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1. WO2006102308 - BETA-LACTAMYL VASOPRESSIN V1B ANTAGONISTS

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BETA-LACTAMYL VASOPRESSIN Vib ANTAGONISTS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. § 119(e) of U.S.
provisional patent application Serial No. 60/664,239, filed March 22, 2005, and U.S.
provisional patent application Serial No. 60/700,673, filed July 19, 2005, the disclosure of each of which are incorporated herein by reference.
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 Vib receptor. In particular, this invention pertains to the use of /3~lactamyl vasopressin antagonists for treating premenstrual disorders.
BACKGROUND
Depression is considered one of the most common serious CNS disorders. Among the potential targets is the hypothalamic-pituitary-adrenal-axis (HPA) axis, which is perturbed in many depressed patients and in stress-related affective disorders, as described by Scott and Dinan, 1998 and Serradiel-Le Gal et al., Progress in Brain Research 139:197-210 (2002), the disclosure of which are incorporated herein by reference. Normalization of HPA axis function appears to be a prerequisite for sustained remission of depressive symptoms when medication is used (Steckler, et al., 1999).
One of the signs of major depression is elevated levels of Cortisol and ACTH associated with dysregulation of the HPA (Owens and Nemeroff, 1993; Plotsky et al. 1998). Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the two main ACTH secretagogues, and recent preclinical and clinical studies have shown that AVP is important in mediating ACTH release during chronic psychological stress (Scott and Dinan, 1997, 1998). 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. The Cortisol response to psychological stress appears under the regulation of AVP but not CRH in anxious healthy human volunteers (Boudarene et al., 1999). Chronic psychological stress accompanied by dysregulation of the HPA axis may contribute to the etiology of affective disorders. It has been found that many patients with major depression show elevated levels of AVP that decline as the mental illness improves (van Londen et al., 1997 & 2000).
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 Vla, Vit>, and V2 have been identified.
AVP is transported to the anterior pituitary where it can stimulate ACTH release by interacting with a Vlb receptor on the cell membranes of corticotrophs. For example, rats selectively bred for high anxiety-related behavior show dysregulation in this hypothalamic-pituitary-adrenal (HPA) axis. Treatment with a Vib receptor antagonist can abolish CRH-stimulated ACTH secretion, demonstrating a shift in ACTH regulation from CRH to AVP (Keck et al., 1999). Antagonism of the Vlb receptor, which blocks the vasopressin receptor subtype that mediates elevated pituitary ACTH secretion under chronic stress, may have significant clinical potential as a treatment for certain types of depression and stress-related affective disorders. The presence of Vlb receptors in several regions of the rat CNS and mouse CNS has also been demonstrated. It is therefore believed that Vlb antagonists that penetrate the CNS may have greater therapeutic potential for stress-related affective disorders. Currently there are no vasopressin antagonists that are able to cross the blood brain barrier (Serradeil-Le Gal et al. 2002). There is also preclincial and clinical evidence that vasopressin, acting through a Vlb receptor, contributes to a subtype of major depression associated with chronic stress and dysregulation of the HPA axis (Boudarene et al., 1999; Griebel et al., 2002; Scott and Dinan, 1997, 1998).
Structural modification of vasopressin has provided a number of vasopressin agonists {see, Sawyer, Pharmacol. Reviews, 13:255 (1961)). In addition, several potent and selective vasopressin peptide antagonists have been disclosed {see, 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)). Further, novel structural classes of non-peptidyl vasopressin antagonists have been disclosed {see, Yamamura et al, Science, 275:572-574 (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)). Finally, the general structural class of substituted 2-(azetidin-2-on-l- yl)acetic acid esters and amides are known as synthetic intermediates for the preparation of β-lactam antibiotics {see, U.S. Patent No. 4,751,299).
SUMMARY OF THE INVENTION
It has been found that certain compounds within the general class of substituted 2-(azetidin-2-on-l-yl)alkanoic acids and derivatives thereof elicit activity at the vasopressin Vib 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 and 2-(azetidin-2-on-l-yl)thiolalkylalkanoic acids, hydroxy, thiol, disulfide, and oxidized thiol and disulfide derivatives thereof, and carboxylic acid derivatives thereof, including but not limited to esters and amides. 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 processes for preparing the alkanedioic acid, alkylalkanoic acid, hydroxyalkyl substituted alkanoic acid, and/or thiolalkyl substituted alkanoic acid
compounds, and various analogs and derivatives thereof.
Also described herein are pharmaceutical compositions that include therapeutically effective amounts of the alkanedioic acid, hydroxyalkyl substituted alkanoic acid, and/or thiolalkyl substituted alkanoic acid compounds described herein. Also described herein are methods useful for treating diseases and disease states and/or symptoms that are associated with vasopressin dysfunction, and responsive to antagonism of the vasopressin Vib receptor in a mammal using the compounds or compositions described herein. In one illustrative embodiment, the disease is selected from depression, anxiety, and stress.
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 optionally substituted alkyl; or B is a carboxylic acid, or an ester or amide derivative thereof; or B is an alcohol or thiol, or a derivative thereof;

- A -

R1 is hydrogen or C1-Ce 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 R8R8N-(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

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



and pharmaceutically acceptable salts thereof, are administered to the patient; 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 Ci-C6 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

R and R are taken together with the attached nitrogen atom to form an heterocycle; and where R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8N-(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 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 another illustrative embodiment of the methods described herein, one or more compounds of formula (II) :



and pharmaceutically acceptable salts thereof, are administered to the patient; 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, 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.
BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the human Vib binding affinity (Ki = 32 nM) of Example 215 through a competitive binding assay conducted in CHO cells transfected with human Vib receptor.
FIG. 2 shows the antagonist activity of Example 215 against AVP as evaluated in CHO cells expressing rat Vib receptor. Example 215 inhibited Vib mediated phosphatidyl inositol turnover with a Ki value at 59 nM.
FIG. 3 shows the activity of Example 215 against vehicle control in a seed finding assay of hamsters as a model of anxiety.

FIG. 4 shows the activity of Example 215 against vehicle control in a biomchemical marker assay measuring plasma testosterone as a model of stress in hamsters, where low testosterone in the control group indicates stress.
FIG. 5 shows the activity of Example 215 against vehicle control in a biomchemical marker assay measuring plasma Cortisol as a model of stress in hamsters, where high Cortisol in the control group indicates stress.
DETAILED DESCRIPTION
In another embodiment of the compounds of formulae (T) and (II), R1 is hydrogen or methyl. In one variation, R1 is hydrogen. In another embodiment of the compounds of formulae (I) and (TT), R2 is hydrogen or methyl. In one variation, R2 is hydrogen. In another embodiment of the compounds of formulae (T) and (II), both R1 and R2 are hydrogen.
In another embodiment of the compounds of formulae (T) and (II), R3 is selected from




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 arylallcylcarbonyloxy, 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.
In another embodiment of the compounds of formulae (T) and (II), R3 is selected from Riov

J )-R11



wherein R10, R11, and R12 are as defined herein.
In another embodiment of the compounds of formulae (T) and (II), R3 is selected from



wherein R10, R11, and R12 are as defined herein.
In another embodiment of the compounds of formulae (I) and (II), R3 is selected from



wherein R10 and R11 are as defined herein.
In another embodiment of the compounds of formulae (I) and (II), R4 is optionally substituted arylalkyl or optionally substituted arylalkenyl. In one variation, R4 is arylalkyl or arylalkenyl. In another variation, R4 is arylalkenyl.
In another embodiment of the compounds of formula (I), the stereochemistry at C(O!) is (S).
In another embodiment of the compounds of foπnula (H), the stereochemistry at C(α) is (R).
In another embodiment of the compounds of formula (I), n is 1 or 2. In one variation, n is 2.

In another embodiment of the compounds of foπnula (H), n is 1 or 2. In one variation, n is 1.
In another embodiment of the compounds of formula (T), A is an amide of a primary amine. In one variation, the primary amine is an optionally substituted
arylalkylamine, including linear and branched alkyl. Illustratively, the primary amine is arylmethyl, 1-arylalkyl, 2-arylalkyl, and the like, each of which is optionally substituted. In another variation, the primary amine is an optionally substituted arylcycloalkylamine, such as 1-aryl and 2-arylcycloalkylamines. Illustratively, the primary amine is 1-arylcyclopropylamine, 1 -arylcyclopentylamine, 2-arylcyclopentylamine,
1-arylcyclohexylamine, 2-arylcyclohexylamine, and the like, each of which is optionally substituted, hi another variation, the primary amine is an partially hydrogenated bicyclic aromatic amine, such as indanylamine, tetrahydronaphthylamine, tetrahydroquinoline, tetrahydroisoquinoline, and the like, each of which is optionally substituted. It is understood that in each embodiment, aryl includes phenyl as well as heteroaryl, such as furyl, thienyl, pyridyl, and the like, each of which is optionally substituted. It is further understood that in each embodiment aryl, or heteroaryl is to the methyl, alkyl, or cycloalkyl at any aryl carbon atom, such as fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like.
In another embodiment of the compounds of formula (I), A' is an amide of an optionally substituted heterocycle, such as morpholine, pyrrolidine, piperidine, piperazine, homopiperazine, quinuclidine, and the like. In one variation, the heterocyclyl is substituted with alkyl, another heterocyclyl, heterocyclylalkyl, or optionally substituted arylalkyl. hi another variation, the heterocycle is substituted with heterocyclylalkyl. In one variation, the heterocycle is pyrrolidine, piperidine, or piperazine, each of which is optionally substituted.
Illustratively, A' is an amide of 2-substituted pyrrolidine, 3-substituted pyrrolidine, 4-substituted piperazine, 4-substituted piperidine, or 4-substituted
homopiperazine. Substituents include alkyl, such as methyl, ethyl, and the like; cycloaklyl, such as cyclopentyl, cyclohexyl, and the like; heterocyclyl, such as pyrrolidinyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidinyl, piperdin-4-yl, piperazinyl, and the like, hi the case of pyrrolidin-2-yl, pyrrolidin-3-yl, piperdin-4-yl, and piperazinyl, the free nitrogen is optionally N-alkylated or N-benzylated.
In another embodiment of the compounds of foπnula (T), A' is an amide of a primary alkyl or heterocyclylamine, each of which is optionally substituted. In one variation, the primary amine is a substituted methyl or ethyl amine, such as 2-heterocyclylmethylamine, where the heterocyclyl group is pyrrolidinyl, pyrrolidin-2-yl, piperidinyl, or piperdin-4-yl, each of which is optionally substituted with alkyl. In another variation, the primary amine is a pyrrolidinyl, piperidinyl, or piperazinylamine, substituted with alkyl, heterocyclyl, heterocyclylalkyl, or optionally substituted arylalkyl. Illustratively, A' is an amide of optionally substituted arylakylpiρeridin-4-ylamine, such as benzylpiperidin-4-ylamine.
In another embodiment of the compounds of formula (IT), A is an amide of an optionally substituted heterocycle, such as morpholine, pyrrolidine, piperidine, piperazine, homopiperazine, quinuclidine, and the like. In one variation, the heterocyclyl is substituted with another heterocyclyl, or heterocyclylalkyl. In another variation, the heterocycle is substituted with heterocyclylalkyl. In another variation, the heterocycle is piperidine, optionally 4-substituted with heterocyclylalkyl, such as 2-piperindinylethyl.
In another embodiment of the compounds of formula (II), Q is oxygen or sulfur. In another embodiment, Q is oxygen.
In another embodiment of the compounds of formula (II), R is optionally substituted arylalkyl, including optionally substituted aryl(C2-C4 alkyl).
In another embodiment of the invention, in compounds of formulae (I) or (II), 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). hi another embodiment of the compounds of formulae (I) or (II), A is monosubstituted amido, disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido.
It is to be understood that in each occurrence of the various embodiments described herein, heterocyclyl is independently selected in each instance. In one illustrative aspect, heterocyclyl is 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 Ci-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl).
It is also to be understood that in each occurrence of the various embodiments described herein, R6 and R7 are each independently selected in each instance. In another illustrative aspect, R6 is independently selected from hydrogen or alkyl; and R7 is
independently selected in each instance from alkyl, cycloalkyl, optionally substituted aryl, 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, moφholinyl, 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.
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 A1 is an ester, and the other is an amide, hi another embodiment, compounds of formula (T) are described that are diamides, where each of A and A' 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-(Ci-C4 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 A' 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-(C1-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(C1-C4 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 A' 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-(C1-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(CrC4 alkyl), and piperidin- ^yI(C1-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-(C1-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(d-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(d-C4 alkyl), and attached at a nitrogen.
In another embodiment of the compounds of formula (T), 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(Ci-C4 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 C1-C4 alkyl or optionally substituted aryl(CrC4 alkyl). In one variation, R5' is optionally substituted heterocyclylalkyl or optionally substituted aminoalkyl, including R6R7N-(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-(Ci-C4 alkyl), as defined herein, hi one embodiment, A is 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 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), R6R7N-, R6R7N-alkyl, including R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(Ci-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), R6R7N-, R6R7N-alkyl, including R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aiyl(Ci-C4 alkyl), and piperidin-l-yl(Ci-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, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R6R7N-, R6R7N-alkyl, including R6R7N-(Cj-C4 alkyl),
diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(Ci-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(Ci-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.
Li another embodiment, A in formula (I) or (H) is an amide of an optionally substituted benzyl, optionally substituted 1 -naphthylmethyl, or optionally substituted 2-naphthylmethyl amine. Optional substitutions include, but are not limited to, 2,3-dichloro, 2,5-dichloro, 2,5-dimethoxy, 2-trifluoromethyl, 2-fluoro-3-trifluoromethyl, 2-fluoro-5-trifluoromethyl, 2-methyl, 2-methoxy, 3,4-dichloro, 3,5-ditrifiuoromethyl, 3,5-dichloro, 3,5-dimethyl, 3,5-difluoro, 3,5-dimethoxy, 3-bromo, 3-trifluoromethyl, 3-chloro-4-fluoro, 3-chloro, 3-fluoro-5-trifluoromethyl, 3-fluoro, 3-methyl, 3-nitro, 3-trifluoromethoxy, 3-methoxy, 3 -phenyl, 4-trifluoromethyl, 4-chloro-3-trifluoromethyl, 4-fluoro-3-trifluoromethyl, 4-methyl, and the like.
In another embodiment, A in formula (I) or (H) is an amide of an optionally substituted benzyl-N-methylamine. In another embodiment, A in formula (I) or (IT) is an amide of an optionally substituted benzyl-N-butylamine, including n-butyl, and t-butyl. In another embodiment, A in formula (I) or (II) 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-trifluoromethyl, 3-chloro, 3-methyl, and the like.
In another embodiment, A in formula (I) or (H) is an amide of an optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, or 1-phenylbenzylamine. In another embodiment, A in formula (I) or (H) is an amide of an optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, 1-phenylbenzylamine-N-methylamine. In another embodiment, A in formula (I) or (II) is an amide of an optionally substituted 2- phenyl-/3-alanine, or derivative thereof, 1 -phenylpropanolamine, and the like. Optional substitutions include, but are not limited to, 3-trifluoromethoxy, 3-methoxy, 3,5-dimethoxy, 2-methyl, and the like.
In another embodiment, A in formula (I) or (II) is an amide of an optionally substituted 1-phenylcyclopropyl, 1-phenylcyclopentyl, or 1-phenylcyclohexylamine. Optional substitutions include, but are not limited to, 3-fluoro, 4-methoxy, 4-methyl, 4-chloro, 2-fluoro, and the like.
In another embodiment, A in formula (I) or (E) is an amide of an optionally substituted heteroarylmethylamine, including but not limited to 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 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 formula (I) or (II) is an amide of a partially saturated bicyclic aryl, including but not limited to 1-, 2-, A-, and 5-indanylamine, 1- and 2-tetrahydronaphthylamine, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like, each of which is optionally substituted.
In another embodiment, A in formula (I) or (IQ is an amide of a substituted piperidine or piperazine. Substituents on the piperidine or piperazine 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)-l-(3-methoxyphenyl)ethylamine, (R)-l-(3-trifluoromethylphenyl)ethylamine, (R)-1,2,3,4-tetrahydro-l-naphtylamine, (R)-l-indanylamine, (R)-α,N-dimethylbenzylamine, (R)-α-methylbenzylamine, (S)- 1 -(3 -methoxyphenyl)ethylamine, (S)-I -(3-trifluoromethylphenyl)ethylamine, (S)- 1 ,2,3 ,4-tetrahydro- 1 -naphtylamine, (S)-I-indanylamine, and (S)-O!-methylbenzylamine, and the like.
In another embodiment of the compounds of formula (E), Q is oxygen or sulfur. In another embodiment of the compounds of formula (E), R" is optionally substituted arylalkyl. In another embodiment of the compounds of fonnula (II), A is an amide of a substituted piperidine or piperazine.
In another embodiment of the compounds of formulae (I) or (II), 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.
In another embodiment of the compounds of formulae (I) or (II), R1 is hydrogen. In another embodiment of the compounds of formulae (I) or (II), R1 is methyl. In another embodiment of the compounds of formulae (I) or (IT), R is hydrogen. In another embodiment of the compounds of formulae (I) or (E), R2 is methyl. In another embodiment of the compounds of formulae (I) or (II), both R1 and R2 are hydrogen.
m another embodiment of the compounds of formulae (I) or (E), R4 is of the formulae:



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) and (E) are chiral at the a-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).
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, isoburyl, 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 "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 "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, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, amino, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, Ci-C4 alkylsulfonylamino, and the like. Such optional substitution may be made on alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, 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 term "acyl," refers to alkyl, alkenyl, aryl, and the like attached through a carbonyl group, and include such groups as formyl, acetyl, propanoyl, pivaloyl, pentanoyl, cyclohexanoyl, optionally substituted benzoyl, and the like.
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 full 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 one or more vasopressin receptors. It is appreciated that illustrative methods described herein require therapeutically effective amounts of vasopressin receptor antagonists; therefore, compounds exhibiting partial antagonism at one or more vasopressin receptors may be administered 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 Ci-Cβ 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 Ci-C4 alkoxy, such as methoxy, pent-3-oxy, and the like; an illustrative variation of alkylthio is Ci-C4 alkylthio, such as ethylthio, 3-methylbuty-2-ylthio, and the like; an illustrative variation of alkylcarbonyl is Ci-C3 alkylcarbonyl, such as acetyl, propanoyl, and the like; an illustrative variation of cycloalkyl is C3-C8 cycloalkyl; an illustrative variation of cycloalkenyl is Q-C9 cycloalkenyl, such as limonenyl, pinenyl, and the like; an illustrative variation of optionally substituted arylalkyl is optionally substituted aryl(Ci-C4 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 (Ci-C4 alkoxy)-(Ci-C4 alkyl); an illustrative variation of optionally substituted heteroarylalkyl is optionally substituted heteroaryl(Ci-C4 alkyl); and an illustrative variation of alkoxycarbonyl is Ci -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 R3 is optionally substituted oxazolidinonyl, and R4 is optionally substituted arylalkenyl are contemplated herein. Further, compounds where R3 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 R1 and R2 are hydrogen, and both A and A' are independently selected amides are contemplated herein.
In another illustrative embodiment, compounds of formula IH are described:



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 a an alkylene, arylalkylene, or heteroarylalkylene ketal, each of which may be optionally substituted;
R1 is hydrogen or Ci-C6 alkyl;
R2 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 Ci-C4 alkylthio, halo, haloalkyl, such as trifluoromethyl, trifluorochloroethyl, and the like, cyano, formyl, alkylcarbonyl, including Ci-C3 alkylcarbonyl, alkoxycarbonyl, or a substituent selected from the group consisting Of -CO2R8, -CONR8R8', and -NR8(COR9);
R3 is a structure selected from the group consisting of

R4 is alkyl, including Ci-Ce 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 Ci-C6 alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxyalkyl, including (Ci-C4 alkoxy)-(Ci-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, morpholinyl, 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 Ci-C6 alkyl;
R7 is alkyl, including Ci-Cg 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;
R8 and R8' 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(Ci-C4 alkyl); or R and R are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
R9 is selected from hydrogen, alkyl, including Ci-C6 alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxyalkyl, including (Ci-C4 alkoxy)-(C]-C4 alkyl), optionally substituted aryl, optionally substituted arylalkyl, including aryl(Ci-C4 alkyl), optionally substituted heteroaryl, optionally substituted heteroarylalkyl, including heteroaryl(Ci-C4 alkyl), and R8R8N-(C1-C4 alkyl);
R10 and R11 are each independently selected from hydrogen, optionally substituted alkyl, including Ci-C6 alkyl, optionally substituted cycloalkyl, including C3-C8 cycloalkyl, alkoxyalkyl, including Ci-C4 alkoxycarbonyl, alkylcarbonyloxy, including C1-Cs alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, including aryl(Ci-C4 alkyl), optionally substituted arylalkyloxy, including aryl(Ci-C4 alkyloxy), optionally substituted arylalkylcarbonyloxy, including aryl(Ci-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 C1-C4 alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, including aryl(Ci-C4 alkyl), and optionally substituted aryloyl; and
and pharmaceutically acceptable salts thereof.
hi one aspect of the compounds of formula (ID), 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, 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.
hi another aspect of the compounds of formula (IB), 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 foπn 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 illustrative embodiment, compounds of the following formulae are described:



wherein Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally-substituted furyl, or optionally-substituted thienyl; 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. The following compound



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



wherein Ar is optionally-substituted phenyl, optionally-substituted pyridinyl, optionally-substituted furyl, or optionally-substituted thienyl; R1 and R2 are hydrogen; A is arylalkyloxy, including optionally substituted benzyloxy; A' is alkylcarbonyl, such as acetyl, propanoyl, pivaloyl, and the like. The following compound

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



where R1, R2, R4, A, A', Q, and R5" are as defined herein, and Ar1 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 R1, R2, Q, and R5" are defined herein, Ar1 and Ar2 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, Ar1 and Ar2 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, Ar1 and Ar2 are each an independently selected optionally substituted phenyl. In another illustrative aspect, R1 and R2 are each hydrogen.
In another illustrative embodiment, compounds of the following formulae are described:



where R1, R2, R4, A, A', and n are as defined in formula I, and R10, R1 \ and R12 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.
In another embodiment, compounds of the following formula are described:



where n and A' are as described above; R2 is illustratively hydrogen, Ci-C6 alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifluoromethyl, chlorodifluoromethyl, tetrafiuoroethyl, and the like; Ci-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.
It is understood that the above formula represents 16 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 is described:



where the stereochemistry at the "of' carbon is either (R) or (S). In one aspect, the stereochemistry at the "of 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)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 4-(phenylethyl)piperazin-l-yl, fur-2-ylmethylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3-trifluoromethylphenyl)piperazin-l-yl, 4-(benzyloxycarbonyl)piperazin-l -yl, 4-[2-(2-hydroxyethoxy)ethyl]piperazin- 1 -yl, A-benzylpiperazin-1-yl, 4-(3,4-methylenedioxybenzyl)piperazin-l-yl, 4-phenylpiperazin-l-yl, A-(3-phenylprop-2-enyl)ρiperazin-l-yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, A-(pyrrolidin- 1 -ylcarbonylmethyl)piperazin- 1 -yl, 4-(l -methylpiperidin-4-yl)piperazin- 1 -yl, A-butylpiperazin-l-yl,4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1 -benzylpiperidin-4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4-(cyclohexyl)piperazin-l-yl, 4-(2-cyclohexylethyl)piperazin- 1 -yl, 4- [2-(morpholin-4-yl)ethyl]piperazm- 1 -yl, A-(A-tert-butylbenzyl)piperazin- 1 -yl, 4-[2-(piperidin- 1 -yl)ethyl]piperazin- 1 -yl, 4-[3 -(piperidin- 1 -yl)propyl]piperazin-l-yl, 4-[2-(N,N-dipropylamino)ethyl]piperazin-l-yl, 4-[3-(N,N-diethylamino)propyl]piperazin-l-yl,4-[2-(dimethylamino)ethyl]piperazin-l-yl, 4-[3-(pyrrolidin- 1 -yl)propyl]piperazin- 1 -yl, 4-(cyclohexylmethyl)piperazin- 1 -yl, A-cyclopentylpiperazin-1-yl, 4-[2-(pyrrolidin-l-yl)ethyl]piperazin-l-yl, 4-[2-(thien-2-yl)ethyl]piperazin- 1 -yl, 4-(3 -phenylpropyl)piperazin- 1 -yl, 4-[2-(N,N-diethylamino)ethyl]piperazin-l-yl, 4-benzylhomopiperazin-l-yl, 4- (bisρhenylmethyl)piperazin- 1 -yl, 3-(4-methylpiperazin- 1 -yl)propylamino, (+)-3 (S)- 1 -benzylpyrrolidin-3-ylamino, 2-pyridylmethylamino, and 4-[2-(piperidin-l-yl)ethyl]piperidin-1-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~ 1 -yl, 4-(benzyloxycarbonyl)piperazin- 1 -yl, 4-[2-(2-hydroxylethoxy)ethyl]piperazin- 1 -yl, 4-benzylpiperazin- 1 -yl, 4-(3 ,4-methylenedioxybenzyl)piperazin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-(3 -phenylprop-2-enyl)piperazin- 1 -yl, 4-ethylpiperazin- 1 -yl, 2-(dimethylamino)ethylamino, 4-(pyrrolidin- 1 -ylcarbonylmethyl)piρerazin- 1 -yl, 4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl, 4-butylpiperazin-1-yl, 4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1-benzylpiperidin-4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4-cyclohexylpiperazin-l-yl, 4-(2-cyclohexylethyl)piperazin-l-yl, 4-[2-(morpholin-4-yl)ethyl]piperazin-l-yl, 4-(4-fe7^-butylbenzyl)piperazin-l-yl, 4-[2-(piperidin-l-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- 1 -yl, 4-(2-dimethylaminoethyl)piperazin- 1 -yl, 4- [3 -(pyrrolidin- 1 -yl)propyl]piperazin- 1 -yl, 4-(cyclohexylmethyl)piperazin- 1 -yl, 4-[2-(piperidin- 1 -yl)ethyl]piperidin- 1 -yl, 4-propyl-piperazin-1-yl, 4-[Ν-(isopropyl)acetamid-2-yl]piperazin-l-yl, and 3-benzyl-hexahydro-(lH)-1,3-diazepin-l-yl.
In another embodiment, compounds having the formula are described:



where n is as described above; R2 is illustratively hydrogen, Ci-C6 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-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 "oj" carbon is only (R), while in another aspect, the stereochemistry at the "ά" 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.
In another illustrative embodiment, compounds of the following formula are described:



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




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



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



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



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, Ci-C6 alkyl, such as methyl, ethyl, propyl, and the like; haloalkyl, such as trifiuoromethyl, 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-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 stereoisomers 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, Ci-C6 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-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, Cj-C6 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 -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 "of" 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-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, (2-trifluoromethylbenzyl)amino, (3-methoxybenzyl)amino, (3-fluorobenzyl)amino, (3,5-difiuorobenzyl)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)amino, (a-methylbenzyl)amino, (N-methylbenzyl)amino, (N-fert-butylbenzyl)amino, (N-butylbenzyl)amino, (3,5-dimethylbenzyl)amino, (2-phenylethyl)amino, (3,5-dimethoxybenzyl)amino, (lR)-(3-methoxyphenyl)ethylamino, (lS)-(3-methoxyphenyl)ethylamino, (c^α-dimethylbenzyl)amino, Ν-methyl-Ν-(3 -trifluoromethylbenzyl)amino, [(S)-α-methylbenzyl]amino, (l-phenylcycloprop-lyl)amino, (ρyridin-2-ylmethyl)amino, (pyridin-3-ylmethyl)amino, (pyridin-4-ylmethyl)amino, (fur-2-ylmethyl)amino, [(5-methylfur-2-yl)methyl]amino, (thien-2-ylmethyl)amino, [(S)-l,2,3,4-tetrahydro- 1 -naphth- 1 -yl] amino, [(R)-1 ,2,3 ,4-tetrahydro- 1 -naphth- 1 -yl] amino, (indan- 1 -yl)amino, (l-phenylcyclopent-l-yl)amino, (α,α-dimethyl-3,5-dimethoxybenzyl)amino, (2,5-dimethoxybenzyl)amino, (2-methoxybenzyl)amino, and (α,α,2-trimeth.ylbenzyl)amino.
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,
p_-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, foπnate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-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, naρhthalene-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.
The compounds described herein possess an azetidinone core structure that includes asymmetric carbon atoms at C(3) and C(4), creating four stereoisomeric
configurations, as illustrated by the following formulae:


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 (3iSr,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, hi another variation, some or all other chiral centers in the compound are optically pure.
It is also understood that the α-carbon bearing R3 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 R3 is 4-substituted oxazolidin-2-on-3-yl, the 4-position of the oxazolidinone ring is asymmetric, hi addition, when R3 is 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin-4-on-3-yl, the 2- and 5-carbons of the imidazolidinone rings are each asymmetric. Finally, when R3 is succinimido and one of R10 and R11 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 (aR,3S,4R) and (aS,3S,4R) absolute configurations. In another illustrative embodiment, the compounds described herein have substantially or only the (aR,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 stereoisomers 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 "oT carbon is only (R), while in another aspect, the stereochemistry at the "α" carbon is only (S).
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(Ci-C4 alkyl), and A' is a disubstituted amino having the formula R14XTST-, 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 are useful in methods for antagonism of the vasopressin Vib receptor. Such antagonism is useful in treating a variety of disorders and diseases that have been linked to this receptor in mammals. Illustratively, the mammal to be treated by the administration of compounds described herein is human.
In another embodiment, compounds are also described herein that cross the blood brain barrier. It is appreciated that compounds that cross the blood brain barrier may have wider application in treating various disease states that are responsive to vasopressin antagonism. For example, it is to be understood that there are currently recognized distinct subtypes within depressive illness.
In another embodiment, pharmaceutical compositions containing one or more

(3-lactamyl alkanoic acid vasopressin receptor antagonists are described herein. The pharmaceutical compositions include one or more carriers, diluents, and or excipients.
The compounds described herein may be administered directly or as part of a pharmaceutical composition that includes one or more carriers, diluents, and/or excipients. Such formulations may include one or more than one of the compounds described herein.

Such pharmaceutical compositions may be administered by a wide variety of conventional routes in a wide variety 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 within such a carrier 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, 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, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile 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, microcrystalline 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 in the art. It is appreciated that the carriers, diluents, and excipients used to prepare the compositions described herein are advantageously GRAS (Generally Regarded as Safe) compounds.
Compounds described 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 severity of the patient's symptoms. Therefore the dosage ranges described 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 boundaries 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 boundaries of the ranges described 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 material calculated to produce the desired therapeutic effect over a predetermined time frame, in combination with a pharmaceutically acceptable carrier, and optionally in association with a suitable pharmaceutical diluent and/or excipient.
hi one illustrative embodiment, single or total divided dosages per day fall within the range from about 100 μg/kg to about 500 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 250 μg/kg to about 50 mg/kg of body weight of the patient being treated. It is appreciated that compounds of formula (II) may be advantageously administered at slightly higher overall daily totals, such as in the range from about 500 μg/kg to about 500 mg/kg of body weight, in the range from about 1 mg/kg to about 100 mg/kg of body weight, or in the range from about 1 mg/kg to about 50 mg/kg of body weight. It is further appreciated that compounds of formula (I) may be advantageously administered at slightly lower overall daily totals, such as in the range from about 100 μg/kg to about 100 mg/kg of body weight, in the range from about 250 μg/kg to about 50 mg/kg of body weight, or in the range from about 250 μg/kg to about 25 mg/kg of body weight. It is appreciated that the vitro binding and functional antagonism of activity at Vib vasopressin receptors of the compounds described herein is relative to the efficacious unit dose to be administered.
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 liydroxyl 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


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 using the appropriate alkoxy-substituted amino acid imines.
Those compounds of formulae I, II, and III requiring R3 to be a 4-substituted oxazolidin-2-on-3-yl or 1,4,5-trisubstituted imidazolidin-2-on-3-yl are prepared from the corresponding (4-substituted oxazolidin-2-on-3-yl) or (1,4,5-trisubstituted imidazolidin-2-on-3-yl)acetyl halide or anhydride. The acid halide or anhydride 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 cyclized to the
4-substituted oxazolidin-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 anhydride (i). Illustrative of the oxazolidinones that are included in this synthetic route, and subsequent synthetic routes described herein, include the following commercially available compounds.







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






Those compounds requiring R3 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, (R11)-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 maybe functionalized with an appropriate reagent to introduce R12 and the 3-position deprotected, where R12 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, (Rn)-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, mefhylisocyanate, 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 N5N-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:



where R2 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.
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:



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 iii, 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 /3-hydroxy amides of alkoxy-substituted amino acids.
Synthetic Scheme II



The azetidinone ring may also be prepared with a deficit of substituents R 5 R , R4, or the R1 -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 maybe prepared via N-C(4) cyclization, such as the cyclization of acylhydroxamates iv to azetidinone intermediates v, as depicted in Scheme IE, where R1, R2, R3, R4, 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 IH



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 may be 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, π, and III may occur by oxidative cyclization of acylhydroxamates vi to intermediate azetidinones vii, as illustrated in Synthetic Scheme TV, 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. Client. 1987, 52, 4471 and Tetrahedron Lett. 1985, 26, 5385, the disclosures of which are incorporated 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


z
vi vπ



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



iv V
Still other useful intermediates, such as the azetidinonyl acetic acid derivatives x, maybe converted into compounds of formulae I, IL, and III, as illustrated for the synthesis of compounds of formula I in Synthetic Scheme VI, where R1, R2, R3, R4, 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 R^-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', maybe 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, or III.
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-tetramethylpiperidinamide, 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, R5X'N-C(O)-(CH2)n-Z, or R6'θ-C(O)-(CH2)n-Z provide the corresponding compounds xi or I, respectively. The analogous synthesis of compounds of formulae II and ELI may be accomplished by this process by using the appropriate electrophile.
As discussed above, the compounds prepared as described in Synthetic Schemes I, π, in, 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 HI, rV, 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 Vib agents in their own right, may also be converted to the corresponding half-carboxylic acids xii, where the integer n and the groups R1, R2, R3, R4, R5', R6', 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 R5XTST-. It is appreciated that the transformation illustrated in Synthetic Scheme VII is equally applicable for the preparation of compounds I where A' is XTSTH- or where a different R6O- 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 R6 is tert-butyl, the ester I-a may be dealkylated by treatment with trifluoroacetic acid. Where R6 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 ammonia. Finally, where R6 is 2-(trimethylsilyl)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 R6 moiety and the comparability 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 halide, preferably the chloride or fluoride, followed by treatment with an appropriate primary or secondary amine to provide the corresponding amide. Alternatively, the acid may be converted under standard conditions to a mixed anhydride. This is typically accomplished by first treating the carboxylic acid with an amine, such as triethylamine, 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 anhydride. 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 N,N'-carbonyldiimidazole (CDI), NjN'-dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), followed by the appropriate amine of formula R5XNH. A polymer-supported form of EDC has been described 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 described herein. It is appreciated that substituting an appropriate amine with an appropriate alcohol in the synthethic scheme presented above will provide the esters described herein, e.g. analogs of I-a with a different ester R6 O-.
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 sulfuric acid, and the like, and with isobutylene in a suitable solvent, such as dioxane, and the like. The reaction is preferably carried out under pressure in an appropriate 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 in Synthetic Scheme VII may also be used to convert in an analogous fashion, the half-ester I where A is R6O- to the corresponding acid and subsequently into derivatives I where A is XNH-, R5XN-, or a different R6O-. 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 derivatives in compounds of formulae II and III.
Compounds of formulae I, II, and III 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 VTIL 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 Vm is chosen such that the substituent R-CC-, R-CHCH-, or R-CH2CH2-corresponds to the desired R4 of formulae I, II, or III 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 II and III may be accomplished by this process.
Compounds of formulae I, II, and III 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 IX for compounds of formula I, where the integer n, and the groups R1, R2, R4, R12, A3 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.



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, R12NCO. 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 °C, 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, R12-C(O)Z or R12-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 °C, 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.
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.
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 CH2Cl2 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=I 8.0 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 (MgSO4) 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), 4.60-4.64/4.65-4.69 (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)-Phenyloxazolidin-2-on-3-yl)propanoic acid. To a solution of methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate (1 g, 4.01 mmol) in 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 azetidinone, the MeOH was removed by evaporation, the crude residue dissolved in CH2Cl2 and treated with saturated aqueous NaCl. The resulting organic layer was dried (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 in 200 mL CH2Cl2 (150 niL / g of propanoic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 μL / mmole of propanoic acid derivative) resulting in vigorous gas evolution. After 45 min., 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 derivative. N-Benzyloxycarbonyl-L-aspartic acid β-^-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-^-butyl ester α-N-hydroxysuccinimide 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-(trifluoromethyl)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-^-buryl ester α-N-hydroxysuccinimide ester was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine.
Example 2A. N-Benzyloxycarbonyl-L-aspartic acid β-^-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; 1H 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), 4.46-4.48 (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.O 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; 1HNMR (CDCl3) δ 1.43 (s, 9H); 1.64-1.73 (m,lH);l.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); 4.66-4.73 (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-^-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; 1H 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 4. N-Benzyloxycarbonyl-L-glutamic acid γ-/-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), 4.19-4.25 (s, IH), 4.46-4.48 (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.O 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); 4.66-4.73 (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 t- 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 dichloromefhane/mefhanol) 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 5 A (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-f-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 1H 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-cyclohexylρiperazine 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-^-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-[(8)-α-methylbenzyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-f-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); 4.50-4.54 (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-^-butyl 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); 4.46-4.50 (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-^-buryl 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)-l-(3-trifluoromethylphenyl)ethylarnine 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-ϊ-butyl ester α-[(R)-l-(3-trifluoromethylphenyl)ethyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-^-butyl ester monohydrate (Novabiochem) (150 mg, 0.44 mmol) and 83 mg of (R)-l-(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-trifluoromethyljbenzylamide. N-benzyloxycarbonyl-D-glutamic acid α-methyl ester (508 mg, 1.72 mmol) and 317 mg (1.81 mmol) of 3-(trifluoromethyl)benzylamine gave 662 mg (85%) of Example 7H as an off-white solid. Example 7H exhibited an 1H NMR spectrum consistent with the assigned structure.
Example 8. General procedure for hydrogenation of a benzyloxycarbonyl amine. L-asρartic 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) δ 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-^-buryl 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; 1HNMR (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-trifluoromethyljbenzylamide. 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 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=I 6.8 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-^-butyl ester α-(3-trifluoromethyljbenzylamide. N-benzyloxycarbonyl-L-glutanαic acid γ-i-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)]piρerazinamide. N-benzyloxycarbonyl-L-glutamic acid γ-^-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; 1HNMR (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 γ-^-butyl ester o>(3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid γ-*-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 13A. L-glutamic acid α-/-butyl ester γ-(4-cyclohexyl)piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid α-i'-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-i-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-f-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-^-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 Hz5 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-^-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; 1HNMR (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=I 7.5 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-f-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-buτyl 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)]ρiρerazinamide. 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; 1HNMR (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-/-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 (bra, 2H); 2.67 (dd, J=7.1 Hz, J=I 6.8 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-trifluoromethyl)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 (rn, 4H); 7.69-7.77 (m, IH).
Example 131. L-glutamic acid γ-f-butyl ester cc-[4-(2-phenylethyl)]piρerazinamide. N-benzyloxycarbonyl-L-glutamic acid γ-^-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; 1HNMR (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-/-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave 1.15 g (94%) of Example 13 J as an off-white oil; 1HNMR (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-^-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-if-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-f-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 (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 Hz5 IH); 7.56 (t, J=7.3 Hz, IH); 7.97-8.02 (m, IH).
Example 13M. D-aspartic acid β-/-butyl ester α-[(S)-l-(3-trifluoromethylphenyl)ethyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-[(S)-l-(3-trifluoromethylphenyl)ethyl]arnide (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-/-buryl ester α-[(R)-l-(3-trifluoromethylphenyl)ethyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-tf-butyl ester α-[(R)-l-(3-τrifluoromethylρhenyl)ethyl]amide (217 mg, 0.44 mmol) gave 158 mg (quantitative yield) of Example 13N as an off-white oil, and exhibited an 1H 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 130 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 foπnation 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 niL 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 (aR,3S,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, n-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(trimemylsilyl)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)-(fer/'-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-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)-(te^-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 18 A. 2(RS)-(tø^Butoxycarbonyl)-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. Example 18A was prepared according to the procedure of Example 18, using 2-fluoro-3-(trifluorometliyl)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 19-25 AF 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)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)~4(R)-(2-styryl)azetidin-2-on- 1 -yljacetic 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 Hz5 IH); 4.58-4.66 (m, 3H); 4.69-4.75 (m, IH); 4.81 (dd, J=3.8 Hz, J=ILl 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, 1 IH); 7.62 (s, IH); 8.27-8.32 (m, IH).
Example 19A. 2(S)-(ter/-Butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(S)-(2-styryl)azetidin-2-on-l-yl]acetic acid N-(3- frifluoromethylbenzyl)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%); 1HNMR (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 Hz3 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)-(tert-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)ben2ylamide 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); 4.14-4.19 (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-t-butyl ester α-[4-(2-phenylethyl)]ρiperazinamide 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); 4.22-4.48 (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=I 5.9 Hz, IH); 6.63 (d, J=15.8 Hz, IH); 7.18-7.42 (m, 15H).
Example 22. 2(S)-(te^-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)]ρiperazinamide. The imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-^-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); 4.08-4.13 (m, IH); 4.33-4.44 (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)-(fe^-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-ρhenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(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=10.7 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=I 5.1 Hz, IH); 4.58-4.67 (m, 3H); 4.70-4.76 (m, IH); 6.27 (dd, J=9.5 Hz, J=I 5.8 Hz, IH); 6.79 (d, J=I 5.8 Hz, IH); 7.25-7.50 (m, 13H); 7.63 (s, IH); 8.50-8.54 (m, IH).
Example 23 A. 2(R)-(ter^-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 23A 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 23 A 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)-(te^-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.15 g (3.20 mmol) of D-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 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); 4.13-4.18 (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 Hz5 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)-(ter/-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidm- 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 mniol) of L-glutamic acid γ-^-butyl ester α-(4-cyclohexyl)piperazinarαide 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); 4.83-4.90 (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-Butyϊ 2(S)-(2-(4-cyclohexylpiperazmylcarbonyl)ethyl)-2-[3(S)-(4(S)-ρhenyloxazolidin-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)-(fer^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-/-butyl ester α-(2-fluoro-3-trifluororαethyl)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=I 0.4 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)-(rert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3 -yi)-4(R)-(2-styryl)azetidin-2-on- 1 -yl]acetic acid N-[(S)-α-methylbenzyl] amide. The imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-t-butyl 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=ILO Hz, J=17.5 Hz, IH); 4.01 (dd, J=3.0 Hz, J=ILO 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)-(ter?-Biαtoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidm-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l -yl]acetic acid N-[(R)-α-methyTbenzyl]amide. The imine prepared from 0,187 g (0.46 mmol) of D-aspartic acid fi-t-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, JN17.8 Hz, IH); 3.93 (dd, J=3.5 Hz, J=I 0.8 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)-(fert-Butoxycarbonylmethyl)-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. The imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-^-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); 1HNMR (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); 4.70-4.79 (m, 2H); 5.27 (dd, J=4.0 Hz, J=I 1.0 Hz, IH); 6.22 (dd, J=9.3 Hz, J=15.8 Hz, IH); 6.73 (d, JN15.8 Hz, IH); 7.33-7.45 (m, 14H).
Example 25F. 2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyr-2-yl)azetidin-2-on-l-yl]acetic acidN-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-ϊ-butyl ester α-(3-trifluoromethyl)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); 1HNMR (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=I 5.0 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)-(ter^-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3 -yl)-4(R)-(2 '-methoxystyr-2-yl)azetidin-2-on- 1 -yl] acetic acid N-(3 -trifluoromethylbenzyl)amide. The imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid /3-^-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 ^-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); 4.71-4.78 (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 (ni, IH); 7.19-7.40 (m, 14H).
Example 251. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazmylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetate. The imine prepared from 0.3 g (0.88 mmol) of L-aspartic 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 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. ter/-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)phenylmethylaminocarbonyl]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%); 1HNMR (CDCl3) δ 1.25 (s, 3H), 1.38 (s, 9H); 3.09 (dd, J=3.0 Hz, J=18.0 Hz, IH); 3.33 (dd, J=12.5 Hz, J=18.0 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); 4.45-4.51 (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)-(to^-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(prop-l-enyl)azetidin-2-on-l-yl]acetic acidN-(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/Me0H); 1H NMR (CDCl3) δ 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 Hz5 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=I 5 Hz, IH); 4.61 (dd, J=6 Hz, J=I 5 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)-(tøY-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 γ-^-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); 1HNMR (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)-(methoxycarbonylethyi)-2-[3(S)-(4(S)-phenyloxazolidin-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-^-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)-(te7t-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-ρhenyloxazolidin-2-on-3-yl)-4(R)-(2-styryi)azetidin-2-on-l-yl]acetate. The imine prepared from 424 mg (2.09 mmol) of L-aspartic acid γ-i-butyl ester α-methyl ester and
cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (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=I 5.5 Hz, IH); 6.61 (d, J=15.5 Hz, IH); 7.25-7.43 (m, 10H).
Example 25L. 2(R)-(te^Butoxycarbonylrnethyl)-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. The imine prepared from 160 mg (0.44 mmol) of D-aspartic acid β-/-butyl ester α-[(R)-l-(3-trifluoromethylpheny)ethyl]amide and
cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (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)-(te^-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-[(S)-l-(3-trifluoromethylpheny)ethyl]amide. The imine prepared from 120 mg (0.22 mmol) of D-aspartic acid β-£-butyl ester α-[(S)-l-(3-trifluoromethylpheny)ethyl]amide and
cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 75 mg (50%) of Example 25N after flash column chromatography purification (70:30 hexanes/EtOAc). Example 25N exhibited an 1H NMR spectrum consistent with the assigned structure.
Example 25Q. Methyl 2(R)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryi)azetidin-2-on-l-yl]acetate. The imine prepared from 517 mg (1.62 mmol) of D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl) acetyl chloride (Example 1) to give 527 mg (51%) of Example 25Q after flash column chromatography purification (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 described herein:











Example 25AF. t-Butyl 2(S)-(2-(3- trifluoromethylberizyl)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 fers-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-hutyl 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; 1H 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); 4.39-4.85 (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-trifiuoromethylbenzyl)amide. Example 19A (41 mg, 0.06 mmol) was hydrolyzed to give 38 mg (quantitative yield) of Example 28 A as an off-white solid; 1HNMR (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(8)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(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); 4.61-4.67 (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); 3.86-4.00 (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); 4.06-4.11 (m, IH); 4.29 (d, J=4.9 Hz, IH); 4.33-4.46 (m, 2H); 4.50-4.58 (m, 2H); 4.67-4.72 (m, IH); 4.95-5.00 (m, IH);

6.18 (dd, J=9.2 Hz, J=I 6.0 Hz, IH); 6.67 (d, J=15.9 Hz, IH); 7.19-7.42 (m, 15H); 8.80 (bra, 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 23A (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)-ρhenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(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-Cyclohexylpiρerazinylcarbonyl)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; 1HNMR (CDCl3) δ 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); 4.06-4.14 (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=I 6.0 Hz, IH); 6.65 (d, J=I 6.0 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=I 5.7 Hz, IH); 6.80 (d, J=I 5.7 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 acid N-[(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=I 5.8 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)-ρhenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-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=I 5.9 Hz, IH); 6.73 (d, J=I 5.9 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 acidN-(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=I 5.8 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, JN9.3 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-Cyclohexylpiρerazinylcarbonyl)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-methyl-4(R)-(styr-2-yl)azetidin-2-on- 1 -yl] -3 - [(3 -trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the general method of Example 26, 120 mg (0.18 mmol) of Example 25 J 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=40.8 Hz, J=18.2 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-l -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 acidN-[(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 1H NMR spectrum consistent with the assigned structure.
Example 34M. 2(S)-(Memoxycarbonylethyl)-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 1H NMR spectrum consistent with the assigned structure.
Example 34N. 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-[(S)-l-(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)azetidin-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 1H NMR spectrum consistent with the assigned structure.
Example 34P. 2(S)-(te^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)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acid.

Example 25Q (150 nag, 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)-(te7^-Butoxycarbonylmethyl)-2-[3(RS)-2-thienylmethyl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(3-trifluoromethylbenzyl)amide. The imine prepared from 290 mg (0.84 mmol) of D-aspartic acid β-^-butyl ester α-(3-trifluoromethyl)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 1H NMR spectrum consistent with the assigned structure.
The following compounds were prepared according to the processes described herein:













Examples 36-42A, 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 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-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an 1H NMR spectrum consistent with the assigned structure.






Example 86B. Example 63 (44 mg, 0.06 mmol) was dissolved in 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-(trifluoromethyl)benzyl amine was replaced with the appropriate amine; all listed Examples exhibited an 1H 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-^-butyl 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)-(fe^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)piperazinamide. Example 132C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-ϊ-butyl ester monohydrate was replaced with Example 34P, and 3~(trifluoromethyl)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-l-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-^-butyl ester monohydrate was replaced with Example 32 A, and 3-(trifluoromethyl)benzyl amine was replaced with A-(piperidinyl)piperidine, and 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.



Example 222. 2(R)-[[4-(Piperidmyl)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-(piρeridinyl)piperidine; Example 222 exhibited an 1H 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 -yljacetic acid N-[(S)-α- methylbenzyljamide. Example 223 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-f-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)-α-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- 1 -yljacetic 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-^-butyl ester monohydrate was replaced with Example 34E, and 3-(trifluoromethyl)benzyl amine was replaced with
4-(piperidinyl)piperidine; Example 223 exhibited an H NMR spectrum consistent with the assigned structure; Calc'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 225A 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-^-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 acid N-[(R)-l-(3-trifluoromethylpheny)ethyl]amide. Example 225C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-^-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 acidN-[(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-(trifluoromethyl)benzyl amine was replaced with

4-(piperidinyl)piρeridine. Example 225D exhibited an 1H NMR spectrum consistent with the assigned structure.
Examples 87-120E, 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 29, 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 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)azetidin-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-^-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)piρerazinyl-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-(trifiuoromethyl)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 (m5 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-/-butyl ester monohydrate was replaced with Example 34A, 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 compounds shown in the following Table were prepared according to the processes described herein.





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 1H NMR spectrum consistent with the assigned structure.




Example 140A. 2(R)-( 2-(3-trifluoromethylbenzyl)ammo-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-^-butyl 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 226-23 OC, shown in the following Table, were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-ϊ-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-(Piperidmyl)piperidinyl]carbonymethyl]-2-[3(S)-(4(R)-ρhenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-(3-trifluoromethylbenzyl)amide. Example 86C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-^-butyl ester monohydrate was replaced with Example 28A, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, and exhibited an 1H NMR spectrum consistent with the assigned structure.
Example 231. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)- (4(S)-ρhenyloxazolidin-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-^-butyl ester monohydrate was replaced with Example 34G, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, and exhibited an 1H 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-^-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-methyl-4(R)-(styr-2-yl)azetidin-2-on-l-yl]-3-[(3-trifluoromethy^phenylmethylammocarbonyljpropanoic acid.



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 34J and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine, the title compound was prepared in quantitative yield; MS (m+H)+ 772.
The compounds shown in the following Table were prepared according to the processes described herein.



Example 235. 2(S)-[[(l-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 acidN-(3-trifluoromethylbenzyl)amide. Example 235 was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-f-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 1HNMR 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-l-yl]acetic acid
N-(3-trifluoromethylbenzyl)amide. 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 acidN-[(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-ϊ-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 236 A exhibited an 1H NMR spectrum consistent with the assigned structure.
Example 237. 2(R)-[[4-(Piperidinyl)ρiperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(propen-l -yl)azetidin-2-on-l -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-^-butyl ester monohydrate was replaced with Example 34K, and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidinyl)piperidine. Example 237 exhibited an 1H NMR spectrum consistent with the assigned structure.
Example 238. (2S)-(Benzylthiomethyl)-2-[3(S)-(4(S)-ρhenyloxazolidin-2-on- 3-yl)-4(R)-(2-styryl)azetidin-2-on-l-yl]acetic acidN-[4-[2-(piperid-l-yl)ethyl]piperidin-l-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-ffiutyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(l-piperidyl)ethyl)]piperidinenamide. N-ήButyloxycarbonyl-(S)-Benzyl-N-(rt)utyloxycarbonyl)-D-cysteine (0.289 g, 0.93 mmole) and 4-[2-(l-piperidyl)ethyl]piperidine (0.192 g, 0.98 mmole) in dichloromethane (20 mL) 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)]piperidinenamide, dihydrochloride. N-^Butyloxycarbonyl-(S)-(ben2yl)-D-cysteine-[4-(2-( 1 -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%). 1H 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); 4.76-4.84 (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 (MH-H)+ parent ion.

Table 16.





METHOD EXAMPLES
In another embodiment, the compounds described herein are useful for antagonism of the vasopressin Vib receptor in methods for treating patients suffereing from disease states and conditions that are responsive to antagonism of the vasopressin Vib receptor. Illustratively, the methods described herein include the step of
administering to a subject or patient in need of such treatment an effective amount of a compound described by the formulae herein. Antagonism of various vasopressin receptor subtypes has been associated with numerous physiological and therapeutic benefits. These benefits may arise from antagonism of both peripheral and central nervous system vasopressin receptors. Peripheral nervous system utilities include administration of vasopressin Via 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 vasopression Vib receptor-expressing cells. Human vasopressin receptor IB (HVlB) cDNA (see, Lolait et al., "Extrapituitary expression of the rat VIb vasopressin receptor gene" Proc. Natl. Acad. Sci. U S A.
92:6783-7 (1995); de Keyzer et al., "Cloning and characterization of the human V3(Vlb) pituitary vasopressin receptor" FEBS Lett. 356:215-20 (1994); Sugimoto et al.,
"Molecular cloning and functional expression of a cDNA encoding the human VIb vasopressin receptor" J. Biol. Chem. 269:27088-92 (1994)) was inserted into a mammalian cell expression vector PCI-neo (Promega) at EcoRl site. The recombinant plasmid carrying HVlB cDNA was identified from transformed E. CoIi clones and used for the transfection of Chinese hamster ovary cell (CHO-Kl, ATCC). Two micrograms of HVlB receptor DNA was introduced into 105 CHO cells cultured in 6-well plate, using Fugene-6 mediated transfection technique (Boehringer Mannheim). Twenty-four hrs post transfection, Cells were then cultured under selection of G-418 (0.25mg/ml)
supplemented to the culture medium. Three days later, limited dilution was carried out to obtain single cell clones in 96-well plates. After a period of 2-weeks of growth, monoclones were expanded into two sets of 12-well plates. When confluence was reached, one set of wells were assayed for their ability to bind tritium-labeled arginine-vasopressin (NEN). Nine positive clones were initially identified out of 60 clones screened, and clones that demonstrated highest AVP binding were saved as permanent cell lines for HVlB affinity screening of Serenix compounds.
Method Example 2. Human or rat vasopression Vib cell-based receptor binding assay. The VIb cell lines (cells expressing either the human or rat Vib receptor) were grown in alpha-MEM medium supplemented with 10% fetal bovine serum and 250ug/ml G418 (Gibco, Grand Island, NY) in 75 cm2 flask. For competitive binding assay, hVlb cells were dissociated with enzyme-free, PBS based cell dissociation solution (Specialty Media, Phillipursburg, NJ), following the manufacturer's protocol. Cells were plated into 12-well culture plates at a rate of one flask to 18 plates (rate should be adjusted according to the extent of confluency), and maintained in culture for 2-3 days. Culture medium was then removed, cells were washed once with 2ml binding buffer (25mM Hepes, 0.25% BSA5 Ix DMEM, PH=7.0) at room temperature. To each well, 990ul binding buffer containing InM 3H-AVP was added, and followed by the addition of lOul series diluted testing compounds or cold AVP, all dissolved in DMSO. AU incubations were in triplicate, and dose-inhibition curves consisted of total binding (DMSO only) and 5 concentrations (0.1, 1.0, 10, 100, and lOOOnm) of test agent, or cold AVP, encompassing the IC50. Cells were incubated for 30 min at 370C in a moisturized incubator. Assay mixture was then removed and each well was washed three times with PBS (pH=7.4). After washing, ImI 2% SDS was added per well and plates were let sit for 15 min at RT. Gently pat the plate to make sure that lysed cells were detached. The whole content in a well was transferred to a scintillation vial. Each well was then rinsed with 0.5ml PBS and added to the corresponding vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, Georgia) was then added at 3ml per vial. Samples were counted in a liquid scintillation counter ( Beckman LS3801). IC50 and Ki values were calculated using Prism Curve fitting software.
Example 215 was tested on cells expressing human Vib receptors, and the data are presented in Table 17. Inhibition curves for Example 215 are shown in FIGS. 1 and 2, which show data from a CHO-rat Vib cell line demonstrating inhibition of phosphatidyl inositol turnover by Example 215. FIG. 1 shows good receptor binding affinity (Kj=32 nM) of Example 215 through a competitive binding assay conducted in CHO cells transfected with human Vib receptor. The antagonist activity of Example 215 against AVP was also evaluated in CHO cells expressing rat Vib receptor. FIG. 2 shows that Example 215 inhibited V^ mediated phosphatidyl inositol turnover with a Kj value at 59 nM in CHO cells expressing rat Vib receptor.
Alkanedioic esters and amides exemplified in the foregoing examples were tested in this assay on cells expressing rat Vib receptors. Binding affinities (IC50) for illustrative compounds are summarized in Table 17. Inhibition constants (Ki) for illustrative compounds are also summarized in Table 17.

Table 17.






Method Example 3. Inhibition of vasopressin Vib-mediated
phosphatidylinositol turnover, a functional assay for antagonist activity. The
physiological effects of vasopressin are mediated through specific G-protein coupled receptors. The vasopressin Vib receptor is coupled to a G protein, which is coupled to cAMP. The agonist or antagonist character of the compounds described herein may be deteπnined by their ability to inhibit vasopressin-mediated turnover of
phosphatidylinositol by using conventional methods, including the procedure described in the following paragraphs.
Cells expressing the human or rat Vib receptors 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 cm 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).
All 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 mM 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, EC5O 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 Ki 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)]}1 Q
Y = B +
1 + {A / [E + (D / K)]}Q
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 Kj for antagonist, and Q is the cooperativity (Hill coefficient).
Experiments 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 in the production of signaling molecule P3, are calculated with prism software based on Cheng and Prusoff equation.
Method Example 4. Seed finding by golden hamsters. It is appreciated that a hamster's ability to find seeds under certain conditions may reflect their level of anxiety. This method for assaying seed finding capabilities in hampsters treated with the compounds described herein is an animal model of anxiety.
Male, Syrian golden hamsters (Mesocricetus auratus) (120-130 g) obtained from Harlan Sprague-Dawley Laboratories (Indianapolis, IN) were housed individually in Plexiglas cages (24 cm x 24 cm x 20 cm), maintained on a reverse lightdark cycle (14:10; lights on at 19:00 hr), and provided food and water ad libitum. All tests were conducted during the dark phase of the circadian cycle under dim red illumination. Prior to testing, all animals were fasted for 20-24 hrs. Ninety min after intraperitoneal (IP) injection of SRX262 (n=10) or saline vehicle (n=10), animals were taken from their home cage and - Il l - placed into a holding cage for 2 min. During their absence, six sunflower seeds were buried under the bedding in one corner of their home cage. Animals were placed back into their home cage randomly facing any one of the empty corners and timed for their latency to find the seeds during a five minute observation period. The latency to find the seeds was dramatically reduced with treatment of SRX262 as shown in FIG. 3 and comparable in magnitude to fluoxetine, buspirone, and chlordiazapoxide.
Method Example 5. Social Subjugation in Hamsters, a biochemical marker assay. There is a body of literature on the neuroendocrine and behavioral consequences of repeated social subjugation in adult male golden hamsters. In adult animals, losing fights and being relegated to low social status is very stressful, resulting in altered levels of adrenal and gonadal steroids together with changes in social behaviors (Rose et al., 1975; Eberhart et al., 1980, 1983). Studies on adult male hamsters show depressed levels of testosterone and elevated levels of glucocorticoids following repeated defeat by dominant conspecifics (Huhman et al., 1991).
Male hamsters were housed and maintained as described above. For 30 minutes each day for fourteen consecutive days, animals were exposed to threat and attack from a larger conspecific (n=14). Following these daily episodes of traumatic stress animals were left undisturbed in their home cages for ten days. During this recovery period animals were treated with Example 215 (lmg/kg/day) (n=7) or saline vehicle (n=7). At the end of this treatment period animals were sacrificed by decapitation and trunk blood collected for the radioimmunoassay of testosterone and Cortisol. As expected, the testosterone levels of chronically subjugated hamsters were very low while the basal Cortisol levels were high. This neuroendocrine profile was altered by treatment with Example 215 as shown in FIGS. 4 & 5. These data indicate that blocking Vib receptors can enhance recovery from traumatic stress like social subjugation. These data are consistent with the findings of Griebel et al. (2002).
Method Example 6. Social Subjugation in Hamsters, a behaviorial assay, screening for antidepression-like activity. The hamster model of social subjugation in the resident intruder paradigm is used. The resident/intruder model of aggression relies on the motivation of a resident animal to chase and fight intruders coming into their territory (Miczek 1974). Smaller animals placed into the home cage of a resident will be more easily defeated and become socially subjugated with repeated encounters. Social subjugation is a significant and natural stressor in the animal kingdom. Animals defeated and subjugated during establishment of dominance hierarchies or territorial encounters can be highly submissive in future agonistic interactions.
For example, defeated mice display less aggression and more submissive behavior (Frishknecht et al., 1982; Williams and Lierle 1988). Rats consistently defeated by more aggressive conspecifϊcs show a behavioral inhibition characterized by less social initiative and offensive aggression, as well as an increase in defensive behavior (Van de Poll et al., 1982). Repeatedly defeated male hamsters respond in a submissive manner when confronted by a non-aggressive intruder (Potegal et al., 1993), in addition their normal reproductive behavior is reduced as measured by latency to mount a receptive female. Moreover, following repeated defeat by a dominant conspecific, a resident hamster will be defensive or fearful of smaller-sized non aggressive intruders (Potegal et al., 1993). The generalization of submissive behavior toward non-threatening, novel stimulus animals is an example of "conditioned defeat" (Potegal et al., 1993).
Conditioned defeat in adult hamsters is not permanent as the flight and defensive behaviors disappear over many weeks. Animals displaying conditioned defeat are treated with the compounds described herein, and observed for a return to normal aggressive and reproductive behaviors.
In addition, social subjugation has a pronounced effect on the animal's neuroendocrinology. In adult animals, losing fights and being relegated to low social status alters levels of adrenal and gonadal steroids (Rose et al., 1975; Eberhart et al., 1908, 1983). Adult male hamsters show depressed levels of testosterone and elevated levels of glucocorticoids following repeated defeat by dominant conspecifics (Huhman et al., 1991). Recovery of normal testosterone and Cortisol levels is assessed in animals treated with the compounds described herein.
Male, Syrian golden hamsters (Mesocricetus auratus) (120-130 g) obtained from Harlan Sprague-Dawley Laboratories (Indianapolis, IN) are housed individually in Plexiglas cages (24 cm x 24 cm x 20 cm), maintained on a reverse lightdark cycle (14:10; lights on at 19:00 hr), and provided food and water ad libitum. All tests are conducted during the dark phase of the circadian cycle under dim red illumination. Each compound is tested in 3 doses (100 μg, 1 mg, and lOmg/kg) plus saline vehicle. Twenty-four animals (six per group) are tested. Animals are socially subjugated by placing them into the home cage of a larger hamster each day for 30 min for 14 consecutive days. Animals are exposed to a different resident each day so that the threat and attack is unremitting. Following the cessation of social subjugation, animals are allowed to recover undisturbed in their home cage for the next two weeks. During this time they are treated with a compound described herein, or with vehicle for one week. At the end of the week, the animals are tested for aggression toward a smaller intruder placed into their home cage. Animals are scored for latency to bite, number of bites, and contract time. On the following day, a receptive female is placed into the animal's home cage, and the animal is scored for latency to mount. At the end of two weeks, animals are sacrificed and trunk blood assayed for testosterone and Cortisol. All animals are sacrificed during the first 2 hrs of the dark phase of the light: dark cycle to minimize circadian variations in Cortisol levels. The data between treatments is compared with one-way, ANOVA followed by Bonferroni post hoc tests.
Method Example 7. Elevated Plus Maze. The elevated plus-maze was developed for screening anxiolytic and anxiogenic drug effects in rodents. The method has been validated behaviorally, physiologically, and pharmacologically. The plus-maze consists of two open arms and two enclosed arms. Rats and mice tend to naturally make fewer entries into the open arms than into the closed arms and will spend significantly less time in open arms. Confinement to the open arms is associated with significantly more anxiety-related behavior and higher stress hormone levels than confinement to the closed arms. Clinically effective anxiolytics, e.g., chlordiazepoxide or diazepam, significantly increase the percentage of time spent in the open arms and the number of entries into the open arms. Conversely, anxiogenic compounds like yohimbin or amphetamines reduce open arm entries and time spent in the open arms.
Male mice are group housed in a normal 12:12 lightdark cycle with light on at 0800 hr and provided food and water ad libitum. The plus-maze consists of two open arms, 40 cm long, 6 cm wide with no walls. The two closed arms have the same dimensions with walls 25 cm high. Each pair of arms are arranged opposite to each other to form the plus-maze. The maze is elevated to a height of 50 cm. Each drug is tested in 3 doses (100 μg, 1 mg, and 10mg/kg) plus saline vehicle. Twenty-four animals (six per group) are tested in the plus-maze 90 min following the EP injection in a volume of ca. 0.1ml. At the start of the experiment, the animal is placed at the end of one of the open arms. Over a five min observation period, animals are scored for the latency to enter the closed arm, time spent in the closed arm, and the number of open arm entries following the first occupation of the closed arm. The data between treatments are compared with one-way, ANOVA followed by Bonferroni post hoc tests.
Method Example 8. Impulsivity/Inappropriate Aggression. Impulsivity and/or inappropriate aggression may be determined using standard animal behavior assays, including the resident-intruder paradigm, the isolation induced aggression paradigm, and the interfemale aggression and/or intermale aggression paradigms. These assays may be applied to mice, rats, and/or hamsters. Arginine vasopressin (AVP) has been implicated in the aggressive behaviors of a number of species, including humans (see, Coccaro et al., "Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects" Arch. Gen. Psychiatry 55:708-14 (1998)). Infusions of AVP receptors antagonists have been shown to reduce aggression (see, Ferris & Potengal, "Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters" Physiol. Behav. 44:235-39 (1988)). A study of the vasopressin Vib knockout mouse indicated reductions in aggressive behavior by these animals (see, Wersinger et al., "Vasopressin Vib receptor knockout reduces aggressive behavior in male mice" MoI. Psychiatry 7:975-84 (2002)).
Adult male Syrian hamsters (Mesocricetus auratus, Charles River Laboratories) are used as subjects. Hamsters to be used as residents are housed individually for at least 2 weeks prior to the beginning of the experiment. A
subpopulation of smaller males are used as intruders, which are group-housed (three/cage) in order to minimize aggression levels. Resident and intruder pairs should have a minimum of about a 10-g weight difference. For example, the weight range for residents is between 105 and 150 g, and intruder weights ranged from 95 to 140 g, although these absolute weights may vary. Animals are housed in Plexiglas cages (46.0 x 24.0 x 21.0 cm) with corn cob bedding in a temperature (e.g. 69 °F) and humidity-controlled room with food and water available ad libitum, which is maintained on a 14: 10 light-dark cycle with lights off at 12:00 noon. Tests are run under red light illumination during the first 3 h of the dark phase of the light-dark cycle. All animals are handled daily for 10 days prior to the start of the study.

A single nondrug screening test (resident-intruder) is run with each individually housed hamster to determine the baseline levels of aggression of the animal. Only resident males that show a minimum of one bite during the test session are used in the drug test. Tests with the compounds described herein are run 48 h after the screening test. Twenty-five minutes after drug administration, residents are moved to the testing room. Intruders are introduced into the resident home cage 5 min later, for a 10- min test. Each resident is confronted with a different intruder than was used in the screening phase. It is to be understood that the protocols used in this experiment are in compliance with the applicable state and federal regulations. Behavioral measures include attack latency, latency to bite, and number of bites. Data are analyzed by one-way ANOVA, optionally followed by Newman-Keuls post hoc tests. Further details of this assay are found in Blanchard et al., "AVP VIb selective antagonist SSR149415 blocks aggressive behaviors in hamsters" Pharmacol., Biochem. Behav. 80:189-94 (2005).
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).
hi 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 foπn 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, microcrystalline 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 described 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 in the art.
The compositions are preferably formulated in 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 material 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 within the range from about 0.01 to about 30 mg/kg of body weight. In illustrative variations, dosages per day may fall in 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 severity 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 in the methods described 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 dried 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 in 150 mg quantities.
Formulation Example 6. Suppositories, 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 in the saturated fatty acid glycerides 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-containing 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 described 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-brain barrier. One such 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.
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 lipid-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-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.
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.