WO2007109615A2

WO2007109615A2 - β -LACTAMYL VASOPRESSIN V2 ANTAGONISTS

Info

Publication number: WO2007109615A2
Application number: PCT/US2007/064309
Authority: WO
Inventors: Gary A. Koppel; Ned D. Heindel
Original assignee: Azevan Pharmaceuticals, Inc.
Priority date: 2006-03-21
Filing date: 2007-03-19
Publication date: 2007-09-27
Also published as: WO2007109615A3

Abstract

β-lactamyl alkanoic acids and pharmaceutical compositions thereof are described. Methods for treating various diseases and disease states using one or more β-lactamyl alkanoic acids are also described. Substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, substituted 2-(azetidin-2-on- l-yl)hydroxyalkylalkanoic acids, and 2-(azetidin-2-on-l-yl)alkylalkanoic acids, and analogs and derivatives thereof are described. Methods for using 2-(azetidin-2-on-l-yl)alkanedioic acids and derivatives thereof in the treatment of disease states responsive to antagonism of the vasopressin V2 receptor are also described.

Description

β-LACTAMYL VASOPRESSIN V₂ ANTAGONISTS

TECHNICAL FIELD

The present invention relates to substituted 2-(azetidin-2-on-l-yl)alkanoic acids and derivatives thereof. The present invention also relates to methods of treating mammals in need of relief from disease states associated with and responsive to the antagonism of the vasopressin V₂ receptor.

BACKGROUND

Arginine vasopressin (AVP) is a neurohypophyseal neuropeptide produced in the hypothalamus, and is involved in many biological processes in both the circulatory system and in the central nervous system (CNS), including water metabolism homeostasis, renal function, mediation of cardiovascular function, non-opioid mediation of tolerance for pain, and regulation of temperature in mammals. Vasopressin also acts as a neurotransmitter in the brain. Three vasopressin receptor subtypes, designated Vi₃, Vib, and V₂ have been identified.

Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the two main ACTH secretagogues. AVP is made in neurons localized to the paraventricular nucleus of the hypothalamus, and activation of these neurons causes the release of AVP into the portal circulation of the median eminence.

AVP has a critical role in water and electrolytic balance, and it has been demonstrated that this neurohormone contributes to the pathophysiology and progression of congestive heart failure (see, e.g., Schrier & Abraham "Hormones and hemodynamics in heart failure," N Engl J Med 341:577-585 (1999); Thibonnier "Vasopressin receptor antagonists in heart failure," Current Opinion in Pharmacology 3:683-687 (2003); Lee et al., "Vasopressin: A new target for the treatment of heart failure," American Heart Journal 146:9-18(2003). The coordinated physiology of the renal/cardiovascular systems contributes to normal cardiac performance and homeostasis. Regulation of blood volume, vascular smooth muscle tone, and cardiac contractility and metabolism are all major factors affecting the performance of the heart and its ability to meets the demands of the body. AVP affects all of these factors through activation of V_la and V₂ receptors. Vasopressin V_]a receptors are localized to vascular smooth muscle and cardiomyocytes, promoting vasoconstriction and myocardial cell protein synthesis and growth, respectively. V₂ receptors are localized to the collecting ducts of nephrons in the kidney promoting free water reabsorption.

Arginine vasopressin (AVP), antidiuretic hormone, is a nonapeptide secreted from the posterior pituitary gland. The primary stimulus for the secretion of AVP is a rise in serum osmolality. The central sensor for serum osmolality, or osmostat, is located in a small, discreet area of the hypothalamus just anterior to the third ventricle. The osmostat controls the release of AVP, stimulating water retention and the thirst response. AVP is also a key element in the regulation of volume. AVP is released in response to a diminished effective circulating volume or diminished blood pressure. In contrast to the osmoregulatory system, which relies solely upon a central sensor, volume regulation is anatomically diffuse and involves many sensors. For example, high-pressure receptors, or baroreceptors, are located in the aorta and carotid sinus, and low-pressure volume receptors are located in the left atrium. Once the baroreceptor response is stimulated, AVP production increases in a logarithmic fashion. Thus, the levels of AVP associated with hypovolemia may be substantially higher than those achieved by osmotic stimulation.

Two cell-surface receptors that mediate the downstream effects of AVP are Via and V₂. The V_la receptor is a cardiovascular AVP receptor, whereas the V₂ receptor is a renal AVP receptor. Via receptors are located on the surface of vascular smooth muscle cells and have been identified in the myocardium. This receptor uses a G_q /phospholipase C second messenger system to increase cytosolic free calcium, and stimulation of the V_]a receptor results in vasoconstriction in the peripheral and coronary circulations. The Vj_a receptor has been shown to mediate increased protein synthesis in cardiomyocytes, and may therefore play a role in cardiac hypertrophy and remodeling. V₂ receptors are located in the cortical collecting duct of each nephron, and act via a G_s/cyclic adenosine monophosphate second messenger system to mobilize aquaporin-2 water channels from the cytosol to the luminal surface of cortical collecting duct epithelial cells. Aquaporin-2 channels make the luminal surface of the cortical collecting duct epithelial cell permeable to water, resulting in retention of free water by the kidney and concentration of the urine. Activation of the ₂ receptor also stimulates expression of the genes coding for aquaporin-2 water channels.

Cardiovascular disease is the largest cause of hospitalizations in individuals 65 years of age and older. It has been observed that plasma levels of AVP are elevated in patients with heart failure, particularly those that present with hyponatremia (see, e.g., Goldsmith, "Congestive heart failure: potential role of arginine vasopressin antagonists in the therapy of heart failure," Congest Heart Fail 8:251-6 (2002); Schrier and Ecder, 2001. In addition, the impaired water diuresis in CHF patients, leading to increased blood volume, hyponatremia, edema, and weight gain, has been linked to elevated AVP. Further, additional evidence suggests that AVP contributes to the hypertrophic myocardium characteristic of the failing heart (see, e.g., Nakamura et al., "Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin V ureceptor," Eur J Pharmacol 391:39-48 (2000); Bird et al., "Significant reduction in cardiac fibrosis and hypertrophy in spontaneously hypertensive rats (SHR) treated with a Vi_areceptor antagonist," (abstract) Circulation 104:186 (2001)).

Small changes in plasma osmolarity are sensed by receptors in the hypothalamus, which regulates the neurosecretory release of AVP from the pituitary gland. With osmotic stimulation, plasma AVP levels can rise from a basal level of 3-4 pg/ml to 9-10 pg/ml. These modest changes in AVP neurohormone level, in concert with the renin-angiotensin-aldosterone system, regulate the day-to-day water and electrolyte balance in healthy subjects. However, it has been reported that the role of AVP in the cardiovascular physiology of healthy subjects is minimal, and for those persons, supraphysiological doses of neurohormone are needed to affect blood pressure, cardiac contractility, and coronary blood flow. In contrast, AVP plays a substantive role in patients with heart failure. For example, several studies demonstrated that basal plasma AVP level is elevated in patients with heart failure as compared to healthy controls, particularly those patients that present with hyponatremia. Further, the impaired water diuresis in CHF patients that leads to increased blood volume, hyponatremia, edema, and weight gain, is linked to AVP. With heart failure, elevations in plasma AVP lead to increased peripheral vascular resistance and pulmonary capillary wedge pressure while reducing cardiac output and stroke volume. AVP contributes to the hypertrophic myocardium characteristic of the failing heart, and cell/molecular studies have demonstrated that it also triggers a signaling cascade that promotes the myocardial fibrosis typically seen with progression of the disease.

Structural modification of vasopressin has provided a number of vasopressin agonists (Sawyer, Pharmacol Reviews, 13:255 (1961)). In addition, several potent and selective vasopressin peptide antagonists have been designed (Lazslo et al, Pharmacological Reviews, 43:73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12:1055-1070 (1987); Manning and Sawyer, Trends in Neuroscience, 7:8-9 (1984)). Finally, novel structural classes of non-peptidyl vasopressin antagonists have been discovered (Yamamura et al, Science, 275:572-57 '4 (1991); Serradiel-Le Gal et al, Journal of Clinical Investigation, 92:224-231 (1993); Serradiel-Le Gal et al, Biochemical Pharmacology, 47(4):633-641 (1994)).

SUMMARY OF THE INVENTION

Methods for treating diseases and disease states responsive to antagonism of vasopressin V₂ receptors are described herein. In one illustrative embodiment, the disease state is a cardiovascular disease, such as congestive heart failure, and the like. The methods described herein include the step of administering one or more β-lactamyl vasopressin antagonists, including the β- lactamylalkanoic acids described herein, to a patient in need of relief from a disease state responsive to antagonism of vasopressin V₂ receptors.

It has been found that certain compounds within the general class of substituted 2- (azetidin-2-on- 1 -yl)alkanoic acids and derivatives thereof elicit activity at the vasopressin V₂ receptor. Described herein are substituted 2-(azetidin-2-on-l-yl)alkanoic acids and alkanedioic acids, and carboxylic acid derivatives thereof, including but not limited to esters, and amides. Also described herein are substituted 2-(azetidin-2-on-l-yl)hydroxyalkylalkanoic acids, hydroxy derivatives thereof, and carboxylic acid derivatives thereof, including but not limited to ethers, esters, amides, carbamates, and ureas. Also described herein are substituted 2-(azetidin-2-on-l- yl)alkylalkanoic acids, substituted alkyl analogs thereof, and carboxylic acid derivatives thereof, including but not limited to esters, and amides. Also described herein are pharmaceutical compositions that include therapeutically effective amounts of the alkanoic acid and alkanedioic acid compounds described herein. In addition, methods useful for treating diseases and disease states that are associated with vasopressin dysfunction, and responsive to antagonism of a vasopressin receptor, such as the V2 receptor in a mammal are described. In addition, processes for preparing substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, substituted 2-(azetidin-2-on-l-yl)hydroxyalkylalkanoic acids, and 2-(azetidin-2-on-l-yl)alkylalkanoic acids, and various analogs and derivatives thereof are described.

In one illustrative embodiment of the methods described herein, one or more compounds of the formula:

and pharmaceutically acceptable salts thereof, are administered to the patient; wherein

A is a carboxylic acid, an ester, or an amide;

B is a carboxylic acid, or an ester or amide derivative thereof; or B is an alcohol or thiol, or a derivative thereof;

R¹ is hydrogen or Ci-Cβ alkyl;

R² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting Of -CO₂R⁸, -CONR⁸R⁸ , and -NR⁸(COR⁹); where R⁸ and R⁸ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R⁸ and R⁸ are taken together with the attached nitrogen atom to form a heterocyclyl group; and where R⁹ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R R N-(Ci-C₄ alkyl); R³ is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R³ is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and

R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl. In one variation, compounds are described herein that are in solvated or hydrated forms. It is understood that such solvated and hydrated forms may be prepared according to the procedures described herein. Accordingly, it is to be understood that the references made to compounds described herein are intended to also refer both individually and collectively to the parent compounds, pharmaceutically acceptable salt forms thereof, hydrates thereof, and solvates thereof. It is also appreciated that such salt forms, hydrates, and/or solvates may exist in one or more crystalline or solid morphologies that are the same as or different from those of the parent compounds.

In another illustrative embodiment of the methods described herein, one or more compounds of formula (I):

A and A¹ are each independently selected from -CO₂H, or an ester or amide derivative thereof; n is an integer selected from 0 to about 3;

R¹ is hydrogen or C₁-C₆ alkyl;

R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CO₂R⁸, -CONR⁸R⁸ , and -NR⁸ (COR⁹); where R⁸ and R⁸ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R and R are taken together with the attached nitrogen atom to form an heterocycle; and where R is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R R N-(Ci-C₄ alkyl); R is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R³ is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and

R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.

In one variation, compounds of formula (I) are described herein that are in solvated or hydrated forms. It is understood that such solvated and hydrated forms may be prepared according to the procedures described herein. Accordingly, it is to be understood that the references made to the compounds of formula (I) are intended to also refer both individually and collectively to the parent compounds, pharmaceutically acceptable salt forms thereof, hydrates thereof, and solvates thereof. It is also appreciated that such salt forms, hydrates, and/or solvates may exist in one or more crystalline or solid morphologies that are the same as or different from those of the parent compounds of formula (I).

In one aspect, compounds of formula (I) are described, wherein A and/or A' is a monosubstituted amino. In another aspect, compounds of formula (I) are described, wherein A and/or A' is an acyclic disubstituted amino. In another aspect, compounds of formula (I) are described, wherein A and/or A^! is a cyclic disubstituted amino.

In another aspect, compounds of formula (I) are described, wherein A and/or A¹ is a monosubstituted amino having the formula XNH- or X¹NH-, where X and X' are selected from the group consisting of alkyl, including Q-C₆ alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxyalkyl, including (Ci-C₄ alkoxy)-(C_rC₄ alkyl), optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C_rC₄ alkyl), and a group Y, Y', Y-(C₁-C₄ alkyl), Y' -(C, -C₄ alkyl), R⁶R⁷N-, R⁶R⁷N-, R⁶R⁷N-(C₂-C₄ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl), where Y is an heterocycle. In another aspect, compounds of formula (I) are described, wherein A and/or A' is a disubstituted amino having the formula R XN- or R X¹N-; where R and R are selected from the group consisting of hydroxy, alkyl, including Q-C₆ alkyl, alkoxycarbonyl, including Ci-C₄ alkoxycarbonyl, and benzyl; and where X and X' are selected from the group consisting of alkyl, including Ci-C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, alkoxyalkyl, including (C₁-C₄ alkoxy)- (Ci-C₄ alkyl), optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C_rC₄ alkyl), and a group Y, Y¹, Y-(Q-C₄ alkyl), V-(C₁-Q alkyl), R⁶R⁷N-, R⁶R⁷N-, R⁶R⁷N-(C₂-C₄ alkyl), and R⁶R⁷N-(Q-C₄ alkyl), where Y is an heterocycle. In another aspect, compounds of formula (I) are described, wherein A and/or A' is a cyclic disubstituted amino having the formula R¹⁴XN-, or R¹⁴X¹N-, where R¹⁴ and X, and/or R¹⁴ and X', are taken together with the attached nitrogen atom to form an heterocycle, such as an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl; where the heterocycle is optionally substituted with R¹⁰, R¹², R⁶R⁷N-, R⁶R⁷N-, R⁶R⁷N-(C₁-C₄ alkyl), or R⁶R⁷N-(C j -C₄ alkyl) as defined above.

In another aspect, compounds of formula (I) are described wherein R¹⁴ and X, and/or R¹⁴ and X¹, are taken together with the attached nitrogen atom to form piperidinyl optionally substituted at the 4-position with hydroxy, alkyl, including Ci-Q alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxy, including Ci-C₄ alkoxy, alkoxycarbonyl, including (Ci-C₄ alkoxy)carbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C₂-C₄ alkyloxy))-(Q-C₄ alkyl), R⁶R⁷N-, R^N-alkyl, including R⁶R⁷N-(Ci-C₄ alkyl), R⁶R⁷N-, R^6'R⁷N-alkyl, including R⁶R⁷N-(Ci-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C₄ alkyl), or piperidin-1 - Yl(C₁-C₄ alkyl).

In another aspect, compounds of formula (I) are described wherein R¹⁴ and X and/or R¹⁴ and X are taken together with the attached nitrogen atom to form piperazinyl optionally substituted at the 4-position with alkyl, including C] -C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(Ci-C4 alkyl), α-methylbenzyl, and the like, N-alkyl acetamid-2-yl, including N-(Ci- C₅ alkyl) acetamid-2-yl, N-(cycloalkyl) acetamid-2-yl, including N-(C₃-C₈ cycloalkyl) acetamid-2-yl, R R N-, R R N-, or alkoxycarbonyl, including (Ci -C₄ alkoxy)carbonyl. Illustrative compounds of formula (I) are described, wherein R¹⁴ and X and/or R¹⁴ and X' are taken together with the attached nitrogen atom to form homopiperazinyl optionally substituted in the 4-position with alkyl, including C1-C4 alkyl, aryl, or aryl(Ci-C4 alkyl).

Illustrative compounds of formula (I) are described, wherein A and/or A' is a disubstituted amino having the formula R¹⁴XN- or R¹⁴X¹N-, where R¹⁴ and X and/or R¹⁴ and X are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinonyl, piperidinonyl, 2-(pyrrolidm-l-ylmethyl)pyrrolidin-l-yl, 1,2,3,4- tetrahydroisoquinolin-2-yl.

In another illustrative embodiment of the methods described herein, one or more compounds of formula (II):

A is -CO₂H, or an ester or amide derivative thereof;

Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof; n is an integer from 1 to 3; R¹ , R², R³, and R⁴ are as defined in formula I; and

R⁵ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.

In one variation, compounds of formula (II) are described herein that are in solvated or hydrated forms. It is understood that such solvated and hydrated forms may be prepared according to the procedures described herein. Accordingly, it is to be understood that the references made to the compounds of formula (II) are intended to also refer both individually and collectively to the parent compounds, pharmaceutically acceptable salt forms thereof, hydrates thereof, and solvates thereof. It is also appreciated that such salt forms, hydrates, and/or solvates may exist in one or more crystalline or solid morphologies that are the same as or different from those of the parent compounds of formula (II).

In one illustrative aspect of the compounds of formula (II), the following compounds are described:

and pharmaceutically acceptable salts thereof; wherein n is an integer in the range from about 1 to about 5, and is illustratively 1, 2, or 3; A is R O-, monosubstituted amino, or disubstituted amino;

R¹ is hydrogen or Q-C_O alkyl;

R² is hydrogen, alkyl, including C₁-C₆ alkyl, alkenyl, including C₂-C₆ alkenyl, such as vinyl, allyl, and the like, alkynyl, including C₂-C₆ alkynyl, such as ethynyl, propynyl, and the like, alkoxy, including C₁-C₄ alkoxy, alkylthio, including C₁-C₄ alkylthio, halo, haloalkyl, such as trifluoromethyl, trifluorochloroethyl, and the like, cyano, formyl, alkylcarbonyl, including C₁-C₃ alkylcarbonyl, alkoxycarbonyl, or a substituent selected from the group consisting of -CO₂R⁸, -CONR⁸R^8', and -NR⁸(COR⁹);

R³ is a structure selected from the group consisting of

R is alkyl, including Ci-C₆ alkyl, alkenyl, including C₂-C₆ alkenyl, alkynyl, including C₂-C₆ alkynyl, cycloalkyl, including C₃-C₈ cycloalkyl, cycloalkenyl, including C₃-C₉ cycloalkenyl, such as limonenyl, pinenyl, and the like, alkylcarbonyl, including Ci-C₃ alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl), optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, including aryl(C₂-C₄ alkenyl), optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl, including aryl(C2-C₄ alkynyl);

R⁵ is selected from hydrogen, alkyl, including Q -C₆ alkyl, cycloalkyl, including C₃- C₈ cycloalkyl, alkoxyalkyl, including (C₁-C₄ alkoxy)-(Q-C₄ alkyl), optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl), Y-, Y-(Ci-C₄ alkyl), Y'-, Y'-(Ci-C, alkyl), R⁶R⁷N-(C₂-C₄ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl); where Y is an heterocycle, including tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, and quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with alkyl, including C₁-C₄ alkyl or optionally substituted arylalkyl, including aryl(C]-C₄ alkyl); R⁶ is hydrogen or alkyl, including C1-C6 alkyl; and R⁷ is alkyl, including Ci-Q alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl); or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substituted with R¹³;

R⁵ is selected from the group consisting OfC₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ alkoxy)-(d-C₄ alkyl), optionally-substituted aryl(Ci-C₄ alkyl), V-(C₁-C₄ alkyl), where Y'- is a second heterocycle, and R R N-(C2-C₄ alkyl); where the second heterocycle Y' is selected from the group consisting of tefrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C₁-C₄ alkyl or optionally- substituted aryl(C_rC₄ alkyl);

R⁶ is hydrogen or alkyl, including C₁-C₆ alkyl; and R⁷ is alkyl, including C₁-C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, including aryl(Cj-C₄ alkyl); or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substituted with R ;

R⁸ and R⁸ are each independently selected from hydrogen, alkyl, including C₁-C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl); or R⁸ and R⁸ are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;

R is selected from hydrogen, alkyl, including C₁-C₆ alkyl, cycloalkyl, including C₃- C₈ cycloalkyl, alkoxyalkyl, including (C₁-C₄ alkoxy)-(Q-C₄ alkyl), optionally substituted aryl, optionally substituted arylalkyl, including aryl(C [-C₄ alkyl), optionally substituted heteroaryl, optionally substituted heteroarylalkyl, including heteroaryl(C 1-C4 alkyl), and R⁸R⁸N-(Ci-C₄ alkyl); R¹⁰ and R¹¹ are each independently selected from hydrogen, optionally substituted alkyl, including C₁-C₆ alkyl, optionally substituted cycloalkyl, including C₃-C₈ cycloalkyl, alkoxyalkyl, including C₁-C₄ alkoxycarbonyl, alkylcarbonyloxy, including C₁-Cs alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, including aryl(d-C₄ alkyl), optionally substituted arylalkyloxy, including aryl(C_rC₄ alkyloxy), optionally substituted arylalkylcarbonyloxy, including aryl(d-C₄ alkylcarbonyloxy), diphenylmethoxy, and triphenylmethoxy;

R¹², R¹³, and R¹³ are each independently selected from hydrogen, alkyl, including C₁- C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, alkoxycarbonyl, including C₁-C₄ alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, including aryl(d-C4 alkyl), and optionally substituted aryloyl. In another illustrative embodiment of the methods described herein, one or more compounds of formula (III):

and pharmaceutically acceptable salts thereof, are administered to the patient; wherein A is R⁵O-, monosubstituted amino, or disubstituted amino;

A" is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, or heteroarylalkylcarbonyl, each of which may be optionally substituted; and where the carbonyl of each is optionally an alkylene, arylalkylene, or heteroarylalkylene ketal, each of which may be optionally substituted; R is hydrogen or Ci -CO alkyl;

R is hydrogen, alkyl, including Ci-C₆ alkyl, alkenyl, including C2-C6 alkenyl, such as vinyl, allyl, and the like, alkynyl, including C₂-C₆ alkynyl, such as ethynyl, propynyl, and the like, alkoxy, including Ci-C4 alkoxy, alkylthio, including C1-C4 alkylthio, halo, haloalkyl, such as trifluoromethyl, trifluorochloroethyl, and the like, cyano, formyl, alkylcarbonyl, including C1-C3 alkylcarbonyl, alkoxycarbonyl, or a substituent selected from the group consisting of -CO₂R⁸, -CONR⁸R^8', and -NR⁸(COR⁹);

R³ is a structure selected from the group consisting of

R⁴ is alkyl, including Ci -C₆ alkyl, alkenyl, including C₂-C₆ alkenyl, alkynyl, including C₂-C₆ alkynyl, cycloalkyl, including C3-C8 cycloalkyl, cycloalkenyl, including C3-C9 cycloalkenyl, such as limonenyl, pinenyl, and the like, alkylcarbonyl, including Ci -C₃ alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, including

alkyl), optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, including aryl(C₂-C₄ alkenyl), optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl, including aryl(C₂-C₄ alkynyl);

R is selected from hydrogen, alkyl, including Ci-C₆ alkyl, cycloalkyl, including C3- C₈ cycloalkyl, alkoxyalkyl, including (C] -C₄ alkoxy)-(Q-C₄ alkyl), optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl), Y-, Y-(Ci-C₄ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl); where Y is selected heterocycle, including tetrahydrofuryl, moφholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, and quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with alkyl, including Ci-C₄ alkyl or optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl);

R⁶ is hydrogen or alkyl, including C₁-C₆ alkyl; and R⁷ is alkyl, including C _rC₆ alkyl, cycloalkyl, including C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl); or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substituted with R¹³;

R and R are each independently selected from hydrogen, alkyl, including Ci-C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, including aryl(C_rC₄ alkyl); or R and R are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, moφholinyl, piperazinyl, and homopiperazinyl;

R⁹ is selected from hydrogen, alkyl, including C₁-C₆ alkyl, cycloalkyl, including C₃- C₈ cycloalkyl, alkoxyalkyl, including (Ci-C₄ alkoxy)-(Ci-C₄ alkyl), optionally substituted aryl, optionally substituted arylalkyl, including aryl(C_!-C₄ alkyl), optionally substituted heteroaryl, optionally substituted heteroarylalkyl, including heteroaryl(C _rC₄ alkyl), and R⁸R⁸N-(Cj-C₄ alkyl); R¹⁰ and R ' ^! are each independently selected from hydrogen, optionally substituted alkyl, including C₁-C₆ alkyl, optionally substituted cycloalkyl, including C₃-C₈ cycloalkyl, alkoxyalkyl, including C₁-C₄ alkoxycarbonyl, alkylcarbonyloxy, including C₁-C₅ alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, including aryl(Ci-C₄ alkyl), optionally substituted arylalkyloxy, including aryl(C_rC₄ alkyloxy), optionally substituted arylalkylcarbonyloxy, including aryl(Cj-C₄ alkylcarbonyloxy), diphenylmethoxy, and triphenylmethoxy;

R¹², R¹³, and R¹³ are each independently selected from hydrogen, alkyl, including Ci- C₆ alkyl, cycloalkyl, including C₃-C₈ cycloalkyl, alkoxycarbonyl, including C]-C₄ alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, including aryl(C_rC₄ alkyl), and optionally substituted aryloyl. In one variation, compounds of formula (HI) are described herein that are in solvated or hydrated forms. It is understood that such solvated and hydrated forms may be prepared according to the procedures described herein. Accordingly, it is to be understood that the references made to the compounds of formula (HI) are intended to also refer both individually and collectively to the parent compounds, pharmaceutically acceptable salt forms thereof, hydrates thereof, and solvates thereof. It is also appreciated that such salt forms, hydrates, and/or solvates may exist in one or more crystalline or solid moφhologies that are the same as or different from those of the parent compounds of formula (III).

In one aspect of the compounds of formula (HI), A" is an alkyl, arylalkyl, or heteroarylalkyl corresponding to a naturally occurring aminoacid, including but not limited to methyl, isopropyl, isobutyl, benzyl, 4-hydroxybenzyl, indolylmethyl, and the like. In another aspect, A¹ is an alkylcarbonyl, arylalkylcarbonyl, or heteroarylalkylcarbonyl, with the alkyl, arylalkyl, or heteroarylalkyl corresponding to a naturally occurring aminoacid, including but not limited to methyl, isopropyl, isobutyl, benzyl, 4-hydroxybenzyl, indolylmethyl, and the like.

In another aspect of the compounds of formula (EI), A" is an alkylcarbonyl, arylalkylcarbonyl, or heteroarylalkylcarbonyl, with the alkyl, arylalkyl, or heteroarylalkyl corresponding to a naturally occurring aminoacid, including but not limited to methyl, isopropyl, isobutyl, benzyl, 4-hydroxybenzyl, indolylmethyl, and the like, and the carbonyl is in the form of a ketal, including but not limited to an alkylene ketals, such as ethylene and propylene ketals, arylalkylene ketals, such as phenylmethylene, tolylmethylene, anisylmethylene, and hydroxyphenylmethylene ketals, and the like. In another embodiment, pharmaceutical compositions are described herein, where the pharmaceutical compositions include one or more of the compounds described herein, including but not limited to the compounds of formulae (I), (II), and (EI), substituted 2-(azetidin-2-on-l- yl)alkanedioic acids, substituted 2-(azetidin-2-on-l-yl)hydroxyalkylalkanoic acids, substituted 2- (azetidin-2-on-l-yl)hydroxyalkylalkanoic acids, and/or substituted 2-(azetidin-2-on-l- yl)alkylalkanoic acids, including analogs and derivatives thereof described herein, and combinations thereof. The substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, substituted 2-(azetidin-2-on-l- yl)hydroxyalkylalkanoic acids, substituted 2-(azetidin-2-on-l-yl)alkylalkanoic acids, and derivatives thereof include compounds of formulae (I), (E), and (EI). The pharmaceutical compositions described herein also include one or moere pharmaceutically acceptable carriers, diluents, and/or excipients. In one illustrative aspect, pharmaceutical compositions are described that exhibit oral activity and/or oral bioavailability. In another illustrative aspect, pharmaceutical compositions are described that allow the substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, substituted 2 -(azetidin- 2-on-l-yl)hydroxyalkylalkanoic acids, substituted 2-(azetidin-2-on-l-yl)alkylalkanoic acids, and analogs and derivatives thereof to cross the blood brain barrier. In another embodiment, methods for treating disease states responsive to the antagonism of a vasopressin V₂ receptor, in a mammal in need of such treatment are described. The methods comprise the step of administering to the mammal a pharmaceutically effective amount of one or more of the compounds described herein, including but not limited to the compounds of formulae (I), (E), and (EI), substituted 2-(azetidin-2-on- 1 -yl)alkanedioic acids, substituted 2- (azetidin-2-on- 1 -yl)hydroxyalkylalkanoic acids, substituted 2 -(azetidin-2-on- 1 -yl)alkylalkanoic acids, and analogs and derivatives thereof described herein, and combinations thereof. In another erabodiment, the methods compπse the step of administering to the mammal a composition containing a pharmaceutically effective amount of one or more substituted 2-(azetidm-2-on-l- yl)alkanedioic acids substituted 2-(azetidm-2-on-l-yl)hydroxyalkylalkanoic acids, substituted 2- (azetidm-2-on-l-yl)alkylalkanoic acids, and analogs and deπvatives thereof descπbed herein, and a pharmaceutically acceptable earner, diluent, or excipient.

Illustrative disease states that are responsive to the antagonism of a vasopressin V₂ receptor and treatable by the methods descπbed herein include vaπous cardiovascular diseases, including, disorders or conditions associated with platelet aggregation, and the like. In addition, methods for treating other disease states and conditions treatable by for example oxytocin receptor antagonism, tachykinin receptor antagonism, neurokinin 1 receptor antagonism, neurokinin 2 receptor antagonism, and the like are descπbed herein, where the method includes the step of administering to a patient m need of relief from such a disease state or condition an effective amount of one or more substituted 2-(azetidm-2-on-l-yl)alkanedioic acids, substituted 2-(azetidm-2-on-l- yl)hydroxyalkylalkanoic acids, substituted 2-(azetidm-2-on-l-yl)alkylalkanoic acids, and analogs and deπvatives thereof descπbed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the antagonism of arginme vasopressin -induced mositol-3-phosphate production by Example 225 (IC₅₀ = 2.68 nM; K₁ = 0.50 nM).

Figure 2 shows the blocking of arginme vasopressm-mduced increases m blood pressure in rats by Example 225.

DETAILED DESCRIPTION

In one embodiment of the compounds of formulae (I), (II), or (III), A is -CO₂R⁵; where R is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C_rQ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl). In another embodiment of the compounds of formulae (I), (II), or (IE), A is monosubstituted amido, disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido.

It is to be understood that m each occurrence of the vaπous embodiments descπbed herein, heterocyclyl is independently selected m each instance. In one illustrative aspect, heterocyclyl is independently selected from tetrahydrofuryl, morphohnyl, pyrrohdmyl, pipeπdmyl, piperazmyl, homoprperazmyl, or qumuchdmyl; where said morphohnyl, pyrrohdmyl, pipeπdmyl, piperazmyl, homoprperazmyl, or qumuchdmyl is optionally N-substituted with Ci -C₄ alkyl or optionally substituted aryl(Ci-C4 alkyl).

It is also to be understood that in each occurrence of the vaπous embodiments descπbed herein, R⁶ and R⁷ are each independently selected in each instance. In another illustrative aspect, R is independently selected from hydrogen or alkyl; and R is independently selected in each instance from alkyl, cycloalkyl, optionally substituted aτyl, or optionally substituted arylalkyl. In another illustrative aspect, R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is also optionally N-substituted with R ; where R is independently selected in each instance from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.

In another embodiment, compounds of formula (I) are described that are diesters, acid-esters, or diacids, including pharmaceutically acceptable salts thereof, where each of A and A' is independently selected. In another embodiment, compounds of formula (I) are described that are ester-amides, where one of A and A' is an ester, and the other is an amide. In another embodiment, compounds of formula (I) are described that are diamides, where each of A and A¹ are independently selected from monosubstituted amido, disubstituted amido, and optionally substituted nitrogen- containing heterocyclylamido. In one variation of the compounds of formula (I), A and/or A' is an independently selected monosubstituted amido of the formula C(O)NHX-, where X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C_rC₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl), where each heterocyclyl is independently selected. In another variation, A and/or A' is an independently selected disubstituted amido of the formula C(O)NR¹⁴X-, where R¹⁴ is selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl -(Ci -C₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl), where each heterocyclyl is independently selected. In another variation, A and/or A' is an amide of an independently selected optionally substituted nitrogen-containing heterocycle attached at a nitrogen. Illustrative nitrogen-containing heterocycles include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3- oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which is optionally substituted. Such optional substitutions include the groups R¹⁰, R¹², R⁶R⁷N-, and R⁶R⁷N-(Ci-C₄ alkyl), as defined herein. In one embodiment, A and/or A' is independently selected from pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted, and attached at a nitrogen.

In another variation, A and/or A¹ is an independently selected amide of an optionally substituted piperidinyl attached at the nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C₄ alkyloxy))-(C₂-C4 alkyl), R⁶R⁷N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(Ci-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C_rC₄ alkyl), and piperidin-l-yl(C_rC₄ alkyl). In one embodiment, A and/or A' is an independently selected piperidinyl substituted at the 4 -position and attached at the nitrogen. In another variation, A and/or A¹ is an independently selected amide of an optionally substituted piperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C₄ alkyloxy))-(C₂-C₄ alkyl), R⁶R⁷N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(Ci-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C]-C₄ alkyl), and piperidin-l-yl(Ci-C₄ alkyl). In one embodiment, A and/or A' is an independently selected piperazinyl substituted at the 4 -position and attached at a nitrogen.

In another variation, A and/or A' is an independently selected amide of an optionally substituted homopiperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C₄ alkyloxy))-(C₂-C₄ alkyl), R⁶R⁷N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(C ,-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C_rC₄ alkyl), and piperidin- l-yl(Ci -C₄ alkyl). In one embodiment, A and/or A' is an independently selected homopiperazinyl substituted at the 4- position and attached at a nitrogen. In another embodiment, A and/or A' is an independently selected homopiperazinyl substituted at the 4-position with alkyl, aryl, aryl(Ci-C₄ alkyl), and attached at a nitrogen.

In another embodiment of the compounds of formula (I), A' is monosubstituted amido, disubstituted amido, or an optionally substituted nitrogen -containing heterocyclylamido. In another embodiment of the compounds of formula (I), A' is -CO2R⁵; where R⁵ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C_rC₄ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C]-C₄ alkyl or optionally substituted aryl(Ci-C₄ alkyl). In one variation, R is optionally substituted heterocyclylalkyl or optionally substituted aminoalkyl, including R R N-(C₂-C₄ alkyl).

In another embodiment, compounds of formula (II) are described wherein A is selected from monosubstituted amido, disubstituted amido, and optionally substituted nitrogen- containing heterocyclylamido.

In one variation, A is a monosubstituted amido of the formula C(O)NHX-, where X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl -(Ci -C₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl), where each heterocyclyl is independently selected.

In another variation, A is a disubstituted amido of the formula C(O)NR¹⁴X-, where R¹⁴ is selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(Ci-C₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl), where each heterocyclyl is independently selected.

In another variation, A is an amide of an optionally substituted nitrogen -containing heterocycle attached at a nitrogen. Illustrative nitrogen-containing heterocycles include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1 ,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which is optionally substituted. Such optional substitutions include the groups R¹⁰, R¹², R⁶R⁷N-, and R⁶R⁷N-(C₁-C₄ alkyl), as defined herein. In one embodiment, A is pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidm-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted, and attached at a nitrogen. In another variation, A is an amide of an optionally substituted piperidinyl attached at the nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy))-(C2-C₄ alkyl), R R N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(C₁-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C_rC₄ alkyl), and piperidin- l-yl(Q -C₄ alkyl). In one embodiment, A is piperidinyl substituted at the 4-position and attached at the nitrogen.

In another variation, A is an amide of an optionally substituted piperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C₄ alkyloxy))-(C2-C₄ alkyl), R R N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(C₁-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C₁-C₄ alkyl), and piperidin- ^yI(C₁ -C₄ alkyl). In one embodiment, A is piperazinyl substituted at the 4-position and attached at a nitrogen.

In another variation, A is an amide of an optionally substituted homopiperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy,

Λ 7 alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy))-(C2-C₄ alkyl), R R N-, R⁶R⁷N-alkyl, including R⁶R⁷N-(C₁-C₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C_rC₄ alkyl), and piperidin- ^yI(C₁ -C₄ alkyl). In one embodiment, A is homopiperazinyl substituted at the 4-position and attached at a nitrogen. In another embodiment, A is homopiperazinyl substituted at the 4-position with alkyl, aryl, aryl(d-C₄ alkyl), and attached at a nitrogen. In another variation, A is an amide of a heterocycle attached at a nitrogen, where the heterocycle is substituted with heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl.

In another embodiment, A m formulae (I), (II), or (IE) is an amide of an optionally substituted benzyl, optionally substituted 1-naphthylmetbyl, or optionally substituted 2- naphthylmethyl amine. Optional substitutions include, but are not limited to, 2,3-dichloro, 2,5- dichloro, 2,5-dimethoxy, 2-tπfluoromethyl, 2-fluoro-3-tπfluoromethyl, 2-fluoro-5-tπfluoromethyl, 2- methyl, 2-methoxy, 3,4-dichloro, 3,5-ditπfluoromethyl, 3,5 -dichloro, 3,5-dimethyl, 3,5-difluoro, 3,5- dimethoxy, 3-bromo, 3-tπfluoromethyl, 3-chloro-4-fluoro, 3-chloro, 3-fluoro-5-tπfluoromethyl, 3- fluoro, 3 -methyl, 3-nitro, 3-tπfluoromethoxy, 3-methoxy, 3 -phenyl, 4-tπfluoromethyl, 4-chloro-3- tπfluoromethyl, 4-fluoro-3-tπfluoromethyl, 4-methyl, and the like. In another embodiment, A in formulae (I), (II), or (III) is an amide of an optionally substituted benzyl-N-methylamme. In another embodiment, A m formulae (I), (II), or (III) is an amide of an optionally substituted benzyl-N-butylamme, including n-butyl, and t-butyl. In another embodiment, A in formulae (I), (II), or (III) is an amide of an optionally substituted benzyl -N- benzylamine. Optional substitutions include, but are not limited to, 2,3 -dichloro, 3, 5 -dichloro, 3- bromo, 3-tπfluoromethyl, 3-chloro, 3-methyl, and the like.

In another embodiment, A m formulae (I), (II), or (IE) is an amide of an optionally substituted 1 -phenylethyl, 2-phenylethyl, 2-phenylpropyl, or 1-phenylbenzylamme. In another embodiment, A m formulae (I), (II), or (III) is an amide of an optionally substituted 1 -phenylethyl, 2- phenylethyl, 2-phenylpropyl, 1-phenylbenzylamme-N-methylamine. In another embodiment, A m formulae (I), (II), or (HI) is an amide of an optionally substituted 2-phenyl-β-alanme, or derivative thereof, 1 -phenylpropanolamine, and the like. Optional substitutions include, but are not limited to, 3-tπfluoromethoxy, 3-methoxy, 3,5-dimethoxy, 2-methyl, and the like.

In another embodiment, A m formulae (I), (II), or (IE) is an amide of an optionally substituted 1 -phenylcyclopropyl, 1-phenylcyclopentyl, or 1 -phenylcyclohexylamme. Optional substitutions include, but are not limited to, 3-fiuoro, 4-methoxy, 4-methyl, 4-chloro, 2-fluoro, and the like.

In another embodiment, A in formulae (I), (II), or (III) is an amide of an optionally substituted heteroarylmethylamme, including but not limited to 2-furyl, 2-thienyl, 2-pyπdyl, 3- pyπdyl, 4-pyπdyl, and the like. Optional substitutions include, but are not limited to, 5 -methyl, 3- chloro, 2-methyl, and the like.

In another embodiment, A in formulae (I), (II), or (III) is an amide of a partially saturated bicyclic aryl, including but not limited to 1 -, 2-, 4-, and 5-mdanylamine, 1- and 2- tetrahydronaphthylamme, lndohnyl, tetrahydroqumolmyl, tetrahydroisoquinolmyl, and the like, each of which is optionally substituted. In another embodiment, A in formulae (I), (II), or (IE) is an amide of a substituted pφeπdme or piperazme. Substituents on the pipeπdme or piperazme include heterocyclyl, heterocyclylalkyl, optionally substituted aryl, and optionally substituted arylalkyl. Illustrative piperidines and piperazines include the formulae:

In another embodiment, A' in formula (I) is an amide of a substituted heterocycle attached at nitrogen. Substituents include alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and arylalkyl. In one variation embodiment, A' in formula (I) is an amide of a heterocycle attached at nitrogen substituented with alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl.

In another embodiment, A' in formula (I) is an amide of an optionally substituted arylheterocyclylamine, arylalkylheterocyclylamine, heterocyclylalkylamine, or heteroarylalkylamine. It is appreciated that in the foregoing illustrative examples of A and/or A' that include a chiral center, either of the optically pure enantiomers may be included in the compounds described herein; alternatively, the racemic form may be used. For example, either or both of the following enatiomers may be included in the compounds described herein (R)-I -(3- methoxyphenyl)ethylamine, (R)-l-(3-trifluoromethylphenyl)ethylamine, (R)-1, 2,3, 4-tetrahydro-l- naphtylamine, (R)-l-mdanylamine, (R)-α,N-dimethylbenzylamine, (R)-α-methylbenzylamine, (S)-I- (3-methoxyphenyl)ethylamine, (S)-l-(3-trifluoromethylphenyl)ethylamine, (S)-l,2,3,4-tetrahydro-l- naphtylamine, (S)-I -indanylamine, and (S)-α-methylbenzylamine, and the like.

In another embodiment of the compounds of formula (II), Q is oxygen or sulfur. In another embodiment of the compounds of formula (II), R" is optionally substituted arylalkyl. In another embodiment of the compounds of formula (II), A is an amide of a substituted piperidine or piperazine.

In another embodiment of the compounds of formula (I), n is 1 or 2. In another embodiment of the compounds of formula (II), n is 1 or 2. In one variation of the compounds of formula (II), n is 1.

In another embodiment of the compounds of formulae (I), (II), or (III), R is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CO₂R and -CONR R , where R and R are each independently selected from hydrogen and alkyl. In another embodiment of the compounds of formulae (I), (II), or (III), R is hydrogen. In another embodiment of the compounds of formulae (I), (II), or (III), R¹ is methyl. In another embodiment of the compounds of formulae (I), (II), or (III), R² is hydrogen. In another embodiment of the compounds of formulae (I), (II), or (III), R² is methyl. In another embodiment of the compounds of formulae (I), (II), or (III), both R¹ and R² are hydrogen.

In another embodiment of the compounds of formulae (I), (II), or (III), R is of the formulae:

wherein R¹⁰ and R¹¹ are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.

wherein R¹⁰, R¹ ' , and R¹² are as defined herein.

In another embodiment of the compounds of formulae (I), (II), or (III), R³ is of the formulae:

wherein R , R , and R are as defined herein.

In another embodiment of the compounds of formulae (I), (II), or (III), R³ is of the formula:

wherein R¹⁰ and R¹¹ are as defined herein.

In another embodiment of the compounds of formulae (I), (II), or (III), R⁴ is of the formulae:

H₂C ^v ^ H₂C ^" ^ H₂C' wherein Y an electron withdrawing group, such as halo, and R is hydrogen or an optional substitution, such as halo, alkyl, and alkoxy, including 2-methoxy. In one variation, Y is chloro.

It is appreciated that the compounds of formulae (I), (II), or (III) are chiral at the α- carbon, except when A = A', and n = 0. In one embodiment of the compounds of formula (I), when n is 1, the stereochemistry of the α-carbon is (S) or (R), or is an epimeric mixture. In another embodiment of the compounds of formula (I), when n is 1, the stereochemistry of the α-carbon is

(R). In another embodiment of the compounds of formula (I), when n is 2, the stereochemistry of the α-carbon is (S). In one embodiment of the compounds of formula (II), when n is 1, the stereochemistry of the α-carbon is (R).

In another embodiment, compounds of formula (II) are described wherein R⁵ is optionally substituted aryl(C₂-C₄ alkyl).

The general chemical terms used in the formulae described herein have their usual ordinary meanings. For example, the term "alkyl" refers to a straight-chain or optionally branched, saturated hydrocarbon, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like. Further, it is to be understood that variations of the term alkyl are used in other terms, including but not limited to cycloalkyl, alkoxy, haloalkyl, alkanoyl, alkylene, and the like, and that such other terms also include straight -chain and optionally branched variations. The term "cycloalkyl" refers to a straight-chain or optionally branched, saturated hydrocarbon, at least a portion of which forms a ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "alkenyl" refers to a straight -chain or optionally branched, hydrocarbon that includes at least one double bond, including but not limited to vinyl or ethenyl, allyl or propenyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, butadienyl, and the like.

The term "alkynyl" refers to a straight-chain or optionally branched, hydrocarbon that includes at least one triple bond, including but not limited to ethynyl, propynyl, 1 -butynyl, hex- 4-en-2-ynyl, and the like. The term "aryl" refers to an aromatic ring or heteroaromatic ring and includes such groups as furyl, pyrrolyl, thienyl, pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzofuranyl, benzothienyl, and the like.

The term "alkoxy" refers to an alkyl or cycloalkyl substituent attached through an oxygen, and includes such groups as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

The term "heterocycle" refers to a non-aromatic cyclic structure possessing one or more heteroatoms, such as nitrogen, oxygen, sulfur, and the like, and includes such groups as tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

The terms "acyl," "alkanoyl," and "aroyl" refer to alkyl, alkenyl, alkyl, aryl, and the like attached through a carbonyl group, and include such groups as formyl, acetyl, propanoyl, butanoyl, pentanoyl, cyclohexanoyl, optionally substituted benzoyl, and the like.

The term "halo" means fluoro, chloro, bromo, and iodo. The term "alkanoyloxy" includes such groups as formyloxy, acetoxy, n-propionoxy, n-butyroxy, pivaloyloxy, and like lower alkanoyloxy groups.

The term "optionally substituted" refers to the replacement of one or more, preferably from one to three, hydrogen atoms with one or more substitutents. Substituents include but are not limited to such groups as Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ alkylthio, hydroxy, nitro, halo, carboxy, cyano, C1-C4 haloalkyl, C1-C4 haloalkoxy, amino, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, C₁-C₄ alkylsulfonylamino, and the like. Such optional substitution may be made on alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and the like.

The terms "optionally substituted Ci -C₄ alkyl," "optionally substituted C3-C8 cycloalkyl," and "optionally substituted C₂-C₄ alkenyl" refer to alkyl, cycloalkyl, or alkenyl, respectively, optionally substituted with a substituent as described herein, including but not limited to hydroxy, protected hydroxy, alkyl, protected carboxyl, carbamoyl, benzylthio, alkylthio, and the like.

The terra "(C₁-C₄ alkyl)" as used in for example "aryl(C ,-C₄ alkyl)", "(C₁-C₄ alkoxy)-(Ci-C₄ alkyl)", and the like, refers to a saturated linear or branched divalent alkyl chain of from one to four carbons having for example aryl, C1-C4 alkoxy, and the like, as a substituent and includes such groups as for example benzyl, phenethyl, phenpropyl, α-methylbenzyl, methoxymethyl, ethoxyethyl, and the like.

The term "optionally substituted aryl" is intended to include an aryl radical, including a heteroaryl radical, optionally substituted with one or more substituents each independently selected, such as substituents selected from C₁-C₄ alkyl, C]-C₄ alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, cyano, carbamoyl, amino, HiOnO(C₁-C₄ alkyl)amino, di(d-C4 alkyl)amino, C₁-C₄ alkylsulfonylamino, and indol-2-yl.

The term "optionally substituted phenyl" is intended to include a phenyl radical optionally substituted with one or more substituents each independently selected, such as substituents selected from C₁-C₄ alkyl, C]-C₄ alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, cyano, carbamoyl, amino, mono(C_rC₄ alkyl)amino, di(C_rC₄ alkyl)amino, C₁-C₄ alkylsulfonylamino, and indol-2-yl.

The term "protected amino" refers to amine protected by a protecting group that may be used to protect the nitrogen, such as the nitrogen in the β-lactam ring, during preparation or subsequent reactions. Examples of such groups are benzyl, 4-methoxybenzyl, 4-methoxyphenyl, trialkylsilyl, for example trimethylsilyl, and the like.

The term "protected carboxy" refers to the carboxy group protected or blocked by a conventional protecting group commonly used for the temporary blocking of the acidic carboxy. Examples of such groups include lower alkyl, for example tert -butyl, halo -substituted lower alkyl, for example 2-iodoethyl and 2,2,2-trichloroethyl, benzyl and substituted benzyl, for example 4- methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for example trimethylsilyl and tert-butyldiethylsilyl and like carboxy-protecting groups.

The term "antagonist", as used herein, refers to a foil or partial antagonist. While a partial antagonist of any intrinsic activity may be useful, the partial antagonists illustratively show at least about 50% antagonist effect, or at least about 80% antagonist effect. The term also includes compounds that are full antagonists of the vasopressin V₂ receptor. It is appreciated that illustrative methods described herein require therapeutically effective amounts of vasopressin V₂ receptor antagonists; therefore, compounds exhibiting partial antagonism at the vasopressin V₂ receptor may be adminstered in higher doses to exhibit sufficient antagonist activity to inhibit the effects of vasopressin or a vasopressin agonist. It is to be understood that in the embodiments described herein, an illustrative variation of alkyl is C₁-C₆ alkyl, such as methyl, ethyl, propyl, prop-2-yl, and the like; an illustrative variation of alkenyl is C2-C6 alkenyl, such as vinyl, allyl, and the like; an illustrative variation of alkynyl is C₂-C₆ alkynyl, such as ethynyl, propynyl, and the like; an illustrative variation of alkoxy is C₁-C₄ alkoxy, such as methoxy, pent-3-oxy, and the like; an illustrative variation of alkylthio is C₁- C4 alkylthio, such as ethylthio, 3-methylbuty-2-ylthio, and the like; an illustrative variation of alkylcarbonyl is C1-C3 alkylcarbonyl, such as acetyl, propanoyl, and the like; an illustrative variation of cycloalkyl is C₃-C₈ cycloalkyl; an illustrative variation of cycloalkenyl is C₃-C₉ cycloalkenyl, such as limonenyl, pinenyl, and the like; an illustrative variation of optionally substituted arylalkyl is optionally substituted aryl(Ci-Gt alkyl); an illustrative variation of optionally substituted arylalkenyl is optionally substituted aryl(C₂-C₄ alkenyl); an illustrative variation of optionally substituted arylalkynyl is optionally substituted aryl(C2-C4 alkynyl); an illustrative variation of alkoxyalkyl is (C1-C4 alkoxy)-(Ci-Cι alkyl); an illustrative variation of optionally substituted heteroarylalkyl is optionally substituted heteroaryl(C_!-C₄ alkyl); and an illustrative variation of alkoxycarbonyl is C₁- C₄ alkoxycarbonyl.

It is also to be understood that each of the foregoing embodiments, variations, and aspects of the compounds described herein may be combined in each and every way. For example, compounds where R is optionally substituted oxazolidinonyl, and R is optionally substituted arylalkenyl are contemplated herein. Further, compounds where R is optionally substituted oxazolidinonyl, R⁴ is optionally substituted arylalkenyl, and both R¹ and R² are hydrogen are contemplated herein. Further, compounds where R³ is optionally substituted oxazolidinonyl, R⁴ is optionally substituted arylalkenyl, both R and R are hydrogen, and both A and A' are independently selected amides are contemplated herein.

In another embodiment, compounds of the following formula are described:

where R , R , R , A, A', Q, and R5" are as defined herein, and Ar is an optionally substituted aryl group.

In another embodiment, compounds of the following formula are described:

where R¹, R², A, A', Q, and R5" are as defined above, and Ar¹ and Ar² are each an optionally substituted aryl group, each independently selected. In another illustrative embodiment, compounds of the following formula are described:

wherein R , R , Q, and R5" are defined herein, Ar and Ar are optionally substituted aryl or heteroaryl groups, X is independently selected in each instance, and is as defined herein, and R¹⁴ is independently selected in each instance, and is as defined herein, or is hydrogen. In one illustrative aspect, Ar and Ar are each an independently selected optionally substituted phenyl. In another illustrative aspect, R¹ and R² are each hydrogen.

In another embodiment, compounds of the following formula are described:

wherein Ar¹ and Ar² are optionally substituted aryl or heteroaryl groups, R¹ and R² are defined herein, X is independently selected in each instance, and is as defined herein, and R¹⁴ is independently selected in each instance, and is as defined herein, or is hydrogen. In one illustrative aspect, Ar and Ar are each an independently selected optionally substituted phenyl. In another illustrative aspect, R and R are each hydrogen.

It is appreciated that the classes of compounds described above may be combined to form additional illustrative classes. An example of such a combination of classes may be a class of compounds wherein A is a monosubstituted amino having the formula XNH-, where X is optionally substitued aryl(C]-C₄ alkyl), and A' is a disubstituted amino having the formula R¹⁴X¹N-, where R¹⁴ and X' are taken together with the attached nitrogen atom to form an heterocycle, such as piperidine, peperazine, and the like. Further combinations of the classes of compounds described above are contemplated in the present invention.

The compounds described herein possess an azetidinone core structure that includes asymmetric carbon atoms at C(3) and C(4), creating four stereoisomers configurations, as illustrated by the following:

The compounds described herein maytherefore exist as single diastereomers, as a racemic mixture, or as a mixture of various diastereomers. It is understood that in some applications, certain stereoisomers or mixtures of stereoisomers may be used, while in others applications, other stereoisomers or mixtures of stereoisomers may be used. In some embodiments, a single stereoisomer is described, such as the azetidinone core structure having the (3S,4J?)-diastereomeric configuration.

It is also understood, that except when A=A' and n=0, the α-carbon bearing R¹ is also chiral. Furthermore, the groups selected for R¹, R², R³, R⁴, A, and A' may also include chiral centers. For example, when R³ is 4-substituted oxazolidin-2-on-3-yl, the 4-position of that ring is asymmetric. In addition, when R³ is 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin4-on-3-yl, the 2- and 5-carbons of those rings are each asymmetric. Finally, when R³ is succinimido and one of R and R is hydrogen, the carbon bearing the non-hydrogen substituent is also asymmetric. Therefore, additional stereoisomers are collectively represented by formulae (I), (II), and (III). While compounds possessing all combinations of stereochemical purity are contemplated by the present description, it is appreciated that in many cases at least one of these chiral centers described above may be present as a single absolute configuration in a compound described herein. In one illustrative aspect, the compounds described herein have the (aR,3S,4R) absolute configuration or the (αS,3S,4R) absolute configuration. The compounds described herein may, therefore, exist as single diastereomers, as racemic mixtures, or as mixtures of various diastereomers. It is appreciated that in some applications, certain stereoisomers or mixtures of stereoisomers may be included in the various embodiments of the invention, while in other applications, other stereoisomers or mixtures of stereoisomers may be included. One illustrative mixture is a racemic mixture of two isomers that is substantially or completely free of any other diastereomers. In other applications, a single stereoisomer may be included in the various embodiments of the invention. In one aspect, certain chiral centers are stereochemically pure in the compounds described herien, such as for example a single enantiomer of the azetidinone core structure corresponding to the (3S,4i?)-diastereomeric configuration is described. In one variation, other chiral centers included in the compounds of this embodiment are epimeric, such that equal amounts of each stereo configuration are present. In another variation, some or all other chiral centers in the compound are optically pure.

It is also understood that the α-carbon bearing R¹ is also chiral. Further, the radicals selected for groups such as R¹, R², R³, R⁴, A, A', may also include chiral centers. For example, when R is 4-substituted oxazolidin-2-on-3-yl, the 4-position of the oxazolidinone ring is asymmetric. In addition, when R is 2,5-disubstituted oxazolidin-4-on-3-yl or l,2,5-trisubstituted imidazolidin4-on- 3-yl, the 2- and 5-carbons of the imidazolidinone rings are each asymmetric. Finally, when R³ is succinimido and one of R and R is hydrogen, the carbon bearing the non -hydrogen substituent is also asymmetric. Therefore, it is to be understood that the various formulae described herein may represent each single diastereomer, various racemic mixtures, and various other mixtures of enantiomers and/or diastereomers collectively. While compounds possessing all combinations of stereochemical purity are contemplated by the present description, it is nonetheless appreciated that in many cases the desired vasopressin antagonist activity may reside in a subset of all possible diastereomers, or even in a single diasteromer. In one illustrative embodiment, the compounds described herein are a diastereomeric mixture of the (oR,3S,4R) and (αS,3S,4R) absolute configurations. In another illustrative embodiment, the compounds described herein have substantially or only the (αR,3S,4R) absolute configuration. In another illustrative embodiment, the compounds described herein have substantially or only the (aS,3S,4R) absolute configuration.

It is understood that the above general formulae represent a minimum of 8 different stereoisomer^ configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of diastereomers at C(α) is described:

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S).

The compounds described herein may also prepared as or converted to pharmaceutically acceptable salt derivatives. Illustrative pharmaceutically acceptable salts of compounds described herein that have a basic amino group include, but are not limited to, salts of inorganic and organic acids. Illustrative inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Illustrative organic acids include p_-toluenesulfonic acid, methanesulfonic acid, oxalic acid, μ-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Illustrative examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like. In one embodiment, pharmaceutically acceptable salts are those formed with hydrochloric acid, trifluoroacetic acid, maleic acid or fumaric acid.

In another embodiment, compounds of the following formula are described:

where R¹, R², R⁴, A, and A' are as defined above, and Ar¹ is an optionally substituted aryl group. In another embodiment, compounds of the following formula are described:

where R¹, R², A, and A' are as defined above, and Ar¹ and Ar² are each an optionally substituted aryl group, each independently selected.

In another illustrative embodiment, compounds of the following formula are described:

wherein Ar¹ and Ar² are optionally substituted aryl or heteroaryl groups; and R⁶, R⁷, R⁶ , and R⁷ are independently optionally substituted alkyl, cycloalkyl, aryl, or arylalkyl groups, where the alkyl portion is optionally substituted, including spiro and fused cyclic variants, or R and R and/or R , and R⁷ are independently taken together with the attached nitrogen to form optionally substituted heterocycles. In another embodiment, compounds of the following formula are described:

wherein Ar¹, Ar², R¹, R², R⁶ and R⁷ are defined for formula (I). In one illustrative aspect, Ar¹ and Ar² are each an independently selected optionally substituted phenyl. In another illustrative aspect, R¹ and R² are each hydrogen.

where R¹, R², R⁴, A, A', and n are as defined in formula (I), and R¹⁰ and R¹¹ are illustratively alkyl, including methyl, ethyl, isopropyl, and tert-butyl, optionally substituted aryl, including phenyl, optionally substituted arylalkyl, including benzyl and diphenylmethyl, optionally substituted heteroarylalkyl, including indol-3-ylmethyl, and the like. In each case, following the 2+2 reaction, the stereochemistry of the β-lactam may be confirmed by circular dichroism/optical rotary dispersion (CD/ORD). Illustratively, examples of the R-cis and S-cis β-lactam platform from prior syntheses may be used as CD/ORD standards.

where R¹, R², R¹⁰, R¹¹, A₃ A¹, and n are as defined in formula (I), and R⁴ is illustratively derived from the following aldehydes:

In another illustrative embodiment, compounds of the following formulae are described:

, 10 -n i l where R¹, R^z, R^1*, A, A', and n are as defined in formula (I), and R'", R", and R , 1^2 are illustratively alkyl, including methyl, ethyl, isopropyl, and tert -butyl, optionally substituted aryl, including phenyl, tolyl, and methoxyphenyl, acyl, including acetyl, tert-butoxycarbonyl, and benzyloxycarbonyl, optionally substituted arylalkyl, including benzyl, and the like. It is to be understood that thiono analogs of the imidazolidinones and imidazolidindiones are also contemplated herein.

where R , R , A, A', and n are as defined in formula (I), and Ar and Ar are each an optionally substituted aryl group, each independently selected. In one aspect of compounds of formula, Ar¹ is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted furyl, or optionally substituted thienyl. In another aspect, the following classes of compounds are described, where the subsitutents R², A, A', n, X, X', R^5', R^β, R^7', and R^8' may be selected as follows:

R is hydrogen; A is XNH-;

A¹ is X¹NH-;

A' is R⁵XN-; n is O, 1, or 2;

X is optionally substituted aryl(C_rC₄ alkyl), and aryl is substituted phenyl; A' is R⁶O-;

R^6' is Ci-C₆ alkyl;

X' is R⁷R⁸N-;

X' is optionally substituted aryl(C_rC₄ alkyl);

X is an heterocycle Y'; R^5' and X' are taken together with the attached nitrogen atom to form piperidinyl, piperazinyl, or homopiperazinyl; where said piperidinyl, piperazinyl, or homopiperazinyl is optionally substituted with C₁-CO alkyl, C3-C8 cycloalkyl, an heterocycle Y', optionally substituted aiyl(C_rC₄ alkyl), R⁷R⁸N-, R⁷R⁸N-(C₁-C₄ alkyl), or R⁷R⁸N-C(O)-(C₁-C₄ alkyl);

R⁸ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted aryl(Ci -C₄ alkyl); and

R⁷ and R⁸ are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; where said piperazinyl is optionally substitued at the 4-position with Ci-C₄ alkyl.

In another embodiment, compounds of the following formula are described:

where n and A' are as described above; K¹ is illustratively hydrogen, CpC₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; C₁-C₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; C₁-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

It is understood that the above formula represents 16 different stereoisomeric configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of diastereomers is described:

In one aspect, the group A¹ includes, but is not limited to 2-(piperidin-l~ yl)ethylamino, 4-(piperidin- 1 -yl)piperidin- 1 -yl, 4-(phenylethyl)piperazin-l -yl, fur-2-ylmethylamino, 4-(pyrrolidin- 1 -yl)piperazin- 1 -yl, 4-(3 -trifluoromethylphenyl)piperazin - 1-yl, 4- (benzyloxycarbonyl)piperazin-l -yl, 4-[2-{2-hydroxyethoxy)ethyl]piperazm-l -yl, 4-benzylpiperazin- 1-yl, 4-(3,4-methylenedioxybenzyl)piperazin-l-yl, 4-phenylpiperazin-l-yl, 4-(3-phenylprop-2- enyl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, 4-(pyrrolidin-l- ylcarbonylmethyl)piperazin- 1-yl, 4-(l -methylpiperidin-4-yl)piperazin- 1 -yl, 4-butylpiperazin- 1 -yl,4- isopropylpiperazin-1-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1 -benzylpiperidin- 4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4-(cyclohexyl)piperazin- 1 -yl, 4-(2-cyclohexylethyl)piperazin- 1 -yl, 4-[2-(moφholin-4-yl)ethyl]piperazin- 1 -yl, 4-(4-tert- butylbenzyl)piperazin- 1-yl, 4-[2-(piperidin- 1 -yl)ethyl]piperazin- 1 -yl, 4-[3-(piperidin- 1- yl)propyl]piperazin- 1 -yl, 4- [2 -(N, N-dipropylamino)ethyl]piperazin - 1-yl, 4 -[3 -(N, N- diethylamino)propyl]piperazin-l-yl,4-[2-(dimethylamino)ethyl]piperazin-l-yl, 4-[3-(pyrrolidin-l- yl)propyl]piperazin-l-yl, 4-(cyclohexylmethyl)piperazin-l-yl, 4-cyclopentylpiperazin-l-yl, 4-[2- (pyrrolidin-l-yl)ethyl]piperazin-l-yl, 4-[2-(thien-2-yl)ethyl]piperazin-l-yl, 4-(3- phenylpropyl)piperazin- 1 -yl, 4-[2-(N,M-diethylamino)ethyl]piperazm- 1 -yl, 4-benzylhomopiperazin- 1-yl, 4-(bisphenylmethyl)piperazin-l-yl, 3-(4-methylpiperazin-l-yl)propylamino, (+)-3(5)-l- benzylpyrrolidin-3-ylamino, 2-pyridylmethylamino, and 4-[2-(piperidin-l-yl)ethyl]piperidin-l-yl.

In another aspect, the integer n is 1 or 2, and the group A' includes, but is not limited to 2-(piperidin- 1 -yl)ethylamino, 4-(piperidin- 1 -yl)piperidin- 1-yl, 2-(pyrid-2-yl)ethylamino, morpholin-4-ylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3-trifluorophenyl)piperazin-l-yl, 4- (benzyloxycarbonyl)piperazin- 1 -yl, 4-[2-(2-hydroxylethoxy)ethyl]piperazin- 1-yl, 4-benzylpiperazin- 1-yl, 4-(3,4-methylenedioxybenzyl)piperazin-l-yl, 4-phenylpiperazin-l-yl, 4-(3-phenylprop-2- enyl)piperazin-l -yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, 4-(pyrrolidin-l- ylcarbonylmethyl)piperazin- 1-yl, 4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl, 4-butylpiperazin- 1 -yl, 4- isopropylpiperazin-1-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1-benzylpiperidin- 4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4-cyclohexylpiperazin- 1-yl, 4-(2-cyclohexylethyl)piperazin-l-yl, 4-[2-(moφholin-4-yl)ethyl]piperazin-l-yl, 4-(4-ter/- butylbenzyl)piperazin-l-yl, 4-[2-(piperidin- 1 -yl)ethyl]piperazin- 1 -yl, 4-[3-(piperidin- 1- yl)propyl]piperazin- 1 -yl, 4- [2 -(diisopropylamino)ethyl]piperazin- 1 -yl, 4 - [3- (diethylamino)propyl]piperazin-l-yl, 4-(2-dimethylaminoethyl)piperazin-l-yl, 4-[3-(pyrrolidin-l- yl)propyl]piperazin- 1 -yl, 4-(cyclohexylmethyl)piperazin- 1-yl, 4- [2-(piperidin- 1 -yl)ethyl]piperidin- 1 - yl, 4-propyl-piperazin-l-yl, 4-[N-(isopropyl)acetamid-2-yl]piperazin-l-yl, and 3 -benzyl -hexahydro- (lH)-l,3-diazepin-l-yl.

In another embodiment, compounds having the following formula are described:

where A' is as described above; R² is illustratively hydrogen, Ci -CO alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; Ci -C₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Ci -CA alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

It is understood that the above formula represents 16 different stereoisomeric configuration possibilities. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of enantiomers is described:

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In one aspect, the group A' includes, but is not limited to 2-(piperidin-l-yl)alkylamino, 4-(piperidin- l-yl)piperidin-l-yl, 4-(2-arylalkyl)piperazin-l-yl, l-arylalkylpiperidin4-ylamino, 4-alkylpiperazin- 1-yl, such as 4-butyl, 4-isopropyl, 4-cyclohexylpiperazin-l-yl, and the like, and 4-[2-(piperidin-l- yl)ethyl]piperidin- 1 -yl .

In another embodiment, compounds having the formula are described:

where n is as described above; R is illustratively hydrogen, CpC₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; CpC₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Cj-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro; W is either carbon or ntrogen, each optionally substituted with a carbocyclyl substituent, such as cyclopentyl, cyclohexyl, and the like, or an an heterocyclyl substituent, such as pyrrolidinyl, piperidinyl, and the like; and the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). The following compounds:

are illustrative of this embodiment. In one aspect, when n is 1, W as defined above is a carbon atom substituted with piperidin-1-yl. In another aspect, when n is 2, W as defined above is a nitrogen atom susbstituted with cyclohexyl. The following compounds are illustrative of this embodiment:

wherein Ar¹ and Ar² are each an independently selected optionally substituted phenyl, R¹ and R² are each hydrogen, X is an optionally substituted phenylalkyl, and X' is heterocycloalkyl, such as piperidin-1-ylalkyl, piperazin-1-ylalkyl, and the like. In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In another illustrative embodiment, compounds of the following formula are described:

wherein R and R are each independently chosen from hydrogen and N-substituted alkanoic acid amides. Illustrative examples of these compounds include:

In another illustrative embodiment, compounds of the following formula are descπbed:

where R2, R3, R4, R5, and R6 are independently chosen substituents, including but not limited to hydrogen, halo, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, optionally substituted ammo, alkanoyl, aryloyl, carboxlate and deπvatives thereof, cyano, and the like. Illustrative examples of these compounds include:

where R substituted amino. Illustrative examples of these compounds include:

In another embodiment, compounds of the following formula are described:

where n and A' are as described above; R² is illustratively hydrogen, C₁-C₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; Ci -Q alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Ci-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro. It is understood that the above formula represents 16 different stereoisomeric configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of enantiomers is described:

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In one aspect, the group A' includes, but is not limited to 4-cyclohexylpiperazin-l -yl, 4-(pyrrolidin- l-yl)piperazin-l-yl, 4-ethylpiperazin- 1-yl, 4-n-butylpiperazin-l-yl, and 4-isopropylpiperazin-l-yl. In another embodiment, compounds of the following formula are described:

where n and A' are as described above; R² is illustratively hydrogen, CpC₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; Ci -C₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; C1-C4 alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

It is understood that the above formula represents 16 different stereoisomeric configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of enantiomers is described:

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In one aspect, the group A' includes, but is not limited to optionally substituted 4-piperidin-l- ylpiperidinyl, optionally substituted 4-arylalkylpiperazinyl, and optionally substituted A- cycloalkylpiperazinyl.

In another embodiment, compounds having the following formula are described:

where n and A' are as described above; R is illustratively hydrogen, Ci-Q alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; C1-C4 alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; C₁-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In one aspect, the group A' includes, but is not limited to 3-trifluoromethylbenzylamino, morpholin- 4-ylamino, 2-(dimethylamino)ethylamino, 3-(dimethylammo)propylamino, cyclohexylamino, piperidin-1-yl, 2-methoxyethylamino, isopropylamino, isobutylamino, ethylamino, dimethylamino, and methylamino. In another embodiment, compounds having the following formula are described:

where n and A' are as described above; R is illustratively hydrogen, Ci-Q alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; C] -C₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Ci-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

In one aspect, the group A' includes, but is not limited to benzylamino, (2- methylbenzyl)amino, (3-methylbenzyl)amino, (4-methylbenzyl)amino, (α-methylbenzyl)amino, N- benzyl-N_-methylamino, N.-benzyl-N.-(?-butyl)ammo, N-benzyl-N-butylamino, (3,5- dimethylbenzyl)amino, (2-phenylethyl)amino, dimethylamino, (3-trifluoromethoxybenzyl)amino, (3,4-dichlorobenzyl)amino, (3,5-dichlorobenzyl)amino, (2,5-dichlorobenzyl)amino, (2,3- dichlorobenzyl)amino, (2-fluoro-5 -trifluoromethylbenzyl)amino, (4-fluoro-3 - trifluoromethylbenzyl)amino, (3-fluoro-5-trifluoromethylbenzyl)amino, (2-fluoro-3- trifluoromethylbenzyl)amino, (4-chloro-3-trifluoromethylbenzyl)amino, indan-1-ylamino, 4-(2- hydroxybenzimidazol- 1 -yl)-piperidin- 1-yl, 3(S)-(/ert-butylaminocarbonyl)- 1 ,2,3,4- tetrahydroisoquinolin-2-yl, (3,3-dimethylbutyl)amino, 4-hydroxy-4-phenylpiperidin-l-yl, (cyclohexylmethyl)amino, (2-phenoxyethyl)amino, 3,4-methylenedioxybenzylamino, 4- benzylpiperidin- 1 -yl, and (3-trifluoromethylphenyl)amino .

In another embodiment, compounds of the following formula are described:

where n and A' are as described above; R is illustratively hydrogen, Cj-C₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; C] -C₄ alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifiuoromethoxy, chlorodifiuoromethoxy, tetrafluoroethoxy, and the like; C₁-C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro.

It is understood that the above formula represents 32 different stereoisomeric configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following stereosiomers are described:

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In another embodiment, compounds of the following formula are described:

where n is as described above; R² is illustratively hydrogen, CpC₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; C₁-C4 alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Ci -C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; formyl; and halo, such as fluoro and chloro; W is either carbon or ntrogen, each optionally substituted with a carbocyclyl substituent, such as cyclopentyl, cyclohexyl, and the like, or an an heterocyclyl substituent, such as pyrollidinyl, piperidinyl, and the like; and the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). The following compounds are illustrative of this embodiment:

where R² is hydrogen, methyl, methoxy, methylthio, trifluoromethyl, cyano, or fluoro.

In another embodiment, compounds of the following formula are described:

where n and A are as described above; R² is illustratively hydrogen, C₁-C₆ alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafluoroethyl, and the like; Ci -Q alkoxy, such as methoxy, ethoxy, and the like; haloalkoxy, such as trifluoromethoxy, chlorodifluoromethoxy, tetrafluoroethoxy, and the like; Cj -C₄ alkylthio, such as methylthio, ethylthio, and the like; cyano; forrayl; and halo, such as fluoro and chloro.

where the stereochemistry at the "α" carbon is either (R) or (S). In one aspect, the stereochemistry at the "α" carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S). In one aspect, the group A includes, but is not limited to (3- trifluoromethoxybenzyl)amino, (3,4-dichlorobenzyl)amino, (3,5<lichlorobenzyl)amino, (2,5- dichlorobenzyl)amino, (2,3-dichlorobenzyl)amino, (2-fluoro-5-trifluoromethylbenzyl)amino, (4- fluoro-3-trifluoromethylbenzyl)amino, (3-fluoro-5-trifluoromethylbenzyl)amino, (2-fiuoro-3- trifluoromethylbenzyl)amino, (4-chloro-3 -trifluoromethylbenzyl)amino, (2- trifluoromethylbenzyl)amino, (3-methoxybenzyl)amino, (3-fluorobenzyl)amino, (3,5- difluorobenzyl)amino, (3-chloro-4-fluorobenzyl)amino, (3-chlorobenzyl)amino, [3,5- bis(trifluoromethyl)benzyl]amino, (3-nitrobenzyl)amino, (3-bromobenzyl)amino, benzylamino, (2- methylbenzyl)amino, (3 -methylbenzyl)amino, (4-methylbenzyl)amrno, (α-methylbenzyl)amino, (N- methylbenzyl)amino, (N-tert-butylbenzyl)amino, (NL-butylbenzyl)amino, (3,5-dimethylbenzyl)amino, (2-phenylethyl)amino, (3,5-dimethoxybenzyl)amino, (lR)-(3-methoxyphenyl)ethylamino, (lS)-(3- methoxyphenyl)ethylamino, (α,α-dimethylbenzyl)amino, N-methyl-N-(3- trifluoromethylbenzyl)amino, [(S)-α-methylbenzyl]amino, (l-phenylcycloprop-lyl)amino, (pyridin- 2-ylmethyl)amino, (pyridin-3-ylmethyl)amino, (pyridin-4-ylmethyl)amino, (flιr-2-ylmethyl)amino, [(5 -methylfur-2-yl)methyl]amino, (thien-2-ylmethyl)amino, [(S)-1 ,2,3 ,4-tetrahydro- 1 -naphth- 1 - yl]amino, [(R)-l,2,3,4-tetrahydro-l-naphth-l-yl]amino, (indan-l-yl)amino, (1-phenylcyclopent-l- yl)amino, (α,α-dimethyl-3,5-dimethoxybenzyl)amino, (2,5-dimethoxybenzyl)amino, (2- methoxybenzyl)amino, and (α,α,2-trimethylbenzyl)amino.

Further illustrative classes of compounds are described by compounds of the following formula:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally- substituted furyl, or optionally-substituted thienyl;

R¹ and R² are hydrogen;

A is XNH-; n' is 1, 2, or 3;

X is optionally-substituted aryl(C 1-C4 alkyl), and aryl is substituted phenyl;

R⁵ is optionally substituted alkyl, optionally substituted arylalkyl, and the like; and

A is mono or disubstituted amino

wherein:

R¹ and R² are hydrogen;

A is cycloamino, such as piperidinyl, piperazinyl, each of which may be substituted, including 4-substitution with piperidin- 1 -ylethyl, piperazin-1-ylethyl, phenylethyl, and the like; and

A' is alkyl, such as ethyl, isopropyl, isobutyl, and the like. Illustrative of such compounds is:

wherein:

R and R are hydrogen;

A is arylalkyloxy, including optionally substituted benzyloxy;

A' is alkylcarbonyl, such as acetyl, propanoyl, pivaloyl, and the like. Illustrative of such compounds is:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally- substituted furyl, or optionally-substituted thienyl; n is an mterger equal to 0, 1, 2, 3, or 4

R¹ and R² are hydrogen;

A and A' are each independently a monosubstituted ammo, including arylalkylammo, and the like, which may be optionally substituted; or a group OR or OR , respectively, where R and R⁵ are each independently alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, such as methyl, ethyl, tert -butyl, benzyl, thienylmethyl, and the like. Illustrative of such compounds are:

where R and R are each independently selected from hydrogen, and alkyl, including methyl, tert- butyl and the like. Illustratively, R⁵ is hydrogen and R^5' is methyl, R⁵ is tert-butyl and R^5' is hydrogen, R⁵ is methyl and R^5' is tert-butyl , and R⁵ is tert-butyl and R^5' is methyl. Further illustrative of such compounds are:

where R⁵ and R^5' are each independently selected from hydrogen, and alkyl, including methyl, tert- bbuuttyyll aamnd the like. Illustratively, R⁵ is hydrogen and R⁵ is tert-butyl, and R⁵ is tert-butyl and R⁵ is methyl.

In another illustrative embodiment, compounds of the following formulae are descπbed:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyπdmyl, optionally- substituted furyl, or optionally-substituted thienyl; n is an interger equal to 0, 1, or 2

R¹ and R² are hydrogen;

A is monosubstituted amino, including optionally substituted benzylamino, and the like; and

A' is monosubstituted amino, including heterocycylalkylamino, such as piperidin-1- ethylamino, piperazin-1 -ethylamino, and the like. Illustrative of such compounds are:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally- substituted furyl, or optionally-substituted thienyl, and illustratively Ar is phenyl; n is an interger equal to 1 or 2;

R¹ and R² are hydrogen;

A is monosubstituted amino, including optionally substituted arylalkylamino, including benzylamino, optionally substituted phenethylamino, optionally substituted 1-phenyleth-l- ylamino, and the like; and A' is a monosubstituted amino, including arylalkylamino, and the like, which may be optionally substituted; or a group OR⁵ , where R⁵ is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, such as methyl, ethyl, tert-butyl, benzyl, thienylmethyl, and the like. Illustrative of such compounds are:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally- substituted furyl, or optionally-substituted thienyl, and illustratively Ar is phenyl; n is an interger equal to 1 or 2; R and R are hydrogen;

A is a monosubstituted amino, including arylalkylamino, and the like, which may be optionally substituted; or a group OR⁵ , where R⁵ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, such as methyl, ethyl, tert- butyl, benzyl, thienylmethyl, and the like; and A¹ is monosubstituted amino, including optionally substituted arylalkylamino, including benzylamino, optionally substituted phenethylamino, optionally substituted 1-phenyleth-l- ylammo, and the like. Illustrative of such compounds are:

In another embodiment, the compounds of the formulae descπbed herein include a basic ammo group. Such amines are capable of forming salts with a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. It is appreciated that in cases where compounds of the formulae descπbed herein are oils rather than solids, those compounds capable of forming addition salts that are solid will ease the handling and administration of the compounds descπbed herein. Acids commonly employed to form such salts are inorganic acids such as hydrochloπc acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfomc acid, oxalic acid, p-bromophenylsulfomc acid, carbonic acid, succinic acid, citπc acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, lsobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dimtrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloπc acid, tπfluoroacetic acid, maleic acid or fumaric acid.

In another embodiment, pharmaceutical compositions containing one or more β- lactamyl alkanoic acid vasopressin receptor antagonists are descπbed herein. The pharmaceutical compositions include one or more earners, diluents, and or excipients.

The compounds descπbed herein may be administered directly or as part of a pharmaceutical composition that includes one or more earners, diluents, and/or excipients. Such formulations may include one or more than one of the compounds descπbed herein. Such pharmaceutical compositions may be administered by a wide vanety of conventional routes m a wide vaπety of dosage formats, including but not limited to oral, rectal, transdermal, buccal, parenteral, subcutaneous, intravenous, intramuscular, intranasal, and the like. See generally, Remington's Pharmaceutical Sciences, (16th ed. 1980).

In making the compositions of the compounds described herein, the active ingredient may be mixed with an excipient, diluted by an excipient, or enclosed withm such a earner which can be in the form of a capsule, sachet, paper, or other container. Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, earner or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositones, stenle injectable solutions, and stenle packaged powders. The compositions may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystallme cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known m the art. It is appreciated that the earners, diluents, and excipients used to prepare the compositions descnbed herein are advantageously GRAS (Generally Regarded as Safe) compounds.

Compounds descnbed herein that are powders may be milled to desirable particle sizes and particle size ranges for emulsion and/or solid dosage forms. Illustrative particle size ranges include particle sizes of less than 200 mesh, particle sizes of less than 40 mesh, and the like.

It is to be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the seventy of the patient's symptoms. Therefore the dosage ranges descnbed herein are intended to be illustrative and should not be interpreted to limit the invention in any way. In cases where the dose is at the upper boundanes of the ranges described herein, the dose may be formatted as divided doses for administration at predetermined time points throughout the day. In cases where the dose is at the lower boundanes of the ranges descnbed herein, the dose may be formatted as a single dose for administration at predetermined time points once a day. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active mateπal calculated to produce the desired therapeutic effect over a predetermined time frame, m combination with a pharmaceutically acceptable earner, and optionally m association with a suitable pharmaceutical diluent and/or excipient.

In one illustrative embodiment, single or total divided dosages per day fall withm the range from about 1 μg/kg to about 100 mg/kg of body weight of the patient being treated. In another illustrative embodiment single or total divided dosages per day fall within the range from about 25 μg/kg to about 25 mg/kg of body weight of the patient being treated. It is appreciated that compounds of formula (I) may be advantageously administered at slightly higher overall daily totals, such as in the range from about 5 μg/kg to about 100 mg/kg of body weight, in the range from about 25 μg/kg to about 25 mg/kg of body weight, or m the range from about 25 μg/kg to about 5 mg/kg of body weight. It is further appreciated that compounds of formula (II) may be advantageously administered at slightly lower overall daily totals, such as in the range from about 1 μg/kg to about 50 mg/kg of body weight, m the range from about 5 μg/kg to about 25 mg/kg of body weight, or m the range from about 5 μg/kg to about 5 mg/kg of body weight. It is appreciated that the vitro binding and functional antagonism of activity at V_]a vasopressin receptors of the compounds descπbed herein is relative to the efficacious unit dose to be administered.

The following preparations and examples further illustrate the synthesis of the compounds of this invention and are not intended to limit the scope of the invention in any way. Unless otherwise indicated, all reactions were performed at ambient temperature, and all evaporations were performed in vacuo. All of the compounds described below were characteπzed by standard analytical techniques, including nuclear magnetic resonance spectroscopy ( ¹H NMR) and mass spectral analysis (MS). Other examples may be prepared by the synthetic routes and processes descπbed herein and exemplified below. Additional details for the synthetic procedures are descπbed in WO 03/031407, the disclosure of which is incorporated herein by reference. The compounds described herein are useful m methods for antagonism of the vasopressin V2 receptor. Such antagonism is useful m treating a vaπety of disorders and diseases that have been linked to this receptor in mammals. Illustratively, the mammal to be treated by the administration of compounds descπbed herein is human.

In another embodiment, compounds are also descπbed herein that cross the blood bram barπer. It is appreciated that compounds that cross the blood bram barπer may have wider application in treating vaπous disease states that are responsive to vasopressin antagonism. For example, it is to be understood that there are currently recognized distinct subtypes withm depressive illness.

Without being bound by theory, it is suggested that the azetidmone πng of the compounds descπbed herein may serve as a platform to display the appended functional groups in a configuration that matches complementary groups on the V2 receptor. For example, side-chams extend into four regions, which are designated as Zones A-D as follows, as illustrated by the following formula:

A B

D

The following preparations and examples further illustrate the synthesis of the compounds of this invention and are not intended to limit the scope of the invention in any way. Unless otherwise indicated, all reactions were performed at ambient temperature, and all evaporations were performed in vacuo. All of the compounds described below were characterized by standard analytical techniques, including nuclear magnetic resonance spectroscopy (¹H NMR) and mass spectral analysis (MS). Other examples may be prepared by the synthetic routes and processes described herein and exemplified below. Additional details for the synthetic procedures are described in WO 03/031407, the disclosure of which is incorporated herein by reference.

The 2-(azetidinon-l-yl)acetic acid esters and amides, and the analogs and derivatives thereof described herein may be prepared by syntheses known in the art, as well as by the various methods described herein. As illustrated for compounds of formula (I), the 2-(azetidinon-l- yl)alkanedioic acid esters described herein are obtainable by the 2+2 cycloaddition of an appropriately substituted acetic acid derivative thereof (i), and an imine ester (ii) upon treatment with a base in an appropriately selected solvent, as described in Synthetic Scheme I, where Z is hydroxyl or a leaving group, and the integer n, and the moieties A, A', R¹, R², R³, and R⁴ are as previously described. The term "leaving group" as used hereinafter refers to a subsitutent, such as halo, acyloxy, benzoyloxy and the like, present on an activated carbon atom that may be replaced by a nucleophile. The chemistry described in Synthetic Scheme I is applicable to imines (ii) bearing ester, thioester, or amide moieties.

Synthetic Scheme I

i ii The preparation of the appropriate imines (ii) and most of the required acetyl halides or anhydrides (i), as well as the cycloaddition procedure, are generally described in U.S. Patent Nos. 4,665,171 and 4,751,299, the desclosure of which are hereby incorporated by reference. The analogous synthesis of compounds of formulae (II) and (III) may be accomplished by this process usmg the appropriate alkoxy -substituted ammo acid lmmes.

Those compounds of formulae (T), (II), and (HI) requiπng R³ to be a 4-substituted oxazohdm-2-on-3-yl or 1 ,4,5-tπsubstituted imidazohdm-2-on-3-yl are prepared from the corresponding (4-substituted oxazohdm-2-on-3-yl) or (1,4,5-tπsubstituted imidazolidm-2-on-3- yl)acetyl hahde or anhydride. The acid halide or anhydπde is available from an appropriately substituted glycine. The glycine is first converted to the carbamate and then reduced to provide the corresponding alcohol. The alcohol is then cychzed to the 4 -substituted oxazolidm-2-one, which is subsequently N-alkylated with a haloacetic acid ester. The ester is hydrolyzed, and the resulting acid is converted to the acetyl halide or anhydπde (i). Illustrative of the oxazohdmones that are included in this synthetic route, and subsequent synthetic routes described herein, include the following commercially available compounds.

Illustrative of the lmidazohdmones and lmidazohdmdiones that are included in this synthetic route, and subsequent synthetic routes described herein, include the following commercially available compounds.

Those compounds requiring R to be 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5- trisubstituted imidazolidin-4-on-3-yl are prepared from the corresponding (2,5-disubstituted oxazolidin-4-on-3-yl) or (1,2,5-trisubstituted imidazolidin-4-on-3-yl)acetyl chlorides or anhydrides respectively. The chemistry to prepare these reagents is described in U.S. Patent No. 4,772,694, hereby incorporated by reference. Briefly, the required oxazolidinone or imidazolidinone is obtained from an α-hydroxyacid or an α-aminoacid, respectively. The imidazolones are prepared by converting the α-aminoacid, (R^π)-CH(NH₂)CO₂H, _{to an} amino-protected amide and then condensing the amide with an aldehyde, (R¹⁰)-CHO, in the presence of an acid to form the 3- protected imidazolidin-4-one, where R¹⁰ and R¹¹ are as defined above. The 1 -position may be functionalized with an appropriate reagent to introduce R and the 3 -position deprotected, where R is as defined above. The imidazolidin-4-one ring is then alkylated with a haloacetic acid ester, the ester deesterified, and the resulting acetic acid converted to the desired acid halide or anhydride (i). The required oxazolidinones are prepared in an analogous manner from the corresponding α- hydroxyacid, (R¹ ^-CH(OH)CO₂H.

Those compounds requiring R³ to be succinimido are prepared from the corresponding 2-{succinimido)acetyl halide or anhydride. The chemistry to prepare these reagents is described in U.S. Patent No. 4,734,498, hereby incorporated by reference. Briefly, these reagents are obtained from tartaric acid or, when one of R¹⁰ and R¹¹ is hydrogen, from malic acid. Tartaric acid is acylated or O-alkylated, the corresponding diacyl or di-O-alkyl tartaric acid is treated with an acid anhydride to form the succinic anhydride, and reaction of this succinic anhydride with an ester of glycine to form first the noncyclic half amide ester which is then cyclized to the 3,4-disubstituted succinimidoacetic acid ester. The ester group is deesterified and the resulting acid converted to the corresponding acid halide or anhydride (i). The mono-substituted succinimidoacetyl halide or anhydride is obtained with malic acid via succinic anhydride formation followed by succinimide formation as described above.

Those compounds requiring R³ to be an N-substituted amine or an N '-substituted urea may be prepared from the corresponding phthalimido protected 3 -amino analogs. The phthalimide protecting group may be removed using conventional procedures, such as by treatment with hydrazine, and the like. Once liberated, the amine may be alkylated with any one of a variety of alkyl and cycloalkyl halides and sulfates, such as methyl iodide, isopropylbromide, diethyl sulfate, cyclopropylmethylbromide, cyclopentyliodide, and the like. Such amines may also be acylated with acid halides, acid anhydrides, isocyanates, isothiocyanates, such as acetyl chloride, propionic anhydride, methylisocyanate, 3-trifluoromethylphenylisothiocyanate, and the like. The bases to be used in Synthetic Scheme I include, among others, aliphatic tertiary amines, such as trimethylamine and triethylamine, cyclic tertiary amines, such as N-methylpiperidine and N-methylmorpholine, aromatic amines, such as pyridine and lutidine, and other organic bases such as l,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

The solvents useful for reactions described in Synthetic Scheme I include, among others, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide.

In one illustrative variation of synthetic Scheme I, a process for preparing compounds of the formulae described herein is described, comprising reacting a compound of formula C:

with a compound of formula D:

where R¹, R², R⁴, A, A', Ar¹, and Ar² are as defined above.

In another illustrative variation of synthetic Scheme I, a process for preparing compounds of the formulae described herein is described, comprising reacting a suitably substituted compound of the formula:

with a compound of the formula:

,2 . where R is as defined above for formula (I). It is appreciated that any desired stereochemical configuration of these compounds may be prepared using this process by selecting the desired configuration at each chiral center noted above. Such a selection may be accomplished by using optically pure starting materials, or by separating mixtures of optical isomers at convenient times during the syntheses of the two foregoing formulae using standard techniques.

Ar .1 ^/ --N

-R^z

HO₂C (G) with a compound of the formula:

where Ar¹, Ar², R¹, R², R⁴, n, A, and A' are as defined in formula (I). It is appreciated that any desired stereochemical configuration of these compounds may be prepared using this process by selecting the desired configuration at each chiral center noted above. Such a selection may be accomplished by using optically pure starting materials, or by separating mixtures of optical isomers at convenient times during the syntheses of the two foregoing formulae using standard techniques.

Alternatively, the compounds of the formulae described herein may be prepared via N-C(4) cyclization, as illustrated for compounds of formula (I) in Synthetic Scheme II, via cyclizatoin of β-hydroxy amides Ui, where R¹, R², R³, R⁴, A, and A' are as defined previously, according to the procedure of Townsend and Nguyen in J. Am. Chem. Soc. 1981, 103, 4582, and Miller and Mattingly in Tetra. 1983, 39, 2563, the disclosures of which are incorporated herein by reference. The analogous synthesis of other compounds described herein may be accomplished by cyclizatoin of β-hydroxy amides of alkoxy-substituted amino acids.

Synthetic Scheme II

iii

The azetidinone ring may also be prepared with a deficit of substituents R², R³, R⁴, or the R -substituted N-alkanedioic acid or alkoxyalkanoic acid moiety, but possessing substituents capable of being elaborated through subsequent chemical transformation to such groups described for compounds of formulae (I)and (II). In general, azetidinones may be prepared via N-C(4) cyclization, such as the cyclization of acylhydroxamates iv to azetidinone intermediates v, as depicted in Scheme III, where R , R , R , R , A, and A' are as defined above, according to the procedure of Mattingly et al. in J. Am. Chem. Soc. 1979, 101, 3983 and Accts. Chem. Res. 1986, 19, 49, the disclosures of which are incorporated herein by reference. It is appreciated that other hydroxamates, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.

Synthetic Scheme III

iv V Subsequent chemical transformation of the acyloxyazetidinone v to introduce for example an R -substituted alkanedioic acid moiety using conventional procedures will illustratively provide compounds of formula (I). The analogous synthesis of compounds of formulae (II) and (III) maybe accomplished by this process using an appropriate R¹ -substituted alkoxyalkanoic acid.

An alternative cyclization to form intermediate azetidinones, which may be further elaborated to compounds of formulae (I), (II), and (III) may occur by oxidative cyclization of acylhydroxamates vi to intermediate azetidinones vii, as illustrated in Synthetic Scheme IV, where R² and R³ are as defined above and L is a leaving group such as halide, according to the procedure of Rajendra and Miller in J. Org. Chem. 1987, 52, 4471 and Tetrahedron Lett. 1985, 26, 5385, the disclosures of which are incoφorated herein by reference. The group R in Scheme IV represents an alkyl or aryl moiety selected to provide R⁴, as defined above, upon subsequent transformation. For example, R may be the group ArCH₂- where Ar is an optionally substituted aryl group, as in vii-a, such that oxidative elimination of HBr will provide the desired R⁴, such as a styryl group, as in vii-b. It is appreciated that elaboration of R to R is not necessarily performed immediately subsequent to the cyclization and may be performed conveniently after other steps in the synthesis of compounds of formulae (I), (II), and (III). It is further appreciated that alternatives to the acylhydroxamates shown, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.

Synthetic Scheme IV

vii-a vii-b

Other useful intermediates, such as the azetidinone-4-carboxaldehyde viii illustrated in Synthetic Scheme V for preparing compounds of formulae (I), (II), and (HI) may be further elaborated to 4-(R⁴)-substituted azetidinones via an olefϊnation reaction. The groups R¹, R², and R³ are as defined above, and the group R in Scheme V is selected such that upon successful olefϊnation of the carboxaldehyde the resulting group R-CHCH- corresponds to the desired alkyl or aryl moiety R⁴, as defined above. Such olefϊnation reactions may be accomplished by any of the variety of known procedures, such as by Wittig olefϊnation, Peterson olefϊnation, and the like. Synthetic Scheme V illustrates the corresponding Wittig olefϊnation with phosphorane ix. The analogous synthesis of compounds of formulae (II) and (III) may be accomplished by this process using an appropriate alkoxy-substituted azetidinone-4-carboxaldehyde derivative. Synthetic Scheme V

Still other useful intermediates, such as the azetidinonyl acetic acid derivatives x, may be converted into compounds of formulae (I), (II), and (HI), as illustrated for the synthesis of compounds of formula (I) in Synthetic Scheme VI, where R , R , R , R , A, A' and n are as defined above. Introduction of the R moiety, and a carboxylic acid derivative A'-C(O)-(CH2)n- for compounds of formula (I), may be accomplished by alkylation of the anion of x.

Synthetic Scheme VI

xi-b Acetic acid derivative x is deprotonated and subsequently alkylated with an alkyl halide corresponding to R -Z, where Z is a leaving group, to provide intermediate xi-a. Illustratively, the anion of xi-a may be alkylated with a compound Z'-(CH₂)_nCOA', where Z' is a leaving group, to provide compounds of formula (I).

Alternatively, acetic acid derivative x is deprotonated and subsequently alkylated with a compound Z'-(CH₂)_nCOA', where Z' is a leaving group, to provide intermediate xi-b.

Illustratively, the anion of xi-b may be alkylated with an alkyl halide corresponding to R¹ -Z, where Z is a leaving group, to provide compounds of formula (I). It is appreciated that the order of introduction of either the substituent R¹ or the acid derivative -(CH₂)_nCOA', may be dictated by steric or electronic considerations, synthetic convenience, or the availability of certain starting materials, and such order of introduction may be different for each compound of formulae (I), (II), and (in).

A solution of the 2-(3,4-disubstituted azetidin-2-on-l-yl)acetic acid derivative x or xi in an appropriate solvent, such as tetrahydrofuran, dioxane, or diethyl ether, is treated with a non- nucleophilic base to generate the anion of x or xi, respectively. Suitable bases for this transformation include lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidinarnide, or lithium bis(trimethylsilyl)amide. The anion is then reacted with an appropriate electrophile to provide the desired compounds. Illustrative electrophiles represented by the formulae R '-Z, R⁵ X¹N-C(O)-

(CKh)_n-Z, or R⁶O-C(O)-(CKh)_n-Z provide the corresponding compounds xi or (I), respectively. The analogous synthesis of compounds of formulae (II) and (111) may be accomplished by this process by using the appropriate electrophile.

As discussed above, the compounds prepared as described in Synthetic Schemes I, II, III, IV, V, and VI may be pure diastereomers, mixtures of diastereomers, or racemates. The actual stereochemical composition of the compound will be dictated by the specific reaction conditions, combination of substituents, and stereochemistry or optical activity of the reactants employed. It is appreciated that diasteromeric mixtures may be separated by chromatography or fractional crystallization to provide single diastereomers if desired, using standard methods. Particularly, the reactions described in Synthetic Schemes III, IV, and VI create a new chiral center at the carbon bearing R¹, except when n=0 and A=A'.

Compounds of formula (I) which are 2-{3,4-disubstituted azetidin-2-on-l- yl)alkanedioic acid half-esters, such as compounds I-a where A' is R⁶O-, while useful vasopressin V₂ agents in their own right, may also be converted to the corresponding half-carboxylic acids xii, where the integer n and the groups R , R , R , R , R , R , A, and X' are as previously defined, as illustrated in Synthetic Scheme VII. These intermediates are useful for the preparation of other compounds described herein, such as I-b where A is R⁵X¹N-. It is appreciated that the transformation illustrated in Synthetic Scheme VII is equally applicable for the preparation of compounds I where A' is X¹NH- or where a different R⁶ O- is desired.

Synthetic Scheme VII

I-a xii I-b

The requisite carboxylic acid xii may be prepared from the corresponding ester via saponification under standard conditions by treatment with hydroxide followed by protonation of the resultant carboxylate anion. Where R is tert-butyl, the ester I-a may be dealkylated by treatment with trifluoroacetic acid. Where R is benzyl, the ester I-a may be dealkylated either by subjection to mild hydrogenolysis conditions, or by reaction with elemental sodium or lithium in liquid ammoma. Finally, where R⁶ is 2-(tπmethylsilyl)ethyl, the ester I-a may be deprotected and converted into the corresponding acid xii by treatment with a source of fluoride ion, such as tetrabutylammonium fluoride. The choice of conditions is dependent upon the nature of the R moiety and the compatability of other functionality in the molecule with the reaction conditions. The carboxylic acid xii is converted to the corresponding amide I-b under standard conditions. The acid may be first converted to the corresponding acid hahde, preferably the chloπde or fluoride, followed by treatment with an appropπate primary or secondary amine to provide the corresponding amide. Alternatively, the acid may be converted under standard conditions to a mixed anhydπde. This is typically accomplished by first treating the carboxylic acid with an amine, such as tπethylamme, to provide the corresponding carboxylate anion. This carboxylate is then reacted with a suitable haloformate, for example benzyl chloroformate, ethyl chloroformate or isobutylchloroformate, to provide the corresponding mixed anhydπde. This anhydride may then be treated with an appropriate primary or secondary amine to provide the desired amide. Finally, the carboxylic acid may be treated with a typical peptide coupling reagent such as N₅N'- carbonyldiimidazole (CDI), NjN'-dicyclohexylcarbodnmide (DCC) and l-(3-dimethylammopropyl)- 3-ethylcarbodnmide hydrochloride (EDC), followed by the appropπate amine of formula R ΛNH. A polymer-supported form of EDC has been descπbed in Tetrahedron Letters, 34(48):7685 (1993), the disclosure of which is incorporated herein by reference, and is useful for the preparation of the compounds of the descπbed herein. It is appreciated that substituting an appropπate amine with an appropπate alcohol in the synthethic scheme presented above will provide the esters descπbed herein, e.g. analogs of I-a with a different ester R⁶O-.

The carboxylic acid may alternatively be converted into the corresponding tert-butyl ester via treatment of the acid with an acid catalyst, such as concentrated sulfuπc acid, and the like, and with isobutylene in a suitable solvent, such as dioxane, and the like. The reaction is preferably earned out under pressure m an appropπate vessel, such as a pressure bottle, and the like. Reaction times of about 18 hours are not uncommon. The desired ester may be be isolated from the organic layer after partitioning the reaction mixture between a suitable organic solvent, such as ethyl acetate, and the like, and a basic aqueous layer, such as cold IN sodium hydroxide, and the like.

It is appreciated that the transformation illustrated m Synthetic Scheme VII may also be used to convert in an analogous fashion, the half-ester I where A is R O- to the corresponding acid and subsequently into deπvatives I where A is XNH-, R XN-, or a different R O-. Finally, it is appreciated that the general synthetic strategy represented by the transformation in Synthetic Scheme VII is equally applicable to changing the carboxylic acid deπvatives m compounds of formulae (II) and (m). Compounds of formulae (I), (II), and (HI) where R⁴ includes an ethenyl or ethynyl spacer, such as for example, compounds I-c and I-d, respectively, may be converted into the corresponding arylethyl derivatives, compounds I-e, via reduction, as illustrated for compounds of formula (I) in Synthetic Scheme VIII. Conversion is accomplished by catalytic hydrogenation, and other like reductions, where the integer n and the groups R¹, R², R³, A, and A' are as previously defined. The corresponding compounds of formulae (II) and (III) may also be converted from ethyne and ethene precursors in an analogous fashion. The moiety R depicted in Scheme VIII is chosen such that the substituent R-CC-, R-CHCH-, or R-CH₂CH₂- corresponds to the desired R⁴ of formulae (I), (II), and (HI) as defined above.

Synthetic Scheme VIII

I-c I-d I-e The hydrogenation of the triple or double bond proceeds readily over a precious metal catalyst, such as palladium on carbon. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of about 20- 80 p.s.i., preferably about 50-60 p.s.i., at a temperature of about 0-60 ⁰C, preferably within the range of from ambient temperature to about 40 ⁰C, for about 1 hour to about 3 days.

Alternatively, the ethynyl spacer of compound I-c may be selectively reduced to the ethenyl spacer of compound I-d using poisoned catalyts, such as Pd on BaSO₄, Lindlar's catalyst, and the like. It is appreciated that either the Z or E double bond geometry of compound I-d may be advantageously obtained by the appropriate choice of reaction conditions. Alternatively, a mixture of double bond geometries may be prepared. The analogous synthesis of compounds of formulae (Et) and (IE) may be accomplished by this process.

Compounds of formulae (I), (II), and (HI) where R³ is phthalimido are conveniently treated with hydrazine or a hydrazine derivative, for example methylhydrazine, to prepare the corresponding 2-(3-amino-4-substituted azetidin-2-on-l-yl)alkanedioic acid derivatives xiii, as illustrated in Synthetic Scheme EK for compounds of formula (I), where the integer n, and the groups R , R , R , R , A, and A' are as previously defined. Intermediate xiii may then be treated with an appropriate alkylating or acylating agent to prepare the corresponding amines or amides I-g, or alternatively intermediates xiii may be treated with an appropriate isocyanate to prepare the corresponding ureas I-h. Synthetic Scheme IX

I-f xiii

I-h I-h

The ureas I-h are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate isocyanate, R NCO. If necessary, an excess of the isocyanate is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient temperature to about 45 ⁰C, for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure. When an excess of isocyanate has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, may be conveniently added to facilitate removal of the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.

The substituted amines and amides I-g are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate acylating or alkylating agent, R -C(O)Z or R -Z, respectively. If necessary, an excess of the acylating or alkylating agent is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient temperature to about 45 ⁰C, for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure. When an excess of the acylating or alkylating agent has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, may be conveniently added to facilitate removal of the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. The analogous synthesis of compounds of formulae (II) and (III) may be accomplished by this process.

Alternative syntheses have also been described, including the syntheses of several members of the structural class of substituted 2-(azetidin-2-on-l-yl)acetic acid esters and amides for the preparation of β-lactam antibiotics. See, e.g. , U.S. Patent No. 4,751,299.

In another embodiment, a method is described for treating a patient suffering from AVP dysfunction, where the method includes the step of administering to the patient in need of relief a compound, or a mixture of compounds in combination, that is capable of antagonizing both the vasopressing Vi_a and the vasopressing V₂ receptors. It is suggested that the vasopressin Ia (Via) receptor is involved in CHF based on its localization and function in vascular smooth muscle, where it promotes vasoconstriction, and in cardiomyocytes, where it is involved in myocardial cell protein synthesis and growth. It is also suggested that a simultaneous or contemporaneous V1A/V2 blockade may be effective for the treatment of CHF because V_1A blockade would reduce blood pressure, improve cardiac hypertrophy, and potentially inhibit fibrosis, and the V₂ blockade would result in improved water regulation. AVP dysfunction may include a number of disease states or symptoms, including multiple edematous conditions, such as congestive heart failure (CHF), dysfunction of ADH secretion, high blood pressure, hyponatremia, and other conditions.

In one embodiment, a method is described that includes the step of administering one or more compounds of the formulae (I), (II), and/or (III) in combination with a vasopressin Via antagonist. Illustrative of vasopressin V_la antagonists that may be included in this method are those described in U.S. Patent No. 6,204,260 and PCT International Application Nos. PCT/US02/32433 and PCT/US04/32401, the disclosures of which are incorporated herein by reference. It is appreciated that other vasopressin V_la antagonists may also be used in the methods described herein. In one aspect, the method further includes administering an acetylcholine esterase

(ACE) inhibitor in combination with the one or more compounds capable of antagonizing the vasopressin V_la and V₂ receptors.

The following preparations and examples further illustrate the compounds that are illustrative of the invention described herein, including the synthesis of such compounds, but such exemplary preparations and examples and are not intended to and should not be interpreted to limit the scope of the invention in any way. Unless otherwise indicated, all reactions were performed at ambient temperature, and all evaporations were performed in vacuo. All of the compounds described below were characterized by standard analytical techniques, including nuclear magnetic resonance spectroscopy (NMR) and mass spectral analysis (MS). The following preparations and examples further illustrate the compounds that are illustrative of the invention described herein, including the synthesis of such compounds, but such exemplary preparations and examples and are not intended to and should not be interpreted to limit the scope of the invention in any way. Unless otherwise indicated, all reactions were performed at ambient temperature, and all evaporations were performed in vacuo. All of the compounds described below were characterized by standard analytical techniques, including nuclear magnetic resonance spectroscopy (NMR) and mass spectral analysis (MS).

EXAMPLES

COMPOUND EXAMPLES

Example 1. (4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride. A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Patent No. 4,665,171) and 1.3 equivalent of oxalyl chloride in 200 mL dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 μL / milliequivalent of acetic acid derivative) resulting in vigorous gas evolution. After 45 minutes all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h under vacuum. Example IA. (4(R)-phenyloxazolidin-2-on-3-yl)acetyl chloride. Example IA was prepared following the procedure of Example 1, except that (4(R)-phenyloxazolidin-2-on-3-yl)acetic acid was used instead of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (see, Evans & Sjogren, Tetrahedron Lett. 26:3783 (1985)).

Example IB. Methyl (4(S)-phenyloxazolidin-2-on -3 -yl)acetate. A solution of (4(S)- phenyloxazolidin-2-on-3-yl)acetic acid (1 g, 4.52 mmol) (prepared according to Evans in U.S. Patent No. 4,665,171) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of the MeOH was redissolved in 30 mL Of CH₂Ch and treated with 50 mL of saturated aqueous Na₂CO₃. The organic layer was evaporated and dried (MgSO₄) to yield the title compound as a colorless oil (1.00 Ig, 94%); ¹H NMR (CDCl₃) δ 3.37 (d, J==18.0 Hz, IH), 3.69 (s, 3H), 4.13 (t, J=8.3 Hz, IH), 4.28 (d, J=18.0 Hz, IH), 4.69 (t, J=8.8 Hz, IH), 5.04 (t, J=8.4 Hz, IH), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).

Example 1C. Methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate. A solution of methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate (1 g, 4.25 mmol) in 10 mL of anhydrous THF at - 78 ⁰C was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 h. at about -70 ⁰C before adding MeI (1.59 mL, 25.51 mmol). Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH₄Cl and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl. The resulting organic layer was dried (MgSθ4) and evaporated to afford the title compound (a mixture of diasteromers) as a white solid (1.06g, 93%); ¹H NMR (CDCl₃) δ 1.07/1.53 (d/d, J=7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3 85/4.48 (q/q, J=7.5 Hz, IH), 4.10-4.14 (m, IH), 4.60-4.64/4.654.69 (m/m, IH), 4.88-4 92/4.98-5 02 (m/m, IH), 7.24-7.40 (m, 5H).

Example ID. 2-(4(S)-Phenyloxazohdin-2-on-3-yl)propanoic acid. To a solution of methyl 2-(4(S)-phenyloxazohdm-2-on-3-yl)propanoate (1 g, 4.01 mmol) m 35 mL of MeOH was added, at O⁰C, 14.3 mL (12.04 mmol) of a 0.84 M solution of LiOH in water. The reaction mixture was then stirred for 3 h. at ambient temperature. Upon complete hydrolysis of the azetidmone, the MeOH was removed by evaporation, the crude residue dissolved in CH₂Cl₂ and treated with saturated aqueous NaCl. The resulting organic layer was dπed (MgSO₄) and evaporated to afford the title compound (racemic mixture) as a white solid (0.906g, 96%); ¹H NMR (CDCl₃) δ 1.13/1.57 (d/d, J=7.5 Hz, 3H), 3.75/4.50 (q/q, J=7.5 Hz, IH), 4.10-4.16 (m, IH), 4.62-4.72 (m, IH), 4.92-5.03 (m, IH), 7.32-7.43 (m, 5H).

Example IE. 2-(4(S)-Phenyloxazolidin-2-on-3-yl)propanoyl chloride. A solution of 1 equivalent of Example ID and 1.3 equivalent of oxalyl chloride m 200 mL CH₂Cl₂ (150 mL / g of propanoic acid deπvative) was treated with a catalytic amount of anhydrous DMF (85 μL / mmole of propanoic acid deπvative) resulting in vigorous gas evolution. After 45 mm., all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h. under vacuum.

Example 2. General procedure for amide formation from an activated ester deπvative. N-Benzyloxycarbonyl-L-aspartic acid β-^-butyl ester α-(3-tnfluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-N-hydroxysuccmimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3 -(tπfluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; ¹H NMR (CDCl₃) δ 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, IH), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39- 7.43 (m, 2H), 7.48-7.52 (m, 2H). Examples 2A-2C and 3-5 were prepared according to the procedure of Example 2, except that N-benzyloxycarbonyl-L-aspartic acid β-£ -butyl ester α-N-hydroxysuccmimide ester was replaced by the appropπate ammo acid deπvative, and 3-(tπfluoromethyl)benzyl amine was replaced with the appropπate amine.

Example 2A. N-Benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-[4-(2- phenylethyl)]piperazmamide. N-benzyloxycarbonyl-L-aspartic acid β-ϊ-butyl ester α-N- hydroxysuccmimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)prperazme 2.27 mL (11.9 mmol) gave 5.89 g (quantitative yield) of the title compound as an off-white oil; H NMR (CDCl₃) δ 1.40 (s, 9H), 2.45-2.80 (m,10H), 3.50-3.80 (m, 4H), 4.87-4.91 (m, IH), 5.08 (s, 2H), 5.62-5.66 (m, IH), 7.17-7.33 (m, 10H).

Example 2B. N-Benzyloxycarbonyl-L-glutamic acid γ-/-butyl ester α-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-L-glutamic acid β-/-butyl ester α-N- hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3- (trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) gave 5.41 g (98%) of the title compound as an off-white solid; ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.88-1.99 (m, IH), 2.03-2.13 (m, IH), 2.23-2.33 (m, IH), 2.38-2.47 (m,lH), 4.19-4.25 (s, IH), 4.464.48 (m, 2H), 5.05-5.08 (m, 2H), 5.67-5.72 (m, IH), 7.27-7 '.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

Example 2C. N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acid γ-?-butyl ester α-N- hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitative yield) of the title compound as an off-white oil; ¹H NMR (CDCl₃) δ 1.43 (s, 9H); 1.64-1.73 (m,lH);1.93-2.01 (m, IH); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.664.73 (m, IH); 5.03-5.12 (m, 2H); 5.69-5.72 (m, IH); 7.16-7.34 (m, 10H).

Example 3. N-Benzyloxycarbonyl-L-aspartic acid β-i-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-N- hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave 5.89 g (quantitative yield) of the title compound as an off-white oil; H NMR (CDCl₃) δ 1.40 (s, 9H), 2.45-2.80 (m,10H), 3.50-3.80 (m, 4H), 4.874.91 (m, IH), 5.08 (s, 2H), 5.62-5.66 (m, IH), 7.17-7.33 (m, 10H).

Example 4. N-Benzyloxycarbonyl-L-glutamic acid γ-f-butyl ester α-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-L-glutamic acid β-f-butyl ester α-N- hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3- (trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) gave 5.41 g (98%) of the title compound as an off-white solid; ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.88-1.99 (m, IH), 2.03-2.13 (m, IH), 2.23-2.33 (m, IH), 2.38-2.47 (m,lH), 4.194.25 (s, IH), 4.464.48 (m, 2H), 5.05-5.08 (m, 2H), 5.67-5.72 (m, IH), 7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

Example 5. N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acid γ-/-butyl ester α-N- hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitative yield) of the title compound as an off-white oil; ¹H NMR (CDCl₃) δ 1.43 (s, 9H); 1.64-1.73 (m,lH);1.93-2.01 (m, IH); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.664.73 (m, IH); 5.03-5.12 (m, 2H); 5.69-5.72 (m, IH); 7.16-7.34 (m, 10H).

Example 5A. N-[(9H-Fluoren-9-yl)methoxycarbonyl]O-(benzyl)-D-serine /-Butyl ester. N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with /-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0 ⁰C. Upon completion (TLC), the reaction was quenched with of dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water, and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane/methanol) to yield the title compound as a colorless oil (0.292 g, 77%); ¹H NMR (CDCl₃) δ 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3 Hz, IH); 3.87 (dd, J=2.9 Hz, J=9.3 Hz, IH); 4.22 (t, J=7.1 Hz, IH); 4.30-4.60 (m, 5H); 5.64-5.67 (m, IH); 7.25-7.39 (m, 9H); 7.58-7.61 (m, 2H); 7.73-7.76 (m, 2H).

Example 5B. O-(Benzyl)-D-serine /-Butyl ester. Example 5A (0.620 g, 1.31 mmol) in dichloromethane (5 mL) was treated with tris(2-aminoethyl)amine (2.75 mL) for 5 h. The resulting mixture was washed twice with a phosphate buffer (pH=5.5), once with saturated aqueous potassium bicarbonate, and evaporated to give 0.329 g (quantitative yield) of the title compound as an off-white solid; ¹H NMR (CD₃OD) δ 1.44 (s, 9H); 3.48 (dd, J=J=4.2 Hz, IH); 3.61 (dd, J=4.0 Hz, J=9.2 Hz, IH); 3.72 (dd, J=4.6 Hz, J=9.2 Hz, IH); 4.47 (d, J=12.0 Hz, IH); 4.55 (d, J=12.0 Hz, IH); 7.26-7.33 (m, 5H). Example 6. General procedure for amide formation from a carboxylic acid. N-

Benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1 -hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, IH); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, IH); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).

Examples 7-7H were prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine. Example 7. N-Benzyloxycarbonyl-D-glutamic acid γ-/-butyl ester α-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid γ-/-butyl ester (1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) of 3-(trifluoromethyl)benzylamine gave 1.67 g (quantitative yield) of Example 7 as an off-white solid. Example 7 exhibited an H NMR spectrum consistent with the assigned structure. Example 7A. N-Benzyloxycarbonyl-L-glutamic acid α-?-butyl ester γ-(4- cyclohexyl)piperazinamide. N-benzyloxycarbonyl-L-glutamic acid α-/-butyl ester (1.36 g, 4.03 mmol) and 0.746g (4.43 mmol) of 1 -cyclohexylpiperazine gave 1.93 g (98%) of Example 7A as an off-white solid; ¹H NMR (CDCl₃) δ 1.02-1.12 (m, 5H); 1.43 (s, 9H), 1.60-1.64 (m, IH); 1.80-1.93 (m, 5H); 2.18-2.52 (m, 8H); 3.38-3.60 (m,4H); 4.20-4.24 (m, IH); 5.03-5.13 (m, 2H); 5.53-5.57 (m, IH); 7.28-7.34 (m, 5H).

Example 7B. N-Benzyloxycarbonyl-D-aspartic acid β-?-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL of (2-fluoro-3-trifluoromethyl)benzylamine gave 0.365 g (quantitative yield) of Example 7B as an off-white solid; ¹H NMR (CDCl₃) δ 1.38 (s, 9H); 2.59 (dd, J=6.5 Hz, J=17.0 Hz, IH); 2.95 (dd, J=4.3 Hz, J=17.0 Hz, IH); 4.46-4.56 (m, 3H); 5.11 (s, 2H); 5.94-5.96 (m, IH); 7.15 (t, J=8.0 Hz, IH); 7.30-7.36 (m, 5H); 7.47-7.52 (m, 2H).

Example 7C. N-Benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-[(S)-α- methylbenzyljamide. N-benzyloxycarbonyl-D-aspartic acid β-7-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (S)-α-methylbenzylamine gave 0.281 g (90%) of Example 7C as an off-white solid; ¹H NMR (CDCl₃) δ 1.41 (s, 9H); 1.44 (d, J=7.0 Hz, 3H); 2.61 (dd, J=7.0 Hz, J=17.0 Hz, IH); 2.93 (dd, J=4.0 Hz, J=17.5 Hz, IH); 4.504.54 (m, IH); 5.04-5.14 (m, 3H); 5.94-5.96 (m, IH); 6.76-6.80 (m, IH); 7.21-7.37 (m, 10H).

Example 7D. N-Benzyloxycarbonyl-D-aspartic acid β-Nbutyl ester α-[(R)-α- methylbenzyl] amide. N-benzyloxycarbonyl-D-aspartic acid β-^-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (R)-α-methylbenzylamine gave 0.281 g (90%) of Example 7D as an off-white solid; ¹H NMR (CDCl₃) δ 1.38 (s, 9H); 1.43 (d, J=6.9 Hz, 3H); 2.54 (dd, J=7.3 Hz, J=17.2 Hz, IH); 2.87 (dd, J=4.1 Hz, J=17.3 Hz, IH); 4.464.50 (m, IH); 4.99-5.15 (m, 3H); 5.92-5.96 (m, IH); 6.78-6.82 (m, IH); 7.21-7.33 (m, 10H).

Example 7E. N-Benzyloxycarbonyl-D-aspartic acid γ-/-butyl ester α-[N-methyl-N- (3-trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid γ-/ -butyl ester (0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol,) of N-methyl-N-(3-trifluoromethylbenzyl)amine gave 0.287 g (65%) of Example 7E as an off-white solid; ¹H NMR (CDCl₃) δ 1.40 (s, 9H); 2.55 (dd, J=5.8 Hz, J=15.8 Hz, IH); 2.81 (dd, J=7.8 Hz, J=15.8 Hz, IH); 3.10 (s, 3H); 4.25 (d, J=15.0 Hz, IH); 4.80 (d, J=15.5 Hz, IH); 5.01-5.13 (m, 3H); 5.52-5.55 (m, IH); 7.25-7.52 (m, 10H). Example 7F. N-Benzyloxycarbonyl-D-aspartic acid β-?-butyl ester α-[(S)-l-(3- trifluoromethylphenyl)ethyl] amide. N-benzyloxycarbonyl-D-aspartic acid β-/ -butyl ester monohydrate (Novabiochem) (84 mg, 0.25 mmol) and 47 mg of (S)-I -(3- trifluoromethylphenyl)ethylamine gave 122 mg (quantitative yield) of Example 7F as an off-white solid. Example 7F exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 7G. N-Benzyloxycarbonyl-D-aspartic acid β-?-butyl ester α-[(R)-l-(3- trifluoromethylphenyl)ethyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-7-butyl ester monohydrate (Novabiochem) (150 mg, 0.44 mmol) and 83 mg of (R)-I -(3- trifluoromethylphenyl)ethylamine gave 217 mg (quantitative yield) of Example 7G as an off-white solid. Example 7G exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 7H. N-Benzyloxycarbonyl-D-glutamic acid α-methyl ester γ-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid α-methyl ester (508 mg, 1.72 mmol) and 317 mg (1.81 mmol) of 3-(trifluoromethyl)benzylamme gave 662 mg (85%) of Example 7H as an off-white solid. Example 7H exhibited an H NMR spectrum consistent with the assigned structure. Example 8. General procedure for hydrogenation of a benzyloxycarbonyl amine. L- aspartic acid β-/-butyl ester α-(3-trifluoromethyl)benzylamide. A suspension of 2.23 g (4.64 mmol) of N-benzyloxycarbonyl-L-aspartic acid β-^-butyl ester α-(3-trifluoromethyl)benzylamide and palladium (5% wt. on activated carbon, 0.642 g) in 30 mL of methanol was held under an atmosphere of hydrogen until complete conversion as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent). The reaction was filtered to remove the palladium over carbon and the filtrate was evaporated to give 1.52 g (96%) of the title compound as an oil; ¹H NMR (CDCl₃) S 1.42 (s, 9H); 2.26 (brs, 2H); 2.63-2.71 (m, IH); 2.82-2.87 (m, IH); 3.75-3.77 (m, IH); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.90 (brs, IH).

Examples 9-13P were prepared according to the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-(3-trifluoromethyl)benzylamide was replaced by the appropriate amino acid derivative.

Example 9. L-aspartic acid β-i-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N- benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g (98%) of Example 9 as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H); 2.61- 2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, IH); 7.17-7.29 (m, 5H).

Example 10. D-aspartic acid β-^-butyl ester α-(3-trifluoromethyl)benzylamide. N- benzyloxycarbonyl-D-aspartic acid β-7-butyl ester α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) gave 0.973 g (96%) of Example 10 as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, IH); 2.84 (dd, J=3.6 Hz, J=16.7 Hz, IH); 3.73-3.77 (m, IH); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, IH). Example 11. L-glutamic acid γ-f-butyl ester α-(3-trifluoromethyl)benzylamide. N- benzyloxycarbonyl-L-glutamic acid γ-ϊ -butyl ester α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) gave 3.94 g (quantitative yield) of Example 11 as an off-white oil; ¹H NMR (CDCl₃): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, IH); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz, IH); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, IH).

Example 12. L-glutamic acid γ-^-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acid y-t -butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 12 as an off-white oil; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.00-2.08 (m, IH); 2.38-2.46 (m, IH); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, IH); 7.17-7.26 (m, 5H).

Example 13. D-glutamic acid y-t -butyl ester α-(3-trifluoromethyl)benzylamide. N- benzyloxycarbonyl-D-glutamic acid γ-7-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave 1.15 g (94%) of Example 13 as an off-white oil; ¹H NMR (CDCl₃) δ 1.41 (s, 9H); 1.80- 2.20 (m, 4H); 2.31-2.40 (m, 2H); 3.51-3.59 (m, IH); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H); 7.71- 7.79 (m, IH).

Example 13 A. L-glutamic acid α-^-butyl ester γ-(4~cyclohexyl)piperazinamide. N- Benzyloxycarbonyl -L-glutamic acid α-?-butyl ester γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) gave 1.30 g (93%) of Example 13A as an off-white oil; ¹H NMR (CDCl₃) δ 1.02-1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, IH); 1.56-1.60 (m, IH); 1.69-1.80 (m, 6H); 3.30 (dd, J=4.8 Hz, J=8.5 Hz, IH); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t, J=9.9 Hz, 2H).

Example 13B. D-aspartic acid β-^-butyl ester α-(2-fluoro-3- trifluorornethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide (0.36 g, 0.72 mmol) gave 0.256 g (92%) of Example 13B as an off- white oil; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, IH); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, IH); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, IH); 7.48 (t, J=7.3 Hz, IH); 7.56 (t, J=7.3 Hz, IH); 7.97-8.02 (m, IH).

Example 13C. D-aspartic acid β-f-butyl ester α-[(S)-α-methyl]benzylamide. N- benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-[(S)-α~methylbenzyl] amide (0.275 g, 0.65 mmol) gave 0.17 g (90%) of Example 13C as an off-white oil; ¹H NMR (CDCl₃) δ 1.40 (s, 9H); 1.47 (d, J=6.9 Hz, 3H); 1.98 (brs, 2H); 2.49 (dd, J=7.9 Hz, J=17.7 Hz, IH); 2.83 (dd, J=3.6 Hz, J=16.7 Hz, IH); 3.69 (brs, IH); 4.99-5.10 (m, IH); 7.19-7.33 (m, 5H); 7.65-7.68 (m, IH).

Example 13D. D-aspartic acid β-/-butyl ester α-[(R)-α-methylbenzyl]amide. N- benzyloxycarbonyl-D-aspartic acid β-t -butyl ester α-[(R)-α-methylbenzyl]amide (0.273 g, 0.64 mmol) gave 0.187 g (quantitative yield) of Example 13D as an off-white oil; ¹H NMR (CDCl₃) δ 1.38 (s, 9H); 1.46 (d, J=6.9 Hz, 3H); 1.79 (brs, 2H); 2.51 (dd, J=7.8 Hz, J=17.5 Hz, IH); 2.87 (dd, J=3.6 Hz, J=16.9 Hz, IH); 4.19 (brs, IH); 4.99-5.11 (m, IH); 7.18-7.34 (m, 5H); 7.86-7.90 (m, IH).

Example 13E. D-aspartic acid β-7-butyl ester α-[N-methyl-N-(3- trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-[N-methyl-N- (3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave 0.195 g (95%) of Example 13E as an off-white oil. Example 13E exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 13F. L-aspartic acid β-?-butyl ester α-[4-{2-phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-aspartic acid β-^-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g (98%) of Example 13F as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, IH); 7.17-7.29 (m, 5H). Example 13G. D-aspartic acid β-f-butyl ester α-{3-trifluoromethyl)benzylamide. N- benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) gave 0.973 g (96%) of Example 13G as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, IH); 2.84 (dd, J=3.6 Hz, J=16.7 Hz, IH); 3.73-3.77 (m, IH); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, IH). Example 13H. L-glutamic acid γ-£-butyl ester α -(3 -trifluoromethyl)benzylamide. N- benzyloxycarbonyl-L-glutamic acid γ-/ -butyl ester α-(3-trifluorornethyl)benzylamide (5.41 g, 10.9 mmol) gave 3.94 g (quantitative yield) of Example 13H as an off-white oil; ¹H NMR (CDCl₃): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, IH); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz, IH); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, IH). Example 131. L-glutamic acid γ-7-butyl ester α-[4-(2-phenylethyl)]piperazinamide.

N-benzyloxycarbonyl-L-glutamic acid γ-7-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 131 as an off-white oil; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.00-2.08 (m, IH); 2.38-2.46 (m, IH); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, IH); 7.17-7.26 (m, 5H). Example 13 J. D-glutamic acid γ-/-butyl ester α-(3-trifluoromethyl)benzylamide. N- benzyloxycarbonyl-D-glutamic acid γ-f-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave 1.15 g (94%) of Example 13J as an off-white oil; ¹H NMR (CDCl₃) δ 1.41 (s, 9H); 1.80- 2.20 (m, 4H); 2.31-2.40 (m, 2H); 3.51-3.59 (m, IH); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H); 7.71- 7.79 (m, IH). Example 13K. L-glutamic acid α-ϊ-butyl ester γ-(4-cyclohexyl)piperazinamide. N-

Benzyloxycarbonyl-L-glutamic acid α-/-butyl ester γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) gave 1.30 g (93%) of Example 13K as an off-white oil; ¹H NMR (CDCl₃) δ 1.02-1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, IH); 1.56-1.60 (m, IH); 1.69-1.80 (m, 6H); 3.30 (dd, J=4.8 Hz, J=8.5 Hz, IH); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t, J=9.9 Hz, 2H). Example 13L. D-aspartic acid β-f-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide (0.36 g, 0.72 mmol) gave 0.256 g (92%) of Example 13L as an off- white oil; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.50 (Jars, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, IH); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, IH); 3.89 (brs, 2H); 4.474.57 (m, 2H); 7.16 (t, J=7.8 Hz, IH); 7.48 (t, J=7.3 Hz, IH); 7.56 (t, J=7.3 Hz, IH); 7.97-8.02 (m, IH).

Example 13M. D-aspartic acid β-f-butyl ester α -[(S)-I -(3- trifiuoromethylphenyl)ethyl] amide. N-benzyloxycarbonyl-D-aspartic acid β-/ -butyl ester α-[(S)-l- (3-trifluoromethylphenyl)ethyl]amide (120 mg, 0.24 mmol) gave 91 mg (91%) of Example 13M as an off-white oil, and exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 13N. D-aspartic acid β-f-butyl ester α -[(R)-I -(3- trifiuoromethylphenyl)ethyl] amide. N-benzyloxycarbonyl-D-aspartic acid β-^ -butyl ester α-[(R)-l- (3-trifluoromethylphenyl)ethyl]amide (217 mg, 0.44 mmol) gave 158 mg (quantitative yield) of Example 13N as an off-white oil, and exhibited an H NMR spectrum consistent with the assigned structure. Example 130. D-aspartic acid β-?-butyl ester α-[N-methyl-N-(3- trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-[N-methyl-N- (3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave 0.195 g (95%) of Example 13O as an off-white oil, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 13P. D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide. N- Benzyloxycarbonyl -D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide (764 mg, 1.69 mmol) gave g (516mg, 96%) of Example 13P as an off-white oil, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 14. General procedure for formation of a 2-azetidinone from an imine and an acetyl chloride. Step 1: General procedure for formation of an imine from an amino acid derivative.

A solution of 1 equivalent of an α -amino acid ester or amide in dichloromethane is treated sequentially with 1 equivalent of an appropriate aldehyde, and a dessicating agent, such as magnesium sulfate or silica gel, in the amount of about 2 grams of dessicating agent per gram of starting α-amino acid ester or amide. The reaction is stirred at ambient temperature until all of the reactants are consumed as measured by thin layer chromatography. The reactions are typically complete within an hour. The reaction mixture is then filtered, the filter cake is washed with dichloromethane, and the filtrate concentrated under reduced pressure to provide the desired imine that is used as is in the subsequent step. Step 2: General procedure for the 2+2 cycloaddition of an imine and an acetyl chloride. A dichloromethane solution of the imine (10 mL dichloromethane/ 1 gram imine) is cooled to 0 ⁰C. To this cooled solution is added 1.5 equivalents of an appropriate amine, typically triethylamine, followed by the dropwise addition of a dichloromethane solution of 1.1 equivalents of an appropriate acetyl chloride, such as that described in Example 1 (10 mL dichloromethane/1 gm appropriate acetyl chloride). The reaction mixture is allowed to warm to ambient temperature over 1 h and is then quenched by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture is partitioned between water and dichloromethane. The layers are separated and the organic layer is washed successively with IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue may be used directly for further reactions, or purified by chromatography or by crystallization from an appropriate solvent system if desired. In each case, following the 2+2 reaction, the stereochemistry of the β-lactam may be confirmed by circular dichroism/optical rotary dispersion (CD/ORD). Illustratively, examples of the (αi?,35,4R) and (aS,3S,4R) β-lactam platform stereochemical configurations from prior syntheses may be used as CD/ORD standards. Example 15. fert-Butyl [3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2- styryl)azetidin-2-on-l-yl]acetate. Using the procedure of Example 14, the imine prepared from 4.53 g (34.5 mmol) glycine tert-buty\ ester and cinnamaldehyde was combined with 2-(4(S)- phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 5.5 g (30%) of Example 15 as colorless crystals (recrystallized, w-chlorobutane); mp 194-195 ⁰C. Example 16. General procedure for acylation of an azetidin-2-on-l-ylacetate. A solution of (azetidin-2-on-l-yl)acetate in tetrahydrofuran (0.22 M in azetidinone) is cooled to -78 ⁰C and is with lithium bis(trimethylsilyl)amide (2.2 equivalents). The resulting anion is treated with an appropriate acyl halide (1.1 equivlants). Upon complete conversion of the azetidinone, the reaction is quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase is washed sequentially with IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The resulting organic layer is dried (magnesium sulfate) and evaporated. The residue is purified by silica gel chromatography with an appropriate eluent, such as 3:2 hexane/ethyl acetate.

Example 17. 2,2,2-Trichloroethyl 2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1 -yl]acetate.

Using the procedure of Example 16, 9.0 g (20 mmol) of Example 15 was acylated with 4.2 g (20 mmol) of trichloroethylchloroformate to give 7.0 g (56%) of Example 17; mp 176-178 ⁰C.

Example 18. 2(RS)-(/ert-Butoxycarbonyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3- yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. A solution of 0.20 g (0.32 mmol) of Example 17 and 52 μL (0.36 mmol) of (3-trifluoromethylbenzyl)amine in THF was heated at reflux. Upon complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform/hexane) to give 0.17 g (82%) of Example 18 as a white solid; mp 182-184 ⁰C.

Example 18A. 2(RS)-(/ert-Butoxycarbonyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3- yl)-4(R)-{2-styryl)azetidm-2-on- 1 -yljacetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. Example 18A was prepared according to the procedure of Example 18, using 2-fluoro-3- (trifluoromethyl)benzylamine instead of (3-trifluoromethylbenzyl)amine. Example 18A was obtained as a white solid (140 mg, 41%), and exhibited an ¹H NMR spectrum consistent with the assigned structure. Examples 19-25AF were prepared according to the procedure of Example 14, where the appropriate amino acid derivative and aldehyde were used in Step 1, and the appropriate acetyl chloride was used in Step 2.

Example 19. 2(S)-(/ert-Butoxycarbonylmethyl>2-[3(S>(4(S)-phenyloxazolidin-2- on-3-yl)-4(R)-{2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.52 g (4.39 mmol) of L-aspartic acid β-/-butyl ester α-(3- trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 2.94 g of an orange-brown oil that gave, after flash column chromatography purification (70:30 hexanes/ethyl acetate), 2.06 g (70%) of Example 19 as a white solid; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.46 (dd, J=I Ll Hz, J=16.3 Hz, IH); 3.18 (dd, J=3.8 Hz, J=16.4 Hz, IH); 4.12-4.17 (m, IH); 4.26 (d, J=5.0 Hz, IH); 4.45 (dd, J=6.0 Hz, J=14.9 Hz, IH); 4.54 (dd, J=5.3 Hz, J=9.8 Hz, IH); 4.58-4.66 (m, 3H); 4.69-4.75 (m, IH); 4.81 (dd, J=3.8 Hz, J=I 1.1 Hz, IH); 6.25 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.70 (d, J=15.8 Hz, IH); 7.14-7.17 (m, 2H); 7.28-7.46 (m, HH); 7.62 (s, IH); 8.27-8.32 (m, IH).

Example 19A. 2(S)-(/er/-Butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2- on-3-yl)-4(S)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(3-trifluoromethylbenzyl)amide. Example 19A was prepared according to the method of Example 19 except that 2-(4(R)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example IA) was used instead of 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride. Example 19A was obtained as a white solid (41 mg, 13%); ¹H NMR (CDCl₃) δ 1.37 (s, 9H); 3.11 (dd, J=3.7 Hz, J=17.8 Hz, IH); 3.20 (dd, J=10.6 Hz, J=17.8 Hz, IH); 4.02 (dd, J=3.7 Hz, J=10.6 Hz, IH); 4.10-4.17 (m, IH); 4.24 (d, J=4.9 Hz, IH); 4.4652-4.574 (dd, J=5.9 Hz, J=15.1 Hz, IH); 4.58-4.76 (m, 4H); 6.27 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.79 (d, J=15.8 Hz, IH); 7.23-7.53 (m, 13H); 7.63 (s, IH); 8.51-8.55 (m, IH).

Example 20. 2(S)-(ter^Butoxycarbonylethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 3.94 g (10.93 mmol) of L-glutamic acid γ-/-butyl ester α-(3- trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 5.53 g (75%) of Example 20 after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.36 (s, 9H); 1.85- 1.96 (m, IH); 2.18-2.49 (m, 3H); 4.144.19 (m, IH); 4.30 (d, J=4.9 Hz, 2H); 4.44 (dd, J=6.1 Hz, J=14.9 Hz, IH); 4.56-4.67 (m, 4H); 4.71-4.75 (m, IH); 6.26 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.71 (d, J=15.8 Hz, IH); 7.16-7.18 (m, 2H); 7.27-7.49 (m, HH); 7.60 (s, IH); 8.08-8.12 (m, IH).

Example 21. 2(S)-(tert-Butoxycarbonylmethyl>2-[3(S>(4(S)-phenyloxazolidin-2- on-3-yl)4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The imine prepared from 4.20 g (11.6 mmol) of L-aspartic acid β-/-butyl ester α-[4-(2- phenylethyl)]piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 4.37 g (55%) of Example 21 after flash column chromatography purification (50:50 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.34 (s, 9H); 2.26- 2.32 (m, IH); 2.46-2.63 (m, 4H); 2.75-2.89 (m, 4H); 3.24-3.32 (m, IH); 3.49-3.76 (m, 3H); 4.07- 4.13 (m, IH); 4.30 (d, J=4.6 Hz, IH); 4.224.48 (m, IH); 4.55-4.61 (m, IH); 4.69-4.75 (m, IH); 5.04-5.09 (m, IH); 6.15 (dd, J=9.3 Hz, J=15.9 Hz, IH); 6.63 (d, J=15.8 Hz, IH); 7.18-7.42 (m, 15H). Example 22. 2(S)-(fert-Butoxycarbonylethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-

3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-f-butyl ester α-[4-(2- phenylethyl)]piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 3.55 g (76%) of Example 22 after flash column chromatography purification (50:50 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.32 (s, 9H); 1.96- 2.07 (m, IH); 2.15-2.44 (m, 6H); 2.54-2.62 (m, 2H); 2.69-2.81 (m, 3H); 3.28-3.34 (m, IH); 3.59- 3.68 (m, IH); 4.084.13 (m, IH); 4.334.44 (m, 2H); 4.48-4.60 (m, 2H); 4.67-4.77 (m, IH); 6.14 (dd, J=8.9 Hz, J=16.0 Hz, IH); 6.62 (d, J=16.0 Hz, IH); 7.16-7.42 (m, 15 H).

Example 23. 2(R)-(/ert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)4(R)-{2-styryl)azetidm-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.973 g (2.81 mmol) of D-aspartic acid β-?-butyl ester α-(3- trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 1.53 g (82%) of Example 23 after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.37 (s, 9H); 3.10 (dd, J=3.7 Hz, J=17.8 Hz, IH); 3.20 (dd, J=IOJ Hz, J=17.8 Hz, IH); 4.02 (dd, J=3.6 Hz, J=10.6 Hz, IH); 4.11-4.17 (m, IH); 4.24 (d, J=4.9 Hz, IH); 4.46 (dd, J=5.8 Hz, J=15.1 Hz, IH); 4.584.67 (m, 3H); 4.704.76 (m, IH); 6.27 (dd, J=9.5 Hz, J=15.8 Hz, IH); 6.79 (d, J=15.8 Hz, IH); 7.25-7.50 (m, 13H); 7.63 (s, IH); 8.50-8.54 (m, IH).

Example 23A. 2(R)-(fer/-Butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2- on-3-yl)4(S)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23 A was prepared according to the method of Example 23 except that 2-(4(R)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example IA) was used instead of 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride. Example 23A was obtained as a white solid (588 mg, 49%); ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.47 (dd, J=I 1.2 Hz, J=16.3 Hz, IH); 3.18 (dd, J=3.8 Hz, J=16.3 Hz, IH); 4.15 (t, J=8.25, Hz IH); 4.26 (d, J=5.0 Hz, IH); 4.45 (dd, J=6.0 Hz, J=15.0 Hz, IH); 4.52-4.57 (m, 3H); 4.63 (t, J=9 Hz, IH); 4.70 (t, J=8 Hz, IH); 4.81 (dd, J=3.8 Hz, J=10.8 Hz, IH); 6.25 (dd, J=9.8 Hz, J=15.8 Hz, IH); 6.70 (d, J=15.8 Hz, IH); 7.15-7.17 (m, 2H); 7.27-7.51 (m, HH); 7.62 (s, IH); 8.27-8.32 (m, IH).

Example 24. 2(R)-(/ert-Butoxycarbonylethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidm-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.15 g (3.20 mmol) of D-glutamic acid γ-7-butyl ester α-(3- trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 1.84 g (85%) of Example 24 after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.37 (s, 9H); 2.23- 2.39 (m, 4H); 3.71-3.75 (m, IH); 4.134.18 (m, IH); 4.31 (d, J=4.9 Hz, IH); 4.44-4.51 (m, 2H); 4.56-4.68 (m, 2H); 4.71-4.76 (m, IH); 6.26 (dd, J=9.5 Hz, J=15.8 Hz, IH); 6.71 (d, J=15.8 Hz, IH); 7.25-7.52 (m, 13H); 7.63 (s, IH); 8.25-8.30 (m, IH).

Example 25. 2(S)-(tert-Butoxycarbonylethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(4-cyclohexyl)piperazinamide. The imine prepared from 2.58 g (5.94 mmol) of L-glutamic acid γ-?-butyl ester α-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride

(Example 1) to give 3.27 g (94%) of Example 25 after flash column chromatography purification (95:5 dichloromethane/methanol); ¹H NMR (CDCl₃) δ 1.32 (s, 9H); 1.10-1.18 (m, IH); 1.20-1.31 (m, 2H); 1.38-1.45 (m, 2H); 1.61-1.66 (m, IH); 1.84-1.89 (m, 2H); 1.95-2.01 (m, IH); 2.04-2.14 (m, 3H); 2.20-2.24 (m, IH); 2.29-2.35 (m, IH); 2.85-2.92 (m, IH); 3.24-3.32 (m, IH); 3.36-3.45 (m, 2H); 3.80-3.86 (m, IH); 4.08 (t, J=8.3 Hz, IH); 4.27 (d, J=5.0 Hz, IH); 4.31-4.55 (m, 4H); 4.71 (t, J=8.3 Hz, IH); 4.834.90 (m, IH); 6.18 (dd, J=9.1 Hz, J=15.9 Hz, IH); 6.67 (d, J=15.9 Hz, IH); 7.25-7.44 (m, 10H); 8.22 (brs, IH).

Example 25A. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S> (4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetate. The imine prepared from 1.282 g (3.63 mmol) of L-glutamic acid α-/-butyl ester γ-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 1.946 g (80%) of Example 25A after flash column chromatography purification (50:50 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.15-1.26 (m, 6H); 1.39 (s, 9H); 1.55-1.64 (m, 2H); 1.77- 1.83 (m, 3H); 2.22-2.35 (m, 2H); 2.40-2.50 (m, 6H); 2.75-2.79 (m, IH); 3.43-3.48 (m, IH); 3.56- 3.60 (m, 2H); 3.75-3.79 (m, IH); 4.10 (t, J=8.3 Hz, IH); 4.31-4.35 (m, 2H); 4.58 (t, J=8.8 Hz, IH); 4.73 (t, J=8.4 Hz, IH); 6.17 (dd, J=8.6 Hz, J=16.0 Hz, IH); 6.65 (d, J=16.0 Hz, IH); 121-1 Al (m, 10H).

Example 25B. 2(R)-(/er/-Butoxycarbonylmethyl>2-[3(S>(4(S)-phenyloxazolidin-2- on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-{2-fluoro-3-trifluoromethylbenzyl)amide. The imine prepared from 0.256 g (0.70 mmol) of D-aspartic acid β-ϊ-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 0.287 g (60%) of Example 25B after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.38 (s, 9H); 3.12 (dd, J=4.0 Hz, J=17.8 Hz, IH); 3.20 (dd, J=10.4 Hz, J=17.8 Hz, IH); 4.05 (dd, J=3.9 Hz, J=10.4 Hz, IH); 4.14 (dd, J=J'=8.2 Hz, IH); 4.25 (d, J=4.9 Hz, IH); 4.59-4.67 (m, 4H); 4.74 (t, J=8.3 Hz, IH); 6.36 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.83 (d, J=15.8 Hz, IH); 7.02-7.07 (m, IH); 7.28-7.55 (m, 12H); 8.44-8.48 (m, IH).

Example 25C. 2(R)-(ter?-Butoxycarbonylmethyl>2-[3(S>(4(S)-phenyloxazolidin-2- on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(S)-α-methylbenzyl]amide. The imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-Nbutyl ester [(S)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 0.219 g (63%) of Example 25C after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.35 (s, 9H); 1.56 (d, J=7.0 Hz, 3H); 2.97 (dd, J=3.5 Hz, J=18.0 Hz, IH); 3.15 (dd, J=I LO Hz, J=17.5 Hz, IH); 4.01 (dd, J=3.0 Hz, J=I LO Hz, IH); 4.14 (t, J=8.5 Hz, IH); 4.24 (d, J=5.0 Hz, IH); 4.57 (dd, J=5.0 Hz, J=9.5 Hz, IH); 4.64 (t, J=8.8 Hz, IH); 5.07 (t, J=8.5 Hz, IH); 5.03-5.09 (m, IH); 6.43 (dd, J=9.5 Hz, J=16.0 Hz, IH); 6.83 (d, J=16.0 Hz, IH); 7.16-7.20 (m, IH); 7.27-7.49 (m, 14H); 8.07-8.10 (m, IH).

Example 25D. 2(R)-(ϊer/-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(R)-<x-methylbenzyl]amide. The imine prepared from 0.187 g (0.46 mmol) of D-aspartic acid β-7-butyl ester [(R)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride

(Example 1) to give 0.25 g (64%) of Example 25D after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.36 (s, 9H); 1.59 (d, J=7.1 Hz, 3H); 3.10 (dd, J=3.5 Hz, J=17.8 Hz, IH); 3.22 (dd, J=10.9 Hz, J=17.8 Hz, IH); 3.93 (dd, J=3.5 Hz, J=10.8 Hz, IH); 4.14 (t, J=8.1 Hz, IH); 4.24 (d, J=5.0 Hz, IH); 4.58 (dd, J=5.0 Hz, J=9.5 Hz, IH); 4.65 (t, J=8.7 Hz, IH); 4.74 (t, J=8.2 Hz, IH); 5.06-5.14 (m, IH); 6.32 (dd, J=9.5 Hz, J=15.8 Hz, IH); 6.74 (d, J=15.8 Hz, IH); 7.19-7.43 (m, 15H); 8.15-8.18 (m, IH).

Example 25E. 2(R)-(ter/-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)-4(R) -(2-styryl)azetidin-2-on- 1 -yljacetic acid N-methyl-N-(3 -trifluoromethylbenzyl)amide. The imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-f-butyl ester α-[N-methyl-N-(3- trifluoromethylbenzyl)]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2- on-3-yl) acetyl chloride (Example 1) to give 0.253 g (69%) of Example 25E after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.36 (s, 9H); 2.53 (dd, J=4.0 Hz, J=17.0 Hz, IH); 3.06 (dd, J=10.8 Hz, J=16.8 Hz, IH); 3.13 (s, 3H); 4.12 (dd, J=8.0 Hz, J=9.0 Hz, IH); 4.26 (d, J=5.0 Hz, IH); 4.38 (d, J=15.0 Hz, IH); 4.46 (dd, J=5.0 Hz, J=9.5 Hz, IH); 4.56 (t, J=6.8 Hz, IH); 4.704.79 (m, 2H); 5.27 (dd, J=4.0 Hz, J=I LO Hz, IH); 6.22 (dd, J=9.3 Hz, J=15.8 Hz, IH); 6.73 (d, J=I 5.8 Hz, IH); 7.33-7.45 (m, 14H).

Example 25F. 2(S)-(te^Butoxycarbonylethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on- 3-yl)-4(R)-(2-chlorostyr-2-yl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-Nbutyl ester α-(3- trifiuoromethyl)benzylamide and α-chlorocinnamaldehyde was combined with 2-(4(S)- phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 0.708 g (22%) of Example 25F after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.35 (s, 9H); 1.68 (brs, IH); 2.19-2.35 (m, 2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, IH); 4.22 (t, J=7.0 Hz, IH); 4.34 (d, J=4.5 Hz, IH); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, IH); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5 Hz, J=8.5 Hz, IH); 6.89 (s, IH); 7.28-7.54 (m, 14H). Example 25G. 2(R)-(fert-Butoxycarbonylmethyl)-2-[3(S>(4(S)-phenyloxazolidin-2- on-3-yl)4(R)-{2'-methoxystyr-2-yl)azetidm-2-on-l-yl]acetic acid N-{3-trifluoromethylbenzyl)amide. The imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid β-f-butyl ester α-(3- trifluoromethylbenzyl)amide and 2'-methoxycinnamaldehyde was combined with 2-(4(S)- phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 0.402 g (59%) of Example 25G after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.35 (s, 9H); 1.68 (brs, IH); 2.19-2.35 (m, 2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, IH); 4.22 (t, J=7.0 Hz, IH); 4.34 (d, J=4.5 Hz, IH); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, IH); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5 Hz, J=8.5 Hz, IH); 6.89 (s, IH); 7.28-7.54 (m, 14H).

Example 25H. tert-Butyl (2R)-(Benzyloxymethyl)-2-[3(S)-(4(S>phenyloxazolidin- 2-on-3-yl>4(R)-(2-styryl)azetidin-2-on-l-yl]acetate. The imine prepared from 0.329 g (1.31 mmol) of O-(benzyl)-D-serine r-butyl ester (Example 5B) and cinnamaldehyde was combined with 2-(4(S)- phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 0.543 g (73%) of Example 25H after flash column chromatography purification (90:10 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 3.56 (dd, J=2.7 Hz, J=9.5 Hz, IH); 3.82 (dd, J=4.8 Hz, J=9.5 Hz, IH); 4.11 (t, J=8.3 Hz, IH); 4.21-4.29 (m, 2H); 4.50-4.58 (m, 3H); 4.714.78 (m, 2H); 6.19 (dd, J=9.1 Hz, J=16.0 Hz, IH); 6.49 (d, J=16.0 Hz, IH); 7.07-7.11 (m, IH); 7.19-7.40 (m, 14H).

Example 251. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)- (4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidm-2-on-l-yl]acetate. The imine prepared from 0.3 g (0.88 mmol) of L-aspartic acid α-^-butyl ester γ-(4-cyclohexyi)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 464 mg (80%) of Example 251 as a white solid after flash column chromatography purification (50:50 hexanes/ethyl acetate). Example 251 exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 25J. tert-Butyl 3(R)-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-3-methyl- 4(R)-(styr-2-yl)azetidin-2-on-l-yl]-3-[(3-trifluoromethyl)phenylmethylammocarbonyl]propanoate. The imine prepared from 0.307 g (0.89 mmol) of D-aspartic acid β-?-butyl ester α-(3- trifluoromethyl)benzylamide (Example 20) and cinnamaldehyde was combined with 2-(4(S)- phenyloxazolidin-2-on-3-yl)propanoyl chloride (Example IE) to give 120 mg (20%) after flash column chromatography purification (hexanes 70% / EtOAc 30%); ¹H NMR (CDCl₃) δ 1.25 (s, 3H), 1.38 (s, 9H); 3.09 (dd, J=3.0 Hz, J=I 8.0 Hz, IH); 3.33 (dd, J=12.5 Hz, J=I 8.0 Hz, IH); 4.01 (dd, J=3.0 Hz, J=I 1.5 Hz, IH); 4.04 (dd, J=3.5 Hz, J=8.8 Hz, IH); 4.42 (d, J=9.0 Hz, IH); 4.454.51 (m, 3H); 4.61-4.66 (m, IH); 4.75 (dd, J=3.5 Hz, J=8.5 Hz, IH); 6.23 (dd, J=9.0 Hz, J=15.5 Hz, IH); 6.78 (d, J=15.5 Hz, IH); 7.23-7.53 (m, 13H); 7.64 (s, IH).

Example 25K. 2(R)-(/ert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)4(R)-(prop-l-enyl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.289 g (0.83 mmol) of D-aspartic acid β-^-butyl ester α-(3- trifluoromethyl)benzylamide and crotonaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on- 3-yl) acetyl chloride (Example 1) to give 381 mg (76%) of Example 25K after flash column chromatography purification (99:1 CH₂Cl₂/MeOH); ¹H NMR (CDCl₃) O 1.36 (s, 9H), 1.69 (dd, J=2 Hz, J=6.5 Hz, 3H); 3.08 (dd, J = 3.3 Hz, J = 17.8 Hz, IH); 3.18 (dd, J = 11 Hz, J = 17.5 Hz, IH); 3.94 (dd, J = 3.5 Hz, J = 11 Hz, IH); 4.12 (d, J=5 Hz, IH); 4.15 (dd, J = 7 Hz, J = 8 Hz, IH); 4.35 (dd, J = 4.8 Hz, J=9.8Hz, IH); 4.44 (dd, J=6 Hz, J=15 Hz, IH); 4.61 (dd, J=6 Hz, J=15 Hz, IH); 4.67-4.75 (m, 2H); 5.52-5.58 (m, IH); 5.92-6.00 (m, IH); 7.33-7.60 (m, 9H); 8.47-8.50 (m, IH).

Example 250. Methyl 2(S)-(?er/-Butoxycarbonylethyl)-2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetate. The imine prepared from 433 mg (1.99 mmol) of L-glutamic acid y-t -butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 682 mg (64%) of Example 250 after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.32 (s, 9H); 2.10-2.26 (m, IH); 2.30-2.41 (m, 3H); 3.66 (s, 3H); 3.95- 3.99 (m, IH); 4.16 (dd, J=7.5 Hz, J=9 Hz, IH); 4.38 (dd, J=5 Hz, J=9 Hz, IH); 4.55 (d, J= 5 Hz IH); 4.61 (t, J= 9 Hz, IH); 4.86 (dd, J=7.5 Hz, J=9 Hz, IH); 6.00 (dd, J=9 Hz, J=16 Hz, IH); 6.60 (d, J=16 Hz, IH); 7.26-7.43 (m, 10H).

Example 25M. tert -Butyl 2(S)-(methoxycarbonylethyl)-2-[3(S>(4(S)- phenyloxazolidm-2-on-3-yl)-4(R)-(2-styryl)azetidin-2~on-l-yl]acetate. The imine prepared from 428 mg (1.97 mmol) of L-glutamic acid γ-f-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 864 mg (82%) of Example 25M after flash column chromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.40 (s, 9H); 2.12-2.27 (m, IH); 2.32-2.55 (m, 3H); 3.50 (s, 3H); 3.72 (dd, J=4.6 Hz, J=10.4 Hz, IH); 4.12-4.17 (m, IH); 4.34 (dd, J=5 Hz, J=9 Hz, IH); 4.50 (d, J= 5 Hz, IH); 4.60 (t, J= 8.9 Hz, IH); 4.81-4.86 (m, IH); 6.06 (dd, J=9 Hz, J=16 Hz, IH); 6.59 (d, J=16 Hz, IH); 7.25-7.42 (m, 10H). Example 25P. Methyl 2(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)- phenyloxazolidm-2-on-3-yl)-4(R)-(2-styryl)azetidm-2-on-l-yl]acetate. The imme prepared from 424 mg (2.09 mmol) of L-aspartic acid γ-ϊ-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazohdm-2-on-3-yl) acetyl chloπde (Example 1) to give 923 mg (85%) of Example 25P after after recrystallization from CH₂Cl₂/hexanes; ¹H NMR (CDCl₃) δ 1.41 (s, 9H); 2.77 (dd, J=7.5 Hz, J=16.5 Hz, IH); 3.00 (dd, J=7 Hz, J=16.5 Hz, IH); 4.16 (dd, J=7. 5Hz, J=9 Hz, IH); 4.41-48 (m, 2H); 4.55 (d, J= 5 Hz, IH); 4.60 (t, J= 8.8 Hz, IH); 4.86 (dd, J=7.5 Hz, J=9 Hz, IH); 5.93 (dd, J=9.5 Hz, J=15.5 Hz, IH); 6.61 (d, J=15.5 Hz, IH); 7.25-7.43 (m, 10H).

Example 25L. 2(R)-(fe^-Butoxycarbonylmethyl)-2-[3(S)-<4(S)-phenyloxazohdin-2- on-3-yl)4(R)-(2-styryl)azetidm-2-on-l-yl]acetic acid N-[(R)-l-(3-tπfluoromethylpheny)ethyl]amide. The imme prepared from 160 mg (0.44 mmol) of D-aspartic acid β-^-butyl ester α- [(R)-I -(3- tπfluoromethylpheny)ethyl] amide and cinnamaldehyde was combined with 2-(4(S)- phenyloxazohdm-2-on-3-yl) acetyl chloπde (Example 1) to give 166 mg (55%) of Example 25L after flash column chromatography purification (70:30 hexanes/ EtOAc). Example 25L exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 25N. 2(R)-(fer/-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazohdin-2- on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(S)-l-(3-tπfluoromethylpheny)ethyl]amide. The imme prepared from 120 mg (0.22 mmol) of D-aspartic acid β-r-butyl ester α-[(S)-l-(3- tπfluoromethylpheny)ethyl] amide and cinnamaldehyde was combined with 2-(4(S)- phenyloxazolidm-2-on-3-yl) acetyl chloπde (Example 1) to give 75 mg (50%) of Example 25N after flash column chromatography puπfication (70:30 hexanes/EtOAc). Example 25N exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 25Q. Methyl 2(R)-(2-(3-tπfluoromethylbenzyl)aminocarbonyl)ethyl)-2- [3(S)-(4(S)-phenyloxazolidm-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetate. The imine prepared from 517 mg (1.62 mmol) of D-glutamic acid α-methyl ester γ-(3- tπfluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazohdm-2- on-3-yl) acetyl chloπde (Example 1) to give 527 mg (51%) of Example 25Q after flash column chromatography puπfication (50:50 hexanes/ EtOAc). Example 25Q exhibited an ¹H NMR spectrum consistent with the assigned structure.

The following compouds were prepared according to the processes descπbed herein:

Example 25AF. t-Butyl 2(S)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2- [3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetate.

Example 26. General procedure for hydrolysis of a tert-butyl ester. A solution of tert-butyl ester derivative in formic acid, typically 1 g in 10 mL, is stirred at ambient temperature until no more ester is detected by thin layer chromatography (dichloromethane 95% / methanol 5%), a typical reaction time being around 3 hours. The formic acid is evaporated under reduced pressure; the resulting solid residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer is evaporated to give an off-white solid that may be used directly for further reactions, or recrystallized from an appropriate solvent system if desired.

Examples 27-34AE were prepared from the appropriate tert-butyl ester according to the procedure used in Example 26. Example 27. 2(R,S)-(Carboxy)-2-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-4(R)-(2- styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 18 (0.30 g, 0.46 mmol) was hydrolyzed to give 0.27 g (quantitative yield) of Example 27 as an off-white solid; H NMR (CDCl₃) δ 4.17-5.28 (m, 9H); 6.21-6.29 (m, IH), 6.68-6.82 (m, IH); 7.05-7.75 (m, 13H); 9.12- 9.18 (m, IH). Example 28. 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl>4(R)-

(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 19 (1.72 g, 2.59 mmol) was hydrolyzed to give 1.57 g (quantitative yield) of Example 28 as an off-white solid; ¹H NMR (CDCl₃) δ 2.61 (dd, J=9.3 Hz, J=16.6 Hz, IH); 3.09-3.14 (m, IH); 4.10-4.13 (m, IH); 4.30 (d, J=4.5 Hz, IH); 4.394.85 (m, 6H); 6.20 (dd, J=9.6 Hz, J=15.7 Hz, IH); 6.69 (d, J=15.8 Hz, IH); 7.12-7.15 (m, 2H); 7.26-7.50 (m, HH); 7.61 (s, IH); 8.41-8.45 (m, IH).

Example 28A. 2(S)-(Carboxymethyl)-2-[3(R)-(4(R>phenyloxazolidin-2-on-3-yl> 4(S)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 19A (41 mg, 0.06 mmol) was hydrolyzed to give 38 mg (quantitative yield) of Example 28A as an off-white solid; ¹H NMR (CDCl₃) δ 2.26 (d, J=7 Hz, IH); 4.03 (t, J=7 Hz, IH); 4.16 (t, J=8 Hz, IH); 4.26 (d, J=4.3 Hz, IH); 4.46 (dd, J=5.7 Hz, J=15.1, IH); 4.53-4.75 (m, 5H); 6.25 (dd, J=9.5 Hz, J=15.7 Hz, IH); 6.77 (d, J=15.7 Hz, IH); 7.28-7.53 (m, 13H); 7.64 (s, IH); 8.65-8.69 (m, IH).

Example 29. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl>4(R)- (2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 20 (4.97 g, 7.34 mmol) was hydrolyzed to give 4.43 g (97%) of Example 29 as an off-white solid; ¹H NMR (CDCl₃) δ 1.92-2.03 (m,lH); 2.37-2.51 (m, 3H); 4.13-4.19 (m, IH); 3.32 (d, J=4.9 Hz, IH); 4.35-4.39 (m, IH); 4.44 (dd, J=5.9 Hz, J=14.9 Hz, IH); 4.50-4.57 (m, 2H); 4.614.67 (m, IH); 4.70-4.76 (m, IH); 6.24 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.70 (d, J=15.8 Hz, IH); 7.18-7.47 (m, 14H). Example 30. 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl>4(R)-

(2-styryl)azetidin-2-on-l-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g (60%) of Example 30 as an off-white solid; ¹H NMR (CDCl₃) δ 2.63 (dd, J=6.0 Hz, J=16.5 Hz, IH); 2.75-2.85 (m, IH); 3.00 (dd, J=8.2 Hz, J=16.6 Hz, IH); 3.13-3.26 (m, 4H); 3.37-3.56 (m, 4H); 3.864.00 (m, IH); 4.05-4.11 (m, IH); 4.24 (d, J=5.0 Hz, IH); 4.46-4.66 (m, IH); 4.65-4.70 (m, IH); 5.10-5.15 (m, IH); 6.14 (dd, J=9.3 Hz, J=15.9 Hz, IH); 6.71 (d, J=15.9 Hz, IH); 7.22-7.41 (m, 15H); 12.02 (s, IH).

Example 31. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-l-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. Example 22 (0.383 g, 0.55 mmol) was hydrolyzed to give 0.352 g (quantitative yield) of Example 31 as an off-white solid; ¹H NMR (CDCl₃) δ 1.93-2.01 (m, IH); 2.07-2.36 (m, 6H); 2.82-2.90 (m, IH); 3.00-3.20 (m, 4H);

3.36-3.54 (m, 4H); 3.74-3.82 (m, IH); 4.064.11 (m, IH); 4.29 (d, J=4.9 Hz, IH); 4.33-4.46 (m, 2H); 4.504.58 (m, 2H); 4.67-4.72 (m, IH); 4.95-5.00 (m, IH); 6.18 (dd, J=9.2 Hz, J=16.0 Hz, IH); 6.67 (d, J=15.9 Hz, IH); 7.19-7.42 (m, 15H); 8.80 (brs, IH).

Example 32. 2(R)-(Carboxymethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)- 4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23 (1.51 g, 2.27 mmol) was hydrolyzed to give 1.38 g (quantitative yield) of Example 32 as an off-white solid.

Example 32A. 2(R)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-on-3-yl)- 4(S)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23 A (550 mg, 0.83 mmol) was hydrolyzed to give 479 mg (95%) of Example 32A as an off-white solid. Example 32A exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 33. 2(R)-(Carboxyethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)4(R)- (2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 24 (0.604 g, 0.89 mmol) was hydrolyzed to give 0.554 g (quantitative yield) of Example 33 as an off-white solid. Example 34. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl>4(R)- (2-styryl)azetidin-2-on-l-yl]acetic acid N-(4-cyclohexyl)piperazinamide. Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492 g (quantitative yield) of Example 34 as an off-white solid; ¹H NMR (CDCl₃) δ 1.09-1.17 (m, IH); 1.22-1.33 (m, 2H); 1.40-1.47 (m, 2H); 1.63-1.67 (m, IH); 1.85- 1.90 (m, 2H); 1.95-2.00 (m, IH); 2.05-2.15 (m, 3H); 2.20-2.24 (m, IH); 2.30-2.36 (m, IH); 2.85- 2.93 (m, IH); 3.25-3.33 (m, IH); 3.36-3.46 (m, 2H); 3.81-3.87 (m, IH); 4.08 (t, J=8.3 Hz, IH); 4.28 (d, J=5.0 Hz, IH); 4.33-4.56 (m, 4H); 4.70 (t, J=8.3 Hz, IH); 4.83-4.91 (m, IH); 6.17 (dd, J=9.1 Hz, J=15.9 Hz, IH); 6.67 (d, J=15.9 Hz, IH); 7.25-7.44 (m, 10H); 8.22 (brs, IH).

Example 34A. 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid. Example 25A (0.787 g, 1.28 mmol) was hydrolyzed to give 0.665 g (92%) of Example 34A as an off-white solid; ¹H NMR (CDCl₃) S 1.05-1.13 (m, IH); 1.20-1.40 (m, 5H); 1.60-1.64 (m, IH); 1.79-1.83 (m, 2H); 2.00-2.05 (m, 2H); 2.22-2.44 (m, 3H); 2.67-2.71 (m, IH); 2.93-3.01 (m, 4H); 3.14-3.18 (m, IH); 3.38-3.42 (m, IH); 3.48-3.52 (m, IH); 3.64-3.69 (m, IH); 4.064.14 (m, 2H); 4.34-4.43 (m, 2H); 4.56 (t, J=8.8 Hz, IH); 4.73 (t, J=8.4 Hz, IH); 6.15 (dd, J=9.1 Hz, J=16.0 Hz, IH); 6.65 (d, J=16.0 Hz, IH); 7.25-7.42 (m, 10H). Example 34B. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl>

4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. Example 25B (0.26 g, 0.38 mmol) was hydrolyzed to give 0.238 g (quantitative yield) of Example 34B as an off-white solid; ¹H NMR (CDCl₃) δ 3.27 (d, J=7.2 Hz, IH); 4.06 (t, J=7.2 Hz, IH); 4.15 (t, J=8.1 Hz, IH); 4.27 (d, J=4.8 Hz, IH); 4.56-4.76 (m, 5H); 6.34 (dd, J=9.5 Hz, J=15.7 Hz, IH); 6.80 (d, J=15.7 Hz, IH); 7.06 (t, J=7.7 Hz, IH); 7.31-7.54 (m, 12H); 8.58 (t, J=5.9 Hz, IH).

Example 34C. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl> 4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-[(S)-α-methylbenzyl]amide. Example 25C (0.215 g, 0.35 mmol) was hydrolyzed to give 0.195 g (quantitative yield) of Example 34C as an off-white solid; ¹H NMR (CDCl₃) δ 1.56 (d, J=7.0 Hz, IH); 3.10 (dd, J=4.5 Hz, J=17.9 Hz, IH); 3.18 (dd, J=9.8 Hz, J=17.9 Hz, IH); 4.00 (dd, J=4.5 Hz, J=9.7 Hz, IH); 4.14 (t, J=8.2 Hz, IH); 4.26 (d, J=4.7 Hz, IH); 5.02-5.09 (m, IH); 6.41 (dd, J=9.4 Hz, J=15.8 Hz, IH); 6.78 (d, J=15.8 Hz, IH); 7.18 (t, J=7.3 Hz, IH); 7.26-7.43 (m, 12H); 8.29 (d, J=8.2 Hz, IH).

Example 34D. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)- 4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(R)-α-methylbenzyl]amide. Example 25D (0.22 g, 0.35 mmol) was hydrolyzed to give 0.20 g (quantitative yield) of Example 34D as an off-white solid; ¹H NMR (CDCl₃) δ 1.59 (d, J=7.0 Hz, IH); 3.25 (d, J=7.0 Hz, 2H); 3.92 (t, J=7.3 Hz, IH); 4.15 (t, J=8.3 Hz, IH); 4.26 (d, J=5.0 Hz, IH); 4.52 (dd, J=4.8 Hz, J=9.3 Hz, IH); 4.65 (t, J=8.8 Hz, IH);

4.72 (t, J=8.3 Hz, IH); 5.07-5.28 (m, IH); 6.29 (dd, J=9.5 Hz, J=15.6 Hz, IH); 6.71 (d, J=16.0 Hz,

IH); 7.20-7.43 (m, 13H); 8.31 (d, J=8.0 Hz, IH).

Example 34E. 2(R)-(Carboxymethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)- 4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. Example

25E (0.253 g, 0.37 mmol) was hydrolyzed to give 0.232 g (quantitative yield) of Example 34E as an off-white solid; ¹H NMR (CDCl₃) δ 3.07-3.15 (m, 4H); 4.13 (t, J=8.2 Hz, IH); 4.30 (d, J=4.9 Hz,

IH); 4.46-4.78 (m, 5H); 5.23 (dd, J=4.6 Hz, J=9.7 Hz, IH); 6.20 (dd, J=9.4 Hz, J=15.9 Hz, IH); 6.73

(d, J=15.9 Hz, IH); 7.25-7.43 (m, 15H). Example 34F. 2(S)-(Carboxyethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)4(R)-

(2-chlorostyr-2-yl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 25F

(0.707 g, 0.99 mmol) was hydrolyzed to give 0.648 g (99%) of Example 34F as an off-white solid;

¹H NMR (CDCl₃) δ 2.22-2.28 (m,2H); 2.49-2.64 (m, 2H); 4.09 (t, J=8.0 Hz, IH); 4.25-4.62 (m, 6H);

4.87 (t, J=8.0 Hz, IH); 6.88 (s, IH); 7.25-7.66 (m, 15H). Example 34G. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-

4(R)-(2'-methoxystyr-2-yl)azetidin-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide.

Example 25G (0.268 g, 0.39 mmol) was hydrolyzed to give 0.242 g (98%) of Example 34G as an off-white solid; ¹H NMR (CDCl₃) δ 3.26 (d, J=7.1 Hz, IH); 3.79 (s, 3H); 4.14 (t, J=8.2 Hz, IH); 4.25

(d, J=4.5 Hz, IH); 4.51 (dd, J=5.9 Hz, J=15.5 Hz, IH); 4.53-4.66 (m, 4H); 6.36 (dd, J=9.4 Hz, J=15.8 Hz, IH); 8.88 (t, J=8.2 Hz, IH); 6.70 (d, J=15.8 Hz, IH); 7.18 (d, J=6.5 Hz, IH); 7.25-7.48 (m,

10H); 7.48 (s, IH); 8.66-8.69 (m, IH).

Example 34H. (2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-

4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid. Example 25H (0.16 g, 0.28 mmol) was hydrolyzed to give 0.144 g (quantitative yield) of Example 34H as an off-white solid; ¹H NMR (CDCl₃) δ 3.65 (dd, J=4.0 Hz, J=9.5 Hz, IH); 3.82 (dd, J=5.5 Hz, J=9.5 Hz, IH); 4.11 (dd, J=7.8 Hz, J=8.8 Hz, IH); 4.33

(s, 2H); 4.50 (d, J=5.0 Hz, IH); 4.57 (t, J=9.0 Hz, IH); 4.67 (dd, J=4.0 Hz, J=5.0 Hz, IH); 4.69 (dd,

J=5.0 Hz, J=9.5 Hz, IH); 4.75 (t, J=8.0 Hz, IH); 6.17 (dd, J=9.3 Hz, J=15.8 Hz, IH); 6.55 (d, J=16.0

Hz, IH); 7.09-7.12 (m, 2H); 7.19-7.42 (m, 13H).

Example 341. 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid. Example 251 (737 mg,

1.12 mmol) was hydrolyzed to give 640 mg (95%) of Example 341 as an off-white solid. Example

341 exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 34J. 3(R)-[3(S>(4(S)-Phenyloxazolidin-2-on-3-yl>3-methyl4(R)-(styr-2- yl)azetidin-2-on-l-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the general method of Example 26, 120 mg (0.18 mmol) of Example 25J was hydrolyzed to give 108 mg

(98%) of Example 34J as an off-white solid; ¹H NMR (CDCl₃) δ 1.22 (s, 3H); 3.25 (dd, J=3.5 Hz, J=18.0 Hz, IH); 3.36 (dd, J=10.8 Hz, J=I 8.2 Hz, IH); 4.01 (dd, J=4.0 Hz, J=10.5 Hz, IH); 4.05 (dd, J=3.8 Hz, J=8.8 Hz, IH); 4.33 (d, J=9.0 Hz, IH); 4.44-4.51 (m, 3H); 4.61-4.66 (m, IH); 4.73 (dd, J=3.8 Hz, J=8.8 Hz, IH); 6.19 (dd, J=9.0 Hz, J=16.0 Hz, IH); 6.74 (d, J=16.0 Hz, IH); 7.22-7.54 (m, 13H); 7.65 (s, IH). Example 34K. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-

4(R)-(propen- 1 -yl)azetidin-2-on-l -yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Using the general method of Example 26, 160 mg (0.27 mmol) of Example 25K was hydrolyzed to give 131 mg (90%) of Example 34K as an off-white solid. ¹H NMR (CDCl₃) δ 1.69 (dd, J=I Hz, J=6.5 Hz, 3H); 3.23 (d, J = 7 Hz, IH); 3.93 (t, J= 7.3Hz, IH); 4.14-4.20 (m, 3H); 4.29 (dd, J = 5 Hz, J = 9.5 Hz, IH); 4.43 (dd, J = 6 Hz, J = 15 Hz, IH); 4.61 (dd, J=6.5 Hz, J=15 Hz, IH); 4.66 -4.74 (m, 2H); 5.50- 5.55 (m, IH); 5.90-5.98 (m, IH); 7.32-7.60 (m, 9H); 8.60-8.64 (m, IH).

Example 34L. 2(R)-(Carboxylmethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)- 4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(R)-l-(3-trifluoromethylpheny)ethyl]amide. Example 25L (166 mg, 0.24 mmol) was hydrolyzed to give 152 mg (quantitative yield) of Example 34L as an off-white solid; and exhibited an H NMR spectrum consistent with the assigned structure. Example 34M. 2(S)-(Methoxycarbonylethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid. Example 25M (875 mg, 1.64 mmol) was hydrolyzed to give 757 mg (97%) of Example 34M as an off-white solid, and exhibited an H NMR spectrum consistent with the assigned structure. Example 34N. 2(R)-(Carboxylmethyl)-2-t3(S)-(4(S>phenyloxazolidin-2-on-3-yl>

4(R)-(2-styryl)azetidin -2-on- l-yl]acetic acid N- [(S)- 1 -(3 -trifluoromethylpheny)ethyl]amide. Example 25N (38.5 mg, 0.057 mmol) was hydrolyzed to give 35 mg (quantitative yield) of Example 34N as an off-white solid, and exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 340. 2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S>phenyloxazolidin-2- on-3-yl)4(R)-(2-styryl)azetidm-2-on-l-yl]acetic acid. Example 250 (97 mg, 0.18 mmol) was dissolved in methanol/tetrahydrofuran (2.5 mL/2 mL) and reacted with lithium hydroxide (0.85 mL of a 0.85M solution in water; 0.72 mmol) for 6 hours at room temperature. The reaction was diluted with 15 mL dichloromethane and aqueous hydrochloric acid (IM) was added until the pH of the aqueous layer reached 5 (as measured by standard pH paper). The organic layer was then separated and evaporated to dryness to give 84 mg (89%) of Example 340 as an off-white solid, and exhibited an H NMR spectrum consistent with the assigned structure.

Example 34P. 2(S)-(/ert-Butoxycarbonylethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on- 3-yl>4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid. Example 25P (200 mg, 0.39 mmol) was hydrolyzed according to the method used for Example 340 to give 155 mg (88%) of Example 34P as an off-white solid; and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 34Q. 2(R)-(2-(3-trifluoromethylbenzyl)amino-l-ylcarbonyl)ethyl)-2-[3(S)- (4(S)-phenyloxazohdm-2-on-3-yl)-4(R)-(2-styryl)azetidm-2-on-l-yl]acetic acid. Example 25Q (150 mg, 0.24 mmol) was hydrolyzed according to the method used for Example 340 to give 143 mg (97%) of Example 34Q as an off-white solid, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 34R. 2(R)-(ter?-Butoxycarbonylmethyl>2-[3(RS)-2-thienylmethyl>4(R)- (2-styryl)azetidin-2-on-l-yl]acetic acid N-(3-tπfluoromethylbenzyl)amide. The imme prepared from 290 mg (0.84 mmol) of D-aspartic acid β-t -butyl ester α-(3-tπfluoromethyl)benzylamide and cinnamaldehyde was combined with 2-thiophene-acetyl chloride to give 42 mg (8%) of Example 34R after flash column chromatography purification (70:30 hexanes/ethyl acetate), and exhibited an H NMR spectrum consistent with the assigned structure.

The following compounds were prepared according to the processes descπbed herein:

Examples 36-42 A, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 27, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Examples 43-86A, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-?-butyl ester monohydrate was replaced with Example 28, and 3-(tπfluoromethyl)benzyl amine was replaced with the appropπate amine; all listed Examples exhibited an H NMR spectrum consistent with the assigned structure.

Example 86B. Example 63 (44 mg, 0.06 mmol) was dissolved m 4 mL dichloromethane and reacted with 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) until the reaction was complete as assessed by TLC (dichloromethane 94%/methanol 6%, UV detection). The reaction was quenched with aqueous sodium sulfite, the dichloromethane layer was washed with 5% aqueous sodium bicarbonate and distilled water. Evaporation of the dichloromethane layer afforded Example 86B as an off-white solid (35 mg, 78%), and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Examples 121-132, shown in The following table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 30, and 3-(tπfluoromethyl)benzyl amine was replaced with the appropπate amine; all listed Examples exhibited an H NMR spectrum consistent with the assigned structure.

Examples 132A-132B, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-Nbutyl ester monohydrate was replaced with Example 341, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 132C 2(S)<ferr-Butoxycarbonylmethyl)-2-[3(S)-(4(S>phenyloxazolidin-2- on-3-yl)-4(R)-{2-styryl)azetidin-2-on-l-yl] acetic acid N-(4-cyclohexyl)piperazmamide. Example 132C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34P, and 3-(trifiuoromethyl)benzyl amine was replaced with 1-cyclohexyl-piperazine. Example 132C exhibited an ¹H NMR spectrum consistent with the assigned structure.

The compounds shown in the following Table were prepared according to the processes described herein.

Examples 133-134G, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-?-butyl ester monohydrate was replaced with Example 32, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 134H. Example 134H was prepared using the procedure of Example 86B, except that Example 133 was replaced with Example 110. Example 134H was obtained as an off- white solid (48 mg, 94%), and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 1341. 2(R)-[[4-(Piperidinyl)piperidinyl]carboxymethyl]-2-[3(S)-(4(R)- phenyloxazolidin-2-on-3 -yl)-4(R)-(2-styryl)azetidin-2-on- 1 -yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Example 1341 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 32A, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 222. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(2-fluoro-3- trifluoromethylbenzyl)carboxamide. Example 222 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34B, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine; Example 222 exhibited an H NMR spectrum consistent with the assigned structure.

Example 223. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(S)-α- methylbenzyl] amide. Example 223 was prepared using the procedure of Example 6, except that N- benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34C, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine; Example 223 exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 224. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N- [(R)-Ot- methylbenzyl]amide. Example 224 was prepared using the procedure of Example 6, except that N- benzyloxycarbonyl-D-aspartic acid β-?-butyl ester monohydrate was replaced with Example 34D, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine; Example 223 exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 225. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-methyl-N-(3- trifluoromethylbenzyl)amide. Example 225 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 34E, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine; Example 223 exhibited an ¹H NMR spectrum consistent with the assigned structure; CaIc 'd for C₄₃H₄₈F₃N₅O₅: C, 66.91; H, 6.27; N, 9.07; found. C, 66.68; H, 6.25; N, 9.01. Example 225 Hydrochloride salt. Example 225 (212.5 mg) was dissolved in 30 mL dry Et₂O. Dry HCl gas was bubbled through this solution resulting in the rapid formation of an off- white precipitate. HCl addition was discontinued when no more precipitate was observed forming (ca. 5 minutes). The solid was isolated by suction filtration, washed twice with 15 mL of dry Et₂O and dried to 213.5 mg (96% yield) of an off-white solid; Calc'd for C₄₃H₄₉ClF₃N₅O₅: C, 63.89; H, 6.11; N, 8.66; Cl, 4.39; found. C, 63.41; H, 5.85; N, 8.60; Cl, 4.86.

Example 225A. 2(R)-[[4-[2-(piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S> (4(S)-phenyloxazolidin-2-on-3-yl>4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(S)-α- methylbenzyl]amide. Example 225A was prepared using the procedure of Example 6, except that N- benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34C, and 3-(trifluoromethyl)benzyl amine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225 A exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 225B. 2(R)-[[ 4-[2-(piperidinyl)ethyl]piperidinyl]carbonylmethyl] -2-[3(S)- (4(S)-phenyloxazolidin-2-on-3-yl>4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(R)-α- methylbenzyl]amide. Example 225B was prepared using the procedure of Example 6, except that N- benzyloxycarbonyl-D-aspartic acid β-ϊ-butyl ester monohydrate was replaced with Example 34D, and 3-(trifluoromethyl)benzyl amine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225B exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 225C. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-[(R)-l-(3- trifluoromethylpheny)ethyl] amide. Example 225C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 34L, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine. Example 225C exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 225D. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-[(S)-l-(3- trifluoromethylpheny)ethyl] amide. Example 225D was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-^-butyl ester monohydrate was replaced with Example 34N, and 3-(tπfluoromethyl)benzyl amine was replaced with 4-(pipeπdmyl)pipeπdme. Example 225D exhibited an H NMR spectrum consistent with the assigned structure.

Examples 87- 120E, shown m the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 29, and 3-(tπfluoromethyl)benzyl amine was replaced with the appropπate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 120F. Example 120F was prepared using the procedure of Example 86B, except that Example 63 was replaced with Example 110 to give an off-white solid (54.5 mg, 98%). Example 120F exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 120G. 2(S)-(Methoxycarbonylethyl)-2-[3(S>(4(S)-phenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidm-2-on-l-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 120G was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-7-butyl ester monohydrate was replaced with Example 34M, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 35. 2(S)-[4-(2-phenylethyl)piperazinyl-carbonylethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Using the procedure of Example 6, except that N-benzyloxycarbonyl- D-aspartic acid β-/-butyl ester monohydrate was replaced with the carboxylic acid of Example 29 and 3-(trifluoromethyl)benzyl amine was replaced with 4-(2-phenylethyl)piperazine, the title compound was prepared; ¹H NMR (CDCl₃) δ 2.21-2.23 (m, IH); 2.25-2.45 (m, 6H); 2.52-2.63 (m, 3H); 2.72-2.82 (m, 2H); 3.42-3.48 (m, 2H); 3.52-3.58 (m, IH); 4.13-4.18 (m, IH); 4.26 (dd, J=5.1 Hz, J=8.3 Hz, IH); 4.29 (d, J=5.0 Hz, IH); 4.44 (dd, J=6.0 Hz, J=15.0 Hz, IH); 4.54 (dd, J=6.2 Hz, J=14.9 Hz, IH); 4.61-4.68 (m, 2H); 4.70-4.75 (m, IH); 6.27 (dd, J=9.6 Hz, J=15.8 Hz, IH); 6.73 (d, J=15.8 Hz, IH); 7.16-7.60 (m, 19H); 8.07-8.12 (m, IH); FAB⁺ (M+H)⁺/z 794; Elemental Analysis calculated for C₄₅H₄₆F₃N₅O₅: C, 68.08; H, 5.84; N, 8.82; found: C, 67.94; H, 5.90; N, 8.64.

Examples 141-171, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Examples 172-22 IR, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 34A, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an H NMR spectrum consistent with the assigned structure.

Examples 135-140, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-^-butyl ester monohydrate was replaced with Example 33, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an H NMR spectrum consistent with the assigned structure.

Example 140A. 2(R)-( 2-(3-trifluoromethylbenzyl)amino-l-ylcarbonyl)ethyl)-2- [3(S)-(4(S>phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l -yl]acetic acid N-(4- cyclohexyl)piperazinamide. Example 140A was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-Nbutyl ester monohydrate was replaced with Example 34Q, and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexyl-piperazine, and exhibited an ¹H NMR spectrum consistent with the assigned structure.

Examples 226-230C, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced with Example 34F, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

The following compounds were prepared according to the processes described herein:

Example 86C. 2(S)-[[4-(Piperidinyl)piperidinyl]carbonymethyl]-2-[3(S)-(4(R)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Example 86C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-7-butyl ester monohydrate was replaced with Example 28A, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, and exhibited an H NMR spectrum consistent with the assigned structure.

Example 231. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2'-methoxystyr-2-yl)azetidin-2-on-l-yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Example 231 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 34G, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, and exhibited an H NMR spectrum consistent with the assigned structure.

Examples 232-233A, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester monohydrate was replaced with Example 34H, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 234. (2RS)-[4-(piperidinyl)piperidinylcarbonyl]-2-methyl-2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3- trifluoromethylbenzyl)amide .

Example 37 (50 mg, 0.067 mmol) in tetrahydrofuran (4 mL) was treated sequentially with sodium hydride (4 mg, 0.168mmol) and methyl iodide (6 μL, 0.094 mmol) at -78 ⁰C. The resulting mixture was slowly warmed to ambient temperature, and evaporated. The resulting residue was partitioned between dichloromethane and water, and the organic layer was evaporated. The resulting residue was purified by silica gel chromatography (95:5 chloroform/methanol) to give 28 mg (55%) of the title compound as an off-white solid; MS (ES⁺): m/z=757 (M⁺).

Example 234A. 4-(Piperidinyl)-piperidinyl 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-on- 3-yl)-3 -methyl4(R) <styr-2-yl)azetidin-2-on- 1 -yl] -3 -[(3 - trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid.

Using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-ϊ-butyl ester monohydrate was replaced with the carboxylic acid of Example 34J and 3- (trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, the title compound was prepared in quantitative yield; MS (m+H)⁺ 772.

Example 235. 2(S)-[[(1 -Benzylpiperidin-4-yl)amino]carbonylmethyl] -2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-l-yl)azetidin-2-on-l-yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Example 235 was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-r-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 63 (50 mg, 0.064 mmol) to give 40 mg (80%) of Example 235 as an off- white solid; Example 235 exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 236. (2S)-[(4-cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S> phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-l -yl)azetidin-2-on- 1 -yl]acetic acid

N-(3-trifluoromethylbenzyl)arnide. Example 236 was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-? -butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 110 (50 mg, 0.065 mmol) to give 42 mg (84%) of Example 236 as an off-white solid; Example 236 exhibited an ¹H NMR spectrum consistent with the assigned structure. Example 236A. (2S)-[(4-cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-l-yl)azetidin-2-on-l-yl]acetic acid N-[(R)-l,2,3,4- tetrahydronaphth-l-yl]amide. Example 236A was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-/ -butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 215 (76 mg, 0.10 mmol) to give 69 mg (90%) of Example 236A as an off white solid. Example 236A exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 237. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S>(4(S)- phenyloxazolidin-2-on-3-yl)-4(R)-(propen- l-yl)azetidin-2-on- 1 -yl]acetic acid N-(3- trifluoromethylbenzyl)amide. Example 237 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-7-butyl ester monohydrate was replaced with Example 34K, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidme. Example 237 exhibited an ¹H NMR spectrum consistent with the assigned structure.

Example 238. (2S)-(Benzylthiomethyl)-2-[3(S)-(4(S>phenyloxazolidin-2-on-3-yl)- 4(R)-(2-styryl)azetidin-2-on- l-yl]acetic acid N-[4-[2-(piperid-l -yl)ethyl]piperidin- 1 -yl]amide. This Example was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D- aspartic acid β-£-butyl ester monohydrate was replaced with the coresponding benzyl protected cycteine analog, and 3-(trifluoromethyl)benzyl amine was replaced with 4-[2-(piperid-l- yl)ethyl]piperidine.

Step 1. N-/Butyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(l- piperidyl)ethyl)]piperidinenamide. N-/Butyloxycarbonyl-(S)-Benzyl-N-(/butyloxycarbonyl)-D- cysteine (0.289 g, 0.93 mmole) and 4-[2-(l-piperidyl)ethyl]piperidine (0.192 g, 0.98 mmole) in dichloromethane (20 niL) gave 0.454 g (quantitative yield) of Example X as an off-white solid. ¹H NMR (CDCl₃) δ 0.89-1.15 (m, 2H); 1.39-1.44 (m, 16H); 1.54-1.61 (m, 4H); 1.62-1.71 (m, IH); 2.21- 2.35 (m, 5H); 2.49-2.58 (m, 2H); 2.66-2.74 (m, IH); 2.79-2.97 (m, IH); 3.67-3.76 (m, 3H); 4.48- 4.51 (m, IH); 4.72-4.75 (m, IH); 5.41-5.44 (m, IH); 7.19-7.34 (m, 5H).

Step 2. (S)-(benzyl)-D-cysteine-[4-(2-(l -piperidyl)ethyl)]piperidinenarnide, dihydrochloride. N-/Butyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(l- piperidyl)ethyl)]piperidinenamide (0.453 g, 0.93 mmole) was reacted overnight with acetyl chloride (0.78 mL, 13.80 mmole) in anhydrous methanol (15 mL). The title compound was obtained as an off-white solid by evaporating the reaction mixture to dryness (0.417 g, 97%). H NMR (CD3OD) δ 0.94-1.29 (m, 2H); 1.49-1.57 (m, IH); 1.62-1.95 (m, 10H); 2.65-2.80 (m, 2H); 2.81-2.97 (m, 4H); 3.01-3.14 (m, 2H); 3.50-3.60 (m, 3H); 3.81-3.92 (m, 2H); 4.41-4.47 (m, 2H); 7.25-7.44 (m, 5H). Step 3. Using the general procedures described herein, the imine prepared from (S)-

(benzyl)-D-cysteine-[4-(2-(l-piperidyl)ethyl)]piperidinenamide, dihydrochloride (0.417 g, 0.90 mmole) and cinnamaldehyde, in the presence on triethylamine (0.26 mL, 1.87 mmole), was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 0.484 g (76%) of Example 238 as an off-white solid after recrytallization from dichloromethane/hexanes. ¹H NMR (CDCl₃) δ 0.89-1.06 (m, 2H); 1.40-1.44 (m, 5H); 1.57-1.67 (m, 6H); 2.25-2.43 (m, 6H); 2.45- 2.59 (m, 2H); 2.71-2.88 (m, 2H); 3.55-3.70 (m, 3H); 4.11-4.17 (m, IH); 4.37-4.47 (m, 2H); 4.54- 4.61 (m, IH); 4.64-4.69 (m, IH); 4.764.84 (m, 2H); 6.05-6.19 (m, IH); 6.66-6.71 (m, IH); 7.12- 7.40 (m, 15H).

Table 16 illustrates selected compounds further characterized by mass spectral analysis using FAB⁺ to observe the corresponding (M+H)⁺ parent ion.

Table 16.

METHOD EXAMPLES

In another embodiment, the compounds descπbed herein are useful for antagonism of the vasopressin V₂ receptor in methods for treating patients sufferemg from disease states and conditions that are responsive to antagonism of the vasopressin V₂ receptor. Illustratively, the methods descπbed herein include the step of administering to a subject or patient m need of such treatment an effective amount of a compound descπbed by the formulae herein. Antagonism of vaπous vasopressin receptor subtypes has been associated with numerous physiological and therapeutic benefits. These benefits may aπse from antagonism of both peπpheral and central nervous system vasopressin receptors. Peπpheral nervous system utilities include administration of vasopressin V_la and/or vasopressin V₂ antagonists as adjuncts in heart failure or as antithrombotic agents. Central nervous system effects include administration of vasopressin Vu and/or vasopressin Vib antagonists of the compounds described herein for the treatment of obsessive-compulsive disorder, aggressive disorders, depression, anxiety, and other psychological and neurological disorders. METHOD EXAMPLE 1. Human or rat vasopression V2 cell -based receptor binding assay. All of the alkanedioic esters and amides exemplified m the foregoing examples were tested in a cell binding assay, where the cells expressed either rat or human vasopressin V₂ receptors. Binding affinities (IC50) for illustrative compounds are summaπzed in Table 17. Inhibition constants (K₁) for illustrative compounds are also summaπzed m Table 17. Table 17.

METHOD EXAMPLE 2. Inhibition of vasopressin V₂-mediated phosphatidylinositol turnover: functional assay for antagonist activity. The physiological effects of vasopressin are mediated through specific G-protein coupled receptors. The vasopressin V₂ receptor is coupled to the G_s family of G proteins, which is in turn coupled to cAMP. The agonist or antagonist character of the compounds described herein may be determined by their ability to inhibit vasopressin-mediated turnover of phosphatidylinositol by using conventional methods, including the procedure described in the following paragraphs.

Human or rat V₂ cells are grown in alpha-modified minimal essential medium containing 10% fetal bovine serum and 0.25 mg/ml G418. Three days prior to the assay, near- confluent cultures are dissociated and seeded in 6-well tissue culture plates, about 100 wells being seeded from each 75 cm² flask (equivalent to 12: 1 split ratio). Each well contains 1 ml of growth medium with 2μCi of [³H] myo-inositol (American Radiolabeled Chemicals, St. Louis, MO).

AU assays are in triplicate except for basal and 10 nM AVP (both n=6). Arginine vasopressin (AVP) is dissolved in 0.1N acetic acid. Candidate drugs are dissolved in DMSO on the day of the experiment and diluted in DMSO to 200 times the final test concentration. Candidate drugs and AVP (or corresponding volumes of DMSO) are added separately as 5 ul in DMSO to 12x75 mm glass tubes containing 1 ml of assay buffer (Tyrode's balanced salt solution containing 50 mM glucose, 10 mM LiCl, 15 niM HEPES pH 7.4, 10 uM phosphoramidon, and 100 uM bacitracin). The order of incubations are randomized. Incubations are initiated by removing the prelabeling medium, washing the monolayer once with 1 ml of 0.9% NaCl, and adding the contents of the assay tubes. The plates are incubated for 1 hr at 37°C. Incubations are terminated by removing the incubation medium and adding 500 ul of ice cold 5% (w/v) trichloroacetic acid and allowing them to stand for 15 min.

The incubates are fractionated on BioRad Poly-Prep Econo-Columns packed with 0.3 ml of AG 1 X-8100-200 formate resin. Resin is mixed 1:1 with water and 0.6 ml added to each column. Columns are then washed with 10 ml water. Scintillation vials (20ml) are placed under each column. For each incubation well, the contents are transferred to a minicolumn, after which the well is washed with 0.5 ml distilled water, which is also added to the minicolumn. The columns are then washed twice with 5 ml of 5 mM myo-inositol to elute free inositol. A 1 ml aliquot of this is transferred to a new 20 ml scintillation vial, plus 10 ml of Beckman Ready Protein Plus, and counted. After the myo-inositol wash is complete, empty scintillation vials are placed under the columns, and [³H] inositol phosphates are eluted with three additions of 1 ml 0.5 M ammonium formate containing 0.1 N formic acid. Elution conditions are optimized to recover inositol mono-, bis-, and trisphosphates, without eluting the more metabolically inert tetrakis-, pentakis-, and hexakis-phosphates. Samples are counted in a Beckman LS 6500 multipurpose scintillation counter after addition of 10 ml Tru-Count High Salt Capacity scintillation fluid.

Inositol lipids are measured by adding 1 ml of 2% sodium dodecyl sulfate (SDS) to each well, allowing the wells to sit for at least 30 min. Lysed content in each well is transferred to a 20 ml scintillation vial. 10 ml Beckman Ready Protein Plus scintillation fluid is added and radioactivity counted.

Concentration-response curves for AVP and concentration-inhibition curves for test agents versus 10 nM AVP were analyzed by nonlinear least -squares curve-fitting to a 4-parameter logistic function. Parameters for basal and maximal inositol phosphates, EC50 or IC50, and Hill coefficient were varied to achieve the best fit. The curve-fitting was weighted under the assumption that the standard deviation was proportional to dpm of radioactivity. Full concentration-response curves for AVP were run in each experiment, and IC₅₀ values were converted to K₁ values by application of the Cheng-Prusoff equation, based on the EC50 for AVP in the same experiment. Inositol phosphates were expressed as dpm per 10⁶ dpm of total inositol incorporation.

Experiments to test for competitivity of test agents consisted of concentration - response curves for AVP in the absence and presence of two or more concentrations of test agent. Data were fit to the following competitive logistic equation:

M x {A/ [E + (D I K)]} Q

Y = B +

1 +{A/ [E + (D / K)]}^L where Y is dpm of inositol phosphates, B is concentration of basal inositol phosphates, M is the maximal increase in concentration of inositol phosphates, A is the concentration of agonist (AVP), E is the EC₅₀ for agonist, D is the concentration of the antagonist, K is the K₁ for antagonist, and Q is the cooperativity (Hill coefficient).

Expeπments to test for competition by test agents consist of concentration-response curves for AVP in the absence and presence of at least five concentrations of test agent. Ki values, which reflect the antagonistic activities against AVP m the production of signaling molecule IP3, are calculated with pπsm software based on Cheng and Prusoff equation.

METHOD EXAMPLE 3. Inhibition of platelet aggregation. Vasopressin V₂ receptors are also known to mediate platelet aggregation. Vasopressin receptor agonists cause platelet aggregation, while vasopressin V₂ receptor antagonists inhibit the platelet aggregation precipitated by vasopressin or vasopressin agonists. The degree of antagonist activity of the compounds descπbed herein may be determined by using conventional methods, including the assay descπbed m the following paragraphs.

Blood from healthy, human volunteers was collected by venipuncture and mixed with heparin (60 mL of blood added to 0.4 mL of heparamzed salme solution (4 mg hepaπn/mL saline)). Platelet-rich plasma (PRP) was prepared by centπfugmg whole blood (150 x g), and mdomethacm (3 μM) was added to PRP to block the thromboxane-mediated release reaction. PRP was continuously stirred at 37 ⁰C and change in optical density was followed after the addition of argmine vasopressin (AVP) (30 nM) to initiate aggregation. Compounds were dissolved in 50% dimethylsulfoxide (DMSO) and added (10 μL/415 μL PRP) before the addition of AVP. The percent inhibition of AVP-mduced aggregation was measured and an IC₅₀ calculated.

In studies using washed platelets, 50 mL of whole blood was mixed with 10 mL of citrate/heparm solution (85 mM sodium citrate, 64 mM citric acid, 111 mM glucose, 5 units/mL heparin) and PRP isolated as descπbed above. PRP was then centrifuged (150 x g) and the pellet resuspended m a physiologic buffer solution (10 mM HEPES, 135 mM sodium chloπde, 5 mM potassium chloπde, and 1 mM magnesium chloπde) containing 10 μM mdomethicm. Human fibπnogen (0.2 mg/mL) and calcium chloπde (1 mM) were added to stirred platelets before initiating aggregation with AVP (30 nM) as previously descπbed.

METHOD EXAMPLE 4. Human oxytocin binding and functional assay. Oxytocin is known for its hormonal role in partuπtion and lactation. Oxytocin agonists are useful clinically to induce lactation; induce or augment labor; control postpartum uteπne atony and hemmorhage; cause utenne contraction after cesarean section or duπng other uterine surgery; and to induce therapeutic abortion. Oxytocin, acting as a neurotransmitter in the central nervous system, also plays an important role m the expression of central functions such as maternal behavior, sexual behavior (including penile erection, lordosis and copulatory behavior), yawning, tolerance and dependance mechanisms, feeding, grooming, cardiovascular regulation and thermoregulation (Argiolas and Gessa, Neurosci Biobehav Rev., 15:217-231 (1991)). Oxytocin antagonists find therapeutic utihty as agents for the delay or prevention of premature labor; or to slow or arrest delivery for brief peπods m order to undertake other therapeutic measures.

Compounds descπbed herein are also believed to be oxytocin agents. Oxytocin preparations and a number of oxytocin agonists are commercially available for therapeutic use. In recent years, oxytocin antagonists with antiuterotonic activity have been developed and evaluated for their potential use in the treatment of preterm labor and dysmenorrhyea (Pavo et al, J. Med Chetn , 37:255-259 (1994); Akerlund et al., Br J Obstet. Gynaecol. , 94:1040-1044 (1987); Akerlund et al., Br. J Obstet. Gynaecol, 86:484-487 (1979)). The oxytocin antagonist atosiban has been studied clinically and resulted in a more significant inhibition of preterm contractions than did placebo (Goodwin et al, Am J. Obstet. Gynecol, 170:474 (1994)).

The human oxytocin receptor has been cloned and expressed (Kimura et al, Nature, 356:526-529 (1992)), it is identified under the accession number X64878. To demonstrate the affinity of the compounds descπbed herein for the human oxytocin receptor, binding studies were performed using a cell line expressing the human oxytocin receptor in 293 cells (henceforth referred to as the OTR cell line) substantially by the procedure descπbed by Morel et al. {Nature, 356:523- 526 (1992)). The 293 cell lme is a permanent line of primary human embryonal kidney cells transformed by sheared human adenovirus type 5 DNA. It is identified as ATCC CRL-1533.

The OTR cell line was grown in DMEM (Delbecco's Modified Essential Medium, Sigma, St. Louis, MO, USA) with 10% fetal bovine serum, 2 mM L-glutamme, 200 μg hygromycm (Sigma, St. Louis, MO, USA) and 250 μg/ml G418 (Gibco, Grand Island, NY, USA). To prepare membranes, OTR cells were grown to confluency in 20 roller bottles. Cells were dissociated with enzyme-free cell dissociation medium (Specialty Media, Lavallette, NJ, USA) and centnfuged at 3200 rpm for 15 minutes. The pellet was resuspended in 40 mL of Tπs-HCl (tπs[hydroxymethyl]ammomethane hydrochloπde) buffer (50 mM, pH 7.4) and homogenized for 1 mmute with a Tekmar Tissumizer (Cmcinnatti, OH USA). The suspension was centnfuged at 40,000 x g for 10 minutes. The pellet was resuspended and centnfuged as above. The final pellet was suspended in 80 mL of Tns 7.4 buffer and stored in 4 mL ahquots at -80 ⁰C. For assay, ahquots were resuspended in assay buffer and diluted to 375 μg protein per mL. Protein concentration was determined by BCA assay (Pierce, Rockford, IL, USA).

Assay buffer was 50 mM Tns-HCl (tns[hydroxymethyl]ammomethane hydrochlonde), 5 mM MgCb, and 0.1% bovine serum albumin at pH 7.4. The radioligand for binding assays was [³H]oxytocm ([tyrosyl-2,6-³H]oxytocm, 48.5 Ci/mmol, DuPont NEN, Boston, MA, USA). The order of additions was 195 μL assay buffer, 200 μL OTR membranes (75 μg protein) in assay buffer, 5 μL of test agent m dimethylsulfoxide (DMSO) or DMSO alone, and 100 μL [ H]oxytocm in assay buffer (final concentration 1.0 nM). Incubations were for one hour at room temperature. Bound radioligand was separated from free by filtration on a Brandel cell harvester (Gaithersburg, MD, USA) through Whatman GF/B glass-fiber filters that had been soaked for 2 hours in 0.3% polyethylenimine. The filters were washed with ice-cold 50 mM Tris-HCl (pH 7.7 at 25 ⁰C) and the filter circles were placed in scintillation vials, to which were then added 5 mL Ready Protein Plus™ scintillation fluid, and counted in a liquid scintillation counter. All incubations were in triplicate, and dose -inhibition curves consisted of total binding, nonspecific binding (100 μM oxytocin, Sigma, St. Louis, MO, USA), and 6 or 7 concentrations of test agent encompassing the IC50. Total binding was typically about 1,000 cpm and nonspecific binding about 200 cpm. IC50 values were calculated by nonlinear least -squares curve-fitting to a 4-parameter logistic model. Certain compounds of formula I have shown affinity for the oxytocin receptor.

Several bioassays are available to determine the agonist or antagonist character of compounds exhibiting affinity at the oxytocin receptor. One such assay is described in U.S. Patent No. 5,373,089, hereby incorporated by reference. Said bioassay is derived from procedures described in a paper by Sawyer et al. {Endocrinology, 106:81 (1980)), which in turn was based on a report of Holton {Brit. J. Pharmacol, 3:328 (1948)). The assay calculations for pA₂ estimates are described by Schild {Brit. J. Pharmacol, 2:189 (1947)).

METHOD EXAMPLE 5. Assay for oxytocin functional activity.

1. Animals: a 1.5 cm piece of uterus from a virgin rat (Holtzman) in natural estrus is used for the assay. 2. Buffer/ Assay Bath: The buffer used is Munsicks. This buffer contains 0.5 mM

Mg²⁺. The buffer is gassed continuously with 95% oxygen/5% carbon dioxide giving a pH of 7.4. The temperature of the assay bath is 37 ⁰C. A lO mL assay bath is used that contains a water jacket for maintaining the temperature and inlet and outlet spikets for adding and removing buffer.

3. Polygraph/transducer: The piece of uterine tissue used for the assay is anchored at one end and connected to a Statham Strain Gauge Force Transducer at the other end which in turn is attached to a Grass Polygraph Model 79 for monitoring the contractions.

4. Assay Protocol:

(a) The tissue is equilibrated in the assay bath for one hour with washing with new buffer every 15 minutes. One gram of tension is kept on the tissue at all times. (b) The tissue is stimulated initially with oxytocin at 10 nM to acclimate the tissue and with 4 mM potassium chloride (KCl) to determine the maximum contractile response.

(c) A cumulative dose response curve is then done with oxytocin and a concentration of oxytocin equivalent to approximately 80% of the maximum is used for estimating the pA₂ of the antagonist. (d) The tissue is exposed to oxytocin (Calbiochemical, San Diego, CA) for one minute and washed out. There is a three minute interval before addition of the next dose of agonist or antagonist. When the antagonist is tested, it is given five minutes before the agonist. The agonist is given for one minute. All responses are integrated using a 7P10 Grass Integrator. A single concentration of oxytocin, equal to 80% of the maximum response, is used to test the antagonist. Three different concentrations of antagonists are used, two that will reduce the response to the agonist by less than 50% and one that will reduce the response greater than 50% (ideally this relation would be 25%, 50% and 75%). This is repeated three times for each dose of antagonist for a three point assay.

(e) Calculations for pA2-The dose-response (DR) ratios are calculated for antagonist and a Schild's Plot is performed by plotting the Log (DR-I) vs. Log of antagonist concentration. The line plotted is calculated by least-squares regression analysis. The pA₂ is the concentration of antagonist at the point where the regression line crosses the 0 point of the Log (DR-I) ordinate. The pA₂ is the negative Log of the concentration of antagonist that will reduce the response to the agonist by one-half.

METHOD EXAMPLE 6. Tachykinin receptor binding assay. Compounds described herein are believed to be tachykinin agents. Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin 1, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See, J.E. Maggio, Peptides, 6 (Supplement 3): 237-243 (1985) for a review of these discoveries.

Tachykinin receptor antagonists are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin. These clinical conditions may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, ATDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculoskeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress -related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, emesis, and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; artherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fasciohasis; irritative symptoms of benign prostatic hypertrophy; disorders of blood flow caused by vasodilation and vasospastic diseases such as angma, migraine, and Raynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain m migraine.

Tachykinins are widely distributed in both the central and peripheral nervous systems. When released from nerves, they exert a variety of biological actions, which, m most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues. The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK- 1 , NK-2, and NK-3, respectively. These receptors are present in a variety of organs.

Substance P is believed inter aha to be involved m the neurotransmission of pain sensations, including the pam associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.

In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide deπvatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability. Recent publications have descπbed novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in European Patent Publication 591,040 Al, published Apnl 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation

Treaty publication WO 94/04494, published March 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993, Patent Cooperation Treaty publication WO 94/26735, published November 24, 1994. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g., J. Jukic et al , Life Sciences, 49:1463-1469 (1991); N. Kucharczyk et al, Journal of Medicinal Chemistry, 36: 1654-1661 (1993); N. Rouissi et al, Biochemical and Biophysical Research Communications, 176:894-901 (1991). METHOD EXAMPLE 7. NK-I Receptor Binding Assay. NK-I antagonists are useful in the treatment of pain, especially chronic pain, such as neuropathic pain, post -operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.

In addition to pain, NK-I antagonists are especially useful in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; artherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, emesis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.

Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan et al, Journal of Immunology, 133:3260-3265 (1984). In this assay an aliquot of M9 cells (1 x 10⁶ cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM ¹²⁵I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4⁰C.

The IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g., Annals of the New York Academy of Science, 190:221-234 (1972); Nature

(London), 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 μg/mL gentamicin sulfate and 10% fetal calf serum.

The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.

METHOD EXAMPLE 8. NK-2 Receptor Binding Assay. NK-2 antagonists are useful in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain. The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm flasks or roller bottles m minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK -2 receptor is given m N.P. Gerard et al , Journal of Biological Chemistry, 265:20455-20462 (1990).

For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by addition of 10 ml of enzyme-free cell dissociation solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centπfuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogemzation of the cell pellets m 300 mL 50 mM Tπs buffer, pH 7.4 with a TEKMAR^® homogenizer for 10- 15 seconds, followed by centπfugation at 12,000 RPM (20,000 x g) for 30 minutes using a BECKMAN JA- 14^® rotor. The pellets were washed once using the above procedure, and the final pellets were resuspended in 100-120 mL 50 mM Tns buffer, pH 7.4, and 4 ml ahquots stored frozen at -70 ⁰C. The protein concentration of this preparation was 2 mg/mL. For the receptor binding assay, one 4-mL aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 mL of assay buffer containing 50 mM Tπs, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg/mL chymostatm. A 200 μL volume of the homogenate (40 μg protein) was used per sample. The radioactive ligand was [¹²⁵I]iodohistidyl-neurokmm A (New England Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared m assay buffer at 20 nCi per 100 μL; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 μM eledoisin. Ten concentrations of eledoism from 0.1 to 1000 nM were used for a standard concentration -response curve.

All samples and standards were added to the incubation in 10 μL dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μL DMSO for IC50 determinations. The order of additions for incubation was 190 or 195 μL assay buffer, 200 μL homogenate, 10 or 5 μL sample in DMSO, 100 μL radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours m 50 mM Tπs buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 mL of cold 50 mM Tns buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter. METHOD EXAMPLE 9. Treatment of Emesis. In addition to the above indications the compounds descπbed herein maybe useful in the treatment of emesis, including acute, delayed, or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and vaπations m mtercramal pressure. In particular, the compounds of the formulae descnbed herein may be of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates, and other compounds with an alkylating action, such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites, for example, folic acid, purine, or pyrimidine antagonists; mitotic inhibitors, for example vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for instance, by DJ.

Stewart in NAUSEA AND VOMITING : RECENT RESEARCH AND CLINICAL ADVANCES, (J. Kucharczyk et al. , eds., 1991), at pages 177-203. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil. RJ. Gralla et al, Cancer Treatment Reports, 68: 163-172 (1984).

The compounds of the formulae described herein may also be of use in the treatment of emesis induced by radiation, including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operaive nausea and vomiting.

While it is possible to administer a compound employed in the methods described herein directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods described herein are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980). In making the pharmaceutical compositions used in the methods described herein, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystallme cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions descπbed herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known m the art.

The compositions are preferably formulated m a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active mateπal calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compounds are generally effective over a wide dosage range. For example, dosages per day normally fall withm the range from about 0.01 to about 30 mg/kg of body weight. In illustrative vaπations, dosages per day may fall m the range from about 0.02 to about 10 mg/kg of body weight, in the range from about 0.02 to about 1 mg/kg of body weight, or in the range from about 0.02 to about 0.1 mg/kg of body weight. Such dosage ranges are applicable for the treatmen of any patient or mammal. In addition, for the treatment of adult humans, illustrative doses fall in the range from about 0.02 to about 15 mg/kg of body weight, or in the range from about 0.1 to about 10 mg/kg/day, in single or divided dose. However, it is to be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the seventy of the patient's symptoms, and therefore the above dosage ranges are intended to be illustrative are not intended to and should not be interpreted to limit the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect. It is appreciated that such larger doses may be first divided into several smaller doses for administration throughout the day.

The type of formulation employed for the administration of the compounds employed m the methods descnbed herein may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.

FORMULATION EXAMPLE 1. Hard gelatin capsules containing the following ingredients are prepared:

The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. FORMULATION EXAMPLE 2. A tablet formula is prepared using the ingredients below:

The components are blended and compressed to form tablets, each weighing 240 mg.

FORMULATION EXAMPLE 3. A dry powder inhaler formulation is prepared containing the following components:

The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

FORMULATION EXAMPLE 4. Tablets, each containing 30 mg of active ingredient, are prepared as follows:

The active ingredient, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dπed at 50-60 ⁰C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.

FORMULATION EXAMPLE 5. Capsules, each containing 40 mg of medicament are made as follows:

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules m 150 mg quantities.

FORMULATION EXAMPLE 6. Suppositoπes, each containing 25 mg of active ingredient are made as follows:

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended m the saturated fatty acid glyceπdes previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7. Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:

The medicament, sucrose, and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. FORMULATION EXAMPLE 8. Capsules, each containing 15 mg of medicament, are made as follows:

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.

FORMULATION EXAMPLE 9. An intravenous formulation may be prepared as follows:

FORMULATION EXAMPLE 10. A topical formulation may be prepared as follows:

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.

FORMULATION EXAMPLE 11. Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:

The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 ⁰C. When the polymers have gone into solution, the resulting solution is cooled to about 50-55 ⁰C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-contaming diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.

FORMULATION EXAMPLE 12. In the methods described herein, another illustrative formulation employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds descπbed herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent No. 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

FORMULATION EXAMPLE 13. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-bram barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is descπbed in U.S. Patent No. 5,011,472, which is herein incorporated by reference. FORMULATION EXAMPLE 14. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into hpid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-bram barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by mtra-artenal infusion of hypertonic solutions that can transiently open the blood-bram barrier.

The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 ⁰C. When the polymers have gone into solution, the resulting solution is cooled to about 50-55 ⁰C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert mateπal to produce a drug-contaming diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropπate size.

Another illustrative formulation for the compounds descπbed herein includes transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent No. 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Another illustrative formulation for the compounds described herein includes direct or indirect introduction to the brain. Direct techniques may include placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One illustrative implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, which is herein incorporated by reference.

Indirect techniques may include formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation may be achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intraarterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.

While the invention has been illustrated and described in detail in the foregoing description, such an illustration and description is to be considered as illustrative and exemplary and not restrictive in character, it being understood that only the illustrative embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a disease state responsive to antagonism of a vasopressin V₂ receptor, the method comprising the step of administering an effective amount a compound to a patient in need of relief from the disorder, where the compound is of the formula

and pharmaceutically acceptable salts thereof, wherein

A is a carboxylic acid, an ester, or an amide;

R is hydrogen or Ci -CO alkyl;

R² is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting Of-CO₂R and -CONR R , where R and R are each independently selected from hydrogen and alkyl; R³ is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R³ is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and

R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.

2. The method of claim 1 wherein the compound is of the formula:

and pharmaceutically acceptable salts thereof, wherein

A and A' are each independently selected from -CO₂H, or an ester or amide derivative thereof; n is an integer selected from 0 to about 3; R¹ is hydrogen or C₁-C₆ alkyl;

R is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting Of -CO₂R⁸ and -CONR⁸R⁸, where R⁸ and R^g are each independently selected from hydrogen and alkyl; R³ is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R³ is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and

3. The method of claim 1 wherein the compound is of the formula:

and pharmaceutically acceptable salts thereof, wherein A is -CO₂H, or an ester or amide derivative thereof;

Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof; n is an integer from 1 to 3;

R¹ is hydrogen or C₁-C₆ alkyl;

R² is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent o S R' 8 5? selected from the group consisting of -CO2R and -CONR R , where R and R are each independently selected from hydrogen and alkyl;

R³ is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;

R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl; and

R^5" is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.

4. The method of any one of claims 1 to 3 wherein R¹ is hydrogen or methyl.

5. The method of any one of claims 1 to 3 wherein R¹ is hydrogen.

6. The method of any one of claims 1 to 3 wherein R² is hydrogen or methyl.

7. The method of any one of claims 1 to 3 wherein R² is hydrogen.

8. The method of any one of claims 1 to 3 wherein R is selected from the group consisting of:

wherein R¹⁰ and R¹¹ are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R¹² is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.

9. The method of claim 8 wherein R³ is selected from the group consisting of:

10. The method of claim 8 wherein R³ is selected from the group consisting of:

11. The method of claim 8 wherein R³ is:

12. The method of claim 8 wherein R is optionally substituted aryl, and R is hydrogen:

13. The method of any one of claims 1 to 3 wherein R⁴ is selected from the group consisting of:

wherein Y an electron withdrawing group, and R is hydrogen, halo, alkyl, or alkoxy.

14. The method of claim 13 wherein Y is halo.

15. The method of claim 13 wherein R is hydrogen or methoxy.

16. The method of any one of claims 1 to 3 wherein A is -CO₂R⁵; where R⁵ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C₄ alkyl), and R⁶R⁷N-(C₂-C₄ alkyl); where R⁶ and R⁷ are each independently selected in each instance, where R⁶ is selected from the group consisting of hydrogen or alkyl; and R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocycle.

17. The method of claim 16 wherein the optionally substituted heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is also optionally N-substituted with R¹³; where R¹³ is independently selected in each instance from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.

18. The method of any one of claims 1 to 3 wherein A is monosubstituted amido, disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido.

19. The method of claim 18 wherein heterocyclyl is selected from the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with Ci-C₄ alkyl or optionally substituted aryl(Ci-C₄ alkyl).

20. The method of any one of claims 1 to 3 wherein A is C(O)NR¹⁴X-, where R¹⁴ is hydrogen, hydroxy, alkyl, alkoxycarbonyl, or benzyl; and X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(Ci-C₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl).

21. The method of any one of claims 1 to 3 wherein A is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen.

22. The method of claim 21 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3- oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.

23. The method of claim 21 wherein the nitrogen-containing heterocycle is substituted with R¹⁰, R¹², R⁶R⁷N-, or R⁶R⁷N-(C₁-C₄ alkyl).

24. The method of claim 21 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin- 1 - ylmethyl)pyrrolidin-l-yl, or l,2,3_>4-tetrahydroisoquinolin-2-yl.

25. The method of claim 2 wherein A' is C(O)NR¹⁴X-, where R¹⁴ is hydrogen, hydroxy, alkyl, alkoxycarbonyl, or benzyl; and X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C_rC₄ alkyl), R⁶R⁷N-, and R⁶R⁷N-(C₂-C₄ alkyl).

26. The method of claim 2 wherein A' is an optionally substituted nitrogen- containing heterocycle attached at a nitrogen.

27. The method of claim 26 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3- oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.

28. The method of claim 26 wherein the nitrogen-containing heterocycle is substituted with R¹⁰, R¹², R⁶R⁷N-, or R⁶R⁷N-(C]-C₄ alkyl).

29. The method of claim 26 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l- ylmethyl)pyrrolidin-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl.

30. The method of claim 3 wherein R^5" is optionally substituted arylalkyl.

31. The method of claim 2 wherein n is 0.

32. The method of claim 2 wherein n is 1 or 2.

33. The method of claim 3 wherein n is 1.

34. The method of any one of claims 1 to 33 wherein the disease state is a cardiovascular disorder.

35. The method of claim 34 wherein the disorder is congestive heart failure.