WO1992000972A1

WO1992000972A1 - Renin inhibiting compounds

Info

Publication number: WO1992000972A1
Application number: PCT/US1991/004914
Authority: WO
Inventors: William R. Baker; Stephen F. Martin
Original assignee: Abbott Laboratories
Priority date: 1990-07-11
Filing date: 1991-07-11
Publication date: 1992-01-23

Abstract

The present invention relates to compounds of formula (a), which are useful for inhibiting renin and for treating hypertension or congestive heart failure, alone or in combination with another antihypertensive agent. The present invention also relates to compositions and a method for treating glaucoma, vascular disease, renal failure or psoriasis with such compounds and a method of inhibiting retroviral proteases and treating a retroviral infection with such compound.

Description

RENIN INHIBITING COMPOUNDS

Technical Field

The present invention relates to novel compounds and compositions which inhibit renin, processes for making such compounds, synthetic intermediates employed in these processes, and a method of treating hypertension or congestive heart failure with such compounds or in

combination with another antihypertensive agent. The present invention also relates to compositions and a method for treating glaucoma, vascular disease, renal failure or psoriasis with such compounds and a method of inhibiting retroviral proteases and treating a retroviral infection with such compounds.

Background Art

Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different

physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or (c) a fall in the

concentration of sodium in the distal tubules of the kidney.

When renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. The renin acts on a circulating protein, angiotensinogen, to cleave out a fragment called angiotensin I (AI). AI itself has only slight pharamacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII). The major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release

aldosterone, a hormone which causes sodium retention.

Sodium retention causes blood volume to increase, which leads 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.

Angiotensinogen, the natural substrate for human renin has the amino acid sequence shown below. Renin cleaves angiotensinogen at the amide bond between amino acid residues 10 and 11 to give angiotensin I (AI).

Compounds which are inhibitors of renin generally comprise two parts. One part of the compound mimics the first 9 amino acid residues of angiotensinogen. The other part mimics the Leu-Val cleavage site of angiotensinogen and is designed to be non-cleavable by renin. When these two parts are combined in one compound, the compound binds to renin but is not cleaved. Thus, renin is inhibited from acting on its natural substrate angiotensinogen.

Inhibitors of renin have been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.

With these objectives in mind, the renin-angiotensin system has been modulated or manipulated, in the past, with ACE inhibitors. However, ACE acts on several substrates other than angiotensin I (AI), most notably the kinins which cause such undesirable side effects as pain, "leaky" capillaries, prostaglandin release and a variety of behavorial and neurologic effects. Further, ACE inhibition leads to the accumulation of AI. Although AI has much less vasoconstrictor activity than AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.

Inhibition of other targets in the renin-angiotensin system such as AII with compounds such as saralasin can block AII activity, but would leave unimpaired and perhaps enhance the hypertensive effects of AIII.

On the other hand, there are no known side effects which result when renin is inhibited from acting on its substrate. Considerable research efforts have thus been carried out to develop useful inhibitors of renin. Past research efforts have been directed to renin antibodies, pepstatin, phospholipids and substrate analogs such as tetrapeptides and octapeptides to tridecapeptides. These inhibitors either demonstrate poor activity in inhibiting renin production or poor specificity for inhibiting renin only. However, Boger et al. have reported that statine-containing peptides possess potent and specific renin-inhibiting activity (Nature, Vol. 303, p. 81, 1983). In addition, Szelke and co-workers have described polypeptide analogs containing a non-peptide link (Nature, Vol. 299, p. 555, 1982) which also cause potent renin inhibition and show a high specificity for this enzyme. Recent patents have disclosed novel small peptide renin inhibitors which contain novel dipeptide isosteres as transition state analogs (Szelke, et al., U.S. Patent No. 4,609,643; Boger, et al., U.S. Patent No. 4,668,770; Baran, et al., U.S.

Patent No. 4,657,931; Matsueda, et al., U.S. Patent No.

4,548,926; Luly, et al., U.S. Patent No. 4,645,759; and Luly, et al., U.S. Patent No. 4,680,284). Disclosure of the Invention

In accordance with the present invention, there are compounds of the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

A is

(I) R₅C(O)- wherein

R₅ is

i) hydroxy,

ii) alkoxy,

iii) thioalkoxy,

iv) loweralkyl,

v) heterocyclic,

vi) amino or

vii) substituted amino;

(II) R₉₀N(R₁₅₀)C(O)- wherein R₁₅₀ is hydrogen or loweralkyl and R₉₀ is

a C₁ to C₈ straight or branched carbon chain substituted with a substituent selected from

1) carboxy,

2) alkoxycarbonyl,

3) alkylsulfonyl,

4) aryl,

5) arylsulfonyl. 6) heterocyclic,

7) (heterocyclic) sulfonyl,

8) amino,

9) alkylamino,

10) dialkylamino,

11) alkoxy,

12) (alkoxy) alkoxy or

13) ( (alkoxy) alkoxy) alkoxy;

(III) R₉₅S(O)_w- wherein w is 0-2 and R₉₅ is

1) loweralkyl,

2) aryl,

3) heterocyclic,

4) -NH₂ or

5) substituted amino;

(IV) R₉₆C(O)N(R₁₅₁)- wherein R₁₅₁ is hydrogen or loweralkyl and R₉₆ is

1) loweralkyl,

2) cycloalkyl,

3) aryl,

4) heterocyclic,

5) alkoxy,

6) thioalkoxy,

7) aryloxy,

8) thioaryloxy,

9) substituted amino,

10) R₉₇NH- wherein R₉₇ is loweralkyl,

cycloalkyl, aryl or heterocyclic

11) (heterocyclic) alkyl,

12) aminoalkyl,

13) alkylaminoalkyl,

14) dialkylaminoalkyl, 15) alkoxyalkyl,

16) (alkoxy) alkoxyalkyl or

17) ( (alkoxy) alkoxy) alkoxyalkyl; or

(V) R₉₆S(O)_xN(R₁₅₁)- wherein x is 1 or 2, R₁₅₁ is hydrogen or loweralkyl and R₉₆ is defined as herein.

R and R₁ are independently selected from

(I) hydrogen,

(II) aryl,

(III) loweralkyl,

(IV) loweralkenyl,

(V) cycloalkyl,

(VI) cycloalkenyl,

(VII) aryloxyalkyl,

(VIII) thioaryloxyalkyl,

(IX) arylalkoxyalkyl,

(X) arylthioalkoxyalkyl and

(XI) a C₁ to C₃ straight or branched

carbon chain substituted with a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl,

4) cycloalkyl,

5) cycloalkenyl and

6) heterocyclic.

R₃ is

(I) loweralkyl,

(II) haloalkyl, (III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl,

(VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl,

(X) -(CH₂)_eeNHR₁₂

wherein

1) ee is 1 to 3 and

2) R₁₂ is

i) hydrogen,

ii) loweralkyl or

iii) an N-protecting group;

(XI) arylalkyl or

(XII) (heterocyclic) alkyl.

T is a mimic of the Leu-Val cleavage site of angiotensinogen.

The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein includes

wherein R₄ is

(I) loweralkyl,

(II) cycloalkylalkyl (III) cycloalkenylalkyl or

(III) arylalkyl; and

D is

wherein R₇₃ is loweralkyl,

wherein

1) M is

i) O,

ii) S or

iii) NH;

2) Q is

i) O or

ii) S;

3) E is

i) O,

ii) S,

iii) CHR₇₃ wherein R₇₃ is loweralkyl, iv) C=CH₂ or v) NR₁₈ wherein R₁₈ is a) hydrogen,

b) loweralkyl, c) hydroxyalkyl,

d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino;

and

4) G is

i) absent,

ii) CH₂ or

iii) NR₁₉ wherein R₁₉ is

hydrogen or loweralkyl,

with the proviso that when G is NR₁₉, then R₁₈ is loweralkyl or

hydroxyalkyl;

(

wherein

1) v is 0 or 1 and

2) R₂₁ is

i) NH,

ii) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group.

The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein also includes the substituents (T) disclosed in the following references: Luly, et al., U.S. Patent No. 4,645,759, issued February 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₈, R₉ and X are as defined therein;

Luly, et al., U.S. Patent No. 4,652,551, issued March 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₈, R₉ and X are as defined therein;

Luly, et al., U.S. Patent No. 4,680,284, issued July 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃ is as defined therein;

Luly, et al., U.S. Patent No. 4,725,584, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃ and R₄ are as defined therein;

Luly, et al., U.S. Patent No. 4,725,583, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄ and R₅ are as defined therein;

Rosenberg, et al., U.S. Patent No. 4,837,204, issued June 6, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇ and X are as defined therein;

Luly, et al., U.S. Patent No. 4,845,079, issued July 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₈ and R₉ are as defined therein;

Sham, U.S. Patent No. 4,826,958, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₉ and X are as defined therein; Rosenberg et al., U.S. Patent No. 4,857,507, issued August 15, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₈, R₉ and E are as defined therein;

Luly, et al., U.S. Patent No. 4,826,815, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅,

R₆, R₇, R₈, R₉ and X are as defined

therein;

Bender, et al., U.S. Patent No. 4,818,748, issued April 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

l

wherein R₁, J, L, M and Q are as defined therein;

Fuhrer, et al., U.S. Patent No. 4,613,676, issued

September 23, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃, R₄, R₅ and R₆ are as defined therein;

Riniker, et al., U.S. Patent No. 4,595,677, issued June 17, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃ and R₄ are as defined therein;

Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃, R₄, R₅ and R₆ are as defined therein;

Buhlmayer, et al., U.S. Patent No. 4,758,584, issued July 19, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₂, R₃, R₄, R₅ and R₆ are as defined therein;

Szelke, et al., U.S. Patent No. 4,609,643, issued

September 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-A-B-Z-W

wherein A, B, Z and W are as defined therein;

Szelke, et al., U.S. Patent No. 4,650,661, issued March 17, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-A-B-Z-W wherein A, B, Z and W are as defined therein;

Szelke, et al., U.S. Patent No. 4,713,445, issued December 15, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-A-B-Z-W

wherein A, B, Z and W are as defined therein;

Iizuka, et al., U.S. Patent No. 4,656,269, issued April 7, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, X and R₂ are as defined therein;

Iizuka, et al., U.S. Patent No. 4,711,958, issued December 8, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein X is as defined therein;

Kleinman, et al., U.S. Patent No. 4,729,985, issued March 8, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₁, R₂, m, W², R₃ and R₄ are as defined therein;

Hoover, U.S. Patent No. 4,668,769, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X and R₂ are as defined therein;

Hoover, et al., U.S. Patent No. 4,814,342, issued March 21, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein X, W and Z¹ are as defined therein;

Bindra, et al., U.S. Patent No. 4,749,687, issued June 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₂ and R₃ are as defined therein;

angiotensinogen having the formula

wherein X, W and Z¹ are as defined therein;

Matsueda, et al., U.S. Patent No. 4,698,329, issued

October 6, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃ and X are as defined therein;

Matsueda, et al., U.S. Patent No. 4,548,926, issued

October 22, 1985, which is hereby incorporated by

reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein But and X are as defined therein;

Wagnon, et al., U.S. Patent No. 4,725,580, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein Z₁, X, Y and R₄ are as defined therein;

Wagnon, et al., U.S. Patent No. 4,746,648, issued May 24, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Z₁, X, Y and R₄ are as defined therein;

Cazaubon, et al., U.S. Patent No. 4,481,192, issued

November 6, 1984, which is hereby incorporated by

-Statyl₁-Ala-Statyl₂-R'

wherein Statyl₁, Ala, Statyl₂ and R¹ are as defined therein;

Hansen, et al., U.S. Patent No. 4,722,922, issued February 2, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄, R₅, n and R₆ are as defined therein;

Hansen, et al., U.S. Patent No. 4,510,085, issued April 9, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂ is as defined therein;

Baran, et al., U.S. Patent No. 4,657,931, issued April 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, n and R₅ are as defined therein;

Hansen, et al., U.S. Patent No. 4,514,332, issued April 30, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

Natarajan, et al., U.S. Patent No. 4,757,050, issued July 12, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₁, R₂, R₃, q, R₉ and R₁₀ are as defined therein;

Gordon, U.S. Patent No. 4,749,781, issued June 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₂, R₃ and R₉ are as defined therein;

Ryono, et al., U.S. Patent No. 4,665,193, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₂, R₃, R₄ and A are as defined therein; Ryono, et al., U.S. Patent No. 4,616,088, issued October 7, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₁, R₂, R₃, R₄ and A are as defined therein;

Ryono, et al., U.S. Patent No. 4,629,724, issued December 16, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₁, R₂, R₃, R₄, R, R₁₂ and A are as defined therein;

Patel, U.S. Patent No. 4,820,691, issued April 11, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁ and R₃ are as defined therein; Thaisrivongs, U.S. Patent No. 4,705,846, issued November 10, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-E₁₀-F₁₁-G₁₂-H₁₃-I₁₄-Z

wherein E₁₀, F₁₁, G₁₂, H₁₃, I₁₄ and Z are as defined therein;

Hudspeth, et al., U.S. Patent No. 4,743,585, issued May 10, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-T-(C)_n-W-(D)_n-V-(E)_n-U

wherein T, C, W, D, V, E, U and n are as defined therein;

Hudspeth, et al., U.S. Patent No. 4,735,933, issued April 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-Y-W-U

wherein Y, W and U are as defined therein;

Kaltenbronn, et al., U.S. Patent No. 4,804,743, issued February 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula -T-U-V-W

wherein T, U, V and W are as defined therein;

Pinori, et al., U.S. Patent No. 4,560,505, issued December 24, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein Tyr and Lys are as defined therein;

Yamato, et al., U.S. Patent No. 4,683,220, issued July 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

Boger, et al., U.S. Patent No. 4,668,770, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃, R₄, q, B, D and E are as defined therein;

Boger, U.S. Patent No. 4,668,663, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃, R₄, m', E, B and F are as defined therein;

Bock, et al., U.S. Patent No. 4,636,491, issued January 13, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃, R₄, m' and E are as defined therein; Bock, et al., U.S. Patent No. 4,663,310, issued May 5, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein G, R₄, J, B and L are as defined therein;

Boger, et al., U.S. Patent No. 4,661,473, issued April 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein G, R₄, J, B and L are as defined therein;

Veber, et al., U.S. Patent No. 4,479,941, issued October 30, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄ and E are as defined therein; Boger, et al., U.S. Patent No. 4,470,971, issued September 11, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄, R₅, B and E are as defined therein;

Veber, et al., U.S. Patent No. 4,384,994, issued May 24, 1983, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₂, R₃, R₄ and B are as defined therein;

Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-G-J

wherein G and J are as defined therein; Evans, U.S. Patent No. 4,665,055, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, B and C are as defined therein;

Evans, et al., U.S. Patent No. 4,609,641, issued September 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₁, R₂, X, Y, B and C are as defined therein;

Patchett, et al., U.S. Patent No. 4,839,357, issued June 13, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

-G-J

wherein G and J are as defined therein; Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-G-J

wherein G and J are as defined therein;

Boger, U.S. Patent No. 4,665,052, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃, R₄, R₅, m and F are as defined therein;

Veber, et al., U.S. Patent No. 4,478,826, issued October 23, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄, R_4a, B and E are as defined therein;

Boger, et al., U.S. Patent No. 4,485,099, issued November 27, 1984, which is hereby incorporated by reference. discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄, R₅, m and F are as defined therein;

Boger, et al., U.S. Patent No. 4,477,440, issued October 16, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₃, R₄, m", E, F and G are as defined therein;

Raddatz, et al., U.S. Patent No. 4,721,776, issued January 26, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₂, R₃, R₄, R₅, n, B and D are as defined therein; Holzemann, et al., U.S. Patent No. 4,709,010, issued November 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, R₁, R₂, n and Y are as defined therein;

Raddatz, et al., U.S. Patent No. 4,812,555, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of

angiotensinogen having the formula

wherein R₂, R₃, R₄, n and E are as defined therein;

Raddatz, et al., U.S. Patent No. 4,755,592, issued July 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-W-E-W'-Y

wherein W, E, W' and Y are as defined therein;

Raddatz, et al., U.S. Patent No. 4,666,888, issued May 19, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, E, G and Y are as defined therein;

Wagnon, et al., U.S. Patent No. 4,840,935, issued June 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, Q and X are as defined therein;

Iizuka, et al., U.S. Patent No. 4,841,067, issued June 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n and X are as defined therein; Raddatz, et al., U.S. Patent No. 4,829,053, issued May 9, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-N(R₂)-CH(R₃)-CR₄-(CHR₅)_n-C(O)-E-N(R₆)-(CH(R₇))_s-D wherein n, s, R₂, R₃, R₄, R₅, R₆, R₇, E and D are as defined therein;

European Patent Application No. EP0264106, published April 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, R₆ and R₇ are as defined therein including R₄ is hydrogen or loweralkyl; R₅ is hydrogen, loweralkyl or an amino acid residue; R₆ is loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and R₇ is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or an N-heterocycle;

European Patent Application No. EP0272583, published June 29, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₅, R₆, R₇ and R₈ are as defined therein including R₅ is hydrogen or loweralkyl; R₆ is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an amino acid residue; and R₇ and R₈ are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl;

European Patent Application No. EP0309766, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₅, R₆ and A are as defined therein including R₅ is hydrogen or loweralkyl; R₆ is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or

heterocyclic; and A is -CH(OH)-(CH)_q-R₇ wherein q is 0-5 and R₇ is hydrogen, loweralkyl, cycloalkyl,

cycloalkylalkyl, aryl, arylalkyl, heterocyclic,

substituted thioalkyl, substituted sulfone, substituted sulfoxide, substituted amine, quaternized amine,

heterocyclic, carboxyalkyl, alkoxycarbonylalkyl or

amidoalkyl; European Patent Application No. EP0300189, published January 25, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄ is as defined therein including R₄ is

loweralkyl;

European Patent Application No. EP0283970, published

September 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄ is as defined therein including R₄ is

loweralkyl;

European Patent Application No. EP0255082, published

February 3, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃ and R₄ are as defined therein including R₂ is hydrogen, alkyl, cyclcoalkyl, cycloalkylalkyl, aryl or arylalkyl; R₃ is hydrogen, alkyl or arylalkyl; and R₄ is -X-(CH₂)n'^_R₇ wherein X is absent, O or S, n' is 0-4 and R₇ is hydrogen, hydroxy, amino, heteroaryl or -CH(R₉) -(CH₂)_p- Y-(CH₂)_q-R₁₀ wherein p, q, Y and R₁₀ are as defined therein;

European Patent Application No. EP0230242, published July 29, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃ and R₄ are as defined therein including R₂ is hydrogen, alkyl, cycloalkylalkyl, aryl or arylalkyl; R₃ is hydrogen, alkyl or alkenyl; and R₄ is -N(Rs) -CH(R₆) - (CH₂)_n-Ar or -N(R₅)-CH(R₆)-CH-CH-(CH₂)_m-Ar wherein n is 0-6, m is 0-4, R₅ is hydrogen or alkyl and R₆ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, thioalkoxyalkyl,

carboxyalkyl, alkoxycarbonylalkyl, haloalkyl,

alkylaminoalkyl, alkoxycarbonylaminoalkyl or

arylalkoxycarbonylaminoalkyl; European Patent Application No. EP0310015, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃, R₄ and R₉ are as defined therein including R₂ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R₃ is hydrogen, alkyl, aryl or arylalkyl; R₉ is hydroxy or fluoro; and R₄ is - (CH₂)_p-X- (CH₂)_q-R₇ wherein p is 0-4, q is 0-4, X is -CF₂-, -C(O)- or -CH(R₈)- wherein R₈ is alkyl, alkoxy, thioalkoxy, alkylamino, hydroxy, azido or halo and R₇ is hydrogen, hydroxy, amino, aryl or heteroaryl;

European Patent Application No. EP0315574, published May 10, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

(B is a boron atom)

wherein R₂, X, Y, R₃ and R₄ are as defined therein

including R₂ is hydrogen, alkyl, cycloalkyl,

cycloalkylalkyl, aryl or heterocyclic; X and Y are

independently selected from O or -N(R₁₃)- wherein R₁₃ is hydrogen, alkyl or substituted alkyl; and R₃ and R₄ are independently selected from hydrogen, alkyl or aryl; or the boron containing substituent is a boron containing cyclic group;

Japanese Patent Application No. J63275552, published

November 14, 1988 discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

European Patent Application No. EP0252727, published

January 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Y and R are as defined therein including Y is O or NH and R is alkyl, cycloalkyl or halogenated alkyl;

European Patent Application No. EP0244083, published

November 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X is as defined therein including X is alkoxy, alkyalamino, cycloalkyloxy, morpholino and haloalkoxy.

European Patent Application No. EP0216539, published April 1, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Y and R₂ are as defined therein including n is 0-1, Y is O or NH and R₂ is alkyl;

European Patent Application No. EP0206807, published

December 30, 1986, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein n, Z and R are as defined therein including n is 0-1, Z is 0 or NH and R is alkyl; European Patent Application No. EP0190891, published

August 13, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n and X' are as defined therein including n is 0-1 and X' is alkoxycarbonyl, aralkoxycarbonyl, or -C(O)NR₁R₂ wherein R₁ is hydrogen, alkyl or aralkyl and R₂ is alkyl or -CH₂-Y-R wherein Y is O or NH and R is alkyl or aralkyl;

European Patent Application No. EP0181110, published May 14, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃ and R₄ are as defined therein including R₃ is -CHO or -CH₂OH and R₄ is isobutyl or benzyl;

European Patent Application No. EP0297816, published

January 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₁ and R₂ are as defined therein including n is 0-1, R₁ is -NH₂, alkylamino, alkoxy, or

2-alkoxycarbonylpyrrolidin-1-yl and R₂ is alkyl, alkenyl, haloalkenyl or azide substituted alkenyl;

European Patent Application No. EP0297815, published January 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Y and R₂ are as defined therein including Y is -CH(OH)- or -C(O)- and R₂ is -CF₂C(O)NHCH₃, -CF₃ or

-CF₂C(CH₂CH(CH₃)₂)CO₂C₂H₅;

European Patent Application No. EP0212903, published March 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, R₁, R₂, R₃, R₄ and W² are as defined therein including m is 0-1, R₁ and R₂ are independently selected from hydrogen, alkyl, alkenyl, phenyl, naphthyl,

cycloalkyl, cycloalkenyl, phenylalkyl, naphthylalkyl, cycloalkylalkyl and cycloalkenylalkyl, R₃ and R₄ are independently selected from alkyl, phenyl, naphthyl, cycloalkyl, adamantyl, phenylalkyl,naphthylalkyl,

cycloalkylalkyl and adamantylalkyl; or R₃ is hydrogen and R₄ is -CH(R₇) (CH₂)_p(Q)_rCH(R₈) (CH₂)_q-Y wherein p and q are independently selected from 0,1,2,3,4,5 and 6, r is 0-1, Q is -CH₂-, -CH=CH-, -O-, -NH-, -CH(OH)- or -C(O)-, Y is methyl, phenyl, -C(O)OR₉, -C(O)NR₉R₁₀, -C (O)NHC(O)OCH₂C₆H₅, -NH₂, -NHC(O)CH₂C₆H₅, -NHCH (CH₂C₆H₅)C(O)OR₉ or

-NHCH(CH₂C₆H₅)C(O)NR₉R₁₀ wherein R₉ and R₁₀ are

independently selecterd from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl, and R₇ and R₈ are independently selecterd from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl; or R₃ and R₄ taken together with the nitrogen to which they are attached form a pyrrole, indoline,

isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydroazepine or

morpholine ring; and W² is -NHCH((CH₂)₃R₆)-C(O)- wherein R₆ is -NH₂, -NHC(=NH)NH₂ or -CH₂NH₂;

PCT Patent Application No. WO 88/03022, published May 5, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Y and D are as defined therein including n is 0- 1, Y is isobutyl, allyl or benzyl and D is 2-carboxypyrrolidin-1-yl or -ZR wherein Z is 0 or NH and R is alkyl, phenyl or substituted alkyl or substituted phenyl;

German Patent Application No. DE3725137, published August 6, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, B and Y are as defined therein including R is hydrogen, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, arylalkyl, heteroaryl or

heteroarylalkyl, R₁ is hdyroxy, alkoxy or aryloxy, R₂ is hydrogen or R₁ and R₂ taken together is oxo (=O), R₃, R₄, R₅ and R₆ are independently selected from hydrogen, fluoro, chloro, alkyl, cycloalkyl, cycloalkylalkyl, aryl,

arylalkyl, heteroaryl and heteroarylalkyl, B is a peptide chain containing from 1 to 10 amino acid residues and Y is hydroxy or a protecting group for the peptide carboxy group; British Patent Application No. GB2203740, published

October 26, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₂, R₃, R₄ and B are as defined therein

including R₁ is a hdyrophobic or hydrophilic side chain, R₂ is hydroxy or amino, R₃ is hydrogen or R₂ and R₃ taken together is oxo (=O) , R₄ is a hydrophobic or hydrophilic side chain and B is

-NHCH(R₆)C(R₇)(R₈)C(R₉)(R₁₀)CH₂C(O)N_R11R₁₂ wherein R₆ is R₁ , R₇ and R₈ are the same as R₂ and R₃, R₉ and R₁₀ are

independently selected from hydrogen and fluoro and R₁₁ and R_l2 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH(R₁₃)C(O)R₁₄ wherein R₁₃ is alkyl or hydroxyalkyl and R₁₄ is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl;

British Patent Application No. GB2200115, published July 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

R₁, R₂, R₃, R₄, R₅, D and Y are as defined therein

including R₁ is hydrogen or alkyl, R₂ is an amino acid side chain, R₃ is hydrogen, hydroxy, aryloxy or amino, R₄ and R₅ are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH(R₁₂)C(O)R₁₃ wherein R₁₂ is alkyl or hydroxyalkyl and R₁₃ is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl; or -NR₄R₅ represents

pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or substituted piperazinyl; D is a bond, O, -N(R₁)- or

-CH(R₁)- and Y is -C(O)-, -S(O)₂- or -P(O)-;

German Patent Application No. DE3830825, published March 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and χ are as defined therein including R₄ is a hydrophilic or hydrophobic amino acid side chain, R₅ is hydroxy or amino. R₆ is hydrogen or R₅ and R₆ taken together are oxo (=O), R₇ and R₈ are independently selected from hydrogen and fluoro, R₉ and R₁₁ are independently selected from hydrogen, alkyl and

-CH(R₁₁)C(O)R₁₂ wherein R₁₁ is alkyl or hydroxyalkyl and R₁₂ is hdyroxy, alkoxy, amino, alkylamino, aminomthylpyridyl, benzyl or -NH- (CH₂CH₂O)_m-R₁ wherein m is 1-20 and R₁ is as defined therein; and X is a bond or O, NH or -C(R₁₃) (R₁₄)- wherein R₁₃ and R₁₄ are independently selected from

hydrogen, fluoro or R₄; Japanese Patent Application No. J62246546, published October 27, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, R₄ and R₅ are as defined therein including m is

0-1, R₄ is alkyl, cycloalkyl or phenyl and R₅ is alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0274259, published July 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₄ and R₅ are as defined therein including R₄ is alkyl, hydroxyalkyl, (heterocyclic) alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and R₅ is hydrogen or alkyl;

European Patent Application No. EP0228192, published July 8, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, n, R₅, R₆ and R₇ are as defined therein

including m and n are independently selected from 0 and 1, R₅ is alkyl, cycloalkyl or phenyl. R₆ is alkyl and R₇ is alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0273893, published July 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₅, R₆ and Y are as defined therein including R₅ is alkyl or cycloalkyl. R₆ is hydrogen or alkyl and Y is -SCH(CH₃)₂ or -S(O)₂CH(CH₃)₂;

European Patent Application No. EP0310070, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₅ and R₇ are as defined therein including R₁ is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,

alkylcycloalkenyl or alkoxycarbonyl, R₅ is hydrogen or alkyl and R₇ is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0310071, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

European Patent Application No. EP0310072, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

alkylcycloalkenyl or alkoxycarbonyl, R₅ is hydrogen or alkyl and R₇ is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl; European Patent Application No. EP0310073, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

European Patent Application No. EP0313847, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, R₅ and R₆ are as defined therein including R₁ is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,

alkylcycloalkenyl or alkoxycarbonyl, R₅ is hydrogen or alkyl and R₈ is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0296581, published

December 28, 1988, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein R₁ and R₃ are as defined therein including R₁ is hydrogen, arylalkyl, aryl, (heterocyclic) alkyl or

heterocyclic and R₃ is hydrogen, alkyl, haloalkyl,

arylalkyl, (heterocyclic) alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, thioalkoxyalkyl,

hydorxyalkoxyalkyl, aminoalkoxyalkyl,

hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl;

European Patent Application No. EP0231919, published

August 12, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁ and R₃ are as defined therein including R₁ is an N-heterocyclic ring and R₃ is hydrogen, alkyl,

cycloalkylalkyl, haloalkyl, arylalkyl, (heterocyclic)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, aminoalkyl,

mercaptoalkyl, tioalkoxyalkyl, hydroxyalkoxyalkyl,

aminoalkoxyalkyl, hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl; PCT Patent Application No. WO 87/05302, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-E₁₀-F₁₁-G₁₂-H₁₃-I₁₄-Z wherein E₁₀, F₁₁, G₁₂, H₁₃, I₁₄ and Z are as defined therein including -E₁₀-F₁₁- is

wherein R₁ is hydrogen, alkyl, aryl, cycloalkyl,

heterocyclic, alkoxy or thioalkoxy, R₁₁ is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,

arylalkyl, (heterocyclic) alkyl, alkoxyalkyl or

thioalkoxyalkyl, R₂₂ is hydrogen or alkyl and R₂₃ is hydroxyalkyl, aminoalkyl, aryl or alkyl, G₁₂ is absent or an amino acid residue, H₁₃ is absent or an amino acid residue, I₁₄ is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;

PCT Patent Application No. WO 87/02986, published May 21, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁ is hydrogen, alkyl, aryl, cycloalkyl,

arylalkyl, (heterocyclic)alkyl, alkoxyalkyl or

thioalkoxyalkyl, R₂₁ is hydroxy or amino, R₂₂ is hydrogen or alkyl and R₂₃ is hydroxy, amino, hydroxyalkyl,

aminoalkyl, aryl or alkyl, G₁₂ is absent or an amino acid residue, H₁₃ is absent or an amino acid residue, I₁₄ is absent or an amino acid residue and Z is hydroxy,

substituted alkoxy, substituted amino or cyclic amino;

PCT Patent Application No. WO 89/00161, published January 12, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₄, R₅, X, Y and Z are as defined therein including R₂ is hydrogen or alkyl, R₄ is hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, hydroxyalkyl or aminoalkyl, R₅ is hydrogen, alkyl, arylalkyl, (heterocyclic)alkyl or cycloalkyl, X is -CH(OH)-, -CH(NH₂)-, -C(O)-,

-CH(OH)CH(OH)-, -CH(OH)CH₂-, -CH (NH₂)CH₂-, -C (O) -CH₂-, -CH₂-NH-, -CH₂-O- or -P(O) (A)B- wherein A is hydroxy or amino and B is absent, O, NH or CH₂, Y is absent or

-NHCH(R₅)C(O)- and Z is hydroxy, substituted alkoxy, substituted amino or N-heterocyclic;

PCT Patent Application No. WO 88/07053, published

Septmeber 22, 1988, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein r, t, R₉₀, R₁₀₀, R₁₁₀, R₁₁₁, G₁₂, H₁₃, I₁₄ and Z are as defined therein including r is 0-3, t is 0-3, R₉₀ is hydrogen or alkyl, R₁₀₀ is hydrogen, alkyl, aryl,

cycloalkyl, heterocyclic, alkoxy or thioalkoxy, R₁₁₀ and R_1l1 are independently selected from hydrogen, alkyl, aryl, arylalkyl and halo, G₁₂ is absent, an amino acid residue or

wherein R₅₀ is hydrogen, alkyl, arylalkyl,

(heterocyclic) alkyl, cycloalkylalkyl or adamantyl, and R₆₀ and R₆₁ are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R₆₀ and R₆₁ taken together form a carbocyclic or heterocyclic

spirocycle, H₁₃ is absent an amino acid residue or

wherein R₅₀ is hydrogen, alkyl, arylalkyl,

(heterocyclic) alkyl, cycloalkylalkyl or adamantyl, and R₆₀ and R₆₁ are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R₆₀ and R₆₀ taken together form a carbocyclic or heterocyclic

spirocycle, I₁₄ is absent an amino acid residue or

wherein R₅₀ is hydrogen, alkyl, arylalkyl,

(heterocyclic)alkyl, cycloalkylalkyl or adamantyl, and R₆₀ and R₆₁ are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R₆₀ and R₆₁ taken together form a carbocyclic or heterocyclic

spirocycle and Z is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or cyclic amino;

PCT Patent Application No. WO 88/02374, published April 7, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula a) -E₁₀-F₁₁-C(=Y)-G₁₂-H₁₃-Z,

b) -E₁₀-F₁₁-W,

c) -E₁₀-F₁₁-G₁₂-H₁₃-W or

d) -E₁₀-F₁₁-G₁₂₁-H₁₃₁-I₁₄-Z wherein E₁₀, F₁₁, G₁₂, H₁3, G₁₂₁, H₁₃₁, I₁₄, W, Y and Z are as defined therein including -E₁₀-F₁₁- is

wherein R and R₁ are independently selected from alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy or thioalkoxy, R₁₁ is alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy, thioalkoxy, hydrogen, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl and thioalkoxyalkyl, R₂₂ is hydrogen or alkyl, R₂₃ is hydroxy, hydroxyalkyl, amino, aminoalkyl, aryl or alkyl, R₂₄ is aryl, amino, alkylamino, dialkylamino, trialkylamino, heterocyclic, hydroxy, alkoxy, alkanoyloxy, mercapto, carboxy, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, aminocarbonyl,

alkylaminocarbonyl, dialkylaminocarbonyl, cyclicamino, cycloalkylamino, guanidinyl, cyano, N-cyanoguanidinyl, cyanoamino, hydroxyalkylamino, di(hydroxyalkyl)amino, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, heterocyclicalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, mercaptoalkyl,

carboxyalkyl, alkoxycarbonylalkyl,

dialkylaminoalkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, cyclicaminoalkyl, cycloalkylaminoalkyl, guanidinylalkyl, cyanoalkyl, N-cyanoguanidinylalkyl, cyanoaminoalkyl, hydroxyalkylaminoalkyl or di(hydroxyalkyl)aminoalkyl, W₁ and W₂ are independently selected from hydroxy and amino, W₃ and W₄ are independently selected from hydrogen and fluoro, W is as defined therein, Y is O, S, NH or

-N (alkyl)-, Z is as defined therein, G₁₂ is absent or an amino acid residue, H₁₃ is absent or an amino acid

residue, G₁₂₁ is absent or an amino acid residue, H₁₃₁ is absent or an amino acid residue and I₁₄ is absent or an amino acid residue;

PCT Patent Application No. WO 86/06379, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-E-F-G-H-Z wherein E, F, G, H and Z are as defined therein including -E-F- is

wherein R_10a is hydrogen or alkyl, R_10b is alkyl,

cycloalkyl, cycloalkylalkyl, arylalkyl,

(heterocyclic)alkyl, cycloalkenyl or cycloalkenylalkyl, R_10c is hydrogen or alkyl, U is -C(O)-, -CH(OH)- or

-CH(NH₂)- and Wi and W₂ are independently selected from hydrogen, fluoro, chloro and bromo, G is absent or an amino acid residue, H is absent or an amino acid residue and Z is hydroxy, thiol, amino, substituted alkoxy, substituted thioalkoxy, substituted alkylamino, Lys-OH, Lys-NH₂, Ser-OH or Ser-NH₂;

European Patent Application No. EP0271862, published June 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-Y-W-U wherein Y, W and U are as defined therein including Y is Sta, Cysta or PhSta, W is Leu, Ile, N-MeLeu, Val or absent and U is -NHCH₂CH(CH₃) CH₂CH₃, -NHCH₂PΪ1,

-NHCH (CH₂OH) CH (CH₃) CH₂CH₃, -NHCH₂CH (OH) CH₂SCH (CH₃)₂,

-NHCH₂CH (OH) CH₂S (O) CH (CH₃)₂, -NHCH₂CH (OH) CH₂S(O)₂CH (CH₃)₂, -NHCH₂CH₂Ph, -NHCH₂(pyrid-2-yl), -NH₂, -NHCH₂CH=CH₂, -OEt, -OMe, -NH (piperidin-4-yl) ,

-

European Patent Application No . EP0275480, published July 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-W-U-V wherein W, U and V are as defined therein including W is Sta, PhSta or Cysta, U is absent. Leu, Ile, Val, N-MeLeu or N-Melle and V is -NHCH₂Ph, -NHCH₂-cyclohexyl,

-NH(piperidin-4-yl), -NHCH₂(pyrid-2-yl),

-NHCH₂CH(CH₃)CH₂CH₃, -OMe, -OEt, -NHCH(CH₂OH)CH(CH₃)CH₂CH₃, -NHCH₂CH₂ (morpholin-1-yl),

PCT Patent Application No. WO 88/03927, published June 2, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-T-(C)_n-W-(D)_n-V-(E)_n-U wherein T, C, W, D, V, E, U and n are as defined therein including nis 0-1, T is Sta, PhSta, Cysta, Leu,

CyclohexylAla or Phe, W is absent. Leu, Gly or Ile, V is absent. Leu or Ile, C is -CH₂NH-, -CH(OH)CH₂- or

-CH(OH)-CH=CH-C(O)-, D is -CH₂NH-, E is -CH₂NH- or

-CH₂N(Cbz)- and U is -NHCH₂Ph, -NHCH₂-cyclohexyl, -NH₂, -NH(piperidin-4-yl), -NHCH₂(pyrid-2-yl),

-NHCH₂CH(CH₃)CH₂CH₃, -OMe, -OEt,

European Patent Application No. EP0314060, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-W-U wherein W and U are as defined therein including W is Sta, Cysta, PhSta, ChSta, DFKSta, DFKCys, DFKChs, ASta or ACys and U is -NHCH₂CH₂(morpholin-1-yl), -NHCH₂CH(CH₃)CH₂CH₃, -NHCH (CH₂OH) CH (CH₃)CH₂CH₃, -LeuNHCH₂Ph,

-LeuNHCH₂-cyclohexyl, -LeuNH(piperidin-4-yl),

-LeuNHCH₂(pyrid-2-yl) or

European Patent Application No. EP0310918, published April 12, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃ and R₄ are as defined therein including R₃ is isobutyl, cyclohexylmethyl or benzyl and R₄ is phenyl, furyl, vinyl, ethyl or 1,2-dihydroxyethyl;

French Patent Application No. FR8700560, published July 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, U and B are as defined therein including R is hydrogen or hydroxyalkyl, U is Leu, Ala, Val or Ile and B is pyridyl;

European Patent Application No. EP0236948, published September 16, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X is as defined therein including X is isobutyl or benzyl;

European Patent Application No. EP0281316, published September 7, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃, R₄ and R₅ are as defined therein including R₃ is allyl, cyclohexyl or phenyl, R₄ is nitromethyl,

alkoxycarbonyl or -CH₂S(O)_n-R^dwherein n is 0-2 and R^d is heterocyclic and R₅ is hydrogen or alkyl;

German Patent Application No. DE3825242, published

February 9, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₃ and Z are as defined therein including R₃ is hydroxy or amino and Z is substituted carbonyl, substituted thiocarbonyl, substituted iminocarbonyl or unsubstituted or substituted phosphono, aminomethyl, thiomethyl,

sulfinylmethyl, sulfonylmethyl or phosphonomethyl;

European Patent Application No. EP0275101, published July 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₂, R₃, R_a, R_b, n, χ and Q are as defined therein including R₂ is an amino acid side chain, R₃ is hydrogen, alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl,

2-pyridylmethyl or an amino acid side chain, R_a is an amino acid side chain, Rb is hydrogen or alkyl or R_a and R_b taken together are -CH₂-CH₂-, n is 1-10, X is hydrogen, CH₂, alkoxy, substituted alkoxy, alkyl, phenyl, benzyl,

cyclohexyl, cyclohexylmethyl or 2-pyridylmethyl and Q is hydrogen, alkyl, arylakyl, alkoxycarbonyl or an amino acid residue; PCT Patent Application No. WO 89/01488, published February 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-E₁₀-F₁₁-G₁₂-H₁₃-I₁₄-Z wherein E₁₀, F₁₀, G₁₂, H₁₃, I₁₄ and Z are as defined therein including -E₁₀-F₁₁- is

wherein R₁ is hydrogen, alkyl, aryl, cycloalkyl,

heterocyclic, alkoxy or thioalkoxy, Rχι is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,

arylalkyl, (heterocyclic) alkyl, alkoxyalkyl or

aminoalkyl, aryl or alkyl, R₂₄ is R₁ hydroxy, amino, hydroxyalkyl or aminoalkyl, G₁₂ is absent or an amino acid residue, H₁₃ is absent or an amino acid residue, I₁₄ is absent or an amino acid residue and Z is hydroxy,

substituted alkoxy, substituted amino or cyclic amino;

wherein R₁, G₁₂, H₁₃ and X are as defined therein including R1 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, G₁₂ is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O, H₁₃ is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O and X is hydrogen, alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0312291, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R₁, Y, X and E are as defined therein including R₁ is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, X is -CH₂-C(R₁₃)(R₁₄)- wherein R₁₃ and R₁₄ are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,

substituted alkyl, alkanoyloxy, substituted

aminocarbonyloxy, substituted carbonylamino, substituted aminocarbonylamino, substituted sulfinyl, substituted sulfonyl, substituted sulfide, amino, alkylamino,

dialkylamino or heterocyclic, Y is CH₂, O, S, SO or SO₂ or X and Y taken together is -(CH₂)₄- and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl; European Patent Application No. EP0312283, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R1, X and E are as defined therein including R₁ is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, X is -CH₂-C(R₁₃)(R₁₄)- wherein R₁₃ and R₁₄ are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,

substituted alkyl, alkanoyloxy, substituted

dialkylamino or heterocyclic and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl;

European Patent Application No. EP0312158, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R₇, R₄, R₁₁, R₉, R_10a, Q and J are as defined therein including r is 1-4, R₇ is alkyl, aryl or cycloalkyl, _R4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, R₁₀ and R_10a are independently selected from hydrogen and alkyl, R₉ is -(CH₂)_s-NR₁₁R₁₂ wherein s is 1-2 and R₁₁ and R₁₂ are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic) alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl

substituted by -SO₃H, aminocarbonylalkyl,

alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is -CH(OH)-, -CH(N(R₈))-, -CH(OH)CH₂- or -CH(N(R₈))CH₂- wherein R₈ is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino or substituted alkoxy;

European Patent Application No. EP0312157, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R₇, R₄, R_10, R₉, R_10a, Q and J are as defined therein including r is 1-4, R₇ is alkyl, aryl or

cycloalkyl, R₄ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, R₁₀ and R_10a are independently selected from hydrogen and alkyl, R₉ is - (CH₂)_s-NR₁₁R₁₂ wherein s is 1-2 and R₁₁ and R₁₂ are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic)alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl substituted by -SO₃H, aminocarbonylalkyl,

alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is -CH(OH)-, -CH(N(R₈))-, -CH(OH)CH₂- or -CH(N(R₈))CH₂- wherein R₈ is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino, substituted alkoxy,

heterocyclic, heterocyclicamino or substiute guanidino;

European Patent Application No. EP0314239, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R₇, R₄, Q and J are as defined therein including r is 1-4, R₇ is alkyl, aryl or cycloalkyl, R₄ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, Q is -CH(OH)-, -CH(N(R₈))-, -CH(OH)CH₂- or -CH(N(R₈))CH₂- wherein R₈ is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is amino, hydroxy, substituted alkylamino or substituted alkoxy;

South African Patent Application No. 866642, published February 24, 1987, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein R' and R" are as defined therein including R' is fluoro and R" is hydrogen or fluoro;

European Patent Application No. EP0273696, published July 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₂, R₁₀ and E are as defined therein including n is 0-5, R₂ is hydrogen or alkyl, R₁₀ is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic) alkyl,

alkoxyalkyl, thioalkoxyalkyl, hydroxyalkyl or aminoalkyl and E is -CH(W)-G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O)-T-U-V wherein Q is a bond or -CH(R₁₃)- wherein R₁₃ is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;

European Patent Application No. EP0278158, published

August 17, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₇, R₁₀ and E are as defined therein including n is 0-3, R₇ is alkyl or substituted alkyl, R₁₀ is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl,

(heterocyclic) alkyl, alkoxyalkyl, thioalkoxyalkyl,

hydroxyalkyl or aminoalkyl and E is -CH(W)-G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O)-T-U-V wherein Q is a bond or -CH(R₁₃)- wherein R₁₃ is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;

German Patent Application No. DE3721855, published

September 22, 1988, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein n, R₂, R₃, R₄, R₅, R₆, E and D are as defined therein including n is 1-2, R₂ is hydrogen or alkyl, R₃ is hydrogen, alkyl, aryl, arylalkyl, (heterocyclic) alkyl, cycloalkyl, alkoxy or cycloalkylalkyl, R₄ is (H,OH),

(H,NH₂) or O, R₅ is hydrogen or alkyl. R₆ is hydrogen or alkyl, E is 0-2 amino acid residues and D is

-CH₂CHOHCH₂OH, substituted sulfonyl, substituted

sulfonylalkyl, substituted carbonyl, substituted phosphonyl, phenyl, phenylalkyl, furyl, furylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl or other (heterocyclic)alkyl;

European Patent Application No. EP0309841, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₃, R₄, R₅, R₆ and E are as defined therein including n is 1-2, R₃ is hydrogen or alkyl, R₄ is

hydrogen, alkyl, aryl, arylalkyl, heterocyclic,

(heterocyclic)alkyl, cycloalkyl, alkoxy or

cycloalkylalkyl, R₅ is (H,OH), (H,NH₂) or O, R₆ is

hydrogen, alkyl or alkenyl and E is -SR₇, -SOR₇, -SO₂R₇, -SO₂OR₇ or -SO₂NR₇R₈ wherein R₇ and R₈ are independently selected from R₄;

European Patent Application No. EP0292800, published

November 30, 1988, discloses mimics of the Leu-Val

cleavage site of angiotensinogen having the formula

wherein n, R₃, R₄, R₅, R₆, E, Q and Y are as defined therein including n is 1-2, R₃ is hydrogen or alkyl, R₄ is hydrogen, alkyl, aryl, arylalkyl, heterocyclic. (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R₅ is (H,OH), (H,NH₂), or O, R₆ is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl;

European Patent Application No. EP0249096, published

December 16, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₃, R₄, R₅, R₆, E, Q and Y are as defined therein including n is 1-2, R₃ is hydrogen or alkyl, R₄ is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,

(heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R₅ is (H,OR₁₂), (H,NR₁₂R₁₃), or O wherein R₁₂ and R₁₃ are independently selected from hydrogen and alkyl. R₆ is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl; and

European Patent Application No. EP0264795, published April 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R₂, R₃, R₄, E and Y are as defined therein including n is 1-2, R₂ is hydrogen or alkyl, R₃ is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,

(heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or

alkoxy, R₄ is hydrogen or alkyl, E is -C(O)NH-, -C(S)NH-, -C(O)O-, -SO2-, -SO2NH-, or -PO(OA)O- wherein A is

hydrogen or alkyl and Y is carboxy, carboxyalkyl,

substituted carboxyalkyl, alkoxycarbonyl,

alkoxycarbonylalkyl, substituted alkoxycarbonylalkyl, aminocarbonyl, substituted aminocarbonyl,

aminocarbonylalkyl, substituted aminocarbonylalkyl,

hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or

cycloalkylalkyl; or E-Y is pyrrolidinocarbonyl,

piperidinocarbonyl, morpholinocarbonyl,

pyrrolidinosulfonyl, piperidinosulfonyl or

morpholinosulfonyl.

The term "substituted amino" as used herein refers to:

I) alkylamino,

II) dialkylamino,

III) (hydroxyalkyl)(alkyl)amino,

IV) (dihydroxyalkyl)(alkyl)amino,

V) alkoxycarbonylalkylamino,

VI) carboxyalkylamino,

VII) (amino)carboxyalkylamino,

VIII) ((N-protected)amino)carboxyalkylamino,

IX) (alkylamino)carboxyalkylamino,

X) ( (N-protected)alkylamino)carboxyalkylamino,

XI) (dialkylamino)caboxyalkylamino,

XII) (amino)alkoxycarbonylalkylamino,

XIII) ((N-protected)amino)alkoxycarbonylalkylamino,

XIV) (alkylamino)alkoxycarbonylalkylamino,

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

XVI) (dialkylamino)alkoxycarbonylalkylamino,

XVII) (alkoxyalkyl)(alkyl)amino,

XVIII) (alkoxyalkoxyalkyl)(alkyl)amino,

XIX) di-(alkoxyalkyl)amino,

XX) di-(alkoxyalkoxyalkyl)amino,

XXI) di-(hydroxyaIkyl)amino,

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

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

wherein aa is 1 to 5 and R₆ and R₇ 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,

wherein dd is 1 to 5,

and

18) R₈-Z- wherein

Z is O, S or NH and R₈ is a C₁ to C₆ straight or branched carbon chain

substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic;

wherein R₉ is

1) O,

2) S,

3) SO₂ or

4 ) C=O ; or

wherein R₁₀ is

1) hydrogen,

2) loweralkyl,

3) an N-protecting group or

4) R₁₁-C(O)- wherein R₁₁ is

aminoalkyl, (N-protected)aminoalkyl, 1- amino-2-phenylethyl or 1-(N- protected)amino-2- phenylethyl.

The term "substituted methylene group" as used herein refers to:

(I) -CHR₁₃ R₁₄ wherein

1) R₁₃ is

i) hydrogen or

ii) hydroxy

and

2) R ₁₄ is

i) hydrogen,

ii) loweralkyl,

iii) hydroxy,

iv) hydroxyalkyl,

v) alkoxy,

vi) alkoxyalkyl,

vii) azido,

viii) azidoalkyl,

ix) amino. x) (N-protected)amino,

xi) aminoalkyl,

xii) (N-protected)aminoalkyl,

xiii) alkylamino,

xiv) (N-protected)(alkyl)amino, xv) alkylaminoalkyl,

xvi) (N-protected)(alkyl)- aminoalkyl,

xvii) dialkylamino,

xviii) dialkylaminoalkyl,

xix) carboxyalkyl,

xx) thioalkoxy,

xxi) thioalkoxyalkyl,

xxii) alkylsulfonyl,

xxiii) alkylsulfonylalkyl,

xxiv) thioaryloxy,

xxv) thioaryloxyalkyl,

xxvi) arylsulfonyl,

xxvii) arylsulfonylalkyl,

xxviii) (unsubstituted heterocyclic)- alkyl,

xxix) (substituted heterocyclic)alkyl, xxx) cycloalkyl or

xxxi) cycloalkylalkyl,

such that when R₁₃ is hydroxy then R₁₄ is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected)amino, (N-protected)(alkyl)amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R₁₃ is hydrogen then R₁₄ is not hydrogen or loweralkyl;

(II) -C(=CH₂)C(O)NHR₁₅,

(III) -C(OH)(R₁₆)C(O)NHR₁₅ or (IV) -CH(R₁₆)C(O)NHR₁₅ wherein

1) R is

i) loweralkyl,

ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl,

v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl,

viii) heterocyclic or ix) (heterocyclic)alkyl and 2) R₁₆ is

i) hydrogen,

ii) loweralkyl,

iii) hydroxyalkyl, iv) haloalkyl or

v) azidoalkyl;

wherein

1) t is 0 to 3,

2) R₂₀ ^is

i) CH₂ or

ii) N and

3) R₂₁ is

i) NH,

ii) O,

iii) S or iv) SO₂,

such that when t is 0 then R₂₀ is CH₂ and

when t is 1 to 3 then R₂₀ is N,

(VI) -CH₂CH(R₂₂)C(O)NHR₂₃ wherein

1) R₂₂ is

i) loweralkyl or

ii) cycloalkylalkyl

and

2) R₂₃ is

i) loweralkyl,

ii) hydroxyalkyl,

iii) alkoxyalkyl,

iv) aminoalkyl,

v) alkylaminoalkyl,

vi) dialkylaminoalkyl,

vii) aryl,

viii) arylalkyl

ix) heterocyclic,

x) (heterocyclic) alkyl or

wherein

a) u is 0 to 3,

b) R₂₄ is CH₂ or N and c) R₂₅ is NH, O, S or

SO₂,

such that when u is 0 then R₂₄ is CH₂ and when u is 1 to 3 then R₂₄ is N;

wherein

1) R₂₂ is as defined above and

2) R₇₄ is

i) hydrogen,

ii) loweralkyl,

iii) an N-protecting group or iv) R₇₅-C(O)- wherein R₇₅ is

aminoalkyl or (N-protected)- aminoalkyl;

wherein

1) R₂₆ is

i) loweralkyl or

ii) cycloalkylalkyl and

2) R₂₇ is

i) loweralkyl or

ii) cycloalkylalkyl;

(IX) -CH₂CH(R₈₁)NHC(O)R₈₂ or

-CH₂CH(R₈₁)NHS(O)₂R₈₂ wherein

1) R₈₁ is

i) loweralkyl or

ii) cycloalkylalkyl and 2) R₈₂ is

i) loweralkyl,

ii) alkoxy,

iii) alkylamino,

iv) dialkylamino,

v) -OR₁₀₀ wherein R₁₀₀ is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or (heterocyclic)alkyl or

wherein R₂₁ is

as defined above;

(X) -CH₂NHC(O)R₈₂ or -CH₂NHS(O)₂R₈₂ wherein R₈₂ is as defined above; or

(XI) -CF₂CH(OH)R₈₃ wherein R₈₃ is

loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl,

heterocyclic or (heterocyclic)alkyl.

The compounds of the invention contain two or more asymmetric carbon atoms and thus can exist as pure diastereomers, mixtures of distereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention includes within its scope all of the isomeric forms. The terms "R" and "S" configuration as used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. When stereochemical designators are followed by " * " , for example "R*" or "S*", the configuration of the carbon atom is meant to be the relative configuration and not the absolute configuration.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, pivaloyl, t-butylacetyl, trichloroethoxycarbonyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or Daminoacyl residue, which may itself be N-protected similarly.

The term "loweralkyl" as used herein refers to

straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "loweralkenyl" as used herein refers to a loweralkyl radical which contains at least one carbon-carbon double bond.

The term "aminoalkyl" as used herein refers to -NH₂ appended to a loweralkyl radical.

The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical.

The term "alkylamino" as used herein refers to a loweralkyl radical appended to an NH radical.

The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms.

The term "cycloalkylalkyl" as used herein refers to an cycloalkyl group appended to a loweralkyl radical, including, but not limited to cyclohexylmethyl and the like.

The term "cycloalkenyl" as used herein refers to an aliphatic ring having 3-7 carbon atoms and also having at least one carbon-carbon double bond including, but not limited to, cyclohexenyl and the like..

The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₃₀O- and R₃₀S-, respectively, wherein R₃₀ is a loweralkyl group or a cycloalkyl group.

The term "alkoxyalkoxy" as used herein refers to an alkoxy group appended to an alkoxy radical, including, but not limited to methoxymethoxy and the like.

The term "((alkoxy)alkoxy)alkoxy" as used herein refers to an alkoxy group appended to an alkoxy group which is itself appended to an alkoxy radical including, but not limited to, methoxyethoxymethoxy and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical.

The term "(thioalkoxy)alkyl" as used herein refers to thioalkoxy appended to a loweralkyl radical.

The term "dialkylamino" as used herein refers to - NR₃₁R₃₂ wherein R₃₁ and R₃₂ are independently selected from loweralkyl groups.

The term "((alkoxy)alkoxy)alkyl" refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.

The term "((alkoxy)alkoxy)alkoxyalkyl" as used here refers to an ((alkoxy)alkoxy)alkoxy group appended to a loweralkyl radical including, but not limited to,

methoxyethoxymethoxymethyl and the like.

The term "(hydroxyalkyl)(alkyl)amino" as used herein refers to -NR₃₃R₃₄ wherein R₃₃ is hydroxyalkyl and R₃₄ is loweralkyl.

The term "alkylamino" as used herein refers to -NHR₂₀₀ wherein R₂₀₀ is a loweralkyl group.

The term "dialkylamino" as used herein refers to -NR₂₀₁R₂₀₂ wherein R₂₀₁ and R₂₀₂ are independently selected from loweralkyl.

The term "(N-protected)(alkyl)amino" as used herein refers to -NR₃₄R₃₅ wherein R₃₄ is a loweralkyl group and R₃₅ is an N-protecting group.

The term "N-protected aminoalkyl" as used herein refers to NHR₃₅ appended to a loweralkyl group, wherein R₃₅ is an N-protecting group.

The term "alkylaminoalkyl" as used herein refers to NHR₃₆ appended to a loweralkyl radical, wherein R₃₆ is a loweralkyl group.

The term "(N-protected)(alkyl)aminoalkyl" as used herein refers to NR₃₅R₃₆, which is appended to a loweralkyl radical, wherein R₃₅ and R₃₆ are as defined above.

The term "dialkylaminoalkyl" as used herein refers to NR₃₉R₄₀ is appended to a loweralkyl radical wherein R₃₉ and R₄₀ are independently selected from loweralkyl.

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

The term "alkoxycarbonylalkyl" as used herein refers to R₄₁COR₄₂- wherein R₄₁ is an alkoxy group and R₄₂ is 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 -NHR₄₃ wherein R₄₃ 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 -NR₄₃R₄₄ wherein R₄₃ is as defined above and R₄₄ is a loweralkyl group.

The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR₄₅R₄₆ wherein R₄₅ and R₄₆ 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)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR₄₃ wherein R₄₃ is as defined above.

The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above. The term "((N-protected)alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR₄₃R₄₄ wherein R₄₃ and R₄₄ are as defined above.

The term "(dialkylamino)alkoxycarbonyalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR₄₅-R₄₄ wherein R₄₅ and R₄₄ are as defined above.

The term "carboxyalkylamino" as used herein refers to -NHR₄₇ wherein R₄₇ is a carboxyalkyl group.

The term "alkoxycarbonylalkylamino" as used herein refers to -NHR₄₈ wherein R₄₈ is an alkoxycarbonylakyl group.

The term "(amino)carboxyalkylamino" as used herein refers to -NHR₄₉ wherein R₄₉ is an (amino)carboxyalkyl group.

The term "((N-protected)amino)carboxyalkylamino" as used herein refers to -NHR₅₀ wherein R₅₀ is an ((N-protected)amino)carboxyalkyl group.

The term" (alkylamino)carboxyalkylamino" as used herein refers to -NHR₅₁ wherein _R51 is an (alkylamino)carboxyalkyl group.

The term "((N-protected)alkylamino)-carboxyalkylamino" as used herein refers to -NHR₅₂ wherein R₅₂ is an ((N-protected)alkylamino)carboxyalkyl group.

The term "(dialkylamino)carboxyalkylamino" as used herein refers to -NHR₅₃ wherein R₅₃ is a

(dialkylamino)carboxyalkyl group. The term" (amino)alkoxycarbonylalkylamino" as used herein refers to -NHR₅₄ wherein R₅₄ is an

(amino) alkoxycarbonylalkyl group.

The term "((N-protected)amino)alkoxycarbonylalkylamino" as used herein refers to -NHR₅₅ wherein R₅₅ is an ((N-protected)amino)alkoxycarbonylalkyl group.

The term "(alkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR₅₆ wherein R₅₆ is an

(alkylamino)alkoxycarbonylalkyl group.

The term "((N-protected)alkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR₅₇ wherein R₅₇ is an ((N-protected)alkylamino)alkoxycarbonylalkyl group.

The term "(dialkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR₅₈ wherein R₅₈ is a (dialkylamino)alkoxycarbonylalkyl group.

The term "polyalkoxy" as used herein refers to -OR₅₉ wherein R₅₉ is a straight or branched chain containing 1-5, C_gg-O-C_hh linkages wherein gg and hh are independently selected from 1 to 3, including, but not limited to

methoxyethoxymethoxy, ethoxyethoxymethoxy and the like.

The term "(dihydroxyalkyl)(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 "NR₆₀R₆₁ wherein R₆₀ and R₆₁ are hydroxyalkyl residues. The term "alkoxyalkyl(alkyl)amino" as used herein refers to -NR₆₂R₆₃ wherein R₆₂ is an alkoxyalkyl group and R₆₃ is a loweralkyl group.

The term "di- (alkoxyalkyl) amino" as used herein refers to -NR₆₄R₆₅ wherein R₆₄ and R₆₅ are alkoxyalkyl groups.

The term "(alkoxyalkoxyalkyl)(alkyl)amino" as used herein refers to -NR ₆₆R₆₇ wherein R₆₆ is an

alkoxyalkoxyalkyl group and R₆₇ is a loweralkyl group.

The term "di-(alkoxyalkoxyalkyl)amino" as used herein refers to -NR₆₈R₆₉ wherein R₆₈ and R₆₉ are

alkoxyalkoxyalkyl groups .

The terms "((unsubstituted

heterocyclic)alkyl)(alkyl)amino and ((substituted

heterocyclic)alkyl)(alkyl)amino" as used herein refer to an amino radical substituted by a loweralkyl group and an (unsubstituted heterocyclic)alkyl group or a (substituted heterocyclic)alkyl group, respectively.

The term "(heterocyclic)alkyl" or "heterocyclic ring substituted alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazolylmethyl and thiazolylmethyl.

The term "azidoalkyl" as used herein refers to -N₃ appended to a loweralkyl radical.

The term "alkylsulfonyl" as used herein refers to R₇₀S(O)₂- wherein R₇₀ is a loweralkyl residue.

The term "alkylsulfonylalkyl" as used herein refers to an alkylsulfonyl group appended to a loweralkyl radical.

The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; or "aryl" refers to a heterocyclic aromatic ring as defined below. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, naphthylmethyl and the like.

The terms "aryloxy" and "thioaryloxy" as used herein refer to R₇₁O- or R₇₁S-, respectively, wherein R₇₁ is an aryl group.

The terms "aryloxyalkyl" and "thioaryloxyalkyl" as used herein refer to an aryloxy group or a thioaryloxy group, respectively, appended to a loweralkyl radical.

The terms "arylalkoxy" and "arylthioalkoxy" as used herein refer to an aryl group appended to an alkoxy radical or a thioalkoxy radical, respectively, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.

The terms "arylalkoxyalkyl" and "arylthioalkoxyalkyl" as used herein refer to an arylalkoxy group or an

arylthioalkoxy group, respectively, appended to a

loweralkyl radical.

The term "arylsulfonyl" as used herein refers to R₇₂S(O)₂- wherein R₇₂ is an aryl group.

The term "arylsulfonylalkyl" as used herein refers to an arylsulfonyl group appended to a loweralkyl radical.

The term "alkylsulfonylamino" as used herein refers to R₇₆NH- wherein R₇₆ is an alkylsulfonyl group.

The term "arylsulfonylamino" as used herein refers R₇₇NH- wherein R₇₇ is an arylsulfonyl group. The term " (heterocyclic) sulfonyl" as used herein refers to R_72aS(O)2- wherein R_72a is a heterocyclic group.

The term "alkylaminocarbonylamino" as used herein refers to R₇₆NHCONH- wherein R₇₈ is a loweralkyl group.

The term "alkylaminocarbonyloxy" as used herein refers to R₇₆NHC(O)O- wherein R₇₆ is a loweralkyl group.

The term "alkoxycarbonyloxy" as used herein refers to R₈₀OC(O)O- wherein R₈₀ is a loweralkyl group.

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

The term "haloalkyl" as used herein refers to a loweralkyl radical in which one or more hydrogen atoms are replaced by halogen including, but not limited to,

fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and the like.

The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups and includes but is not limited to substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and tehahydropyranyl; substituted ethyl ethers, for example, 2,2,2-trichloroethyl, t-butyl, benzyl and triphenylmethyl; silyl ethers, for example, trimethylsilyl,

t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal,

acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates.

The term "heterocyclic group" or "heterocyclic" as used herein refers to any 3-, 4-, 5- or 6-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5- or 6-membered ring containing two or three nitrogen atoms; or one nitrogen and one oxygen atom; or one nitrogen and one sulfur atom; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 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 or another 5- or 6-membered heterocyclic ring independently as defined above. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocyclics include: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl,

piperazinyl, N-methyl piperazinyl, azetidinyl, N-methyl azetidinyl, pyrimidinyl, pyridazinyl, oxazolyl,

oxazolidinyl, 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 substitutents independently selected from hydroxy, halo, oxo (=O), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.

The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N- methyl azetidinyl, thiazolyl, thienyl, triazolyl and the following:

wherein b is 1 or 2 and W is N, NH, O S, provided that-W is the point of connection only when T is N,

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

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

The terms "His", "Phe", "HomoPhe", "Ala", "Leu" and "norLeu" as used herein refer to histidine, phenylalanine, homophenylalanine, alanine, leucine and norleucine, respectively.

The compounds of the invention can be prepared as shown in Schemes I - VI. The syntheses of the mimics of the Leu-Val transition state of angiotensinogen (T) are described herein, or in Fung, et al., PCT Patent

Application No. WO90/03971, published April 19, 1990, which is hereby incorporated by reference, or in the references previously incorporated by reference herein.

In particular, the process shown in Scheme I

illustrates the preparation of substituted cyclopropane dicarboxylates wherein A is -C(O)NR'R" wherein -NR'R" represents -NH₂, a substituted amino group as defined herein or a nitrogen containing heterocyclic group; and R and R₁ are as defined herein. The relative

stereochemistry is cis between the R₁ and R'R"NC(O)-groups (when R = H), the carboxylic acid being trans to R₁ and R'R"NCO (when R = H). As illustrated in Scheme I, cyclopropanation of the appropriately protected cis

allylic alcohol (TBS represents t-butyldimethylsilyl) provides the cyclopropyl isomers III and IV, which are then separated. The epimer indicated is oxidized to V and the resulting acid is coupled with the amine (HNR'R") to give amide VI. Acid hydrolysis furnishes the cyclopropane carboxylic acid VII. Using standard peptide coupling reagents (such as dicyclohexylcarbodiimide/dimethylaminopyridine or N-methylmorpholine/1-hydroxybenzo triazole/N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and the like), compounds VII can be coupled to the amine XXX to give the desired compound 1 (Scheme VI).

Using the methods shown in scheme II, the epimeric trans series (R trans to R'R"NCO- when R₁ = H) ) is

prepared. The half acid chloride of fumaric acid VIII is reacted with the amine (HNR'R") to give the amide IX.

Reaction of IX with the ylide produces the cyclopropane carboxylic ester X. Acid hydrolysis of X yields the cyclopropane carboxylic acid XI which can be coupled to the amine XXX to give compound 1.

An alternative synthesis of the substituted

cyclopropane carboxylic acids is shown in Scheme III. The stabilized phosphonium ylide XIV is reacted with an aldehyde (RCHO) to produce the trans unsaturated amide XV. The unsaturated amide, when reacted with ethyl- (dimethylsulfuranylidine)-acetate or 2-substituted

dimethylsulfuranylidme acetates, affords the cyclopropane ester XVI. Acid hydrolysis of XVI gives the cyclopropane carboxylic acid XVII.

Schemes IV and Va illustrate the preparation of compounds wherein A is -S(O)₂NR'R" or A is -NHC(O)R₉₆ wherein R₉₆ is as defined herein, respectively.

Cyclopropanation of the cis vinyl sulfide XVIII affords the cyclopropyl sulfide XIX which is oxidized with

chlorine/water to give the crude sulfonyl chloride XX.

The crude sulfonyl chloride is treated with an amine

(HNR'R") to give the sufonamide XXI. Hydrolysis produces the cyclopropane sulfonamide XXII.

The substituted amino cyclopropane series,

illustrated by compound XXIX, is prepared by the process outlined in Scheme Va. Dibromocarbene addition to the protected allylic alcohol (TBS represents t-butyldimethylsilyl) and selective metallation using the

procedure of Danheiser et al., J. Org. Chem. 1985, 50 , 2403, gives the bromocyclopropane XXV. A second

metallation produces the cyclopropyllithium species XXVI, which is trapped by carbon dioxide to give the acid XXVII. Curtius rearrangement affords the intermediate isocyanate which reacts with an alcohol, amine or Grignard reagent to produce a carbamate, urea or amide XXVIII.

Deprotection and oxidation gives the carboxylic acid XXIX.

The sulfoxide and sulfone substituted cyclopropanes can be obtained by the process outlined in Scheme Vb.

Compound XXVI is trapped by a disulfide (for example, R** is loweralkyl, aryl, arylalkyl, etc.) to give the sulfide XXVIIa. Deprotection, oxidation of the sulfur and

oxidation of the alcohol provides XVIIc (z is 1 or 2).

The process disclosed in Scheme VI describes the coupling of the substituted cyclopropyl carboxylic acids XXXI (wherein A is as defined herein) with the mimic of the Leu-Val transition state of angiotensinogen, such as amine XXX (wherein T is as defined herein) using standard peptide coupling reagents such as N-methylmorpholine

(NMM), 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDAC) to give the desired compound 1.

Scheme VII discloses an intramolecular route to substituted cyclopropanes XXXI wherein A is exemplified by a morpholinocarbonyl group and R₁ is hydrogen. AIIylic alcohol XXXII is transformed to the corresponding

diazoacetic ester XXXIII. Copper catalyzed cyclopropanation gives lactone XXXIV. Reaction of the lactone with a nucleophile (in this case, morpholine) provides amide XXXV. Oxidation to the aldehyde, followed by epimerization of the aldehyde group and further

oxidation, provides the carboxylic acid XXXVI, which can be coupled to XXX (according to Scheme VI) to give 1.

The process outlined in Scheme VIII allows

epimerization of the amide substituent, leading to XXXVII.

Routes to optically active intermediate XXXIV are shown in Schemes IX and X. Enzymatic oxidation (horse liver alcohol dehydrogenase (HLADH)) of diol XXXVIII yields enantiomerically pure XXXIX, which can be oxidized to enantiomerically pure XL. Alternatively (Scheme X), intramolecular cyclopropanation of XXXIII catalyzed by a chiral catalyst (Rhodium (II) methyl(S)-pyroglutamic acid (Rh2(5S-MEPY)4) or (Rhodium (II) methyl(R)-pyroglutamic acid (Rh2(5R-MEPY)4) provides the enantiomers XLI and XLII, respectively.

Particularly useful intermediates for the preparation of the novel compounds of this invention are compounds of the formula:

or an acid halide or activated ester derivative thereof.

A is

(I) R₅C(O)- wherein

R₅ is

i) hydroxy,

ii) alkoxy, iii) thioalkoxy,

iv) loweralkyl,

v) heterocyclic,

vi) amino or

vii) substituted amino;

a C₁ to C₈ straight or branched

carbon chain substituted with a

substituent selected from

1) carboxy,

2) alkoxycarbonyl,

3) alkylsulfonyl,

4) aryl,

5) arylsulfonyl,

6) heterocyclic,

7) (heterocyclic)sulfonyl,

8) amino,

9) alkylamino,

10) dialkylamino,

11) alkoxy,

12) (alkoxy)alkoxy or

13) ((alkoxy)alkoxy)alkoxy;

(III) R₉₅S(O)_w- wherein w is 0-2 and R₉₅ is

1) loweralkyl,

2) aryl,

3) heterocyclic,

4) -NH₂ or

5) substituted amino;

(IV) R₉₆C(O)N(R₁₅₁)- wherein R₁₅₁ is hydrogen or loweralkyl and R₉₆ is 1) loweralkyl,

2) cycloalkyl,

3) aryl,

4) heterocyclic,

5) alkoxy,

6) thioalkoxy,

7) aryloxy,

8) thioaryloxy,

9) substituted amino,

10) R₉₇NH- wherein R₉₇ is loweralkyl, cycloalkyl, aryl or heterocyclic

11) (heterocyclic)alkyl,

12) aminoalkyl,

13) alkylaminoalkyl,

14) dialkylaminoalkyl,

15) alkoxyalkyl,

16) (alkoxy)alkoxyalkyl or

17) ((alkoxy)alkoxy)alkoxyalkyl; or

(V) R₉₆S(O)_xN(R₁₅₁) - wherein x is 1 or 2, R₁₅₁ is hydrogen or loweralkyl and R₉₆ is defined as herein.

R and R₁ are independently selected from

(I) hydrogen,

(II) aryl,

(III) loweralkyl,

(IV) loweralkenyl,

(V) cycloalkyl,

(VI) cycloalkenyl,

(VII) aryloxyalkyl,

(VIII) thioaryloxyalkyl, (IX) arylalkoxyalkyl,

(X) arylthioalkoxyalkyl and

(XI) a C₁ to C₃ straight or branched

carbon chain substituted with a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl,

4) cycloalkyl,

5) cycloalkenyl and

6) heterocyclic.

Other useful intermediates for the preparation of the novel compounds of the invention are compounds of the formula:

or an acid halide or activated ester derivative thereof.

A is

(I) R₅C(O)- wherein

R₅ is

i) hydroxy,

ii) alkoxy,

iii) thioalkoxy,

iv) loweralkyl,

v) heterocyclic, vi) amino or

vii) substituted amino;

a C₁ to C₈ straight or branched

carbon chain substituted with a

substituent selected from

1) carboxy,

2) alkoxycarbonyl,

3) alkylsulfonyl,

4) aryl,

5) arylsulfonyl,

6) heterocyclic,

7) (heterocyclic)sulfonyl,

8) amino,

9) alkylamino,

10) dialkylamino,

11) alkoxy,

12) (alkoxy)alkoxy or

13) ((alkoxy)alkoxy)alkoxy;

(III) R₉₅S(O)_w- wherein w is 0-2 and R₉₅ is

1) loweralkyl,

2) aryl,

3) heterocyclic,

4) -NH₂ or

5) substituted amino;

1) loweralkyl,

2) cycloalkyl,

3) aryl. 4) heterocyclic,

5) alkoxy,

6) thioalkoxy,

7) aryloxy,

8) thioaryloxy,

9) substituted amino,

10) R₉₇NH- wherein R₉₇ is loweralkyl,

cycloalkyl, aryl or heterocyclic

11) (heterocyclic)alkyl,

12) aminoalkyl,

13) alkylaminoalkyl,

14) dialkylaminoalkyl,

15) alkoxyalkyl,

16) (alkoxy)alkoxyalkyl or

17) ((alkoxy)alkoxy)alkoxyalkyl; or

(V) R₉₆S (O)_xN(R₁₅₁)- wherein x is 1 or 2, R₁₅₁ is hydrogen or loweralkyl and R₉₆ is defined as herein.

R and R₁ are independently selected from

(I) hydrogen,

(II) aryl,

(III) loweralkyl,

(IV) loweralkenyl,

(V) cycloalkyl,

(VI) cycloalkenyl,

(VII) aryloxyalkyl,

(VIII) thioaryloxyalkyl,

(IX) arylalkoxyalkyl,

(X) arylthioalkoxyalkyl and

(XI) a C₁ to C₃ straight or branched carbon chain substituted with a substituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl,

4) cycloalkyl,

5) cycloalkenyl and

6) heterocyclic.

R₃ is

(I) loweralkyl,

(II) haloalkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenylalkyl,

(VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy)alkyl,

(IX) hydroxyalkyl,

(X) -(CH₂)_eeNHR₁₂

wherein

1) ee is 1 to 3 and

2) R₁₂ is

i) hydrogen,

ii) loweralkyl or

iii) an N-protecting group;

(XI) arylalkyl or

(XII) (heterocyclic)alkyl.

Acid halide derivatives of the above intermediates include the acid chloride. Activated ester derivatives of the above intermediates include activated esters commonly used by those skilled in the art for activating carboxylic acid groups for coupling with an amine to form a peptide bond, including, but not limited to formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.

Compounds of the invention include the following: (1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morρholinyl)-carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*)-2-(4-Morpholinyl)carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3R*)-3-Benzyl-2-(4-morpholinyl)carbonylcyclopropanecabonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-3-Ethyl-2-(4-morpholinyl)carbonylcyclopropanecarbonyl-L-thiazolylalanineamide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-3-(2-Methylpropyl)-2-(4-morpholinyl)-carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl -L-thiazolylalanine amide of 2(S)- Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-histidyl amide of 2(S)-Amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl

cyclopropanecarbonyl -L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-cyclohexyl methylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-benzyl

cyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl

cyclopropanecarbonyl-L-histidyl amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-leucyl amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-nor-leucyl amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-4-thiazolylalanyl amide of N-Butyl 5(S)-Amino-6-cyclohexyl-4(S)-hydroxy-5(S)-isopropylhexamide;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-4-thiazolylalanyl amide of (2'S, 1'R, 5'S)-3-Ethyl-5-(1'-hydroxy-2'amino- 3'cyclohexylpropyl)-oxazolidin-2-one;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-4-thiazolylalanyl amide of

(2S,4S,1'R,2'S)-2-(2-Amino-3-cyclohexyl-1-hydroxy)-4-methyl-tetrahydrofuran;

(1R*, 2R*, 3S*)-2-Phenylsulfonyl-3-ρhenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane;

(1R*, 2S*, 3S*)-2-Phenylsulfonyl-3-phenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2 (S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane; and (1R,2R,3R),-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane.

The following examples will serve to further

illustrate preparation of the novel compounds of the invention.

Example 1

( Z )-(1,1-Dimethylethyl)dimethyl(2-pentenyloxy)siIane

To a solution of 1.5 g (17.4 mmol) of (Z)-2-penten-1-ol in anhydrous DMF (5.7 mL) was added t-butyldimethylsilyl chloride (3.16 g, 20.9 mmol) followed by imidazole (1.42 g, 20.9 mmol) at room temperature. The mixture was stirred 1.5 h at room temperature. The reaction was then poured into an equal volume of Et₂O and washed sequentially with 10 mL of water, 1 N HCl, and water. The organic fraction was dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by reduced pressure distillation to furnish 3.36g (96%) of the protected allylic alcohol as a clear oil; bp 90 °C (32 mm Hg); ¹H NMR (CDCl) δ 5.50-5.40 (comp,

2H), 4.22 (d, 2H, J = 5.4 Hz), 2.04 (dq, 2H, J = 7.2, 7.5 Hz), 0.96 (t, 3H, J = 7.5 Hz) 0.90 (s, 9H) , 0.07 (s, 6H); 1³C NMR (CDCI₃) δ 132.5, 128.9, 59.3, 26.0, 25.6, 18.3, 14.2, -5.1; IR (neat) V 2940, 2840, 1270, 1105, 850, 800. Mass spectrum m/e: 200, 143, 75.

Example 2

(Z ) - (1 ,1-Dimethylethyl)dimethyl((5-methyl-2-hexenyl)oxy) silane

Using the procedure in example 1 and 1.5 g (13.2 mmol) of (Z)-5-methyl-2-hexen-1-ol, 2.38 g (15.8 mmol) of t-butyldimethylsilyl chloride and 1.07 g (15.8 mmol) of imidazole gave 2.51 g (83%) of the protected alcohol; ¹H NMR (CDCI₃) δ 5.60-5.50 (m, 1H), 5.50-5.40 (m, 1H), 4.22

(d, 2H, J = 6.1 Hz), 1.92 (t, 2H, J = 7.0 Hz), 1.61 (m, 1H), 0.80-0.90 (comp, 15H), 0.07 (s, 6H); ¹³C NMR (CDCI₃) δ 130.3, 129.5, 59.5, 36.7, 28.6, 26.0, 22.3, 18.3, -5.1; IR (neat) V 3000, 2900, 1280, 1120, 870, 810. Mass spectrum m/e: 171, 115, 75.

Example 3

(1 R*, 2R*,3S*) -2-[(1,1-Dimethylethyl)dimethyl siloxymethyl]-3-ethylcyclopropanecarboxylic acid ethyl ester

To a solution of 716 mg (3.58 mmol) of protected allylic alcohol from example 1 in anhydrous CH₂Cl₂ (1 M) was added Rh₂ (OAc) 4 (18 mg, 0.04 mmol). Ethyl diazoacetate (474 mg, 4.16 mmol) in 3.6 mL of CH₂Cl₂ was then added dropwise via a syringe pump to the green solution over a period of 5-8 h at room temperature.

During the course of the addition, the evolution of N2 was evident. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue

(approx. 1 g) was passed through a plug of silica gel (10 g) using a 20:1 hexanes:EtOAc as eluant. The ratio of product isomers was (1.2 : 1) as determined by ¹H NMR. The major product was isolated in 21% yield by flash chromatography (40:1 hexanes:EtOAc). ¹H NMR (CDCI₃) δ

4.09 (q, 2H, J = 7.2 Hz), 3.74 (dd, 1H, J = 6.3, 11.1 Hz),

3.58 (dd, 1H, J= 7.8, 11.1 Hz), 1.80-1.70 (m, 1H), 1.50- 1.40 (m, 2H), 1.20-1.30 (comp, 5H), 1.01 (t, 3H, J = 7.2

Hz), 0.87 (comp, 12H), 0.09 (s, 6H); ¹³C NMR (CDCI₃) δ

173.8, 60.9, 60.1, 29.1, 28.8, 25.8, 24.7, 20.6, 18.1, 14.1, 13.8, -5.4, -5.4; IR (neat) v 3000, 1750, 1280,

1200, 1120, 870, 810. Mass spectrum m/e 229,103, 83, 75; Exact mass calculated for CιsH3iθ3Si: 287.204249. Found 287.203239.

Example 4

(1R*, 2R*, 3S*)-2-[(1,1-Dimethylethyl)dimethyl siloxymethyl]-3-(2-methyl-propyl)cyclopropanecarboxylic acid ethyl ester

Using the procedure in example 3 and 630 mg (2.75 mmol) of protected alcohol from example 2, 313 mg (2.75 mmol) of ethyl diazoacetate and 12 mg (0.027 mmol) of Rh₂(OAc)₄ in 4 mL of CH₂Cl₂, the diastereomeric

cyclopropane adducts were obtained in a 2:1 ratio. The major product was isolated in 35% yield by HPLC (50:1 hexanes:EtOAc). ¹H NMR (CDCI₃) δ 4.10 (q, 2H, J = 7.1 Hz), 3.70 (dd, 1 H, J = 6.4, 11.1 Hz), 3.60 (dd, 1H, J = 7.4, 11.1 Hz), 1.80-1.60 (comp, 2H), 1.55-1.35 (comp, 2H), 1.30-1.10 (comp, 5H), 1.00-0.80 (comp, 18H) 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (CDCI₃) δ 174.0, 61.1, 60.3, 36.1,

28.7, 28.5, 25.8, 25.7, 25.2, 22.7, 22.2, 18.2, 14.3, -5.3, -5.3; IR (neat) V 2970, 1730, 1270, 1200, 1110, 860,

800. Mass spectrum m/e: 315, 299, 257, 183; Exact mass calculated for C₁₇H₃₅O₃Si: 315.235549. Found 315.233119

Example 5

(1R*,2R*,3S*)-3-Ethylcyclopropanedicarboxylic acid monoethyl ester

To a solution of the silyl ether from example 3 (46 mg, 0.16 mmol) in 0.8 mL acetone (0.25 M) at 0°C was added 1.9 mg (0.32 mmol) of anhydrous potassium fluoride followed by 0.11 mL of 8 N Jones reagent (0.7mL/mmol).

The reaction was stirred for 2 h in an ice bath before diluting with 2 mL of water. The mixture was extracted with CH₂Cl₂ (3 × 1 volume) and the combined extracts were dried (MgSO₄) and concentrated under reduced pressure.

The product was found to be pure by NMR spectroscopy and used without purification.

1H NMR (CDCI₃) δ 9.70 (br s, 1H), 4.14 (q, 2H, J = 7.2

Hz), 2.28 (dd, 1H, J = 4.6, 9.5 Hz), 2.14 (dd, 1H, J = 4.7, 6.0 Hz), 1.83 (m, 1H), 1.73-1.53 (m, 2H), 1.26 (t, 3H, J = 7.2 Hz), 0.98 (t, 3H, J = 7.4 Hz); ¹³C NMR (CDCI₃) δ 176.5, 171.7, 61.1, 31.9, 28.3, 19.4, 14.1, 13.4; IR (neat) v 2800, 1740, 1700, 1280, 1200. Mass spectrum m/e: 186, 141, 113, 95; Exact mass calculated for C₉H₁₅O₄ :

187.087034. Found: 187.096533. Example 6

(1R*,2R*,3S*)-3-(2-Methylpropyl)cyclopropanedicarboxylic acid monoethyl ester

Using the procedure in example 5, 40 mg (0.13 mmol) of cyclopropyl ester from example 4, 15 mg (0.25 mmol) of anhydrous potassium fluoride and 0.089 mL of 8N Jones Reagent afforded 31 mg of the crude acid in 92% yield; ¹H NMR (CDCI₃) δ 9.60 (br s, 1H), 4.14 (q, 2H, J = 7.2 Hz),

2.28 (dd, 1H, J = 4.7, 9.6 Hz), 2.13 (dd, 1H, J = 4.7, 5.9 Hz), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 1H), 1.51 (t, 1H, J = 6.9 Hz), 1.26 (dd, 1H, J = 6.6, 7.1 Hz), 0.93 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz); ¹³C NMR (CDCI₃) δ

176.5, 171.8, 61.1, 34.5, 28.9, 28.3, 27.0, 22.4, 22.1, 14.2; IR (neat) v 2970, 1720, 1700, 1190. Mass spectrum m/e: 215, 197, 169; Exact mass calculated for C₉H₁₅O₄:

215.1277. Found: 215.1277.

Exampl e 7

(1R*,2R*,3S*)-3-Ethyl-2- (4-morpholinyl)carbonyl - cyclopropane carboxylic acid ethyl ester

To a solution of the acid prepared in example 5 (26 mg, 0.14 mmol) in 1.0 mL of anhydrous CH₂Cl₂ (0.14 M) was added 41 mg (0.15 mmol) of dicyclohexylcarbodiimide (DCC) and 2 mg (0.014 mmol) of 4-dimethylaminopyridine (DMAP), and the resulting mixture was cooled to 0 °C.

Anhydrous morpholine (13 mg, 0.15 mmol, 1.1 equiv) was added in one portion and the reaction was warmed to room t_emperature. After stirring for 12 h, the solution was filtered through a pad of celite and concentrated under reduced pressure to yield 19 mg of morpholinoamide. ¹H NMR (CDCI₃) δ 4.12 (m, 2H), 3.80-3.50 (comp, 8H), 2.35- 2.25 (comp, 2H), 1.85-1.60 (comp, 2H), 1.42 (m, 2H, J = 7.3 Hz), 1.25 (t, 3H, J = 7.2 Hz), 0.95 (t, 3 H, J = 7.3 Hz); ¹³C NMR (CDCI₃) δ 173.1, 166.8, 66.9, 66.7, 60.9,

45.9, 42.4, 30.7, 28.0, 25.6, 20.0, 14.2, 13.5; IR (neat) V 3100, 1740, 1660, 1210, 1150. Mass spectrum m/e: 255, 182, 95; Exact mass calculated for C₁₃H₂₁NO₄: 255.1474. Found: 255.1474.

Example 8

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl)- carbonylcyclopropane-carboxylic acid ethyl ester

Using the procedure of example 7, 31 mg (0.18 mmol) of acid from example 6, 43 mg (0.16 mmol) of DCC, 2 mg (0.15 mmol) of DMAP and 14 mg (0.16 mmol) of morpholine gave 30 mg of morpholinoamide. ¹H NMR (CDCI₃) δ 4.13 (m,

2H), 3.80-3.50 (comp, 8H), 2.35-2.25 (comp, 2H), 1.80-1.70 (comp, 2H), 1.60 (m, 1H, J = 6.8 Hz), 1.40-1.30 (m, 1H), 1.25 (t, 3H, J = 7.1 Hz), 0.91, (d, 3H, J = 6.7 Hz), ) 0.88 (d, 3H, J = 6.7 Hz); ¹³C NMR (CDCI₃) δ 173.1, 166.9,

66.9, 66.7, 60.8, 45.9, 42.3, 35.2, 28.3, 27.7, 27.4, 26.0, 22.5, 22.1, 14.2; IR (neat) V 2880, 1730, 1650,

1330, 1260, 1210, 1140. Mass spectrum m/e: 283, 210, 129, 95; Exact mass calculated for C₁₅H₂₅NO₄: 283.178359. Found: 283.178100.

Example 9

(1R*,2R*,3S*)-3-Ethyl-2-(4-morpholinyl)carbonyl- cyclopropanecarboxylic acid

To a solution of 18 mg (0.071 mmol) of ester that was prepared in example 7 in 1.0 mL of THF was added 1 mL of 2 N HCl and the mixture heated to 50 °C for 40 h. The solution was then cooled to room temperature and extracted with CH₂Cl₂ (3 × 1 volume) and the combined extracts dried (MgSθ4) and concentrated under reduced pressure. The crude acid was purified by flash chromatography on 150 mg silica gel using 1:2 hexanes:EtOAc plus 1% acetic acid as eluant to furnish 15 mg of the title compound in 94% yield. ¹H NMR (CDCI₃) δ 6.00 (br s, 1H), 3.80-3.50 (comp,

8H), 2.37, (dd, 1H, J = 4.3, 9.7 Hz), 2.30 (br s, 1H), 1.90-1.70 (m, 1H), 1.50-1.40 (comp, 2H), 0.96 (t, 3H, J = 7.3 Hz); ¹³C NMR (CDCI₃) δ 177.9, 166.7, 66.9, 66.7, 46.0, 42.4, 31.3, 28.5, 25.5, 20.1, 13.5; IR (CH₂CI₂) V 2980,

1730, 1650, 1450, 1280. Mass spectrum m/e: 227, 182, 129, 95; Exact mass calculated for C₁₁H₁₇NO₄ : 227.1149.

Found: 227.1149

Example 10

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl)- carbonylcyclopropanecarboxylic acid Using the procedure in example 9, 25 mg (0.088 mmol) of ester from example 8, 1 mL of 2N HCl and 1 mL of THF, the crude acid was obtained in 80% yield (18 mg) after purification by flash chromatography (1:2 hexanes:EtOAc plus 1% acetic acid). ¹H NMR (CDCI₃) δ 7.6 (br s, 1H),

3.80-3.50 (comp, 8H), 2.40-2.30 (comp, 2H), 1.85-1.75 (m,1H), 1.62 (m, 1H, J = 6.7 Hz), 1.39 (m, 1H), 1.21 (m, 1H), 0.92 (d, 3H, J = 6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz); ¹³C NMR (CDCI₃) δ 178.0, 166.7, 66.9, 66.7, 46.0, 42.4, 35.2, 28.3, 27.9, 25.8, 22.5, 22.1; IR (CH₂Cl₂) V 2980, 1740, 1650, 1450, 1290, 1260, 1140. Mass spectrum m/e: 225, 210, 129, 95; Exact mass calculated for C₁₃H₂₁NO₄:

255.1472. Found: 255.1472.

Example 11

Methyl (E)-4-morpholinyl-4-oxo-2-butenoate Methyl (E) -4-chloro-4-oxo-2-butenoate (250 mmol, 37.1 g) was added dropwise to a stirring solution of morpholine (250 mmol, 21.8 mL) in 20% aqueous NaOH (63 g) and CH₂Cl₂ (94 mL) over 30 min at -20 °C. The bath was allowed to slowly warm to 0 °C (1 h) and the reaction poured into a separatory funnel. The organic layer was drawn off and the aqueous portion was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic fractions were washed sequentially with 2 N HCl (100 mL), saturated NaHCO₃ (100 mL), and water (100 mL). The solution was dried (MgSO₄) and

concentrated under reduced pressure to give 14.9 g of amide. ¹H NMR (CDCI₃) δ 7.39 (d, 1H, J = 15.4 Hz), 6.78

(d, 1H, J= 15.4 Hz), 3.81 (s, 3H) , 3.80-3.50 (comp, 8H); ¹³C NMR (CDCI₃) δ 165.4, 162.9, 133.0, 130.6, 66.1, 51.1,

42.0; IR (CH₂Cl₂) V 1740, 1660.

Example 12

(1R*,2R*,3S*)-3-Ethyl-2-(4-morpholinyl)carbonyl- cyclopropane carboxylic acid methyl ester To a solution of 4.36 g (11.3 mmol) of n-butyltriphenylphosphonium bromide in 62 mL of anhydrous THF (0.18 M) at room temperature was added 4.40 mL of n-BuLi (2.5 M in hexanes, 11.1 mmol). The mixture was stirred for 30 min and 1.1 g (5.53 mmol) of the fumarate which was prepared in example 11 in 8 mL THF was added via cannula and the resulting solution heated to reflux for 12 h. The reaction was then cooled to room temperature and quenched with a quarter volume of water and concentrated under reduced pressure to about 20% of the original volume. This solution was passed through a plug of silica gel (1:1 hexanes:EtOAc) and then further concentrated under reduced pressure to provide the crude cyclopropane. The ester amide was purified by HPLC (1:1 hexanes:EtOAc) to afforded 189 mg (14%) of the product. ¹H NMR (CDCI₃) δ

3.70 (s, 3H), 3.80-3.50 (comp, 8H), 2.36 (dd, 1H, J = 4.6,

9.4 Hz), 2.24 (dd, 1H, J = 4.8, 5.7 Hz), 1.90 (m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 0.96 (t, 3H, J = 7.4 Hz); ¹³C NMR (CDCI₃), δ 171.5, 169.2, 66.7, 52.0, 46.0, 42.5, 30.9,

26.8, 26.1, 19.5, 13.6.

Example 13

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl )- carbonylcyclopropane-carboxylic acid methyl ester

Using the procedure in example 12, 2.89 g (7.01 mmol) of 3-methylbutyltriphenylphosphonium bromide, 2.73 mL of

2.5 M n-butyllithium, 680 mg (3.42 mmol) of fumarate from example 11 in 46 mL of THF gave the title compound in 18% yield (163 mg) after flash chromatography. ¹H NMR (CDCI₃) δ 3.70 (s, 3H), 3.80-3.50 (comp, 8H), 2.35 (dd, 1H, J =

4.6, 9.5 Hz), 2.23 (m, 1H, J = 4.6, 6.0 Hz), 1.83 (m, 1H), 1.61 (m, 1H), 1.50-1.40, (comp, 2H), 0.93 (d, 3H, J = 6.5 Hz), 0.89 (d, 3H, J = 6.5 Hz); ¹³C NMR (CDCI₃) δ 171.4,

169.2, 66.6, 51.8, 45.9, 42.5, 34.7, 28.3, 27.8, 26.8, 25.8, 22.2, 22.1. Example 14

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3- phenylcyclopropanecarboxylic acid methyl ester Using the procedure in example 13, 4.30 g (11.0 mmol) of 2-phenylethyltriphenylphosphonium bromide, 4.30 mL, 2.5 M n-butyllithium, 1.07 g (5.4 mmol) of fumarate from example 11 in 10 mL of THF gave 500 mg the title compound in 32% yield after flash chromatography. ¹H NMR (CDCI₃) δ

7.30-7.20 (comp, 5H), 3.76 (s, 3H), 3.80-3.50 (comp, 8H), 3.11 (dd, 1H, J = 6.5, 9.8 Hz), 2.95 (dd, 1H, J= 4.9, 6.4 Hz), 2.69 (dd, 1H, J = 4.9, 9.8 Hz).

Example 15

(1R*,2R*,3S*)-3-Ethyl-2-(4-morpholinyl)carbonyl- cyclopropanecarboxylic acid

Using the procedure in example 9, 189 mg (0.78 mmol) of the ester from example 12, 8 mL of 2 N HCl and 8 mL of THF gave the crude acid which was purified by HPLC (1:2 hexanes :EtOAc plus 1% acetic acid) to furnish 110 mg of the title compound in 62% yield. ¹H (CDCI₃) δ 10.00 (br s, 1H), 3.80-3.50 (comp, 8H), 2.40-2.30 (m, 1H), 2.30-2.20 (br s, 1H), 1.87 (m, 1H) 1.64 (comp, 2H), 1.00 (t, 3H, J= 6.8 Hz); ¹³C NMR (CDCI₃) δ 174.3, 169.4, 66.5, 46.0, 42.6,

31.0, 26.6, 26.4, 19.5, 13.3.

Example 16

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl)- carbonylcyclopropanecarboxylic acid Using the procedure in example 9, 163 mg (0.61 mmol) of the ester prepared in example 13, 6 mL of 2 N HCl and 6 mL THF, the crude acid was isolated and purified by HPLC (1:2 hexanes:EtOAc plus 1% acetic acid) to give 70 mg (43%) of the title compound. ¹H NMR (CDCI₃) δ 9.80 (br s, 1H), 3.80-3.50 (comp, 8H), 2.35 (dd, 1H, J= 4.5, 9.5 Hz), 2.24 (m, 1H, J = 4.5, 6.2 Hz), 1.90 (m, 1H), 1.65 (m, 1H), 1.50 (comp, 2H), 0.92 (m, 6H); ¹³C NMR (CDCI₃) δ 175.6,

169.3, 66.6, 46.0, 42.6, 34.7, 28.3, 26.7, 26.4, 22.4, 22.2.

Example 17

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarboxylic acid

Using the procedure in example 9, 500 mg (1.73 mmol) of the ester prepared in example 14, 15 mL of 2 N HCl and 15 mL THF, the crude acid was isolated and purified by HPLC (1:2 hexanes :EtOAc plus 1% acetic acid) to give 200 mg (42%) the title compoud. ¹H NMR (CDCI₃) δ 9.80 (br s, 1H), 7.30-7.20 (comp, 5H), 3.80-3.50 (comp, 8H), 3.09 (dd, 1H, J = 6.5, 9.9 Hz), 2.90 (m, 1H, J = 4.8, 6.5 Hz), 2.60 (dd, 1H, J = 4.8, 10.0 Hz); ¹³C NMR (CDCI₃) δ 172.4,

168.7, 134.2, 128.6, 128.0, 127.1, 66.4, 45.9, 42.6, 32.6, 29.2, 24.4.

Example 18

4-(Chloroacetyl)-morpholine

To a stirred heterogeneous mixture of morpholine (0.40 mol, 34.8 g), 20% aq NaOH (100 g), and 1,2-dichloroethane (150 mL), was added dropwise

chloroacetylchloride (0.50 mol, 56.0 g, 38.7 mL) over 45 min at -15 °C. The temperature was allowed to rise to 10°C, and the aqueous layer was separated and washed (2 × 20 mL) with 1,2-dichloroethane. The organic phases were combined, washed (2 × 50 mL, each) with 5% HCl, 5% NaHCO₃, and H₂O, and dried (MgSO₄). The combined organic phases were concentrated under reduced pressure to yield the title compound (40.6 g, 62%) as a clear oil. ¹H NMR

(CDCI₃) δ 3.95 (s, 2H), 3.59-3.37 (comp, 8H); ¹³C NMR (CDCI₃) δ 164.9, 66.2, 46.3, 42.1, 40.4.

Example 19

4-(Triphenylphosphoniumacetyl)-morpholine chloride A stirred solution of amide from example 18 (0.03 mol, 4.86 g) and triphenylphosphine (0.03 mol, 7.86 g) in benzene (300 mL) was heated at reflux during which time a white precipitate formed. After 24 h, half of the benzene was evaporated, the white solid was removed by vacuum filtration and dried under reduced pressure to yield the phosphonium salt (7.50 g, 59%) as a fine white solid, mp 168-170 °C; ¹H NMR (CDCI₃) δ 7.45-7.25 (comp, 15H), 5.90- 5.76 (d, 2H, J = 12 Hz), 3.76-3.36 (comp, 8H).

Example 20

4-(Triphenylphosphoranylideneacetyl)-morpholine

To a stirred solution of salt from example 19 (15.0 mmol, 6.42 g) in H₂O (60 mL) was added 15% aq NaOH (8.0 mL), whereupon a white precipitate formed. The

precipitate was removed by vacuum filtration and dried under reduced pressure to yield the phosphorous ylide (5.53 g, 95%) as a white solid, mp 208-210 °C; ¹H NMR (CDCI₃) δ 7.83-7.33 (comp, 15H), 3.76-3.56 (comp, 4H),

3.50-3.36 (comp, 4H), 2.95-2.70 (d, 1H, J = 22.5 Hz). Example 21

4-[(E)-4-Phenyl-1-oxo-2-butenyl]-morpholine A solution of phenylacetaldehyde (7.70 mmol, 0 . 93 g) and ylide from example 20 (6.40 mmol, 2.50 g) in benzene (75 mL) was heated at reflux for 24 h. The benzene was concentrated under reduced pressure. The residue was triturated with hexanes:EtOAc (9:1) to remove the bulk of the triphenylphosphine oxide, the excess solvents were removed under reduced pressure, and the residue was purified by flash chromatography (hexanes:EtOAc, 7:1) to yield the trans alkene (0.77 g, 52%) as a clear oil. ¹H NMR (CDCI₃) δ 7.26-7.07 (comp, 5H), 7.01-6.92 (dt, 1H, J

= 15.2, 7.1 Hz), 6.10-6.05 (d, 1H, J = 15.2 Hz), 3.61-3.41 (comp, 10H); ¹³C NMR (CDCI₃) δ 165.4, 145.1, 131.9,

128.6, 128.5, 128.4, 120.5, 66.7, 46.3, 41.9, 38.6.

Example 22

(1R*,2R*-3R*)-3-Benzyl-2-(4-morpholinyl)carbonylcyclopropanecarboxylic acid ethyl ester A solution of amide from example 21 (2.21 mmol, 0.51 g) and ethyl-(dimethylsulfuranylidine)-acetate (11.04 mmol, 1.65 g) (Payne, G.B. J. Org. Chem. 1983, 32, 3351-3355.) in anhydrous DME (7.5 mL) was heated at reflux for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash

chromatography (hexanes-EtOAc, 1:1) to yield the title compound (0.05 g, 7%) as a clear oil. ¹H NMR (CDCI₃) δ

7.26-7.13 (comp, 5H), 4.14-4.07 (q, 2H, J = 7.1 Hz), 3.66-3.32 (comp, 8H), 2.90-2.86 (dd, 2H, J = 1.8, 5.8 Hz), 2.46-2.42 (dd, 1H, J = 4.7, 9.3 Hz), 2.31-2.27 (dd, 1H, J = 4.7, 6.1 Hz), 2.07-2.02 (ddt, 1H, J = 6.1, 9.3, 1.5 Hz), 1.22-1.17 (t, 3H, J = 7.1-Hz).

Example 23

(1R*,2R*,3S*)-3-benzγl-2-(4-morpholinyl)carbonylcyclopropanecaboxylic acid

A solution of ester from example 22 (0.16 mmol, 0.05 g) in THF-2N HCl (1:1) (3.1 mL) was heated at reflux for 48 h. The H₂O was azeotropically removed by distillation with benzene. The residue was purified by HPLC (hexanes-EtOAc, 1:2 containing 1% AcOH) to yield the carboxylic acid (13.40 mg, 30%) as a clear oil. ¹H NMR (CDCI₃) d 7.60-7.10 (comp, 5H), 4.10 (br s, 1H), 3.70-3.30 (comp, 8H) 2.90-2.86 (comp, 2H), 2.46-2.42 (m, 1H), 2.31-2.27 (m, 1H), 2.07-2.02 (m, 1H).

Example 24

(1R*,2R*)-2-(4-morpholinyl)carbonylcyclopropane carboxylic acid

To a solution of trimethylsulfoxoniumiodide (7.98 mmol, 1.76 g) in anhydrous DMSO (13 mL), was added NaH (7.98 mmol, 0.19 g) as a 60% dispersion in mineral oil. The mixture was stirred for 20 min at room temperature. A solution of the compound prepared in example 8 (7.98 mmol, 1.59 g) in anhydrous THF (13 mL) was added dropwise over 10 min. The reaction mixture was heated at 50 °C with stirring for 24 h. The reaction was quenched with cold H₂O (20 mL) and extracted (3 × 50 mL) with CH₂Cl₂. The organic extracts were dried (MgSO₄), and concentrated under reduced pressure to yield a yellow oil which was disolved in a 1:1 solution of THF-2N HCl (25 mL) and heated at 50 °C for 48 h. The reaction mixture was extracted (3 × 25 mL) with CH₂Cl₂. The organic extracts were dried (MgSO₄), concentrated under reduced pressure and purified by HPLC (hexanes-EtOAc, 1:2 containing 1% AcOH) to yield the cyclopropyl carboxylic acid (0.24 g, 15%) as a clear oil. ¹H NMR (CDCI₃) δ 7.10 (br s, 1H),

3.72-3.64 (comp, 8H) , 2.36-2.30 (ddd, 1H, J= 3.5, 5.0, 9.1 Hz), 2.24-2.18 (ddd, 1H, J = 3.7, 5.3, 9.0 Hz), 1.55-1.49 (ddd, 1H, J = 3.5, 5.7, 9.2 Hz), 1.44-1.38 (ddd, 1H, J = 3.6, 5.4, 9.0 Hz); ¹³C NMR (CDCI₃) δ 177.0, 168.9,

66.6, 46.1, 42.7, 21.5, 21.0, 15.5; LRMS, El, (CH2C12), 199, 184, 154, 113, 86, 72, 55, 56, 57, 42, 41, 39.

Example 25

Diethyl 4-Thiazolylmethylacetamidomalonate Using the procedure of Sakata et. al. (Bull. Chem. Soc. Japan 1966, 39, 2473), to a cold solution (ice-water bath) of sodium ethoxide, prepared from 6.6 g (287.0 mmol) of sodium metal, in 300 mL of absolute ethanol was added 30 g (138.1 mmol) of diethyl acetamidomalonate. The resulting suspension was stirred at room temperature for 1 h, recooled in an ice-water bath and 23.5 g (138.2 mmol) of 4-chloromethylthiazole hydrochloride was added. The reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate and filtered through celite. The solvents were removed under vaccum and the residue dissolved in dichloromethane, dried (MgSO₄) and the solvents filtered and concentrated to give a yellow solid which was recrystallized from ethanol at 0 °C. Yield: 28.93 g (67%). mp 104-5 °C. Example 26

D,L-Ethyl N-Acetyl-4-thiazolylalanine To a solution of diester from example 25 (3 g, 9.54 mmol) in 35 mL ethanol was added 1.7 mL of 6N NaOH (10.2 mmol) and the reaction stirred for 3 h, diluted with 35 mL water and concentrated. Concentrated HCl was added dropwise until pH 5 to 5.5. The entire reaction mixture was concentrated and the residue evaporated with several volumes of toluene. The resulting solid was suspended in 150 mL dioxane and heated at reflux temperature for 3 h, cooled, diluted with chloroform and filtered through celite. The filtrate was concentrated to yield the ester as a colorless oil (2.05 g) in 89% yield. The crude ester was used without further purification.

Example 27

L-N-Acetyl-4-thiazolylalanine and L-4-Thiazoylalanine Using the procedure of Narasimha Rao et. al. (Int. J. Peptide Protein Res. 1987, 29, 118), the crude ester (16 g) from example 26 was dissolved in 250 mL water and 1 N KCl was added. Subtilisin carlsburg (200 mg) in 10 mL of 0.1 N KCl was added in one portion. The pH dropped rapidly and was controlled by the addition of 1 N NaOH to keep the pH between 6.25 to 7.25. After 1 h the pH was controlled with 0.1 N NaOH and the reaction brought to pH 7. The entire solution was concentrated to one-half its volume with a bath temperature not exceeding 50 °C. The aqueous solution was extracted with chloroform to remove unwanted D isomer. The aqueous layer was acidified with 1 N HCl until pH 5 and the water removed by evaporation and chasing several times with toluene. Ethanol was added to the solid residue, heated and filtered. The filtrate was concentrated to give 8.5 g of solid. This material was dissolved in 300 mL of 6N HCl and heated at reflux temperature for 4 h, cooled and the water removed under vaccum to give 10.0 g of amino acid hydrochloride which was used without further purification.

Example 28

L-Boc-4-thiazolylalanine

A saturated sodium bicarbonate solution

(approximately 100 mL) was added to 9.18 g of amino acid hydrochloride prepared in example 27 to bring the pH to 7, then 3 M NaOH solution was added to bring the pH to 10. Di-t-butyl-dicarbonate (8.5 g, 38.95 mmol) in 25 mL of THF was added and then an additional 150 mL of THF was added and the reaction stirred for 18 h. The THF was removed by rotary evaporation, diluted with ethyl acetate and 3 N HCl added until the solution was pH 1. The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSθ4), filtered and evaporated to give a light yellow oil which was dissolved in 100 mL of ethyl acetate and 125 mL hexane. The solution was cooled to -25 °C for 18 h and pure Boc 4-thiazolylalanine was obtained (7.72 g). mp 115-6 °C, [α]^D25 = +125.48 (C = 1.04, CHCI₃).

Example 29

Boc-L-Histidine Amide of 2( S)-Amino-1-cyclohexyl- 3(R) ,4(S)-dihydroxy-6-methylheptane 2(S)-t-Butyloxycarbonylamino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (1.26 g, 3.67 mmol, U.S. Patent No. 4,680,284, issued July 14, 1987) was treated with 2.3 M HCI/CH₃OH (32 mL, anhydrous) for 16 hours at which time evaporation and drying provided the corresponding amine hydrochloride (1.01 g, 98%)

To a stirred -20 °C solution of the above salt (0.6 g, 2.1 mmol), Boc-L-Histidine (0.548 g), 1-hydroxybenzotriazole (HOBT, 0.43 g), and N-methylmorpholine (0.239 g) was added 1,3-dicyclohexyl carbodiimide (DCC, 0.442 g). The mixture was warmed to room temperature over 3 hours and then stirred for an additional 18 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO₃ and brine. Drying and evaporation of solvents provided a solid which was recrystaUized to give the desired

compound (0.51 g, 50%, 2 crops). Mass spectrum m/e = 480

Anal, calcd. for C₂₅H₄₄N₄O₅: C, 60.8; H, 9.1; N, 11.3. Found: C, 60.9; H, 9.2; N, 11.0.

Example 30

Boc-L-4-Thiazolylalanine Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-4-thiazolylalanine (2.77, 10.17 mmol), Boc-amine (3.49 g, 10.16 mmol), HOBT (3.71g, 27.46 mmol), EDAC HCl (2.8g, 10.22 mmol), N-methylmorpholine (2.37 mL) gave 3.72 g (74%) of the title compound after recrystallization from 1:20 dichloromethane:diethyl ether: mp 159-160 °C; TLC (10% methanol/ 90% chloroform) R_f = 0.57.

Anal, calcd. for C₂₅H₄₃N₃O₅S: C, 60.33; H, 8.71; N, 8.44. Found: C, 60.43; H, 8.68; N, 8.51. Example 31

Boc-L-Leucine Amide of 2(S)-Αmino-1-cyclohexyl-3(R),4(S)- dihydroxγ-6-methylheptane

Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-leucine gives the title compound.

Example 32

Boc-L-norLeucine Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-norleucine gives the title

compound.

Example 33

Boc-L-4-Thiazolylalanine Amide of N-Butyl 5(S)-Amino-6- cyclohexyl-4(S)-hydroxy-5(S)-isopropylhexamide

Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-4-thiazolylalanine and substituting N-butyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-5(S)-isopropylhexamide for 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane gave the title compound: TLC ( ethyl acetate) R_f = 0.30.

Anal, calcd. for C₃₀H₅₂N₄O₅S: C, 62.04; H, 9.02; N, 9.65. Found: C, 62.11; H, 8.928; N, 9.74.

Example 34

Boc-L-4-Thiazolylalanine Amide of (2'S, 1'R, 5' S)-3-Ethyl-5-(1'-hydroxy-2'amino-3'cyclohexylpropyl)-oxazolidin-2-one

Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-4-thiazolylalanine and substituting (2'S, 1'R, 5'S)-3-Ethyl-5-(1'-hydroxy-2'-amino- 3'cyclohexylpropyl)-oxazolidin-2-one

(European Patent Application No. EP307837, published March

22, 1989) for 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy- 6-methylheptane gave the title compound: mp 135-147 °C;

TLC (15% methanol/ 85% chloroform) R_f = 0.61; ¹H NMR

(CDCI₃) δ 8.79 (d,1H), 7.12 (d, 1H), 6.79 (br d, 1H), 6.57

(br d, 1H), 4.95 (br d, 1H), 4.62-4.53 (m, 1H) , 1.49 (s, 9H), 1.16 (t, 3H).

Example 35

Boc-L-4-Thiazolylalanine Amide of (2S,4S,1'R,2'S)-2-(2- Amino-3-cyclohexyl-1-hydroxy)-4-methyl-tetrahydrofuran Using the procedure in example 29 but replacing Boc-L-histidine with Boc-L-4-thiazolylalanine and substituting (2S,4S,1'R,2'S)-2-(2-Amino-3-cyclohexyl-1-hydroxy)-4-methyltetrahydrofuran (European Patent Application No. EP307837, published March 22, 1989) for 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane gave the title compound: TLC (15% methanol/ 85% chloroform) R_f = 0.44; ¹H NMR (CDCI₃) d 8.77 (d, 1H), 7.12 (d, 1H), 6.79 (br d, 1H), 6.58 (br d, 1H), 6.31 (br d, 1H), 4.57-4.48 (m, 1H), 1.46 (s, 9H), 1.02 (d, 3H).

Example 36

Boc-L-4-Thiazolγlalanine Amide of N-Isobutyl 4(S)-Amino-5- cyclohexyl-3(S)-hydroxypentamide

Using the procedure in example 29 but replacing Boc- L-histidine with Boc-L-4-thiazolylalanine and substituting isobutyl ACHPA amide for 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane gives the title compound.

Example 37

(1R*,2R*,3S*)-3- (2-Methylpropvl) -2- (4-morpholinγl) - carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of

2 (S) -Amino-1-cyclohexyl-3 (R) , 4 (S) -dihydroxy-6- methylheptane

The resultant compound from example 30 (6.27g, 12.6 mmol) was stirred in 1:1 trifluoroacetic

acid:dichloromethane at 0-5 °C for 3 hours. The solvents were removed and the residue made basic with saturated sodium carbonate until pH 10. The free base was extracted with CHCI₃ dried (MgSO₄) and concentrated to give the solid amine which was recrystaUized from 1:4

dichloromethane:hexane to give 4.99 g (100%) of amine.

A solution of cyclopropyl carboxylic acid (16 mg, 0.06 mmol) from example 10, N-methylmorpholine (7 mcL), 1-hydroxy benztriazole (HOBT, 25 mg, 0.18 mmol) and the amine (22 mg, 0.06 mmol) in 1.2 mL DMF was cooled in a carbon tetrachloride-dry ice bath and 12 mg (0.06 mmol) of EDC HCl was added. The reaction was stirred to room temperature over a 24 h period. Excess DMF was removed under high vaccum and the residue redissolved into

dichloromethane. The dichloromethane was washed with saturated sodium bicarbonate, dried (MgSO₄) and

concentrated. The crude product was purified by flash chromatography using 3% methanol/dichloromethane as eluant. Two diastereomers were obtained in 71% yield (24 mg). Mass spectrum (M+H)⁺: 635. Example 38

(1R*,2R*)-2-(4-Morpholinyl)carbonylcyclopropanecarbonyl-L- thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 24 (16 mg, 0.078 mmol), N-methylmorpholine (9.4 mL), HOBT (34 mg), EDC HCl (16.4 mg) and amine (30 mg) gave after flash chromatography (FC) 11.3 mg of the diastereomeric product. Mass spectrum (M+H)⁺: 579.

Exact mass calculated for C₂₉H₄₇N₄O₆S: 579.3216. Found: 579.3225.

Example 39

(1R*,2R*,3S*)-3-Benzyl-2-(4-morpholinyl)carbonylcyclopropanecabonyl-L-thiazolylalanine amide of 9(S)- Amino-1-cyclohexyl-3(R) ,4(S)-dihydroxy-6-methγlheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 23 (13 mg, 0.045 mmol), N-methylmorpholine (6 mL), HOBT (20 mg), EDC HCl (9.5 mg) and amine (17 mg) gave the diastereomeric product. Mass spectrum (M+H)⁺: 669. Exact mass calculated for C₃₆H₅₂N₄O₆S: 669.6688. Found: 669.3688.

Example 4Q

(1R*,2R*,3S*)-3-Ethyl-2-(4-morpholinyl)carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)- Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 15 (47 mg, 0.206 mmol), N-methylmorpholine (27 mL), HOBT (89 mg), EDC HCl (47 mg) and amine (79 mg) gave 82 mg (65%) of the product as a mixture of

diastereomers. Mass spectrum (M+H)⁺: 607. Exact mass calculated for C31H51N4O6S: 607.3529. Found: 607.3529.

The two diastereomers were separated by FC to give 10 mg of the less polar isomer(40A): ¹H NMR (CDCI₃) δ 8.79

(d, J = 1.5 Hz, 1H, 2-thiazole CH) , 7.60 (br d, J - 6 Hz, 1H, amide NH), 7.16 (d, J = 1.5 Hz, 5-thiazole CH) , 6.18

(br d, J = 6Hz, 1H, amide NH) , 4.72 (q, J = 6 Hz, 1H, CHOH), 4.32-4.20 (m, 1H, NCHCO), 3.74-3.58 (br m, 9H, four morpholino CH₂ and 1H, CHOH), 3.39 (d of d, J = 4.5 and 15 Hz, 1H, CH-thiazole) , 2.35-2.26 (m, 2H, two cyclopropyl CHCO) , 0.97-0.85 ( m, 9H, three CH₃) ; Mass spectrum

(M+H)⁺: 607.

The more polar isomer (40B) was obtained as a white solid (7.8 mg): 1H NMR (CDCI₃) δ 8.79 (d, J = 1.5 Hz, 1H,

2-thiazole CH), 7.63 (br d, J = 6 Hz, 1H, amide NH), 7.17 (d, J = 1.5 Hz, 5-thiazole CH) , 6.18 (br d, J = 6Hz, 1H, amide NH), 4.72 (q, J = 6 Hz, 1H, CHOH), 4.32-4.20 (m, 1H, NCHCO), 3.74-3.58 (br m, 9H, four morpholino CH₂ and 1H, CHOH), 3.39 (d of d, J = 4.5 and 15 Hz, 1H, CH-thiazole), 2.35-2.26 (m, 2H, two cyclopropyl CHCO), 0.99-0.85 ( m, 9H, three CH₃); Mass spectrum (M+H)⁺: 607.

Example 41

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl)- carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of

2(S)-Amino-1-cyclohexyl-3(R) ,4(S)-dihydroxy-6- methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 16 (46 mg), 0.18 mmol), N-methylmorpholine (24 mL), HOBT (78 mg), EDC HCl (41 mg) and amine (69 mg) gave the product as a mixture of diastereomers (87 mg, 71%). Mass spectrum (M+H)⁺: 635. Exact mass calculated for C₃₃H₅₅N₄O₆S: 635.3842. Found: 635.3842.

The two diastereomers were separated by FC to give 18 mg of the less polar isomer (41A) : ¹H NMR (CDCI₃) δ 8.79

(d, J = 1.5 Hz, 1H, 2-thiazole CH), 7.63 (br d, J = 6 Hz, 1H, amide NH), 7.16 (d, J = 1.5 Hz, 5-thiazole CH), 6.27 (br d, J = 6Hz, 1H, amide NH), 4.72 (q, J = 6 Hz, 1H, CHOH), 4.32-4.20 (m, 1H, NCHCO), 3.74-3.58 (br m, 9H, four morpholino CH₂ and 1H, CHOH), 3.38 (d of d, J = 4.5 and 15 Hz, 1H, CH-thiazole), 2.34-2.25 (m, 2H, two cyclopropyl CHCO), 0.98-0.84 (6 line m, 12H, four CH₃); Mass spectrum (M+H) ⁺: 635.

The more polar isomer (4IB) was isolated next, yielding 9 mg: ¹H NMR (CDCI₃) δ 8.79 (d, J = 1.5 Hz, 1H,

2-thiazole CH), 7.62 (br d, J = 6 Hz, 1H, amide NH) , 7.17 (d, J = 1.5 Hz, 5-thiazole CH) , 6.17 (br d, J = 6Hz, 1H, amide NH) , 4.72 (q, J = 6 Hz, 1H, CHOH), 4.32-4.20 (m, 1H, NCHCO), 3.74-3.58 (br m, 9H, four morpholino CH₂ and 1H, CHOH), 3.41 (d of d, J = 4.5 and 15 Hz, 1H, CH-thiazole), 2.36-2.26 (m, 2H, two cyclopropyl CHCO), 0.95-0.83 (6 line m, 12H, four CH₃); Mass spectrum (M+H)⁺: 635. Example 42

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanerarbonyl -L-thiazolylalanine amide of 2(S)- Amino-1-cyclohexyl-3(R) ,4(S)-dihydroxy-6-methylheptane Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with 100 mg (0.36 mmol) of the acid from example 17, 48 mL N-methylmorpholine, 157 mg (1.1 mmol) HOBT, 84 mg (0.44 mmol) EDC HCl and 139 mg (0.38 mmol) of amine gave 167 mg (70% yield) the product. Mass Spectrum (M+H)⁺: 655. Exact mass calculated for C₃₅H₅₁N₄O₆S: 655.3532. Found: 655.3532.

Anal, calcd. for C₃₅H₅₁N₄O₆S: C, 64.19; H, 7.70; N, 8.56. Found: C, 63.07; H, 7.63; N, 8.73.

Example 43

(1R*,2R*,3S*)_ -2- (4-Morpholiny l) carbonyl-3-phenyl cyclopropanecarbonyl-L-histidyl amide of 2(S)-Amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with 36 mg (0.14 mmol) of the acid from example 17, 19 mL N-methylmorpholine, 61 mg (0.45 mmol) HOBT, 90 mg (0.47 mmol) EDC HCl and 1.3 equivalent of the amine prepared in example 29 gave 49 mg (55% yield) of the product.

Mass Spectrum (M+H)⁺: 638.

Anal, calcd. for C35H51 N506: C, 63.23; H, 8.19; N, 10.53. Found: C, 63.18; H, 7.91; N, 10.86.

Example 44 (Z)-(1 ,1-Dimethylethyl)dimethyl((3-phenyl-2-propenyl)- oxy)silane

Using the procedure in example 1 and 2.90 g (21.5 mmol) of (Z)-3-phenyl-2-propen-1-ol, 3.90 g (25.8 mmol) of t-butyldimethylsilyl chloride and 1.75 g (25.8 mmol) of imidazole, the protected alcohol was obtained in 82% yield; ¹H NMR (CDCI₃) δ 7.34-7.16 (comp, 5H), 6.48 (d, 1H,

J = 11.8 Hz), 5.86-5.78 (comp, 1H), 4.44 (d, 1H, J = 6.1 Hz), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (CDCI₃) d 136.8, 132.5, 129.5, 128.7, 128.1, 127.0, 60.3, 25.9, 18.3, -5.2; IR (neat) V 2960, 2940, 2860, 1270,

1100, 850, 790; Mass spectrum m/e: 248, 191, 117; Exact mass calculated for C₁₄H₂₁OSi: 233.136169. Found:

233.134717.

Example 45

(Z )-((4-Cyclohexyl-2-butenyl)oxy)(1,1-dimethylethyl)- dimethylsilane

Using the procedure in example 1 and 1.00 g (6.49 mmol) of (Z)-4-cyclohexyl-2-buten-1-ol, 1.18 g (7.79 mmol) of t-butyldimethylsilyl chloride and 0.530 g (7.79 mmol) of imidazole, the protected alcohol was obtained in 77% yield; ¹H NMR (CDCI₃) δ 5.58-5.39 (comp, 2H), 4.20 (d, 2H,

J = 5.9 Hz), 2.10-2.06 (m, 1H), 1.91 (t, 2H, J = 7.0 Hz), 1.81-1.62 (comp, 6H), 1.32-1.10 (comp, 5H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR (CDCI₃) δ 130.3, 129.3, 59.5, 37.3, 33.2, 32.7, 26.6, 26.3, 25.8, 18.3, -5.1; IR (neat) V 2920, 2830, 1280, 1110, 870, 810; Mass spectrum m/e: 253, 211, 137, 135, 95, 81, 75; Exact mass calculated for

C₁₅H₂₉OSi: 253.198769. Found: 253.198562. Example 46

(1R*,2R*,3S*)-7- ((1,1-Dimethylethyl) dimethyl siloxymethyl)-3-phenylcyclopropanecarboxylic acid ethyl ester Using the procedure in example 3 and 114 mg (0.460 mmol) of protected alcohol from example 45, 193 mg (1.70 mmol) of ethyl diazoacetate and 8.0 mg (0.017 mmol) of Rh₂ (OAc) 4 in 1 ml CH₂Cl₂, the diastereomeric cyclopropane adducts were obtained in a 2:1 ratio. The major product was isolated in 37% yield by HPLC (60:1 hexanes:EtOAc). 1H NMR (CDCI₃) δ 7.48-7.35 (comp, 5H), 4.36 (q, 2 H, J =

7.2 Hz), 3.67 (dd, 1H, J = 5.8, 11.1 Hz), 3.50 (dd, 1H, J = 7.3, 11.0 Hz), 3.04 (dd, 1H, J = 5.5, 9.1 Hz), 2.24-2.17 (comp, 2H), 1.47 (t, 3H, J= 7.2 Hz) 0.99 (s, 9H) , 0.08 (s, 3H), 0.06, (s, 3H); ¹³C NMR (CDCI₃) δ 173.3, 135.9,

129.2, 128.2, 126.7, 61.0, 60.6, 30.1, 30.3, 25.8, 23.7, 18.2, 14.8, -5.5; IR (neat) V 3020, 3000, 2920, 1760,

1300, 1220, 1130, 880, 820, 740; Mass spectrum m/e: 277, 129, 103, 75; Exact mass calculated for C₁₈H₂₇O₃Si:

319.172948. Found: 319.173345.

Example 47

(1R*,2R*,3S*)-3-Cyclohexylmethyl-2-((1,1-Dimethylethyyl) dimethylsiloxymethyl)-cyclopropanecarboxylic acid ethyl ester

Using the procedure in example 3 and 355 mg (1.32 mmol) of protected alcohol from example 46, 302 mg (2.65 mmol) of ethyl diazoacetate and 12.0 mg (0.0260 mmol) of Rh₂ (OAc) 4 in 2.0 mL CH₂Cl₂/ the diastereomeric

cyclopropane adducts were obtained in a 2:1 ratio. The major product was isolated in 16% yield by HPLC (80:1 hexanes:EtOAc). ¹H NMR (CDCI₃) δ 4.10 (q, 2H, J = 7.1 Hz), 3.71 (dd, 2H, J = 6.3, 11.1 Hz), 3.59 (dd, 2H, J = 7.5, 11.1 Hz), 1.81-1.61 (comp, 7H), 1.47-1.56 (m, 1H), 1.28- 1.42 (comp, 2H), 1,26-1.09 (comp, 9H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); ¹³C NMR (CDCI₃) δ 174.0, 61.1,

60.2, 38.0, 34.9, 33.5, 33.1, 28.8, 26.6, 26.3, 25.9,

25.3, 18.2, 14.3, -5.2, -5.3; IR (neat) V 2940, 2860,

1730, 1280, 1200, 1110, 860, 810; Mass spectrum m/e: 355, 339, 297, 223, 177, 149; Exact mass calculated for

Cl9H35θ3Si: 339.235549. Found: 339.235682.

Example 48

(1R*,2R*,3S*)-3-Phenylcyclopropanedicarboxylic acid monoethyl ester

Using the procedure in example 5, 58 mg (0.17 mmol) of cyclopropyl ester from example 47, and 121 mL of 8N Jones Reagent afforded the crude acid in 96% yield (39 mg); ¹H NMR (CDCI₃) δ 9.15 (br s, 1H), 7.36-7.13 (comp,

5H), 4.20 (q, 2H, J = 7.0 Hz), 3.11 (dd, 1H, J = 6.5, 10.3 Hz), 2.79 (m, 1H) , 2.57 (m, 1H), 1.30 (t, 3H, J = 7.1 Hz); ¹³C NMR (CDCI₃) δ 173.6, 171.2, 133.7, 128.9, 128.2,

127.4, 61.3, 33.2, 29.5, 26.4, 14.1; IR (neat) V 2980,

1720, 1710, 1300, 1190, 920, 740; Mass spectrum m/e: 234, 189, 133, 115; Exact mass calculated for C₁₃H₁₄O₄:

234.089209. Found: 234.088554.

Example 49

(1R*,2R*,3S*)-3-Cyclohexylmethylcyclopropan dicarboxylic acid monoethyl ester

Using the procedure in example 5, 60 mg (0.17 mmol) of cyclopropyl ester from example 48, and 118 mL of 8N Jones Reagent afforded the crude acid in 93% yield (40 mg); ¹H NMR (CDCI₃) δ 9.50 (br s, 1H), 4.14 (q, 2H, J = 7.1 Hz), 2.29-2.25 (m, 1H), 2.16-2.10 (m, 1H) , 1.89-1.82 (m, 1H), 1.80-1.62 (comp, 5H), 1.59-1.43 (comp, 2H), 1.42-1.05 (comp, 6H), 1.00-0.82 (comp, 3H) ; ¹³C NMR (CDCI₃) δ 176.0,

171.7, 61.0, 37.9, 33.3, 33.1, 32.9, 28.5, 28.4, 26.5,

26.2, 14.2; IR (neat) V 2960, 2900, 1750, 1730, 1480,

1340, 1250, 1200, 760; Mass spectrum m/e: 255, 237, 209; Exact mass calculated for C₁₄H₂₃O₄: 255.159634. Found: 255.158748.

Example 50

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl

cyclopropanecarhoxylic acid ethyl ester Using the procedure of example 7, 41 mg (0.18 mmol) of acid from example 49, 51 mg (0.19 mmol) of DCC, 2.0 mg (0.017 mmol) of DMAP and 17 mg (0.19 mmol) morpholine gave 31 mg of morpholinoamide. ¹H NMR (CDCI₃) δ 7.17 (comp,

3H), 7.14-7.11 (comp, 2H), 4.18 (q, 2H, J= 7.1 Hz), 3.75- 3.65 (m, 1H), 3.58-3.26 (comp, 4H), 3.21-3.03 (comp, 2H),

2.98 (dd, 1H, J= 5.0, 5.7), 2.89 (dd, 1H, J = 5.7, 10.2

Hz), 2.73-2.80 (m, 1H), 2.66 (dd, 1H, J = 5.0, 10.2 Hz),

1.29 (t, 3H, J = 7.1 Hz); ¹³C NMR (CDCI₃) δ 172.4, 164.8,

134.9, 128.4, 127.4, 127.2, 66.6, 61.2, 45.7, 42.2, 33.9,

32.3, 32.1, 25.6, 14.1; IR (neat) V 3000, 2940, 2880,

1740, 1660, 1480, 1250, 1320, 1210, 1130, 750; Mass spectrum m/e: 303, 230, 115; Exact mass calculated for C₁₇H₂₁NO₄: 303.147058. Found: 303.147214. F.xample 51

(1R*,2R*,3S*)-3-Cyclohexγlmethyl-2-(4-morpholinyl) carbonylcyclopropanecarboxylic acid ethyl ester

Using the procedure of example 7, 29 mg (0.11 mmol) of acid from example 50, 33 mg (0.13 mmol) of DCC, 1.4 mg (0.012 mmol) of DMAP and 11 mg (0.13 mmol) morpholine gave 23 mg of the title morpholinoamide. ¹H NMR (CDCI₃) δ 4.13

(comp, 2H), 3.81-3.46 (comp, 8H), 2.33-2.27 (comp, 2H), 1.80-1.57 (comp, 6H) , 1.42-1.04 (comp, 9H) , 0.97-0.81 (comp, 2H); ¹³C NMR (CDCI₃) δ 173.1, 167.0, 67.0, 66.8,

60.8, 46.1, 42.4, 37.9, 34.0, 33.9, 32.9, 27.4, 26.5, 26.3, 14.2; IR (neat) v 2950, 2890, 1740, 1660; Mass spectrum m/e: 323, 250, 129, 81; Exact mass calculated for C₁₈H₂₉NO₄: 323.209659. Found: 323.211043.

Example 52

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl

cyclopropanecarboxylic acid

Using the procedure in example 9, 41 mg (0.14 mmol) of ester from example 51, 1 mL of 2 N HCl and 1 mL of THF, the acid was obtained in 56% yield (21 mg) after

purification by flash chromatography (1:2 hexanes:EtOAc plus 1% acetic acid). ¹H NMR (CDCI₃) δ 7.60 (bs, 1H),

7.31-7.26 (comp, 3H), 7.23-7.06 (comp, 2H), 3.76-3.63 (m, 1H), 3.59-3.40 (comp, 4H), 3.23-2.90 (comp, 4H), 2.79-2.69 (comp, 2H); ¹³C NMR (CDCI₃) δ 176.3, 165.1, 134.6, 128.5,

128.2, 127.4, 66.5, 45.8, 42.4, 32.7, 32.4, 25.4; IR

(neat) V 2980, 2940, 2880, 1730, 1650, 1450, 1290, 1140,

940, 760; Mass spectrum m/e: 275, 230, 115; Exact mass calculated for C₁₅H₁₇NO₄: 275.115758. Found:

275.115884. Example 53

(1R*,2R*,3S*)-3-Cyolohexylmethyl-2-(4-morpholinyl)- carbonylcyolopropanecarboxylic acid Using the procedure in example 9, 16 mg (0.050 mmol) of ester from example 52, 1 mL of 2 N HCl and 1 mL of THF, the acid was obtained in 68% yield (10 mg) after

purification by flash chromatography (1:2 hexanes:EtOAc plus 1% acetic acid). ¹H NMR (CDCI₃) δ 5.90 (br s, 1H),

3.82-3.48 (comp, 8H), 2.37 (dd, 1H, J = 4.4, 9.7 Hz), 2.32 (m, 1H), 1.88-1.66 (comp, 6H) , 1.42-1.10 (comp, 6H), 0.97-0.85 (comp, 2H); ¹³C NMR (CDCI₃) δ 178.0, 166.7, 66.9,

66.7, 46.0, 42.4, 37.8, 33.9, 33.2, 32.8, 28.0, 26.4, 26.2, 25.9; IR (neat) V 2940, 2880, 1740, 1640, 1460,

1250, 1140; Mass spectrum m/e: 295, 250, 187, 129; Exact mass calculated for C₁₆H₂₅NO₄: 295.178359. Found:

295.178407.

Example 54

(1 ,1-Dimethylethyl)dimethyl(3-propynyloxy)silane

Using the procedure in example 1 and 14 g (0.25 mol) of propargyl alcohol, 45 g (0.30 mol) of t-butyldimethylsilyl chloride, and 20.4 g (0.30 mol) of imidazole in 125 mL of dry DMF the protected propargyl alcohol was obtained in 68 % yield as a colorless oil. ¹H NMR (CDCI₃) δ 4.29-4.28 (d, 2H, J = 2.5 Hz), 2.37-2.36 (t, 1H, J = 2.3), 0.89 (s, 9H), 0.1 (s, 6H); ¹³C NMR (CDCI₃) δ 82.5, 72.8, 51.5, 25.8, 18.3, -5.2; IR (neat) V 3140, 2960, 2950, 2930, 2910, 1480, 1470, 1370, 1260, 1110, 1010, 850, 790, 670, 630. Example 55

(1,1-Dimethylethyl)dimethyl((4-phenyl-3-butynyl)oxy)- silane

To a stirring solution of 19.4 g (114 mmol) of protected propargyl alcohol from example 55 in 29 mL of dry THF at -78 °C, was added 31 mL (122 mmol) of a 3.98 M solution of n-butyl lithium in hexane. The mixture was allowed to stir for 15 min, and 13 g (76 mmol) of benzyl bromide was added. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 100 mL of H2θ and extracted with (3 × 100 mL) Et₂O. The organic extracts were combined, washed with (1 × 100 mL) brine, dried (MgSO₄), and concentrated under reduced pressure to yield 9% (1.7 g) of the alkyne as a colorless oil after purification by flash chromatography (100:1 hexanes:EtOAc). ¹H NMR (CDCI₃) δ 7.24-7.17 (comp,

5H), 4.28-4.27 (t, 2H, J = 2.2 Hz), 3.55-3.53 (t, 2H, J = 2.0 Hz), 0.82 (s, 9H), 0.03 (s, 6H).

Example 56

(Z) - (1,1-Dimethylethyl)dimethyl((4-phenyl-3-bntenγl)oxy) silane

To a suspension of 0.73 g (2.9 mmol) of NiOAc4.4H2θ in 23 mL of EtOH, was added dropwise 3 mL of a 1 M

solution of NaBH4 in 0.1 N NaOH in EtOH. The flask was flushed with H2, and 0.4 mL of ethylenediamine was added. To this solution, was added 2.3 g (8.8 mmol) of the alkyne from example 56, and the mixture stirred for 3 h. The mixture was diluted with 250 mL of hexane:EtOAc (1:1), and filtered through a pad of florisil. The filtrate was dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography (75:1 hexanes:EtOAc) to yield 56 % (1.3 g) of the alkene as a colorless oil. ¹H NMR (CDCI₃) δ 7.35-7.21 (comp, 5H),

5.75-5.65 (comp, 2H), 4.40-4.38 (d, 2H, J = 4.7 Hz), 3.47- 3.45 (d, 2H, J = 6.2 Hz), 0.98 (s, 9H), 0.15 (s, 6H); ¹³C NMR δ (CDCI₃) 140.5, 130.6, 129.1, 128.4, 128.3, 126.0, 59.4, 33.8, 26.0, 18.4, -5.1; IR (neat) V 3030, 2990,

2980, 2960, 2950, 1680, 1630, 1520, 1490, 1280, 1120, 870, 800, 770, 730.

F.xamp] e 57

(1R*,2R*,3S*)-2-((1,1-Dimethylethyl)dimethylsiloxymethyl)-3-benzylcyclopropanecarhoxylic acid ethyl ester

Using the procedure in example 3 and 294 mg (1.12 mmol) of protected alcohol from example 57, 255 mg (2.24 mmol) of ethyl diazoacetate and 9.9 mg of Rh2 (OAc) 4 in 1.3 mL CH₂Cl₂, the diastereomeric cyclopropane adducts were obtained in a 1.25:1 ratio. The major product was

isolated in 27 % yield (105 mg) by HPLC (60:1

hexanes:EtOAc) as a clear oil. ¹H NMR (CDCI₃) δ 7.30-7.16

(comp, 5H), 4.11-4.04 (q, 2H, J = 7.1 Hz), 3.85-3.80 (dd, 1H, J = 5.0, 11.2 Hz), 3.72-3.66 (dd, 1H, J = 6.4, 11.1 Hz), 2.85-2.77 (dd, 1H, J= 6.4, 15.3 Hz), 2.76-2.69 (dd, 1H, J = 6.4, 15.3 Hz), 1.83- 1.77 (comp, 2H), 1.50-1.47 (t, 1H, J = 4.7 Hz), 1.23- 1.18 (t, 3H, J = 7.1 Hz), 0.87 (s, 9H), 0.03 (s, 6H); ¹³C NMR (CDCI₃) δ 173.4, 140.8, 128.4,

128.3, 126.1, 60.9, 60.4, 33.1, 29.0, 27.4, 25.9, 24.9, 18.3, 14.2, -5.3; IR (neat) V 2980, 2970, 2950, 2930,

1740, 1480, 1410, 1390, 1340, 1280, 1240, 1390, 1110, 860, 800, 750, 720. Example 58

(1R*,2R*,3S*)-3-Benzylcγclopropanedicarboxylic acid monoethyl ester

Using the procedure in example 5, 335 mg (0.963 mmol) of the cyclopropyl ester from example 58, 112 mg (1.93 mmol) of KF, and 481 mL of 8N Jones Reagent in 5 mL of acetone afforded the acid in 87 % yield (208 mg) after purification by HPLC (1:2 hexanes:EtOAc plus 1% acetic acid) as a white solid (m.p. 79-81 °C). ¹H NMR (CDCI₃) δ

7.36-7.17 (comp, 6H), 4.20-4.13 (q, 2H, J = 7.2 Hz), 3.10-3.03 (dd, 1H, J = 6.9, 15.0 Hz), 3.00-2.93 (dd, 1H, J = 7.7, 15.0 Hz), 2.44-2.36 (comp,2H), 2.20-2.16 (comp, 1H), 1.32-1.27 (t, 3H, J = 7.2 Hz); ¹³C NMR (CDCI₃) δ 176.4,

171.3, 139.6, 128.6, 128.2, 126.4, 61.2, 31.7, 30.6, 28.6, 27.1, 14.1; IR (neat) V 3120, 3000, 1740, 1710, 1470,

1390, 1240, 1190, 1110, 1060, 750, 710.

Examp]e 59

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-benzyl

cyclopropanecarboxylic acid ethyl ester Using the procedure in example 7, 122 mg (0.49 mmol) of the acid from example 59, 112 mg (0.54 mmol) of DCC, 6.0 mg (0.049 mmol) of DMAP and 47.1 mg of morpholine gave the morpholinoamide in 62% yield (97 mg) after

purification by HPLC (1:1 hexanes:EtOAc) as a clear oil. ¹H NMR (CDCI₃) δ 7.29-7.12 (comp, 5H), 4.12-4.08 (q, 2H, J

= 7.2 Hz), 3.65-3.35 (comp, 6H), 3.15-3.00 (comp, 3H), 2.58-2.50 (comp, 2H), 2.34-2.29 (comp, 1H), 2.18-2.10 (comp, 1H), 1.27-1.23 (t, 3H, J = 7.2 Hz); ¹³C NMR (CDCI₃) δ 172.6, 166.6, 140.0, 128.9, 128.3, 126.3, 66.5, 66.2, 60.9, 45.6, 42.2, 33.9, 32.4, 29.4, 27.3, 14.1; IR (neat)

V 2980, 2970, 2960, 2930, 1730, 1480, 1390, 1290, 1210,

1120, 1080, 870, 810.

Examp]e 60

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-henzyl

cyclopropanecarboxylic acid

Using the procedure in example 9, 97 mg (0.306 mmol) of the ester from example 60, 2.5 mL of 2N HCl and 2.5 mL of THF, the acid was obtained in 45% yield (40 mg) after purification by flash chromatography (1:2 hexanes:EtOAc plus 1% acetic acid) as a white solid (m.p. 150-152 °C) ¹H NMR (CDCI₃) δ 7.21-7.02 (comp, 5H), 7.75-6.00 (br s, 1H), 3.53-3.25 (comp, 6H), 3.09-2.87 (comp, 3H), 2.52-2.40 (comp, 2H), 2.33-2.22 (comp, 1H), 2.14-2.03 (comp, 1H); ¹³C NMR (CDCI₃) δ 175.0, 166.9, 139.5, 128.9, 128.2, 126.9,

66.6, 66.3, 62.6, 45.8, 42.3, 32.5, 30.3, 28.1; IR (neat)

V 3240, 3000, 2980, 2950, 1740, 1640, 1460, 1300, 1260,

1200, 1140.

Example 61

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl cyclopropanecarbonyl -L-thiazolylalanine amide of 2 (S) - Amino-1-cyclohexγl-3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with 21 mg (0.076 mmol) of the acid from example 53, 9 μL N-methylmorpholine, 33 mg (0.24 mmol) HOBT, 16 mg (0.08 mmol) EDC HCl and 29 mg (0.076 mmol) of amine gave 38 mg (76% yield) of the product. Mass Spectrum (M+H)⁺: 655. Exact mass calculated for C₃₅H₅₁N₄O₆S: 655.3532. Found:

655.3532.

Example 62

(1R*,2R*,3S*) -2- (4-Morpholinγl) carbonγl-3-cγclohexγl methylcyclopropanecarbobyl-L-thiazolylalanine amide of 2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with 10 mg (0.034 mmol) of the acid from example 54, 4 mL N-methylmorpholine, 14.7 mg (0.11 mmol) HOBT, 7.2 mg (0.038 mmol) EDC HCl and 13 mg (0.034 mmol) of amine gave 18 mg (78% yield) of the product. Mass Spectrum (M+H)⁺: 675. Exact mass calculated for C₃₆H₅₉N₄O₆S: 675.4155. Found:

675.4148.

Example 63

(1R*,2R*,3S*)-2-(4-Morpholinylicarbonyl-3-benzyl cyclopropanecarhobyl -L-thiazolylalanine amide of 2 (S) - Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with 20 mg (0.069 mmol) of the acid from example 61, 8.3 mL N-methylmorpholine, 30 mg (0.22 mmol) HOBT, 14.6 mg (0.076 mmol) EDC HCl and 26.4 mg (0.069 mmol) of amine gave 29.1 mg (63% yield) of the product. Mass Spectrum (M+H)⁺: 669. Exact mass calculated for C₃₆H₅₃N₄O₆S: 669.3688. Found: 669.3686. F.x?_mp]e 64

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl cyclopropanecarbobyl-L-histidyl amide of 2 (S)-Amino-1- cyclohexy]-3(R),4(S)-dihydroxy-6-methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 29 gives the desired product.

Example 65

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-pheny]- cyclopropanecarbobyl-L-leucyl amide of 7 ( S) -Amino-1- cyclohexyl-3(R),4 (S)-dihydroxy-6-methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 31 gives the desired product.

Example 66

(1R*,2R*,3S*)-2-(4-Morpho]inyl)carhony]-3-pheny]- cyclopropanecarhobyl-L-nor-leucyl amide of 2 (S)-Amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 32 gives the desired product. Example 67

(1R*,2R*,3S*)-2-(4-Morpholinylicarbonyl-3-phenylcyclopropanecarhobyl-L-4-thiazolylalanyl amide of N-Butyl

5 ( S)-Amino-6-cγclohexyl-4( S)-hydroxy-5(S) - isopropylhexamide

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 33 gives the desired product.

Example 68

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarhobyl-L-4-thiazolylalanyl amide of (2 ' S,

1'R, 5'S)-3-Ethyl-5-(1'-hydroxy-2'amino- 3'cyclohexylpropyl)-oxazolidin-2-one Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 34 gives the desired product.

Example 69

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbobyl-L-4-thiazolylalanyl amide of (7S,4S,1'R,2'S)-2-(2-Amino-3-cγclohexyl-1-hydroxy)-4- meehyl-tetrahydrofuran

Using the procedure in example 37 and replacing cyclopropyl carboxylic acid from example 10 with the acid from example 53 and the amine prepared in example 35 gives the desired product. Example 70

Z-Trimethyl((3-phenyl-2-propenyl)_oxy) silane A solution of 102 g (0.76 mol) of z-cinnamyl alcohol, 122 g (161 mL, 0.76 mol) of hexamethyldisilazane, and five drops of trimethylsilyl chloride were heated at 65 °C for 18 h. The product was isolated by vacuum distilation to give 147 g (78%) yield of a water white liquid: bp 85-89 °C(0.4 mm Hg).

Example 71

(2R*, 3S*)-1,1-Dibromo-2-hydroxymethyl-3-phenylcyclopropane

A suspension of 9.4 g (.017 mol) of

phenyltribromomethyl mercury and 14.0 g (.068 mol) of the silyl ether from example 70 in 50 mL of benzene was heated at reflux temperature for 1 h. The reaction mixture was cooled, filtered and the precipitate washed with ether. The organic solutions were combined and concentrated. The residue was dissolved into 5 mL of THF and 50 mL of 1N HCl was added. The two phase mixture was stirred at room temperature for 15 m, ethyl acetate was added and the aqueous layer was separated. The organic layer was dried (MgSO₄), filtered and concentrated. TLC showed product and cinnamyl alcohol. The crude mixture was dissolved into 100 mL of dichlromethane, cooled to 0-5 °C in an ice-water bath and 22 g of 50-60% meta-chloroperbenzoic acid was added. The reaction was stirred for 1.5 h and a saturated solution of sodium thiosulfate was added. The aqueous layer was separated extracted with

dichloromethane. The combined dichloromethane extracts were dried (MgSO₄), filtered and concentrated to give 8.64 g of residue. The product was purified by FC using a.1:4 and 1:3 ethyl, acetate :hexane gradient. Yield 3.07 g (59% based on phenyltribromomethyl mercury) : mp 58-59 °C; ¹H NMR (CDCl₃) δ 7.44-7.23 (m, 5H, C₆H₅), 4.15-4.03 (8 line m, 1H, CH-O), 3.91-3.78 (8 line m, 1H, CH-O), 2.73 (d, J = 9 Hz, 1H), 2.28 (d of d of d, J = 5 Hz, 1H) , 1.88 (d of d, 5 and 9 Hz, 1H, OH).; IR (CDCL₃) v 3600 (OH);

Anal, calcd. for C₁₀H₁₀Br₂O: C, 39.21; H, 3.26.

Found: C, 39.21, H, 3.32.

Example 72

(2R*, 3S*)-1,1-Dibromo-2-[1,1-dimethylethyl) dimethylsiloxymethyl)-3-phenyl-cyclopropane

A solution od 2.2 g (7.2 mmol) of alcohol from example 71, t-butyldimethylsilyl chloride (1.6 g, 10.7 mmol) and imidazole (0.73 g, 10.7 mmol) in 6 mL of DMF were stirred in an ice-water bath for 1 h. Reaction mixture was diluted with saturated sodiun bicarbonate and the product was extracted with diethyl ether. The ether layers were dried (MgSO₄) , filtered, and concentrated to give an oil. The crude oil was purified by FC using 98:2, hexane:ether as eluant. Product was isolated as clear oil, 2.4 g (80%). ¹H NMR (CDCI₃) δ

7.40-7.24 (m, 5H, C₆H₅) , 4.01-3.88 (8 line m, 2H, CH₂O), 2.65 (d, J = 9 Hz, 1H, CH-Ph), 2.23-2.14 (m, 1H), 0.93 (s, 9H, t-buyl), 1.3 (s, 3H, CH₃), 1.2 (s, 3H, CH₃); Mass spectrum (M+NH₄ ⁺) 436 and 440

Anal, calcd. for C₁₆H₂₄Br₂OSi: C, 45.71; H, 5.71.

Found: C, 44.77, H, 5.52. Example 73

(1S*,2R*, 3S*) and (1R*,2R*,3S*)-1-Thiopheny]-2- hydroxymethyl-3-phenylcyclopropane

To a cooled solution (-100 °C internal temperature) of 2.46 g (5.85 mmol) of dibromide from example 72 in 10 mL of dry THF was added 02.5 mL of a 2.5 M (6.2 mmol) solution of n-butyllithium in hexanes. The reaction was stirred for 10 min and excess acetic acid in THF was added. The reaction mixture was warmed to room

temperature, diluted with water, and the product extracted with ethyl acetate. TLC and NMR revealed the presence of two monobromide products. The crude mixture was used without further purification.

Example 74

(1S*,2R*, 3S*) and (1R*,2R*,3S*)-1-Phenylsulfony]-2- hydroxymethyl-3-phenylcyclopropane

The individual isomers were treated with meta- chloroperbenzoic acid at room temperature for 3 h. The reaction was quenched with saturated sodium thiosulfate and the product extracted with chloroform and purified by FC using 1:1 ethyl acetate:hexane The less polar sulfide from example 73 gave 57 mg of a less polar sulfone: mp 118-19 °C; ¹H NMR (CDCl₃) δ 8.02-7.95 (m, 1H,), 7.71-7.54

(m, 3H), 7.30-7.17 (m, 5H), 7.04-6.97 (m, 1H), 4.34-4.22 (8 line m, 1H, CH-O), 4.22-4.10 (8 line m, 1H, CH-O), 3.04 (d of d, J = 7 and 6 Hz, 1H, CHSO₂), 2.78 (d of d , J = 6 Hz, 1H, CHPh), 2.44 (d of d, 6 Hz, 1H, OH), 2.29-2.17 (m, 1H,).

Single crystals suitable for X-ray analysis were obtained by diffusion crystallization from ethyl acetate / hexane. Clear orthorhombic neddles belonging to the Pna2₁ space group were Isolated. X-ray analysis revealed that the phenylsulfone and hydroxymethyl groups were cis to each other and both were trans to the phenyl group. The configuration of the less polar sulphone isomer was 1R*, 2R*, 3S*.

Anal, calcd. for C₁₆H₁₆SO₃: C, 66.66; H, 5.55. Found: C, 65.75, H, 5.47.

The more polar sulfide from example 73 gave 20 mg of a more polar sulfone: mp 85-86 °C; ¹H NMR (CDCI₃) δ 7.62- 7.56 (m, 1H,), 7.44-7.36 (m, 4H), 7.25-7.16 (m, 3H), 7.14-7.08 (m, 2H), 3.78-3.70 (m, 2H, CH₂O), 2.98 (d of d, J = 3 and 6 Hz, 1H, CHSO₂), 2.80-2.73 (m, 1H), 2.68 (d of d, J = 3 and4 Hz, 1H, CHPh). The relative stereochemistry of the more polar isomer was assigned the 1S*, 2R*, 3S*

configuration.

Example 75

(1R*,2R*, 3S*)-2-Phenylsulfonyl-3-phenylcyolopropanecarboxylic acid

Using the procedure of example 4 (deleting anhydrous potassium fluoride) and 50 mg of the less polar sulfone alcohol from example 74, in 1 mL acetone and 1 mL Jones reagent at 0-5 °C for 2 h. The reaction was quenched with excess isopropyl alcohol. The crude acid (48 mg) was obtained as a white solid after concentration and

extraction of the reaction mixture with CHCI₃.

Mass spectrum (M+NH4⁺) 320. Example 76

(1R*,2S*, 3S*)-2-Phenylsulfonyl-3-phenylcyclopropanecarboxylic acid

Using the procedure of example 75 and the more polar sulfone alcohol from example 74 (20 mg) gave 25 mg of the crude carboxylic acid. Mass spectrum (M+NH₄ ⁺) 320.

Example 77

(1R*, 2R*, 3S*)-2-Phenylsulfonyl-3- phenylcyclopropanecarbonyl-L- thiazolylalanine amide of

2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6- methylheptane

Using the procedure of example 37 and replacing the cyclopropyl carboxylic acid from example 10 with 24 mg of the acid from example 75, EDAC (18 mg) , and HOBT (34 mg) gave 42 mg (76%) of the product.as a mixture of

diastereomers. Mass spectrum (M+H⁺) 682.

Example 78

(1R*, 2S*, 3S*)-2-Phenylsulfony]-3- phenylcyclopropanecarbonyl-L- thiazoylalanine amide of

2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6- methylheptane

Using the procedure of example 37 and replacing the cyclopropyl carboxylic acid from example 10 with 16 mg of the acid from example 76, EDAC (12 mg), and HOBT (23 mg) gave 22 mg (62%) of the product.as a mixture of

diastereomers. Mass spectrum (M+H⁺) 682. Example 79

(Z)-2-Pentenyl diazoacetate

Glyoxylic acid chloride p-toluenesulfonylhydrazone (439 mg, 1.68 mmol) was added to an ice-cooled solution of (Z)-2-penten-1-ol (111 mg, 1.29 mmol) in 6.3 mL of dry CH₂CI₂ under a nitrogen atmosphere. Dimethylamine (204 μL, 195 mg, 1.61 mmol) was added and the solution was stirred for 15 min prior to injection of triethylamine (920 μL, 668 mg, 6.61 mmol). The resulting dark suspension was stirred 15 min at 0 °C then for 30 min at room temperature before water (6 mL) was introduced. The reaction was extracted with Et₂O (3 × 10 mL), dried (MgSO₄), and concentrated in vacuo. Flash chromatography (25:1 hexanes:EtOAc) afforded 166 mg (1.08 mmol, 84% yield) (Z)-2-pentenyl diazoacetate as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 5.67-5.59 (m, 1H), 5.52-5.43 (m, 1H), 4.73 (s, 1H), 4.68 (d, J = 6.9 Hz, 2H), 2.10 (dq, J = 7.0, 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 166.6, 137.1, 122.7, 60.5, 46.0, 20.8, 14.0.

Example 80

(Z)-5-Methyl-2-hexenyl diazoacetate

The crude diazoester was prepared using the procedure in example 79 and glyoxylic acid chloride p-toluenesulfonylhydrazone (1.50 g_Λ 5.73 mmol), (Z)-5-methyl-2-hexen-1-ol (525 mg, 4.40 mmol), 22 mL CH₂CI₂, dimethylaniline (700 μL, 666 mg, 5.50 mmol), and triethylamine (3.14 mL, 2.28 g, 22.6 mmol) . Flash chromatography (15:1 hexanes:EtOAc) afforded 778 mg (4.27 mmol, 93% yield) (Z)-5-methyl-2-hexenyl diazoacetate as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 5.71-5.54 (comp, 2H), 4.77 (s, 1H), 4.70 (d, J = 6.5 Hz, 2H) , 2.00 (t, J = 6.9 Hz, 2H), 1.64 (m,. J = 6.7 Hz, 1H) , 0.90 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCI₃) d 166.0, 134.2, 123.8, 60.5, 46.0, 36.4, 28.3, 22.1; IR (neat) v 3000, 2160, 1720, 1410, 1380, 1270, 1210 cm^-1; Mass spectrum m/e : 182, 167, 154, 139, 111, 96.

Example 81

(Z)-4-Cyclohexyl-2-butenyl diazoacetate The crude diazoester was prepared using the procedure in example 79 and glyoxylic acid chloride p-toluenesulfonylhydrazone (329 mg, 1.25 mmol), (Z)-4-cyclohexyl-2-buten-1-ol (103 mg, 0.671 mmol), 3.3 mL CH₂Cl₂, dimethylaniline (155 μL, 149 mg, 1.23 mmol), and triethylamine (479 μL, 348 mg, 3.44 mmol) . Flash chromatography (15:1 hexanes:EtOAc) afforded 99.7 mg (0.449 mmol, 67% yield) (Z)-4-cyclohexyl-2-butenyl diazoacetate as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 5.68-5.49 (comp, 2H), 4.72 (s, 1H), 4.66 (d, J = 6.5 Hz, 2H), 1.97 (t, J = 6.9 Hz, 2H), 1.68-1.59 (comp, 5H), 1.33-1.08 (comp, 4H), 0.93-0.82 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 166.0, 134.0, 123.7, 60.6, 46.0, 37.8, 35.1, 32.9, 26.3, 26.1.

Example 82

(Z)-3-Phenyl-2-propenyl diazoacetate The crude diazoester was prepared using the procedure in example 79 and glyoxylic acid chloride p-toluenesulfonylhydrazone (3.34 g, 12.7 mmol), (Z)-3-phenyl-2-propen-1-ol (1.34 g, 10.0 mmol), 49 mL CH₂CI₂, dimethylaniline (1.58 mL, 1.51 g, 12.5 mmol), and triethylamine (7.14 mL, 5.18 g, 51.3 mmol). Flash chromatography (15:1 hexanes:EtOAc) afforded 1.72 g (85.1 mmol, 85% yield) (2) -3-phenyl-2-propenyl diazoacetate as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 7.40-7.18 (comp, 5H), 6.69 (d, J = 11.1 Hz, 1H) , 5.83 (dt, J = 11.1, 6.6 Hz, 1H), 4.96 (d, J = 6.6 Hz, 2H) , 4.79 (s, 1H); ¹³C NMR (75 MHz, CDCI₃) δ 166.3, 135.9, 133.0, 128.6, 128.3, 127.4, 125.7, 61.6, 46.0; Mass spectrum m/e : 202, 139, 129, 115, 91; Exact mass calculated for C₁₁H₁₀N₂O₂: 202.074228. Found 202.074723.

Example 83

[1R*, 5S*, 6R*]-6-Ethyl-3-oxabicyclo[3.1.0]hexan-2-one A solution of the diazoester from example 79 (235 mg, 1.53 mmol) in 25 mL toluene was added via a syringe pump to a refluxing solution of bis-(N-t-butylsalicyladimmato)copper (II) catalyst (31.7 mg, 0.076 mmol) in 38 mL toluene over a period of 17 h. The reaction was concentrated at atmospheric pressure. Kugelrohr distillation (10 mm, 170 °C) provided the bicyclic lactone (168 mg, 1.33 mmol) in 87% yield as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 4.38 (dd, J = 5.4, 9.8 Hz, 1H), 4.12 (d, J = 9.8, 1H), 2.27-2.14 (comp, 2H), 1.44-1.31 (comp, 3H), 1.04 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 174.9, 65.9, 29.5, 23.8, 22.6, 22.5, 13.1. Example 84

[1R*, 5S*, 6R*]-6-(2-Methylpropyn-3- oxabicyclo[3.1.0]hexan-2-one

The crude bicyclic lactone was prepared using the procedure from example 83 and the diazoester from example 80 (254 mg, 1.40 mmol) in 3 mL toluene and bis- (N-t-butylsalicyladiminato)copper (II) catalyst (116 mg, 0.279 mmol) in 12 mL toluene. The reaction was cooled and concentrated in vacuo . Flash chromatography (4:1 hexanes:EtOAc) provided the bicyclic lactone (202 mg, 1.31 mmol) in 94% yield as a yellow oil. ¹H NMR (300 MHz, CDCI₃) δ 4.41 (dd, J = 5.4, 9.8 Hz, 1H) , 4.12 (d, J = 9.8 Hz, 1H), 2.30-2.16 (comp, 2H), 1.79-1.70 (m, 1H), 1.48-1.40 (m, 1H), 1.37-1.19 (comp, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 175.1, 66.0, 31.4, 28.1, 22.6, 22.3, 22.3, 20.6.

Example 85

[1R*, 5S*, 6R*]-6-Cyclohexylmethyl-3- oxabicyclo[3.1.0]hexan-2-one

The crude bicyclic lactone was prepared using the procedure in example 83 and the diazoester from example 81

(107 mg, 0.482 mmol) in 10 mL toluene and bis-(N-t-butylsalicyladiminato)copper (II) catalyst (10 mg, 0.0241 mmol) in 10 mL toluene. The reaction was cooled and concentrated in vacuo . Flash chromatography (4:1 hexanes: EtOAc) provided the bicyclic lactone (80.7 mg,

0.416 mmol) in 86% yield as a yellow oil. ¹H NMR (300

MHz, CDCI₃) δ 4.39 (dd, J = 5.5, 9.9 Hz, 1H), 4.14 (d, J =

9.9 Hz, 1H), 2.26-2.14 (comp, 2H), 1.80-1.62 (comp, 5H),

1.49-1.06 (comp, 7H), 1.01-0.87 (comp, 2H) ; ¹³C NMR (75 MHz, CDCI₃) δ 175.2, 66.1, 37.7, 33.1, 30.2, 26.4, 26.2, 22.7, 22.4, 20.5; IR (neat) v 2940, 2890, 1800, 1480, 1410, 1210, 1080, 1030 cm^-1; Mass spectrum m/e : 163, 134, 112, 85, 81, 67, 55, 41; Exact mass calculated for C₁₂H₁₈O₂: 194.130680. Found 194.132160.

Example 86

[1R*, 5S*, 6R*]-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one

The crude bicyclic lactone was prepared using the procedure in example 83 and the diazoester from example 82 (1.82 g, 9.01 mmol) in 186 mL toluene and bis-(N-t-butylsalicyladiminato) copper (II) catalyst (187 mg, 0.450 mmol) in 186 mL toluene. The reaction was cooled and concentrated in vacuo . Flash chromatography (2:1 hexanes:EtOAc) provided the bicyclic lactone (1.18 g, 6.78 mmol) in 75% yield as a yellow solid, m.p. 73-74°; ¹H NMR (300 MHz, CDCI₃) δ 7.36-7.26 (comp, 5H), 4.36 (dt, J = 9.8, 2.5 Hz, 1H), 4.05 (d, J = 9.8 Hz, 1H), 2.78 (t, J = 8.5 Hz, 1H), 2.60-2.57 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ

174.7, 132.4, 129.4, 128.9, 127.7, 65.7, 26.2, 23.9, 23.5; IR (neat) v 1800, 1410, 1230, 1090, 1040, 960, 790 cm^-1; Mass spectrum m/e : 174, 129, 115; Exact mass calculated for C₁₁H₁₀O₂: 174.068080. Found 174.067826.

Example 87

[1R*, 2S*, 3R*]-3-Ethyl-2-hydroxymethyl-1-(4- morpholinyl)carbonylcyclopropane

Trimethylaluminum (2.5 M in hexanes, 589 μL, 1.18 mmol) was slowly added at room temperature under nitrogen to a solution of morpholine (103 μL, 103 mg, 1.18 mmol) in

3 mL of dry CH₂CI₂ at room temperature. The mixture was stirred for 20 min and the lactone from example 83 (49.5 mg, 0.393 mmol) was added in 2 mL CH₂CI₂. The reaction was heated at 40 °C for 40 h and then cooled to 0 °C. The reaction was carefully quenched with 1 N HCl (4 mL), extracted with CH₂CI₂ (3 × 10 mL), dried (MgSO₄), and concentrated under reduced pressure. Flash chromatography (100% EtOAc) provided the hydroxy amide in 70% yield (58.2 mg, 0.273 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 4.08-3.98 (m, 1H), 3.90-3.81 (m, 1H), 3.76-3.41 (comp, 8H), 2.37 (s, 1H), 1.66 (t, J = 8.5 Hz, 1H), 1.57-1.40 (comp, 2H), 1.32-1.11 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 169.6, 66.6, 58.5, 46.1, 41.8, 24.0, 23.4, 22.2, 18.0, 13.7; Mass spectrum m/e : 213, 82, 75, 59; Exact mass calculated for C₁₁H₁₉NO₃: 213.136494. Found 213.138641.

Example 88

[1R*, 2S*, 3R*]-2-Hydroxymethyl-3-(2-methylpropyl)-1-(4- morpholinyl)carbonylcyclopropane

The crude hydroxy amide was prepared using the procedure from example 87 and trimethylaluminum (2.5 M in hexanes, 672 μL, 1.35 mmol), morpholine (117 μL, 117 mg, 1.35 mmol) in 2 mL CH₂CI₂, and the lactone from example 84 (69.0 mg, 0.450 mmol) in 1 mL CH₂CI₂. Flash chromatography (1:9 hexanes : EtOAc) provided the hydroxy amide in 81% yield (88.0 mg, 0.365 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 4.09 (d, J = 10.3 Hz, 1H), 3.94-3.85 (m, 1H), 3.78-3.49 (comp, 8H), 1.73 (t, J = 8.7 Hz, 1H), 1.63-1.27 (comp, 4H, C(2)H), 1.20-1.12 (m, 1H), 0.90

(d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H) ; ¹³C NMR (75 MHz, CDCI₃) δ 169.8, 66.7, 58.9, 46.1, 41.9, 33.2, 28.3, 23.8, 22.5, 22.1, 21.7, 20.9; IR (neat) v 3420, 2960, 1650, 1480, 1260, 1150 cm^-1; Mass spectrum m/e : 241, 210, 184, 129, 114, 95; Exact mass calculated for C₁₃H₂₃NO₃: 241.167794. Found 241.168206.

Example 89

[1R*, 2S*, 3R*]-3-Cyclohexylmethγl-2-hydroxymethyl-1-(4- morpholinyl)carbonylcyclopropane The crude hydroxy amide was prepared using the procedure from example 87 and trimethylaluminum (2.5 M in hexanes, 624 μL, 1.25 mmol), morpholine (109 μL, 109 mg, 1.25 mmol) in 3 mL CH₂CI2, and the lactone from example 85 (80.7 mg, 0.416 mmol) in 1 mL CH₂ Cl₂. Flash chromatography (50:1 CH₂Cl₂:MeOH) provided the hydroxy amide in 80% yield (93.8 mg, 0.334 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 4.09 (d, J = 10.3 Hz, 1H), 3.94- 3.80 (comp, 2H), 3.77-3.46 (comp, 8H), 1.77-1.46 (comp, 7H), 1.42-1.02 (comp, 7H), 0.90-0.78 (comp, 2H) ; ¹³C NMR (75 MHz, CDCI₃) δ 169.9, 66.7, 59.0, 46.2, 41.9, 38.0, 33.0, 31.8, 26.4, 26.2, 24.9, 21.7, 20.6; Mass spectrum m/e : 281, 250, 129, 81, 67, 55, 41; Exact mass calculated for C₁₆H₂₇NO₃: 281.199094. Found 281.199493.

Example 90

[1R*, 2S*, 3R*]-2-Hydroxymethyl-1-(4-morpholinyl)carbonyl- 3-phenylcyclopropane

The crude hydroxy amide was prepared using the procedure from example 87 and trimethylaluminum (2.5 M in hexanes, 582 μL, 1.16 mmol), morpholine (101 μL, 101 mg, 1.16 mmol) in 2 mL CH₂CI₂, and the lactone from example 86 (67.5 mg, 0.388 mmol) in 2 mL CH₂ Cl₂. Flash chromatography (20:1 CH₂Cl₂:MeOH) provided the hydroxy amide in 79% yield (80 mg, 0.307 mmol) as a pale yellow solid. m.p. 130-131°C; ¹H NMR (300 MHz, CDCI₃) δ 7.30-7.11 (comp, 5H), 4.25 (dd, J - 4.3, 9.6 Hz, 1H), 3.91-3.51 (comp, 8H), 3.11-3.04 (m, 1H), 2.58 (t, J = 9.6 Hz, 1H), 2.15 (t, J = 9.2 Hz, 1H), 1.97-1.89 (m, 1H); ¹³C NMR (75 MHz, CDCI₃) δ 169.1, 136.0, 128.5, 128.3, 126.7, 66.5, 66.2, 58.6, 46.3, 42.1, 27.2, 25.4, 24.7; IR (neat) v 3480, 2980, 2870, 2290, 1650, 1470, 760 cm^-1; Mass spectrum m/e : 261, 230, 170, 144, 129, 115; Exact mass calculated for C₁₅H₁₉NO₃: 261.136494. Found 261.136793.

Example 91

[1R*, 2S*, 3R*]-2-Carboxaldehyde-3-ethyl-1-(4- morpholinyl)carbonylcyclopropane

PCC (59 mg, 0.255 mmol) was taken up in 1 mL CH₂Cl₂ at room temperature and the hydroxy amide from example 87

(66.2 mg, 0.170 mmol) was added in 1 mL CH₂Cl₂ and the reaction stirred for 48 h. The dark mixture was diluted with 5 mL Et₂O, filtered through glass wool, and concentrated under reduced pressure. The residue was purified by flash chromatography (1:3 hexanes :EtOAc) to provide the aldehyde in 69% yield (24.8 mg, 0.173 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 9.65 (d, J = 6.1 Hz, 1H), 3.85-3.49 (comp, 8H), 2.42 (t, J = 8.6 Hz, 1H), 2.02-1.51 (comp, 4H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 199.8, 166.7, 66.9, 66.7, 46.6, 42.3, 31.5, 29.0, 17.4, 14.0; Mass spectrum m/e : 211, 182, 95; Exact mass calculated for C₁₁H₁₇NO₃: 211.120844. Found 211.120945. Example 92

[1R*, 2S*, 3R*]-2-Carboxaldehyde-3-(2-methy]propyl)-1-(4- morpholinyl)carbonylcyclopropane

The crude aldehyde was prepared using the procedure in example 91 and PCC (115 mg, 0.535 mmol), 1 mL CH₂CI₂, and the hydroxy amide from example 88 (86.0 mg, 0.357 mmol) in 1 mL CH₂CI₂. The residue was purified by flash chromatography (1:2 hexanes:EtOAc) to provide the aldehyde in 82% yield (69.6 mg, 0.291 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 9.64 (d, J = 6.1 Hz, 1H), 3.75-3.42 (comp, 8H), 2.42 (t, J = 8.8 Hz, 1H), 1.96-1.88 (m, 1H), 1.85-1.73 (comp, 1H), 1.71-1.56 (comp, 2H), 1.24-1.14 (m, 1H), 0.94 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 199.8, 166.9, 66.8, 66.6, 46.6, 42.3, 32.3, 31.6, 29.6, 28.8, 25.7, 22.3, 22.2; IR (neat) v 2970, 2880, 1700, 1650, 1490, 1150 cm^-1; Mass spectrum m/e : 239, 210, 169, 154, 129, 114, 95, 81, 70; Exact mass calculated for C₁₃H₂₃NO₃: 239.152144. Found 239.152061.

Example 93

[1R*, 2S*, 3R*]-2-Carboxaldehyde-3-cyc]ohexylmethyl-1-(4- morpholinyl)carbonylcyclopropane

The crude aldehyde was prepared using the procedure in example 91 and PCC (48.2 mg, 0.220 mmol) in 1 mL

CH₂CI₂, and the hydroxy amide from example 89 (42.0 mg,

0.149 mmol) in 1 mL CH₂CI₂. The residue was purified by flash chromatography (100% EtOAc) to provide the aldehyde in 73% yield (30.5 mg, 0.109 mmol) as a clear oil. ¹E NMR

(300 MHz, CDCI₃) δ 9.67 (d, J = 6.2 Hz, 1H), 3.79-3.49

(comp, 8H) , 2.40 (t, J = 8.7 Hz, 1H), 1.96-1.86 (m, 1H), 1.84-1.67 (comp, 8H), 1.37-1.06 (comp, 4H), 0.99-0.91 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 200.0, 166.9, 66.9, 66.7, 46.6, 42.3, 38.3, 33.1, 31.7, 31.0, 29.7, 26.4, 26.2, 25.4; Mass spectrum m/e : 279, 250, 168, 154, 129, 114, 81, 55; Exact mass calculated for C₁₆-H₂₅NO₃: 279.183444. Found 279.181863.

Example 94

[1R*, 2S*, 3R*]-2-Carboxaldehyde-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane

The crude aldehyde was prepared using the procedure in example 91 and PCC (110 mg, 0.510 mmol) in 1 mL CH₂CI₂, and the hydroxy amide from example 90 (66.5 mg, 0.255 mmol) in 1 mL CH₂CI₂. The residue was purified by flash chromatography (1:3 hexanes:EtOAc) to provide the aldehyde in 68% yield (44.8 mg, 0.173 mmol) as a white solid, m.p.

155-160°C; ¹H NMR (300 MHz, CDCI₃) δ 9.56 (d, J = 6.3 Hz, 1H), 7.34-7.23 (comp, 5H), 3.78-3.49 (comp, 8H), 3.06 (t,

J = 9.2 Hz, 1H), 2.73 (t, J = 9.2 Hz, 1H), 2.31-2.23 (m, 1H); ¹³C NMR (75 MHz, CDCI₃) δ 199.5, 166.3, 133.2, 129.3,

128.7, 127.6, 66.8, 66.5, 46.8, 42.5, 32.4, 30.9, 30.4; IR

(CDCI₃) v 1720, 1670, 1160, 960, 770 cm^-1; Mass spectrum m/e : 259, 230, 145, 117, 115, 91, 70; Exact mass calculated for C₁₅H₁₇NO₃: 259.120844. Found 259.120282.

Example 95

[1R*, 2S*, 3R*]-2-Carboxaldehyde-3-ethy]-1-(4- morpholiny])carbonyloyclopropane

To the cis aldehyde amide from example 91 (15.5 mg, 0.0735 mmol) was added 1 mL MeOH which had been purged with nitrogen for 30 min prior to use. K₂CO₃ (40.5 mg, 0.294 mmol) was added in one portion and the reaction stirred at room temperature for 23 h. The reaction was diluted with 4 mL saturated ammonium chloride and extracted with CH₂CI₂ (3 × 10 mL), dried (MgSO₄), and concentrated under reduced pressure. Flash chromatography (1:3 hexanes:EtOAc) provided the epimerized aldehyde in 87% yield (13.5 mg, 0.0640 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 9.69 (d, J = 2.7 Hz, 1H), 3.81-3.47 (comp, 8H), 2.70-2.55 (m, 1H) , 2.50 (dd, J = 4.4, 9.6 Hz, 1H), 1.87-1.77 (m, 1H), 1.55-1.38 (comp, 2H) , 0.96 (t, J = 7.4 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 199.7, 166.3, 66.9,

66.8, 46.0, 42.5, 34.3, 32.5, 29.3, 20.1, 13.5; Mass spectrum m/e : 211, 182, 95; Exact mass calculated for C₁₁H₁.₇NO₃: 211.120844. Found 211.120586.

Example 96

[1R*, 2R*, 3R*]-2-Carboxaldehyde-3-(2-methylpropyl)-1-(4- morpholinyl)carbonylcyclopropane

The epimerized aldehyde was prepared using the procedure in example 95 and the cis aldehyde amide from example 92 (32.5 mg, 0.136 mmol), 1 mL MeOH, and K₂CO₃ (75.1 mg, 0.544 mmol). Flash chromatography (1:3 hexanes :EtOAc) provided the epimerized aldehyde in 81% yield (26.4 mg, 0.110 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 9.70 (d, J = 2.4 Hz, 1H), 3.84-3.48 (comp, 8H), 2.70-2.66 (m, 1H), 2.49 (dd, J = 4.4, 9.7 Hz, 1H), 1.90-1.80 (m, 1H), 1.60 (m, J = 6.8 Hz, 1H), 1.44-1.34 (m, 1H), 1.32-1.19 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 199.7, 166.4,

66.9, 66.7, 46.1, 42.5, 35.3, 34.7, 29.2, 28.7, 28.4, 22.4, 22.1; IR (neat) v 2940, 2860, 1720, 1650, 1480, 1250, 1130 cm^-1; Mass spectrum m/e : 239, 210, 129, 123, 114, 95; Exact mass calculated for C₁₃H₂₃NO₃: 239.152144.

Found 239.152023.

Example 97

[1R* , 2R* , 3R* ] -2-Carhoxa ldehyde-3-cyclohexylmethyl-1 - (4- morpholinγl) carbonylcyclopropane

The epimerized aldehyde was prepared using the procedure in example 95 and the cis aldehyde amide from example 93 (30.5 mg, 0.109 mmol), 1 mL MeOH, and K₂CO₃

(60.3 mg, 0.437 mmol). Flash chromatography (1:3 hexanes:EtOAc) provided the epimerized aldehyde in 72% yield (23.0 mg, 0.0824 mmol) as a clear oil. ¹H NMR (300

MHz, CDCI₃) δ 9.68 (d, J = 2.3 Hz), 3.80-3.46 (comp, 8H),

2.69-2.65 (m, 1H) , 2.48 (dd, J = 4.3, 9.7 Hz, 1H), 1.93-1.65 (comp, 6H), 1.55-1.04 (comp, 6H), 1.01-0.86 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 199.8, 166.4, 66.9, 66.7, 46.0, 42.5, 37.9, 34.8, 33.9, 33.1, 32.9, 29.0, 28.8, 26.4, 26.2; Mass spectrum m/e : 279, 250, 129; Exact mass calculated for C₁₆H₂₅NO₃: 279.183444. Found 279.182342.

Example 98

[1R*, 2R*, 3R*]-2-Carboxa]dehyde-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane

The epimerized aldehyde was prepared using the procedure in example 95 and the cis aldehyde amide from example 94 (62.0 mg, 0.239 mmol), 2 mL MeOH, and K₂CO₃

(132 mg, 0.958 mmol). Flash chromatography (1:3 hexanes:EtOAc) provided the epimerized aldehyde in 80% yield (49.5 mg, 0.191 mmol) as a clear oil. ¹H NMR (300

MHz, CDCI₃) δ 9.93 (d, J = 2.0 Hz, 1H), 7.33-7.14 (comp, 5H), 3.76-3.70 (m, 1H), 3.60-3.36 (comp, 5H), 3.22-3.05 (comp, 2H), 2.99 (dd, J = 5.6, 9.1 Hz, 1H), 2.81 (dd, J = 5.1, 9.1 Hz, 1H) , 2.77-2.71 (m, 1H); ¹³C NMR (75 MHz, CDCI₃) δ 198.9, 164.6, 134.7, 128.5, 127.5, 127.4, 66.6, 45.8, 42.4, 33.9, 33.6, 33.3; IR (CDCI₃) v 1720, 1640, 1450, 1290, 1140, 760 cm^-1; Mass spectrum m/e : 259, 230, 145, 115, 70; Exact mass calculated for C₁5H₁₇NO₃: 259.120844. Found 259.121309.

Example 99

(1R*, 2R*, 3S*)-3-Ethyl-2-(4- morpholinyl)carbonylcyclopropanecarboxylic acid

To an ice cooled solution of the aldehyde from example 95 (9.5 mg, 0.045 mmol) in 0.5 mL acetone was added 8 N Jones reagent (32 μL) and the reaction stirred 2 h. The reaction was diluted with 4 mL 1 N HCl, extracted with CH₂CI₂ (3 × 10 mL), dried (MgSO₄), and concentrated under reduced pressure. Flash chromatography (99:1 EtOAc :HOAc) provided the carboxylic acid in 93% yield (9.6 mg, 0.042 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 6.00 (s, 1H), 3.80-3.50 (comp, 8H) , 2.37 (dd, J = 4.3, 9.7 Hz, 1H), 2.30 (s, 1H), 1.90-1.70 (m, 1H), 1.50-1.40 (comp, 2H), 0.96 (t, J = 7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 177.9, 166.7, 66.9, 66.7, 46.0, 42.4, 31.3, 28.5, 25.5, 20.1, 13.5; IR (CH₂Cl₂) v 2980, 1730, 1650, 1450, 1280 cm- ¹; Mass spectrum m/e : 227, 182, 129, 95; Exact mass calculated for C₁₁H₁₇NO₄: 227.1149. Found 227.1149. Example 100

(1R*, 2R*, 3S*)-3-(2-Methylpropyl)-2-(4- morpholinyl)carbonylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure from example 99 and the aldehyde from example 96 (6.0 mg, 0.025 mmol) in 0.5 mL acetone, and 8 N Jones reagent (18 μL) in 84% yield (5.4 mg, 0.021 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 7.60 (s, 1H), 3.80-3.50 (comp, 8H), 2.40-2.30 (comp, 2H), 1.85-1.75 (m, 1H), 1.62 (m, J = 6.7 Hz, 1H), 1.39 (m, 1H), 1.21 (m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCI₃) δ 178.0, 166.7, 66.9, 66.7, 46.0, 42.4, 35.2, 28.3, 27.9, 25.8, 22.5, 22.1; IR (CDCI₃) v 2980, 1740, 1650, 1450, 1290, 1260, 1140 cm^-1; Mass spectrum m/e : 255, 210, 129, 95; Exact mass calculated for C₁₃H₂₁NO₄: 255.1472. Found 255.1472.

Example 101

(1R*, 2R*, 3S*)-3-Cyclohexy]methyl-2-(4- morpholinyl)carbonylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure from example 99 and the aldehyde from example 97 (12.5 mg,

0.0448 mmol) in 1 mL acetone and 8 N Jones reagent (31 μL). Flash chromatography (99:1 EtOAc:HOAc) provided the carboxylic acid in 88% yield (11.7 mg, 0.0397 mmol) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 5.90 (s, 1H), 3.82- 3.42 (comp, 8H), 2.37 (dd, J = 4.4, 9.7 Hz, 1H), 2.32 (m, 1H), 1.88-1.66 (comp, 6H), 1.42-1.10 (comp, 6H), 0.97-0.85

(comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 178.0, 166.7, 66.9,

66.7, 46.0, 42.4, 37.8, 33.9, 33.2, 32.8, 28.0, 26.4,

26.2, 25.9; IR (neat) v 2940, 2880, 1740, 1640, 1250, 1140 cm^-1; Mass spectrum m/e : 295, 250, 187, 129; Exact mass calculated for C₁₆H₂₅NO₄: 295.178359. Found 295.178407.

Example 1Q2

(1R*, 2R*, 3S*)-2-(4-morpholinyl)carbonyl-3- phenylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure from example 99 and the aldehyde from example 98 (10.0 mg,

0.0386 mmol) in 0.5 mL acetone and 8 N Jones reagent (27.0 μL). Flash chromatography (1:2 hexanes:EtOAc + 1% HOAc) provided the carboxylic acid in 84% yield (8.9 mg, 0.032 mmol) as a clear oil which solidified on standing. ¹H NMR

(300 MHz, CDCI₃) δ 7.60 (s, 1H), 7.31-7.26 (comp, 3H), 7.23-7.06 (comp, 2H), 3.76-3.63 (m, 1H), 3.59-3.40 (comp, 4H), 3.23-2.90 (comp, 4H), 2.79-2.69 (comp, 2H); ¹³C NMR

(75 MHz, CDCI₃) δ 176.3, 165.1, 134.6, 128.5, 128.2, 127.4, 66.5, 45.8, 42.4, 32.7, 32.4, 25.4; IR (neat) v 2920, 2940, 2880, 1730, 1650, 1450, 1290, 1140, 940, 760 cm^-1; Mass spectrum m/e : 275, 230, 115; Exact mass calculated for C₁₅H₁₇NO₄: 275.115758. Found 275.115884.

Example 103

(1R*, 2R*, 3S*)-2-(4-Morpholinyl)carbony]-3- phenylcyclopropanecarboxylic acid

To a r oom t emp e r ature s o lut i on o f hexamethyldisilazane (34 . 6 μL, 26.5 mg, 0.164 mmol) in 1 mL of dry THF was added n-BuLi in hexanes (2 . 48 M, 66 . 0 μL, 0.164 mmol) . After 15 min, the amide alcohol from example 90 (14.3 mg, 0.0548 mmol) was added in 1 mL of THF via a cannula needle . 30 min later the reaction was quenched with a saturated solution of ammonium chloride (5 mL) and extracted with CH₂CI₂ (3 × 20 mL). The combined extracts were dried (MgSO₄) and concentrated under reduced pressure.

The residue from the above reaction was taken up in acetone (0.5 mL) and cooled to 0 °C. A solution of 8 N Jones reagent was added (38 μL) and the mixture stirred for 2 h. The yellow solution was diluted with 1 N HCl (4 mL) and extracted with CH₂CI₂ (3 × 20 mL). The combined filtrates were dried (MgSO₄) and concentrated under reduced pressure. Flash chromatography (99:1. EtOAc :HOAc) afforded the epimerized acid (10.0 mg, 0.0364 mmol, 66% yield) as a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 9.80 (br s, 1H), 7.20-7.30 (comp, 5H), 3.50-3.80 (comp, 8H), 3.09 (dd, J = 6.5, 9.9 Hz, 1H), 2.90 (m, J = 4.8, 6.5 Hz, 1H), 2.60 (dd, J = 4.8, 10.0 Hz, 1H); ¹³C NMR (75 MHz, CDCI₃) δ

172 . 4 , 168.7, 134.2, 128.6, 128.0, 127.1, 66.4, 45.9, 42.6, 32.6, 29.2, 24.4; IR (CDCI₃) v 3200, 1730, 1630, 1450, 1240, 770 cm^-1; Mass spectrum m/e : 275, 230, 115; Exact mass calculated for C₁5H₁₇NO₄ : 275.0115758. Found 275.115460.

Example 104

cis-1 ,2-Bis(hydroxymethyl)-3-pheny]cyclopropane

To a solution of LAH (109 mg, 2.87 mmol) in 4 mL dry Et₂O at 0 °C was added a solution of the lactone from example 86 (499 mg, 2.87 mmol) in 4 mL dry THF. After 30 min the reaction was quenched sequentially with 0.1 mL water, 0.1 mL of a 15% aqueous solution of NaOH, and 0.3 mL water. The resulting white fluffy solid was removed by filtration through celite and washed several times with 10 mL portions of Et₂O. The filtrates were concentrated under reduced pressure to yield a clear oil which was further purified by flash chromatography (25:1, CH₂Cl₂:MeOH) to provide the meso diol (490 mg, 2.75 mmol, 96% yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.16 (comp, 3 H), 7.07-7.04 (comp, 2H), 4.06 (dd, J = 5.0, 11.7 Hz, 2H), 3.60 (br, 2H), 3.25 (comp, 4H), 2.46 (t, J = 8.9 Hz, 1H) , 1.68-1.55 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 136.0, 130.2, 128.3, 126.4, 60.1, 25.3, 21.3; Mass spectrum m/e : 178, 130, 129, 91; Exact mass calculated for C₁₁H₁₄O₂: 178.099380. Found 178.099223.

Example 105

[1R-(1α, 2β, 5α, 6α)]-2-Hydroxy-6-phenyl-3- oxabicyclo[3.1.0]hexane

The diol from example 104 (433 mg, 2.44 mmol), NAD⁺

(730 mg, 1.02 mmol), and flavin mononucleotide (FMN) (1.37 g, 2.85 mmol) were dissolved in a 0.1 M glycine-NaOH buffer (pH 9.0, 83 mL) in a 250 mL Erlenmeyer flask. Horse liver alcohol dehydrogenase (37 mg) was added and the pH readjusted to 9.0 with 10% aqueous NaOH. The reaction was stirred for 45 h at room temperature adjusting the pH back to 9.0 with the NaOH solution periodically. 3.5 mL of a

50% aqueous NaOH solution was added to bring the pH to 13.

The dark mixture was extracted with chloroform (3 × 100 mL), dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography (25:1 CH₂CI₂ :MeOH) to afford the bicyclic lactol (365 mg, 2.07 mmol, 85% yield) as a clear oil which was found to be enantiomerically pure by chiral shift experiments. ¹H NMR (300 MHz, CDCI₃) δ 7.30-7.15 (comp,

5H), 5.18 (s, 1H), 4.09 (dd, J = 2.5, 8.7 Hz, 1H), 3.77 (d, J - 8.7 Hz, 1H), 3.16 (br, 1H), 2.26 (t, J = 8.1 Hz, 1H), 2.07-2.04 (comp, 2H); ¹³C NMR (75 MHz, CDCI₃) δ 135.1, 129.0, 128.2, 126.4, 97.2, 65.2, 28.2, 23.2, 20.8; Mass spectrum m/e : 176, 145, 130, 129, 115, 91; Exact mass calculated for C₁₁H₁₂O₂: 176.083730. Found 176.083645; [α]_D ²¹ -68.7° (c=1.02, CHCI₃).

Example 106

[1R-(1α, 5α, 6α)]-6 Phenyl-3-oxabicyclo[3.1.0]hexan-2-one To a solution of the lactol from example 105 (109 mg, 0.612 mmol) in 8 mL CH₂CI₂ was added PCC (266 mg, 1.24 mmol). The reaction was stirred for 44 h before diluting with 12 mL Et₂O and filtering through glass wool, washing the residue several times with 2 mL portions of Et₂O. The filtrates were concentrated under reduced pressure and the residue purified by flash chromatography (2:1, hexanes:EtOAc) to afford the lactone (99.6 mg, 0.572 mmol, 92% yield) as a white solid which was identical with the racemic material prepared in example 86. m.p. 114-115°C; [α]_D ²¹ -100° (c=0.960, CHCI₃).

Example 107

[1R-(1α, 2α, 3α)]-2-Hydroxymethyl-1-(4- morpholinyl)carbonyl-3-phenyloyclopropane The hydroxy amide was prepared using the procedure in example 90 and trimethylaluminum (2.5 M in hexanes, 862 μL, 1.72 mmol), morpholine (151 μL, 150 mg, 1.72 mmol) in 4 mL CH₂CI₂, and the lactone from example 106 (98.5 mg, 0.566 mmol) in 2 mL CH₂CI₂. It was isolated in 68% yield (100 mg, 0.383 mmol) as a white solid and was found to be identical spectroscopically with the racemic material, m.p. 101-103°C; [α]_D ²¹ -206° (c=0. 940, CHCl3) .

Example 108

[1R-(1α, 2β, 3α)]-2-Carboxaldehyde-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane The aldehyde amide was prepared using the procedure in example 94 and PCC (124 mg, 0.575 mmol) and the hydroxy amide from example 107 (100 mg, 0.383 mmol) in 4 mL CH₂CI₂ to provide the aldehyde in 62% yield (62.0 mg, 0.239 mmol) as a clear oil. It was found to be identical spectroscopically with the racemic material. [α]_D ²¹ -51.2° (c=0.930, CHCI₃).

Example 109

[1R-(1α, 2β, 3α)]-2-Carboxaldehyde-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane The epimerized aldehyde was prepared using the procedure in example 98 and the cis aldehyde amide from example 108 (62.0 mg, 0.239 mmol), 2 mL MeOH, and K₂CO₃ (132 mg, 0.958 mmol) provided the epimerized aldehyde in 80% yield as a clear oil. It was found to be identical spectroscopically with the racemic material. [α]_D ²¹ 87.6° (c=1.22, CHCI₃) .

Example 110

[1R-(1α, 2β, 3α)-2-(4-Morpholinyl)carbonyl-3- phenylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure in example 102 and the aldehyde from example 109 (48.8 mg,

0.188 mmol) in 1 mL acetone and 8 N Jones reagent (132 mL) to provide the carboxylic acid in 76% yield (39.6 mg, 0.144 mmol) as a clear oil which solidified on standing. It was found to be identical spectroscopically with the racemic material. m.p. 175-180°C; [α]_D ²¹ 51.9° (c=0.740, CHCI₃) .

Example 111

[1S-(1α, 2β, 3α)]-2-(4-Morpholinyl)carbonyl-3- phenylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure in example 103 and hexamethyldisilazane (121 μL, 93.0 mg,

0.575 mmol) in 2 mL THF, n-BuLi in hexanes (2.06 M, 280 μL, 0.575 mmol), and the amide alcohol from example 107

(50.0 mg, 0.192 mmol) in 2 mL THF. The residue was taken up in acetone (2 mL) and 8 N Jones reagent (134 μL) to afford the epimerized acid (34.8 mg, 0.126 mmol, 66% yield) as a clear oil. It was found to be identical spectroscopically with the racemic material. m.p. 165-

170°C; [α]_D ²¹ -19.0° (c=1.20, CHCI₃).

Example 112

Rhodinm(II) methyl (S)-pyroylutamic acid (Rh₂ (5S-MEPY ₄) A mixture of rhodium(II) acetate (198 mg, 0.448 mmol) and methyl (S)-2-oxopyrrolidine-5-carboxylate (1.28 g, 8.95 mmol) in 140 mL of chlorobenzene was refluxed under nitrogen in a Soxhlet extraction apparatus. The thimble was charged with an oven dried mixture of 2 parts sodium carbonate and 1 part sand. After 7 hours of reflux, the solvent was removed under reduced pressure. The residue was purified by reverse phase chromatography using Baker cyano packing material and 1% acetonitrile in methanol as eluant. The purity of each fraction was ascertained using HPLC and a m-Bondapak-CN column eluting with 1% acetonitrile in methanol. The fractions containing pure tetrasubstituted compound were combined and concentrated under reduced pressure to recover a blue solid (290 mg, 0.375 mmol, 84% yield).

Example 113

[1R-(1α, 5α, 6α)]-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one As an alternative to the three step procedure for preparing the enantiomerically pure lactone described above, the compound may be made directly with a slightly lower enantiomeric excess. To a solution of the catalyst prepared in example 112 (1.03 mg, 1.34 μmol) in 4 mL refluxing CH₂CI₂ was added the diazoester prepared in example 82 (27.0 mg, 0.134 mmol) in 1 mL CH₂CI₂ vi a syringe pump over a period of 4 h. The reaction was concentrated under reduced pressure and the residue purified by flash chromatography (2:1, hexanes :EtOAc) to recover the lactone (10.0 mg, 0.0574 mmol, 41% yield) as a pale yellow solid which was identical to that prepared in example 86. [α]_D ²¹ -97° (c=0.46, CHCI₃).

Example 114

Rhodium (XI) methyl (R)-pyroglutamic acid (Rh₂(5R-MEPY)₄) The catalyst was prepared using the procedure in example 112 and rhodium(II) acetate (383 mg, 0.867 mmol) and methyl (R)-2-oxopyrrolidine-5-carboxylate (2.48 g, 17.3 mmol) in 140 mL of chlorobenzene to recover a blue solid (600 mg, 0.775 mmol, 89% yield). Example 115

[1S-(1α, 5α, 6α)]-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one

The lactone was prepared according to the procedure of example 113 and the catalyst prepared in example 114

(10.3 mg, 0.0133 mmol) in 40 mL CH₂CI₂ and the diazoester prepared in example 82 (269 mg, 1.33 mmol) in 10 mL

CH₂CI₂. The bicyclic lactone was recovered in 45% yield

(103 mg, 0.593 mmol). m.p. 101-105°C; [α]_D ²¹ 85.6°

(c=1.09, CHCI₃).

Example 116

[1S-(1α, 2α, 3α)]-2-Hydroxymethyl-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane The hydroxy amide was prepared using the procedure in example 90 and trimethylaluminum (2.5 M in hexanes, 876 μL, 1.75 mmol), morpholine (255 μL, 254 mg, 2.92 mmol) in 6 mL CH₂CI₂, the lactone from example 115 (102 mg, 0.584 mmol) in 2 mL CH₂CI₂. It was isolated in 65% yield (98.4 mg, 0.377 mmol) as a white solid and was found to be identical spectroscopically with the racemic material, m.p. 101-102°C; [α]_D ²¹ 182° (c=0.790, CHCI₃).

Example 117

[1S-(1α, 2α, 3α)]-2-Carboxaldehyde-1-(4- morpholinyl)carbonyl-3-phenyloyclopropane The aldehyde amide was prepared using the procedure in example 94 and PCC (63.3 mg, 0.294 mmol) and the hydroxy amide from example 116 (51.2 mg, 0.196 mmol) in 2 mL CH₂CI₂ to provide the aldehyde in 68% yield (44.8 mg, 0.173 mmol) as a clear oil. It was found to be identical spectroscopically with the racemic material. [α]_D ²¹ 49.7°

(c=1.50, CHCl₃).

Example 118

[1S-(1α, 2β, 3α)]-2-Carboxaldehyde-1-(4- morpholinyl)carbonyl-3-phenylcyclopropane

The epimerized aldehyde was prepared using the procedure in example 98 and the cis aldehyde amide from example 117 (30.0 mg, 0.116 mmol), 2 mL MeOH, and K₂CO₃

(64.0 mg, 0.463 mmol) to provide the epimerized aldehyde in 79% yield (23.6 mg, 0.0911 mmol) as a clear oil. It was found to be identical spectroscopically with the racemic material. [α]_D ²¹ -82.5° (c=1.18, CHCI₃).

Example 119

The carboxylic acid was prepared using the procedure in example 102 and the aldehyde from example 118 (23.6 mg,

0.0911 mmol) in 1 mL acetone and 8 N Jones reagent (46.0 μL) to provide the carboxylic acid in 70% yield (17.6 mg,

0.0640 mmol) as a clear oil which solidified on standing.

It was found to be identical spectroscopically with the racemic material. m.p. 165-172°C; [α]_D ²¹ -35.9° (c=0.850,

CHCI₃).

Example 120

[1R-(1α, 2β, 3α)]-2-(4-Morpholinyl)carbonyl-3- phenylcyclopropanecarboxylic acid

The carboxylic acid was prepared using the procedure in example 103 and hexamethyldisilazane (69.0 μL, 52.7 mg, 0.328 mmol) in 2 mL THF, n-BuLi in hexanes (2.06 M, 159 μL, 0.328 mmol), and the amide alcohol from example 116

(28.5 mg, 0.109 mmol) in 2 mL THF. The residue was taken up in acetone (2 mL) and 8 N Jones reagent (76 μL) to afford the epimerized acid (19.1 mg, 0.0721 mmol, 64% yield) as a clear oil. It was found to be identical spectroscopically with the racemic material. [α]o²¹ 15.2°

(c=0.955, CHCI₃).

Example 121

(1R,2R,3R),-2-(4-Morpholinyl)carbonyl-3- phenylcyclopropanecarbonyl-L-thiazolylalanine amide of

2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane

Using the procedure of Example 37 and replacing the product of Example 10 with the optically pure carboxylic acid product of Example 110, the product of Example 110 (10 mg, 0.036 mmol) was reacted with 16 mg (0.115 mmol) HOBT, 8 mg (0.043 mmol) EDC HCl and 17 mg (0.043 mmol) of amine to give the desired product. Mass spectrum (M+H)⁺: 655. ¹H NMR (CDCl3) δ 8.79 (d, J=l Hz, 1 H, thiazolyl-H),

7.67 (d, J=6 Hz, 1 H, CONH), 7.34-7.10 (m, 6 H, C₆H₅ and thiazolyl-H), 6.26 (d, J=6 Hz, 1 H, CONH), 4.76 (m, 1 H, CHOH), 4.26 (m, 1H, CHOH), 4.06 (d, J=6 Hz, 1 H), 0.94 (d, J=7 Hz, 3 H, CH₃), 0.87 (d, J=7 Hz, 3 H, CH₃).

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate,

glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,

2-hydroxy-ethanesulfonate, lactate, maleate,

methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,

3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and

undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl

halides, such as methyl, ethyl, propyl, and butyl

chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

The compounds of the present invention can also be used in the form of prodrugs which include esters.

Examples of such esters include a hydroxyl-substituted compound of formula (1) which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glycine and lysine;

however, other amino acid residues can also be used. Other esters include the compounds of formula (1) 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 the parent compound of formula (1). The preparation of the pro-drug esters is carried out by reacting a hydroxyl-substituted compound of formula (1) with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired prodrug ester. Prodrugs which are esters of carboxylic acid group containing compounds of formula (1) are prepared by methods known in the art.

The novel compounds of the present invention possess an excellent degree of activity and specificity in treating hypertension in a human or animal. The novel compounds of the present invention are also useful for treating

congestive heart failure in a human or animal. The novel compounds of the invention are also useful for treating vascular abnormalities in a human or animal, in particular microvascular diseases associated with diabetes such as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. In addition, the novel compounds of the invention are useful for treating renal diseases in a human or animal, in particular acute and chronic renal failure. The compounds of the invention are useful for the treatment of psoriasis.

The ability of the compounds of the invention to inhibit human renal renin can be demonstrated in vitro by reacting a selected compound at varied concentrations with human renal renin, free from acid proteolytic activity, and with renin substrate (human angiotensinogen) at 37 degrees C and pH of 6.0. At the end of the incubation, the amount of angiotensin I formed is measured by radioimmunoassay and the molar concentration required to cause 50% inhibition, expressed as the IC₅₀ is calculated. When tested in accordance with the foregoing procedure, compounds of the invention demonstrated IC₅₀'s in the range of 10 ^-8 to 10^-10

M as seen in Table I.

Table I

Example IC₅₀(nM)

37 2.8

39 38

40B 27

4IB 9

61 1.1

62 11

63 11

77 1.4

78 1.2

121 0.7

Total daily dose administered to a human or animal in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the

particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be

administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations

containing conventional nontoxic pharmaceutically

acceptable carriers, adjuvants, and vehicles as desired.

Topical compositions comprising the compounds of the invention can be in the form of shampoos, salves, powders, sprays, ointments, lotions, creams, solutions, suspensions and the like, These topical compositions can be prepared by mixing the compound of the invention iwth non-toxic, inert solid or liquid carriers which are suitable for topical administration. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.

The term parenteral as used herein includes

subcutaneous injections, intravenous, intramuscular, intrasterπal 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, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are

conventinally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable

nonirritating excipient such as cocoa butter and

polyethylene glycols which are solid at ordinary

temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening,

flavoring, and perfuming agents.

The present invention also relates to the use of novel compounds, pharmaceutical compositions containing the novel compounds and the use of the compounds and compositions to inhibit renin for treating glaucoma or reducing and/or controlling intraocular pressure. The present invention also relates to the use of novel compounds and

pharmaceutical compositions which inhibit renin in

combination with a beta-adrenergic antagonist agent or an angiotensin converting enzyme inhibiting compound for treating glaucoma or reducing and/or controlling

intraocular pressure.

The present invention also relates to pharmaceutical compositions for treating the increase in intraocular pressure associated with the administration of steroidal antiinflammatory agents comprising novel renin inhibiting compounds in combination with a steroidal antiinflammatory compound in a pharmaceutically acceptable vehicle.

The present invention also relates to a kit comprising in individual containers in a single package a novel renin inhibiting compound in a suitable pharmaceutical vehicle and a steroidal antiinflammatory compound in a suitable pharmaceutical vehicle and/or a beta-adrenergic antagonist agent in a suitable pharmaceutical vehicle or an angiotensin converting enzyme inhibiting compound in a suitable pharmaceutical vehicle.

The compositions of the invention are administered as topical or systemic pharmaceutical compositions when used for treating or reducing and/or controlling intraocular pressure.

These compositions are preferably administered as topical pharmaceutical compositions suitable for ophthalmic administration, in a pharmaceutically acceptable vehicle such as pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions, emulsions, ointments and solid inserts.

Examples of suitable pharmaceutically acceptable vehicles for ophthalmic administration are water, propylene glycol and other pharmaceutically acceptable alcohols, sesame or peanut oil and other pharmaceutically acceptable vegetable oils, petroleum jelly, water soluble

ophthalmologically acceptable non-toxic polymers such as methyl cellulose, carboxymethyl cellulose salts,

hydroxyethyl cellulose, hydroxypropyl cellulose; acrylates such as polyacrylic acid salts; ethylacrylates;

polyacrylamides; natural products such as gelatin,

alginates, pectins, tragacanth, karaya, agar, acacia;

starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch; as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, carbopol and xantham gum; and mixtures of these polymers. Such compositions may also contain adjuvants such as buffering, preserving, wetting, emulsifying, and dispersing agents. Suitable preserving agents include antibacterial agents such as quaternary ammonium compounds, phenylmercuric salts, benzyl alcohol, phenyl ethanol; and antioxidants such as sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene. Suitable buffering agents include borate, acetate, gluconate and phosphate buffers.

The pharmaceutical ophthalmic compositions of the invention may also be in the form of a solid insert. A solid water soluble or water swellable polymer such as dextran, hydroxyloweralkyl dextran, carboxymethyl dextran, hydroxyloweralkyl cellulose, loweralkyl cellulose,

carboxymethyl cellulose, polyvinyl alcohol, dextrin, starch, polyvinyl pyrrolidone and polyalkylene glycols may be used as the carrier for the drug.

Dosage levels of the active compound in the

compositions for treating glaucoma or reducing and/or controlling intraocular pressure in a human or an aminal may be varied so as to obtain a desired therapeutic response to a particular composition. Generally, the active compound will be administered as an isotonic aqueous solution of from 0.00001 to 1.0 (w/v) percent

concentration. More preferably the active compound will be administered as an isotonic aqueous solution of from

0.00001 to 0.1 (w/v) percent concentration.

The term "controlling intraocular pressure" as used herein means the regulation, attenuation and modulation of increased intraocular tension. The term also means that the decrease, in the otherwise elevated intraocular pressure, obtained by the methods and compositions of the invention is maintained for a significant period of time as, for example, between consecutive doses of the

composition of the invention.

The novel renin inhibiting compounds of the invention may be the only active ingredient for controlling

intraocular pressure in the methods and compositions of the invention or may be used in combination with other

ingredients which control intraocular pressure such as beta-adrenergic antagonist compounds. The term "beta- adrenergic antagonist" as used herein means a compound which by binding to betaadrenergic plasma membrane

receptors reduces or eliminates sympathetic activity or blocks the effects of exogenously adminstered

catecholamines or adrenergic drugs. Examples of beta-adrenergic antagonists are atenolol, metopropol, nadolol, propranolol, timolol, labetalol, betaxolol, carteolol and dilevalol and pharmaceutically acceptable salts thereof. Most preferably the beta-adrenergic antagonist is timolol.

Timolol is currently used for treating glaucoma or reducing and/or controlling intraocular pressure, but it has a number of adverse side effects. Accordingly,

administration of a composition comprising a combination of a beta-adrenergic antagonist and a novel renin inhibiting compound of the invention could produce a reduction in intraocular pressure equivalent to that produced by a beta-adrenergic antagonist alone, but at a reduced dose level of the beta-adrenergic antagonist. This will result in a reduced level of the beta-adrenergic antagonist related adverse side effects.

The combination composition is administered as a single dosage form containing both the novel renin

inhibitor and the beta-adrenergic antagonist. The beta adrenergic antagonist may comprise from 5 mg to about 125 mg of the composition of the invention. The preferred ranges of the components in the composition of the

invention in unit dosage form are:

Renin inhibitor: 1 ng to 0.1 mg

Beta-adrenergic antagonist: 5 ug to 125 ug

When the beta-adrenergic antagonist and the novel renin inhibitor are administered as separate compositions the present invention relates to a kit comprising in two separate containers a pharmaceutically acceptable beta- adrenergic antagonist composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises a beta-adrenergic antagonist composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical ophthalmological beta-adrenergic antagonist composition and a topical ophthalmological novel renin inhibitor

composition.

The novel renin inhibiting compounds of the invention may also be administered in combination with an angiotensin converting enzyme (ACE) inhibiting compound. Examples of angiotensin converting enzyme inhibiting compounds are captopril and enalapril. As was previously mentioned, ACE inhibitors have some undesirable side effects.

Accordingly, administration of an ACE inhibitor in

combination with a renin inhibitor could produce a

reduction in intraocular pressure greater than or

equivalent to that of an ACE inhibitor alone, but at a reduced dose level of the ACE inhibitor. This will result in a reduced level of the ACE inhibitor related adverse side effects. The combination composition is administered as a single dose form containing both the novel renin inhibitor and the angiotensin converting enzyme inhibitor. The ACE inhibitor may comprise from 5 ng to about 50 ug of the compositon of the invention. The preferred ranges of the components in the composition of the invention in unit dosage form are:

Renin inhibitor: 1 ng to 0.1 mg

ACE inhibitor: 5 ng to 50 ug

When the ACE inhibitor and the novel renin inhibitor are administered as separate compositions the present invention relates to a kit comprising in two separate containers a pharmaceutically acceptable ACE inhibitor composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises an ACE inhibitor composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical ophthalmological ACE inhibitor

composition and a topical novel renin inhibitor

composition.

Dosage levels of the active compounds in the

compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.

Topical, ophthalmic and systemic administration of steroidal antiinflammatory agents can cause an increase in intraocular pressure. The increase in intraocular pressure can be reduced by the administration of a novel renin inhibiting compound of the invention. Steroidal

antiinflammatory agents include hydrocortisone, cortisone, prednisone, prednisolone, dexamethasone,

methylprednisolone, triamcinolone, betamethasone,

alclometasone, flunisolide, beclomethasone, clorocortolone, diflorasone, halcinonide, fluocinonide, fluocinolone, desoximetasone, medrysone, paramethasone, and

fluorometholone, and their pharmaceutically acceptable salts and esters. Preferred steroidal antiinflammatory agents are hydrocortisone, prednisolone, dexamethasone, medrysone and fluorometholone and their pharmaceutically acceptable salts and esters. The novel renin inhibitor is administered after use of a steroidal antiinflammatory agent or at the same time, causing reduction and/or control of intraocular pressure.

Various combinations of a topical or oral or

injectible dosage form of a steroidal antiinflammatory agent and a topical or oral dosage form of the novel renin inhibitor may be used. A preferred combination comprises a topical steroidal antiinflammatory and a topical novel renin inhibitor. More preferred is a topical ophthalmic dosage form comprising both a steroidal antiinflammatory and a novel renin inhibitor.

When the steroidal antiinflammatory agent and the novel renin inhibitor are administered as separate

compositions the present invention relates to a kit

comprising in two separate containers a pharmaceutically acceptable steroidal antiinflammatory agent composition and a pharmaceutically acceptable novel renin inhibitor

composition, in a single package. A preferred kit

comprises a steroidal antiinflammatory composition and a topical novel renin inhibitor composition. A most

preferred kit comprises a topical ophthamological steroidal antiinflammatory composition and a topical ophthamological novel renin inhibitor composition.

The combination composition of the invention may contain from about 0.00001 to 1.0 (w/v) percent of the novel renin inhibitor for combined or separate topical administration. More preferably the amount of the novel renin inhibitor is about 0.00001 to 0.1 (w/v) percent of the composition. The amount of the novel renin inhibitor in a unit dosage form for topical administration to the eye is from about 5 ng to about 0.5 mg, preferably from about 5 ng to about 25 ng. The dose required will depend on the potency of the particular novel renin inhibitor, the severity of the intraocular pressure increase and the response of the individual patient.

The combination composition of the invention may contain from about 0.05 to 1.5 (w/v) percent of the

steroidal antiinflammatory for combined or separate topical administration. The amount of the steroidal

antiinflammatory in a unit dosage form for topical

administration to the eye is from about 20 ug to about 600 ug. The dose required will depend on the potency of the particular steroidal antiinflammatory, the severity of the disease and the response of the individual patient.

When the steroidal antiinflammatory agent of the combination therapeutic method of the invention is

administered other than ophthalmically, appropriate doses are well known in the art.

The compositions of the invention may include other therapeutic agents in addition to the novel renin

inhibitor, and other agents which reduce and/or control intraocular pressure. The effect on intraocular pressure of the novel compounds of the invention can be determined in rabbits by using the following method.

Effects of Topically Administered Renin Inhibiting

Compounds on Intraocular Pressure of Rabbits a. Method The antiglaucoma activity of the compounds was tested by measuring the effect on intraocular pressure in rabbits as described by Tinjum, A.M., Acta

Ophthalmologica, 50, 677 (1972). Male albino. New Zealand rabbits were placed in restraining devices and the

intraocular pressure was measured with an applamatic tonometer. Exactly 0.1 ml of an isotonic saline solution containing a test compound was instilled into the

conjuctival sac and the intraocular pressure was measured at 5, 15, 30, 60, 90, 120 and 180 minutes afterwards.

The present invention is also directed to the use of compounds of the formula (1) in combination with one or more antihypertensive agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, potassium channel activators and other antihypertensive agents for treating (in a human or an animal) hypertension, congestive heart failure, vascular disease related to diabetes or for treating renal diseases such as acute or chronic renal failure.

Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof. Representative adrenergic blocking agents include phentolaraine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.

Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.

Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil,

gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.

Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.

Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.

Other representative antihypertensive agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.

Synergistic combinations of a compound of formula (1) with one or more of the above-mentioned antihypertensive agents are useful for the treatment of hypertension or congestive heart failure, vascular disease related to diabetes or for treating renal diseases such as acute or chronic renal failure.

The compound of formula (1) and the antihypertensive agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents.

In addition, the present invention is directed to the use of a compound of formula (1) to inhibit retroviral proteases and in particular to inhibit HIV-1 protease and HIV-2 protease. Compounds of formula (1) are useful for treatment or prophylaxis of diseases caused by

retroviruses, especially acquired immune deficiency

syndrome or an HIV infection.

The inhibitory potency of the compounds of the invention against HIV protease can be determined by the following method.

Fluorogenic Assay for Screening Inhibitors of HTV

Protease

A compound of the invention is dissolved in DMSO and a small aliquot further diluted with DMSO to 100 times the final concentration desired for testing. The reaction is carried out in a 6 X 50 mm tube in a total volume of 300 microliters. The final concentrations of the components in the reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 uM fluorogenic substrate, 2% (v/v)

dimethylsulfoxide, pH 4.5. After addition of inhibitor, the reaction mixture is placed in the fluorometer cell holder and incubated at 30°C for several minutes. The reaction is initiated by the addition of a small aliquot of cold HIV protease. The fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time. The reaction rate is determined for the first six to eight minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X (1 - (rate in presence of

inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Ser-Gln-Asp-Tyr-Pro-Ile-Val-Gln-EDANS wherein DABCYL = 4-(4-dimethylaminophenyl) azobenzoic acid and EDANS = 5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid.

The antiviral activity of compounds of the invention can be demonstrated using the following method.

A mixture of 0.1 ml (4 X 10⁶ cells/ml) of H9 cells and 0.1 ml (100 infectious units) of HIV-13B was incubated on a shaker for 2 h. The resulting culture was washed three times, resuspended into 2 ml of medium, and treated with 10 μl of the compound of the invention (5 mM in

dimethylsulfoxide). The control culture was treated in an identical manner except the last step was omitted. After incubation of the culture for eight days without change of medium, an aliquot (0.1 ml) of the supernatent was

withdrawn and incubated with fresh H9 cells on a shaker for 2 h. The resulting culture was washed three times,

resuspended into 2 ml of medium, and incubated. Virus infectivity was determined using the Abbott HTLV-III antigen E.I.A. method (Paul, et al., J. Med. Virol., 22 357 (1987)).

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMS What is claimed is :

1. A compound of the formula:

wherein A is

(I) R₅C(O)- wherein

R₅ is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) loweralkyl, v) heterocyclic, vi) amino or vii) substituted amino;

(II) R₉₀N(R₁₅₀)C(O) - wherein R₁₅₀ is hydrogen or loweralkyl and R₉₀ is a C₁ to C₃ straight or branched carbon chain substituted with a substituent selected from 1) carboxy,

2) alkoxycarbonyl, 3) alkylsulfonyl,

4) aryl, 5) arylsulfonyl, 6) heterocyclic,

7) (heterocyclic) sulfonyl, 8) amino,

9) alkylamino, 10) dialkylamino, 11) alkoxy,

12) (alkoxy) alkoxy or

13) ( (alkoxy) alkoxy) alkoxy;

(III) R₉₅S(O)_w- wherein w is 0-2 and R₉₅ is 1) loweralkyl, 2) aryl, 3) heterocyclic,

4) -NH₂ or 5) substituted amino;

2) cycloalkyl, 3) aryl, 4) heterocyclic,

5) alkoxy, 6) thioalkoxy, 7) aryloxy, 8) thioaryloxy, 9) substituted amino,

10) R₉₇NH- wherein R₉₇ is loweralkyl, cycloalkyl, aryl or heterocyclic

11) (heterocyclic) alkyl, 12) aminoalkyl, 13) alkylaminoalkyl, 14) dialkylaminoalkyl, 15) alkoxyalkyl, 16) (alkoxy) alkoxyalkyl or 17) ( (alkoxy) alkoxy) alkoxyalkyl; or

(V) R₉₆S(O)_xN(R₁₅₁)- wherein x is 1 or 2, R₁₅₁ is hydrogen or loweralkyl and R₉₆ is defined as herein;

R and R₁ are independently selected from

(I) hydrogen, (II) aryl, (III) loweralkyl,

(IV) loweralkenyl, (V) cycloalkyl,

(VI) cycloalkenyl, (VII) aryloxyalkyl,

(VIII) thioaryloxyalkyl, (IX) arylalkoxyalkyl, (X) arylthioalkoxyalkyl and (XI) a C₁ to C₃ straight or branched carbon chain substituted with a substituent selected from 1) alkoxy,

2) thioalkoxy, 3) aryl, 4) cycloalkyl,

5) cycloalkenyl and 6) heterocyclic;

R₃ is (I) loweralkyl, (II) haloalkyl,

(III) loweralkenyl, (IV) cycloalkylalkyl,

(V) cycloalkenylalkyl, (VI) alkoxyalkyl,

(VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl, (X) -(CH₂)_eeNHR₁₂ wherein 1) ee is 1 to 3 and 2) R₁₂ is

i) hydrogen, ii) loweralkyl or iii) an N-protecting group; (XI) arylalkyl or (XII) (heterocyclic) alkyl; and

T is a mimic of the Leu-Val cleavage site of

angiotensinogen;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. The compound of Claim 1 wherein R₁ is loweralkyl or benzyl; R₃ is (heterocyclic) alkyl; and T is

wherein R₄ is loweralkyl or cycloalkylmethyl and D is

(

wherein R₇₃ is loweralkyl,

wherein

1) M is

i) O,

ii) S or

iii) NH;

2) Q is

i) O or

ii) S;

3) E is

i) O,

ii) S,

iii) CHR₇₃ wherein R₇₃ is

loweralkyl,

iv) C=CH₂ or

v) NR₁₈ wherein R₁₈ is

a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl,

d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino;

and

4) G is

i) absent,

ii) CH₂ or

iii) NR₁₉ wherein R₁₉ is

hydrogen or loweralkyl,

with the proviso that when G is NR₁₉, then R₁₈ is loweralkyl or

hydroxyalkyl; (

wherein

1) v is 0 or 1 and

2) R₂₁ is

i) NH,

ii) O,

iii) S or

iv) SO₂; or

(IV) a substituted methylene group.

3. A compound of the formula

wherein A is

(I) R₅C(O)- wherein

R₅ is i) hydroxy, ii) alkoxy,

iii) thioalkoxy, iv) loweralkyl,

v) heterocyclic, vi) amino or

vii) substituted amino;

(II) R₉₀N(R₁₅₀)C(O) - wherein R₁₅₀ is hydrogen or loweralkyl and R₉₀ is a C₁ to C₈ straight or branched carbon chain substituted with a substituent selected from 1) carboxy, 2) alkoxycarbonyl, 3) alkylsulfonyl,

4) aryl, 5) arylsulfonyl, 6) heterocyclic,

7) (heterocyclic) sulfonyl, 8) amino,

9) alkylamino, 10) dialkylamino, 11) alkoxy,

12) (alkoxy) alkoxy or

13) ( (alkoxy) alkoxy) alkoxy;

(III) R₉₅S(O)_w- wherein w is 0-2 and R₉₅ is

1) loweralkyl, 2) aryl, 3) heterocyclic,

4) -NH₂ or 5) substituted amino;

2) cycloalkyl, 3) aryl, 4) heterocyclic,

5) alkoxy, 6) thioalkoxy, 7) aryloxy,

8) thioaryloxy, 9) substituted amino,

10) R₉₇NH- wherein R₉₇ is loweralkyl, cycloalkyl, aryl or heterocyclic

R and R. are independently selected from

(I) hydrogen, (II) aryl, (III) loweralkyl,

(IV) loweralkenyl, (V) cycloalkyl,

(VI) cycloalkenyl, (VII) aryloxyalkyl,

(VIII) thioaryloxyalkyl, (IX) arylalkoxyalkyl, (X) arylthioalkoxyalkyl and (XI) a C₁ to C₃ straight or branched carbon chain substituted with a substituent selected from 1) alkoxy, 2) thioalkoxy, 3) aryl, 4) cycloalkyl,

5) cycloalkenyl and 6) heterocyclic;

R₃ is (I) loweralkyl, (II) haloalkyl,

(III) loweralkenyl, (IV) cycloalkylalkyl,

(V) cycloalkenylalkyl, (VI) alkoxyalkyl,

(VII) thioalkoxyalkyl, (VIII) (alkoxyalkoxy) alkyl,

(IX) hydroxyalkyl, (X) -(CH₂)_eeNHR₁₂

wherein 1) ee is 1 to 3 and 2) R₁₂ is

i) hydrogen, ii) loweralkyl or iii) an

N-protecting group; (XI) arylalkyl or

(XII) (heterocyclic) alkyl; and T is

wherein R₄ is

(I) loweralkyl,

(II) cycloalkylalkyl

(III) cycloalkenylalkyl or

(III) arylalkyl; and

D is

wherein R₇₃ is loweralkyl.

wherein

1) M is

i) O,

ii) S or

iii) NH;

2) Q is

i) O or

ii) S;

3) E is

i) O,

ii) S,

iii) CHR₇₃ wherein R₇₃ is loweralkyl, iv) C=CH₂ or

v) NR₁₉ wherein R₁₈ is a) hydrogen,

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

e) alkoxy,

f) amino or

g) alkylamino;

and

4) G is

i) absent,

ii) CH₂ or iii) NR₁₉ wherein R₁₉ is

hydrogen or loweralkyl,

with the proviso that when G is NR₁₉, then R₁₈ is loweralkyl or

hydroxyaIkyl;

wherein

1) v is 0 or 1 and

2) R₂₁ 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.

4. The compound of Claim 3 wherein D is

(a) -CH(OH)CH₂CH(CH₃)₂,

wherein M is O, S or NH; Q is O or S; E is O, S, C=CH₂, CHR₇₃ wherein R₇₃ is loweralkyl, or NR₁₈ wherein R₁₈ is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino or alkylamino; and G is absent, CH₂ or NR₁₉ wherein R₁₉ is hydrogen or loweralkyl, with the proviso that when G is NR₁₉, then R₁₈ is loweralkyl or hydroxyalkyl, or

(c) -CH₂CH(R₂₂)C(O)NHR₂₃ wherein R₂₂ is loweralkyl and R₂₃ is (heterocyclic) alkyl; and

A is R₅C(O)- wherein R₅ is selected from the group

consisting of:

wherein aa is 1 to 5 and R₆ and R₇ 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.

wherein dd is 1 to 5,

and

18) R₈-Z- wherein

Z is O, S or NH and R₈ is a C₁ to C₆ straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, phenyl and substituted phenyl;

wherein R₉ is

1) O,

2) S,

3) SO₂ or

4) C=O; or

wherein R₁₀ is

1) hydrogen,

2) loweralkyl,

3) an N-protecting group or

4) R₁₁-C(O)- wherein R₁₁ is

aminoalkyl, (N-protected) aminoalkyl, 1-amino-2-phenylethyl or

1-(N-protected)amino-2-phenylethyl.

5. A compound of Claim 3 wherein the compound is selected from:

(1R*,2R*,3S*)-3-(2-Methylpropyl)-2-(4-morpholinyl)-carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*)-2-(4-Morpholinyl)carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3R*)-3-Benzyl-2-(4-morpholinyl)carbonylcyclopropanecabonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-3-Ethyl-2-(4-morpholinyl)carbonylcyclopropanecarbonyl-L-thiazolylalanineamide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R )-3-(2-Methylproρyl)-2-(4-morpholinyl)-carbonylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane;

(1R*,2R*,3R*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl -L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane; (1R*,2R*,3R*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-histidyl amide of 2 (S) -Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane;

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenyl

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-benzyl

(1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-4-thiazolylalanyl amide of N-Butyl 5 (S)-Amino-6-cyclohexyl-4(S)-hydroxy-5(S)-isopropylhexamide; (1R*,2R*,3S*)-2-(4-Morpholinyl)carbonyl-3-phenylcyclopropanecarbonyl-L-4-thiazolylalanyl amide of (2'S, 1'R, 5'S)-3-Ethyl-5-(1'-hydroxy-2'amino-3'cyclohexylpropyl)-oxazolidin-2-one;

(2S,4S,1*R,2'S)-2-(2-Amino-3-cyclohexyl-1-hydroxy)-4-methyl-tetrahydrofuran;

(1R*, 2R*, 3S*)-2-Phenylsulfonyl-3-phenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane;

(1R*, 2S*, 3S*)-2-Phenylsulfonyl-3-phenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane; and

(1R,2R,3R),-2-(4-Morpholinyl)carbσnyl-3-phenylcyclopropanecarbonyl-L-thiazolylalanine amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane.

6. A pharmaceutical composition for inhibiting renin, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

7. A method for inhibiting renin comprising

administering to a human or animal in need of such

treatment a therapeutically effective amount of a compound of Claim 1.

8. A pharmaceutical composition for treating

hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

9. A method for treating hypertension or congestive heart failure comprising administering to a human or animal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

10. A method for treating glaucoma or reducing and/or controlling intraocular pressure, comprising administering to a human or animal in need a therapeutically effective amount of a compound of Claim 1.

11. A method for inhibiting a retroviral protease, comprising administering to a human or animal in need a therapeutically effective amount of a compound of Claim 1.

12. A method for treating a retroviral infection, comprising administering to a human or animal in need a therapeutically effective amount of a compound of Claim 1.

13. A method for treating hypertension or congestive heart failure comprising administering to a human or animal in need of such treatment a therapeutically effective amount of a compound of Claim 1 and another

antihypertensive agent.

14. A pharmaceutical composition for treating

hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1 and another antihypertensive agent.