₂ is a loweralkyl group.

The term "alkoxycarbonylalkyl" as used herein refers to R₇₃COR₇₄-, wherein R₇₃ is an alkoxy

group and R₇₄ 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 -N₃ 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 -NR₇₅R₇₆ group appended to a loweralkyl radical wherein R₇₅ is an alkoxy group and R₇₆ is a. loweralkyl group.

The term "loweralkylsulfinylalkyl" as used herein refers to a R₇₇S(O)- group appended to a

loweralkyl radical wherein R₇₇ is a loweralkyl group. The term "loweralkylsulfonylalkyl" as used herein refers to a R₇₈S(O)₂- group appended to a

loweralkyl radical wherein R₇₈ is a loweralkyl group.

The term "phenylthioalkyl" as used herein refers to a R₇₉S- group appended to a loweralkyl

radical wherein R₇₉ is a phenyl group.

The term "(substituted phenyl)thioalkyl" as used herein refers to a R₈₀S- group appended to a loweralkyl radical wherein R₈₀ is a substituted phenyl group.

The term "naphthyl thioalkyl" as used herein refers to a R₈₁S- group appended to a loweralkyl

radical wherein R₈₁ is a naphthyl group.

The term "(substituted naphthyl)thioalkyl" as used herein refers to a R₈₂S- group appended to a loweralkyl radical wherein R₈₂ is a substituted

naphthyl group.

The term "phenylsulfonylalkyl" as used herein refers to a R₈₃S(O)₂- group appended to a loweralkyl radical wherein R₈₃ is a phenyl group.

The term "(substituted phenyl)sulfonylalkyl" as used herein refers to a R₈₄S(O)₂- group appended to a loweralkyl radical wherein R₈₄ is a substituted phenyl group.

The term "naphthylsulfonylalkyl" as used herein refers to a R₈₅S(O)₂- group appended to a loweralkyl group wherein R₈₅ is a naphthyl group.

The term "(substituted naphthyl)sulfonylalkyl" as used herein refers to a R₈₆S(O)₂- group appended to a loweralkyl group wherein R₈₆ is a substituted naphthyl group.

The term "carboxyalkoxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to an alkoxy group whichis appended to a loweralkyl radical. The term "alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R₈₇CO- wherein R₈₇ 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

(-NH₂).

The term "((N-protected) amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR₈₈ wherein R₈₈ 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 -NR₈₉R₉₀ wherein R₈₉ is as defined above and R₉₀ is a loweralkyl group.

The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and

-NR₉₁R₉₂ wherein R₉₁ and R₉₂ 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) alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR₉₃ wherein R₉₃ 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 -NR₉₄R₉₅ wherein R₉₄ is an N-protecting group and R₉₅ 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 -NR₉₆R₉₇ wherein R₉₆ and R₉₇ are independently

selected from loweralkyl.

The term "carboxyalkylamino" as used herein refers to -NHR₉₈ wherein R₉₈ is a carboxyalkyl group.

The term "alkoxycarbonylalkylammo" as used herein refers to -NHR₉₉ wherein R₉₉ is an

alkoxycarbonylakyl group.

The term "(amino)carboxyalkylamino" as used herein refers to -NHR₁₀₀ wherein R₁₀₀ is an

(amino)carboxyalkyl group.

The term "((N-protected)amino)carboxyalkylamino" as used herein refers to -NHR₁₀₁ wherein

R₁₀₁ is an C(N-Protected)-amino)carboxyalkyl group.

The term" (alkylamino)carboxyalkylamino" as used herein refers to -NHR₁₀₂ wherein R₁₀₂ is an

(alkylamino)carboxyalkyl group.

The term "((N-protected)alkylamino)- carboxyalkylamino" as used herein refers to -NHR₁₀₃ wherein R₁₀₃ is an ( (N-protected) alkylamino ) - carboxyalkyl group .

The term " ( dialkylamino ) carboxyalkylamino" as used herein refers to -NHR₁₀₄ wherein R₁₀₄ is a

(dialkylamino)carboxyalkyl group.

The term"(amino) alkoxycarbonylalkylammo" as used herein refers to -NHR₁₀₅ wherein R ₁₀₅ is an

(amino)alkoxycarbonylalkyl group.

The term "((N-protected)amino)alkoxy- carbonylalkylamino" as used herein refers to -NHR₁₀₅ wherein R₁₀₆ is an ((N-protected) amino)- alkoxycarbonylalkyl group.

The term "(alkylamino) alkoxycarbonylalkylammo" as used herein refers to -NHR₁₀₇ wherein R₁₀₇ is an (alkylamino) alkoxycarbonylalkyl group.

The term "((N-protected) alkylamino) alkoxycarbonylalkylammo" as used herein refers to -NHR₁₀₈ wherein R₁₀₈ is an ((N-protected)alkylamino)- alkoxycarbonylalkyl group.

The term "(dialkylamino)alkoxycarbonylalkylammo" as used herein refers to -NHR₁₀₉ wherein R₁₀₉ 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. The term "amino" as used herein refers to an -NH₂ substituent.

The term "alkylamino" as used herein refers to -NHR ₁₁₀, wherein R ₁₁₀ is a loweralkyl group.

The term "dialkylamino" as used herein refers to -NR₁₁₁R₁₁₂, wherein R₁₁₁ and R₁₁₂ are

independently selected from loweralkyl groups.

The term "arylalkylamino" as used herein refers to R_{1 13}NH-, wherein R_{11 3} is an arylalkyl residue.

The term "arylalkyl(alkyl)amino" as used herein refers to R₁₁₄R₁₁₅N-, wherein R _{1 1 4} is an arylalkyl residue and -R₁₁₅ is a loweralkyl residue.

The term "phenylalkylamino" as used herein refers to a phenylalkyl group appended to an amino radical, including, but not limited to benzylamino and the like.

The term "(substituted phenyl)alkylamino" as used 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-naphthy Imethyl amino 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 R₁₁₆R₁₁₇N-, wherein R₁₁₆ is a

phenylalkyl residue and R₁₁₇ is a loweralkyl residue.

The term "((substituted phenyl) alkyl)- (alkyl) amino" as used herein refers to R₁₁₈R₁₁₉N- wherein R₁₁₈ is a (substituted phenyl)alkyl group and R₁₁₉ is a loweralkyl group. The term "(naphthylalkyl) (alkyl) amino" as used herein refers to R₁₂₀R₁₂₁N- wherein R ₁₂₀ iS a

naphthylalkyl group and R₁₂₁ is a loweralkyl group.

The term "((substituted naphthyl) alkyl)- (alkyl)amino" as used herein refers to R₁₂₂R₁₂₃N- wherein R₁₂₂ is a (substituted naphthyl) alkyl group and R ₁₂₃ is a loweralkyl group.

The term "aminoalkylamino" as used herein refers to R₁₂₄NH- where R₁₂₄ is an aminoalkyl

residue.

The term "dialkylamino( alkyl) amino" as used herein refers to R₁₂₅R₁₂₆N-, wnerein R₁₂₅ is a

dialkylamino residue appended to a loweralkyl residue and R ₁₂₆ is a loweralkyl residue.

The term "((dialkylamino) alkyl) (alkyl) amino" as used herein refers to -NR₁₂₇R₁₂₈ wherein R₁₂₇ is a dialkylamino residue appended to a loweralkyl residue and R₁₂₈ is a loweralkyl residue.

The term "(hydroxyalkyl) (alkyl) amino" as used herein refers to -NR₁₂₉R₁₃₀ wherein R₁₂₉ is a

hydroxyalkyl group and R₁₃₀ is a loweralkyl group.

The term "(di-hydroxyalkyl) (alkyl) amino" as used 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 R₁₃₁R₁₃₂N-, wherein R₁₃₁ and

R₁₃₂ are hydroxyalkyl residues.

The term "alkoxyalkyl(alkyl) amino" as used herein refers to R₁₃₃R₁₃₄N-, wherein R₁₃₃ is a

loweralkyl group and R₁₃₄ is an alkoxyalkyl group. The term "di-(alkoxyalkyl) amino" as used herein refers to R ₁₃₅R₁₃₆N-, wherein R₁₃₅ and R₁₃₆ are

alkoxy residues appended to loweralkyl residues.

The term "di-(polyalkoxyalkyl) amino" as used herein refers to R₁₃₇R₁₃₈N-, wherein R₁₃₇ and

R₁₃₈ are polyalkoxy residues appended to loweralkyl residues.

The term "((polyalkoxy) alkyl) (alkyl)amino" as used herein refers to R₁₃₉R₁₄₀N-, wherein R₁₃₉ is a polyalkoxy residue appended to a loweralkyl radical and R ₁₄₀ is a loweralkyl residue.

The term "( (heterocyclic) alkyl) (alkyl)amino" as used herein refers to -NR₁₄₁R₁₄₂ wherein R₁₄₁ isa heterocyclicalkyl group and R₁₄₂ is a loweralkyl group.

The term "(heterocyclicalkyl) amino" as used herein refers to -NHR₁₄₃ wherein R₁₄₃ is a

heterocyclic alkyl group.

The term "(heterocyclic) (alkyl) amino" as used herein refers to -NR₁₄₄R₁₄₅ wherein R₁₄₄ is a

substituted or unsubstituted heterocyclic group and

R₁₄₅ is a loweralkyl group.

The term "(alkylaminoalkyl) (alkyl) amino" as used herein refers to -NR₁₄₆R₁₄₇ wherein R₁₄₆ is an alkylaminoalkyl group and R₁₄₇ is a loweralkyl group.

The term "(dialkylaminoalkyl) (alkyl)amino" as used herein refers to -NR₁₄₈R₁₄₉ wherein R₁₄₈ is a dialkylaminoalkyl group and R₁₄₉ is a loweralkyl group.

The term "( (alkoxy) (alkyl)aminoalkyl)- (alkyl)amino" as used herein refers to -NR ₁₅₀R₁₅₁ wherein R₁₅₀ is -NR₁₅₂R₁₅₃ appended to a

loweralkyl radical wherein R₁₅₂ is an alkoxy group and R₁₅₃ is a loweralkyl group and R ₁₅₁ is a loweralkyl group. The term "((alkoxy) aminoalkyl) (alkyl) amino" as used herein refers to ^_NR₁₅₄R₁₅₅ wherein R₁₅₄ is

-NHR ₁₅₆ appended to a loweralkyl group and wherein

R₁₅₆ is an alkoxy group and R₁₅₅ is a loweralkyl

group.

The term "(alkoxyalkoxyalkyl) (alkyl) amino" as used herein refers to -NR₃₀₅R₃₀₆ wherein R₃₀₅ is

an alkoxyalkoxyalkyl group and R₃₀₆ is a loweralkyl group.

The term "di( alkoxyalkoxyalkyl)amino" as used herein refers to -NR₃₀₇R₃₀₈ wherein R₃₀₇ and

R₃₀₈ are alkoxyalkoxyalkyl groups.

The term "alkylsulfonylamino" as used herein refers to R₃₀₉NH- wherein R₃₀₉ is an alkylsulfonyl gorup .

The term "arylsulfonylamino" as used herein refers to R₃₁₀NH- wherein R₃₁₀ is an arylsulfonyl group.

The term "alkylaminocarbonylamino" as used herein refers to R₃₁₁C(O)NH- wherein R₃₁₁ is an

alkylamino group.

The term "alkylammocarbonyloxy" as used herein refers to R₃₁₂C(O)O- wherein

R ₃₁₂ is an alkylamino group.

The term "alkoxycarbonyloxy" as used herein refers to R₃₁₃C(O)O- wherein R₃₁₃ is an alkoxy group.

The term "loweralkylcarbonyl" as used herein refers to R₁₅₇C(O)- wherein R₁₅₇ is a loweralkyl

group, including, but not limited to acetyl, propionyl and the like.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₁₅₈O- and R₁₅₈S-, respectively, wherein R₁₅₈ 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 (R₃₀₃O- wherein R₃₀₃ is an aryl group) appended to a loweralkyl radical.

The term "thioaryloxyalkyl" as used herein refers to a thioaryloxy group (R₃₀₄S- wherein R₃₀₄ 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 R₁₅₉O-, wherein R₁₅₉ 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 te R₁₆₀O- wherein R₁₆₀ 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 "(substituted phenyl)alkoxy" as used herein refers 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 "(substituted naphthyl) alkoxy" as used herein refers to a substituted naphthyl group appended to an alkoxy radical.

The term "polyalkoxy" as used herein refers to

R₁₆₁O-, wherein R₁₆₁ is a straight or branched chain containing 1-5, C_m-O-C_m, linkages where m and m' are independently 1 to 3.

The terms "halo" or "halogen" as used herein refer to Cl , Br, F or I substituents.

The term "haloalkyl" as 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 R₃₀₀s(o)₂- wherein R₃₀₀ is a loweralkyl group. The term " (aryl) sulfonyl" as used herein refers to R₃₀₁S(O)₂- werein R₃₀₁ is an aryl group.

The term "(heterocyclic) sulfonyl" as used herein refers to R₃₀₂S(O)₂- wherein R₃₀₂ 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 unsubstituted or substituted with one, two or three substituents

independently selcted from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

The term "substituted phenyl" as used herein refers to a phenyl 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 halophenyl, loweralkylphenyl, alkoxyphenyl and the like.

The term "substituted 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. The term "alkylaryl" as used herein refers to a loweralkyl group appended to an aryl radical.

The term "heterocylcic group" or "heterocyclic" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected 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, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,guinolinyl, isoquinolinyl, benzimidazolyl,

benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyland benzothienyl.

Heterocyclics can be unsubstituted or monosubstituted 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, O, or S, provided that X is the point of connection only when X is N,

wherein Y is NH, N-loweralkyl, O, S, or SO₂, or

wherein the symbols (i), (ii) and (iii) represent 5-membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z₁ is N, O, or S and not the point of connection and Z₂ is N when it is the point of connection and NH, O or S when it is not the point of connection; with the proviso that when Z₂ is the point of connection, then Z₁ 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 exopeptidases on the compounds 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. 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)alkoxycarbonylalkylamino,

XIV) (alkylamino)alkoxycarbonylalkylamino,

XV) ((N-protected)alkylamino)alkoxycarbonylalkylamino,

XVI) (dialkylamino)alkoxycarbonylalkylamino,

XVII) (alkoxyalkyl) (alkyl)amino,

XVIII) (alkoxyalkoxyalkyl) (alkyl) amino,

XIX) di-(alkoxyalkyl)amino,

XX) di-(alkoxyalkoxyalkyl)amino,

XXI) di-(hydroxyalkyl)amino,

XXII) ((unsubstituted heterocyclic)alkyl) (alkyl)- amino,

XXIII) ((substituted heterocyclic)alkyl) (alkyl)- amino, XXIV)

wherein aa' is 1 to 5 and R_{6 q} and R_7q are independently selected 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,

17)

wherein dd' is 1 to 5,

and

18) R_8q-Z_q- wherein

Z_q is O, S or NH and R_8q is a C₁ to C₆ straight or branched carbon chain

substituted by a substituent selected from hydroxy, alkoxy,

thioalkoxy, alkoxyalkoxy, amino,

alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic;

XXV)

wherein R_9q is

1) O,

2 ) S,

3 ) SO₂ or

4) C=O; or

XXVI)

wherein R_{1 0q} is

1) hydrogen,

2) loweralkyl,

3) an N-protecting group or

4) R_{11 q}-C(O)- wherein R_11q is

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_13qR_14q wherein

1) R_13q is 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_13q is hydroxy then R_{14 q} is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected) amino,

(N-protected) (alkyl) amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R_13q is hydrogen then R_14q is not hydrogen or loweralkyl;

(II) -C(=CH₂)C(O)NHR_15q;

(III) -C(OH) (R₁₆ )C(O)NHR_15q or

(IV) -CH (R _16q) C (O) NHR_15q wherein

1] R_15q iS

i) loweralkyl,

ii) hydroxyalkyl,

iii) alkoxyalkyl,

iv) aminoalkyl,

v) alkylaminoalkyl,

vi) dialkylaminoalkyl,

vii) aryl,

viii) heterocyclic or

ix) (heterocyclic) alkyl and

2) R_16q is

i) hydrogen,

ii) loweralkyl,

iii) hydroxyalkyl,

iv) haloalkyl or

v) azidoalkyl; (V)

wherein

1) t' is 0 to 3,

2) R_20q is

i) CH₂ or

ii) N and

3) R_21q is

i) NH,

ii) O,

iii) S or

iv) SO₂,

such that when t' is 0 then R_20q is CH₂ and when t' is 1 to 3 then R_20q is N, (VI) -CH₂CH(R₂₂ )C(O)NHR_23q 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. x) (heterocyclic) alkyl or

xi)

wherein

a) u' is 0 to 3,

b) R_24q is CH₂ or N and

c) R_25q is NH, O, S or

SO₂,

such that when u' is 0 then R _24q is CH ₂ and when u' is 1 to 3 then R _24q is

N;

(VII)

wherein

1) R _22q is as defined above and

2) R _74q is

i) hydrogen,

ii) loweralkyl,

iii) an N-protecting group or iv) R_75q-C(O)- wherein R_75q is aminoalkyl or (N-protected)- aminoalkyl;

(VIII)

wherein

1) R_26q is

i) loweralkyl or

ii) cycloalkylalkyl and

2) R_27q is

i) loweralkyl or

ii) cycloalkylalkyl;

(IX) -CH₂CH(R_81q)NHC(O)R_82q or

-CH₂CH(R_81q)NHS(O)₂R_82q 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 R_21q is

as defined above;

(X) -CH₂NHC(O)R_82q or -CH₂NHS (O)₂R_82q wherein R_82q is as defined above; or

(XI) -CF₂CH(OH)R_83q wherein R_83q is

loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyenylalkyl, aryl, aryalkyl, heterocyclic or (heterocyclic) alkyl.

The terms "lipophilic or aromatic amino acid side chains" as used 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, CH₃SCH₂- 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, respectively. In general, the amino acid abbreviations 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. 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. WO87/02986).

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 amination 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 R₃ 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 IIA, 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, R₂= 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 R₁ substituent.

The process of Scheme IVA discloses the preparation of compounds of the general structure (1) wherein A is a carboxy derivative R₅CO- wherein R₅ 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 R₅-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 8} is a C₁ to C₄ 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 R₅CO- wherein R₅ is a substituted amine and X is O 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 CH₂ and A is R₅CO- wherein R₅ is hydroxy, alkoxy, thioalkoxy or an amine.

Compound (XXX) (J. Med. Chem. 26 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 R₅ 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 R₅-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, R₅-H is an amine and X is O or S. In Scheme XIIIA, R₅-H is an amine.

The process in scheme XIVA describes the preparation of compounds of the general structure XLII wherein R₃ is a C₁ to C₆ 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. R₁ 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 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 ( H₂ Pd/C or PdOH) and oxidized to the

corresponding carboxylic acids XLI using a variety of oxidants (KMnO₄, Jones, PDC, RUO₄, Pt/O₂). 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 R₁ is a C₁ to C₆ 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, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a C₁ to C₆

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 (CrO₃·2Pyr) gives the

optically pure lactone XLVI. Reaction of the lactone with LiHMDS in THF or THF/HMPA followed by the addition of R₁-I or R₁-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 Weinreb et. al. Org. Syn. 1980, 59, 49, to give the alcohol

XLVIII. Oxidation of the alcohol using a variety of oxidants (KMnO₄, Jones, PDC, RUO₄, Pt/O2) 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 ( I₂ 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 R₁ is a C₁ to C₆ 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, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a C₁ to C₆

straight or branched alkyl/alkenyl carbon chain or

heteroatom substituted carbon chain substituted by O, 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 R₁ are the same as previously described for scheme XVIIA and R₂ is selected from C₁ to C₆ 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 R₁ substituents reversed.

The syntheses of hydroxyethylene dipeptide isosteres are depicted in Schemes XVII IA 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 LX (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. W.

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 (RNH₂) 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' 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, ureas LXXII and carbamates LXXIII. 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. W. 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, 52, 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' retro-inverted amide derivatives. Intermediate aldehyde LX 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 sulfamoyl 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.

a: NaOAc, NaCNBH₃; b: separate diastereomers; c: as a; d: LiOH, H₂O, dioxane; e: (VI), NMM, HOBT, EDAC; f: as b; g: as d; h: as e; i; riinxane//Cl. SCHEME IIA

a: 2 eq TEA, CH₂Cl₂, 0-25°; b: selective hydrolysis; c: coupled to (VI).

SCHEME IIIA

a: NaOAc, NaCNBH₃: b: separate diastereomers; c: H ₂, Pd/C; d: NMM, HOBT, EDAC SCKEMEIVA

_ Diosane/HCl; b: R₅-H, HOBT.EDAC; c: H₂Pd/C or LiOH/H₂O; iNMM.HOBT,EDAC. SCHEMEVA

a: NaOAC, NaCNBH₃; b: separate diastereomers; c: H₂, Pd/C; d: (VI), NMM.HOBT, EDAC. SCHEME VIA

a: NaH, THF-, b:( VI )NMM.HOBT.EDAC.

SCHEMEVIIA

a: NMM, HOBT, EDAC; b: LiOH/H₂O/dioxane; c: R₅-H, HOBT, EDAC. SCHEMEVIΠA

a: CH₂CI₂, -72°C; b: protect; c: H₂, Pd/C;

d: Jones [O]; e: R₅-H, HOBT, EDAC; f: LiOH/H₂O; g: (VI). HOBT, EDAC; h: deprotect.

X A

A

A

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 R₅ 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. WO87/02986).

Scheme 1B 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/H₂O) and then coupled to the appropriately functionalized amine (in this case 2-amino-1-cyclohexyl-3,4-dihydroxy-6-methyl heptane) using a EDAC, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, or other standard peptide coupling methods to provide the desired product 4.

Scheme 2B discloses a general method for the synthesis of compounds of the invention containing N-substituted benzyl piperazines. The dipeptide 5 is synthesized using a mixed anhydride coupling method. The diketopiperazine 6, 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 8. The amine 8 is protected (Boc-anhydride in CH₂Cl₂) and then the ester is hydrolyzed (LiOH/MeOH/H₂O). The free acid 9 is then coupled to the hydrochloride salt of the appropriately functionalized amine ( in this case 2-amino-1-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 11 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 lactam forming agents. The lactam-ester 13. is hydrolyzed

(LiOH/dioxane/H₂O) and then coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-1-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 16. Aldehyde 16 is coupled to an amino acid by reductive amination and then cyclized. The lactam-ester 18. is hydrolyzed (LiOH/water/dioxane) and then coupled to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-1-cyclohexyl-3,4-dihydroxy-6- methyl 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 2 4 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-1-cyclohexyl-3,4-dihydroxy-6- methyl heptane) to give the. desired product 26 .

Scheme 6B discloses a general method for synthesizing compounds of the invention containing amino substituted gamma- and delta-lactams. Compound 27 (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 29. Oxidation of 29 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 3 1a, which is cyclized to the corresponding lactam 32 (n=1). The lactam ester 32 is hydrolyzed to the corresponding acid. The acid is coupled to the hydrochloride salt of the appropriately

functionalized amine (in this case 2-amino-1-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=1.

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 3 1 b . Lactam ester 32 (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-1-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 33, which is esterified to produce 34. The free hydroxy group is allylated with allyl bromide to provide ester 35, which is oxidized to the aldehyde 36. The aldehyde 36 is reductively aminated with the appropriate amino acid ester (in this case L-His-OMe) to give amino ester 37, which is thermally cyclized to lactam 38. Lactam ester 38. 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-1-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 40 is converted to acids 41 or 42, which are reduced to alcohols 43 or 44, respectively. Alcohols 43 and 44 are then oxidized to aldehydes 45 and 46. Reductive amination of 46 with the appropriate amino acid ester (in this case L-His-OMe di-p- toluenesulfonic acid salt) provides amino ester 48. This compound is converted to the free acid, which is then cyclized to 49. Similarly, reductive amination of 45 leads directly to the cyclic derivative 47 . Protection of the imidazole nitrogen of 47 and 49 as the N-t-Boc derivative, followed by ester hydrolysis, leads to acids 50 and 51. Amide formation with the hydrochloride salt of the

appropriately functionalized amine (in this case 2-amino-1- cyclohexyl-3,4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods, followed by imidazole deprotection, affords 52. and 53, 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 54. 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 56. 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-1- cyclohexyl-3,4-dihydroxy-6-methyl heptane) using EDAC or other standard peptide coupling methods, followed by imidazole deprotection, affords 58.

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 60. The ester is reduced to the alcohol and the alcohol is oxidized to the aldehyde 61. 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 63 provides alcohol 64. Oxidation and reductive amination of 64 gives diamine 65. Ring closure to 66, followed by coupling to the hydrochloride salt of the appropriately functionalized amine (in this case 2-amino-1-cyclohexyl-3,4-dihydroxy- 6-methyl heptane) using EDAC or other standard peptide coupling methods to provide 67.

Scheme 12B discloses a general method for synthesizing compounds of the invention containing a sulf onyl

substituted ketopiperazine. Compound 68 is sulfonylated, followed by ring formation, to give compounds such as 70 and 72. Deprotection and coupling of the resulting acid with the appropriately functionalized amine provides products such as 71 and 73.

Scheme 13B discloses a general method for synthesizing compounds of the invention containing amino substiuted delta-lactams. Compound 32 (Scheme 6, n=2) is treated with H₂ and Pd/C in acetic acid, followed by treatment with toluenesulfonyl chloride, to produce di-tosylate 75.

Treatment of 75 with LiOH, followed by

ditertbutyldicarbonate, produces acid 76. Acid 76 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 77.

Treatment of 77 with HBr/HOAc, followed by reaction with sulfonyl chlorides or sulfamoyl chlorides, produces the amino protected compound 78. 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 82 was reduced with LAH at room temperature in 5 min and then cyclized under Mitsonobu condition to give the tetrahydrofuran derivative 84 in high yield. The free amine 85 was obtained by deprotection of 84 under acidic condition followed by a basic work-up with saturated NaHCO₃.

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 78 with various aldehydes and sodium cyanoborohydride in inert solvents produces the N-alkyl compound 79. 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 32 and 77 which are used in the synthesis of compounds of the invention.

Compound 86 (J. Chem. Soc. (c), 329, 1971) is deprotonated and alkylated with allyl bromide to provide 87. 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 88 (9-BBN then NaOOH) and oxidation to the aldehyde (PCC) is followed by reductive alkylation with amino acid esters to provide the lactams.

a: Mixed anhydride coupling followed by HCI/Dioxane b: Heating in Xylene for 6 h

c: LAH in THF, Reflux overnight

d: Ethyl Bromohexanoate, K₂CO₃, Dioxane. Reflux for 2 h e: ^tBOC-Anhydride, CH₂CI₂

f: Hydrolysis followed by EDAC coupling of the amine

a: SO₃-Pyricine

b: nor-Leu-CM e, NaCNBH₃

c: Benzyl bromoacetate, Na₂CO₃, Dioxane d: H₂-Pd, MeOH

e: EDAC, HOBT, DMF

f: LiOH, H₂O-Dioxane

g: EDAC, HOBT. Amine.HCl, DMF

a: ^tBOC-Anhydride, CH₂CL₂ b: NaN(TMS)₂, Allyl Bromide, DMF c: Ozone, CH₂CI₂

d: nor-Leu-OMe, NaCNBH₃ e: Reflux in Xylene

f: LiOH, H₂O-Dioxane

g: EDAC, HOBT, Amine.HCl, DMF

a- LDA, Benzyl Bromide, THF b: Methanol/Sulphuric Acid followed by Benzyl Alcohol/ TsOH , Reflux c: Oxalyl Chloride. DMSO.TEA d: L-nor-Leu-OMe, Sodium Cyanoborohydride IPA e:' Hydrogen; 10% Pd-C. MeOH f: EDAC. HOBT.TEA.DMF g: LiOH. Diox-Water h: HClA. mine. EDAC. HOBT, TEA, DMF

a: KHMDS.THF, -78°C,allyl bromide e: His-OMe.NaOAc,NaCNBH₃ b: aq. NaOH; H⁺; CH₂ N₂ f: HOBT,Tolucne:DME.rctlux c: O₃,-78ºC,thenMe₂S g: 2 eq. isopropvlamine.MeOH, retlux d: 9-BBN/THF,NaOOH;PCC h: aq.LiOI I-EDΛCAmine

a: HNO₂

b: MeO H, TsOH, reflux

c: NaH, DMF, allyl bromide

A O₃, -78°C. Me₂S

e: His-OCH₃.NaOAc.NaCNBH₃ fr MeOH.reflux

g: L:OH, BocOBoc. amine, EDAC. HOAc

a: CF₃CO₂H; b: H₂, Pd/C; c: EH₃/THF; d: CICOCOCI. DMSO. TEA;

e: H-His-OBn TsOH₂, NaOAc, NaCNEH₃; f: OF₃CO₂H, then EDAC, HOST; g: Eoc-O-Eoc, then H₂, Pd/C; h: EDAC, HOBT, Amine, then HOAc.

a: CICOCOCl, DMSO, TEA; b: H-His-OBnTsOH₂, NaOAc, NaCNBH₃;

c: CF₃CO₂H, then CDI; d: Ecc-O-Bcc, then H₂, Pd/C; e: EDAC, HOST, Amine, then HOAc; f: (CH₃)₂CHCHO, NaOAC, NaCNBH₃, then Eoc-O-Eoc; g: Ca(EH₄)₂. t

a) Benzyl bromoacetate, TEA, THF b) BOC-Anhydride, Methylene Chloride c) Pyridine-SO₃

d) L-nor-Leu-OMe, NaCNBH₃, IPA e) Reflux in Xylene

f) NaOH, MeOH-H₂O

g) Amine, EDAC, HOBT, DMF, TEA

a:H₂, Pd/CHOAc e: Amine,EDAC, HOBT b:TsCI,NMM,DMAP,CH₂Cl₂ f: HOAc,THF,H₂O c:LiOH,H₂O

d:BocOBoc

a: Thiazolvlalanine-OCH₃, d: RSO₂Cl.DMAP. NMM, DMF NaCNBH₃, NaOAc

b: MeOH, NaOAc, Reflux e: LiOH,H₂O

c: HBr / HO Ac f: AmincED AC. H OBT

a: R'CHO, NaCNBH₃ , CH₃CN b: LiOH,H₂O

c: Amine, EDAC, HOBT

8.8

a: LiHMDS,DMPU,Allyl Bromide f: 9-BBN

b: LiOH.H₂O g: NaOOH

c: IN HCl h: PCC

d: Cbz-Nos i: Thiala-OCH,. NaCNBH₃ 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

2 (S)-(1(S) - ( 4-(Methoxymethoxylpiperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 3-(4- morpholinyl)propyl 5 (S ) -amino-6-cyclohexyl-4(S )-hyriroxy-

2 (S )-isopropvlhexanamide

Example 1A: 4 (S)-t-Butyloxycarbonylamino-5-cyclohexyl- 3 (R,S)-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 C₁₆H₂₉NO₃ .1/4 H₂O: C, 66.8; H, 10.3; N,

4.9.

Found: C, 66.9; H, 10.2; N, 4.7. Example 1B: 3-(t-Butyloxycarbonyl)-4-(cvclohexylmethyl)- 2.2-dimethyl-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 1A 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 (CDCI₃) 1690 (C=O

carbamate) cm^-1; ¹H NMR (CDCl₃) δ 5.95 (m, 1H) , 5.32

(m,lH), 5.20 (dt,1H), 4.27 (dd, 1H), 1.47 (s, 9H).

Anal. Calcd. for C₁₉H₃₃NO₃: 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 1B 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 them 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 entire reaction mixture extracted with two 300 ml portions of dichloromethane. The combined dichloromethane extracts were decanted, dried (MgSO₄), 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 (CDCl₃) 1735 (C=O aldehyde), 1690 (C=O carbamate) cm^-1; ¹H NMR (CDCl₃) δ 9.83 (s,1H,CHO), 9.73

(d, 1H,CHO cis diastereomer), 4.14 (m, 1H) , 1.46 (s,9H).

Anal. Calcd. for C₁₈H₃₁NO₄: C, 66.43; H, 9.60; N, 4,30.

Found: C, 65.27; H, 9.79; N, 4.20.

Equilibration 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 (MgSO₄), filtered, and concentrated. The aldehyde was purified by flash chromatography using (1:4) ethyl acetate thexane to give 19.5 g of the desired compound as an 8:1 mixture of trans:cis diastereomers.

Example 1D: 3-(3(R)-(3-(tert-Butvloxvcarbonvl)-2.2- dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-3-hγriroxy-h(R )- isopropyl- 1-oxopropyl)-4(R )-methvl-5(S)-phenvl-2-oxazolidinone. 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, 1H), 2.3 (m, 1H), 3.81 (dd, 1H), 3.94 (td, 1H), 4.04 (bm, 1H), 4.22 (dd, 1H), 4.84 (dq, 1H), 5.61 (d, 1H), 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 1E: 3-(3(R )-(3-(tert-Butyloxvcarbonγl) -2 . 2- dimethyl-4( S ) - cyclohexylmethyl-5(R)-oxazolidinyl)-3-((1- imidazolyl)thionyloxy)-2(R)-isopropyl-1-oxopropyl) -A (R ) - methyl-5(S)-phenyl-2-Pxazolidinone.

The resultant compound from Example 1D (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. ¹H 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, 1H), 4.13 (bm, 1H), 4.23 (dd, 1H), 4.81 (dd, 1H), 4.94 (dq, 1H), 5.70 (d, 1H), 6.33 (dd, 1H), 7.06 (bs, 1H), 7.3-7.5 (m, 5H), 7.61 (bs, 1H), 8.40 (bs, 1H). 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.

Eyample 1F: 3-(3-(3-(tert-Butyloxycarbonyl) -2 ,2-dimethyl- 4 (S ) -cyclohexylmethyl-5 (S )-oxazolidinyl)-2(R)-isopropyl-1- oxopropyl)-4(R)-methyl-5(S )-phenyl-2-oxazolidinone.

A solution of the resultant product from Example 1E (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, 1H), 3.97 (m, 1H), 4.85 (dq, 1H), 5.68 (d, 1H), 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 1G : 2 (S ) -((3-ftert-Butyloxycarbonyl-2.2-dimethyl-

4 (S)-cyclohexylmethyl-5(S)-oxazolidinyl)methyl)-3- methylbutanoic 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. ¹ H 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, 1H), 2.66 (m, 1H), 3.7 (bm, 1H), 3.90 (m, 1H). 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 1H: 3-(4-Mnrphnlinyl)Propyl 2(S)-((3-(tert- butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)- oxazolidinyl)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. NaHCO₃. The aqueous phase was extracted 3X with CH₂CI₂, and the combined organic phases were washed with brine, dried (Na2SO₄) and concentrated. Purification by flash chromatography (4% MeOH-CH₂Cl₂) provided the desired compound. ¹H 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, 1H), 2.46 (bm, 6H), 3.37 (m, 2H), 3.64 (bm, 1H), 3.75 (bm, 5H), 6.80 (bt, 1H).

High resolution mass spectrum. Calcd. for (M+H)⁺ of

C₃₀H₅₆N₃O₅: 538.4220. Found: 538.4220.

Example 1I: 1 (S) -(4-(Methoxymethoxyl)piperidin-1-yl- 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 HCl (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, 1H), 4.62 (t,1H), 4.68 (s,2H).

Example 1J: 2(S)-M(S)-(4-(Methoxvmethoxy)piperidin-1-yl- rarbonyl)-2-phenylethoxy)hexanoic acid.

The resultant compound of Example 1I (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 N₂ atmosphere. It was then allowed to warm up to room temperature and stirred overnight. Quenched with cold H₂O 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 CH₂Cl₂ : CH₃OH: AcOH (19.4 = 0.3:0.3) to obtain 0.79 g of desired acid (43 % yield).

¹H NMR (CDCl₃, TMS) δ 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,lH), 4.6 (m, 1H), 4.64 (s,2H), 7.38 (m, 5H). Mass spectrum: (M+H)⁺ = 408.

Example 1K: 2(S)-(1(S)-(4-(Methoxvmethoxy)pjperidin-1- yl)carbonyl-2-phenyl)ethoxyhexanoic acid amide of 3-(4- morpholinyl)propyl 5(S)-amino-6-cyclohexγl-4(S)-hydroxy-

2 (S)-isopropylhexanamide .

The resultant compound from Example 1H (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. Na₂CO₃, 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 (Na₂SO₄), 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. NaHCO₃ 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 (Na₂SO₄) and concentrated.

Purification by flash chromatography yielded the title compound as a hygroscopic glassy solid, m.p. 49-51 °C. ¹H 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, 1H), 2.45 (bm, 6H), 2.95 (m, 1H), 3.05 (dd, 1H), 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, 1H), 4.68 (s, 2H), 5.80 (d) and 5.88 (d, 1H total), 6.87 (bt, 1H), 7.3 (bm, 5H).

Mass spectrum: (M+H)⁺ = 787.

Example 2

(2S)-((3S)-((N-methylpiperazinsulfonyl) amino-3-phenylmethvl-2-oxo-1-piperidinyl)-3-

(4-thiazolyl)propionic acid amide of (2S,4S.1'R,2'S)-2-

(2'-aminn-3'-cyclohexyl-1'-hydroxypropyl)-4- methyltetrahydmfuran

Example 2A: (2S.4S) -3-Benzyloxvcarbonyl-2-phenyl-

4-phenylmethyl-5-oxo-oxazolidine 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 NaHCO₃

(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+NH₄)⁺, 388 (M+H)⁺.

Example 2B; (2S,4S)-3-Benzyloxycarbonyl-2-phenyl-4- phenylmethyl-4-(1-(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 NH₄CI (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 Na₂SO₄ 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+NH₄)⁺, 428

(M+H)⁺.

Example 2C; (2S,4S)-3-Bftnzyloxycarhonyl-2-pheny1-4- phenylmethyl-4-(1-(3-hydmxypropyl))-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 N NaOH (23 ml, 69 mmol) and 30% H₂O₂ (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 extracted with ether (3x50 ml). The combined organic extracts were washed with saturated aqueous NaHCO₃ (2x50 ml), dried over Na₂SO₄ 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+NH₄)⁺, 446

(M+H)⁺.

Example 2D: (2S,4S)-3-Benzylpxycarbpnyl-2-phenyl-4- phenylmethyl-4-( 2-(ethvlcarboxaldehvde))- 5-oxo-oxazolidine

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+NH₄)⁺, 444 (M+H)+. Example 2E: (2S)-Methyl-((3S)-((Benzyloxycarbonyl) amino-3-phenylmethyl-2-oxo-1-piperidinyl)- 3-(4-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 NaHCO₃ solution and extracted wilth ethyl acetate which was dried over Na₂SO₄ 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 NaHCO₃. The aqueous layer was further extracted with ethyl acetate and the combined organic extracts were dried over Na₂SO₄ 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 2F : (2S)-Methyl-((3S)-((amino-3-phenvlmethyl-2- oxo-1-piperidinyl)-3-(4-thiazolyl)propionate. 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 NaHCO₃ 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 (Na₂SO₄) and concentrated in vacuo to afford a yellow oil (1.8 g). MS (DCI): 374 (M+H)⁺.

Example 2G: (2S)-Methyl-((3S)-((N-methylpiperazinsulfonyl) amino-3-phenylmethyl-2-oxo-1-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 (Na₂SO₄) 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: (2S)-((3S)-((N-methylpiperazinsulfonyl) amino-3-phenylmethyl-2-oxo-1-piperidinyl)-3- (4-thiazolyl)propionic acid amide of (2S,4S,1'R,2'S)-2- (2'-amino-3'-cyclohexyl-1'-hydroxypropyl)-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 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 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 NaHCO₃ (50 ml) and extracted with ethyl acetate (4X). The combined organic extracts were washed with saturated aqueous NaCl (2X) dried over Na2Sθ4 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-methylpiperazi nsu l fonyl ) -ami no-3- phenylmethyl-2-oxo-1-piperidinyl) -3- (4-thiazol yl ) propi onic acid amide of (2S. 3R. 4S) -2-amino-1-cycl ohexyl - 3 , 4-dihydroxy-6-methylheptane .

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 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-1-cyclohexyl-3 (R), 4 (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 NaHCO₃ (50 ml) and extracted with ethyl acetate (4X). The combined organic extracts were washed with saturated aqueous NaCl (2X) dried over Na₂SO₄ 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 C₃₇H₅₉N₆O₆S₂=747.3937

Measured Mass=747.3929.

Example 4

3-(3-Thiazolyl)-2-(3R-benzyl-4-N-(N-methylpiperazyl)- snlfnnyl-2-keto-piperazin-1-yl)-propionic acid Amide of Butyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(R)- isopropy]hexan-amide.

This compound was synthesized following the same procedure as described in Scheme 4B. A minor change was made (see Scheme 10B) at the allylamine stage 68. The intermediate 68 was sulfonated with N-methylpiperazyl sulfonyl chloride (J. Med. Chem. 15, 538, 1972) to give 69 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%); ¹ H 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.

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, pierate, 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 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 administration may also involve the use of ocular inserts. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable 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

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_10f is hydrogen,

loweralkyl or aminoalkyl, -NR_11fR_12f therein R_11f and R _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, O, CH₂ or CHOH and

R_13f 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,

(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) 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=O or CHOH;

U_f is CH₂ or NR₂, provided that when W_f is CHOH then U_f is CH₂; R_1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl,

(2-naphthyl)methyl, (4-imidazolyl)methyl,

(alpha, alpha)-dimethylbenzyl, 1-benzyloxyethyl,

phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_1f is phenoxy, thiophenoxy or anilino, then B_f is CH₂ or CHOH or A_f is hydrogen;

R_2f is hydrogen or loweralkyl;

R_3f is loweralkyl, loweralkenyl,

((alkoxy)alkoxy) loweralkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl;

R_6f is loweralkyl, cycloalkylmethyl or benzyl;

R_af is vinyl, formyl, hydroxymethyl or hydrogen;

R_df is hydrogen or loweralkyl;

R_bf and R_ef are independently selected from OH and NH₂; and

R_cf is hydrogen, loweralkyl, vinyl or arylalkyl;

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 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,

loweraklyl, haloalkyl or polyhaloalkyl, or A_g is

(unsubstituted heterocyclic) alkyl or (substituted heterocyclic) alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A_g is -OR_7g or -SR_7g wherein R_7g 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(O)- wherein unsubstituted or substituted heterocyclic is as defined above; or A_g is -NR_8gR_9g wherein R_8g and

R_9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and

hydroxyalkyl; or A_g is -

wherein B_g is NH, alkylamino, S, O, CH₂, NHCH₂ or

CH(OR_52g) wherein R_52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R_10g 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, 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 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)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_g is R_41gCH(OH)CH₂- or

R_41gCH(OH)CH(OH)- wherein R_41g 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, 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 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_g is C=O, CHOH or NR_2g wherein R_2g is hydrogen or loweralkyl;

U_g is C=O, CH₂ or NR_2g wherein R_2g is hydrogen

or loweralkyl, with the proviso that when W_g is CHOH then U_g is CH₂ and with the proviso that U_g is C=O or CH₂ when W_g is NR_2g;

V_g is CH, C(OH) or C(halogen) with the proviso that

V_g is CH when U_g is NR_2g; R_1g is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthyl)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_g is CH₂ or CHOH or A_g is hydrogen when R_1g is phenoxy, thiophenoxy or anilino;

R_3g is loweralkyl, loweralkenyl,

((alkoxy)alkoxy) alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl,

dialkylaminoalkyl, (alkoxy) (alkyl)aminoalkyl,

(alkoxy)aminoalkyl, benzyl or heterocyclic ring

substituted methyl;

R_4g is loweralkyl, cycloalkylmethyl or benzyl;

R_5g is OH or NH₂; and

Z_g is

wherein M_g is O, S or NH, T_g is C=O, C=S, S, S(O),

S(O)₂ or CH₂, E_g is O, S, NR_6g wherein R_6g is

hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E_g is CR_6gR_42g wtιereih R_6g is as defined above and R_42g is hydrogen or loweralkyl or E is C=CR_43gR_44g wherein R_43g and

R_44g are independently selected from hydrogen and loweralkyl, G_g is absent, CH₂, or NR_11g wherein

R_11g is hydrogen or loweralkyl, with the proviso that when G_g is NR_11g then R_6g is loweralkyl or

hydroxyalkyl, Q_g is CR_45gR_46g wherein R_45g and

R_46g are independently selected from hydrogen and loweralkyl or Q_g is C=CR_47gR_48g wherein R_47g and R_48g are independently selected from hydrogen and loweralkyl, and R _{4 9g} is -CH₂OH, carboxy,

alkoxycarbonyl or -CONR_50gR_51g wherein R_50g is hydrogen or loweralkyl and R_51g is hydrogen,

loweralkyl, aminoalkyl, alkylaminoalkyl,

dialkylaminoalkyl or alkoxyalkyl;

wherein A_i is

( I) R_{5 i}C (O) - (CH₂ ) _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_90iNHC(O)- wherein R_90i is a C₁ to C₄ 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_{1 i} is

(I) hydrogen,

(II) loweralkyl, (III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl,

(VI) aryloxyalkyl,

(VII) thioaryloxyalkyl,

(VIIII) arylalkoxyalkyl,

(IX) arylthioalkoxyalkyl or

(X) a C₁ to C₃ straight or branched

carbon chain substituted by a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl and

6) heterocyclic;

X_i is

(I) CH₂,

(II) CHOH,

(III) C(O),

(IV) NH,

(V) O,

(VI) S,

(VII) S(O),

(VIII) SO₂,

(IX) N(O) or

(X) -P(O)O-;

R_3i is

(I) loweralkyl,

(II) haloalkyl,

(Ill) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl, (VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl,

(X) -(CH₂)_eeNHR_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

^R4i ^1S

(I) loweralkyl,

(II) cycloalkylalkyl

(III) cycloalkenylalkyl or (III) arylalkyl; and

O _i is

wherein R_{73 i} is loweralkyl,

wherein

1) M_i is

i) O,

ii) S or

iii) NH;

2) Qi is

i) O or

ϋ) S;

3) Ei is

i) O,

ii) S,

iii) CHR_{73 i} wherein R_{73 i} is loweralkyl, iv) C=CH₂ or v) NR_18i wherein R_{18 i} is a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl, d) hydroxy,

e) alkoxy, f) amino or

g) alkylamino;

and

4) G_i is

i) absent,

ii) CH₂ or

iii) NR_19i wherein R_19i is

hydrogen or loweralkyl,

with the proviso that when G_i is NR_19i, then R_18i is loweralkyl or

hydroxyaIkyl;

(III)

wherein

1) v" is 0 or 1 and

2) R_21i is

i) NH,

ii) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group; and

wherein X_j is

( I) N,

(II) O or

(III) CH;

^R1j ^is

(I) absent,

(II) hydrogen,

(III) an N-protecting group,

(IV) aryl,

(V) heterocyclic, or

(VI) R_6j-Q_j- wherein

1) R_6j 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''' is 1 to 5 and R_{7 j} is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or

dialkylamino; or

xiv)

wherein R_{8 j} is O, S, SO₂, O=C or R_{9 j}N wherein R_{9 j} is hydrogen, loweralkyl or an N-protecting group; and

2) Q_j is

i) C=O or

ii) CH₂,

with the proviso that X_j is N when R_1j is an N-protecting group;

(VII) R_{54 j}S(O)₂- wherein R_{54 j} is

1) amino,

2) alkylamino,

3) dialkylamino, 4) loweralkyl,

5) haloalkyl,

6) aryl,

7) p-biphenyl,

8) heterocyclic or

(VIII) (R_{55 j} ) -Ε (O) - wherein R_55j is

1) alkoxy,

2) alkylamino or

3) dialkylamino;

A_j and L_j are independently selected from

(I) absent,

(II) C=O,

(III) SO₂ and

(IV) CH₂; is

(I) C=O,

(II) SO₂ or

(III) CH₂; Y_j is

(I) N or

(Il) CH;

R_2j is

(I) hydrogen,

(II) loweralkyl,

(III) cycloalkylalkyl,

(IV) -CH₂-R_10j-(CH₂)_{q'' '}-R_11j wherein 1) q''' is 0, 1 or 2, 2) R_10j is absent or R_{10 j} is O, NH or S only when q' '' is 1 or 2, and

3) R_{11 j} is

i) aryl or

ii) heterocyclic;

Z_j is

(I) hydrogen or

(II) -R_{28 j}C(O)R_29j, -R_28jS(O)₂R_29j or -R_28jC(S)R_29j wherein

1) R_28j is

i) NH,

ii) -N(R_200j)- wherein R_200j is loweralkyl or benzyl or

iii) CH₂ and

2) R_29j is

i) alkoxy,

ii) benzyloxy,

iii) alkylamino,

iv) dialkylamino,

v) aryl or

vi) heterocyclic;

R_{3 j} is

(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_4j is

(I) loweralkyl,

(II) cycloalkylalkyl or

(III) arylalkyl; and

R_{5 j} is

wherein R_73j is loweralkyl,

(II)

wherein

1) M_j is

i) O,

ii) S or

iii) NH;

2) Q_j is

i) O or

ii) S;

3) E_j is

i) O,

ii) S,

iii) CHR_{61 j} wherein R_{61 j} is loweralkyl, iv) C=CH₂ or

v) NR_18j wherein R_18j is a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl, d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino; and

4) G_j is

i) absent, ii) CH₂ or

iii) NR_19j wherein R_19j is

hydrogen or loweralkyl,

with the proviso that when G_j is NR_19j, then R_18j is loweralkyl or hydroxyalkyl;

wherein

1) v''' is 0 or 1 and

2) R_21j is

i) NH,

ii) O,

iii) S or

iv) SO₂; 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-((beta,beta-dimethyl)-beta-Ala)-(4-OCH₃)Phe-His

amide of 2(S)-amino-1-cyclohexyl-3(R),4(S)- dihydroxy-6-methylheptane;

2(S)-(1(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-methylpiperazinsulfonyl ) amino-3-phenyl- methyl-2-oxo-1-piperidinyl)-3-(4-thiazolyl )propionic acid amide of

(2S,4S,1'R,2'S)-2-(2'-amino-3'-cylcohexyl-1'-hydroxy- propyl)-4-methyltetrahydrofuran;

2(S)-((3(S)-((N-methylpiperazinsulfonyl)amino-3-phenyl- methyl-2-oxo-1-piperidinyl)-3-(4-thiazolyl)propionic acid amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6- methylheptane;

3-(3-Thiazolyl)-2-(3R-benzyl-4-N-(N-methylpiperazinyl)- sulfonyl-2-keto-piperazin-1-yl)propionic aicd amide of

Butyl 5(S)-amino-66cyclohexyl-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_10f or -SR_10f wherein R_10f is hydrogen,

loweralkyl or aminoalkyl, -NR_11fR_12f wherein R_11f and R_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, O, CH₂ or CHOH and

R_13f 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)alkylamino)carboxyalkylamino,

(dialkylamino)carboxyalkyl,

(dialkylamino)carboxyalkylamino,

(amino)alkoxycarbonylalkyl,

(amino)alkoxycarbonylalkylamino,

((N-protected)amino)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=O or CHOH;

U_f is CH₂ or NR₂, provided that when W_f is CHOH then U_f is CH₂;

R_1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl,

(2-naphthyl)methyl, (4-imidazolyl)methyl,

( alpha, alpha)-dimethylbenzyl, 1-benzyloxyethyl,

phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_1f is phenoxy, thiophenoxy or anilino, then B_f is CH₂ or CHOH or A_f is hydrogen;

R_2f is hydrogen or loweralkyl;

R_3f is loweralkyl, loweralkenyl,

((alkoxy) alkoxy) loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;

R_6f is loweralkyl, cycloalkylmethyl or benzyl;

R_af is vinyl, formyl, hydroxymethyl or hydrogen; R _{d f} is hydrogen or loweralkyl;

R_bf and R_ef are independently selected from

OH and NH₂; and

R_cf is hydrogen, loweralkyl, vinyl or arylalkyl;

wherein A_g 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 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,

loweraklyl, haloalkyl or polyhaloalkyl, or A_g is

(unsubstituted heterocyclic) alkyl or (substituted heterocyclic) alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or A is -OR_7g or

-SR_7g wherein R_7g is hydrogen, loweralkyl,

aminoalkyl, (alkyl)aminoalkyl, alkylaminoalkyl,

(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(O)- wherein unsubstituted or substituted heterocyclic is as defined above; or A_g is -"NR_8gR_9g wherein R_8g and

R_9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and

hydroxyalkyl; or A_g is

wherein B_g is NH, alkylamino, S, O, CH₂, NHCH₂ or CH(OR₅₂ ) wherein R_52q is hydrogen, loweralkyl or loweralkylcarbonyl, and R _10g 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, 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 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, aminocycloalkyl,

aminoalkylamino, (dialkylaminoalkyl) (alkyl)amino, phenylalkylammo, (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,

((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_g is R_41gCH(OH)CH₂- or

R_41gCH(OH)CH(OH)- wherein R_41g is loweralkyl,

cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above,

phenylalkyl, (substituted phenyl) alkyl wherein

substituted phenylis 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, 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 substituted phenylis 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_g is C=O, CHOH or NR_2g wherein R_2g is hydrogen or loweralkyl;

U_g is C=O, CH₂ or NR_2g wherein R_2g is hydrogen

or loweralkyl, with the proviso that when W_g is CHOH then U_g is CH₂ and with the proviso that U_g is C=O or CH₂ when W_g is NR_2g;

V_g is CH, C(OH) or C(halogen) with the proviso that

V_g is CH when U_g is NR_2g;

R_1g is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthyl)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_g is CH₂ or CHOH or A_g is hydrogen when R_1g is phenoxy, thiophenoxy or anilino;

R_3g is loweralkyl, loweralkenyl,

((alkoxy)alkoxy) alkyl, carboxyalkyl, (thioalkoxy) alkyl, azidoalkyl, aminoalkyl, (alkyl) aminoalkyl,

dialkylaminoalkyl, (alkoxy) (alkyl)aminoalkyl,

(alkoxy) aminoalkyl, benzyl or heterocyclic ring

substituted methyl; R_4g is loweralkyl, cycloalkylmethyl or benzyl;

R_5g is OH or NH₂; and Z_g is

wherein M is O, S or NH, T_g is C=O, C=S, S, S(O), S(O)₂ or CH₂, E_g is O, S, NR_6g wherein R_6g is

hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E_g is CR_6gR_42g wherein

R_6gis as defined above and R_42g is hydrogen or loweralkyl or E_gis C=CR_43gR_44g wherein R_43g and

R_44g are independently selected from hydrogen and loweralkyl, G_g is absent, CH₂, or NR_11g wherein

R_11g is hydrogen or loweralkyl, with the proviso that when G_g is NR_11g then R_6g is loweralkyl or

hydroxyalkyl, Q_g is CR_45gR_46g wherein R_45g and

R_46g are independently selected from hydrogen and loweralkyl or Q_g is C=CR_47gR_48g wherein R_47g and R_48g are independently selected from hydrogen and loweralkyl, and R_49g is -CH₂OH, carboxy,

alkoxycarbonyl or -CONR_50gR_51g wherein R_50g is hydrogen or loweralkyl and R_51g is hydrogen,

loweralkyl, aminoalkyl, alkylaminoalkyl,

dialkylaminoalkyl or alkoxyalkyl;

wherein A_i is

( I ) R_5i C (O) - (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_90iNHC(O)- wherein R_90i is a C₁ to C₄ 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_{1 i} is

(I) hydrogen,

(II) loweralkyl, (III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl,

(VI) aryloxyalkyl,

(VII) thioaryloxyalkyl,

(VIIII) arylalkoxyalkyl,

(IX) arylthioalkoxyalkyl or

(X) a C₁ to C₃ straight or branched

carbon chain substituted by a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl and

6) heterocyclic;

X_i is

(I) CH₂,

(II) CHOH,

(III) C(O),

(IV) NH,

(V) O,

(VI) S,

(VII) S(O),

(VIII) SO₂,

(IX) N(O) or

(X) -P(O)O-;

R_3i is

(I) loweralkyl,

(II) haloalkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl, (VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl,

(X) -(CH₂)_eeNHR_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 is

(I) loweralkyl,

(II) cycloalkylalkyl

(III) cycloalkenylalkyl or (III) arylalkyl; and

D_i is

(I)

O

wherein R_{73 i} is loweralkyl,

(II)

where in

1) M_i is

i) O,

ii) S or

iii) NH;

2) Q_i is

i) O or

ϋ) S;

3) Ei is

i) O,

ii) S,

iii) CHR_{73 i} wherein R_{73 i} loweralkyl, iv) C=CH₂ or v) NR_18i wherein R_{18 i} is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy,

e) alkoxy, f ) amino or

g) alkylamino;

and

4) G_i is

i) absent,

ii) CH₂ or

iii) NR_19i wherein R_19i is

hydrogen or loweralkyl,

with the proviso that when G_i is NR_19i, then R_18i is loweralkyl or

hydroxyalkyl;

(III)

wherein

1) v" is 0 or 1 and

2) R_21i is

i) NH,

ii) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group; and

wherein X_j is

( I) N,

(II) O or

(III) CH;

^R1j ^is

(I) absent,

(II) hydrogen,

(III) an N-protecting group,

(IV) aryl,

(V) heterocyclic, or

(VI) R_6j-Q_j- wherein

1) R_{6 j} 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''' is 1 to 5 and R_{7 j} is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or

dialkylamino; or

xiv)

wherein R_8j is O, S, SO₂, O=C or R_9jN wherein R_{9 j} is hydrogen, loweralkyl or an N-protecting group; and

2) Q_j is

i) C=O or

ii) CH₂,

with the proviso that X_j is N when R_1j is an N-protecting group;

(VII) R_{54 j}S(O)₂- wherein R_54j is

1) amino,

2) alkylamino,

3) dialkylamino, 4) loweralkyl,

5) haloalkyl,

6) aryl,

7) p-biphenyl,

8) heterocyclic or

(VIII) (R_{55 j})₂P(O)- wherein R_{55 j} is

1) alkoxy,

2) alkylamino or

3) dialkylamino;

A_j and L_j are independently selected from

(I) absent,

(II) C=O,

(III) SO₂ and

(IV) CH₂;

D_j is

(I) C =O,

(Il) SO₂ or

(III) CH₂;

Y_j is

(I) N or

(Il) CH;

R_2j is

(I) hydrogen,

(II) loweralkyl,

(III) cycloalkylalkyl,

(IV) -CH₂-R_10j-(CH₂) ,-R_11j wherein 1) q' ' ' is 0, 1 or 2, 2) R_10j is absent or R_10j is O, NH or S only when q''' is 1 or 2, and

3) R_{11 j} is

i) aryl or

ii) heterocyclic;

Z_j is

(I) hydrogen or

(II) -R_{28 j}C(O)R_29j, -R_28jS(O)₂R_29j or -R_28jC(S)R_29j wherein

1) R_28j is

i) NH,

ii) -N(R_200j)^_ wherein R_200j is loweralkyl or benzyl or

iii) CH₂ and

2) R_29j is

i) alkoxy,

ii) benzyloxy,

iii) alkylamino,

iv) dialkylamino,

v) aryl or

vi) heterocyclic; R_3j is

(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_{4 j} is

(I) loweralkyl,

(II) cycloalkylalkyl or

(III) arylalkyl; and

R_5j is

wherein R_73j is loweralkyl,

wherein

1) M_j is

i) O,

ii) S or

iii) NH;

2) Q_j is

i) O or

ii) S;

3) E_j is

i) O,

ii) S,

iii) CHR_{61 j} wherein R_{61 j} is loweralkyl, iv) C=CH₂ or

v) NR_{18 j} wherein R_18j is a) hydrogen, b) loweralkyl, c) hydroxyalkyl,

d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino; and

4) G_j is

i) absent, ii) CH₂ or

iii) NR_19jwherein R_19j is

hydrogen or loweralkyl,

with the proviso that when G_j is

NR_19j, then R_18j is loweralkyl or hydroxyalkyl;

(III)

wherein

1) v'" is 0 or 1 and

2) R_21j is

i) NH,

ϋ) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof.