US 5,366,973 AGrant

Mercaptoacetylamido Pyridazo [1,2]pyridazine, Pyrazolo[1,2]pyridazine Pyrazolo[1,2]pyridazine, Pyridazol[1,2-A][1,2]diazepine and Pyrazolol[1,2-A][1,2]diazepine

Issue Date:1994-11-22

•31 Claims

Abstract

The present invention relates to certain novel mercaptoacetylamido pyridazo[1,2]pyridazine, pyrazolo[1,2]pyridazine, pyridazo[1,2- a] [1,2]diazepine and pyrazolo[1,2- a ][1,2]diazepine derivatives useful as inhibitors of enkephalinase and of ACE.

Metadata

Assignee

Merrell Dow Pharmaceuticals Inc.

Inventors

Gary A. Flynn
Patrick W. Shum

Application Information

Application Number:US 146857&

Filing Date:1993-11-03

Priority Date:1992-05-15

Art Unit:122

Classifications

IPC:

C07D48704A61K 3150A61K 31415

Field of Search:

514544548540405;248;221235363.1500

Patent Drawings

This patent does not have any drawings.

Description

BACKGROUND OF THE INVENTION

Enkephalinase or, more specifically, endopeptidase-24.11, is a mammalian ectoenzyme which is involved in the metabolic degradation of certain circulating regulatory peptides. This enzyme, which is a Zn.sup.+2 -metallopeptidase, exerts its effect by cleaving the extracellular peptides at the amino group of hydrophobic residues and thus inactivates the peptides as regulatory messengers.

Enkephalinase is involved in the metabolic degradation of a variety of circulating regulatory peptides including endorphins, such as .beta.-endorphin and the enkephalins, atrial natriuretic peptide (ANP), and other circulating regulatory peptides.

Endorphins are naturally-occurring polypeptides which bind to opiate receptors in various areas of the brain and thereby provide an analgesic effect by raising the pain threshold. Endorphins occur in various forms including .alpha.-endorphin, .beta.-endorphin, .gamma.-endorphin as well as the enkephalins. The enkephalins, i.e., Met-enkephalin and Leu-enkephalin, are pentapeptides which occur in nerve endings of brain tissue, spinal cord and the gastrointestinal tract. Like the other endorphins, the enkephalins provide an analgesic effect by binding to the opiate receptors in the brain. By inhibiting enkephalinase, the metabolic degradation of the naturally-occurring endorphins and enkephalins are inhibited, thereby providing a potent endorphin- or enkephalin-mediated analgesic effect. Inhibition of enkephalinase would therefore be useful in a patient suffering from acute or chronic pain. Inhibition of enkephalinase would also be useful in providing an antidepressant effect and in providing a reduction in severity of withdrawal symptoms associated with termination of opiate or morphine administration. In addition, inhibition of enkephalinase would also be useful in the treatment of irritable bowel syndrome.

ANP refers to a family of naturally-occurring peptides which are involved in the homeostatic regulation of blood pressure, as well as sodium and water levels. ANP have been found to vary in length from about 21 to about 126 amino acids with a common structural feature being one or more disulfide-looped sequences of 17 amino acids with various amino- and carboxy-terminal sequences attached to the cystine moiety. ANP have been found to bind to specific binding sites in various tissues including kidney, adrenal, aorta, and vascular smooth muscle with affinities ranging from about 50 pico-molar (pM) to about 500 nano-molar (nM) [Needleman, Hypertension 7, 469 (1985)]. In addition, it is believed that ANP binds to specific receptors in the brain and possibly serves as a neuromodulator as well as a conventional peripheral hormone.

The biological properties of ANP involve potent diuretic/natriuretic and vasodilatory/hypotensive effects as well as an inhibitory effect on renin and aldosterone secretion [deBold, Science 230, 767 (1985)]. By inhibiting enkephalinase, the metabolic degradation of the naturally-occurring ANP are inhibited, thereby providing a potent ANP-mediated diuretic, natriuretic, hypotensive, hypoaldosteronemic effects. Inhibition of enkephalinase would therefore be useful in a patient suffering from disease states characterized by abnormalities in fluid, electrolyte, blood pressure, intraocular pressure, renin, or aldosterone homeostasis, such as, but not limited to, hypertension, renal diseases, hyperaldosteronemia, cardiac hypertrophy, glaucoma and congestive heart failure.

In addition, the compounds of the present invention are inhibitors of Angiotensin-Converting Enzyme (ACE). ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE would therefore be useful in a patient suffering from disease states such as hypertension and congestive heart failure [See William W. Douglas, "Polypeptides--Angiotensin, Plasma Kinins, and Others", Chapter 27, in GOODMAN AND GILLMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th edition, 1985, pp. 652-3, MacMillan Publishing Co., New York, N.Y.]. In addition, it has been discovered that ACE inhibitors are useful in treating cognitive disorders [German Application No. 3901-291-A, published Aug. 3, 1989].

Bradykinin refers to a naturally-occurring peptide which is a very powerful vasodilator and causes increased capillary permeability. By inhibiting enkephalinase and ACE, the metabolic degradation of bradykinin is inhibited, thereby providing increased levels of bradykinin in the circulation.

In addition, the compounds of the present invention are useful as inhibitors of smooth cell proliferation. Smooth muscle cell proliferation in the intima of muscular arteries is a primary cause of vascular stenosis in arteriosclerosis, after vascular surgery, and after coronary angioplasy. Several animal studies have indicated the renin-angiotensin system plays an important role in this vascular response to injury. Chronic treatment with angiotensin converting enzyme (ACE) inhibitors reduced myointimal thickening following balloon injury in rat carotid artery or aorta. Powell, J. S., Muller, R. K. M. and Baumgartner, H. R.; Suppression of the vascular response to injury: The role of angiotensin-converting enzyme inhibitors. J. Am. Coll. Cardiol. 17:137B-42B, 1991. More recently, atrial natruiuretic peptide (ANP) has been found to decrease myointimal proliferation. ANP is rapidly metabolized by receptor mediated clearance and by neutral endopeptidase (NEP). Inhibition of NEP significantly reduces proliferation in the balloon-injured rabbit vasculature. Davis, H. R., McGregor, D.C., Hoos, L., Mullins, D. E. and Sybertz, E. J.: Atrial naturiuretic factor and the neutral endopeptidase inhibitor SCH42495 prevent myointimal proliferation after vascular injury. Circ. 86:I-220, 1992. These studies imply that a dual inhibitor of ACE and NEP should be therapeutically useful in the treatment of conditions which require inhibition of smooth cell proliferation. Davis and Sybertz, European Patent Application 533084-A1, Mar. 24, 1993.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of the Formula (I)

wherein

B represents a methylene, ethylene or vinylene group; ##STR1## R.sub.1 represents a hydrogen, C.sub.1 -C.sub.8 alkyl, --CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 or an Ar--Y-- group;

R.sub.2 represents a hydrogen, acetyl, --CH.sub.2 O--C(O)C(CH.sub.3).sub.3 or benzoyl;

R.sub.3 represents a carboxyl, alkoxycarbonyl or Ar--Y--O carbonyl group;

R.sub.4 and R.sub.5 each represent a hydrogen atom or R.sub.4 and R.sub.5 together represent an oxo group;

n stands for zero, 1 or 2, and

pharmaceutically acceptable salts and individual optical isomers thereof.

The present invention further provides a method of inhibiting enkephalinase in a patient in need thereof comprising administering to said patient an effective enkephalinase inhibitory amount of a compound of Formula (I). The present invention also provides a method of inhibiting ACE in a patient in need thereof comprising administering to said patient an effective ACE inhibitory amount of a compound of Formula (I).

In addition, the present invention provides a composition comprising an assayable amount of a compound of Formula (I) in admixture or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective inhibitory amount of a compound of Formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "C.sub.1 -C.sub.8 alkyl" refers to saturated straight or branched chain hydrocarbyl radicals of one to eight carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.

As used herein, an alkoxy group and the alkoxy moiety of an alkoxycarbonyl group can be straight or branched chain and contain from i to 8 carbon atoms, preferably from 1 to 4, carbon atoms. Specific examples of alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, t-butyoxycarbonyl and the like. Specific examples of alkoxy groups are methoxy, ethoxy, t-butoxy and the like.

As used herein, the term "AR--Y--" refers to a radical wherein Ar is an aryl group and Y is a C.sub.0 -C.sub.4 alkyl. The term "Ar" refers to a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C.sub.1 -C.sub.4 alkoxy, amino, nitro, fluoro and chloro. The term "C.sub.0 -C.sub.4 alkyl" refers to a saturated straight or branched chain hydrocarbyl radical of zero to four carbon atoms and includes a bond, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and the like. Specifically included within the scope of the term "Ar--Y--" are phenyl, naphthyl, phenylmethyl or benzyl, phenylethyl, 3,4-methylenedioxyphenyl, m-aminophenyl, m-nitrophenyl, p-aminophenyl, p-nitrophenyl, p-methoxybenzyl, p-fluorobenzyl and p-chlorobenzyl.

As used herein, the designation ".intg..intg." refers to a bond to a chiral atom for which the stereochemistry is not designated.

The compounds of Formula (I) can be prepared by utilizing procedures and techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme A wherein all substituents, unless otherwise indicated, are previously defined. ##STR2##

In step a, the appropriate amino compound of structure (1) is reacted with the appropriate (S)-bromoacid of structure (2) to give the corresponding (S)-bromoamide compound of structure (3). For example, the appropriate amino compound of structure (1) can be reacted with the appropriate (S)-bromoacid compound of structure (2) in the presence of a coupling reagent such as EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), or diethylcyanophosponate in a suitable aprotic solvent, such as methylene chloride to give the appropriate (S)-bromoamide compound of structure (3).

Alternatively the appropriate amino compound of structure (1) is reacted with the appropriate (R)-bromoacid to give the corresponding (R)-bromoamide compound or the appropriate amino compound of structure (1) is reacted with the appropriate enantiomeric mixture of the bromoacid to give the corresponding enantiomeric mixture of bromoamide as described previously in Scheme A, step a.

In step b, the (S)-bromo functionality of the appropriate (S)-bromoamide compound of structure converted to the corresponding (R)-thioacetate or (R)-thiobenzoate of structure (5a).

For example, the appropriate (S)-bromoamide compound of structure (3) is reacted with thiolacetic acid or thiolbenzoic acid of structure (4) in the presence of a base, such as cesium carbonate. The reactants are typically contacted in a suitable organic solvent such as a mixture of dimethylformamide and tetrahydrofuran. The reactants are typically stirred together at room temperature for a period of time ranging from 1 to 8 hours. The resulting (R)-thioacetate or (R)-thiobenzoate of structure (5a) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by chromatography.

Alternatively, the (R)-bromo functionality of the appropriate (R)-bromoamide is converted to the corresponding (S)-thioacetate or (S)-thiobenzoate of structure (5b) or the bromo functionality of the appropriate enantiomeric mixture of of the bromoamide is converted to the corresponding enantiomeric mixture of thioacetate or thiobenzoate compounds as described previously in Scheme A, step b.

As summarized in Table 1, the R.sub.2 and R.sub.3 groups on the thioacetate or thiobenzoate compounds of structures (5a) and (5b) can be manipulated using techniques and procedures well known and appreciated by one of ordinary skill in the art to give the corresponding compounds of structures (6a)-(10a) and (6b)-(10b).

For example, the t-butyl ester functionality of the appropriate (R)-thioacetate or (R)-thiobenzoate compound of structure (5a) can be removed using trifluoroacetic acid to give the appropriate (R)-thioacetate or (R)-thiobenzoate carboxylic acid compound of structure (6a). Similarly, the t-butyl ester functionality of the appropriate (S)-thioacetate or (S)-thiobenzoate compound of structure (5b) can be removed using trifluoroacetic acid to give the (S)-thioacetate or (S)-thiobenzoate carboxylic acid compound of structure (6b).

The (R)-thioacetate or (R)-thiobenzoate functionality of the appropriate (R)-thioacetate or (R)-thiobenzoate carboxylic acid compound of structure (6a) can be removed with lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol to give the appropriate (R)-thio carboxylic acid compound of structure (7a). Similarly, the (S)-thioacetate or (S)-thiobenzoate functionality of the appropriate (S)-thioacetate or (S)-thiobenzoate carboxylic acid compound of structure (6b) can be removed with lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol to give the appropriate (S)-thio carboxylic acid compound of structure (7b).

Alternatively, the carboxylic acid functionality of the appropriate (R)-thioacetate or (R)-thiobenzoate carboxylic acid compound of structure (6a) can be re-esterified using techniques and procedures well known and appreciated in the art. For example, a (R)-thioacetate or (R)-thiobenzoate compound of structure (5a) can be prepared by treating the (R)-thioacetate or (R)-thiobenzoate carboxylic acid compound of structure (6a) with the appropriate alkyl halide or Ar--Y halide in a suitable aprotic solvent, such as dimethylformamide along with a non-nucleophilic base, such as cesium carbonate. Similarly, the carboxylic acid functionality of the appropriate (S)-thioacetate or (S)-thiobenzoate carboxylic acid compound of structure (6b) can be esterified to the appropriate (S)-thioacetate or (S)-thiobenzoate compound of structure (5b) as described above for the (R)-thioacetate or (R)-thiobenzoate compound of structure (5a).

The (R)-thioacetate or (R)-thiobenzoate functionalities of the appropriate (R)-thioacetate or (R)-thiobenzoate compound of structure (5a) can be hydrolyzed to the corresponding (R)-thiol compounds of structure (Sa) with ammonia in a suitable protic solvent, such as methanol. Similarly, the (S)-thioacetate or (S)-thiobenzoate functionalities of the appropriate (S)-thioacetate or (S)-thiobenzoate compounds of structure (5b) can be hydrolyzed to the corresponding (S)-thiol compounds of structure (8b).

The thiol functionality of the appropriate (R)-thio carboxylic acid compound of structure (7a) can be alkylated using techniques and procedures well known and appreciated in the art. For example, a (R)-pivaloyloxymethylthio carboxylic acid compound of structure (9a) can be prepared by treating the (R)-thio carboxylic acid compound of structure (7a) with the appropriate with chloromethyl pivalate in a suitable aprotic solvent, such as dimethylformamide along with a non-nucleophilic base, such as cesium carbonate. Similarly, the thiol functionality of the appropriate (S)-thio carboxylic acid compound of structure (7b) can be alkylated to the appropriate (S)-pivaloyloxymethylthio carboxylic acid compound of structure (9b) as described above for (9a).

The thiol functionality of the appropriate (R)-thiol compound of structure (Sa) can be alkylated using techniques and procedures well known and appreciated in the art. For example, a (R)-pivaloyloxymethylthio compound of structure (10a) can be prepared by treating the (R)-thiol compound of structure (8a) with the appropriate with chloromethyl pivalate as described above for the conversion of (7a) to (9a). Similarly, the thiol functionality of the appropriate (S)-thiol compound of structure (8b) can be alkylated to the appropriate (S)-pivaloyloxymethylthio compound of structure (10b) as described above for the (R)-pivaloyloxymethylthio compound of structure (10a).

Starting materials for use in the general synthetic procedures outlined in Scheme A are readily available to one of ordinary skill in the art. For example, certain amino compounds of structure (1) are described in U.S. Pat. No. 4,512,924 of Attwood et al. (Apr. 23, 1985).

The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; ".degree. C." refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; ".mu.L" refers to microliters; ".mu.g" refers to micrograms; and ".mu.M" refers to micromolar.

EXAMPLE 1

Preparation of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

Scheme A, step a: 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

Mix D-phenylalanine (186.4 g, 1.128 mol) and 49% hydrobromic acid (372.8 g), cool to -5.degree. C. and add, by dropwise addition, a solution of sodium nitrite (77.9 g) in water (565 mL) over a period of about 1 hour (vigorous gas evolution). Stir at -5.degree. C. to 0.degree. C. for 4 hours, extract into ethyl ether (3.times.1 L), dry (MgSO.sub.4) and evaporate the solvent in vacuo. Purify by chromatography (5% acetic acid/95% methylene chloride) and distillation to give 3-phenyl-2(R)-bromopropionic acid (112 g, 43%); bp 128.degree.-135.degree. C. @0.25 torr.

Mix 3-phenyl-2(R)-bromopropionic acid (3.94 g, 17.2 mmol) and 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxyl ic acid, t-butyl ester (3.75 g, 13.2 mmol) in methylene chloride (50 mL). Add EEDQ (4.24 g, 17.7 mmol). Stir at room temperature overnight, dilute with methylene chloride, wash with saturated sodium hydrogen carbonate, water, 1M HCL, water and brine. Dry (MgSO.sub.4) and evaporate the solvent in vacuo to give an oily residue. Purify by silica gel chromatography (60:40 hexane/ethyl acetate) to give the title compound as a white foam (4.86 g, 74%).

.sup.1 H NMR (CDCl.sub.3) 8 7.39 (d, 1, J=6.4 Hz), 7.15-7.37 (m, 5), 5.23 (dt, 1, J=6.4, 8.8 Hz), 4.91 (m, 1), 4.39 (dd, 1, J=6.6, 8.0 Hz), 3.54-3.65 (dd, 1, J=6.7, 14.1 Hz), 3.34-3.47 (m, 1), 3.03-3.24 (m, 2), 2.90-3.03 (m, 1), 2.51-2.65 (m, 1), 2.29-2.40 (m, 1), 2.05-2.20 (m, 1), 1.59-1.96 (m, 4), 1.27-1.59 (m, 11); .sup.13 C NMR (CDCl.sub.3) .delta. 172.17, 169,80, 167.02, 137.19, 129.16, 128.32, 126.93, 82.06, 52.54, 51.52, 51.29, 50.85, 50.47, 41.74, 29.64, 27.98, 26.13, 24.95, 16.56.

Scheme A, step b: 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine -1(S)-carboxylic acid, t-butyl ester

Dissolve thiolacetic acid (0.92 mL, 12.9 mmol) in degassed methanol (50 mL) and treat with cesium carbonate (2.00 g, 6.1 mmol). Stir the yellow solution for 30 minutes then evaporate the solvent in vacuo and dry in vacuo for 1.5 hours. Dilute the resulting cesium salt with dimethylformamide (50 mL) and treat with a solution of a mixture of 9-[(S)-(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester (3.03 g, 6.1 mmol) in dimethylformamide (50 mL). Stir at room temperature for 1.5 hours, dilute with ethyl acetate, wash with water (2.times.) and brine. Dry (MgSO.sub.4), filter and evaporate the solvent in vacuo to give an oily residue. Purify by silca gel chromatography (50:50 hexane/ethyl acetate) to give the title compound as a yellow foam (2.56 g, 85%).

IR (KBr) 3389, 3086, 3065, 3030, 2974, 2933, 2863, 1738, 1690, 1655, 1499, 1447, 1427, 1368, 1154, 1127 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.12-7.37 (m, 6), 5.14-5.25 (m, 1), 4.87-4.95 (m, 1), 4.29 (t, 1, J=7.5 Hz), 3.25-3.46 (m, 2), 2.88-3.15 (m, 3), 2.49-2.62 (m, 1), 2.25-2.38 (m, 4), 2.08-2.22 (m, 1), 1.32-1.94 (m, 15); .sup.13 C NMR (CDCl.sub.3) .delta. 194.28, 172.21, 169.89, 168.20, 137.55, 129.11, 128.22, 126.61, 81.96, 52.47, 51.51, 50.96, 50.72, 48.35, 36.96, 30.43, 29.63, 27.98, 26.07, 25.02, 16.59; MS (FAB) m/z 490 [M.sup.+ +H], 434, 414, 392, 358, 267, 211 [base peak]; Anal. Calcd for C.sub.25 H.sub.35 N.sub.3 O.sub.5 S: C, 61.33; H, 7.21; N, 8.58; Found: C, 61.20; H, 7.16; N, 8.55.

EXAMPLE 2

Preparation of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

Dissolve 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester (0.40 g, 0.82 mmol) in absolute ethanol (20 mL) and saturated ethanolic ammonia (20 mL). Stir the reaction mixture at room temperature for 2 hours, evaporate the solvent in vacuo, dilute with methylene chloride, wash with water and brine. Dry (MgSO.sub.4), filter and evaporate the solvent in vacuo to give the title compound as a clear glass (0.30 g, 82%).

IR (KBr) 3389, 3337, 2974, 2934, 2863, 1738, 1645, 1499, 1427, 1368, 1227, 1154 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.38-7.49 (br d, 1, J=6.6 Hz), 7.14-7.36 (m, 5), 4.86-4.96 (m, 1), 3.50-3.62 (m, 2), 3.35-3.47 (m, 1), 3.23-3.33 (dd, 1, J=6.4, 13.9 Hz), 3.02-3.17 (m, 2), 2.88-3.01 (m, 2), 2.51-2.66 (m, 1), 2.12-2.41 (m, 2), 1.99 (d, 1, J=8.7 Hz), 1.58-1.96 (m, 4), 1.29-1.58 (m, 11); .sup.13 C NMR (CDCl.sub.3) .delta. 172.51, 170.57, 169.90, 137.62, 129.34, 128.31, 126.76, 82.11, 52.63, 51.61, 51,03, 50.86, 44.88, 41.51, 29.72, 28.04, 26.23, 25.01, 16.63; MS (FAB) m/z 448 [M.sup.+ +H], 414, 392, 358, 211 [ base peak]; Anal. Calcd for C.sub.23 H.sub.33 N.sub.3 O.sub.4 S: C, 61.72; H, 7.43; N, 9.39; Found: C, 61.58; H, 7.36; N, 9.34.

EXAMPLE 3

Preparation of 9-[(S)-(1-Oxo-2(S)-acetylthio-3phenylpropyl)amino]-octahydro-10-oxo-6H-Pyr idazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid

The synthesis of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-Py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid is the same as that of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid described in Example 11, but substituting 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro- 10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester.

Yield 58%; IR (film) 3354, 3086, 3063, 3030, 2945, 2870, 1734, 1688, 1651, 1520, 1499, 1454, 1209, 1173, 912, 733 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.14-7.39 (m, 6), 5.10-5.26 (br s, 1), 4.19-4.46 (br m, 2), 3.17-3.36 (br m, 2), 2.78-3.06 (br m, 4), 2.30 (s, 3), 1.24-2.28 (br m, 11); .sup.19 F NMR (CDCl.sub.3) .delta. -76.30; .sup.13 C NMR (CDCl.sub.3) .delta. 195.03, 174.62, 172.81, 170.11, 137.14, 129.07, 128.33, 126.84, 52.52, 52.07, 51.43, 50.09, 48.39, 36.48, 30.35, 28.92, 25.50, 23.98, 15.36; MS (FAB) m/z 434 [M.sup.+ +H, base peak], 392, 358, 211; HRMS Calcd for C.sub.21 H.sub.28 N.sub.3 O.sub.5 S: 434.1750; Found: 434.1744.

EXAMPLE 4

Preparation of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [ 1,2-a][1,2]diazepine-1(S)-carboxylic acid

The synthesis of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid is the same as that of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-l(R)carboxylic acid described in Example 11, but substituting 9-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester.

Yield 83%; IR (film) 3318, 3066, 3063, 3030, 2938, 2864, 1728, 1630, 1452, 1211, 1173, 1155, 910, 733 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.54-7.70 (d, 1, J=7.1 Hz), 6.98-7.45 (m, 5), 5.21- 5.39 (m, 1), 4.92-5.08 (m, 1), 3.56-3.71 (m, 1), 2.86-3.43 (m, 5), 2.48-2.66 (m, 1), 2.31-2.48 (m, 1), 2.08-2.24 (m, 1), 2.04 (d, 1, J=8.7 Hz), 1.66-1.95 (m, 4), 1.33-1.51 (m, 2); .sup.19 F NMR (CDCl.sub.3) .delta. -76.30; .sup.13 C NMR (CDCl.sub.3) .delta. 173.74, 172.95, 171.27, 136.90, 128.95, 128.00, 126.54, 51.97, 51.06, 50.72, 49.40, 44.23, 40.95, 28.97, 25.39, 24.08, 15.83; MS (FAB) m/z 392 [M.sup.+ +H, base peak], 358, 211; HRMS Calcd for C.sub.19 H.sub.26 N.sub.3 O.sub.4 S: 392.1644; Found: 392.1635.

EXAMPLE 5

Preparation of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, benzyl ester

Dissolve 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid (4.33 mmol) in methylene chloride (25 mL) and dry over anhydrous MgSO.sub.4. Filter and wash with methylene chloride (3.times.200 mL). Evaporate in vacuo to a residue. Dissolve the residue in anhydrous dimethylformamide (25 mL) and place under nitrogen atmosphere. Add cesium carbonate (1.65 g, 5.0 mmole) in one portion. Stir for 45 minutes at ambient temperature. Add benzyl bromide (550mg, 5.0 mmol). Stir the resulting mixture at ambient temperature for 18 hours. Quench the reaction with ethyl acetate (50 mL) and water (50 mL). Separate the organic phase and wash with water (7.times.50 mL), 1/4 saturated potassium hydrogen carbonate (50 mL), water (50 mL), and saturated sodium chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate in vacuo to yield the title compounds.

EXAMPLE 6

Preparation of 9-[(S)-(1 -Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylic acid, benzyl ester

Stir 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, benzyl ester (4 mmol) and saturated methanolic ammonia at ambient temperature until hydrolysis is complete. Evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compounds.

EXAMPLE 7

9-[(S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino]-octahydro-10 -oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid

Dissolve 9-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid (0.28 mmol) in methylene chloride (1 mL) and dry over anhydrous MgSO.sub.4 (60mg). Filter and wash with methylene chloride (3.times.20 mL). Evaporate in vacuo to a residue. Dissolve the residue in anhydrous dimethylformamide (10 mL) and place under nitrogen atmosphere. Add cesium carbonate (100mg, 0.3 mmol) in one portion. Stir for 45 minutes at ambient temperature. Add chloromethyl pivalate (42 g, 0.28 mmol). Stir the resulting mixture at ambient temperature for 18 hours. Quench the reaction with ethyl acetate (3 mL) and water (10 mL). Separate the organic phase and wash with water (7.times.10 mL), 1/4 saturated potassium hydrogen carbonate (10 mL), water (10 mL), and saturated sodium chloride (10 mL). Dry (MgSO.sub.4), filter and evaporate in vacuo to yield the title compounds.

EXAMPLE 8

9-[ (S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino]-octahydro-10-o xo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, benzyl ester

Dissolve 9-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid, benzyl ester (0.28 mmol) in methylene chloride (1 mL) and dry over anhydrous MgSO.sub.4 (60mg). Filter and wash with methylene chloride (3.times.20 mL). Evaporate in vacuo to a residue. Dissolve the residue in anhydrous dimethylformamide (10 mL) and place under nitrogen atmosphere. Add cesium carbonate (100mg, 0.3 mmol) in one portion. Stir for 45 minutes at ambient temperature. Add chloromethyl pivalate (42 g, 0.28 mmol). Stir the resulting mixture at ambient temperature for 18 hours. Quench the reaction with ethyl acetate (3 mL) and water (10 mL). Separate the organic phase and wash with water (7.times.10 mL), 1/4 saturated potassium hydrogen carbonate (10 mL), water (10 mL), and saturated sodium chloride (10 mL). Dry (MgSO.sub.4), filter and evaporate in vacuo to yield the title compounds.

EXAMPLE 9

Preparation of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester

Scheme A, step a: 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester

The synthesis of 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester is the same as for 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 1, Step a, but substituting 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(R)-carboxyl ic acid, t-butyl ester for 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxyl ic acid, t-butyl ester.

Yield 84%; IR (KBr) 3351, 3059, 3030, 3000, 2974, 2951, 2928, 1707, 1690, 1676, 1541, 1452, 1368, 1304, 1165, 702 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.08-7.51 (m, 6), 5.06-5.23 (br m, 1), 4.31-4.50 (br m, 1), 4.07-4.30 (br s, 1), 3.45-3.60 (m, 1), 3.14-3.38 (br m, 2), 2.76-3.07 (br m, 3), 1.15-2.28 (m, 17); .sup.13 C NMR (CDCl.sub.3) .delta. 171.69, 169.65, 166.78, 136.99, 129.28, 128.31, 126.98, 81.66, 52.82, 51.69, 51.02, 50.44, 41.87, 41.23, 29.35, 27.96, 25.96, 24.40, 15.80; Anal. Calcd for C.sub.23 H.sub.32 BrN.sub.3 O.sub.4 : C, 55.87; H, 6.52; N, 8.50; Found: C, 56.07; H, 6.49; N, 8.48.

Scheme A, step b: 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

The synthesis of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester is the same as for 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 1, Step b, but substituting 9-[(S)-(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester.

Yield 75%; IR (CHCl.sub.3) 3391, 3065, 3032, 3009, 2982, 2945, 2872, 1734, 1684, 1655, 1507, 1454, 1370, 1306, 1236, 1154, 955 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.16-7.39 (m, 6), 5.07-5.23 (br m, 1), 4.12-4.32 (br m, 2), 3.19-3.38 (br m, 2), 2.76-3.04 (br m, 4), 2.28 (s, 3), 1.19-2.23 (br m, 17; MS (Cl, 70 ev) m/z 490 [M.sup.+ +H]434 [base peak]; Anal. Calcd for C.sub.25 H.sub.35 N.sub.3 O.sub.5 S: C, 61.33; H, 7.21; N, 8.58; Found: C, 61.23; H, 7.12; N, 8.57.

EXAMPLE 10

Preparation of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester

The synthesis of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(R)-carboxylic acid, t-butyl ester is the same as that of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo- 6H-pyridazo[1,2a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 2, but substituting 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester for 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester.

Yield 81%; IR (KBr) 3393, 2974, 2936, 2870, 1738, 1653, 1499, 1452, 1368, 1154 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.03-7.43 (m, 6), 5.09-5.34 (br m, 1), 4.08-4.29 (br s, 1), 3.46-3.58 (m, 1), 3.20-3.39 (br m, 2), 2.75-3.14 (br m, 5), 1.18-2.30 (br m, 17); .sup.13 C NMR (CDCl.sub.3) .delta. 172.15, 170.39, 169.70, 137.66, 129.34, 128.31, 126.78, 81.60, 53.05, 52.92, 51.34, 50.38, 44.76, 41.44, 29.61, 27.98, 26.15, 24.37, 15.79; MS (FAB) m/z 448 [M.sup.+ +H, base peak], 414, 392, 358, 211; Anal. Calcd for C.sub.25 H.sub.33 N.sub.3 O.sub.4 S: C, 61.72; H, 7.43; N, 9.39; Found: C, 61.40; H, 7.35; N, 9.34.

EXAMPLE 11

Preparation of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo- 6H-pyridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid

Dissolve 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester (1.33 g, 2.7 mmol) and anisole (1 mL, excess) in methylene chloride (20 mL) and treat with trifluoroacetic acid (5 mL). Stir for 6 hours at room temperature, evaporate the solvent in vacuo triturate the residue with hexane (3.times.) and dry in vacuo overnight. Dissolve the resulting gum in a minimal amount of methylene chloride and precipitate from hexane. Decant the solvent, dry in vacuo and triturate from hexane to give the title compound as a light tan powder (0.88 g, 59%).

IR (film) 3335, 3088, 3065, 3030, 2940, 2864, 1780, 1734, 1694, 1634, 1522, 1454, 1356, 1211, 1171, 1130, 913, 733 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.40-7.50 (d, 1, J=7.1 Hz), 7.13-7.35 (m, 5), 5.20-5.34 (m, 1), 4.95-5.04 (m, 1), 4.31 (t, 1, J=7.3 Hz), 3.22-3.41 (m, 2), 2.90-3.22 (m, 3), 2.48-2.64 (m, 1), 2.35-2.47 (m, 1), 2.32 (s, 3), 2.04-2.21 (m, 1), 1.67-1.98 (m, 4), 1.30-1.52 (m, 3); .sup.19 F NMR (CDCl.sub.3) .delta. -76.28; .sup.13 C NMR (CDCl.sub.3) .delta. 198.65, 174.28, 173.13, 170.17, 137.13, 129.11, 128.36, 126.86, 52.20, 51.43, 51.13, 49.74, 48.43, 36.62, 30.41, 29.22, 25.61, 24.37, 16.13; MS (FAB) m/z 434 [M.sup.+ +H, base peak], 358, 211; HRMS Calcd for C.sub.21 H.sub.28 N.sub.3 O.sub.5 S: 434.1750; Found: 434.1733.

EXAMPLE 12

Preparation of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(R)-carboxylic acid

The synthesis of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(R)-carboxylic acid is the same as that of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid described in Example 11, but sustituting 9-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester.

Yield 74%; IR (film) 3339, 3086, 3063, 3030, 2945, 2870, 1778, 1728, 1635, 1454, 1209, 1173, 910, 733 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.04-7.81 (br m, 6), 5.12-5.36 (br m, 1), 4.20-4.47 (br s, 1), 3.64 (q, 1, J=7.4 Hz), 2.74-3.43 (br m, 6), 1.23-2.35 (br m, 9); .sup.19 F NMR (CDCl.sub.3) .delta.-76.31; .sup.13 C NMR (CDCl.sub.3) .delta. 174.24, 172.93, 171.66, 137.13, 129.32, 128.32, 126.91, 52.62, 52.16, 51.38, 55.20. 44.55, 41.17, 29.11, 25.85, 23.93, 15.35; MS (FAB) m/z 392 [M.sup.+ +H, base peak], 358, 211; HRMS Calcd for C.sub.19 H.sub.26 N.sub.3 O.sub.4 S: 392.1644; Found: 392.1663.

EXAMPLE 13

Preparation of 9-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

Scheme A, step a: 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6H-pyr idazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

The synthesis of 9-[(S)-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-6 ,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester is the same as for 9-[(S)-(1-Oxo-2(R)- bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo[1, 2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 1, Step a, but substituting 9(S)-amino-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carb oxylic acid, t-butyl ester for 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxyl ic acid, t-butyl ester.

Yield 84%; IR (KBr) 3385, 3337, 2978, 2936, 1736, 1676, 1518, 1456, 1445, 1425, 1370, 1339, 1310, 1273, 1250, 1235, 1157, 1132 748 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.16-7.42 (m, 5), 6.93 (d, 1, J=7.2 Hz), 5.23 (dd, 1, J=3.0, 6.0 Hz), 4.75-4.89 (m, 1), 4.56-4.68 (dt, 1, J=3.6, 12.9 Hz), 4.39 (t, 1, J=7.5 Hz), 3.36-3.63 (m, 2), 3.13-3.25 (dd, 1, J=7.9, 14.2 Hz), 2.79-2.94 (m, 1), 2.58-2.76 (m, 1), 2.16-2.40 (m, 2), 1.77-1.96 (m, 1), 1.36-1.77 (m, 12); .sup.13 C NMR (CDCl.sub.3) .delta. 171.47, 169.43 168.00, 167.39, 136.91, 129.19, 128.43, 127.13, 83.16, 53.35, 49.88, 48.98, 41.74, 41.32, 31.05, 30.02, 28.06, 25.69, 20.20; MS (FAB) m/z 508 [M.sup.+ +H]452 [base peak], 428, 408, 372, 197; Anal. Calcd for C.sub.23 H.sub.30 BrN.sub.3 O.sub.5 : C, 54.34; H, 5.95; N, 8.26; Found: C, 54.25; H, 6.02; N, 8.41.

Scheme A, step b: 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester

The synthesis of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester is the same as for 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 1, step b, but substituting 9-[(S)-(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6H-pyr idazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridaz o[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester.

Yield 84%; IR (film) 3325, 3086, 3063, 3007, 2980, 2938, 1736, 1678, 1518, 1456, 1445, 1424, 1370, 1341, 1312, 1273, 1250, 1233, 1155, 1130, 754 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.14-7.40 (m, 5), 6.90-7.02 (d, 1, J=7.2 Hz), 5.20-5.30 (m, 1), 4.70-4.86 (m, 1), 4.27 (t, 1, J=7.5 Hz), 3.37-3.54 (m, 1), 3.23-3.36 (dd, 1, J=7.5, 14.1 Hz), 2.94-3.07 (dd, 1, J=7.8, 14.1 Hz), 2.64-2.88 (m, 2), 2.15-2.41 (m, 5), 1.56-1.92 (m, 4), 1.45 (s, 9); .sup.13 C NMR (CDCl.sub.3) .delta. 195.13, 171.58, 169.43, 168.06, 137.27, 129.11, 128.31, 126.76, 83.04, 53,10, 48.72, 47.75, 41.25, 36.19, 30.83, 30.45, 30.02, 28.03, 25.73, 20.20; MS (CI, 70 ev) m/z 504 [M.sup.+ +H]448 [base peak], 374; HRMS Calcd for C.sub.25 H.sub.34 N.sub.3 O.sub.6 S: 504.2168, Found: 504.2193; Anal. Calcd for C.sub.25 H.sub.33 N.sub.3 O.sub.6 S: C, 59.62; H, 6.60; N, 8.34; Found: C, 59.39; H, 6.58; N, 8.17.

EXAMPLE 14

Preparation of 9-((S)-(1-Oxo-2( S)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]d iazepine-1(S)-carboxylic acid, t-butyl ester

The synthesis of 9-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyri dazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester is the same as that of 9-[(S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester described in Example 2, but substituting 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester for 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester.

Yield 88%; IR (KBr) 3349, 2978, 2936, 1736, 1676, 1518, 1499, 1456, 1445, 1424, 1370, 1273, 1250, 1231, 1157, 1132 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.02-7.43 (m, 6), 5.18-5.29 (m, 1), 4.74-4.89 (m, 1), 4.55-4.68 (m, 1), 3.55-3.68 (m, 1), 3.36-3.55 (m, 1), 3.10-3.30 (m, 2), 2.66-2.92 (m, 2), 2.17-2.40 (m, 2), 1.99 (d, 1, J=8.9 Hz), 1.21-1.93 (m, 13); .sup.13 C NMR (CDCl.sub.3) .delta. 171.58, 170.83, 169.69, 168.02, 137.08, 129.38, 128.34, 126.93, 83.15, 53.28, 48.79. 44.66, 41.35, 41.21, 31.00, 30.06, 28.07, 25.73, 20.26; MS (FAB) m/z 462 [M.sup.+ +H], 429, 406 [base peak], 372; Anal. Calcd for C.sub.23 H.sub.31 N.sub.3 O.sub.5 S: C, 59.84; H, 6.77; N, 9.10; Found: C, 59.59; H, 6.73; N, 9.10.

EXAMPLE 15

Preparation of 9-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid

The synthesis of 9-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid is the same as that of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid described in Example 11, but sustituting 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6 H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester.

Yield 58%; IR (CHCl.sub.3) 3380, 3088, 3065, 3032, 3011, 2957, 2938, 1782, 1723, 1680, 1520, 1458, 1447, 1425, 1233, 1171, 1134 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.08-7.39 (m, 6), 5.36-5.47 (m, 1), 4.74-4.88 (m, 1), 4.53-4.68 (m, 1), 4.29 (t, 1, J=7.4 Hz), 3.18-3.48 (m, 2), 2.83-3.07 (m, 2), 2.58-2.79 (m, 1), 2.18-2.49 (m, 5), 1.61-2.02 (m, 4); .sup.13 C NMR (CDCl.sub.3) .delta. 195.44, 172.87, 172.55, 170.63, 169.37, 136.83, 129.07, 128.42, 126.97, 52.62, 48.83, 47.96, 41.78, 36.12, 30.63, 30.46, 29.54, 25.15, 20.29; MS (FAB) m/z 448 [M.sup.+ +H, base peak], 406; HRMS Calcd for C.sub.21 H.sub.26 N.sub.3 O.sub.6 S: 448.1542; Found: 448.1523.

EXAMPLE 16

Preparation of 9 -((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyrid azo[1,2-a][1,2]diazepine-1(S)-carboxylic acid

The synthesis of 9-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyri dazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid is the same as that of 9-[(S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid described in Example 11, but sustituting 9-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-octahydro-6,10-dioxo-6H-pyri dazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, t-butyl ester for 9-[(S)-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-octahydro-10-oxo-6H-py ridazo[1,2-a][1,2]diazepine-1(R)-carboxylic acid, t-butyl ester.

Yield 95%; IR (CHCl.sub.3) 3347, 3088, 3065, 3034, 3009, 2957, 2940, 2872, 1782, 1726, 1672, 1516, 1456, 1447, 1429, 1277, 1235, 1173 cm.sup.-1l ; .sup.1 H NMR (CDCl.sub.3) .delta. 7.06-7.49 (m, 6), 5.35-5.47 (dd, 1, J=2.7, 3.1 Hz), 4.77-4.93 (m, 1), 4.53-4.71 (m, 1), 3.63-3.76 (m, 1), 3.31-3.48 (m, 1), 3.09-3.31 (m, 2), 2.82-2.98 (m, 1), 2.61-2.89 (m, 1), 2.24-2.45 (m, 2), 2.05 (d, 1, J=8.7 Hz), 1.61-2.01 (m, 4); .sup.13 C NMR (CDCl.sub.3) .delta. 172.73, 172.25, 169.59, 136.67, 129.31, 128.42, 127.08, 52.69, 48.87, 44.42, 41.79, 41.07, 30.73, 29.60, 25.16, 20.25; MS (FAB) m/z 406 [M.sup.+ +H, base peak]; HRMS Calcd for C.sub.19 H.sub.24 N.sub.3 O.sub.5 S: 406.1437; Found: 406.1427.

The following compounds can be prepared by procedures analogous to those described above in Examples 1-16:

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5 ,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5 ,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5,9-dio xo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5,9-dio xo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-2,3,6,7,8,9- hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-2,3,6,7,8,9- hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3 ,6,7 8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3 ,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxyl ic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3,6,7,8 ,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3,6,7 8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine -1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine -1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyri dazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyri dazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyridazo[1 ,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyridazo[1 ,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,5,7,8,9- hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,5,7,8,9- hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,5,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,5,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxyl ic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxyl ic acid, benzyl ester;

2-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyra zolo[1,2-a]pyridazine-5-carboxylic acid, t-butyl ester;

2-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyra zolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyrazolo[1 ,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyrazolo[1 ,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-3- oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-3- oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, t-butyl ester;

2-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-hexahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-hexahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-hexahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-hexahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-9-oxopyridazo[ 1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-1,4,6,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-1,4,6,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-1,4,6,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-1,4,6,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,6,7,8,9- hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,6,7,8,9- hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,6,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,6,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,6,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,6,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,6,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxyl ic acid;

8-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,6,7,8,9-hexahydro- 6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

9-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H -pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid, t-butyl ester;

9-((S)-(1-Oxo-2(R)-acetylthio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H -pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyrid azo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-thio-3-phenylpropyl)amino)-octahydro-6,10-dioxo-6H-pyrid azo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

9-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

9-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid, t-butyl ester;

9-((S)-(1-Oxo-2(R)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

9-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid;

9-((S)-(1-Oxo-2(R)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5 ,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5 ,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5,9-dio xo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-2,3,6,7,8,9-hexahydro-5,9-dio xo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-2,3,6,7,8,9- hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-2,3,6,7,8,9- hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3 ,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxyl ic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3 ,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxyl ic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3,6,7,8 ,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-2,3,6,7 8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-2,3,6,7 8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine -1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyri dazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyri dazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyridazo[1 ,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-6,9-dioxopyridazo[1 ,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-6, 9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,9dioxopyridazo[1,2-a]pyridazine-i-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo [1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-octahydro-9-oxopyridazo[1,2-a ]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-octahydro-9- oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-oct ahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3,(3,4-methylenedioxyphenyl)propyl)amino)-octahydro -9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-octahydro-9oxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6 ,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-1,4,5,7,8,9-hexahydro-6,9-dio xopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,5,7,8,9- hexahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-1,4,5,7,8,9- hexahydro-6,9dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, t-butyl ester;

8-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4 ,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,5,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid;

8-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-1,4,5,7,8 ,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxylic acid, benzyl ester;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxyl ic acid;

8-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-1,4,5,7,8,9-hexahydro-6,9-dioxopyridazo[1,2-a]pyridazine-1-carboxyl ic acid, benzyl ester;

2-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyra zolo[1,2-a]pyridazine-5-carboxylic acid, t-butyl ester;

2-((S)-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyra zolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyrazolo[1 ,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-thio-3-phenylpropyl)amino)-hexahydro-3-oxo-1H-pyrazolo[1 ,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-3- oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-phenylpropyl)amino)-hexahydro-3- oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, t-butyl ester;

2-((S)-(1-Oxo-2(S)-acetylthio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hex ahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-thio-3-(3,4-methylenedioxyphenyl)propyl)amino)-hexahydro -3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;

2-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid;

2-((S)-(1-Oxo-2(S)-pivaloyloxymethylthio-3-(3,4-methylenedioxyphenyl)propyl )amino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, benzyl ester;