CA2003382A1 - Method for treating vascular diseases - Google Patents

Abstract

METHOD FOR TREATING VASCULAR DISEASES

ABSTRACT OF THE DISCLOSURE

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.
( 11-1100P/macII-SRC)

Description

2~33~32 METHOD FOR TREATING VASC AR DISEASES

Technical Field The present invention relates to the use of renin inhibitors a~d 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 mos~
prominent of which is the inability o~ the body to ~)33~

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 a~fect 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 micro~ascular complications and ~he renin-angiotensin-aldosterone system (R~AS) have been observed. Eleva~ed plasma levels of inactive renin (prorenin3 have been found in patients with incipient nephropathy, frank nephropathy, retinopathy and neuropathy. (See Luetscher, et al., Arch. Intern. ~ed. 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)).

333~

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. ~. 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., Hyper~ension 11 339 (1988)~.
Suppressed plasma renin activity has not been, however, a consis~ent finding. Elevated plasma renin activity has been observed in diabetic patients wi~h retinopathy and hypertension. (See Drury, et al., Clin.
Endo. 16 453 (1982) and Drury, et al., Hypertension, 7 (Suppl. II) II-84 (1985)). Hyperte~sion, 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 si~e and thus function as active renin. Renin is a highly specific enz~me 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 (AI). AI
itself has only slight pharmacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII3. The major pharmacological effects of AII 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. AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to AII, 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 lowerlng 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 rèversing or halting the progression of microangiopathy in the diabetic kidney and possibly other diabetic microvascular diseases. In addition, it has recently been shown (Science 24s 186 (1989)) that ACE inhibitors have a protective and corrective efect 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 ~AI), most notably the kinins which cause such undesirable side efects as pain, "leaky"
capillaries, prostaglandin relea~e and a variety of behavorial and neurologic effec~s. Further, ACE

inhibition leads to the accumulation of AI. Although AI
has much less vasoconstrictor ac~ivity than AII, its presence may negate some of the hypotensive effects of - the blockade of AII 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 referen~e.

References Disclosinq Renin Inhibitinq 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 ~o. 4,680,284, issued July 14, 19~7.

- 4. Luly, et al., U.S. Patent No. 4,725,583, issued February 16, 1988.

2~

s. 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 3une 17, 1986.
7. Fuhrer, et al., U.S. Patent No. 4,613,676, issued September ~3, 19~6.
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, 198~.
10. Iizuka, et al., U.S. Patent No.
4,656,269, issued April 7, 19~7.
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, e~ 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,~41, issued Oc~ober 30, 1984.
17. Boger, et al., U.S. Patent No. 4,485,09~, issued ~ovember 27, 1984.
1~. Boger, et ~1., 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.

~33~

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 ~.2, 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.

3~:~

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 Aprll 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.
~,722,922, issued February 2, 19~.
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, e~ 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.~. Paten~ 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 Augu~t 15, 1989.

33~

56. Luly, et al., U.S. Patent No. 4,826,815, issued May 2, 1989.
57. Rosenberg, et al., U.S. Patent No.
4,837,20~, 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, e~ 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, 19~7.
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, e~ al., U.S. Patent No. ~,478,~26, issued October 23, 1984.
72. Raddatz, et al., U.S. Patent No.
4,812,555, issued March 14, 1989.

3~

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, ls~g.
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 ~ay 2, 1989; U.S. Patent No.
4,857,507, issued August, 15, 1g89; 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. paten~ 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 (W088/05050, published July 14, 1988); PCT/US89/043~5, filed October 3, 1989;
and PCT/US89/04649, filed October 18, 1989, which are hereby incorporated by reference.
The preferred renin inhibiting compounds of this invention are selected from the group consisting of compounds of the formula:

( 1 ) . R3 I HO R7 'I' ~ U ~J~N ~<~ V~ R1 0 Rl R6 R8 Rg ~33~

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 - R23 ~ ~- R23\ /B-O o~ ~o 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;
Rl is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino: provided ~hat when Rl is phenoxy, ~hiophenoxy or anilino, then B is C~2 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 Rg ar~ hydrogen or loweralkyl 333~;~

nd may be the same or different;
V is NH, O, S, SO, SO2, or CH2i Rlo is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or V and Rlo taken together are N3; with the proviso that Rlo may be an N-protecting group only when V is NH;

2).
~3~ I Sb \~ b~ /~ N y R 13 b ~ R 1 5b R l o~

wherein Ab is hydrogen, loweralkyl, arylalkyl, OR20b or SR20b wherein R20b is hydrogen, loweralkyl or Y ~ NR21bR2~b wherein R21b and R22b are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
or Ab is R23b Bb R23b~ ~Bb-~ 0~ ~0 wherein Bb is NH, alkylamino, S, O, CH~, or CHOH;
and R23b is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl~(alkyl)amino, - 211~1~333~;2 (dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or a substitutsd or unsubstituted heterocyclic;
Wb is C=O or CHOH;
Ub is CH2 or NR2b' wherein R2b is hydrogen or loweralkyl, provided that when Wb is CHOH
then Ub is CH2;
Rlb is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha~alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino: provided that when Rlb is phenoxy, thiophenoxy or anilino, then Bb is CH2 or CHOH or Ab is hydrogen;
R3b is loweralkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl;
R5b is hydrogen or loweralkyl;
R6b is loweralkyl, cycloalkylmethyl, or benzyl;
Rlob is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or Lb and Rlob taken together can be N3, with the proviso that when Lb is NH ~hen Riob is an N-protecting group;
R13b is CHOH or CO;
R14b is CH2, CF2 or CF with the proviso that when R13b is CO then R14b is 2 R15b is CH2~ CHR25b wherein R25b is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or -2~ 2 -~.4-Y 14b and R15b taken together can be C = r _ I
F H

with the proviso that when R14 is CF~ then R15 is CH2;
Lb is 0, S, SO, S02, NR26b wherein R26b is hydrogen or loweralkyl, or NR27bC(O) wherein R27b is hydrogen or loweralkyl;

(3).
R1c R6c lR17c Ac Wc ~ J ~ R160 ~ N Y Dc R3c Rsc OH R13C

wherein A~ is R23c ~ Bc-.ll o wherein Bc is NH, or CH2; and R23C is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;
- Wc is C=O;
Uc is NR2C, wherein R~c is hydrogen or loweralkyl;

33~8~

RlC is loweralkyl, cycloalkylalXyl, benzyl, 4-methoxybenzyl, 4 hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, or phenethyl;
R3c is loweralkyl, benzyl or heterocyclic ring substituted methyl;
R5c is hydrogen or loweralkyl;
R6C is loweralkyl, cycloalkylmethyl, benzyl~
2R24C, where R24C is selected from 1,3-dioxan-2-yl; 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl;
216C is CH2, CF2 or CHR63C where R53c is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl;
R17C is hydrogen or loweralkyl;
R18C is loweralkyl or lipophilic or aromatic amino acid side chain;
c is hydrogen, loweralkyl or -CH20R28C, wherein R28C is hydrcgen, loweralkyl or arylalkyl;

(4).
R3d H HO (Zd)n Td ~ R5d Ad~R~Wd~UJ~N~ ~XyN~R12d O R5d Rl ld O

wherein Ad is hydrogen, loweralkyl, arylalkyl, -OR20d or -S220d wherein R20d is hydrogen, loweralkyl or aminoalkyl, -NR21dR22d 21d 3~3~

and R22~ are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
or Ad is R23d\ / B d - R2~d ~ ~ B d -o r ~s~
o o o wherein Bd is NH, alkylamino, S, O, CH2, or NHCH2, and R23d is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(al3cyl)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;
Wd is C=O or CHOH;
Ud is CH2 or NR2d' wherein R2d is hydrogen or loweralkyl, provided that when Wd is CHOH
then Ud is CH2;
ld CHR24d wherein R24d is loweralkyl~
cycloalkylalkyl, benzyl, 4-metho~ybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, (alpha, alpha)-dimethylben7.yl, l-benzyloxyethyl, or phenethyl, or Rld is C=CHR25d wherein R25d is aryl;
R3d is loweralkyl, alkenyl, benzyl or heterocyclic ring substituted methyl;
R5d is hydrogen or loweralkyl;

~33~%

R6d is loweralkyl, cycloalkylme~hyl, or benzyl;
Rlld is hYdrogen or hydroxy;
n is 0 or 1; when n is 0 then Td is alkylidene or alkylidene oxide; and when n is 1 then Zd is hydrogen or hydroxy and Td is loweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl;
R12d iS hYdrogen, loweralkyl~
cycloalkylalkyl, arylalkyl, aminoalkyl, or dialkylaminoalkyl;

(5).
R~ H OH R~
Ae ~ We ~ U ~ N ~ M ' R 1 Oe wherein Ae is hydrogen, loweralkyl, arylalkyl, -OR20e or -SR20e wherein R20e is hydrogen, loweralkyl or aminoalkyl, -NR21eR22e 21e and R22e are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
or Ae is R23e E~ e- \ /
~( o r ~S~

wherein Be is NH, alkylamino, S, O, CH2, or CHOH;
and R23e is loweralkyl, cycloalkyl, aryl, arylalkyl, 33~

alkoxy, alkenyloxy, hydroxyalkoxy, dihydro~yalkoxy, 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;
We is C=O;
Ue is NR2e, wherein R2e is hydrogen or loweralkyl;
Rle is ioweralkyl, cycloalkylalkyl, benzyl, ~-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when Rle is phenoxy, thiophenoxy or anilino, then Be is CH2 or CHOH or Ae is hydrogen;
R3e is loweralkyl, benzyl or heterocyclic ring substituted methyl;
R5e is hydrogen or loweralkyl;
R6e is loweralkyl, cycloalkylmethyl, or benzyl;
Me is O, NH ox S;
Rloe is hydrogen, loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group;

- 20~33BZ

~6) .

R3, H Rbf Af ~ W, ~ ~ N ~;

wherein Ac is hydrogen, loweralkyl, arylalkyl, -ORlof or -SRlof wherein Rlof is hydrogen, loweralkyl or aminoalkyl, -NRllfR12~ llf and R12f are independently selected from hydrogen, loweralkyi, 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 Af is R 23 f E~
~ Or ~S~
O O O

wherein Bf is NH, alkylamino, S, O, CH2 or CHOH:and R13f is loweralkyl, cycloalkyl, aryl, arylalkyl, - alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalXyl, amino, alkylamino, 3~:~

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-pro~ected)amino)-carboxyalkyamino, (alkylamino)carboxyalkyl, (alkylamino)carboxyalkylamino, ((N-protected)alkylamino)-carboxyalkyl, ((N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl, (amino)alkoxycarbonylalkylamino, ((N-pro~ected~amino~alkoxycarbonylalkyl, ((N-protected)amino)- alkoxycarbonylalkylamino, (alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylamino, ((N-pxotected)alkylamino)- alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonyl- alkylamino, (dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylamino, aminocycloalkyl, 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, ~3338~

monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydro~y, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl;
W~ is C=O or CHOH;
Uf is CH2 or NR2, provided that when Wf - is CHOH then U is CH2;
Rlf is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidaæolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when Rlf is phenoxy, thiophenoxy or anilino, then Bf is CH2 or CHOH or Af is hydrogen;
R2~ is hydrogen or loweralkyl;
R3~ is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
R6f is loweralkyl, cycloalkylmethyl or benzyl;
Raf is vinyl, formyl, hydroxymethyl or hydrogen;
Rdf is hydrogen or loweralkyl;
Rbf and Ref are independently selected from OH and NH2; and Rcf is hydrogen, loweralkyl, vinyl or arylalkyl;

(7).

I39 H R~

~ ug R19 o R*g wherein Ag 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 thre~ substituents independently selected from loweralko~y, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, subs~ituted or unsubs~ituted heterocyclic, where saturated heterocyclics may be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylami~o, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyhaloalkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalko~y, loweraklyl, haloalkyl or polyhaloalkyl, or Ag is (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubskituted or substikuted 2~

heterocyclic is as defined above, or Ag is -OR7g or -SR7g wherein R7g 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 he~erocyclic 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 Ag is ~NR8gRgg wherein R8g and Rgg are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or Ag is Rlo9 Bg- R109~ ~Bg-~ o~S~

wherein Bg is NH, alkylamino, S, O, CH2, NHCH2 or CH(OR52g) wherein R52g is hydrogen, loweralkyl or loweralkylcarbonyl, and RlOg 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, naphthylalko~y, (substituted naphthyl)alkoxy wherein substituted ~ 0033a%

naphthyl is as defined above, phenylalkoxyalkyl, (substitu~ed 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, phenylalkylamino, ~substituted phenyl)alkylamino wherein substituted phenyl is as defined above, naphthylalkylamino, (substituted naphthyl)alkylamino wherein subs~ituted 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, ~33~3~

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 Ag is R41gCH(OH)CH2~ or R41gCH(OH)CH(OH)- wherein R41g is loweralkyl, cycloalkyl, phenyl, substitu~ed 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)~hioalkyl 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 3~2 heterocyclic as defined above, aminocycloalkyl or (polyalkoxy)alkyl;

Wg is C=O, CHOH or NR2g wherein R2g is hydrogen or loweralkyl:

Ug is C=O, CH2 or NR2g wherein R2g is hydrogen or loweralkyl, with the proviso that when Wg is CHOH
then Ug is CH2 and with the proviso that Ug is C=O
or CH2 when Wg is NR2g;

Vg is CH, C(OH) or C(halogen) with the proviso that Vg is CH when Ug is NR2g;

Rlg is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (l-naphthyl)methyl, (2-naphthyl~methyl, (unsubstituted heterocyclic)methyl, (substituted heterocyclic)methyl wherein unsubstituted or substituted heterocyclic is as defined above, phenethyl, l-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B~ is CH2 or CHOH or Ag is hydrogen when Rlg is phenoxy, thiophenoxy or anilino;

R3g is loweralkyl, loweralkenyl, (~alkoxy)alkoxy)a}kyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzyl or h~terocyclic ring substituted methyl;

R4g is loweralkyl, cycloalkylmethyl or benzyl;

~;3 3~Z

R5g is OH or NH2; and Zg is OH

Or / ~/~
Mg ~ T ~' Eg g wherein Mg is O, S or NH, Tg is C=O, C=S, S, S(O~, S()2 or CH2, Eg is O, S, NR6g wherein R6g is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or Eg is CR6gR42g wherein R6g is as defined above and R42g is hydrogen or loweralkyl or Eg is C=CR43gR44g wherein R43g and R44g are independently selected from hydrogen and loweralkyl, Gg is absent, CH2, or NRllg wherein Rllg is hydrogen or loweralkyl, wi~h the proviso that when Gg is NRllg then R6g is loweralkyl or hydroxyalkyl, Qg is CR45gR46g wherein R~5~ and R46g are independently selected from hydrogen and loweralkyl or Qg is C=CR47gR48g wherein R47g and R48g are independen~ly selected from hydrogen and loweralkyl, and R~sg is -CH20H, carboxy, alkoxycarbonyl or CONR50gR51g wherein R50g s hydrogen or loweralkyl and R51g is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl;

33i~z (8~.
R3h RSh Rsh H

Rsh R1h R6h H
O
.

wherein Ah is hydrogen, loweralkyl, arylalkyl, -R20h or -sR20h wherein R20h is y g loweralkyl or aminoalkyl, -NR21hR22h whe~ein R21h and R22h are independently selected from hydrogen, loweralkyl, amino~lkyl, cyanoalkyl and hydroxyalkyl;
or Ah is R23h ~Bh- R23h~ ~Bh-~T o r 0~ S~
o o wherein Bh is NH, alkylamino, S, o, CH2, NHCH2 or CHOH; and R23h 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 suhstituted or unsubstituted heterocyclic;

Wh is C=O or CHOH;

Uh is CH2 or NR2h' wherein R2h is hydrogen or loweralkyl, provided that when Wh is CHOH

l32 then Uh is CH2;
Rlh is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, l-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when Rlh is phenoxy, thiophenoxy or anilino, then Bh is CH2 or CHOH or Ah is hydrogen;
R3h is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
R5h is hydrogen or loweralkyl;
R6h is loweralkyl, cycloalkylmethyl, or benzyl;

3~:Z

(9) .
o T
Rll ~31 wherein Ai is (I) R5iC(O)-(CH2)w,,- wherein 1) w" is O to 4 and 2) R5i 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) Rgoi~ or RgoiNHC(O)~ wherein Rgoi is a Cl 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);
l i (I) hydrogen, -æ~3~, (II) loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (VIIII) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a C1 to C3 skraight or branched carbon chain substituted by a substituent selected from 1) alkoxy, 2) thioalkoxy,-3) aryl and 6) heterocyclic;
Xi 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--;
R3i iS
(I) Ioweralkyl, (II) haloalkyl, (III) loweraIkenyl, (IV) cycloalkylalkyl, 2~1~33~

(v) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy)alkyl, (IX) hydroxyalkyl, (X) - (CH2 ) eeNHR12i wherein 1) ee is 1 to 3 and 2) R12i i) hydrogen, ii) loweralkyl or iii) an N-protecting group;
(XI) arylalkyl or (XII) (heterocyclic)alkyl; and Ti is R~, --NH /~/
OH
wherein R9i is (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and Di is (I) ~ ~731 ~0~

wherein R73i is loweralkyl, (II) M1 ~ E
Q~
wherein 1) Mi is i) O, ii) S or iii) NH;
2) Qi is i) O or ii) S;
3) Ei is i) O, ii) S, iii) CHR73i wherein R73i loweralkyl, iv) C=CH2 or v) NRl8i wherein Rl8i is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, 33~

f) amino or - g) alkylamino;
and 4) Gi is i) absent, ii) CH2 or iii) NR1gi wherein R1gi is hydrogen or loweralkyl, wi~h the proviso that when Gi is N~19i, then Rl~i is loweralkyl or hydroxyalkyl;
( I I I ) - (CH2)V.. - C(O~--N~ ~21i wherein 1) v" is O or 1 and 2) R21i is i) NH, ii) O, iii) S or iv) S02; or ~IV) a substituted methylene group; and 3~

( 10 ) .

~ R
wherein Xj is (I) W, (II) O or (III) CH;

1 j (I) absent, (II) hydrogen, (III) an N-protecting group, (IV) aryI, (V) heterocyclic, or (VI) R6j-Qj- wherein ) 6j i) loweralkyl, ii) amino, iii) alkylamino, iv) dialkylamino, v) (alkoxyalkyl)(alkyl)amino, vi)(alkoxyalkoxyalkyI)(alkyl)amino, vii) aryl, viii) arylalkyl, ix) aminoalkyl, x) (N-protected)aminoalkyl, 33~8%

xi) alkoxy, xii) substituted loweralkyl wherein the substituent is selected from alkoxy, thioalkoxy, halogen, alkylamino, (N-protected)(alkyl)amino and dialkylamino, xiii ) R7~ 1~\ N--((~H2)m"' wherein m''' is 1 to 5 and R7~ is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino~
(N-protected)amino, alkylamino, (N-protected)(alkyl)amino or dialkylamino; or xiv) R~ N -wherein R8j is 0, S, S02, O=C or R9jN
wherein Rgj is hydrogen, loweralkyl or an N-protecting~group; and 2) Qj is i) C=O or ii) CH2i with the proviso that Xj is N when Rlj is an N-protecting group;
(VII) R54jS~)2- wherein R54j i~
1) amino, 2) alkylamino, 3) dialkylamino, 2~33~32 ~) loweralkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl, 8) heterocyclic or (VIII) ~R55j)2P(o)- wherein R55j is 1) alkoxy, 2) alkylamino or 3) dialkylamino;

Aj and Lj are independently selected froln (I) absent, (II) C=O, (III) S02 and (IV) CH2;

Dj is (I) C=O, (II) S02 or (III) CH2, Yj iS
~I) N or (II) CH;

2j (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, H2 Rloj (CH2) ql l ,-Rllj wherein 1) q''' is 0, 1 or 2, ~33~

2) R1oj is absent or R1oj is 0, NH
or S only when q''' is 1 or 2, and 1 1 j - i) aryl or ii) heterocyclic;

Zj is (I) hydrogen or (II) ~R28jC(O)R2gjr -R28js(o)2R29i or -R2gjC(S)R2g; wherein 1) R28j iS
i) NH, ii) -N(R20oi)- wherein R200j is loweralkyl or benzyl or iii) CH2 and 29j i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) d.ialkylamino, v) aryl or vi) heterocyclic;

3j tI) hydro~en, (II) loweralkyl, (III~ loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, 33~:

(VIIII) (alkoxyalkoxy)alkyl, (IX) (polyalkoxy)alkyl, (X) arylalkyl or (XI) (heterocyclic)alkyl;

n''' is 0 or 1; and T
R
~ Rs~
H OH
wherein R4j is (I) loweralkyl, (II) cycIoalkylalkyl or (III) arylalkyl; and R5j is (I) Q
wherein R73j is loweralkyl, 3~

--~ o--(II) Ml~" E
Il Ql wherein 1) Mj is i) O, ii) S or iii) NH;
2) Qj is i) O or ii) S;
3) Ej is i) O, ii) S, iii) CHR61j wherein R61j is loweralkyl, iv) C=CH2 or v) NR18j wherein R18j is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino;
and 4) Gj is i) absent, -- 2~ 3~3~

ii) CH2 or iii) NR1gj wherein R1gj is hydrogen or loweralkyl, with the proviso that when Gj is NR1gj, then R1gj is loweralkyl or hydroxyalkyl;
(III) ~\
- ~CH2)V... ' C(O)~N~R2 wherein 1) v''' is O ox 1 and 2) 21j i) NH, ii) O, iii) S or iv) S02; or (IV) a substituted methylene group;
or a pharmaceutically acceptable salt, ester or prodrug thereof.

3~8~
-~2-The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including but not llmited 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 ~o 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 ~erm "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 re~ers 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 alkoxyben2yl.
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.

2~3q~

The term "(substituted phenyl)alkyl" as used herein refers to a substituted phenyl qroup 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 l-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 halonaphthylmethyl, alkoxynaphthylmethyl and the like.
The term "theterocyclic)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 imidazolylmethyl, thiazolylmethyl 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.

2~ 3~

The term "phenylalkoxyalkyl" as used herein refers to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to phenylmethoxyme~hyl 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 l-naphthylmethoxymethyl and the like.
.he 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 methoxyethoxymetho~ymethyl 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 lower~lkyl radical.

33~32 The term ~dialkylaminoalkyl~ as used herein refers to a dialkylamino appended to a loweralkyl radical.
The term "aminocycloalkyl" as used herein refers to an -NH2 appended to a cycloalkyl radical.
The term "N-protected aminoalkyl" as used herein refers to -NHR71 appended to a lowerall~yl group, wherein R71 is an N-protecting group.
The term "(N-protected)(alkyl)amino alkyl" as used herein refers to NR71R72 which i5 appended to a loweralkyl radical, wherein R71 is defined as above and R72 is a loweralkyl group.
The term "alkoxycarbonylalkyl" as used herein refers to R73COR74-, wherein R73 group and R74 is a lowexalkyl 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 -NR75R~6 group appended to a loweralkyl radical wherein R75 i5 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.

3~2:

-~6-The term "loweralkylsulfonylalkyl" as used herein refers to a R78S(0)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 R~3S(0)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(0)2- group appended to a loweralkyl radical wherein R~4 is a substituted phen~l group.
The term "naphthylsulfonylalkyl" as used herein refers to a R~5S(0)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(0)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 which is appended to a loweralkyl radical.

~ 3 ~ .

The term ~alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R87CO-wherein R87 is an alkoxy group) appended ~o 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 (-COOH) 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 -NR89Rgo wherein R89 is as defined above and Rgo is a loweralkyl group.
The term '1(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylie acid group (-COOH) and -~RglR92 wherein Rgl 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 (-NH2).
The term "((N-protected)amino)alkoxy-carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as 2~ 2 defined above and -NHR~3 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-protec~ed)alkylamino)-alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to ~hich 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 "alko~ycarbonylalkylamino" as used herein refers to -NHRg9 wherein Rg9 is an alkoxycarbonylakyl group.
The term "(amino)carboxyalkylamino" as used herein refers to NHRloo wherein Rloo is an (amino)carboxyalkyl group.
The term "((N-protected)amino)carboxy-alkylamino" as used herein refers to -NHRlol wherein Rlol is an ((M-protected)amino)carboxyalkyl group.
The term"~alkylamino)carboxyalkylamino" as used herein refers to -NHRlo~ wherein Rl02 is an (alkylamino)carboxyalkyl group.
The term "((N-protected)alkylamino)-carboxyalkylamino" as used herein refers ~o -NHR103 21~1~33~

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)alkoxycarbonylalkylamino" as used herein refers to -NHR105 wherein R105 is an (amino)alkoxycarbonylalkyl group.
The term "((N-protected)amino)alkoxy-carbonylalkylamino" as used herein refers to -NHR106 wherein R106 is an ((N-protected)amino)-alkoxycarbonylalkyl group.
The term "(alkylamino)alkoxycarbonylalkylamino"
as used herein refers to -NHR107 wherein R107 is an (alkylamino)alkoxycarbonylalkyl group.
The term "((N-protected)alkylamino)alkoxy-carbonylalkylamino" as used herein refers to -NHR108 wherein R108 is an ((N-protected)alkylamino)~
alkoxycarbonylalkyl group.
The term "(dialkylamino)alkoxycarbonyl-alkylamino" as used herein refers to -NHRlog wherein Rlog is a (dialkylamino)alkoxycarbonylalkyl group.
The term "alkylidene" as used herein refers to a straight or branched chain alkyl radical which is atta~hed via a carbon-carbon double bond and includes but is not limited to methylidene, ethylidene, l-propylidene, l-butylidene, l-pentylidene, 2-propylidene, 2-butylidene, 2-pentylidene, 3-p~ntylidene, 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 -~ 2 ~ubstituent.
The term ~'alkylamino~ as used herein refers to -NHRllo, wher2in Rllo is a loweralkyl group.
The term "dialkylamino~ as used herein refers lllR112, wherein Rlll and X112 are independently selected from loweralkyl groups.
The term "arylalkylamino" as used herein refers to R113NH-, wherein R113 is an arylalkyl residue.
The term "arylalkyl(alkyl)amino" as used herein 114RllsN-~ wherein R114 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 l-naphthylmethylamino 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 re ers 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 Rll~R119N-wherein R118 is a (substituted phenyl)alkyl group and Rllg is a loweralkyl group.

~033~3~

The term "(naphthylalkyl)(alkyl)amino" as used herein refers to R120R121N- wherein R120 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 (substitu~ed naphthyl)alkyl group and R123 is a loweralkyl group.
The ~erm "aminoalkylamino" as used herein R124NH- wh~re R124 is an aminoalkyl residue.
The term "dialkylamino(alkyl)amino" as used herein refers to R125 126 ' 125 dialkylamino residue appended to a loweralkyl residue and R126 is a loweralkyl residue.
The term "((dialkylamino)alkyl)(alkyl)amino" as used herein refers to NR127R128 127 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 , e e 133 loweralkyl group and R134 is an alkoxyalkyl group.

The term "di-(alkoxyalkyl)amino~' as used herein Rl35Rl36N-~ wherein R135 and R136 are alkoxy residues appended to loweralkyl residues.
The term "di-(polyalkoxyalkyl)amino" as used herein refers to R137R138 ' 137 R138 are polyalkoxy residues appended to loweralkyl residues.
The term "~(polyalkoxy)alkyl)(alkyl)amino" as used herein refers to R139 140 ~ 139 a polyalkoxy residue appended to a loweralkyl radical and R140 is a loweralkyl residue.
The term "((heterocyclic)alkyl)~alkyl)amino" as used herein refers to ~R141R142 ~herein R141 is a 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 144 substituted or unsubstituted heterocyclic group and R145 is a loweralkyl group.
The term "(alkylaminoalkyl)(alkyl)amino" as used herein refers to NR1~6R147 e 146 an alkylaminoalkyl group and R147 is a loweralkyl group.
The term "(dialkylaminoalkyl)(alkyl)amino" as used herein refers to NR148R149 where 148 dialkylaminoalkyl group and R14g is a loweralkyl group.
The term "((alkoxy)(alkyl)aminoalkyl)-talkyl)amino" as used herein refers to -NR150R
wherein R150 is -NR152R153 appended to a loweralkyl radical wherein R152 is an alkoxy group and R153 is a loweralkyl group and R151 is a loweralkyl group.

33~

The term "((alkoxy)aminoalkyl)(alkyl)amino" as used herein refers to -NR154R155 wherein R154 is -NHR156 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 ~erm "di(alkoxyalkoxyalkyl)amino" as used herein referS to NR307R308 wherei 307 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 310NH 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 "alkylaminocarbonyloxy" as used herein refers to R312C(O)O- wherein R312 is an alkylamino group.
The term "alkoxycarbonyloxy" as used herein R313C(O)O- wherein R313 is an alkoxy group The term "loweralkylcarbonyl" as used herein R157C(O)- wherein R157 is a loweralkyl group, including, but not limited to acetyl, proplonyl and the like.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R158O- and R15~S-, respectively, wherein R158 is a loweralkyl group.

3~

-5~-The term "alkoxyalkoxy" as used herein refers to an alkoxy group appended to an alkoxy radlcal including, but not limited to, methox~metnoxy and the like.
The term "aryloxyalkyl~ as used herein refers to an aryloxy group (R3030- 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 "arylthioalko~y" as used herein refer to an aryl group appended to an alkoxy radical o. 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 aryl~hioalkoxy group, respectively, appended to a loweralkyl radical.

The term "alkenyloxy" as used herein refers to R1590-, 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 "dihydro~yalko~y" as used herein refers to an alkoxy radical which is disubs~ituted with -OH radicals.
The term "arylalkoxy" as used herein refers to an aryl group appended to an alkoxy radical.
The term "alkylaryloxy" as used herein refers to R1600- wherein R160 is an alkylaryl group.

2~ 3;38~2 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 appendsd 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 R1610-, wherein R161 is a straight or branched chain containing l-S, Cm-O-Cm, 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 ~wo 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 "haIophenyl" 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.

z The term " (aryl)sulfonyl~ as used herein 301S()2 werein R301 is an aryl group The term ~(heterocyclic)sulfonyl" as used herein refers to R302S(0)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 aroma~ic 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, 'out no~ 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, thioal~oxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthyl, alkoxynaphthyl and the like.

338%

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 ~he 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 quaternized, 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, pyra701idinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxa~olidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected ~rom hydroxy, halo, oxo (=0), alkylimino (R*N= wherein R* is a loweralk~l group1, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, haloalkyl or cycloalkyl.

~D33~2 The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-~ethylazetidinyl, thiazolyl, thienyl, triazolyl and the following:

N~ O ~ OH
O ~
a~

( q ~ k~\H~-)k 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, _ ~y) wherein Y is NH, N-loweralkyl, O, S, or S02, or ~ 'J~ L-~-JZ~

wherein the symbols (i), (ii) and (iii) represent .. 5-membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z
is N, O, or S and not the point of connection and Z2 33~8%

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 Zl is N.
The term ~N~protecting group" or ~N-protected"
as used herein refers ~o those groups intended to protec~ 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 triphenylmethyl; 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.

2al~38X

The term "substituted amino'l as used herein refers to:
I) alkylamino, II) dialkylamino, III) (hydroxyalkyl)(alkyl)amino, IV) (dihydroxyalkyl)(alkyl)amino, v) alkoxycarbonylalkylamino, VI) carboxyalkylamino, VII) (amino)carboxyalkylamino, VIII) ((N-protected)amino)carboxyalkylamino, IX) (alkylamino)carboxyalkylamino, X) ((N-protected)alkylamino)carboxyalkylamino, XI~ (dialkylamino)caboxyalkylamino, XII) (amino)alkoxycarbonylalkylamino, XIII) ((N-protected)amino)alkoxycarbonylalkyl-amino, XIV) (alkylamino)alkoxycarbonylalkylamino, XV) ((N-protected)alkylamino)alkoxycarbonyl-alkylamino, XVI) (dialkylamino)alkoxycarbonylalkylamino, XVII) (alkoxyalkyl)(alkyl)amino, XVIII) (alkoxyalkoxyalkyl)(alkyl)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, 3~

XXIV) R~q ~ / R7q /\ \
(C~2)~- N -wherein aa' is 1 to 5 and R6q and R7q 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) (CH2)~ - N -wherein dd' is 1 to 5, and 18) R8q-Zq- wherein Zq is 0, S or NH and R8q is a C1 to C6 2~338~

straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, - alkoxycarbonyl, aryl and heterocyclic;
XXV) r~
R~q N -wherein Rgq is 1) O, 2) S, 3) S2 or 4) C=O; or XXVI) R1~q-N N

wherein R1Oq is 1) hydrogen, 2) loweralkyl, 3) an N-protecting group or Rllq C (O) ~ wherein Rllq is aminoalkyl, (N-protected)aminoalkyl, 1-amino-2-phenylethyl or 1-(N-protected)amino-2-phenylethyl.
The term "substituted methylene group" as used hexein refers to:
(I) ~CHR13qR14q wherein ) 13q 2~)~)33~

i) hydrogen or ii) hydroxy and ) 14q 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) (~-protected)(alkyl)-aminoalkyl, xvii) dialkylamino, xviii) dialkylaminoalkyl, xix) carboxyalkyl, xx) thioalkoxy, xxi) thioalkoxyalkyl, xxii) alkylsulfonyl, xxiii) alkylsulfonylalkyl, xxiv) thioaryloxy, xxv) ~hioaryloxyalkyl, xxvi) arylsulfonyl, ~33~

xxvii) arylsulfonylalkyl, xxviii) (unsubstituted heterocyclic)alkyl or xxvix) (substituted heterocyclic)alkyl such that when R13q is hydroxy then R14q is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected)amino, (N-protected)(alkyl)amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R13q is hydrogen then R14q is not hydrogen or loweralkyl;
(II) ~C(=CH2)C(O)NHR15q;
(III) -C(OH)(R16q)C(O)NHR15q or (IV) -CH(R16q)C(O)NHR15q wherein 1 ) R15q S
i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl, v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl, viii) heterocyclic or ix) (heterocyclic)alkyl and 2) R16q s i) hydro~en, ii) loweralkyl, iii) hydroxyalkyl, iv) haloalkyl or v) azidoalkyl;

3~

(V) CH2C(O)NH ~ (CH2),~ - R20q~ R21q wherein 1) t' is 0 to 3, 2) 20q i) CH2 or ii) N and ) 21q i) NH, ii) o, iii) S or iv) SO2 ~
such that when t' is 0 then R20q is CH2 and when t' is ]. to 3 then R20q is N~
(VI) ~CH2CH(R22q)C(O)NHR23q wherein 1) 22q s i) loweralkyl or ii) cycloalkylalkyl and ) 23q i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl, v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl, viii) arylalkyl ix) heterocyclic, ~33~

-~6-x) ~heterocyclic)alkyl or xi) ~(CH~)u~--R24q ~25q \
wherein a) u' is O to 3, b~ R24q is CH2 or N and c) R25q is NH, O, S or SO2 ~
such that when u' is O then R24q is CH2 and when u' is 1 to 3 then R24q is N;
(VII) r~
CH2CH(R22q)C(o)- N N -R74q - wherein 1) R22q is as defined above and ) 74q i) hydrogen, ii) loweralkyl, iii) an N-protecting group or iv) R75q-C(O)~ wherein R75q is aminoalkyl or (N-protected)-aminoalkyl;
~VIII) -~ H2t H(R26q)~0)NHCH(R27q)C(O)NllCH2~3 N

~33~3%

wherein 1) R26q iS .' i) loweralkyl or ii) cycloalkylalkyl and ) 27q i) loweralkyl or ii) cycloalkylalkyl;
(IX) ~CH2CH(R8lq)NHC(O)R82q or -cH2cH(R8lq)NHs(o)2R82q wherein 1) 81q i) loweralkyl or ii) cycloalkylalkyl and 2) 82q i) loweralkyl, ii) alkoxy, iii) alkylamino, iv) dialkylamino, v) -OR* wherein R* is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or (heterocyclic)alkyl or vi) ~21q ~ N -wherein R21q is as defined above;
(X) -CH2NHC(O)Rg2q or ~cH2NHs(o)2R82q wherein R82q is as defined above; or (XI) ~CF2CH(OH)R83q wherein R83q is loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, .

2~

~68-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-hydro~ybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl)methyl, (thiazolyl)methyl, cyclohex~lmethyl, (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.

3~3%

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. W087/02986).
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=loweral~yl) provides a diastereomeric mixture which is separated. Each of the diastereomers is hydrolyzed and coupled to the amine ~VI) using standard peptide coupling reagents sùch 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 o~ (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-2~33~3~

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 tXV, 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, R2=loweralkyl) by (X) provides a mixture of diastereomers which can be separated.
A further alternative illustrated by Scheme IIIA
involves reductiv~ 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).

2~33~;~

-7l-The process in Scheme VA discloses the preparation of compounds of the general structure (XXV) wherein R28 is a C1 to C4 straight or branched carbon chain substituted by a substituent selec-ted 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 sùbstituted 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 general structure (1) wherein X is CH2 and A is R5CO-wherein R5 is hydroxy, alkoxy, thioalkoxy or an amine.
Compound (XXX) (J. Med. Chem. 2~ 1277 (1983)) is coupled to amine (VI) to provide the amide ester (XXXI) which -is hydrolyzed to give the carboxylic acid (XXXII). Coupling to the appropriate amine provides ~XXXIII) wherein 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. lQ~ 2127 (1981)) provides ~33~:

(XXXVI). After protection of the secondary alcohol, the ben~yl 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 substi~utent 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. Rs 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 subsequent anion is trapped with the appropriate 2-substituted-3-benzyloxypropyl 33~3~

iodide (prepared from the alcohlol by the procedure of M.
Holladay; J. Med. Chem. 1983, 26, 1277 ), p-toluenesulfonyl chloride and sodium iodide. The resulting diastereomeric sulfonyl ethers XL are deprotected ( H2 Pd/C or PdOH) and oxidized to the corresponding carboxylic acids XLI using a variety of oxidants (KMnO4, Jones, PDC, Ru04, Pt/02). Coupling of the acids with mimics of the Leu-Val cleavage site of angiotensinogen (T-~) using standard co~lpling 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 Rl is a C1 to C6 straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, S, N. or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl, alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a C1 to C6 straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, 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 (l.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, Ru04, Pt/02) gives the acid XLIX which is ready for coupling to T-H using known methods.
An alternative synthesis of the disubstituted lactone LIII and related lactone LVII is shown in scheme XVIA.
The 2(S)-hydroxyacid L is first converted to the ethyl ester by Fisher esterification. Trans esterification with the Z-allylic alcohol and titanium isopropoxide (using the procedure of Seebach et. al. Org. Syn. 1986, 65, 230) gives the hydroxy ester LI. Halo ( ~2 or NBS) or mercuric trifluoroacetate cyclization of the hydroxy olefin gives the disubstituted lactone LII. Reduction of LII with tributyltinhydride or sodium borohydride affords the reduced lactone intermediate LIII.
Scheme XVIIA discloses an alternative synthesis of carboxylic acids LVIII and LIX wherin Rl is a C1 to C6 straight or branched alkyl~alkenyl carbon chain or heteroatom substituted carbon chain substituted by 0, S, N
or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl, alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is 338~

substituted with groups V selected from a Cl 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 L~ 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 LVIb and LVIIb 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 o~ the Leu-Val cleavage site of angiotensinogen. The five step sequence from LVI to LVIb 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 Rl substituents reversed.
The syntheses of hydroxyethylene dipeptide isosteres are depicted in Schemes XVIIIA and XIXA. The chirality of the valine-mimic isopropyl group is established via a highly diastereoselective aldol condensation. Scheme XVIIIA details the use of technology developed by D. A.
Evans and coworkers (sèe D. A. Evans, J. Bartroli and T.
L. Shih, J. Am. Chem. Soc. 1981, 103, 2127), in which the 3~:2 aldehyde h~ (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 h~l. 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 L~I~, 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 L~III, thereby avoiding the hydrolysis step in Scheme XVIIIA. The secondary hydroxyl group is deoxygenated to produce the same protected amides h~Y.
The synthesis of P2' retro-inverted amine derivatives is described in Scheme XXA. The intermediate carboxylic acid h~IY is transformed into isocyanate L~ 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 L~I, ureas L~ll and carbamates L~LLI.

33~

These various hydroxyethylene dipeptide isosteres are then deprotected under the conditions listed in Scheme XXIA. The resulting free-base forms of the aminoalcohols LXxIy and L~ 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 .~X~VI (J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist and N. Yi, JO Org. Chem.
1987, ~2, 1487) is opened with a primary amine to provide aminoalcohols L~II. 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 (L~ ) 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 L~ is condensed with a primary amine under standard reductive alkylation conditions, and the resulting amine L~ is derivatized to the desired protected amine derivative LX~XII. 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 L~l can be employed to produce sulfamide derivatives. Deprotection produces aminoalcohols LXXXIIT, available for coupling reactions.

t33~2 SC~IEIA
O O
NH2 ~ tBuO J~ CH (V I 11) BuO ~~ ~la R3 C, d ~ Rl --~
(I) a,b ! ' ~ (III) tBuOJ~ sBuOJ~ - CR
Rl R3(IVa) Rl R3 (IVb) tBuOJ~ ~ C~tBuO~ J~OH
Rt 3 (V ~) Rl I R3 (Vb) FuOJ~ ~D tBuOJ~ ~L ~D

)~,NH~LNH ~I`D t O)~ J' ~ D

C~
(VI)-- NH2y~D
R4 Ha a: NaOAc, NaCNBH3; b: separate diastereomers; c: as a; d: LiOH, H ~O, dioxane; e: (Vl), NMM, HOBT, EDAC; f: as b; 9: as d; h: as e;
i: tiio~(~n~/Ht',l.

7~a~~ ~ ~-;b --7 g~

SC~E~IE 11 A

J~, I~rH \~ OCH~P h )~

Rl Ha (XVI) (~VII~
c O OrI
RO )~r . D
Rl R3 R.
(XvIII) a: 2 eq TEA, CH2CI2, 0-25; b: selec~ive hydrolysis:
c: coupled to (Vl).

.

~3382 SC~rvrE ~

O Cl l CrT
R~ OR2 NH2~ D R2~ \~TJL ~ D
R3 R4 a, b R~ R3 R4 (IX) (X) (Xl) O O O
- J~ Ocl-T~- P h (1~ R~ HJI~R' (X~ HJ~ T, p R3 a, b R~ R3 R~ R3 - O O
R2C~ HJ~ C~T C'T
Rl R3 (XIVI) Rl R3 (XIV;
(VI) / (V 1) / d d O C~ ~ C,ll R2tX~ ~ TJL 1 R2 J~ ~ D
Rl R3 R4 R~ R3 R~
- (XI~) . (Xlb) a: NaOAc, N~C;~'BH3; b: scparate di~stcreomcrs: c~ , Pd/C;
d: N~ l, HOBT, EDAC.

3~

~81--SC~E~IE IVA

}~
(lV b) a RlI R3 (XIX) b O

Rs I~
Rl l R3 (X~C) c o R5 1 _ R~ I P`3 (~
(Vl)~ d (VIII ) _ _ Rs)~ D
(~CII) ~: Diox~ne/HCI; b: R5-H,HOBT,EDAC; c: H~,rd/C or LiOH/H~O:
d: N~l~l,HOB~,EDAC.

33~2 ~ ~3 2 -SCHE~IE YA
_ R28 NE~. J~C(X}CH2-Ph R2S\~NH COOC}-l,Ph \~ + R3 - y (X~CIV~) 0 a, b Rl R3 (XXIII) (II~ /R~s ~H COOal.PI~
c, d / 1 ~
Rl R3 (~IV~) R~ R3 R4 c, d (X~;V~) ' C.l R28\1~HJL D
Rl R3 Rl (X~Vb) a: NaOAC, NaCNBH3; b: sep~r~e diastcreomers; c: H,. Pd/C;
d: (Vl), N~lM,HOBT, EDAC.

26~33~

SC~F, vlA
_ A~X-H Br~CCCt~ A ,X~ COC~I
Rl R3 a Rl R3 (~XVIIl) (X~;VI) (XXVII) b ~ \~ D
Rl R3 R~
(X~YLY) a: NaH, THF; b:( Vl ),NMM,HOBT,EDAC.

2~33~3 --8~ --SCHE;~IE VI:I A
.

E O)~ E~O~f--~ ~D

( XXX ) l ( XXX I ) o o as ~lD ~f ~J' ~ D
R, R3 R~
( X~;~; ll ) O O Cil R5~ ~\ D

( XXX III ) a: N~l~l, HOBT, EDAC; b: LiOH/H20/dio,~ne;
c: ~5-H, HOBT, ED.~C.

3~2 SC~ E vm A

B

Ph--O~H + 3~NJ~o R~ ~4 (XXXIV) `Ph (~
a Phf~ G~ b, c, d Ph (XXXVII) r;
(,~VI) e, f, g, n Rs ~ - D
V~II) a: CH~CI2, -72C; b: protect; c: H2,Pd/C;
d: Jones [O]; e: Rs-H, HOBT, EDAC; f: LiOH/H20;
9: (Vl), HOBT, EDAC; h: deprotect.

2 ~ 3 3T 8~2 --~ 6--SC~iE~ H.SO~ a (l) Rl diox;lne R~
O O
SC:H~EX P~ R3~ D~ R3~ (II) SC~
, ~ P ~ P
R-SH + TsO ¦ NaH R-S/--r -- RO~S
R~ T~- ~ - R oxonc depro~ect ~ Rl 0-25 c (~;:'~111) a) isobutyl-NH-Cbz CH.~2 ElO~NH-Cbz E:O~NH~
H10 R~ b) PhCOOAg / ~I dcprotcct R

EtOH /LiOH
HO~INH-Cbz E~r/~ a) S ~1. Nll.
Rl a) ~,1 A. R~ b) deprotect ~N Rt b) HBr SCHEME ~ ~ o HCCC X-H R~ - H ~ X-~I
HOBTEDAC R5 1 (X~v 1) \R-OH R
H,SO ~\
ROX~X-H
(XXVI) R, SC~E~ 11i A
O NH~
HCCC~ I~CbZ RC-II ~,NH-CbZ L ~H1 R5/
Rt IIOUTD~C S b. Pl.l/C. IT7 Rl 33~

SCHEME XIVp\
o n-BuLi o S THF / HMPA ..
R ~S~OBn Rl l OBn R1 R3 /

1. H2 PdlC
2. Jones or PDC
oxidation o O EDC, HOBT o C) ' ~OH T-H R -S~T Rs o ~ _ T

XLI XLil XLIII

SCI IEME XV A
1. EtOH, H2SO4 1. LAH
HO~CO2H O~O~ CO2Et R 2. allylbromide, NaH R 2. 03 XLIV XLV 3. Collins reagent LiHM[~S, THF/HMPA
~ R D~ --0~ R~-Br (I) O
R V N Al(Me)~
XLVI (~n"
XLVII

Jones oxidation V--~N ~r ~ _ ~ V ~N J~

SCHEME XVI P' 1. EtOH, H2S4 O NBS, 12 ~
HO~C02H ~ . oj~ HgTFAc2 R 2. Ti (O-isopropyl)4 R R~J

L R~CH2ou L~

~ Bu3SnH ( X Br or 1) J`1 NaBH4 (X = HgTFAG) ~"0 R R
X= Br, 1, HgTFAc Lll Llll 33~'~

SCHEME XVII P~
1. DrCH~CO2E~I
H2N ~,CH20H 0~ ~ R NaHMBS, THFMMPA
R z ~ec~l~4 o~NBoc R B (~ ;
LIV rollur~ LV

~R .. L~HH20 ~l - 1~ OH Boc o~NBoc 2. CH2N2 ~ N_CO2CH3 R1 R F~1 LVI LVII
V ~ 1. Swom oxldatlon ,~NAl(Me )2 2 KMrlO~orA~20 3. EDc,HoaT
2. Sworn ox dallon 3. KMnO. r~r A920 V~ H

4. LiOH
0 80c 0 Boc ~n~ R1 R V ~-~NJ~rN~C02H
LVII~ LIX
~ couple T H ~ rupleT-H
O Boc O Boc J~ ' V ~NJ~' ~ ;

~33~3Z

SCHEME XVII A~
o~.~R 1~ LiOH H20 - - ~ OH Boc s~NBoc 2. TBDSCI, imidazole l~N~CO-T
3. coupleT-H ~ :
R1 HOBT, EDC R R
LVI 4.F LVII

1. L~H H20 1. Swern oxidatlon 2. R2CHN2 or AgO, R21 2. KMnO4 or Ag20 3 SwQrn oxidation 3. R2CHN2 or AgO, R21 5. couple T-H
HOBT, EDC

O Boc O Boc R20~N ~CO-T R20J~N~CO-T
Rl R R R
LVlb LVllb - 2ai~33~

~ME XVI I I P-- ~" ~Ph 1. su2RoTI,iPr2NEl ~Lo ~,.~,,Ph N N~IN N ~Lo ~ ,Ph .N O CH2CI2,-78C BocN~N~,O ~_ ~ BocN~N~O
2. '~L o OH O O CICH2CH2Ct ~ O O
BocN ~ H V N

~( LX ) ( LXI ) ( LX I I ) -7B lo O C

_ Boc~N~fO ~ BocN-~xOH ~ BocN~ NHR
teilux 0~ THF,H20 0~ Couple 0~ 0 (LXIII) (LXIV) (LXV) SCHEME Xl X A

C2CH31. Bu2BOTI, iP~2NEt `,L C02CH3 ~N'--S CH2CI2.0C ", BocN~N'~S RNH2 ~, ~X~NHR
O S2 Y~o ~ OHO S ~ OHO
BocN 7~ H ~,J ~J
(LXVI) O~ O (LXVII) (LXVIII) (LX) -78 ~o O C
NaH. CS2 ~L o Bu~SnH ~L O
D~ BocN~,NHR ~ BocN~NHR
loluene THF 0~ O~ ref lux O'~

(LXIX) (LXV) 3~

SCHEME XXp~

~0 0 BocN ~N J' R
O~ H

(LXXI) ~0 y (PhO)2PtO)N3, E~3N ~Q~f ~2 ~,~ O
E~ocN_~c02H e BocN N=C=O ~,_ BocN N NR
C~ ~oluene, 65 ~C O~ P~ ( LXXI I ) (LXIV) (LXX) ~
~OYO
BocN ~ N J~o R

(LXXIII) ~133~2 _99 _ SCHEME XXI A

~Lo 1. TFA/CH2CI2/0C OH~
BocN~X~NHR~5 ~H2N~NHR1s O 2. H20/THF ~
O~ 3. Na2CO3 ~J
(LXV) (LXXIV) ~Lo o 1. TFA/CH2CI2/0C ,~
BocN ~N ~ R82 ~ H2N N J~ R82 H 2. H20/rHF ~ H
3. Na2CO3 1 ~
--~ (LXXV) ( LXXI -LXXI I I ) SCHEME XXII f'~

BocNH ~ ~2~1~ BocNH~_NHR ~ 2 BocNH~,~,NR So2R32 O~ ~ O~ Et3N O~
( LXXVI ~ ( LXXVI I ) CH2CI2 ( LXXV I I I ) TFA/CH2CI2/o C OH
,_ H2N_~NR SO2R82 2. Na2CO3 O~ (LXXIX) R = H, loweralkyl 2~ 3;3~3~

SCH~ XXIII~

BocN~H ,_ BocN~ NHR Et3NlcH2cl2 O~ NaBH3CN 0~ ,,~OSO2NHR
HOAc/iPrOH ~OH
(LX) (LXXX) (LXXXI) dioxane, reflux BocNJ~,NR so2R82 1 TFA/CH2CI2/O C H2NJ~ NR SO2R82 2. H2O/THF~FA ~
3.Na2CO3 (LXXXIII) (LXXXII) R= H, loweralkyl In the above schemes, optically active or racemic starting materials can be used to obtain products of known or mixed stereochemistry.
Renin inhibitors having the general structure shown in group ~10) can be made as shown in Schemes lB-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 ~338~

Applicatlon No. 0228192; Ten Brink, PCT Patent Application No. W087/02986).
Scheme lB discloses a general method for the synthesis of compounds of the invention containing su~stituted piperazines. The process involves reaction of the appropriately substituted piperazine with an alph-halo ester. The ester ~ 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 texcess lithium aluminum hydride (LAH) in THF) to give l. Reaction of l with an alpha-bromo ester (in this case ethyl 2-bromo hexanoate) gives ~. The amine ~ 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 [)3;38~

reacted with an alpha-bromo ester such as benzyl bromoacetate to give 1~, which is deprotected by hydrogenolysis and then cyclized with EDAC-HOBT
(hydroxybenzotriazole) or other peptide or lactam forming agents. The lactam-ester 1~ is hydrolyzed (LiOH/dioxane/H20) 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 15 is oxidized to aldehyde 1~. 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 ~Q.
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 -78C in THF followed by an alkyl halide (benzyl bromide). The resulting lactone ~1 is transesterified with benzyl alcohol. The primary alcohol ~2 is oxidized using Swern conditions and then reductively aminated with an amino acid ester such as L-~orleucine methyl ester. The benzyl ester ~ is subjected to hydrogenolysis to remove the benzyl group and the amino 33~

acid is cycllzed to give lactam 25 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 ~.
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 ~. Hydrolysis (aq. sodium hydroxide) followed by acidification provides the acid corresponding to 29, which is treated with excess ethereal diazomethane to provide ~. Oxidation of ~ gives aldehyde ~Q~.
Reductive amination of ~Q~ with the methyl ester of the desired amino acid hydrochloride salt (in this case His-OMe) provides the amino ester 31a, which is cyclized to the corresponding lactam ~2 (n-1). The lactam ester ~ 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 ~ followed by oxidation gives the aldehyde ~Q~. Reductive amination of ~Q~ with the methyl ester of the desired amino acid hydrochloride salt (in this case L-His-OMe) provides ~1~. Lactam ester ~ (n=2) is produced by refluxing a mèthanolic solution of ~1~ with isopropyl amine. Ester hydrolysis, followed by coupling to 33~Z:

the hydrochloride salt of the appropriately functionallzed 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 ~, which is esterified to produce ~. The free hydroxy group is allylated with allyl bromide to provide ester 35, which is oxidized to the aldehyde ~. The aldehyde ~6 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 ~. 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 ~1 or ~2, which are reduced to alcohols g~ or 44, respectively. Alcohols 43 and 44 are then oxidized to aldehydes ~ and ~. Reductive amination of ~ 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 4~ leads directly to the cyclic derivative ~1. Protection of the 33~32 imidazole nitrogen of 47 and 49 as the N-t-Boc derivative, followed by ester hydrolysis, leads to acids ~Q and ~1.
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, af~ords ~ and ~, 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 59 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 ~. 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 ~.
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 ~n. The ester is reduced to the alcohol and the alcohol is oxidized to the aldehyde ~1. Treatment of this aldehyde as described in Scheme 9 provides the desired compound ~.

Scheme llB 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 ~ 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 functionali~ed 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 containin~ a sulfonyl substituted ketopiperazine. Compound 68 is sulfonylated, followed by ring formation, to give compounds such as 7Q
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 ~ (Scheme 6, n=2) is treated with H2 and Pd/C in acetic acid, followed by treatment with toluenesulfonyl chloride, to produce di-tosylate l~.
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 synthesi~ing 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 38~

the corresponding amino acid methyl ester and the resulting product is thermally cycli~ed to delta-lactam 77.
Treatment of 77 with HBr/HOAc, followed by ~eaction 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 ~itsonobu condition to give the tetrahydrofuran derivative ~ in high yield. The free amine ~ 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 ~2 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 C~Z-NOS and then paraformaldehyde to give chiral oxazolidinone 88.

33~3~

Hydroboration of ~ (9-BBN then NaOOH) and oxidation to the aldehyde ~PCC) is followed by reductive alkylation with amino acid esters to provide the lactams.

33~

--10~--Scheme-1 B

~ ~ \ + BrJ~COOEt - ~ ~ N~ ~lN--< COOE~
~ b /= N ~ Bu ~ r~
~)~ N N~ /~ N N--<
O
a: K2CO3, EtOH; b: LiOH, MeOH-H20; c: HOBT, EDAC,Amine.HCI

338;;~

Scheme-2 ~
~Ph Ph ~Pn BOC-NH~ CCCH a ,_ ~ b ~ ~

NH2~ Jb 5 < N~ ~ ~H
COCMe 6 1 C

~,Ph ~Ph ~Ph t~C~ -- _ _ l~N~ CCCH q ~N~ COC~t ,_ B,J 8 BU

~ Ph t N~ CCNH
~r H E3u ) Otl ~ 1 0 Mixture of Diastereomers a: Mixed anhydride coupling followed by HCI/Dioxane b: Heating in Xylene for 6 h c: LAH in THF, Reflux overnight d: Ethyl Bromohexanoate, K2C03, Dioxane, Reflux for 2 h e: tBOC-Anhydride, CH2C12 f: Hydrolysis followed by EDAC coupling of the amine 3~3~

--10 ~--Scheme 36 ~Ph ~Ph Ph C8Z-NH/\~ CBZ-NH/\
C8Z-NH~ -- H~ /b C ~N~
1 1 8u 8zOOC BU 1 2 /Pn I /

r ~ r eu ~ 0~ 13 8u a: ~03-~yricire b: r;or-Le~-C;i;a, NaCNBH3 c: Benzyl bromoacetate, Na2C03, Dioxane d: H2-Pd, MeOH
e: EDAC;, HOBT, DMF
f: LiOH, H20-Dioxane g: EDAC, HOBT, Amine.HCI, DMF

Scheme-4 B
~Ph ~Ph NH/\COO;~e a b ~ . N COO~lc H
d~
Ph Ph\ Ph N~ e tsoc Nv COOH ~ N~, COO~lc ~", NH~ COO~e 9 Bu \ 1 8 Bu 1 7 Bu Ph\

t ~ OH
~N~,CONH~
Bu ,~ OH
~ > 20 a: tBOC-Anhydride, CH2CL2 b: NaN(TMS)2, Allyl 8romide, DMF
c: Ozone, CH2C12 d: nor-Leu-OMe, NaCNBH3 e: Reflux in Xylene f: LiOH, H20-Dioxane 9: EDAC, HOBT, Amine.HCI, DMF

Z~i338~

- 1 o ~ -Scheme-5B
~Ph ~Ph C~s ~ o b ~ coc 2 1 ~ c ~ Ph Ph ~ _~ ~cocaz _~ d ~( N~ b N l COC``-b 2 5 ~ Ph 8u 2 4G~:) 2 ~.
~0 1~
N~CCNH W\~
Bu~J a~ ~ 6 a: LDA, Benzyl Bromide, T5 IF b: Methanol/Sulphuric Acid followed by ~enzyl AlcohoU
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 9: LiOH, Diox-Water h: HCl.Amine, EDAC, HOBT, TEA, DMF

33~Z~

Schcme~6'~

o o o PhCH2~ , CH ~ H2C \ ~

Cbz Rl ' Cbz 29 R'=HorPh I d ¦ c o o , PhCH~ ~ e PhC'rl~ ~ PhC~ OcH
CO~Crl3 NH ~ ~ ~ 0~` ,N~ ,~H 3() ~1 - Cbz ,1 ~ Rl Cbz Rl Cbz Im 3!) h ~g /Im /Im O
PhCH2~, N l -- ~ ~OCH3 j~ CO2CH3 ~ CH30 C ' Cbz~'H
CbzNH(CH2)n ' 1 n= I or 2 h ( Im 0 7~ OH
~ N ~ C ~ ~. /
CbzNH ~ (CI~Z)A O ~_~ OH
n= I or 2 ~

~: KH~IDS,THF, -7SC,;Illyl bromidc e: His-O~.le.N;IO-~c.~T.lC~.lBH., b: ~q. ~ OH~ H'~ CH~.N2 f: HOBT,Tolucne~D~!lE,rctlu.
- c: 0~,-7S"C,thcn.~ S g: '7 eq. isopropyl:lmine.~.lcOH, rctlu~
d: 9 BBN/THF,N;IOOH;PCC 11: ~q.LiOII:EDf~C.\minc 2~033~

Scheme-76 PhCH2; ~o a PhCH2;.~l~oH b 2; ~J~CCH c I' cc~ d ¦ cc~ PhCH2 ~

3a 36 37 _~N ~ON
C~J C~
3 8 ~ H
a: HNO2 ~J
b: MeOH, TsOH, reflux c: NaH, DMF, allyl bromide d: 03, -78C, Me2S
e: His OCHl,NaOAc,l~aCNBH3 f: MeOH,reflux 9: LiOH, BocOaoc, amine, EDAC, HOAc SCHE~JlE 8g ~c~c~2 ^1; b~ Buo2c ~ H

~C 4 -BuO2C ~ C~

~d 4~ ~
- - 09~,_CC2E~ '- O
H A t-8uO~C--~H
~e ~ lf O ~
~--cc2~ t-zuo~c~~
~:¦ O~ ~ ~ H

e22-N~ N e52-N~`'~J HI~J

--C2H - ~ ~2H ~ ~--C2 3 \h ~N~ N 5 1 ~ oH~J~J

~N ,~ ~N~

,~_ 53 a: Cr3CO2H; b: H2,P~'C; c: eH3/THF; d: Cicococl~D;~so~TcA;
- e: H-His-GanTsoH2~ NaOAc, NaC,''BH3; f: CF3CO~H, then EDAC, H03T;
9: ecc-0-2cc. then H2, PclC; h: EDAC, HGZT, Amine, then HOAc.

~33~3~

--1 l2--trl HN,~ O
3~N~,~ 1~8n C IN~~co2Bn 5 4s s ~3 ~d e~.r~ N
~r~

~57 SCHE~.IE 10B

H-Phe-CCH3 HCI f , BGc-N C~C~ 9' a ~ H
5~ 60 ~/6t eocN~N Ml~``N
)'N~N ~ ~N~H J~ ~N--C02en ~J O ~ ~ ^0~,_n -a: CICOCOCI, DMSO, TEA; b: H-His-OBn TsOH2, NaOAc, NaCNBH3;
c: CF3CO2H,thenCDI; d: Bo^0-80c,~hen H2,Pd/C; e: EDAC,H03T,Amine, then HOAc; f: (CH3)2CHCHO, NaOAC, NaCNBH3, then Eoc-O-Boc; 9: Ca(BH.)2.

2~

Scheme 11 B
~Ph ~Ph - __~ N~
1~ 3 l 6 4 --CO~z ¦ c,d ~ `I ~Ph E~ ~ - t N~
N~ .b ~ Bu BU 6 ~

If g t~C ' I P
I Y Jl\NH~ 6 7 a) E3enzy3 bromoacetate, TEA, THF
b) BOC-Anhydride, IMethylene Chloride c) Pyridine-SO3 d) L-nor-Leu-OMe, NaC~lBH31 IPA
- . e) Reflux in Xylene f) NaOH, MeOH-H20 ~) Amine, EDAC, HOBT, DMF, TEA

33~

Schcme~
/Ph /Ph H,NCOO~le ~ 1 Bromidc ~ ' CCO:~le 5~

Pr.EL~I, D~IAP, D!.IF
Ph RT Ph 1)1~ in CH~CU
2) Ozonc in CH~C12 --NN-SO.--N CO ~ 78C --N N-SO--N~COO~le I I, COo~ ) rh~ c ~/ NIC,~'BHl, IPA-?-lcOH
- ~ NaOAc(c~lccs;) ~9 3 Ozone 3) L.Hir-08z I) LiOU in Dio~c~ne-W;~lct Ph NaCNBil~, IPA
2~ EDAC, HOBT, TE~, Amine , in D~SS- ~ 0 C ~ .~ S O~ ~' CO ~ OBz --~ ~-SO. ~CI ~ ~)EDAC~oupLn~ -BOC

7~ r~N SO,-N~ ,CO O
73 ~ ~
~ N-BOC
J_~ HCI-Dio~3ne HN~ NH Bu _ ~ . SO i~ ~ CO

7~ .z ~ICI <~,21 1 1 38~

~ 1 1 s -SC~3FME 13g Im ~ Im(Tos) PhCH.~ ,3,b PhCH~" ~1~ 1 j~N CO~CH~ ' COlCH3 Cb2NH \--(cH~)n I 2 TosNH \--(cH~)n n= I or2 Im(Boc) cd O 1~ e,f PhCH2X~N~COOH
TosNH (CH2)n n= I or 2 ` 1l,7 OH
PhCH~(CH2)n ~

n=l or2 \

a:H2, Pd/C,HOAc e: Amine,EDAC. HOBT
b:Tscl~NMM~DMAp~cH2cl2 f: HOAc,THF,H,O
C:LiOH.H20 d:BocOBoc 2101~33~2 Schemc 14g Thi~zolyl o o 1~
Phcili J~ ~,b PhCH
O ~ N COOCH~
~ N~ CbZ,'`~ 2)n Cbz ~Ph l:Z. n= I or 2 3n~

f Thi~2olyl c,d PhCH2" ~ ~ e,f RS02NH (cH2)n 78 n= I or 2 Thi~zolyl PhCH., ~/ OH
jj~ N~C
RSO,NH (CH2)n 0 OH
n=l or 2 \

~: Thi~zolyl~l~nirle-OCI13, d: RSO~CI.D~IAP. N~-1~1, D~IF
N~CN'BH3, N;~OAc b: IvleOH, ~'~OAc, Rcnu:c e: LiOH.H20 c: HBr/ HOAc f: Amine.EDAC. IiOBT

8~

~ichemc- l S B

~sQC--N o ~ tsoC--N~, Zn, THF ~` /\
C~Q \ .
n ~1 V ~

H~ / Pd-C
MeoH

tBoc--N taQC--N
~ Mo RT. 5 m~n ~ Mc ~ ~b ,coo~lc Ph~P in THF N
RT,4hrs N
~lcooC' ~;BOC--N O H.:`~ OH
H(~l in Dio~tnne ,~Mo i~riUrun ` b ,~ ~

2C~ 3~

SCHEI~IIE 16B

Thi.~olyl /Thi~olyl ccoc~3PhCH
RS02NH _(CH2)n n= I or 2 R502NR' (CH2)n 1 2 R = Tosyl or N-mclhylpipc-c2inyl R' = Mclhyl, Elhyl, elC.

Thiazolyl O ~ 0~
b,c PhCH2~N,lC~ \~
RSO2NR ~(CH2)n O OH
n=l or2 G~

a: R'CHO, NaCNBH3, CH3CN
b: LiOH,H20 c: Amine, EDAC, HOBT

33~3Z

SCHE.~lE 17 B

Ph H~
H ~CH CHC13 ~ + ~J + Na + COCI
H3N CO~}
1~2CO3 Ph ~O
Ph ~O

~S7 ,I~Thiazolyl Ph y~ O f, g, h ,i ,j PhCH2X~ N OCCCH3 CbzN~/O Cb2NH ~CH2)n 1 or a: LiH`,~lDS,D~PU,Allyl Bromide f: 9-BBN
b: LiOH,H20 g: N:IOOH
c: IN HCI h: PCC
d: Cb~ 'os i: Thi;~ OCH~, ~'aC~'B11 e: HCHO, TsOH j: NuOAc,~1~0H,Reflu:c 2~JI()33~2 The followlng examples will serve to further illustrate preparation of the novel compounds of the invention.

Example 1 2(S)-~l(S)-(4-(MethQxymethox~
phenyl)ethoxyhexanoic ~cid ~mide of 3~(4-morpholinyl)~ropyl 5(S)-amino-6-cyclohexvl-~(S)-h~Loxy-2(S)-isoDropylhexanamide 3(R.S)-hvdrox~-1-pentene To a strired -78C 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 solution in toluene). After 30 min, vinyl magnesium bromide (108 ml of 1 ~ solution in tetrahydrofuran (THF)) was added. After stirring for 15 h at 0C, the mixturte was carefully quenched with methanol, treated wi.th 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 C16H2gNO3 .1/4 H2O: G, 66.8; H, 10.3; N, 4.9.
Found: C, 66.9; H, 10.2; N, 4.7.

3~3~

E~ample lB: 3-(t-But~lox~carbQnyl)-~-(c~clohexylmethyl)-2,2-di~ethyl-5-Yi~yl~azQli~i~e-The procedure of S. Thaisrivong (J. Med. Chem. i987, 30, 976) was employed. A solution of 40 g of the resultant compound of Example lA 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 (CDCl3) 1690 (C=O
carbamate) cm ; 1H NMR (CDC13) ~ S.9S (m,lH), 5.32 (m,lH), 5.20 (dt,lH), 4.27 (dd,lH), 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 lC: 3-~t-ButylQxycarbQnyl~-4-~cycLohexylmethyl) 2~2-dimethyloxazolidine-S-carboxaldehyde.
A solution of 10 g of the resultant compound of Example lB in 150 ml of 2:1 dichloromethane: methanol was cooled in an dry-ice acetone bath. Ozone was bubbled through the solution until a blue color persisted (1 h). Dry nitrogen was then bubbled through the reaction mixture to remove excess dissolved ozone. The reaction mixture was cannulated into a suspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and 200 ml of methanol cooled to -45C. 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 ~33~3~

entire reaction mixture extracted with two 300 rnl portions of dlchloromethane. 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 (CDC13) 1735 (C=O aldehyde), 1690 (C=O
carbamate) cm 1; 1H NMR (CDC13) ~ 9.83 (s,lH,CHO), 9.73 (d,lH,CHO cis diastereomer), 4.14 (m,lH), 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.

Equilibratlon of Aldehvde Isomera 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 ~ 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:hexane to give l9.S g o~ the desired compound as an 8:1 mixture of trans:cis diastereomers.

Example lD: 3-(3~R)-(3-(tert-~utyloxycarbonyl~-2~2-dimethyl-9(~)-cyclohexylmethyl=5(R~-oxazolidinyl)-3-hydroxy-2(R)-isopropyl-1-oxopropyl)-4(~)-methyl-S(S)~phenyl-~=QxazolidinQne.

~33~3~

The title compound was prepared in analogy to the procedure of S. Thaisrivongs, D. T. Pals, L. T. Kroll, S.
R. Turner and F. S. Han, J. Med. Chem. 1987, 30, 976-82, from the resultant compound of Example lC, in 63% yield.
M. p. 97 C. 1H NMR (CDC13) ~ 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, lH), 2.3 (m, lH), 3.81 (dd, lH), 3.94 (td, lH), 4.04 (bm, lH), 4.22 (dd, lH), 4.84 (dq, lH), 5.61 (d, lH), 7.31-7.95 (m, 5H). High resolution mass spectrum. Calcd. for (M+H)+ of C33H51N27: 587-369B-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 lE: 3-(3(~L-l3-~tert~Bu~ylQ~carbonvL~-2-2-dimethyl-4(S)-cyclohexylme~hyl-5(R)-oxa~olidinvl)-3-(~1-imidazolyl)thionylQxy)-2(R)-i~Q~ropyl-l-Qxopropyl)-4!R)-methyl-5(~)-phenyl-2-oxazolidinone.
The resultant compound from Example 1~ (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 (CDCl3) ~ 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, lH), 4.13 ~bm, lH), 4.23 (dd, lH), 4.81 (dd, lH), 4.94 (dq, lH), 5.70 (d, lH), 6.33 (dd, lH), 7.06 (bs, lH), 7.3-7.5 (m, 5H), 7.61 (bs, lH), 8.40 2~38~

(bs, lH). High resolution mass spectrum. Calcd. for (M+H)+ of C37Hs3N407S: 697.3635. Found: 697.3629.
Analysis. Calcd. for C37Hs2N407S: C, 63.77; H, ` 7.52; N, 8.04. Found: C, 63.58; H, 7.44; N, 7.94.

- E~m~le lF: 3-(3-(3-(tert-BlAtvloxv~arbQnyl)-2 2-dimethvl-oxopropyl)-4(R)-~ethyl~ henvl-2-oxazolidinQne~
A solution of the resultant product from Example lE
(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
(CDCl3) ~ 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, lH), 3.97 (m, lH), 4.85 (dq, lH), 5.68 (d, lH), 7.3-7.46 (m, 5H). Mass spectrum:
(M+H)+ = 571.
Analysis. Calcd. for C33HsoN206: C, 69.44; H, 8.83;
N, 9.91. Found: C, 69.31; H, 8.82; N, 4.89.

Example lG: 2(S)-~(3-~tert-~u~yloxycarbonyl 2,2-dimethyl-4~S)-cyclohexylme~hyl-5~S)-oxazolidinyl)methyl)-3-methylbu~nQic acid.
Usi~ng 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 lF (6.10 g, 10.7 mmol) was 33~32 hydroly~ed with aq. LiOH an~ 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. 1H NMR
(CDCl3) ~ 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 ~otal), 2.0 (m, lH), 2.66 (m, lH), 3.7 (bm, lH), 3.90 (m, lH). 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 lH: 3-(4-Morpholinvl)~ropyl 2(S)~ =(ter~=
butyloxycarbQnyl)= ~-dime~hyl-4(S2-cy~lohexylmethYl-S(S)-~ c~Lhyl)-3-methvlbutanamide.
The procedure of P. suhlmayer, et. al., J. Med. Chem.
1988, 31(9), 1839-46 is adapted. The resultant compound from Example lG (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 CH2C12 and aq. NaHCO3. The aqueous phase was extracted 3X with CH2C12, and the combined organic phases were washed with brine, dried (Na2SOq) and concentrated.
Purification by flash chromatography (4% MeOH-CH2Cl2) provided the desired compound.

2~33~

H NMR (CDCl3) ~ 0.92 (d, 3H), 0.95 (d, 3H), 1.46 ~s) and 1.48 (s, 12~ total), 1.57 (bs, 3H), 0 8-1.8 (several bm, 18H total), 2.01 (m, lH), 2.46 (bm, 6H), 3.37 (m, 2H), 3.64 (bm, lH), 3.75 (bm, 5H), 6.80 (bt, lH).
High resolution mass spectrum. Calcd. for (M+H)+ of C30H56N3O5: 538.4220. Found: 538.4220.
~x~mRle lI: l(S)-(4-(MethQxymethoxy~ eridin-1-vl-carbonyl)-2-phe~yletha~Ql.
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 0C (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 (MgSO4) 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%).
1H NMR (CDCl3, TMS) ~ 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,lH), 4.62 (t,lH~, 4.68 (s,2H).
Example lJ: 2~S)-(~L~L=~4-(Methoxymethoxy)piperidln-1-yl-carbony~ h~nvl ~thoxv) hexanoic acid.
The resultant compound of Example lI ~1.45 g, 4.95 mmol), in 10 ml THF was added drop~ise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (O-5OC). The suspension was 21~338~:

stirred for 20 mins at 0-50C 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 (0-50C) at N2 atmosphere. It was then allowed to warm up to room temperature and stirred overnight. Quenched with cold H20 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: CH30E~: AcOH ~19.4 = 0.3:0.3) to obtain 0.79 g of desired acid (43 ~ yield).
1H NMR ~CDC13, TMS) ~ 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,lH), 4.6 (m,lH), 4.64 (s,2~), 7.38 ~m,SH). Mass spectrum: (M+H)+ = 408.

Example _lK: 2(S~-(1($)-(4-~Methoxymetho~y)p~eeridin-l-yl)carbon~l-2-phenyl)ethoxyhexanoic acid amide of 3-(4-morpholinyl)propyl 5(S)-amino-6-cy~lohexyl-4(S~-hydroxy-2(S)-isopro~vlhe~anamide.
The resultant compound from Example lH (0.161 mmol) was deprotected ~y dissolving in 1 0 ml dry CH2Cl2, cooling the solution to -10 C (under nitrogen), and treating with 1.0 ml of trifluoroacetic acid. The resulting solution was stirred at -10 to 0 C for 4 h.
The solvents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolved in 1.0 ml THF and 0.3 ml water at 0 C. The solution was allowed to warm slowly to ambient temperature over 18 h. The crude aminoalcohol was isolated by basifying the reaction with an excess of 1.0 M aq. Na2C03, saturating the solution with NaC1, and 21)C~33~;3Z
-128~

extracting with 5 x 10 ml of 5% EtOH-CHC13. 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 lJ (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 CH2C12, 9 ml sat. aq. NaHCO3 and 1 ml H2O.
The aqueous phase was further extracted (3 X 10 ml CH2Cl2), 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.
lH NMR (CDCl3) ~ 0.90 (m), 0.91 (d) and 0.92 (d, 9H
total), 0.65-1.90 (several bm, approx. 28H total), 2.02 (m, lH), 2.45 ~bm, 6H), 2.95 (m, lH), 3.05 (dd, lH), 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, lH), 4.68 (s, 2H), 5.80 (d) and 5.88 (d, lH total), 6.87 (bt, lH), 7.3 (bm, 5H).
Mass spectrum: (M+H)+ = 787.

~1~0~38~

~am~
- (2S)-((3S)-((N-rneth l~;~erazinsuLfonvl) ~m.ln.c ~ phenylmethyl-2-c,xo-1-piDerid~nyl)-3-(4-thiazolyl)p~QRi~n~ ci~-~mide of (2S,4SIllR,2~-2-(2'-am1no-3'-cyclohexyl-1'-~ydroxy~ro~yl)-~-m~hylte~rahydrnfuran E~ample 2A: (2S,4S)-3-3enzyloxycarbonyl-2-~henyl-4-phenylmethyl-5-oxo-oxaznl.ld Following the procedure of ~arady, Tett. Lett.
4337 (1384), N-Cbz-L~phenylalanine (25 g, 83.5 mmol), benzaldehyde (18 ~, 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 (lx50 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 y, 12%); mp 120-122C. MS (CI):
405 (M+NH4)+, 388 (M+H)+.

Exam~le 2B: ~2S,4 pheny_methvl-4-(1-(2-~ropenyll)-5-Q~=
oxa~olidine A 250 ml round-bottom flask was charged with the resultant compound from Example 2A (3.75 g, 9.7 mmol), THF

~33~

(100 ml) and a magnetic stir bar. While under a nitrogen atmosphere, the flask was cooled to -78C and via a syringe potasslum hexamethyldisilylamide (25 ml, 12.5 mmol, 0.5 ~ solution in toluene) was added dropwise.
~fter 15 min at -78C, 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 NH4Cl (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 102-104C. MS (DCI): 445 (M+NH4)+, 428 (M+H)+.
xam~le 2C: (2S.9S)-3-Benzyloxycar~o~1-2-~h~nyl-4-h~nvlmethy~-4-(1-(3-hydL~xyDro~yl~ -5-oxQ=oxazoli~in~
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). ~fter 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~ H22 (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 2~ 33~

~131-extracted with ether ~3x50 ml). The combined organic extracts were washed with saturated aqueous NaHCO3 (2x50 ml), dried over Na2S04 and concentrated in_~a59Q 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 130-131C. MS (DCI): 463 (M+NH4)+, 446 (M+H)+.
x~m~le 2D: (2~f 4S)-3-Benzyloxycarbonyl-2-~he~yl-4-phenylmethyl-4-(2-(ethvlca~Q~aldehYde))-5-oxo-oxaæQlidine 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, 9.9 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 Va~UQ 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_~a~ to afford the title compound as a light yellow oil (450 mg, 52%). MS (DCI):
961 (M+NH4~+, 444 (M~H)+.

~0~3~

E~m~le 2E: (2s)-Methy]~-((3~L--((Benzvlo~vcarbQnylL
ami~o-3-phenylmethvl-2-oxo-l-~in~li~LhI~
3-(4-thiaznly1LQLQeiQnaS~
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 Na~SO4 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 110C 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 aceta~e and the combined organic extracts were dried over Na2SO4 and concentrated.
Flash chromato~raphy with ethyl acetate/hexane mixtures provided the desired compound as a light yellow semi-solid. MS (FAB): 508 (M+H)+.

Exam~le 2F: (2s)-M~thyl-((3s)-((aml~Q-3-~henyl~ethvl-2 oxo-1-pi~xLdinylL=~-~4-thia~ly~ ~ro~ionate.
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 i~ ~Q. The residue was dissolved in 50 ml H2O and washed with CCl4 3~32 ~9x). Solid NaHCO3 was added to the aqueous layer to bring the pH to 9 and the aqueous layer was extracted with CH2Cl2 (2X) and ethyl acetate (2X). The combined organic extracts were dried (Na2S04) and concentrated i~ vacuQ to afford a yellow oil (1.8 g). MS(DCI): 374 tM+H)+-Exam~le 2G: t2s)-Me~h~l-((3s~-((N-~eth~ erazinsllL~n~LL
amino-3-~henylmethyl-2-oxo-1-pi;oeridinvLI-3-(4-thiazolylLQropiQna~e.
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-dimèthylaminopyridine (42 mg, 0.34 mmol) and N-me~hylpiperidinesulfamoyl 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 ln ~n 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)+.

~xample 2H: (2s)-(l3s)-((N-methylDi~erazinsulfQnyl) amino-3-~h~nylm~hyl-2-oxo-1-~l~eridinvLL-3-~_~
l2'-amino-3'=~y~1Qhexyl-1'-hydrQxypropyl)-4-m~..hyl~etrahydrofuran.
The resultant compound from Example 2G (500 mg, 0.93 mmol) was dissolved in dioxane (9 ml) and cooled to 0C
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 0C and at 1 hr at 33~Z
-13~-25C. The reaction was neutralized with HCl/dioxane (500 ~1, 2.3 mmol) and the solution was concentrated ln vacuo and dried overnight on the HI-vac. The resultant colorless acid, the amine hydrochloride resulting from HCl/dioxane treatment of (4S,5R, 2'S,4'S)-3-(t-butyloxycarbonyl)-4-(cyclohexylmethyl)-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 (109 mg, 1.02 mmol) were dissolved in dry DMF and cooled to -23C. To this solution was added EDAC (178 mg, 0.93 mmol) in one portion. The reaction was stirred for 3 h at -23C, warmed to 25C, 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 i~ Yacuo to afford a yellow foam. Flash chromatography with methanol/methylene chloride mixtures afforded the product as a colorless powder.Mp 85-89C. MS(DCI): 746 (M+H)+.

~am~

propiQnlc acid amide Q ~1-~,4-dihydroxy-6-meth~lheptane.
The resultant compound from Example 2G (500 mg, 0.93 mmol) was dissolved in dioxane (9 ml) and cooled to 0C
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 0C and at 1 hr at 3~3Z

25C. The reaction was neutralized with HCl/dioxane (500 ~1, 2.3 mmol) and the solution was concentrated in y~Q
and dried overnight on the HI-vac. The resultant colorless acid, 2(S)-Amino-l-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 -23C. To this solution was added EDAC (178 mg, 0.93 mmol) in one portion. The reaction was stirred for 3 h at -23C, warmed to 25C, and stirred overnight. The reaction was poured into saturated aqueous NaHCO3 (SO ml) and extracted with ethyl acetate (4X). The combined organic extracts were washed with saturated aqueous NaCl (2X) dried over Na2SO4 and concentrated ln vacuo to afford a yellow oil.
Flash chromatography with methanol/methylene chloride mixtures afforded the product as a colorless powder (110 mg, 16~).
Mp 93-97C. MS(DCI): 747 (M+H)+.
MS(Hi-Res): Calcd. Mass for C37H59N6o6s2=747~3937 Measured Mass=747.3929.

~d~&~
3-(3-ThiazolylL~2-L~R-benzyl-4-N-lN-~ethy~ erazyl) ~u~yl_5~mino-6-cyclohexyl-4lS~-hydroxy-2lR)-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 ~. The intermediate fi~ was sulfonated with N-methylpiperazyl 3~

sulfonyl chloride (J. Med. Chem. 1~, 538, 1972) to give in moderate yield (40-65~). The acid ob~ained following the hydrolysis of 70 with LiOH was coupled under standard EDAC condition with 5(S)-amino-6-cyclohexyl-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%); 1H N~R ~300 MHz, CDCl3) ~: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-3~Z

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, benæenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionat 2, dodecylsulfate, ethanesulfate, glucoheptonate, glycerophosphate, hemislufate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfate, lactate, malea~e, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, ~artrate, 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 àcid 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 inven~ion can also be used in the form of prodrugs which include esters.

~0~33~3~

Examples of such esters include a hydroxyl-subs~ituted compound of the invention which has been acyla~ed 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 carri~ed 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 me~hod of this invention is directed to the use of a renin inhibitor or 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 circula~ion, diseases of the kidney, or peripheral, central or autonomic nervous system. All of these diseases may occur as symptoms ~33~

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, inhibi~ing, 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 inven~ion 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.

7~33~'2 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 lQ mg/kg body weight daily and more usually 0.01 to l mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to maXe 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 ~reated and the particular mode of adminis~ration.
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, ra~e 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 )33~

administration may also involve the use of ocular inserts. The term paren~eral 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 tempera~ures but liquid at the rectal ~emperature 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 Z~3~%

agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering ag~nts. 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 co~monly used in the art, sucn 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 sXilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims (9)

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 Af is hydrogen, loweralkyl, arylalkyl, -OR10f or -SR10f wherein R10f is hydrogen, loweralkyl or aminoalkyl, -NR11fR12f where R11f and R12f 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 Af is or wherein Bf is NH, alkylamino, S, O, CH2 or CHOH and R13f 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, aminocycloalkyl, 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, oxc, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl;
Wf is C=O or CHOH;
Uf is CH2 or NR2, provided that when Wf is CHOH then Uf is CH2;

R1f 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 R1f is phenoxy, thiophenoxy or anilino, then Bf is CH2 or CHOH or Af is hydrogen;
R2f is hydrogen or loweralkyl;
R3f is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
R6f is loweralkyl, cycloalkylmethyl or benzyl;
Raf is vinyl, formyl, hydroxymethyl or hydrogen;
Rdf is hydrogen or loweralkyl;
Rbf and Ref are independently selected from OH and NH2; and Rcf is hydrogen, loweralkyl, vinyl or arylalkyl;

wherein Ag 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 Ag is (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or Ag is -OR7g or -SR7g wherein R7g 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 Ag is -NR8gR9g wherein R8g and R9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or Ag is or wherein Bg is NH, alkylamino, S, O, CH2, NHCH2 or CH(OR52g) wherein R52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R10g 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, 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 Ag is R41gCH(OH)CH2- or R41gCH(OH)CH(OH)- wherein R41g 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, aminocycloalkyl or (polyalkoxy)alkyl;

Wg is C=O, CHOH or NR2g wherein R2g is hydrogen or loweralkyl;

Ug is C=O, CH2 or NR2g wherein R2g is hydrogen or loweralkyl, with the proviso that when Wg is CHOH
then Ug is CH2 and with the proviso that Ug is C=O
or CH2 when Wg is NR2g;

Vg is CH, C(OH) or C(halogen) with the proviso that Vg is CH when Ug is NR2g;

R1g 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 Bg is CH2 or CHOH or Ag is hydrogen when R1g is phenoxy, thiophenoxy or anilino;

R3g 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;

R4g is loweralkyl, cycloalkylmethyl or benzyl;

R5g is OH or NH2; and Zg is or wherein Mg is O, S or NH, Tg is C=O, C=S, S, S(O), S(O)2 or CH2, Eg is O, S, NR6g wherein R6g is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or Eg is CR6gR42g wherein R6g is as defined above and R42g is hydrogen or loweralkyl or Eg is C=CR43gR44g wherein R43g and R44g are independently selected from hydrogen and loweralkyl, Gg is absent, CH2, or NR11g wherein R11g is hydrogen or loweralkyl, with the proviso that when Gg is NR11g then R6g is loweralkyl or hydroxyalkyl, Qg is CR45gR46g wherein R45g and R46g are independently selected from hydrogen and loweralkyl or Qg is C=CR47gR48g wherein R47g and R48g are independently selected from hydrogen and loweralkyl, and R49g is -CH2OH, carboxy, alkoxycarbonyl or -CONR50gR51g wherein R50g is hydrogen or loweralkyl and R51g is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl;

wherein Ai is (I) R5iC(O)-(CH2)w"- wherein 1) w" is 0 to 4 and 2) R5i 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) R90i- or R90iNHC(O)- wherein R90i 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);
R11 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;
Xi 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-;
R3i is (I) loweralkyl, (II) haloalkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy)alkyl, (IX) hydroxyalkyl, (X) - (CH2)eeNHR12i wherein 1) ee is 1 to 3 and 2) R12i i) hydrogen, ii) loweralkyl or iii) an N-protecting group;
(XI) arylalkyl or (XII) (heterocyclic)alkyl; and Ti is wherein R4i is (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and Di is (I) wherein R73i is loweralkyl, (II) wherein 1) Mi is i) O, ii) S or iii) NH;
2) Qi is i) O or ii) S;
3) Ei is i) O, ii) S, iii) CHR73i wherein R73i is loweralkyl, iv) C=CH2 or v) NR18i wherein R18i is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino;
and 4) Gi is i) absent, ii) CH2 or iii) NR19i wherein R19i is hydrogen or loweralkyl, with the proviso that when Gi is NR19i, then R18i is loweralkyl or hydroxyalkyl;
(III) wherein 1) v" is 0 or 1 and 2) R21i is i) NH, ii) O, iii) S or iv) SO2; or (IV) a substituted methylene group; and wherein Xj 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) R6j-Qj- wherein 1) 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 R7j is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected)amino, alkylamino, (N-protected)(alkyl)amino or dialkylamino; or xiv) wherein R8j is O, S, SO2, O=C or R9jN
wherein R9j is hydrogen, loweralkyl or an N-protecting group; and 2) Qj is i) C=O or ii) CH2, with the proviso that Xj is N when R1j is an N-protecting group;
(VII) 54jS(O)2- wherein R54j is 1) amino, 2) alkylamino, 3) dialkylamino, 4) loweralkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl,

8) heterocyclic or (VIII) (R55j)2P(O)- wherein R55j is 1) alkoxy, 2) alkylamino or 3) dialkylamino;

Aj and Lj are independently selected from (I) absent, (II) C=O, (III) SO2 and (IV) CH2;

Dj is (I) C=O, (II) SO2 or (III) CH2;

Yj is (I) N or (II) CH;

R2j (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, (IV) -CH2-R10j-(CH2)q'''-R11j wherein 1) q''' is 0,1 or 2, 2) R10j is absent or R10j is O, NH
or S only when q''' is 1 or 2, and 3) R11j is i) aryl or ii) heterocyclic;

Zj is (I) hydrogen or (II) -R28jC(O)R29, -R28jS(O)2R29j or -R28jC(S)R29j wherein 1) R28j is i) NH, ii) -N(R200j)- wherein R200j is loweralkyl or benzyl or iii) CH2 and 2) R29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic;

R3j 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 Tj wherein R4j is (I) loweralkyl, (II) cycloalkylalkyl or (III) arylalkyl; and R5j is (I) wherein R73j is loweralkyl, (II) wherein 1) Mj is i) O, ii) S or iii) NH;
2) Qj is i) O or ii) S;
3) Ej is i) O, ii) S, iii) CHR61j wherein R61j is loweralkyl, iv) C=CH2 or v) NR18j wherein R18j is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino;
and 4) Gj is i) absent, ii) CH2 or iii) NR19j wherein R19j is hydrogen or loweralkyl, with the proviso that when Gj is NR19j, then R18j is loweralkyl or hydroxyalkyl;
(III) wherein 1) v''' is 0 or 1 and 2) R21j 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)carbonyl-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-6-cyclohexy1-4(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'cyclohexy1-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 Af is hydrogen, loweralkyl, arylalkyl, -OR10f or -SR10f wherein R10f is hydrogen, loweralkyl or aminoalkyl, -NR11fR12f wherein R11f and R12f 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 Af is or wherein Bf is NH, alkylamino, S, O, CH2 or CHOH and R13f 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, aminocycloalkyl, 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;
Wf is C=O or CHOH;
Uf is CH2 or NR2, provided that when Wf is CHOH then Uf is CH2;
R1f 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 R1f is phenoxy, thiophenoxy or anilino, then Bf is CH2 or CHOH or Af is hydrogen;
R2f is hydrogen or loweralkyl;
R3f is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
R6f is loweralkyl, cycloalkylmethyl or benzyl;
Raf is vinyl, formyl, hydroxymethyl or hydrogen;

Rdf is hydrogen or loweralkyl;
Rbf and Ref are independently selected from OH and NH2; and Rcf is hydrogen, loweralkyl, vinyl or arylalkyl;
wherein Ag is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substitutad 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 Ag is (unsubstituted heterocyclic)alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or Ag is -OR7g or -SR7g wherein R7g is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)aminoalkyl, talkoxy)(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 Ag is -NR8gR9g wherein R8g and R9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or Ag is or wherein Bg is NH, alkylamino, S, O, CH2, NHCH2 or CH(OR52g) wherein R52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R10g 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, 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 Ag is R41gCH(OH)CH2- or R41gCH(OH)CH(OH)- wherein R41g 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, aminocycloalkyl or (polyalkoxy)alkyl;

Wg is C=O, CHOH or NR2g wherein R2g is hydrogen or loweralkyl;

Ug is C=O, CH2 or NR2g wherein R2g is hydrogen or loweralkyl, with the proviso that when Wg is CHOH
then Ug is CH2 and with the proviso that Ug is C=O
or CH2 when Wg is NR2g;

Vg is CH, C(OH) or C(halogen) with the proviso that Vg is CH when Ug is NR2g;

R1g 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 Bg is CH2 or CHOH or Ag is hydrogen when R1g is phenoxy, thiophenoxy or anilino;

R3g 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;

R4g is loweralkyl, cycloalkylmethyl or benzyl;
R5g is OH or NH2; and Zg is or wherein Mg is O, S or NH, Tg is C=O, C=S, S, S(O), S(O)2 or CH2, Eg is O, S, NR6g wherein R6g is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or Eg is CR6gR42g wherein R6g is as defined above and R42g is hydrogen or loweralkyl or Eg is C=CR43gR44g wherein R43g and R44g are independently selected from hydrogen and loweralkyl, Gg is absent, CH2, or NR11g wherein R11g is hydrogen or loweralkyl, with the proviso that when Gg is NR11g then R6g is loweralkyl or hydroxyalkyl, Qg is CR45gR46g wherein R45g and R46g are independently selected from hydrogen and loweralkyl or Qg is C=CR47gR48g wherein R47g and R48g are independently selected rom hydrogen and loweralkyl, and R49g is -CH2OH, carboxy, alkoxycarbonyl or -CONR50gR51g wherein R50g is hydrogen or loweralkyl and R51g is hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl;

wherein Ai is (I) R5iC(O)-(CH2)w"- wherein 1) w" is 0 to 4 and 2) R5i 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) R90i- or R90iNHC(O)- wherein R90i 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);
R1i 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;
Xi 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-;
R3 is (I) loweralkyl, (II) haloalkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy)alkyl, (IX) hydroxyalkyl, (X) -(CH2)eeNHR12i wherein 1) ee is 1 to 3 and 2) R12i is i) hydrogen, ii) loweralkyl or iii) an N-protecting group;
(XI) arylalkyl or (XII) (heterocyclic)alkyl; and Ti is wherein R4i is (I) loweralkyl, (II) cycloalkylalkyl (III) cycloalkenylalkyl or (III) arylalkyl; and Di is (I) wherein R73i is loweralkyl, (II) wherein 1) Mi is i) O, ii) S or iii) NH;
2) Qi is i) O or ii) S;
3) Ei is i) O, ii) S, iii) CHR73i wherein R73i is loweralkyl, iv) C=CH2 or v) NR18i wherein R18i is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino;
and 4) Gi is i) absent, ii) CH2 or iii) NR19i wherein R19i is hydrogen or loweralkyl, with the proviso that when Gi is NR19i, then R18i is loweralkyl or hydroxyalkyl;
(III) wherein 1) v" is 0 or 1 and 2) R21i is i) NH, ii) O, iii) S or iv) SO2; or (IV) a substituted methylene group; and wherein Xj 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) R6j-Qj- wherein 1) R6j 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 R7j is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected)amino, alkylamino, (N-protected)(alkyl)amino or dialkylamino; or xiv) wherein R8j is O, S, SO2, O=C or RgjN
wherein R9j is hydrogen, loweralkyl or an N-protecting group; and 2) Qj is i) C=O or ii) CH2, with the proviso that Xj is N when R1j is an N-protecting group;
(VII) R54jS(O)2- wherein R54j is 1) amino, 2) alkylamino, 3) dialkylamino, 4) loweralkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl, 8) heterocyclic or (VIII) (R55j)2P(O)- wherein R55j is 1) alkoxy, 2) alkylamino or 3) dialkylamino;

Aj and Lj are independently selected from (I) absent, (II) C=O, (III) SO2 and (IV) CH2;

Dj is (I) C=O, (II) SO2 or (III) CH2;

Yj is (I) N or (II) CH;

R2j is (I) hydrogen, (II) loweralkyl, (III) cycloalkylalkyl, (IV) -CH2-R10j-(CH2)q'''-R11j wherein 1) q''' is 0, 1 or 2, 2) R10j is absent or R10j is 0, NH
or S only when q''' is 1 or 2, and 3) R11j is i) aryl or ii) heterocyclic;

Zj is (I) hydrogen or (II) -R28jC(O)R29j, -R28jS(O)2R29j or -R28jC(S)R29j wherein 1) R28j is i) NH, ii) -N(R200j)- wherein R200j is loweralkyl or benzyl or iii) CH2 and 2) R29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic;

R3j 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 Tj wherein R4j is (I) loweralkyl, (II) cycloalkylalkyl or (III) arylalkyl; and R5j is (I) wherein R73j is loweralkyl, wherein 1) Mj is i) 0, ii) S or iii) NH;
2) Qj is i) O or ii) S;
3) Ej is i) O, ii) S, iii) CHR61j wherein R61j is loweralkyl, iv) C=CH2 or v) NR18j wherein R18j is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino;
and 4) Gj is i) absent, ii) CH2 or iii) NR19j wherein R19j is hydrogen or loweralkyl, with the proviso that when Gj is NR19j, then R18j is loweralkyl or hydroxyalkyl;
(III) wherein 1) v''' is 0 or 1 and 2) R21j is i) NH, ii) O, iii) S or iv) S02; or (IV) a substituted methylene group;
or a pharmaceutically acceptable salt, ester or prodrug thereof.