CA2274958A1 - Inhibitors of the enzymatic activity of psa - Google Patents

Inhibitors of the enzymatic activity of psa Download PDF

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Publication number
CA2274958A1
CA2274958A1 CA002274958A CA2274958A CA2274958A1 CA 2274958 A1 CA2274958 A1 CA 2274958A1 CA 002274958 A CA002274958 A CA 002274958A CA 2274958 A CA2274958 A CA 2274958A CA 2274958 A1 CA2274958 A1 CA 2274958A1
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phenyl
compound
azetidinone
alkyl
ethen
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French (fr)
Inventor
Gerald Wayne Becker
Benjamin Alan Anderson
Tony Yantao Zhang
John Robert Rizzo
Blake Lee Neubauer
James Alan Carty
Nancy Kay Harn
Lowell Deloss Hatfield
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Eli Lilly and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

This invention is directed to novel azetidinone compounds, to certain intermediates and processes for preparing these azetidinone compounds, and to formulations containing the same. The present invention also relates to the use of these azetidinones as inhibitors of the enzymatic activity of Prostate-Specific Antigen (PSA) as well as for treating prostatic cancer (Pca), Pca metastasis, benign prostatic hyperplasia (BPH) and breast cancer (Bc). Another aspect of the invention relates to inventive methods for treating Pca, Pca metastasis, BPH and Bc by administering any PSA inhibiting compound.

Description

Field of the Invention This invention relates to novel azetidinone compounds, to certain intermediates and processes for preparing these azetidinone compounds, and to formulations containing the same. The present invention also relates to the use of these azetidinones as inhibitors of the enzymatic activity of Prostate-Specific Antigen (PSA) as well as for treating prostatic cancer (Pca), Pca metastasis, benign prostatic hyperplasia (BPH), breast cancer (Bc) and Bc metastasis.
Another aspect of the invention relates to methods for treating Pca, Pca metastasis, BPH, Bc and Bc metastasis by administering any PSA inhibiting compound.
Background of the Invention PCa is the second most common cancer in American men.
According to Wingo et a [P.A. Wingo, et al., CA Cancer J.
Clin., 41 (1), 8-30, (I995)], 244,000 new cases are diagnosed and 40,400 cancer related deaths occurred in the United States in 1995. The statistics represent 36~ of all male cancers and 13~ of male cancer-related deaths.
Presently, there are no effective preventive or treatment methods for Pca. When the cancer is in its early, hormone-dependent stage, it is commonly treated by orchiectomy or chemical castration, and the androgen flutamide is sometimes administered. In the later stages of Pca, the disease becomes hormone-independent and metastasizes widely, usually metastasizing through the skeleton. In the advanced stage of the disease, radiation is used to alleviate pain and to slow metastasis in the radiated areas, but there are no effective methods which can put Pca into remission in late stage disease. Thus, Pca is not only relatively common, but is refractory to treatment once the disease advances into the hormone-independent stage.
BPH is another prostatic disease. BPH is a non-cancerous condition characterized by excessive prostatic cellular growth resulting in an enlarged prostate gland.
The enlarged prostate gland causes obstruction of the urethra and associated symptoms often include hesitancy and straining to urinate, slow or intermittent urinary stream, frequent urination and postmicturition dribbling.
Additional symptoms not directly related to the urinary tract may also include hernias, hemorrhoids, change in bowel habits, and other manifestations of increased abdominal pressure and straining during voiding. It is estimated that BPH affects about 80~ of males over age 50 and that 20~ of males over age 80 require surgical intervention to relieve resulting symptoms. P. Narayan and R. Indudhara, The Western Journal of Medicine, 161, 495 (1994).
Bc is another devastating disease for which improved therapies are greatly needed. Bc is a major cause of mortality in women, as well as a cause of disability, psychological trauma, and economic loss. A large number of women contracting this disease eventually die from its effects either directly or indirectly from complications, e.g., metastasis, loss of general health, or collateral effects from therapeutic interventions, such as surgery, radiation, or chemotherapy. Even with the best combinations of treatment modalities (surgery, radiation, and/or chemotherapy), the long-term prognosis for breast cancer patients is variable, and is poor if metastatic disease is present.
PSA is believed to be a causative factor in Pca, Pca metastasis, BPH, Bc and Bc metastasis. PSA is an androgen-dependent, 28-kDa glycoprotein produced almost exclusively by the prostatic epithelium, and its presence is most abundant in seminal fluid [A.F. Prestigiacomo, et al., J.
Urol., 152, 1515-9 (1994) and G.G. Klee, et al., Uroloav, 44, 76-82 (1994)].
PSA is currently used as a serum marker for PCa diagnosis and monitoring. A wealth of data has accumulated over the last decade on the association of elevated serum PSA levels and PCa. In normal males, 85-95% of the circulating PSA is bound to either ocl-antichymotrypsin (ACT) or a2-macroglobulin. Id. Bound PSA is enzymatically inactive or unable to interact with its physiological substrate. Changes in the ratios of bound PSA to free PSA
occur in the serum of patients with BPH and PCa. PSA has also been discovered in breast tumor extracts and this has led to the suggestion that PSA can be used as a prognostic indicator for Bc. H. Yu, et al., Cancer Research, 55, 2104-10 (1995) .
In addition, a physiological role for PSA in male reproductive function has been hypothesized, based upon the enzymatic activity of this serine protease on the liquefaction of seminal plasma. More recently, PSA has been demonstrated to be expressed in non-prostatic tissues and to mediate proliferative and metastatic responses in cell culture systems. Critical evaluation of these recently reported preclinical data supports potential pathophysiological roles for PSA as a growth factor mediator in the stimulation and metastasis of Pca and in BPH.
Evidence also supports a correlation between PSA and IGFBPs (insulin growth factor binding proteins) in the serum of PCa patients. H. Kanety, et al., J. Clin. Endocrinol Metab., 77, 229-33 (1993). PSA has been shown to degrade certain IGFBPs and this action has been proposed as contributory to prostatic cellular growth, leading to BPH and Pca. P. Cohen, et al., J. Endocrinol., 142, 407-415 (1994). PSA has also been shown to directly stimulate in vitro growth of prostate epithelial cells. Additionally, the ability of certain IGFBPs to inhibit the growth of Bc cells is consistent with PSA playing a similar role in the treatment of Bc as in the treatment of of Pca.
It would be advantageous to find additional means of arresting the growth of cancer cells and tumors that can either be used alone or in conjunction with other treatments. In addition, it would be advantageous to find a means of preventing, delaying or decreasing the likelihood of the onset of Pca, Pca metastasis, BPH, Bc, and Bc metastasis.
Summarv of the Invention The present invention is directed to a compound of the Formula I:
R' R2 N
O \ R3 I
wherein:
Rl is aryl; aryl(C1-C6 alkylene); where the aryl or ring of the aryl(C1-Cg alkylene) is optionally substituted with one or two substituents independently selected from halo, Cl-C6 alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene; phthalimido; or a moiety selected from:
O Ra Rs R \ N Rs O
N o O ~ Rs N O Rs N

(a) (b) (c) R8 Rs ~N O Ra 0i\ O N
N
O
and (d) (e) where R4 is hydrogen;
C1-C6 alkyl;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, C1-C~ alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
R5 is:
hydrogen;
Cl-C4 alkyl;
C3-C~ cycloalkyl;
Cl-C4 alkoxycarbonyl;
phenyl; or naphthyl;
- 20 where the phenyl or naphthyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, WO 98125895 PCTli1S97122573 mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and vitro;
R6 is:
hydrogen C1-C4 alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, benzylthio and C1-C4 alkylthio;
phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and vitro; or Cl-C4 alkoxycarbonyl;
R~ is:
C1-C4 alkoxycarbonyl;
benzyloxycarbonyl;
benzoyl;
where the phenyl ring in benzyloxycarbonyl or benzoyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, Cl-C4 alkoxy, halogen, cyano, vitro, amino, carbamoyl, hydroxy, mono(C1-C4 alkyl)amino, and di(C1-C4 alkyl)amino;
Rg and R9 are independently:
hydrogen;
C1-C5 alkanoyloxy;
benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, vitro, amino and C1-C4 alkoxycarbonyl;
benzyloxy;
diphenylmethoxy; or triphenylmethoxy;
with the proviso that only one of Rg or R9 can be hydrogen;

WO 98!25895 PCTIITS971225'13 -R2 is:
C2-C6 alkenyl;
aryl; or heterocycle;
where the aryl or heterocycle is optionally _ substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;

where R10 is carboxy;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-Cg alkyl, carboxy, vitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
-CH=C(R12)-R11 where R11 is hydrogen or phenyl and R12 is:
nitrile;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, vitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
with the proviso that when R11 is phenyl, R12 is aryl; or -C=C-R13;
where R13 is:

- g _ aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene; and R3 is a heterocycle, C02R14, or H
~NwRis r I IS
where R14 is C2-C6 alkenyl, C1-C6 alkyl, Cl-Cg haloalkyl, C3-C~ cycloalkyl, substituted C3-C~ cycloalkyl, aryl-(Cl-C6 alkyl), aryl, or heterocycle; where the aryl or heterocycle, or the ring of the aryl(Cl-C6 alkylene), is optionally substituted with one or two substituents independently selected from the group consisting of halo, C1-C6 alkoxy, methoxycarbonyl, phenyl, Cl-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
R15 is aryl or heterocycle-(Cl-C6 alkylene); where the aryl or the ring of the heterocycle-(C1-C6 alkylene), is optionally substituted with 1-4 substituents independently selected from the group consisting of halo) C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, trifluoromethyl, and hydroxymethylene; and pharmaceutical salts and solvates thereof.

- 9 _ The present invention also provides a method for inhibiting the proteolytic activity of Prostate-Specific Antigen (PSA) by administering a compound of Formula I.
The present invention also provides methods for treating Pc, Pca metastasis BPH, Bc and Bc metastasis by . administering to a mammal in need of such treatment a prostatic specific antigen inhibiting compound. Preferred prostatic specific antigen inhibiting compounds include those of Formula I. This aspect of the invention resides in the discovery that PSA inhibiting compounds have a therapeutic effect on such diseases. Persons skilled in the art can readily determine if a compound is a PSA inhibiting compound by known methods.
Another aspect of the invention includes processes and intermediates useful in preparing the compounds of Formula I
and formulations containing the same compounds of Formula I.
Detailed Description of the Inven ion The terms and abbreviations used in the instant specification have their normal meanings unless otherwise designated. For example, "°C" refers to degrees Celsius;
"N" refers to normal or normality; "mmol" refers to millimole or millimoles; "g" refers to gram or grams; "ml"
means milliliter or milliliters; "M" refers to molar or molarity; "MS" refers to mass spectrometry; "IR" refers to infrared spectroscopy; "NMR" refers to nuclear magnetic resonance spectroscopy.
The term "aryl", as used herein, represents an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (such as phenyl) or a multiple fused ring system (such as naphthyl and anthracyl).
When substituted, the substituents may be located at any available position on the aryl rings) that are sterically feasible and afford a stable structure. The aryl may optionally be substituted with one or two moieties.
Examples of substituted aryl groups include 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-nitrophenyl, 4-carbomethoxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 1-naphthyl, 2-naphthyl, 2-chloronaphthyl, 2,3-dichloronaphthyl, 2-iodonaphthyl, 3-iodonaphthyl, 2-fluoronaphthyl, 3-fluoronaphthyl, 2-methylnaphthyl and 3-methylnaphthyl.
The term "substituted C3-C~ cycloalkyl", as used herein, represents a cycloalkyl group of 3 to 7 carbon atoms substituted with one or two moieties chosen from the group consisting of halo and C1-C6 alkyl. Examples of substituted cycloalkyls include 2-isopropylcyclohexyl, 5-methylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-chlorocyclohexyl, 3-chlorocyclohexyl, 4-iodocyclohexyl, 3-iodocyclohexyl, 3-chlorocyclopentyl, and 3-chlorocycloheptyl.
The term "heterocycle", as used herein, represents a monovalent saturated or unsaturated group having a single ring (5 or 6 membered) or a multiple fused ring system (9 or 10 membered), and up to 4 nitrogen atoms and/or up to 2 oxygen atoms and/or up to 2 sulfur atoms, arranged to afford a stable structure that is sterically feasible. Exemplary heterocycles include: 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl and benzofurazanyl. The heterocycle may optionally be substituted with one or two moieties such as, Cl-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy and oxo. Examples of substituted heterocyclic groups include n-oxide-pyridin-3-yl, n-oxide-pyridin-4-yl, and 4-methyl-pyridin-3-yl and the like.
The term "C1-C6 alkyl", as used herein, represents a branched or linear, monovalent alkyl group having from one to six carbon atoms. Typical C1-C6 alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like. Also encompassed within the term Cl-C6 alkyl are more narrow ranges such as Cl-C4 alkyl and C2-C5 alkyl.
The term "C2-C6 alkenyl", as used herein, represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms with one double bond. Typical C2-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 1-butenyl, 2-pentenyl, and the like.
The term "C1-C6 alkoxy", as used herein, represents a straight or branched -O-(C1-C6 alkyl) chain. The oxygen atom bonds at the point of attachment to the parent molecule. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
The term "C1-C6 haloalkyl", as used herein, represents straight or branched alkyl chain having from one to six carbon atoms with one or more halogen atoms bonded thereto.
Typical C1-C6 haloalkyl groups include 3-chlorobutyl, 4-chlorobutyl, 3-iodobutyl, 4-iodobutyl, 3-fluorobutyl, 4-fluorobutyl, and the like.
The term "C1-C6 alkylene", as used herein, represents a straight chain having from one to six carbon atoms with two bonds thereto. Typical C1-C6 alkylene groups include ethylene, trimethylene, tetramethylene and the like.
The term "aryl(C1-C6 alkylene)", as used herein, represents an aryl(C1-C6 alkylene)- substituent where the alkylene group is linear, such as phenylethylene or the like. The alkylene portion bonds at the point of attachment to the parent molecule. The ring of the aryl(C1-C6 alkylene) may optionally be substituted with one or two moieties. The substituents may be located at any available position on the aryl ring.
The term "halo" or "halogen", as used herein, means fluorine, chlorine, bromine, or iodine.
The term "C1-C4 alkoxycarbonyl", as used herein, represents a C1-C4 alkoxy group attached to a carbonyl group [-C(O)-(C1-C4 alkoxy)]. The alkoxycarbonyl is bonded to the parent molecule via the carbonyl group.
The term "benzylthio", as used herein, represents a benzyl group attached to a sulfur atom (-S-CH2-phenyl). The sulfur atom bonds at the point of attachment to the parent molecule.
The term "C1-C4 alkylthio", as used herein, represents a 1 to 4 carbon alkyl chain attached to a sulfur atom [-S-(C1-C4 alkyl)]. The sulfur atom bonds at the point of attachment to the parent molecule.
The term "carbamoyl", as used herein, represents the radical NH2C0-.
The term "hydroxymethylene", as used herein, represents the radical -CH20H.
The term "n-oxide", as used herein, refers to the radical O bonded to an available nitrogen atom.
The term "C1-C5 alkanoyloxy", as used herein, refers to the group (C1-C5 alkyl)-C(O)-O-. Examples of C1-C5 alkanoyloxy's include acetoxy, pivaloyloxy, and the like.
The term "treating" as used herein includes prophylaxis of the named physical condition or delay in the onset of the named physical condition or amelioration or elimination of the disease or condition once it has been established.
The compounds of the present invention, broadly expressed as azetidinones, are a new class of compounds useful for inhibiting the proteolytic activity of PSA
(hereinafter "PSA inhibitors"). Representative compounds of the present invention have an increased selectivity for inhibiting the proteolytic activity of the serine protease, PSA, compared to the inhibition of other serine proteases [i.e., HLE (Human Leukocyte Elastase), tPA (tissue Plasminogen Activator) and thrombin].
The compounds of the present invention are known to form solvates with appropriate solvents. Preferred solvents for the preparation of solvate forms include water, alcohols, tetrahydrofuran (THF), DMF, and DMSO. Preferred alcohols are methanol and ethanol. Other appropriate WO 98/25895 PCT/US97l22573 solvents may be selected based on the size of the solvent molecule. Small solvent molecules are preferred to facilitate the corresponding solvate formation. The solvate is typically formed in the course of recrystallization or in the course of salt formation. One useful reference : concerning solvates is Sykes, Peter, A Guidebook to Mechanism in Oraanic Chemistry, 6, 56 (1986), John Wiley &
Sons, New York. The term "solvate" as used herein includes hydrate forms such as monohydrate and dihydrates.
The compounds claimed herein can also form acid addition salts with a wide variety of inorganic and organic acids. Typical acids which can be used include sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric, hydroiodic, sulfamic, citric) acetic, malefic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, g-toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like. The preferred pharmaceutically acceptable salts are those formed with hydrochloric acid or acetic acid.
While the compounds of Formula I are useful as PSA
inhibitors, certain groups of compounds of Formula I are preferred for such use. Accordingly, the preferred embodiments of the present invention includes compounds of Formula I above wherein:
R1 is benzyl, phthalimido, or a moiety of the formula:
Rs Rs O~N~
~~ I(O
where R5 is hydrogen, C1-Cg alkyl, or phenyl;
R6 is hydrogen, isopropyl, or phenyl;
- R2 is phenyl, C2-C4 alkenyl, -CH2CH2R10, -CH=C(R11)-R12~ or C=C-R13;
where R10 is carboxy or phenyl;
R11 is hydrogen or phenyl;
R12 is cyano, phenyl, naphthyl, furan-2-yl, or furan-3-yl, pyridinyl, pyrimidinyl, or quinolinyl;
where the phenyl group is optionally substituted once with C1-C4 alkyl, C1-C4 alkoxy, or nitro and where the pyridinyl group is optionally substituted once with n-oxide;
R13 is phenyl;
R3 is a heterocycle, C02R14, or H
NWRis ~S
where the heterocycle is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinazolinyl, or benzoxazolyl where said heterocycle is optionally substituted 1 or 2 times independently with nitro, trifluoromethyl, C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-C4 alkyl, C1-C4 haloalkyl, C4-C~ cycloalkyl, 2-isopropyl-5-methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally substituted once with halo, C1-C4 alkoxy, carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or furan-3-ylmethyl;
where phenyl is optionally substituted one to four times independently with halo or trifluoromethyl; and pharmaceutical acid addition salts and solvates thereof.
A most preferred embodiment of the present invention includes the compounds of Formula:

/~ ,,,, w o ,1., -O R
where R3 is a heterocycle, C02R14, or H
~NwRis f IS
where the heterocycle is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinazolinyl, or benzoxazolyl where said heterocycle is optionally substituted 1 or 2 times independently with nitro, trifluoromethyl, C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-Cg alkyl, C1-C4 haloalkyl, C4-C~ cycloalkyl, 2-isopropyl-5-methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally substituted once with halo, Cl-C4 alkoxy, carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or furan-3-ylmethyl;
where phenyl is optionally substituted one to four times independently with halo or trifluoromethyl; and pharmaceutical acid addition salts and solvates thereof.
As used herein, the numbering system noted below shall apply. The compounds of the present invention are comprised of an azetidinone nucleus, said nucleus bearing asymmetric carbons at the 3- and 4-positions as illustrated in the following figure:

R' R2 N~Rs The compounds of the invention may, therefore, exist as single diastereomers, mixtures of diastereomers or as a racemic mixture, all of which are within the scope of the present invention. The individual enantiomers can be isolated using well-known classical resolution techniques.
One particularly useful reference which describes such methods is Jacques et al., Enantiomers, Racemates, and Resolutions (John Wiley and Sons 1982). Appropriate resolution methods include direct crystallization, entrainment, and crystallization by optically active solvents. Chrisey, L.A. Heterocvcles, 257, 30 (1990).
The compounds of the above formula can exist in the form of two geometric isomers, a trans isomer and a cis isomer, or in the form of a mixture of such isomers. The "trans" isomers are considered to be those isomers in which the R1 moiety will be in the opposite or trans-position with regard to the R2 moiety. The "cis" isomers are considered to be those isomers in which the R1 moiety will be in the same or cis-position with regard to the R2 moiety.
The present invention therefore encompasses both the R
and the S configurations with regard to the 3- and 4-positions. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote the specific configuration of a chiral center. See, R.T. Morrison and R.N. Boyd) Organic Chemistry, pp. 138-139 (4th Ed. Allyn &
Bacon, Inc., Boston) and Orchin, et ai. The Vocabulary of Organic Chemistry, p. 126, (John Wiley and Sons, Inc.).
In one preferred embodiment of the present invention, the R1 moiety will be in the cis-position with regard to the R2 moiety, and in the configuration:

3 4~
N\
O 3S,4R
Racemic mixtures of the cis isomers (both the 3S,4R and 3R,4S configuration) 1 , R R1 H

i,, ,..,,,v 3 4~
N\ N
O 3S,4R ~ 3R,4S
are also contemplated within the present invention. In an alternative embodiment of the present invention, the R1 moiety will be in the trans-position with regard to the R2 moiety, and in the 3R,4R configuration:
R~ H H R2 ,,,..
~3 41 3R,4R
or 3R,4S configuration:
R~ H H z ",~,,vR

' N
3S,4S

Racemic mixtures of the trans isomers (both the 3R,4R and 3S,4S orientation) are also included within the present invention. In still a third embodiment, mixtures of the cis and trans isomers are contemplated.
In the more preferred embodiments the azetidinone nucleus exists as the trans isomer, preferably in the trans, 3R,4R configuration.
Racemic mixtures of the cis isomers, the trans isomers and mixtures of the cis and trans isomers are contemplated.
While compounds possessing all combinations of stereochemical purity are contemplated, it is preferred that the chiral centers be of a single absolute configuration.
The skilled artisan will also appreciate that when R1 is 4-substituted oxazolidin-2-on-3-yl, the 4 position on that ring is asymmetric.
The following group is illustrative of compounds contemplated within the~scope of this invention:
-1-[4-(fluoro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-[4-(nitro)benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-[(4-iodobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-[(propen-2-yl)oxycarbonyl]-3-(phthalimid-2-0)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-[(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; trans-1-[4-(methoxy)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; traps-1-[(propyl-1-ene)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethyl]azetidinone; traps-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(carboxy)ethyl]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(diphenyl)ethen-1-yl]azetidinone; cis-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; traps-1-[4-(chloro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen- 1-yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethyne-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-phenylazetidinone; 1-phenoxycarbonyl-3-[5-phenyl-oxazolidin-2-on-3-yl]-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-phenoxycarbonyl-3-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-phenoxycarbonyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yi]-4R-[2-(quinoline)ethen-1-yl]azetidinone hydrochloride; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-benzyl-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride; cis-1-phenoxycarbonyl-3-benzyl-4-[2-(cyano)ethen-1-yI]azetidinone; 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-buten-1-ylazetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3 yl)ethen-1-yl]azetidinone carboxylic acid; cis-1 phenoxycarbonyl-3-[oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-2-yl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3R-[5-(isopropyl)oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenyloxycarbonyl-3R-[4R-phenyl-oxazolidin-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone;
1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone; 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-4-yl)ethen-1-yl]azetidinone hydrochloride; 1-[(4-chlorobutyl)oxycarbonyl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone;
1-phenoxycarbonyl-3R-[4R-phenyl-oxazolidine-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone; cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-buten-1-ylazetidinone; trans-1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(naphthyl)ethen-1-yl]azetidinone; trans-1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(naphthyl)ethen-1-yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(3-methoxyphenyl)ethen-1-yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(3-nitrophenyl)ethen-1-yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-ethen-1-ylazetidinone; tracts-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-thiophenyl)ethen-1-yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(3-furanyl)ethen-1-yl]azetidinone; trans-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(5-pyrimidinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(3,5-dimethylphenyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-nitrophenyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-(2-(4-nitrophenyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-nitronaphthyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(4-nitronaphthyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-quinolinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(4-quinolinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(7-quinolinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(3-isoquinolinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(8-isoquinolinyl)ethen-1-yl]azetidinone; traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-benzothiazolyl)ethen-1-yl]azetidinone; and traps-1-phenyloxycarbonyl-3R-[4-phenyl-oxazolidin-2-on-3y1]-4R-[2-(2-benzoxazolyl)ethen-1-yl]azetidinone; -1-isopropoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-sec-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-p-nitrobenzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; tr ns-1-[2-(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-ylJazetidinone; trans-1-methoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-benzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-cyclohexyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-cyclobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-cyclopentoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-allyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-isobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-vinyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone.trans-1-[4-trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[6-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone;
traps-1-[2-phenylquinazol-4-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; trans-1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[4,6-dimethoxy-1,3,5-triazin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone. traps-1-benzylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[2-bromophenylthioamido]-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[3-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-[2-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; traps-1-[4-fluorophenylthioamido]oxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone;
traps-1-[2,3,5,6-tetrafluorophenylthioamido]-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; trans-1-[3-furfurylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone; trans-1-naphthylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-.
yl]azetidinone; trans-1-[4-trifluoromethylphenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-(2-(pyridin-3-yl)ethen-1-yl]azetidinone.
The compounds of the present invention can be prepared using chemical methods known in the art as well as by the additional processes disclosed below. Scheme I depicted below illustrates the general methods used to synthesize the compound which serves as the backbone for the Formula I
compounds of Examples 1 through 46. In all Schemes and Examples, unless otherwise indicated, preparation of the racemic mixtures of the invention are illustrated by disclosure of a single isomer.
SCHEME I

O
H2N OCH3 Solvent N
H R \ (tu) (i) /
LOCH

R, O (v) R, (vi) CI ~CI

Solvent Solvent (iv) Base FOR TRANS

Li-t-OBu O ~ ~ Solvent O

R' R2 ~ R' R2 (ix) N i (xii) N~
O 'H O H
Base O O
Solvent Base /R3 R3 Solvent S CI O

(x) (x) R1 n2 R1 R2 (X111) (xi) N
O ~O~Rs O
According to Scheme I, the preferred starting material is an aldehyde (i) in which R2 is defined above for Formula I and p-anisidine (ii). Reactive moieties within the R2 definition may be blocked by procedures well-known to those skilled in the art. Many of the aldehydes utilized are available from commercial sources. The aldehydes which are not commercially available, were prepared by methods known in the art such as those noted below in Method A. The aldehyde (i) and p-anisidine (ii) are reacted to produce an imine (iii) [STEP 1]. In a separate reaction, an acid chloride (vi) is produced by reacting oxalyl chloride (v) with an acid (iv) in which R1 is as defined above for Formula I [STEP 2]. Reactive moieties within the R1 definition may be blocked by procedures well-known to those skilled in the art. The 1-(4-methoxy)phenylazetidinones (vii) are obtainable by the 2+2 cycloaddition of the appropriately substituted, reactive imine (iii) and acid chloride (vi) [STEP 3]. The preparation of the appropriate imines (iii) and most of the required acid chlorides (vi), as well as the cycloaddition procedure, are generally described in U.S. Patent No. 4,665,171 and U.S. Patent No.
4,751,299, each incorporated herein by reference. Those not described are commercially available or are prepared by analogous procedures or procedures well known in the art.
The next step depends upon whether a traps compound or a cis compound is desired. For traps compounds, the 1-(methoxy)phenylazetidinone (vii) compounds are epimerized with Li-t-OBu at the 3 position to give the traps configuration [STEP 4A]. When the compound epimerized is a racemic mixture, then a mixture of racemic traps products will be obtained. For example, when a racemic mixture of a cis compound in which R1 is phthalimido is epimerized, a mixture which contains traps compounds having the 3(R),4(R) and 3(S),4(S) configuration will result. When a chiral auxiliary is used, the corresponding traps enantiomer will result. The epimerized compound (viii) is then subjected to CAN (cerric ammonium nitrate) oxidation to remove the p-methoxyphenyl substituent [STEP 5A]. The resulting compound (ix) is then acylated with the appropriate chloroformate (x) to produce the substituted oxycarbonylazetidinone (xi) having the traps configuration [STEP 6A].
Alternatively, for the is compounds, the 1-(methoxy)phenylazetidinone (vii) compound is subjected to CAN oxidation to remove the g-methoxyphenyl substituent [STEP 4B]. The resulting compound (xii) is then acylated with the appropriate chloroformate (x) to produce the substituted oxycarbonylazetidinone (xiii) having the corresponding cis configuration.
As discussed supra, the compounds prepared as described in Synthetic Scheme I may be pure diastereomers, mixtures of diastereomers, or racemates. The exact stereochemical composition of the compound will be dictated by the specific reaction conditions, combination of substituents, and stereochemistry of the reactants employed in Synthetic Scheme I. The skilled artisan will appreciate that diastereomeric mixtures may be separated by chromatography or fractional crystallization to provide single dia-stereomers if desired.
The bases that can be used in Synthetic Scheme I
include, among others, lithium bis(trimethylsilyl) amide, aliphatic tertiary amines, such as trimethylamine and triethylamine (TEA), dimethylaminopyridine (DMAP), cyclic tertiary amines such as N-methyipiperidine and N-methylmorpholine, aromatic amines, such as pyridine and lutidine, and other organic bases such as 1,8-diazabicyclo[5,4,0]under-7-ene (DBU).
The solvents useful for the reactions described in Synthetic Scheme I include those solvents in which the reactants may be dissolved without interfering with the reaction. The solvents which are useful include, among others, solvents such as dioxane, ethyl acetate, acetonitrile (CH3CN), dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran (THF), ethyl formate, N,N-dimethylacetamide, hexane, diethyl ether, benzene, toluene, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, and 1,2-dichloroethane, either alone or in the form of a mixed solvent.
In order to obtain acid addition salts for the present compounds, the acids noted above were also added to the product along with solvent following acylation.

Appropriate selection of the primary amine, substituent or protective group on the primary amine, reaction solvent and reaction temperature, among other things, leads to the preferential formation of one of the two isomers.
The following is a more detailed description of the steps described in Synthetic Step I. While the chemistry described below is applicable to azetidinones bearing the moieties defined in R1 and R2, for purposes of simplicity, R1 is depicted as phenyl oxazolidinone or phthalimido, R2 is depicted as (2-phenyl)ethen-1-yl and (2-pyridine)ethen-1-yl and R3 is depicted as phenyl oxycarbonyl. Those of ordinary skill in the art will recognize that the various R groups can be replaced by other moieties for which the R groups are defined without changing the overall general chemistry. The following descriptions and examples further illustrate the synthesis of the compounds of the present invention, are merely illustrative, and are not meant to limit the invention in any manner.' Other methods for preparing the compounds of the present invention, although not explicitly depicted are contemplated within the scope of the present invention.
METHOD A: Preparation of Aldehvdes (i) As indicated above, many of the aldehydes utilized can be purchased from commercially available sources. The aldehydes that are not commercially available are prepared for example by methods known in the art such as by oxidation of a primary alcohol in the presence of pyridinium chlorochromate or by reducing acyl chlorides by treating them with lithium tri-t-butoxyaluminium hydride at -78 C.
Preferably, the aldehydes are prepared according to the procedure disclosed in Anaew. Chem., 87, 486 (1975) by reacting one equivalent of an appropriately substituted carboxyaldehyde with one equivalent of FMTTP [formyl methylene triphenylphosphorane, (Ph)3PCHCHO}] in the presence of a solvent, preferably benzene or toluene. The reaction is stirred at a temperature from about 75°C to about 85°C, preferably about 80°C until all of the reactants WO 98/25895 PCTlLTS97122573 are consumed as indicated by NMR. When excess starting material is present, additional formyl methylene triphenylphosphorane can be added to further react with the excess carboxyaldehyde. The final product can be recovered using standard techniques such as filtration and/or the removal of organics by vacuum.
More specifically, by way of example, the aldehydes are produced by the method depicted below:
N / N / / H
O
O
Purpose: Large scale aldehyde production.
Procedure:
Materials FW Amt. Mole Eauiv.
pyridine 107.11 1008 .9336 1.0 FMTPP 304.33 284.138 .9336 1.0 To a 12 L round bottom flask (RBF) was charged 1008 of 3-(pyridine)carboxaldehyde (pyridine), &L of benzene (solvent) and 284.138 of (Ph)3PCHCHO (FMTPP). The resulting slurry was then heated to 80°C and stirred overnight at 80°C. The mixture was checked by NMR for completion of the reaction. NMR showed remaining starting material. Another 20% of the FMTPP was added and the mixture was stirred overnight. NMR analysis showed only a tiny amount of starting material remaining. The reaction mixture was cooled to room temperature and organics were removed by vacuum. 3L of chilled diethyl ether was added to the residue and stirred. Solids were filtered off and organics were removed by vacuum. The residue was recovered (123 g) as a dark solid. Yield=99.8 MS=132 STEP 1: Preparation of Imines (iii) The imines of the present invention are prepared by methods known in the art, for example by charging one equivalent of the aldehyde to be utilized into a reaction vessel with a solvent, preferably dichloromethane. One equivalent of a primary amine (p-anisidine) is then added to the mixture. To the mixture is added a drying agent, typically magnesium sulfate, sodium sulfate or silica gel in the amount of approximately one gram of drying agent per 3.8 grams of amine. The reaction is stirred overnight at room temperature until all of the reactants are consumed as measured by readily available techniques. The mixture is then filtered and the organics removed by vacuum to provide the desired imine.
More specifically, by way of example, the imines can be prepared as follow:
\ NHz CH30 \
H
Solvent ~ / N
N

Purpose: Large scale imine production.
Procedure:
Materials FW Amt. Mole Eauiv.
Aldehyde 132.1 2208 .9311 1.0 Anisidine 123.2 114.78 .9311 1.0 To a 2 L RBF was charged about 120 g of the aldehyde and 1 L of dichloromethane. To this mixture was charged 114.78 of g-anisidine. The mixture was rinsed with about 0.8 L of dichloromethane. Thirty (30)8 of magnesium sulfate was then added as a drying agent. The mixture was stirred overnight at room temperature. NMR showed a complete reaction. The magnesium sulfate was filtered off and the organics were removed by vacuum to afford 210.65 g of imine.
Yield=94.98 MS=238 STEP 2: Preparation of Acid Chloride (vi) The acid chlorides used in the present invention are also produced by methods known in the art such as the method disclosed in U.S. Patent No. 4,665,171, incorporated herein by reference. For example, 1.8 molar equivalents of oxalyl chloride is reacted with one equivalent of the appropriately substituted acid in the presence of a solvent (preferably toluene or benzene) to produce the acid chloride. The reaction is heated to about 60°C for about 3-4 hours under inert gas (i.e., nitrogen gas, helium gas or argon gas).
The reaction mixture is cooled to room temperature and the organics removed by vacuum.
By way of example, the acid chlorides are produced as follows:

cl ci Solvent o~ O~
o 0 o C-ci Purpose: Acid chloride formation.
Procedure:
Materials FW Amt. Mole Eauiv.
Acid 221.7 100g .4511 1.0 OC 126.3 103.68 .8162 1.8 The acid was slurried in 2840 ml of toluene at room temperature. Oxalyl chloride (103.6 g) was added all at once. The solution was heated to 60°C for 4 hours under a nitrogen purge. The mixture was then cooled to room temperature and the toluene was removed by vacuum to give an oil. The oil solidified upon standing at a sub-zero temperature. 113 g of the acid chloride was produced.
STEP 3: 2+2 Cvcloaddition The process of 2+2 cycloaddition is well known in the art. Specific reference to this procedure is noted in G.I.
Georg, Ed.; The Oraanic Chemistrv of J3-lactams, Verlag Chemie, New York, 1992, Chapter 6 as well as in U.S. Patent No. 4,751,299 and U.S. Patent No. 4,665,171, each incorporated herein by reference. Generally, 1 equivalent of the appropriate acid chloride and dichloromethane are charged into a reaction vessel and the mixture is cooled to about -78°C. 1.5 equivalents of an appropriate tri(C1-. C4)amine, typically TEA, was then added to the mixture while keeping the temperature < 70°C. The reaction mixture is stirred thoroughly. The imine, dissolved in dichloromethane (lOml dichloromethane/2 g imine), is slowly added keeping the temperature around approximately -70°C. While the addition time is not critical, best results are achieved when the addition generally takes place dropwise over a period of from about 1 to about 6 hours. The reaction mixture is then stirred for an additional period of time, from about 2 to about 4 hours. The reaction is carried out at a temperature from about -78°C to about 25°C, preferably from about -78°C to about 0°C and even more preferably from about -78°C to about -75°C in a solvent in the present of tri(C1-C4)amine. The reaction mixture is then allowed to warm to room temperature and the reaction is quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture is separated and the organics are removed by vacuum. Ethyl acetate is added to the solid residue and stirred 1 hour. The resulting wet cake is rinsed in large amounts of ethyl acetate. A final rinse with ether is performed. The resulting product is then dried in vacuum overnight at 40°C.
More specifically) by way of example, the 2+2 cycloaddition is performed as follows:

:.\ .\ I
..
~N
\ / N ~ Amme i O ~ \
~ Solvent N + O
\ O O N
I / O I \

Purpose: Large scale 2+2 Cycloaddition to form the ~i-lactam.
Procedure:
Materials FW Amt. Mole Eauiv.
Imine 238 21o.65g .8851 1.0 Acid C1 239 210.9 .8825 1.0 TEA 101.2 133.96g 1.324 1.5 To a 12 L RBF was charged 210.9g of the acid chloride and 2 L of dichloromethane. The mixture was cooled to -78°C. To this pink/purple mixture was added 133.96 g of TEA
keeping the temperature around 70°C. The reaction mixture was stirred for 15 minutes. The imine, dissolved in 2 L
dichloromethane, was slowly added keeping the temperature around -70°C. The addition time was approximately 5 hours.
The reaction mixture was stirred for 2 hours at -75°C. The reaction mixture was then slowly warmed to room temperature.
TLC was done at 0°C. TLC performed at room temperature showed no difference from that performed at 0°C. The reaction was quenched with 3 L of saturated NH4C1 (about 5008 NH4C1), separated and the organics were removed by vacuum. 1 L of ethyl acetate was added to the solid residue and stirred 1 hour. The resulting wet cake was rinsed in large amounts of ethyl acetate. A final rinse with diethyl ether was performed. The resulting product was dried in vacuum overnight at 40°C. Gross Weight=176 %Yield=46%
MS=441.3 WO 98125895 PCTlfJS97/22573 Theory Found C 70.73 70.60 H 5.25 5.14 N 9.52 9.43 STEPS 4A-6A: Preparation of TRAMS Isomers STEP 4A: Epimerization Epimerization of the 2+2 cycloaddition product with Li-t-OBu was performed in order to obtain the isomers having the trans configuration. Surprisingly, it was discovered that higher yields and better purity resulted from epimerization with Li-t-OBu than other reagents, such as, K-t-OBu.
The substituted cis azetidinone can readily be epimerized into a substituted trans azetidinone by the addition of 1.1 equivalent of Li-t-OBu to a mixture of 1 equivalent of the material [the substituted (methoxy)phenylazetidinone) dissolved in a solvent, preferably dry tetrahydrofuran, at a temperature of about 0°C. The reaction is quenched with saturated NH4C1 and partitioned. The organic layer is DarcoTM treated (activated carbon), dried with magnesium sulfate, filtered and dried by vacuum.
More specifically, by way of example, epimerization may be carried out as follows:

_ 34 -Li-t-OBu THF p C
I /
~OCH OCH3 Purpose: Epimerization of the 2+2 product using Li-t-OBu.
Procedure:
Materials FW Amt. Mole Eauiv.
Cis 2+2 441 50.Og .1134 1.0 Li-t-OBu 80.05 9.988 .1247 1.1 To a 12 L RBF was charged 50.Og of 1-methoxyphenyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (cis 2+2) and 2500m1 of dry tetrahydrofuran at room temperature. The mixture was cooled to 0°C in an ice bath. 9.988 of Li-t-OBu was added all at once. The mixture was stirred for about 20 minutes. The ice water was removed from the bath and the mixture was slowly allowed to warm to room temperature. The intermediate which had come out of solution went back into solution at 2°C. NMR at room temperature showed a slight amount of the cis material. The mixture was stirred overnight at room temperature. NMR
showed a slight amount of cis still remaining. The reaction was quenched with 2 L of saturated NH4C1 solution. The organic layer was DarcoTM treated, dried with magnesium sulfate and filtered. The organics were removed by vacuum.
Gross=42.78 oYield=85.4 MS=441 Theorv Found C 70.74 70.96 H 5.25 5.39 N 9.52 9.55 STEP 5A: CAN (Cerric Ammonium Nitrate) Oxidation CAN oxidation is known in the art as depicted in J.
Ora. Chem., 47, 2765-68 (1982). Treatment of a compound with CAN in the presence of acetonitrile under relatively mild conditions yields a product in which the methoxyphenyl - group has been removed. More specifically, by way of example, oxidation of the trans isomer is achieved as follows:
:W
II ' v N%. ~ \ N CAN O N ' \ N
aq. CH3CN O
\ O H
O

Purpose: CAN Oxidation.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 441 35.788 .0821 1.0 CAN 548.2 177.98 .3245 4.0 To a 12 L flask was charged 35.788 of 1-(4-(methoxy)phenyl-3R-[4-phenyl-oxaxolidin-2-on-3-yl]-4R-[2-pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) and 3.5L of the solvent acetonitrile. The mixture was cooled to -10°C.
To this mixture was slowly added a solution containing 177.98 of CAN and 3.5 L of deionized H20 keeping the temperature at -10°C. The mixture was stirred at -10°C and the progress of the reaction was monitored by TLC(ETOAC).
. Since the reaction did not go to completion, another 0.5 equivalents of CAN was added and the mixture was stirred for 1 hour. TLC indicated that the reaction was complete.
7.0 L sodium bicarbonate and 3.0 L of ethyl acetate were added and the mixture was warmed to room temperature. The mixture was then filtered through CeliteTM. The layers were separated and the aqueous layer was back extracted with 2 X
2 L ethyl acetate. The combined organic layers were washed with 4 L of 10~ sodium sulfite. The organic layer was then DarcoT~'' treated and dried with magnesium sulfate. Organics were removed by vacuum. Gross=16.9g Yield=62.36 MS=335.2 Theory Found C 68.05 68.06 H 5.11 5.11 N 12.53 12.43 STEP 6A: Acvlation Acylation is carried out by dissolving the substituted azetidinone in a solvent, preferably dichloromethane. Base is then added to the reaction mixture. The substituted chloroformate is then added and the reaction is stirred until completion. The reaction is then quenched with ammonium chloride, DarcoTM treated and dried with a drying agent. The resulting solid is then washed in solvent and then dried. Mare specifically, by way of example, acylation was performed generally as follows:
/ ~ Solvent N \ N DMAP O N~
\ TEA
O NvH O \ O I/
O ~O ~ O
CI /
Purpose: Acylation of free amine.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 334.0 l5.Og .0449 1.0 DMAP 122.2 CAT
TEA 101.2 9.09m1 .0898 2.0 PCF 156.6 14.06m1 .0898 2.0 To a 12 L RBF was charged lS.Og of the 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) and 4690m1 of dichloromethane.
DMAP (dimethylaminopyridine) was added at room temperature and the mixture was stirred for 10 minutes. TEA was added . all at once and the mixture was stirred for 10 minutes.
Phenyl chloroformate (PCF) was then added slowly. TLC at end of the addition showed starting material remaining. The mixture was stirred for about 2 hours at room temperature.
TLC showed no change. Another 2 equivalents each of TEA and PCF were added and the mixture was stirred for 1 hour at room temperature. TLC showed no change. Still another 2 equivalents each of TEA and PCF were added and the mixture was stirred for 1.5 hours. TLC showed little change. An addition 4.0 equivalents each of TEA and PCF were added along with 0.1 equivalents of DMAP. The mixture was allowed to stir overnight at room temperature. TLC showed little change. The reaction was quenched with 4 L of saturated NH4C1, DarcoTM treated and dried with magnesium sulfate.
The organics were removed to give a white solid. The solid was slurried in diethyl ether and filtered. The solid would not dissolve in 4L ethyl acetate so 4L of dichloromethane was added to get dissolvation. 72m1 of 1M hydrochloric acid in ether was added and the mixture was stirred for 1 hour.
Organics were removed by vacuum to produce a white solid.
The solid was slurried in ether and filtered. Extended drying at 60°C was needed to get rid of residual solvents.
Gross=6.2 %Yield=30.4 MS=455.5 Theory Found C 63.48 63.27 H 4.51 4.46 N 8.54 8.44 C1 7 . 21 6 . 97 STEPS 4B-5B' Preparation of Cis Isomers The compounds of the present invention that are cis isomers are generally prepared by subjecting the product obtained from the 2+2 cycloaddition step above to CAN
oxidation followed by acylation as depicted below:
STEP 4B: CAN (ferric Ammonium Nitrate) Oxidation CAN Oxidation is known in the art as depicted in ,7.
Ora. Chem., 47, 2765-2768 (1982). The procedure is carried out in the same manner as noted above in STEP 5A. More specifically, by way of example, the oxidation was carried out as follows:
O
CAN O
aq. CH3CN
O 'H
~OCH3 Materials FW Amount Mole Eauiv Intermed. 424.5 20.08 47.12mmole 1 CAN 548.2 77.688 141.36mmole 3-4 The cis-1-methoxyphenyl-3S-(phthalimid-2-o)-4R-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was slurried in 600m1 acetonitrile and cooled to 0°C. A solution of CAN in 600m1 H20 was then added dropwise to the slurry at 0°C. The mixture was covered and allowed to sit for a 30 minute period. The mixture was then stirred an additional 30 minutes at 0°C before being extracted with 500 ml ethyl acetate. The aqueous component was then back extracted with 2 X 300m1 ethyl acetate. The wash was then combined with 1 X 500m1 5o sodium bicarbonate and 3 X 500m1 10~ sodium sulfite. The combined organics were slurried with 508 DarcoTM for 30 minutes and then 1008 magnesium sulfate was added. The mixture was stirred for an additional 15 minutes before being filtered through Celite. The solution was concentrated under vacuum to give an oil. The oil was dissolve in 60m1 ethyl acetate and triturated with 250m1 ether. The mixture was filtered and a fine white solid 2.708 pure product was collected. The filtrates were purified over silica gel to obtain an additional 4.048 pure product. Gross=6.748 Yield=44.99 MS=317.5 STEP 5B: Acvlation Acylation was performed in the same manner as noted above in STEP 6A. More specifically, by way of example, acylation was performed as follows:
PCF
N LIHMDS
p ~ THF
H
Purpose: Acylation of free amine.
Procedure:
Materials FW Amt. Mole Eauiv.
Intermed. 318 .2g .629 1.0 PCF 156.6 0.16m1 1.26mM 2 LHMDS 0.63m1 .629mM 1.0 The 3-phthalimid-2-o-4-[2-(phenyl)ethene-1-yl]azetidinone (Intermed.) was combined with 6 ml dry tetrahydrofuran. The mixture was cooled to -75QC. 1. OM
LHMDS (lithium bis(trimethylsilyl)amide) was added to the reaction dropwise under nitrogen via syringe. The mixture was stirred at -75gC for 30 minutes. PCF was added all at once and the mixture was stirred at room temperature for one hour. The reaction was then quenched with NH4C1 and extracted with ethyl acetate. The organics were purified over silica gel. 0.1058 of a white solid were obtained.
MS=438 Theorv Found C 71.23 71.53 H 4.14 4.27 N 6.39 6.49 Preparation of 1:I mixtures of cis-trans isomers Alternatively, 1:1 mixtures of the cis:trans isomers of the present invention may be prepared by combining the steps as follows:
Et~imerization and Acylation / O / o ~ / o N \ ~ N ~ \
\ .) O N CI OPh O
Solvent N O
o H TEA o \
O
CIS TRANS
Materials FW Amt. Mole E iv Intermed. 318 2g 6.29mmole 1 PCF 156.6 1.58m1 12.58mmole 2 TEA 101.2 8.77m1 62.90mmole 10 DMAP 222.2 CAT
The cis Intermed. was combined with 50m1 dichloromethane at room temperature. TEA was added to the mixture all at once. A solution of phenyl chloroformate in 20m1 dichloromethane was added to the reaction dropwise, slowly at room temperature. The solution was stirred overnight at room temperature. The reaction was quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel using 100% Hexane (1:1 Hexane/ethyl acetate). A 1.698 mixture of cis/trans isomers was obtained. The mixture was dissolved in 100m1 ethyl acetate, 300m1 of hexane was added, and seeded with pure traps. The mixture was allowed to stand overnight. The mixture was filtered and a fine white crystal was collected. 99.4 traps 0.6~ cis Obtained 0.898 traps MS=438 Theorv Found C 71.23 71.46 4.14 4.35 N 6.39 6.18 The following Examples further illustrate the compounds of the present invention and the methods for their synthesis. The Examples are not intended to limit the scope of the invention in any respect, and should not be construed as such. The starting materials for Examples 1 through 46 were prepared according to the general procedures set forth in Synthetic Scheme I.
Example 1 traps-1-[4-(fluoro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone N
O
O
Materials FW Amt Mole E iv Intermed. 318 0.1508 0.4716mM 1 4-FPCF 174.56 0.124m1 0.9432mM 2 T~ 101.2 0.651m1 4.716mM 10 DMP~P 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-ylazetidinone (Intermed.) was dissolved in 10 ml dichloromethane at room temperature. DMAP
(4-dimethylaminopyridine) and TEA were added all at once.
4-fluorophenyl chloroformate (4-FPCF) in 10m1 dichloromethane was added dropwise to the reaction at room temperature under nitrogen. The mixture was stirred at room temperature for 24 hours and then quenched with 1N
hydrochloric acid. The organics were separated and purified over silica gel. 106 mg of a white solid were obtained at a yield of 49.3%. MS=456 Example 2 trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole Ectuiv Intermed. 318 2g 6.29mM 1 PCF 156.6 1.58m1 12.58mM 2 TEA 101.2 8.77m1 62.90mM 10 DMAP 222.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was combined with 50m1 dichloromethane at room temperature. TEA and DMAP were added to the mixture all at once. A solution of phenyl chloroformate (PCF) in 20 ml dichloromethane was added to the reaction dropwise, slowly at room temperature. The solution was stirred overnight at room temperature. The mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel using ~ / \

100% hexane (1:1 hexane/ethyl acetate). A 1.69g mixture of cis/trans isomers was obtained. The mixture was then dissolved in 100 ml ethyl acetate, 300 ml of hexane was . added and then the mixture was seeded with pure trans. The mixture was allowed to stand overnight. A fine white crystal was collected by filtration. 1H-NMR showed no cis isomers. HPLC showed 99.337% trans and 0.553% cis. 0.89 g of trans were obtained. MS=438 Theory Found C 71.23 71.47 H 4.14 4.35 N 6.39 6.18 Example 3 trans-1-[4-(nitro)benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole E iv Intermed. 318 O.lg 0.3144mM 1 4-nitro 215.6 0.136g 0.6288mM 2 T~ 101.2 0.438m1 3.144mM 10 DMAP 122.2 CAT
3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 4m1 dichloromethane under dry tube at room temperature. TEA and DMAP were added all at once. 4-nitrobenzyl chloroformate (4-nitro) in 6 ml dichloromethane was then added dropwise to the mixture at room temperature. The resulting mixture was stirred overnight then quenched with 1N hydrochloric acid. The organics were then separated and purified over silica gel.
123 mg of a white solid were obtained at a yield of 79~.
MS=497 Example 4 1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone O /
N
O
.. ~O
/jO
O
CI
Materials FW Amt Mole Ecruiv Intermed. 318 0.5g 1.57mM 1 TEA 101.1 2.18m1 15.70mM 10 4C 171.02 0.43m1 3.14mM 2 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in l0ml dichloromethane. TEA and DMAP were added all at once followed by the dropwise addition of 4-chlorobutylchloroformate (4C) in 10m1 dichloromethane at 25°C. The mixture was stirred at room temperature with dry tube for 72 hours. The mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified over silica gel. 204 mg of a 1:1 cis/trans mixture was obtained. Yield=57 MS=451.9 Example 5 trans-1-[(4-chlorobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone O
O
~N O
O~~
O
CI
The trans isomer was obtained in the same manner as Example 4. The trans isomer was isolated from the silica gel instead of the cis isomer. Yield=57 MS=451.2 Example 6 trans-1-[(4-iodobutyl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole E iv ' 452 0.18 0.2212mM 1 NaI 150 0.1668 1.106mM 5 . The product of~Example 5 and sodium iodide were combined in 10 ml of acetone. The mixture was stirred overnight at room temperature. The mixture was then filtered. The filtrate was concentrated under vacuum to give 73mg of a yellow solid. oYield=60.6 MS=544 Example 7 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole E iv Intermed. 318 0.2 0.629mM 1 PCF 150.6 0.26m1 1.26mM 2 TEA 101.2 0.88m1 6.19mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was combined with 5m1 dichloromethane at room temperature. TEA and DMAP were added all at once. Phenyl chloroformate (PCF) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with NH4C1 solution followed by extraction with ethyl acetate. The organics were purified over silica gel to obtain 120mg of a white solid as a 1:1 cis/trans mixture.
Yield=43.5 MS=438 o / \

WO 98/25895 PCTlUS97122573 Example 8 trans-1-benzyloxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole Eauiv Intermed. 3I8 0.1508 0.4716mM 1 BCF 110.6 0.135m1 0.9432mM 2 TEA 101.2 0.657m1 4.716mM 20 DMAP 122.2 CAT
The 3S-(phthalimid-2-o)-4R-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5m1 dichloromethane at room temperature. TEA and DMAP were added all at once followed by benzyl chloroformate (BCF) dropwise at room temperature. The mixture was stirred at room temperature for 24 hours. The mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 160 mg of a white solid was obtained. Yield=75 MS=452.2 Theorv Found C 71.67 71.86 H 4.45 4.95 - N 6.19 6.17 O
O

Example 9 1-[(2-propen-1-yl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole E iv Intermed. 318 0.2g 0.6289mM 1 AC 120.54 0.13m1 1.2578mM 2 TEA 101.2 0.88m1 6.289mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in approximately 8 ml dichloromethane at room temperature. TEA and DMAP were added all at once. A solution of allyl chloroformate (AC) in dichloromethane was added dropwise at room temperature.
The mixture was stirred at room temperature overnight and then quenched with 1N hydrochloric acid. Organics were separated and purified over silica gel. 185 mg of a white solid was obtained. °sYield=73 MS=402.4 O

Example 10 1-[(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole- Eauiv Intermed. 315 0.2g 0.629mM 1 5MC 219 0.288 1.26mM 2 TEA 101.2 0.88m1 6.29mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5ml dichloromethane at room temperature. TEA and DMAP were added all at once followed by 2-mentayl chloroformate dropwise. The mixture was stirred at room temperature for 24 hours and then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 105 mg of a white solid were obtained. Yield=33.4 MS=500 O
O
::

Example 11 traps-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-0)-4-[2-(phenyl)ethen-1-yl]azetidinone O
O
O
Materials FW Amt Mole E iv Intermed. 318 1g 3.14mM 1 TEA 101.2 4.38m1 31.45mM 10 MCPCF 214.6 1.358 6.28mM 2 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 25m1 of dichloromethane at room temperature under dry tube. TEA was added all at once with DMAP. A solution of 4-methoxy carbonylphenyl chloroformate (MCPCF) in 10m1 dichloromethane was added slowly dropwise to the rapidly stirred reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified over silica gel using 100°s hexane (1:1 hexane/ethyl acetate). 750mg of a white solid were obtained.
Yield=48.2 MS=496 Examble 12 trans-1-[4-(methoxy)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone O

O-Materials FW Amt Mole E iv Intermed. 318 0.5g 1.57mM 1 TEA 101.2 2.19m1 15.72mM 10 p-OCH3PCF 186.6 0.467m1 3.14mM 2 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 25m1 dichloromethane at room temperature. TEA and DMAP, followed by 4-methoxy phenylchloroformate (p-OCH3PCF) were added dropwise. The mixture was stirred for 16 hours at room temperature and then quenched with 1N hydrochloric acid.
Organics were separated and purified over silica gel. 370 mg of a white solid were obtained. Yield=50.4 Ms=468 Theorv Found C 69.23 69.11 H 4.30 4.28 N 5.98 5.94 Example 13 traps-1-[(2-propen-1-yl)oxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone ~o / I

o N oU

Materials FW Amt Mole Ecruiv Intermed. 318 0.1508 0.4716mM 1 chloroformate 256.6 0.2428 0.9432mM 2 TEA 101.2 0.657m1 4.716mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in tetrahydrofuran at room temperature. TEA and DMAP were added all at once.
A solution of chloroformate in tetrahydrofuran was added to the reaction dropwise at room temperature. The mixture was stirred overnight then partitioned between ethyl acetate/1N
hydrochloric acid. Organics were purified over silica gel.
150 mg of a white solid were obtained. Yield=61 MS=522 Example 14 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone ~O /
O
O
O
Materials FW Amt Mole E iv Intermed. 319 100mg 0.3134mM 1 TEA 101.2 0.437m1 3.134mM 10 PCF 156.6 0.074m1 0.6268mM 2 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in dichloromethane at room temperature. TEA and DMAP were added all at once.
A solution of phenyl chloroformate (PCF) in dichloromethane was added to the reaction dropwise via a syringe. The reaction was protected with dry tube. The mixture was then quenched with 1N hydrochloric acid. Organics were separated and purified over silica gel. 89mg of a white solid were obtained. Yield=64.5 MS=440 Example 15 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride o ' o 50 mg of the compound of Example 14 was dissolved in 2 ml ethyl acetate. 0.5 ml of 1N hydrochloric acid in ether was added. The mixture was stirred for 1 hour at room temperature. A white solid was filtered from the mixture.
44 mg of product were obtained. oYield=81.3 MS=440 Example 16 cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-(2-(phenyl)ethyl]azetidinone O
Materials FW Amt Mole E iv Intermed. 316 -- 0.4716mM 1 PCF 156.6 0.118m1 0.9432mM 2 TEA 101.2 0.66m1 4.716mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.), PCF and DMAP were combined in 10 ml dichloromethane at room temperature under nitrogen. A
solution of TEA in 10m1 dichloromethane was added dropwise under nitrogen. The mixture was stirred at room temperature until the reaction appeared complete. The mixture was then quenched with 1N hydrochloric acid and the organics were separated and purified over silica gel. 130mg of a white solid were obtained. Yield=63 MS=440 Theory Found C 70.94 70.64 H 4.58 4.53 N 6.36 6.07 Example 17 trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(carboxy)ethen-1-yl]azetidinone OH
0 ~
50mg of (t) trans-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(carboxybenzyl)ethen-1-yl]azetidinone (Intermed.) in 3m1 dichloromethane was combined at room temperature with lOmg of 5% Pd-c. The mixture was stirred under a balloon hydrogen. Thin layer chromatography indicated a new spot forming. The mixture was stirred overnight under hydrogen.
Organics were separated and purified over silica gel.
25.5mg of a white solid were obtained. %Yield=62 MS=408 Example 18 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2,2-(diphenyl)ethen-1-yl]azetidinone WO 98/25895 PCTlUS97/22573 Materials FW Amt Mole Eauiv Intermed. 394 125mg 0.3172mM 1 PCF 156.6 0.08m1 0.6344mM 2 TEA 101.2 0.442m1 3.172mM 10 DMAP 222.2 CAT
5m1 of 3-(phthalimid-2-o)-4-[2,2-(diphenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in dichloromethane at room temperature. TEA and DMAP were added all at once.
Phenyl chloroformate (PCF) was added dropwise to the mixture at room temperature and stirred overnight. The mixture was then quenched with 1N hydrochloric acid. Organics were separated and purified over silica gel. 104mg of a white solid were obtained. oYield=63.7 MS=514 Examt~le 19 cis-1-[4-(methoxycarbonyl)phenoxycarbonyl]-3-(phthalimid-2-0)-4-[2-(phenyl)ethen-1-yl]azetidinone O ~v O
O
Materials FW Amt Mole E iv Intermed. 318 0.1g 0.3144mM 1 MCP 152 96mg 0.6288mM 2 Phosgene 1.93M 0.326m1 0.6288mM 2 Pyridine 79.10 0.069m1 0.6288mM 2 4-methoxyc arbonylphenol was combined (MCP) with dichloromethane at room temperature. solution of A 1.93M

phosgene was added via syringe under nitrogen. The solution WO 98!25895 PCT/US97I22573 was cooled to -60°C. Pyridine was added dropwise via syringe. The mixture was stirred at -60°C for 15 minutes and then warmed to -10°C for 1 hour. 3-(phthalimidin-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was added via syringe all at once. The mixture was warmed to room temperature. No reaction by TLC. 10 eq. RA was added all at once. The mixture was then stirred at room temperature overnight. Complete reaction by TLC was then observed. The reaction mixture was quenched with 1N hydrochloric acid.
Organics were separated and purified over silica gel. 84 mg of a white solid were obtained. Yield=54 MS=496 Example 20 cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yI]azetidinone 20mg of 3-(phthalimid-2-o)-4-[2-(phenyl)ethyn-1-yl (Intermed.) azetidinone were dissolved in ethanol in a Parr bottle. 5~ Pd on calcium carbonate poisoned with lead (Lindar's Catalyst-CAT) was added. The mixture was placed on a Parr shaker at 20 psig/room temperature for 2 hours.
The solid was purified over silica gel. l6mg of product were obtained. Yield=79.6 MS=438.
O

Example 21 cis-1-[4-(chloro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone CI
Materials FW Amt Mole E iv Intermed. 318 0.1168 0.3647mM 1 TEA 101.2 0.508m1 3.647mM 10 PC1PCF 190 O.lml 0.7194mM 2 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5m1 dichloromethane under nitrogen. TEA and DMAP were added all at once. A solution of 4-chlorophenyl chloroformate (PC1PCF) in 5m1 dichloromethane was added dropwise at room temperature under nitrogen. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel for a total yield of 79~. 68mg of the desired were obtained. MS=472.1 Theorv Found 66.04 66.21 3.62 3.60 N 5.92 6.04 Examt~ 1 a 2 2 traps-1-[4-(chloro)phenoxycarbonyl]-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone CI
The product was obtained in the same manner as Example 21 with the exception that the traps isomer was isolated from the silica gel. 68 mg were obtained.
MS=472.1 Theorv Found C 66.04 66.19 H 3.62 3.57 N 5.92 6.04 Example 23 cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt Mole E iv Intermed. 318 0.2g 0.629mM 1 PCF 156.6 0.16m1 1.26mM 2 LHI~IDS 1.OM 0.63m1 0.629mM 1 The 3-(phthalimid-2-o)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was combined in 6m1 dry tetrahydrofuran. The mixture was cooled to -75°C. 1. OM
LHI~S (lithium bis(trimethylsilyl) amide) in tetrahydrofuran was added to the reaction dropwise under nitrogen via syringe. The mixture was stirred at -75°C for 30 minutes.
Phenyl chloroformate (PCF) was added all at once and the mixture stirred at room temperature for 1 hour. The reaction was then quenched with NH4C1 solution followed by extraction with ethyl acetate. The organics were purified over silica gel. 0.1058 of a white solid were obtained.
Yield=38.1 MS=438 Theorv Found C 71.23 71.53 H 4.14 4.27 N 6.39 6.49 Exam>Jle 24 cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-[2-(phenyl)ethyn-1-yl]azetidinone ~N
O ~O
O

Materials FW Amt Mole Ecruiv Intermed. 316 0.1g 0.3164mM 2 PCF 156.6 0.08m1 0.6328mM 2 TEA 101.2 0.441m1 3.164mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-j2-(phenyl)ethyn-1-yl]azetidinone (Intermed.) was dissolved in dichloromethane at room temperature. TEA and DMAP were added all at once.
A solution of phenyl chloroformate (PCF) in dichloromethane was added to the reaction dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was quenched with 1N hydrochloric acid. The organics were purified over silica gel. 83mg of a white solid were obtained.
%Yield=60.1 MS=436 Example 25 cis-1-phenoxycarbonyl-3-(phthalimid-2-o)-4-phenylazetidinone o /r -N
~O
//O
Materials FW Amt Mole E iv Intermed. 296 0.1g 0.3424mM 1 TEA 101.2 0.48m1 3.424mM 10 PCF 156.6 0.085m1 0.6848mM 2 DMAP 122.2 CAT

The 3-(phthalimid-2-o)-4-phenylazetidinone (Intermed.) was dissolved in 5ml dichloromethane at room temperature.

TEA and DMAP were added all at once. Phenyl chloroformate (PCF) was then added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 48mg of a white solid were obtained. Yield=33.9 MS=412 Example 26 1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone 0~,,~~~~
N \ ~N
ii., ~/ v O
~--N
O ~O
O
Materials FW Amt Mole E iv Intermed. 333 0.1g 0.6006mM 1 TEA 101.2 0.167mM 1.2012mM 2 PCF 156.6 0.150m1 1.2012mM 2 DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in dichloromethane. The mixture was cooled to -10°C under nitrogen. DMAP was added followed by TEA at -10°C. The mixture was stirred for 5 minutes. Phenyl chloroformate was added dropwise via syringe. TLC 1 hour after addition showed complete reaction. The mixture was stirred for an additional hour at +10°C. The reaction was quenched with saturated NH4C1. Organics were dried over magnesium sulfate and concentrated under vacuum to residue. The residue was then slurried in ether at room temperature. The mixture was filtered and 87mg of off white solid were collected.
Theorv Found C 68.56 68.45 H 4.65 4.74 N 9.23 9.04 Example 27 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride O~,,w\
N
Nip., \ /
O I
O~-N
O
O
87mg of free-base Example 26 were dissolved in ethyl acetate. 5 eq. of 1N hydrochloric acid in ether was added at room temperature dropwise. An immediate precipitant was noted. The mixture was stirred at room temperature for 30 minutes. Solvents were removed under vacuum to give 105mg of a white solid. MS=455.
Theorv Found C 63.48 63.27 H 4.51 4.46 N 8.54 8.44 C1 7.22 6.91 Example 28 1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride /
O ~ /N
N
O
O
Materials FW Amt Mole E iv Intermed. 333 0.1g 0.3003mM 1 PCF 156.6 0.075m1 0.6006mM 2 TEA 101.2 0.4186m1 3.003mM 10 DMAP 122.2 CAT
The 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl}ethen-1-yl]azetidinone (Intermed.} was dissolved in dichloromethane at room temperature under nitrogen. TEA and DMAP were added all at once. A solution of phenyl chloroformate (PCF) in dichloromethane was added to the reaction dropwise under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 43mg of a 1:1 cis/trans product were obtained.
Example 29 1-phenoxycarbonyl-3S-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride O

l~
'1 O , /N
N
_ O
N
O ~O
O
I~
The product was obtained in the same manner as Example 28 with the exception that the cis isomer was isolated. 30mg were obtained. 'MS=491 Examt~le 30 1-phenaxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(quinoline)ethen-1-yl)azetidinone hydrochloride O
O
Materials FW Amt Mole Ecruiv Intermed. 335 0.1578 0.4686mM 1 PCF 156.6 0.118m1 0.9377mM 2 TEA 101.2 0.635m1 4.686mM 10 DMAP 122.2 CAT

The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(quinoline)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5 ml dichloromethane at room temperature. TEA and DMAP
were added all at once followed by the dropwise addition of phenylchloroformate (PCF) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with 1N hydrochloric acid.
Organics were separated and 5 eq 1N hydrochloric acid in ether was added to the organics. 43 mg of a white solid were obtained. %Yield=16.3% MS=528 Examble 31 1-phenoxycarbonyl-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone \
O~,.wv N~~. \
O I
O/r N
~O
O//
Materials FW Amt Mole Ecruiv Intermed. 334 0.1668 0.497mM 1 TEA 101.2 0.416m1 2.98mM 6 PCF 156.6 0.125m1 0.994mM 2 DMAP 122.2 CAT
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5m1 dichloromethane at room temperature. TEA and DMAP were added all at once followed by phenyl chloroformate (PCF) dropwise. The reaction mixture was stirred at room temperature for 24 hours. The mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 60mg trans were obtained.

Example 32 1-phenoxycarbonyl-35-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-. (phenyl)ethen-1-yl)azetidinone off,,,,,, , N \ \
O I
-N
O ~O
O
The same procedure was used as in Example 30 with the exception that 55mg of the cis isomer was obtained from the silica gel.
Example 33 1-phenoxycarbonyl-3-(phthalimid-2-o)-4-(3-buten-1-yl)azetidinone Materials FW Amt Mole E iv Intermed. 270 0.2g 0.741mM 1 PCF 156.6 0.186m1 1.48mM 2 TEA 101.2 1.03m1 7.407mM 10 DMAP 122.2 CAT
The 3-(phthalimid-2-o)-4-(3-buten-1-yl)azetidinone (Intermed.) was combined in 20m1 dichloromethane at room temperature. TEA and DMAP were added all at once. A
solution of PCF in 10 ml dichloromethane was added under nitrogen to the reaction dropwise at room temperature. The mixture was stirred for 24 hours and then quenched with 1N
hydrochloric acid. The mixture was purified over silica gel to obtain a pure product. lO8mg of a white solid (a 1:1 cis/trans mixture) was obtained. oYield=37o MS=390 Example 34 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl']azetidinone acetate l~
o , /N
N~' O I
O~--N
O O
O \ H3C OH
1 g of the azetidinone of Example 26 was dissolved in 10 ml ethyl acetate. 1 ml of acetic acid was then added.
The mixture Was stirred at room temperature for 5 hours.
The mixture was then filtered and 0.758 of a white solid was collected. Yield=66.2 MS=455 Examble 35 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-2-yl)ethen-1-yl]azetidinone (,,W\ ~ /
O
N~. \ ~ N
O
~--. N
O ~O
/O
Materials FW Amt Mole E iv Intermed. 333 0.1g 0.6006mM 1 TEA 101.2 0.167m1 1.2012mM 2 PCF 156.6 0.150m1 1.2012mM 2 DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-2-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5ml dichloromethane at room temperature. TEA and DMAP were added all at once followed by phenyl chloroformate dropwise.
The reaction mixture was stirred at room temperature for 16 hours. The reaction was then quenched with 1N hydrochloric acid. The organics were separated and 5 eq. 1N hydrochloric acid in ether. The mixture was filtered and 63mg of a white solid was obtained. Yield=21.4 MS=455.

Example 36 1-phenyloxycarbonyl-3R-[4R-phenyl-oxazolidin-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone O
Nii., \
O I
O
i' Materials FW Amt Mole E iv Intermed. 334 32.9mg 0.0985mM 1 PCF 157 0.025m1 0.197mM 2 TEA 101.2 0.137m1 0.985mM 10 DMAP 122.2 CAT
The 3R-[4R-phenyl-oxazolidin-2-on-3-yl]-45-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 2 ml dichloromethane at room temperature. The reaction was protected with a dry tube. DMAP and TEA were added all at once. PCF was then added via syringe and the reaction was stirred at room temperature. TLC showed a complete reaction within minutes. The reaction was quenched with NH4C1. The product was purified over a silica gel to obtain a pure trans product. 28 mg of a white solid was obtained.
Yield=63 MS=454 Example 37 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone off.....,, , \
N \ ~ / N
ice,, ~ O
O
--N
O ~O
/O
Materials FW Amt Mole E iv Intermed. 455 0.138 g 0.3032 mmole 1 MCPBA 172.6 0.115 g 0.6670 mmole 2.2 The 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(n-oxide-pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 10 ml dichloromethane at room temperature.
MCPBA (3-chloroperoxybenzoic acid) was added all at once and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with a solution of 10°s Na2S203. The organics were removed and the resulting mixture was dried over MgS04, filtered. The organics were concentrated to a white foam.
1H-NMR and TLC indicate the N-oxide. Obtained 105mg of a white powder. Yield=73.5 MS=471 Example 38 1-phenoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-4-yl)ethen-1-yl]azetidinone hydrochloride l p ,,,,,~~
..,, o i O~N O ~ Hci O
Materials FW Amt Mole Ectuiv Intermed. 333 606 mg 1.82 mM 1 PCF 156.6 0.457m1 3.64 mM 2 TEA 101.2 0.507 ml 3.64 mM 2 DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-4-yl)ethen-1-yl]azetidinone (Intermed.) was combined with 10m1 of dichloromethane at room temperature. TEA and DMAP
were then added all at once. A solution of phenyl chloroformate (PCF) in approximately 10 ml dichloromethane was slowly added dropwise to the mixture at room temperature (protected with dry tube). TLC analysis showed a complete reaction. The mixture was adsorbed directly onto a silica gel and purified using hexane (1:1 hex/ethyl acetate) The solid was dissolved in ethyl acetate and 5 equivalents of 1N
hydrochloric acid in ether was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was then filtered. 202 mg of an off white solid were collected.
Ms=455 Theory Found C 68.56 68.80 H 4.65 ' 4.70 N 9.23 9.48 WO 98/25895 PCTlUS97I22573 Example 39 1-[4-methoxycarbonylphenoxycarbonyl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone y ,.,,,~
N,,,, --N
° ~O
O
O
O~
Materials FW Amt Mole- Eauiv Intermed. 334 248mg 0.7425mM 1 MCPCF 214.6 175mg 0.817mM 1.1 TEA 101.2 0.207m1 1.485mM 2 DMAP 122.2 CAT
3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5m1 dichloromethane at room temperature. DMAP followed by TEA
was added to the mixture. A solution of 4-methoxy carbonylphenyl chloroformate (MCPCF) in 10m1 dichloromethane was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight with dry tube. The reaction mixture was then quenched with 1N
hydrochloric acid. The organics were separated and purified over silica gel. 274mg of a white solid was obtained.
Yield=72 MS=512 WO 98125895 PCTlUS97l22573 Examble 40 1-j(4-chlorobutyl)oxycarbonyl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone O ,,~~~\
Nip.. \
O I
~O
O~

CI
Materials FW Amt Mole E iv Intermed. 334 43.2mg 0.1293mM 1 TEA 101.2 0.18m1 1.293mM 10 4-BCF 171 0.035m1 0.2586mM 2 DMAP 122.2 CAT
The 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl)azetidinone (Intermed.) was dissolved in dichloromethane at room temperature. DMAP and TEA were added via syringe followed by the dropwise addition of chlorobutylchloroformate (4-BCF). The mixture was stirred at room temperature with dry ice. The reaction mixture was then quenched with 1N hydrochloric acid and the organics separated. The organics were purified over silica gel.
38.77mg was obtained. %Yield=64 MS=468 Example 41 1-phenoxycarbonyl-3-[4R-phenyl-oxaxolidin-2-on-3-yl)-4S-[2-(phenyl)ethen-1-yl]azetidinone - O
N
\~~~ \
O
~N~
O ~~ O
O
Materials FW Amt Mole Ecruiv Intermed. 334 0.1g 0.244mM 1 PCF 157 0.075m1 0.599mM 2 TEA 101.2 0.42m1 2.994mM 10 DMAP 112.2 CAT
The 3R-[4R-phenyl-oxaxolidin-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was combined with TEA and DMAP in 10 ml dichloromethane at room temperature under nitrogen. PCF in 5m1 of dichloromethane was added to the reaction dropwise at room temperature. Completion of the reaction was tested by TLC. The reaction was quenched with 1N hydrochloric acid. The mixture was purified over silica gel. 4lmg of a 1:1 mixture of trans:cis product was obtained. MS=454 Example 42 1-phenoxycarbonyl-3-[4R-phenyl-oxaxolidin-2-on-3-yl]-4S-[2-(phenyl)ethen-1-yl]azetidinone O
N~~
O
--N
O ~O
I/O
23mg of the cis chiral product was obtained from the silica gel of Example 41. MS=454 Example 43 cis-1-phenoxycarbonyl-3-(phthalimid-2-o?-4-buten-1-ylazetidinone 0 ~v l5mg of the pure cis isomer was isolated from the silica gel of Example 33. MS=390 - 77 _ Example 44 cis-1-phenoxycarbonyl-3-[oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone Materials FW Amt ( Mole E iv Intermed. 258 0.448 0.0017M 1 LHMDS/THF 1N 1.7m1 0.00187M 1.1 PCF 156.6 0.32m1 0.00255M 1.5 The 3-(2-oxazolidirione-3-yl)-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 17 ml of tetrahydrofuran. The mixture was kept cool in a dry ice acetone bath (at a temperature of from about -73°C to about -78°C).
l.7ml of 1N LHMDS/THF was added dropwise via syringe to the mixture. 0.32 ml PCF was added all at once and the mixture was stirred until all of the components of the reaction were consumed. The reaction mixture was quenched with 20m1 of 0.5N
hydrochloric acid and extracted with 20 ml of diethyl ether and 30m1 of dichloromethane. A solid formed. The solid was dissolved in 50m1 of dichloromethane. The combined organic layers were washed with 50 ml of 10°s sodium bicarbonate, washed with 50 ml of 12.5 sodium chloride and dried over magnesium sulfate. The mixture was then filtered concentrated. The residue was dissolved in 20 mL of dichloromethane and added to 20m1 of ice cold Diethyl ether. The white solid was vacuum filtered, washed with 10 mL of diethyl ether, and vacuum dried.
MS=378.38 - 78 _ Example 45 trans-1-phenoxycarbonyl-3R-[5-(isopropyl)-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone O O \
N~~~) ~ /
N
O ~O
O
Materials FW Amt Mole Ecruiv Intermed. 300.36 0.118 0.00036M 1 LHMDS/THF 1N 0.40m1 0.0004M 1.1 PCF 156.6 0.07m1 0.005M 1.5 The 3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 10m1 of tetrahydrofuran. The mixture was kept cool in a dry ice acetone bath (at a temperature of from about -73 C to about -78 C). 1N LHMDS/THF (0.40m1) was added dropwise via syringe to the solution. PCF (0.07m1) was added all at once and the mixture was stirred until all of the components of the reaction were consumed. The reaction mixture was removed from the ice bath and quenched with 20m1 of 0.5N

hydrochloric acid and extracted twice with 20m1 of dichloromethane. The dichloromethane extract was washed with 20m1 of 10~ sodium bicarbonate, washed with 20m1 of 12.5% sodium chloride and dried over magnesium sulfate. The mixture was then filtered and concentrated. The product was obtained by subjecting the dichloromethane solution of residue to silica gel chromatography.

_ 79 _ Example 46 cis-1-phenoxycarbonyl-3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone Q O
N%'. ,~~y \
i N
Q ~O
/O
Materials FW Amt Mole E iv Intermed. 300.36 0.1g 0.00033M 1 LF~DS/THF 1N 0.37m1 0.00036M 1.1 PCF 156.6 0.06m1 0.005M 1.5 The 3-[(5-isopropyl)oxazolidin-2-on-3-yl]-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 10 ml of tetrahydrofuran. The mixture was kept cool in a dry ice acetone bath (at a temperature of from about -73° C to about -78° C). 1N LHIKDS/THF (.37 ml) was added dropwise via syringe to the solution. PCF (.06 ml) was added all at once and the mixture was stirred until all of the components of the reaction were consumed. The reaction mixture was removed from the ice bath and quenched with 20 ml.of 0.5N hydrochloric acid and extracted with ml of dichloromethane. The dichloromethane extract was washed 20 with 20 ml of 10~ sodium bicarbonate, washed with 20 ml of 12.5%
sodium chloride and dried over magnesium sulfate. The mixture was then filtered and concentrated. The residue was dissolved in 20 ml of dichloromethane and was added dropwise to a mixture of 10 ml of diethyl ether and 10 ml of hexane in an ice bath. A
white solid formed. The white solid was vacuum filtered.
MS=420.3 Scheme II depicted below illustrates the general method used to synthesize the compounds of Examples 47-50.
SCHEME II
O
STEP 1 ~ R,2 \ ~ \ ~/
H Wittig or Horner-Emmons Rxn BaseISolvent ~ / N
o / \ o / \
(i) ~- (ii) o,- o, CAN
O / ~ Solvent STEP 2 ,2 ~
\ \ R CI" O
\ R,2 / O N~O BaseIDMAP
O \ Sovent . / N
/ O ~H
(iv) STEP 3 (iii) The bases and solvents useful for the reactions described in Synthetic Scheme II are the same as those described as useful for Synthetic Scheme I.
The following is a more detailed description of the steps described in Synthetic Scheme II. Those of ordinary skill in the art will recognize that the chemistry is merely a slight variation of the chemistry described for Synthetic Scheme I. The following descriptions and examples are intended to further illustrate the synthesis of the compounds of the present invention and are not meant to limit the invention in any manner. Other methods for preparing the compounds of the present invention, although not explicitly described are contemplated within the scope of the present invention.
The starting aldehyde (i) is prepared according to the procedures detailed in Tet. Lett., 32 (5), 803-6 (1991). An acid chloride is dissolved in solvent and added dropwise to a mixture of an appropriately substituted imine, solvent and amine to produce the starting aldehyde (i). The reaction mixture is stirred at room temperature under inert gas until the reaction was completed. 5~ hydrochloric acid is added and the reaction mixture is allowed to stir for about 1.5 hours. Solvent is added to the organic layer and the layer is washed with 5~ hydrochloric acid, followed by water and . brine. The resulting product is then dried and the solvent is removed by evaporation under reduced pressure. The preferred solvent used is toluene and the preferred amine is TEA. The appropriately substituted olefin can then be prepared from the starting aldehyde (i) by either the Wittig Reaction or the Horner-Emmons Reaction as outlined in Orcr.
React., 14, 270 (1965) and Acc. Chem. Res., 16, 411 (1983).
[STEP 1] Alkenes are synthesized from carbonyl compounds by the Wittig Reaction by reacting the starting compounds by the base treatment of an alkyl triphenylphosphanium salt or alternatively by the Wadsworth-Emmons Reaction (Horner-Emmons modification of the Wittig Reaction) in which phosphonate esters are reacted with carbonyl compounds in the present of base to form alkenes. The CAN Oxidation [STEP 2] and Acylation [STEP 3] procedures are the same as described in Synthetic Scheme I, Steps 5A and 6A or Steps 4B
and 5B.
Examr~le 47 1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone 0 ~v O/

Materials FW Amt Mole Ecruiv Intermed. 263 223mg 0.8479mM 1 LI~75/THF 1.OM 0.8479m1 0.8479mM 1 PCF 156.6 0.212m1 1.6953mM 3 The 3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 8m1 dry tetrahydrofuran. The mixture was cooled to -78°C. 1. OM LHIKDS in tetrahydrofuran was added to the reaction dropwise via syringe under nitrogen. The reaction mixture was stirred at -78°C for 30 minutes. PCF was added at -78°C. The mixture was stirred for 30 minutes. The external cooling was removed and the reaction was quenched with saturated NH4C1. The reaction mixture was stirred at room temperature. The mixture was purified over silica gel. 237mg of a white solid was obtained. %Yield=73 Theorv Found C 78.31 78.05 H 5.52 5.68 N 3.65 3.46 Example 48 cis-1-phenoxycarbonyl-3-benzyl-4-[2-(pyridin-3-yl)ethen-1-yl]azetidinone hydrochloride O
O

Materials FW Amt Mole E iv Intermed. 264 O.lg 0.379mM 1 TEA 101.2 0.53m1 3.787mM 10 PCF 156.6 0.095m1 0.7574mM 2 DMAP 122.2 CAT
The cis-1-benzyl-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (Intermed.) was dissolved in 5ml dichloromethane at room temperature. TEA and DMAP were added all at once. A solution of phenyl chloroformate was then added dropwise. The solution was stirred overnight at room temperature. The reaction was quenched with 1N
hydrochloric acid. The organics were separated and the resulting product was purified over silica gel. 78mg of a white solid was obtained. Yield=48.9 MS=421 Example 49 cis-2-phenoxycarbonyl-3-benzyl-4-[2-(cyano)ethen-1-yl]azetidinone / N
/ ~ /
N
O ~O
O
Materials FW Amt Mole E iv Intermed. 212 O.lg 0.4716mM 1 PCF 156.6 0.118m1 0.9432mM 2 LHI4I77S 1.OM 0.4716m1 0.4716mM 1 The 3-benzyl-4-[2-(cyano)ethen-1-yl)azetidinone _ 25 (Intermed.) was combined in 4 ml dry tetrahydrofuran at around -70°C under nitrogen. 1. OM LHIKDS in tetrahydrofuran was added to the ruction mixture dropwise via syringe. The reaction mixture was then stirred at around -70°C for 30 minutes. PCF was added to the mixture. The mixture was stirred for another 30 minutes at around -70°C. The reaction mixture was then quenched with 1N hydrochloric acid. The organics were separated and purified over silica gel. 105mg was obtained. aYield=67 MS=332 Theorv Found C 72.28 72.02 H 4.85 5.05 N 8.43 8.38 Example 50 trans-1-phenoxycarbonyl-3-benzyl-4-[2-(phenyl)ethen-1-yl]azetidinone The trans isomer was isolated from Example 47.
The present invention also provides the following novel and favored process for preparing certain azetidinones within the scope of Formula I and provides intermediates useful in preparing azetidinones. More specifically, an invention is directed to the individual steps and the entire process for preparing a compound of the formula Ia O ~.,.v~ /
R~s O
NwRm O
U
O

Ia wherein R16 represents: phenyl, 2-nitrophenyl, 4-nitrophenyl, naphthyl, 3-nitro-1-naphthyl, 4-nitro-2-_ naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thienyl, 3-furanyl, 3-pyridinyl, 3-pyridin-1-N-oxide) 5-pyrimidinyl, or 3,5-dimethylphenyl; and R1~ represents: 1-phenoxycarbonyl, 4-chlorophenoxycarbonyl, 4-fluorophenoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobutyloxycarbonyl, 4-methoxycarbonylphenoxycarbonyl, 4-methoxyphenoxycarbonyl or 1-propyleneoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof, which comprises:
reacting an aldehyde of the formula II
O
H
R' B
II
wherein R18 is a trialkylsilane, with an N-protected amine of the formula III
2 5 H2N R'9 III
wherein R19 is a nitrogen-protecting group, to afford an N-protected imine of the formula IV

R,s i N
H
R' 8 IV
reacting the N-protected imine of the formula IV, with 4S-phenyloxazolidin-2-on-3-ylacetyl chloride V
.~~~~ \
O
O~N~CI
V
to afford an N-protected azetidinone VI
I \ Rsa ~ /
O N
~~
O i N
~R~s ;
VI
desilylating and epimerizing the N-protected azetidinone VI
to afford a desilylated 4-acetylenic azetidinone intermediate of the formula VII

_ 87 _ _ C
VII
reducing and N-deprotecting the 4-acetylenic azetidinone intermediate of the formula VII to afford a 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula IX
,,, O I' N~,.
O NH
O
Ix functionalizing the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX), in the presence of a catalyst, with an electrophile selected from the group X-R16 wherein X is a leaving group, to give the alkenyl substituted azetidinone of the formula XI
N \ R~s O NH
and XI

WO 98/25895 PCTlUS97/22573 _ 88 _ acylating the alkenyl substituted azetidinone XI, to produce the substituted oxycarbonylazetidinone of the formula Ia.
Preferred intermediates of the invention have the formulas VIII and IX:
O~,,av\\
N
O
N~R,s O
VIII
where R19 is a nitrogen-protecting group; and lw 0~.,,,,v /
N
~i~,. \
O
NH
O
IX
Scheme III depicted below further illustrates this preferred process for preparing certain azetidinones of this invention.

_ 89 _ SCHEME III

R' 9 i O N
H .i.. H2N R'9 ---~~ ~H
R, a R
II III IV

/ I R,9 \
N i (''\\\ I / R, 8 ,~~~~~ \
O + ( bas O
O N~ . ~ H N~
CI
R, s O
O ~ N
O ~R,s V IV VI

R, a H
O R~n VI VII

H .,.~~\ /
O
~N, !O/~~ I
N
o R~y ~ ~R,s VII VIII

O O~~w\ /
II Ni lI Ni O N O NH
O vR,e O
VIII IX

\ ~ \
/ ~,,.v\
O \ Rys '/N, ~N~
NH ~,O ~ NH
O p IX XI

C R,s O~ R,s ~ 1,/Ni O
O ~ ~R,~
XI Ia where R16, R17 R18 and R19 are as previously defined.
The N-protected imine (IV) is prepared by methods known in the art, for example by treating the aldehyde (II) with an N-protected primary amine (III), for example, Q-anisidine, in the presence of a solvent, preferably methylene chloride or dichloromethane [STEP 1]. The aldehyde (II) can be made by methods known in the art, for example, according to the method of Hauptman, H. and Mader, M., Svnthesis, 307 (1978). Suitable R18 groups include, for example, trimethylsilane or other alkylsilanes. In addition, various nitrogen-protecting groups (R19) familiar to one skilled in the art can be used. A drying agent, typically magnesium sulfate, sodium sulfate, silica gel or the like, is preferably added to the reaction mixture. The reaction is stirred overnight at room temperature until all of the reactants are consumed as measured by readily available techniques. The mixture is then filtered and the solvent removed by vacuum to provide the desired N-protected imine (IV).
2+2 cycloaddition of 4S-phenyloxazolidin-2-on-3-ylacetyl chloride (V) with the N-protected imine (IV) yields the N-protected azetidinone (VI), primarily as the cis isomer [Step 2]. The process of 2+2 cycloaddition is ' generally well known in the art. See: G.I. Georg, Ed.; The Organic Chemistry of (3-lactams, Chapter 6, Verlag Chemie, New York, (1992); U.S. Patent No. 4,751,299; and, U.S.

Patent No. 4,665,171, each incorporated herein by reference.
One equivalent of 4S-phenyloxazolidin-2-on-3-ylacetyl chloride (V) and a solvent, for example, dichloromethane are charged into a reaction vessel and the mixture is cooled to about -78 °C. An appropriate base, for example, tri(C1-C4)amine, typically triethylamine, is then added to the mixture while keeping the temperature around -70 °C.
The reaction mixture is stirred thoroughly. The imine, dissolved in solvent, is slowly added keeping the temperature around -70 °C. While the addition time is not critical, best results are achieved when the addition takes place dropwise over a period of from about 1 to about 6 hours followed by stirring the reaction mixture for 2 to about 4 hours. The reaction is carried out at a temperature 25 from about -78 °C to about 25 °C, preferably from about -78 °C to about 0 °C and even more preferably from about -78 °C to about -75 °C, in a solvent in the presence of tri(C1-C4)amine.
4S-phenyloxazolidin-2-on-3-ylacetyl chloride (V) may be prepared by methods known in the art such as the method disclosed in U.S. Patent No. 4,665,171, incorporated herein by reference. For example, 1.8 equivalents of an oxalyl chloride is reacted with one equivalent of the appropriately substituted acid in the presence of a solvent, preferably toluene or benzene, to produce the acid chloride.
Preferably, the reaction is heated to about 60°C for about 3-4 hours under inert gas, for example, nitrogen gas, helium gas or argon gas. The reaction mixture is cooled to room temperature and the solvent removed by vacuum.
The N-protected azetidinone (VI) is then desilylated and epimerized at the 3 position to give an approximately 4:1 mixture of a trans:cis N-protected, desilylated 4-acetylenic azetidinone intermediate [STEP 3]. The N-protected azetidinone (VI) can be desilylated and epimerized by various methods known in the art. However, the N-protected azetidinone (VI) is preferably desilylated and epimerized by employing tetrabutylammonium fluoride (TBAF) at reaction temperatures below -50°C. Tetrahydrofuran is a preferred solvent.
The trans desilylated 4-acetylenic azetidinone - intermediate (VII) is partially reduced and N-deprotected to yield the ~i-lactam trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX) [STEPS 4 and 5]. The partial reduction is preferably accomplished by hydrogenation of trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (vii) with Lindlar's catalyst and quinoline. The deprotection is preferably accomplished employing cerric ammonium nitrate in the presence of acetonitrile, for example, according to the method outlined at J. Ora. Chem., 47, 2765-68 (1982). One skilled in the art would understand that either the partial reduction or the deprotection may be accomplished first.
The resulting trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX) is functionalized by reaction with an electrophile, X-R16, in the presence of a solvent, and is acylated to produce the substituted oxycarbonylazetidinone of the formula I [STEPS 6 and 7]. In the formula X-R16, X
is a leaving group such as halogen, sulfonate or the like and R16 is as previously defined. Functionalization is best accomplished employing a catalyst, such as, palladium acetate, and preferably in the presence of potassium acetate and tetrabutylammonium chloride hydrate dissolved in dimethylformamide. See: A. Satake, et al., Synlett, 839 (1994). The following R16 groups are preferred: 2-vitro-4-phenyl, 4-vitro-2-phenyl, 3-vitro-1-naphthyl, 4-vitro-2-naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-benzothiazolyl, 2-benzoxazolyl. More preferred R groups include: 2-thienyl, 3-furanyl, 5-pyrimidinyl, and 3,5-dimethylphenyl. One skilled in the art would understand that either the functionalization or the acylation of trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX) may be accomplished first, although the functionalization _ 9Q _ with X-R16 to yield the alkenyl substituted azetidinone (XI) preferably precedes the acylation.
Acylation is preferably accomplished with an appropriate chloroformate to produce the substituted oxycarbonylazetidinone of the formula Ia. Examples of appropriate chloroformates include: phenyl chloroformate, 4-chlorophenyl chloroformate, 4-fluorophenyl chloroformate, benzyl chloroformate, 4-nitrobenzyl chloroformate, 4-chlorobutyl chloroformate, 4-methoxy carbonylphenyl chloroformate, 4-methoxyphenyl chloroformate, and allyl chloroformate.
Scheme III provides an illustration of the preferred sequence of steps for the present invention. However, the order of certain steps may be altered and still afford the compounds of formula Ia. For example, the compounds of formula Ia may be prepared from the 4-acetylenic azetidinone intermediate VII by reduction to the compound VIII, followed by: 1-deprotecting compound VIII to the compound IX, followed by functionalizing with an electrophile, X-R16 and acylating (in either order); or 2-functionalizing compound VIII with an electrophile, X-R16, followed by deprotecting the compound, followed by acylating. The 4-acetylenic azetidinone intermediate VII may also be deprotected first, followed by reduction to the compound IX, followed by functionalizing with an electrophile, X-R16 and acylation (in either order).
The following Preparations and Examples further illustrate the synthesis of the compounds of the present invention and are not meant to limit the invention in any manner.

Preparation of IVa ~ OCH3 . ~ H + I / Mg~
TMS H2N ~% H
TMS
IIa IIIa IVa The aldehyde IIa (4.89 g) was dissolved in 10 ml methylene chloride. Anhydrous magnesium sulfate (9.43 g) was added, followed by a solution of g-anisidine (4.77 g) in 20 ml methylene chloride. After stirring at room temperature for 90 minutes, the mixture was filtered and the solvent evaporated to give a brown liquid. The material was dissolved in hexane. The hexane solution was decanted from the insolubles and then washed with 1% hydrochloric acid solution. After drying over anhydrous sodium sulfate, the solvent was evaporated to give the imine (7.36 g) as an orange liquid.
TLC 0.74 (3/1 hexane/ethyl acetate); 1H NMR (CDC13, 500 Rf MFiz) 7.73 (s, 1 H), 7.20 (d, 1 H, J 8.9 Hz), &.91 (d, 8 = 1 H, J 8.9 Hz), 3.83 (s, 3 H), 0.29 (s, 9 H).
=

Preparation of V
4S-phenyloxazolidin-2-on-3-ylacetyl chloride o cl I
0 o v o N~ IC-OH Solvent ~O p~ C-CI
~~O
Va V

The acid Va (100 g) was slurried in toluene at room temperature. Oxalyl chloride (103.6 g) was added all at once. The solution was heated to 60°C for 4 hours under a nitrogen purge. The mixture was then cooled to room temperature and the toluene was removed by vacuum to give an oil. The oil solidified upon standing at a sub-zero temperature. The acid chloride V (113 g) was produced.
Pret~aration of VIa 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone.
~ ~OCH3 TMS
O~' ~ O + >
O N O N
CI ~ H O v/~
TMS I , O

V IVa VIa The 2+2 Cycloaddition was performed by dissolving 3.4g of the acid chloride V in 40 ml dichloromethane and cooling the solution with a dry ice/acetone bath. Triethylamine (3.0 ml) was added dropwise, giving a lavender solution.
After 15 minutes) the imine IVa (3.6g in 24 ml toluene) was added dropwise. After 15 minutes, the dry ice/acetone bath was replaced with an ice bath. After 3 hours, the solution was warmed to room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10a hydrochloric acid solution (3x), brine (1x), saturated sodium bicarbonate (2x) and brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation. The amber solid (5.5g) was recrystallized with 60% ethyl acetate/40~ hexane to give 3.72 g of the ~i-lactam 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone.

WO 98125895 PCTlI1S97122573 _ 97 -TLC Rf 0.25 (2/1 ethyl acetate/hexane); 1H NMR (CDC13, 500 MHz) 8 7.51-7.40 (m, 7 H), 6.90-6.87 (m, 2 H), 4.99 (t, 1 H, J = 8.8 Hz), 4.72-4.68 (m, 2 H), 4.42 (d, 1 H, J = 5.0 Hz), 4.21 (t, 1 H, J' = 8.9 Hz), 3.81 (s, 3 H), 0.26 (s, 9 H).
Preparation of VIIa 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone.
,.
.W TAA H
O TBAF

o O

VIa VIIa 6.0 g of 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone was dissolved in 150 ml tetrahydrofuran and the solution was cooled with a dry ice/acetone bath. TBAF (4.34g) was added in three portions. The reaction mixture was allowed to warm slowly to room temperature in the presence of the cold bath overnight. The volume of the reaction solution was reduced by two-thirds by rotary evaporation. The solution was diluted with ethyl acetate and washed with 10~ hydrochloric acid solution (2x), brine (1x), saturated sodium bicarbonate (2x) and brine (lx). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give 4.43 g of a 4.3:1 trans:cis mixture of the desired (3-lactam 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-ylJ-4-ethyn-1-yl]azetidinone. This material was carried on without further purification.
TLC Rf 0.45 (trans); 0.37 (C1S) (1/1 ethyl acetate/hexane);
spectral data recorded from a 4.3:1 trans:cis mixture, integrations include corrected values for coincident resonances; 1H NMR (CDC13, 500 MHz) trans isomer 8 7.48-7.37 (m, 7 H), 6.87 (d, 2 H, J = 8.9 Hz), 5.03-4.99 (m, 1 H), 4.91 (t, 1 H, J = 2.1 Hz), 4.75 (t, 1 H, J = 8.8 Hz), 4.42 (d, 1 H, J = 2.5 Hz), 4.30-4.24 (m, 1 H), 3.78 (s, 3 H), 2.38 (d, 1 H, J = 1.6 Hz); unobscured resonances for cis isomer $ 4.53 (d, 1 H, J = 4.8 Hz), 2.67 (d, 1 H, J =
1.8 Hz).
Pret~aration of VIIIa 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(2-trimethylsilyl)ethyn-1-yl]azetidinone.
.,, ~ 1 ,,,~ 1 H
o~ ~~ H2 o --.-s o Lindlar quinoline O ~ O
/ /

VIIa VIIIa 1-Methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethyn-1-ylazetidinone (2.0 g) was dissolved in methanol/60 ml dichloromethane (140 ml). Quinoline (0.55m1) and Lindlar~s catalyst (0.15 g) were added. The mixture was stirred under hydrogen atmosphere for 5 hours. The mixture was then filtered through a pad of Celite and the solvent removed by rotary evaporation. The residue was dissolved in ethyl acetate and washed with 10~ hydrochloric acid solution (3x) and brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give 2.00 g of a 4.3:1 trans:cis mixture of the desired (3-lactam 1-methoxyphenyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone. This material was carried on without further purification.
TLC Rf 0.41 (trans); 0.45 (cis) (1/1 ethyl acetate/hexane);
spectral data recorded from a 4.3:1 trans:cis mixture, integrations include corrected values for coincident resonances; 1H NMR (CDC13, 500 MHz) traps isomer 8 7.45-7.30 (m, 7 H), 6.85 (m, 2 H), 5.57-5.47 (m, 1 H), 5.23 (d, 1 H, J
- 17.1 Hz), 5.12 (d, 1 H, J = 10.3 Hz), 4.95-4.91 (m, 1 H), 4.76 (dd, 1 H, J = 2.3, 7.8 Hz), 4.69 (t, 1 H, J = 8.7 Hz), 4.26-4.19 (m, 1 H), 4.06 (d, 1 H, J = 2.5 Hz) 3.78 (s, 3 H);
unobscured resonances for cis isomer S 5.75-5.67 (m, 1 H), 5.5 (d) 1 H, J = 17 Hz) , 5.39 (d, 1 H, J = 10.4 Hz) .
Preparation of IX
3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone o~~ ., \ o ~ ~ ~!
N o i O ~~ NH
O

VIIIa IX
1-Methoxyphenyl-3-[4S-phenyl-axazolidin-2-on-3-yl]-4-ethenylazetidinone (0.92 g) was dissolved in acetonitrile (70 ml) and the solution was cooled with an ice/acetonitrile bath. Ceric ammonium nitrate (5.50g) in 70 ml water was added dropwise. Thirty minutes after addition was complete, ethyl acetate (100 ml) was added. Saturated sodium bicarbonate solution was added to raise the pH of the reaction mixture to 7. The reaction mixture was stirred for 1 hour and then filtered through a pad of Celite. The solution was diluted with ethyl acetate and washed with 100 sodium sulfite solution (3x), brine (lx), saturated sodium bicarbonate (2x) and brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give a 4.6:1 trans:cis mixture of the desired ~3-lactam 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone. Trituration with ethyl acetate/hexane gave 0.47 g of a yellow solid.
TLC Rf 0.16 (4/1 CHC13/ethyl acetate); spectral data recorded from a 4.6:1 trans:cis mixture, integrations include corrected values for coincident resonances; 1H NMR
(CDC13, 500 MHz) trans isomer 8 7.47-7.38 (m, 5 H), 6.24 (m, 1 H), 5.49-5.43 (m, 1 H), 5.15 (d, 1 H, J = 17.1 Hz), 5.02 (d, 1 H, J = 10.3 Hz), 4.94-4.87 (m, 1 H), 4.74 (t, 1 H, J =
8.8 Hz), 4.47 (d, 1 H, J = 2.5 Hz), 4.30-4.20 (m, 1 H), 3.88 (d, 1 H, J = 2.7 Hz); unobscured resonances for cis isomer S
6.37 (m, 1 H), 5.85-5.78 (m, 1 H), 5.33-5.27 (m, 2 H), 4.69 (t, 1 H, J = 8.9 Hz).
Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(1-naphthyl)ethen-1-ylazetidinone ,, w ---~ o~..
1r N,..
O
~NH
O /~NH
O
O
IX
1-Iodonaphthalene (0.1625g), palladium acetate (0.019 g), potassium acetate (0.125 g) and tetrabutylammonium chloride hydrate (0.142 g) were dissolved in 1 ml dimethylformamide. 3-[4S-Phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone (0.11 g) in dimethylformamide (2 ml) was added. The solution was heated at 80°C for 2.5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The organic solution was washed with brine (lx), saturated ammonium chloride (3x), brine (1x) and saturated sodium bicarbonate (3x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to WO 98!25895 PCTIUS97/22573 give a black oil. The product was purified by a silica plug with chloroform to remove residual 1-iodonaphthalene then ethyl acetate to remove the product. Further . purification with column chromatography (chloroform, then 1/1 chloroform/ethyl acetate, then ethyl acetate) gave 0.052 g of a 10:1 trans:cis mixture of the desired ~i-lactam [3-[4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-(1-naphthyl)ethen-1-ylazetidinone.
TLC Rf 0.36 (1/1 ethyl acetate/hexane); spectral data recorded from a 10:1 trans:cis mixture, integrations include corrected values for coincident resonances; 1H NMR (CDC13, 500 MHz) trans isomer 8 7.99-7.96 (m, 1 H), 7.87-7.85 (m, 1 H), 7.81-7.79 (m, 1 H), 7.58-7.52 (m, 2 H), 7.43-7.23 (m, 7 H), 6.75 (s, 1 H), 6.50 (s, 1 H), 5.82-5.76 (m, 1 H), 4.96-4.92 (m, 1 H), 4.79-4.70 (m, 2 H), 4.30-4.25 (m, 1 H), 4.15-4.13 (m, 1 H); unobscured resonances for cis isomer S 8.10-8.07 (m, 1 H), 6.55 (s, 1 H), 6.15-6.10 (m, 1 H).
Example 51 1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl)-4-j2-(1-naphthyl)ethen-1-yl]azetidinone ~w 0 ~ 1. LiHMDS
~,,av\\ ~N~~, 2. CICOOPh O
... _ O~-N
~O
NH
O O
3-[45-Phenyl-oxazolidin-2-on-3-yl)-4-[2-(1-naphthyl)ethen-1-ylazetidinone (0.062 g) was dissolved in 3 ml tetrahydrofuran and the solution was cooled with a dry ice/acetone bath. Lithium bis (trimethylsilyl) amide solution (0.15, 1 M in tetrahydrofuran) was added. After 15 minutes, 22 ul phenyl chloroformate in 1 ml tetrahydrofuran was added. After 20 minutes, saturated ammonium chloride solution was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with chloroform (2x) and the organic fraction washed with brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give 0.11 g of a trans:cis mixture of the desired (3-lactam.
Column chromatography with 8/1 chloroform /ethyl acetate gave 0.018 g of the desired trans ~i-lactam.
TLC Rf 0.42 (1/1 ethyl acetate/hexane); 1 H NMR (CDC13, 500 MHz) 8 7.94-7.91 (m, 1 H), 7.89-7.86 (m, 1 H) 7.82 (d, 1 H, J=88.2 Hz), 7.56-7.47 (m, 3 H), 7.45-7.34 (m, 9H), 7.32-7.23 (m, 1 H) 7.19 (d, 2H, J=7.9Hz), 5.90 (dd, 1 H, J=8.2, 15.4 Hz), 5.23 (dd, 1 H, J=3.5, 8.2 Hz), 5.05-5.02 (m, 1 H), 4.82 (t, 1 H, J= 8.7 Hz) , 4.38-4.34 (m, 1 H) ~ 4.25 (d, 1 H, J=3.7).
Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-methoxyphenyl)ethen-1-yl]azetidinone W W
w I \ -~Ni~, ~Ni, ~ ~ OCH3 O I O'/
NH NH
O O
3-Iodoanisole (0.203g), palladium acetate (0.026g), potassium acetate (0.171g) and tetrabutylammonium chloride hydrate (0.244g) were dissolved in 1 ml dimethylformamide.
3-[4S-Phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone (0.15g) in 2 ml dimethylformamide was added. The solution was heated at 80°C for 3 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The organic solution was washed with brine (1x), saturated ammonium chloride (3x), brine (1x) and saturated sodium bicarbonate (3x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give a black oil. The product was purified by column chromatography (chloroform, then 1/1 chloroform/ethyl acetate, then ethyl acetate) gave 0.068 g of the desired (3-lactam [3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-methoxyphenyl)ethen-1-yl]azetidinone].
Example 52 1-phenoxycarbonyl-3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[2-(naphthyl)ethen-1-yl]azetidinone 0~,,.vv N ~ /
O
N
O ~O
O
The procedure of Example 51 resulted in 0.007 g of the (3-lactam of Example 52 in the cis configuration.
TLC Rf 0.3 (1/1 ethyl acetate/hexane); 1 H NMR (CDC13, 500 MHz) b 8.11 (d, 1 H, J=7.71 1Iz), 7.96-7.80 (m, 2H), 7.65-7.19 (m, I5 H), 6.32 (dd, 1 H, J=8.6, 15.7 Hz) 5.08 (dd, 1 H, J=6.2, 8.5 Hz), 4.93 (t, 1 H, J=8.1 Hz), 4.73-4.65 (m, 2 H), 4.27-4.24 (m, 1 H).

Example 53 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl}-4R-[2-(3-methoxyphenyl)ethen-1-yl]azetidinone \ \
-1. LiHMDS O~'~~~,\\ /
~NG \ ~ OCH 2. CICOOPh ~Ni~, \ ~ OCH3 O N
NH O O
O
O
3-[45-phenyl-oxazolidin-2-on-3-yl]-4-[(3-methoxyphenyl)ethen-1-yl]azetidinone (0.068 g) was dissolved in tetrahydrofuran {3 ml) and the solution was cooled with a dry ice/acetone bath. Lithium bis (trimethylsilyl) amide solution {0.19 ml, 1 M in tetrahydrofuran) was added. After minutes, 27 ul phenyl chloroformate in 1 ml tetrahydrofuran was added. After 20 minutes, saturated ammonium chloride solution was added. The reaction mixture was allowed to warm to room temperature. The reaction 15 mixture was extracted with chloroform (2x) and the organic fraction washed with brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give 0.082 g of the desired ~i-lactam. Column chromatography with 9/1 chloroform/ethyl acetate gave 0.0321 g.
TLC Rf 0.38 ((9/1 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz) $ 7.38 - 7.29 {m, 7H), 7.25-7.21 (m, 2 H), 7.18-7.16 (m, 2 H), 6.85-6.80 (m, 2H), 6.78 (s, 1 H), 6.42 (d, 1 H, J=15.8 Hz), 5.85 (dd, 1 H, J=7.7, 15.8 Hz)) 5.05-5.03 (m, 1 H), 5.00-4.97 (m, 1 II), 4.80 {t, 1 H, J=8.8 Hz), 4.37-4.34 {m, 1 H), 4.20 (d, 1 H, J=3.5 Hz), 3.82 (s, 3 H).

Preparation of 3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-nitrophenyl)ethen-1-yl]azetidinone y y o~,,,,,,, I
~N ~N /
i,,~, i,~ a ~ No2 O O
NH NH
O O
1-Iodo-3-nitrobenzene (0.217 g), palladium acetate (0.026g), potassium acetate (0.171g) and tetrabutylammonium chloride hydrate (0.244g) were dissolved in 1 ml dimethylformamide. 3-[4S-Phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone (0.15 g) in dimethylformamide (2 ml) was added. The solution was heated at 80°C for 3 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The organic solution was washed with brine (1x), saturated ammonium chloride (3x), brine (1x) and saturated sodium bicarbonate (3x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to give a black oil. The product was purified by column chromatography (chloroform, then 1/1 chloroform/ethyl acetate, then ethyl acetate) gave 0.033 g of the desired (3-lactam [3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-nitrophenyl)ethen-1-yl]azetidinone].
TLC Rf 0.28 (1/1 CHC13/ethyl acetate); 1H NMR (CDC13, 500 I~iz) b 8.13-8.11 (m, 1 H), 8.02 (s, 1 H), 7.49 (d, 2 H, J =
5.1 Hz), 7.46-7.33 (m, 5 H), 6.45 (d, 1 H, J = 15.9 Hz), 6.17 (s, 1 H), 5.75 (dd, 1 H, J = 6.6, 15.9 Hz), 4.94-4.89 (m, 1 H), 4.80 (t, 1 H, J = 8.8 Hz), 4.61 (dd, 1 H, J = 2.2, 6.5 Hz), 4.39 (dd, 1 H, J = 5.5, 8.9 Hz), 3.98 (d, 1 H, J =
2.6 Hz).

Example 54 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl)-4R-(2-(3-nitrophenyl)ethen-1-yl]azetidinone \ \
,,,v\
/ ~ N~ \
\ ~N02 ~', v N02 O
-NH ~N O
O O ~ \
O /
3-(4S-phenyl-oxazolidin-2-on-3-yl]-4-[(3-nitrophenyl)ethen-1-yl)azetidinone (0.033 g) was dissolved in tetrahydrofuran (3 ml) and the solution was cooled with a dry ice/acetone bath. Lithium bis (trimethylsilyl) amide solution (0.10 ml, 1 M in tetrahydrofuran) was added. After minutes, phenyl chloroformate (12.7 ul in 1 ml tetrahydrofuran) was added. After 20 minutes, saturated ammonium chloride solution was added. The reaction mixture 15 was allowed to warm to room temperature. The reaction mixture was extracted with chloroform (2x) and the organic fraction washed with brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to the desired (3-lactam. Trituration with chloroform, and a water wash gave 0.0078.
TLC Rf 0.52 (4/1 chloroform/ethyl acetate); 1 H NMR (CDC 13, 500 MHz) b 8.12-8.09 (m, 2H), 7.72 (d, 1 H, J=7.7 Hz), 7.63 (t, 1 H, J=7.9 Hz), 7.46-7.42 (m, 4H), 7.34-7.28 (m, 3 H), 7.21-7.17 (m, 3 H), 6.66 (d, 1 H, J=15.9 Hz) 6.30 (dd, 1 H, J=8.3, 15.9 Hz), 5.13 (dd, 1 H, J=5.6, 8.6 Hz), 4.93 (dd, 1 H, J= 3.4, 8.3 Hz), 4.86 (t, 1 H, J=8.8 Hz), 4.73 (d, 1 H, J=3.6 Hz), 4.32 (dd, 1 H, J=5.6, 8.9 Hz) Example 55 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-ethen-1-ylazetidinone O ~,,,~~~~ /
N~i~,.
O
N
O ~O
O
0.168 of [3-[4S-phenyl-oxazolidin-2-on-3-yl]-4-ethenylazetidinone was dissolved in 10 ml tetrahydrofuran and the solution was cooled with a dry ice/acetone bath.
Lithium bis (trimethylsilyl) amide solution (0.62 ml, 1 M in tetrahydrofuran) was added. After 15 minutes, phenyl chloroformate (90 ul) in 1 ml tetrahydrofuran was added.
After 15 minutes, saturated ammonium chloride solution was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with chloroform (2x) and the organic fraction washed with brine (1x). The organic solution was dried over sodium sulfate and concentrated by rotary evaporation to the desired ~i-lactam. Column chromatography with 9/1 chloroform/ethyl acetate followed by recrystallization with hexane/ethyl acetate gave 0.07 g. (31~) TLCRf 0.42 (9/1 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz) b 7.49-7.43 (m, 3H), 7.40-7.36 (m, 4 H), 7.29-7.24 (m, 1 H), 7.20-7.18 (m, 2 H), 5.65-5.57 (m, 1 H), 5.22 (d, 1 H, J=17.OHz), 5.17 (d, 1 H, J=10.5 Hz), 4.98-4.92 (m, 2H), 4.80 (t, 1 H, J=8.8,Hz), 4.34 (dd, 1 H, J= 6.7, 8.8 Hz), 4.07 (d, 1 H, J=3.5Hz).

The present invention also provides an additional novel and favored process for preparing azetidinones and provides intermediates useful in preparing azetidinones. More specifically, an invention is directed to the individual steps and a process for preparing a compound of the formula Ia !~
0~,,,,~~~ /
R, s N, \
i~, O
NwR,~
O
Ia wherein R16 and Rl~ are as previously defined, which comprises:
reacting an aldehyde of the formula II
O
H
R, a II
wherein R18 is a trialkylsilane, with an N-protected amine of the formula III
H2N R's III
wherein R19 is a nitrogen-protecting group, to afford an N-protected imine of the formula IV

R' 9 i N
'H
R,e IV
reacting the N-protected imine of the formula IV, with 4S-phenyloxazolidin-2-on-3-ylacetyl chloride V
fl O
V
to afford an N-protected azetidinone VI
~ R, O N~
O I
N
O ~R~s VI;
desilylating and epimerizing the N-protected azetidinone VI
to afford a desilylated 4-acetylenic azetidinone intermediate of the formula VII

\
H
O Ni O I
N
O ~R,e VII;
reducing and N-deprotecting the 4-acetylenic azetidinone intermediate of the formula VII to afford a 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula IX
,~~\\ /
O~ R2o i O
NH
O
IX' wherein R20 is SnBu3 or B(OH)2;
functionalizing the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX'), in the presence of a catalyst, with an electrophile selected from the group X-R16 wherein X
is a leaving group, and acylating the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX'), to produce the substituted oxycarbonylazetidinone of the formula Ia.
The preferred intermediates of the invention have the formulas VI, VII, VIII, IX', IXa and IXc:

WO 98!25895 PCT/US97/22573 (y\ / ~Rie O N
~~
O I
~ N
~~19 VI
/ H
O
N/
O I
N
~R19 VII
,.v\ / H
O Ni O I
NH
O
VIII
Rzo O.
IX' 0~.; , SnBu3 O
NH
O
IXa i O
(~y~. ~ B(OHk O
/~NH

IXc wherein R16, R1~, R18, R19 and R20 are as previously de f fined .
Scheme IV depicted below further illustrates a preferred sequence of steps for this process which is a subject of this invention.
scHEME Iv R' 9 N~
H + H2N R'9 -.
H
Rie II III IV

i \ Ni ,'\\\\~ ,e i base O ~' ~ --~,- O
O N~ ~ H N1 CI
R, a O
O / N
O ~R,s V IV VI

R, 8 \
H

~N~
O~ I
N
U R,J ~ ~R,s VI VII

\ \
~,v\ / H
/
O O
II Ni II Ni O N O I
N
O
VII VIII

WO 98!25895 PCT/US97122573 / ~~~\~ /
O N p~ Rzo i i O
/ N O / NH
O \R,s O
VIII IX' .N R2o p. N R,s / NH O / NH
O O
IX' XI

/~ .~~\~ / ,w\\ /
O~ R, s O. 1 R
,6 i ~ N~
O NH O I
O 0 \Rn XI Ia where R16, R1~, R18, R19, and R20 are as previously defined.

The traps desilylated 4-acetylenic azetidinone intermediate (VII), prepared according to Scheme III, is partially reduced and N-deprotected to yield the ~3-lactam traps 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX) [STEPS 4 and 5]. Preferably, the desilylated 4-acetylenic azetidinone intermediate (VII) is first N-deprotected to yield the (3-lactam traps 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (VIII), followed by the partial reduction to afford the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX). The deprotection is preferably accomplished employing cerric ammonium nitrate in the presence of acetonitrile, for example, according to the method outlined at J. Ora. Chem., 47, 2765-68 (1982).
The partial reduction of the desilylated 4-acetylenic azetidinone intermediate (VII) or the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethynylazetidinone (VIII), is accomplished with, for example, an organotin hydride, such as, tributyltin hydride to furnish the desired vinyl tin derivative as a mixture of isomers. A catalyst, for example, a palladium catalyst, such as, dichlorobis(triphenylphosphine)palladium, may be employed.
Alternatively, hydrostannylation of the triple bond may be afforded by thermolysis in the presence of, for example, 2,2~-azobisisobutyronitrile (AIBN). Other reducing reagents may be employed to afford the vinyl boronic acid intermediate, for example catecholborane or the like. The isomers may be separated by methods known in the art, for example, by silica chromatography, to afford the desired 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX'). One skilled in the art would understand that either the partial reduction or the deprotection may be accomplished first.
- 35 The resulting traps 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX') is functionalized by reaction with an electrophile, X-R16, in the presence of a solvent, and is acylated to produce the substituted azetidinone of the formula Ia [STEPS 6 and 7]. In the formula X-R16, X is a leaving group such as halogen, sulfonate or the like and R16 is as previously defined.
Functionalization is best accomplished employing a catalyst, such as, tetrakis(triphenylphosphine)palladium(O), and preferably in the presence of copper(I)iodide dissolved in tetrahydrofuran. The following R groups are preferred:
2-nitrophenyl, 4-nitrophenyl, 3-vitro-1-naphthyl, 4-nitro-2-naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-benzothiazolyl, 2-benzoxazolyl. More preferred R groups include: 2-thienyl, 3-furanyl, 5-pyrimidinyl, and 3,5-dimethylphenyl. One skilled in the art would understand that either the partial functionalization or the acylation of trans 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-[2-ethen-1-yl]azetidinone (IX') may be accomplished first, although the functionalization with X-R16 to yield the alkenyl substituted azetidinone (XI') preferably precedes the acylation.
Acylation is preferably accomplished with an appropriate chloroformate to produce the substituted azetidinone of the formula Ia. Examples of appropriate chloroformates include: phenyl chloroformate, 4-chlorophenyl chloroformate, 4-fluorophenyl chloroformate, benzyl chloroformate, 4-nitrobenzyl chloroformate, 4-chlorobutylchloroformate, 4-methoxycarbonylphenyl chloroformate, 4-methoxyphenyl chloroformate, and allylchloroformate.
Scheme IV provides an illustration of the preferred sequence of steps for the present invention. However, the order of certain steps may be altered and still afford the compounds of formula Ia. For example, the compounds of formula Ia may be prepared from the 4-acetylenic azetidinone intermediate (VII) by reduction followed by deprotection to afford the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX'), followed by functionalizing with an electrophile X-R16 and acylating (in either order).
The 4-acetylenic azetidinone intermediate (VII) may also be deprotected first, followed by reduction to the 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone (IX'), followed by functionalizing with an electrophile, X-R16 and acylation (in either order).
The following Preparations and Examples are intended to further illustrate the synthesis of the compounds of the present invention and are not meant to limit the invention in any manner.
Preparation of VIII
H
O ,.~~~\
H
N~ CAN O
--O Nip..
N O I
O

O
Vlla VIII
The azetidinone (VIIa) (2.0 g, 5.5 mmol) was dissolved in 140 mL of acetonitrile and the solution was cooled with an ice/acetone bath to -15°C. Ceric ammonium nitrate (12.1 g, 22.0 mmol) in 140 mL water was added dropwise. At the end of the addition, ethyl acetate (200 mL) was added.
Saturated sodium bicarbonate solution was added to obtain pH 7. After stirring for 1 hour, the mixture was vacuum filtered through Celite. The organic layer was separated _ 25 and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with 10°s sodium sulfite solution, brine, and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The yellow solid was triturated with ethyl acetate to give 0.55 g of (VIII). The remaining material was purified by column chromatography to give 0.25 g. Total yield: 0.80 g.
TLC Rf 0.20 (4/1 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz) d 7.49-7.44 (m, 3 H), 7.37-7.35 (m, 2 H), 6.05 (s, 1 H), 4.96 (dd, J = 6.9, 8.7 Hz, 1 H), 4.76 (t, J = 8.9 Hz, 1 H), 4.69 (t, J = 2.3 Hz, 1 H), 4.28 (m, 2 H), 2.29 (d, J =
2.1 Hz, 1 H).
Preparation of IXa and IXb N
O (,vv O
~N Bu3SnH
ice, --O PdCl2(PPh3)2 ~N~~, \ Sn8u3 N\ O
O H NH
O
VIII
IXa The azetidinone VIII (1.78 g, 7.0 mmol) was dissolved in 70 mL tetrahydrofuran.
dichlorobis(triphenylphosphine)palladium (0.10 g, 0.14 mmol) was added and the mixture was stirred under nitrogen.
Tributyltin hydride (2.3 mL, 8.4 mmol) was added dropwise.
Near the end of the addition, hydrogen evolution and a slight exotherm were noted. After addition was complete, the solvent was evaporated to yield an orange oil. Column chromatography (3/1 to 1/1 hexane/ethyl acetate) provided 2.54 g (66°s) of the desired tin intermediate (IXa) contaminated with approximately 7~ of the oc-substituted tin derivative. The desired tin intermediate (IXa) was carried forward without further purification.

WO 98!25895 PCT/US97122573 TLC Rf 0.38 (1/1 hexane/ethyl acetate); 1H NMR (CDC13, 500 MHz) d 7.40-7.33 (m, 5 H), 6.32 (s, 1 H), 6.12 (m, 1 H), 5.53 (m, 1 H), 4.91 (dd, J = 6.3, 8.6 Hz, 1 H), 4.73 (t, J =
. 8.8 Hz, 1 H), 4.43 (m, 1 H), 4.24 (dd, J = 6.2, 8.8 Hz, 1 H) , 3 . 84 (d, J = 2 . 5 Hz, 1 H) , 1 .41 (m, 6 H) , 1 .27 (m, 6 H) , 0:85 (m, 15 H).
Example 56 \ \
I ,,a~~ ~ /
S O
~Nl ~ SnBu3 + ~ ~ -Pd(PPh~)a ~N~~'~
v -Cul o o NH NH
O O
IXa The tin intermediate IXa (0.198 g, 0.362 mmol) was dissolved in 5 mL of deoxygenated tetrahydrofuran (subsurface nitrogen purge for 1 hour). 2-Iodothiophene (0.052 mL, 0.471 mmol), tetrakis(triphenylphosphine)palladium(O) (0.042 g, 0.036 mmol) and copper iodide (0.0138 g, 0.0724) were added.
After stirring for 1.25 hours at room temperature, the mixture was refluxed under a nitrogen atmosphere for 1.5 hours. Ethyl acetate (200 ml) was added and the solution was washed with brine, saturated sodium bicarbonate solution, and water. The organic solution was dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was dissolved in acetonitrile and washed with hexane. Evaporation gave 0.17 g of a yellow solid. The material was purified by column chromatography and the desired product was obtained (0.06 g).
TLC Rf 0.24 (3/2 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz) $ 7.41-7.32 (m, 5 H), 7.17 (d, J = 5.0 Hz, 1 H), 6.96 (m, 1 H), 6.89 (d, J = 3.4 Hz, 1 H), 6.52 (d, J = 15.7 Hz, H), 6.23 (s, 1 H), 5.50 (dd, J = 7.1, 15.7 Hz, 1 H), 4.90 (dd, J 5.8,8.6 Hz, 1 H), 4.76 (t, J = 8.8 Hz, 1 H), =

4.54 (dd, J 2.3,7.1 Hz, 1 H), 4.33 (dd, J = 5.8, 8.9 Hz, =

1 3.96 (d, J 2.6 Hz, I H).
H), =

1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]=4R-[2-(2-thienyl)ethen-1-yl]azetidinone.
O ~,.v~ /
,.v\\ ~ /
~N -~ 1. LiHMDS ~N \
_, v _ p 2. CICOOPh O
NH N O
O O
O /
The indicated azetidinone (0.06 g, 0.176 mmol) was dissolved in 5 mL tetrahydrofuran and the solution was cooled with a dry ice/acetone bath. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.18 mL, 0.18 mmol) Was added. After 15 minutes, phenyl chloroformate (0.024 mL, 0.19 mmol) in 1 mL tetrahydrofuran) was added. After 30 minutes, saturated ammonium chloride solution was added. After warming to room temperature, the reaction mixture was extracted with chloroform (2x) and the organic fraction was washed with brine (lx). The organic solution was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give 0.09 g of a yellow solid. Column chromatography with 9/1 chloroform/ethyl acetate gave 0.055 g (68°s) of the trans (3-lactam, contaminated with approximately 70 of the cis ~3-lactam.
TLC Rf 0.38 (9/1 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz) $ 7.33 (m, 11 H), 6.96 (m, 1 H), 6.90 (d, J = 3.3 Hz, 1 H), 6.53 (d, J = 15.6 Hz, 1 H), 5.65 (dd, J = 7.8, 15.6 Hz, 1 H), 4.97 (m, 2 H), 4.81 (t, J = 8.8 Hz, 1 H), 4.37 (dd, J = 6.3, 8.9 Hz, 1 H), 4.16 (d, J = 3.5 Hz, 1 H).
Examt~le 57 \ \
O (,~~~~ i' C Pd2(dba)3 O ,,,,w ~ / O
S Br TFP
nBu3-1- ~ /
is N,,~ \
O ~ Cul O
NH NH
O O
The compound was prepared by reacting the indicated tin derivative IXa (0.20 g, 0.37 mmol) with 3-bromofuran (0.042 mL, 0.475 mmol) according to the same method of Example 7A. Tetrakis(triphenylphosphine)palladium(0) was replaced with IO mold tris(dibenzylideneacetone)dipalladium and 80 mold tri-2-furylphosphine. After stirring for 1 hour at room temperature, the reaction mixture was refluxed for 16 hours. The material obtained after workup was purified by silica plug (1/1 chloroform/ethyl acetate, then ethyl acetate). The product collected was dissolved in acetonitrile and washed with hexane. Evaporation gave a yellow solid (14 mg).
TLC Rf 0.23 (ethyl acetate); 1H NMR (CDC13, 500 l~iz) 8 7.70 (m, 1 H) , 7 .35 H) , 7.00 (m,1 H) , 6 .55 (m, 1 H) , 6.25 (m, 6 (m, 1 H), 5.81 (m, H), 5.17 (m,1 H), 4.88 (m, 1 H), 4.42 (m, 1 H), 4.25 (m, H), 3.88 (m,1 H).

WO 98!25895 PCT/US97/22573 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(3-furanyl)ethen-1-yl]azetidinone.
\ ~\

o~.,,,,v i o~,,,~~~ i l 0 \ ~ ~ TEA N~~,, \
CICOOPh NH
O \
O
The indicated azetidinone (14 mg, 0.043 mmol) was dissolved in methylene chloride (1 mL). A catalytic amount of 4-dimethylaminopyridine was added, followed by triethylamine (0.06 mL, 0.43 mmol). After 5 minutes, phenyl chloroformate (0.022 mL, 0.17 mmol) was added. After 30 minutes, chloroform was added and the solution was washed with saturated ammonium chloride solution (3x) and brine (1x). The organic solution was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give 0.039 g of an orange solid. Trituration with hexane/ethyl acetate followed by a silica plug with 1/2 hexane/ethyl acetate gave the desired compound (5.5 mg).
TLC Rf 0.27 (2/1 chloroform/ethyl acetate); 1H NMR (CDC13, 500 MHz)8 7.31 13 H), 5.87 (d, J = 14.1 Hz, 1 H), 5.33 (m, (m, 1 H), 4.93 2 H), 4.79 (t, J = 8.8 Hz, 1 H), 4.35 (m, (dd, J = 6.6, 8.5 Hz, 1 H), 4.07 (d, J = 3.3 Hz, I H).

Example 58 O ,,w ~ /
Pd2(dba)3 .,~~~~ J , N
g~ ASPH3 O~' ~ N
~N~~ ~ SnBu3~-N ~ N~, . o ~ ~ Cul NH o O N NH
O
!Xa The indicated azetidinone was prepared by reacting the indicated tin derivative IXa (0.30 g, 0.55 mmol) with 5-bromopyrimidine (0.11 g, 0.71 mmol) according to the method of Example 7A.
Tetrakis(triphenylphosphine)palladium(0) was replaced with mol% tris(dibenzylideneacetone)dipalladium and 80 mold triphenylarsine. The reaction mixture was refluxed for 4 hours. The material obtained was dissolved in ethyl acetate and washed with 1 N hydrochloric acid solution (4x). The pH
of the aqueous fractions was adjusted to 6 with 5 N sodium hydroxide solution, then to 8.5 with saturated sodium 15 bicarbonate solution. The product was extracted from the basic aqueous fraction with ethyl acetate (3x). The organic solution was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to yield the desired product as a white solid (28 mg).
TLC Rf 0.23 (ethyl acetate); 1H NMR (CDC13, 500 MHz) 8 9.09 (s, 1 H), 8.55 (s, 2 H), 7.35 (m, 5 H), 6.54 (s, 1 H), 6.31 (d, J = 16.1 Hz, 1 H), 5.80 (dd, J = 6.5, 16.0 Hz, 1 H), 4, 90 (dd, J = 5.4, 8.7 Hz, 1 H) , 4.79 (t, J = 8.9 Hz, 1 H) , 4.59 (dd, J = 2.1, 6.6 Hz, 1 H), 4.37 (dd, J = 5.3, 8.9 Hz, 1 H)) 3.98 (d, J = 2.7 Hz, 1 H).

1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(5-pyrimidinyl)ethen-1-yl]azetidinone.
N
O ~,,~w / / N ~ / N
O ~,.,~~~~ / N
N~~~, ~ TEA
N~~~
I CICOOPh NH ~
O N
p (ix) fix) O, i The indicated azetidinone compound (28 mg) was utilized to prepare compound 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(5-pyrimidinyl)ethen-1-yl]azetidinone. by the same method as Example 8B.
Recrystallization with diethyl ether/ethyl acetate provided the desired compound (18 mg).
TLC Rf 0.52 (ethyl acetate); 1H NMR (CDC13, 500 Ngiz) b 9.15 (s, 1 H), 8.59 (s, 2 H), 7.35 (m, 8 H), 7.19 (d, J = 7.9 Hz, 1 H), 6.33 (d, J = 16.1 Hz, 1 H), 5.98 (dd, J = 7.5, 16.1 Hz, 1 H), 5.02 (dd, J = 3.5, 7.4 Hz, 1 H), 4.95 (dd, J =
5.8, 8.5 Hz, 1 H) , 4.84 (t, J = 8.8 Hz, 1 H) , 4.43 (dd, J =
5.8, 8.9 Hz,l H), 4.18 (d, J = 3.6 Hz, 1 H).

Examt~le 59 \ \ HsC
~ o~,aAV
I CH3 Pd2{dba)s ,,w N~~ ~ SnBu3-~- ~ ASPh3 C~ CH3 I ~N,,.
o ( \ Cul ~
NH NH

IXa The indicated azetidinone compound was prepared by reacting the indicated tin derivative IXa (0.20 g, 0.37 mmol) with 5-iodo-m-xylene (0.11 g, 0.48 mmol) according to the same method as Example 7A.
Tetrakis(triphenylphosphine) palladium(0) was replaced with 10 mol% tris(dibenzylideneacetone)dipalladium and 80 mol%
triphenylarsine. The reaction mixture was refluxed for 1.5 hours. The material obtained after workup was purified by silica plug (1/1 chloroform/ethyl acetate). The product collected was dissolved in acetonitrile and washed with hexane (4x). Evaporation gave a yellow solid (0.044 g) which was further purified by radial chromatography (1/1 hexane/ethyl acetate) to provide >90o pure product by NMR.
TLC Rf 0.20 (1/1 hexane/ethyl acetate); 1H NMR (CDC13, 500 MHz) 8 7.35 (m, 5 H), 6.91 (s, 1 H), 6.82 (s, 2 H), 6.45 (s, 1 H), 6.35 (d, J = 15.8 Hz, 1 H), 5.66 (dd, J = 7.1, 15.8 Hz, 1 H), 4,90 (dd, J = 6.0, 8.5 Hz, 1 H), 4.75 (t, J = 8.8 Hz, 1 H), 4.57 (dd, J = 1.6, 6.9 Hz, 1 H), 4.29 (dd, J =
6.0, 8.8 Hz, 1 H), 3.98 (d, J = 2.4 Hz, 1 H).

I-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(3,5-dimethylphenyl)ethen-1-yl]azetidinone.

~ HsC
cH ° .,,,,,, l ice. \ \
TEA ~N''~
O -NH CICOOPh O N
O ~° \
O
The indicated compound (0.044 g) was utilized to prepare 1-phenyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(3,5-dimethylphenyl)ethen-1-yl]azetidinone by the same method as Example 8B. Recrystallization with diethyl ether/ethyl acetate provided the desired compound (0.032 g).
TLC Rf (CDC13, 500 0.65 (1/1 hexane/ethyl acetate);

NMR

MHz) 8 7 H), 7.24 (m, H), 7.18 (d, = 7.9 Hz, 7.38 1 J 2 (m, H) , 6 (s, H) , 6 .84 (s, 6.43 (d, J = 15 . 8 Hz, .93 1 2 H) , 1 H), 5.85 (dd, = 7.7, 15.8 Hz, H), 5.07 (dd, J = 3.6, 7.6 Hz, 1 4.98 (dd, J = 6.7, 8.5 Hz, 1 H), 4.81 (t, J = 8.8 H), Hz, 1 4.36 (dd, J = 6.7, 8.8 Hz, 1 H), 4.16 (d, J = 3.6 H), Hz, 1 H) .

Example 50 trans-1-isopropoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (,~~~~~ , / Solvent O DMAP ,..~~~ ~ / /
O
TEA
\ \ N
\ \ N
O O .,, O
O ~ ~R N O-CH(CH ) O
The trans deprotected azetidinorie (vi) (0.1 g, 0.3003 mmol) was dissolved in 5 ml methylene chloride at room temperature. Triethylamine (0.084 ml, 0.6006 mmol) and DMAP
(catalytic) were added all at once. Isopropyl chloroformate (1.0 M soln. in toluene, 0.6 ml) was added dropwise at room temperature. The resulting solution was stirred overnight at room temperature, and then purified over silica gel to provide 73 mg product. FD-MS=420.9 Theory Found C 65.55 65.67 H 5.50 5.36 N 9.97 9.86 The compounds of Examples 61 through 73 were prepared according to the procedure of EXAMPLE 60, employing 5 equivalents of the appropriate chloroformate.
Exam>Jle 61 trans-1-sec-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-- 25 yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone Nip \ / N
,, ,.
O
N
O ~O

O

Yield: 41 mg white solid: MS=435 Example 62 traps-1-g-nitrobenzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone 0~,~,~\1\
/ \
Nip \ / N
,, ,.
O
--N
O ~O
O
O~N
O
Yield: 75 mg product off-white solid: MS=
Theorv Found C 58.56 59.09 H 4.21 3.96 N 10.17 10.14 Example 63 traps-1-ethoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone N \ ~ /N
~i~~ ~/ v O
O
O
HsC
Yield: 52 mg product; MS=406 Example 64 traps-1-[2-(2-isopropyl-5-methyl)cyclohexyl]oxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone Nor \ / N
,, ,.
O

Yield: 34 mg product; M5=517.6 Example 65 trans-1-methoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone Nip \ / N
,, O
-N
O ~O
/O
~CH3 Yield: 61 mg white solid; MS=393.1 Example 66 trans-1-benzyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl,)ethen-1-yl]azetidinone Nip \ / N
,, O
~---N
O ~O
O
Yield: 69 mg solid; MS=469 WO 98!25895 PCT/US97I22573 Example 67 trans-1-cyclohexyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone O
/ N
v O
O
Yield: 24 mg solid; MS=461.5 Example 68 trans-1-cyclobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone I~
O ~,,,,~~
Nip ~ / N
O
-N
O ~O
O
Yield: 31 mg white solid; MS=433.4 Examble 69 trans-1-cyclopentyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone l~

Nip \ / N
,, ~- N
O ~O
O
Yield: 27 mg foam; MS=447.5 Examble 70 trans-1-allyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl}ethen-1-yl]azetidinone O ~,,~w\\
Nip \ / N

~~--N
O ~O
O
1o CH2 Yield: 63 mg white foam; MS=419 Example 71 trans-1-n-butoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone O ~,,.~~\\
/ ~ \~
N~~ \ / N
,, O
Yield: 71 mg yellow solid; MS=435.2 Example 72 trans-1-isobutoxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone / \
O ~,..~\\\
Nip \ / N
,, O
O

CHs Yield: 50 mg white solid; MS=435.2 Example 73 traps-1-vinyloxycarbonyl-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone lw I
N~. \ / N
O
O
O

Yield: 17 mg solid; MS=405.4 Example 74 traps-1-[benzoxazol-2-yl)-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (vii) \ \
(,,.w / \~ O ,,.w / \
\ ~ N ~ ~ ~~CI ~N~~ \ ~ N
U ~ N ~ U
O N CH2C12,Et3N O N
O H DMAP p ~O
(vi) (vii) To a solution of the traps deprotected azetidinone (vi) (0.23 g, 0.67 mmol) in 4 mL of dichloromethane were added triethylamine (0.68 g, 6.7 mmol), catalytic dimethylaminopyridine (DMAP) and 2-chlorobenzoxazole (0.21 g). The resulting mixture was stirred for 5 hours then diluted with ethyl acetate. The organic solution was extracted with one portion each of a 0.5 N hydrochloric acid and 1 N hydrochloric acid aqueous solution. The aqueous extracts were combined and the pH was adjusted to approximately 7 by the addition of a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the organic solution was dried over sodium sulfate, filtered and concentrated by rotary evaporation.
The residue was purified by silica gel chromatography (ethyl acetate). The product was concentrated from chloroform (2X) and dried at 40 °C to give 0.12 g of the compound of Formula (vii) (34~ yield).
Spectral data were collected from two lots of material prepared in similar fashion which contained approximately 0.5 equivalents of water.
TLC Rf (EtOAc) 0.44; 1H NMR (CDC13, 300 MHz) 8 8.5 (br s, 1H), 8.4 (br s, 1H), 7.57-7,21 (m, 21H), 6.45 (d, 1H, J=15.9Hz), 5.94 (dd, 1H, J=7.5, 15.9Hz), 5.19 (dd, 1H, J=3.15, 7.5Hz), 4.97 (dd, 1H, J=5.8, 8.6 Hz), 4.82 (t, 1H, J=8.8 Hz), 4.40 (dd, 1H, J=5.8, 8.8 Hz), 4.35 (d, 1H, J=3.3 Hz); IR (CHC13) 1799, 1760, 1624, 1574 cm 1; MS (FD+) 452;
Anal. Calcd. for C17H15N105 (1/2 H20): C, 67.67; H, 4.59; N, 12.14; Found: C, 67.88; H, 4.57; N, 11.96.
Examt~le 7 5 trans-1-[4,6-dimethoxy-1,3,5-triazin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (viii) \ CI \ OCH3 N /N ~ /
N~ ~ /N ~ O N~~ ~ /N
OCH,, ~ ~ _ O N CH2CI2,i-Pr2NEt O
O H DMAP O N
OCH
N ~ s >=N

(vi) (viii) To a solution of the trans deprotected azetidinone (vi) (0.18 g, 0.53 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.19 g, 1.1 mmol) in 5 mL dichloromethane, was added N,N-diisopropylethylamine (0.34 g, 2.63 mmol) and a catalytic amount of dimethylaminopyridine (DMAP). The contents were stirred under a nitrogen atmosphere for 3 hours. The mixture was diluted with dichloromethane and washed with a saturated ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (gradient 100% hexane to 75% ethyl acetate in hexane) to give 0.04 grams of the desired compound (viii) (16~ yield).
TLC Rf (EtOAc) 0.26; 1H NMR (CDC13, 300 MHz) b 8.4 (br s, 2H), 7.5-7.3 (m, 7H), 6.31 (d, 1H, J=15.9 Hz), 5.90 (dd, 1H, J=7.2, 15.9 Hz), 5.08 (dd, 1H " J=2.5, 6.8 Hz), 4.95 (m, 1H), 4.80 (t, 1H, J=8.6 Hz), 4.37 (dd, 1H, J=5.4, 8.6 Hz), 4.17 (d, 1H, J=3.1 Hz), 3.96 (s, 5H).
The compounds of Examples 76, 77 and 78 (trans-1-[4-trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (ix);
trans-1-[6-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (x); and trans-1-[2-phenylquinazol-4-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yI)ethen-1-yl]azetidinone (xi)) were prepared by dissolving the traps deprotected azetidinone (vi, 100 mg, 0.3003 mmole) in methylene chloride (5 ml) at room temperature. Triethylamine (0.21 ml, 4.5 mmole) and catalytic DMAP were added all at once and the mixture was stirred. The appropriate chlorinated heterocycle (5 equivalents) (2-chloro-4-(trifluoromethyl)pyrimidine; 2-chloro-5-nitropyridine; or 4-chloro-2-phenylquinazoline) was added to the stirred reaction mixture and the reaction was stirred over night at room temperature. The resulting residue was purified using silica gel to give the desired product.
Example 76 traps-1-[4-trifluoromethylpyrimid-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (ix) !~
,, ,N
O

(ix) Yield: 27 mg; MS=481.1 Example 77 traps-1-[5-nitropyridin-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (x) ' 25 O
N
O
N~

!w o ,,,,,\\
i N
N~
(x) Yield: 33 mg; MS=457.1 Examble 78 trans-1-[2-phenylquinazol-4-yl]- 3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (xi) O
N
N~~~) ~ wr O
O N ~N
r N
i (xi) Yield: 18 mg; MS=539 Example 79 trans-1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone (~~~\\ ~ /
N~, O
N
O O
N
To a solution of (vi) (0.134 g, 0.40 mmol) in 10 mL
dichloromethane. Diisopropylethylamine (0.2 g, 1.2 mmol) was added followed by 2-chlorobenzoxazole. The resulting mixture was stirred overnight. Dimethylaminopyridine (0.098 g, 0.8 mmol) was added and stirring was continued for 4 h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to an oil. The residue was purified by silica gel chromatography (1:1 hexane: ethyl acetate). Further purification was accomplished by recrystallization from acetonitrile to give 20 mg of the desired product.
1H NMR (CDC13, 300 MHz) 8 7.59 - 7.19 (m, 14 H), 6.54 (d, 1H, J=15.9Hz), 5.88 (dd, 1H, J=7.7, J=15.8 Hz), 5.22 (dd, 1H, J=3.0, J=7.6 Hz), 4.96 (dd, 1H, J=6.3, J=8.6 Hz), 4.80 (t, 1H, J=8.8Hz), 4.36 (dd, 1H, J=6.3, J=8.9 Hz), 4.32 (d, 1H, J=3.3 Hz).

WO 9$/25895 PCT/US97/22573 Example 80 cis-1-[benzoxazol-2-yl]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(phenyl)ethen-1-yl]azetidinone o n To a solution of the indicated 3,4-cis-~3-lactam isomer (0.4 g, 1.2 mmol) in 4 mL dichloromethane was added triethylamine (1.2 g, 11 mmol) followed by 2-chlorobenzoxazole (0.36 g, 2.4 mmol). Dimethylaminopyridine (--0.05 g, 0.4 mmol). The resulting mixture was stirred overnight. The mixture was diluted with ether and washed with 0.5 N HC1 followed by sequential washes with a saturated solution of sodium bicarbonate then brine. The organic phase was dried over sodium sulfate, filtered and concentrated to an oil. The residue was purified by silica gel chromatography (1:1 hexane: ethyl acetate).
TLC Rf (1:1 hexane:ethyl acetate) 0.64; 1H NMR (CDC13, 300 MHz) d 7.56-7.20 (m, 14H), 6.90 (d, 1H, J=l6Hz), 6.31 (dd, 1H, J=8.6, J=l6Hz), 5.10 (dd, 1H, J=5.8) J=8.7 Hz), 4.90 (t, 1H, J=8.4 Hz), 4.76 (d, 1H, J=5.7 Hz), 4.68 (t, 1H, J=8.9Hz), 4.23 (t, 1H, J=8.0 Hz).
The thioamidoazetidinone compounds of the present invention may be prepared by various methods known in the art. Scheme V is a preferred method for preparing certain preferred thioamidoazetidinone compounds of the formula Ib:
_ /
,,~~ \
O /
w \ N
p t H
O N~N.R2s S
Ib where R23 is phenyl, benzyl, naphthyl or furfuryl;
where the phenyl, naphthyl or aromatic ring of benzyl may be substituted with one to four halo, trifluoromethyl or C1-C6 alkyl groups; or a pharmaceutically acceptable salt or solvate thereof.
SCHEME V
/ S=C=N-R2a O N,, ~ (N
O~N~, ~ N LiHMDS O N N-R2s THF p N. S
O H
(vi) (Ib) where R23 is as previously defined.
Preparation of the compound of Formula Ib is carried out by dissolving the trans deprotected azetidinone (250 mg, 0.7462 mmole, vi) in dry tetrahydrofuran. The mixture is ' cooled to around -78 °C using an ice/acetone bath. Lithium (bis(triethylsilyl)amide (125 mg, 0.7462 mmole) in tetrahydrofurnan (0.75 ml, 1M) is then slowly added to the reaction mixture. The reaction is stirred for 30 minutes.
The appropriate isothiocyanate (2 equivalents) is then added and the reaction is stirred for 30 minutes. The appropriate isothiocyanate is commercially available and can be made by methods known in the art. The reaction is allowed to warm to room temperature. The reaction is then purified over silica gel to give the compound of Formula Ic.
The following Examples are intended to further illustrate the synthesis of the compounds of the present invention and are not meant to limit the invention in any manner.
Example 81 traps-1-phenylthioamido-3R-[45-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone (,, ~ il \
O O
~. ~ N ~-N N
O N O S I \
O vH /
(vi ) The traps deprotected azetidinone (vi) (250 mg, 0.7462 mmol) was dissolved in 125 ml of dry tetrahydrofuran and cooled to -78 °C using an ice/acetone bath. Lithium bis(triethylsilyl)amide (125 mg, 0.7462 mmole) in 0.75 ml of tetrahydrofuran (1M) was slowly added to the mixture. The mixture was stirred for 30 minutes. Phenyl isothiocyanate (263 mg) was added and the reaction mixture was stirred for minutes. The resulting solution was stirred overnight, allowed to reach room temperature, and then purified over silica gel to provide the desired product. MS=470 The compounds of Examples 82 through 89 were prepared according to the procedure of EXAMPLE 81, employing 2 equivalents of the appropriate isothiocyanate.
Example 82 trans-1-[2-bromophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone ~~ /
O~N
O

(2-bromophenyl isothiocyanate) Yield: 266 mg white solid: MS=549 Example 83 trans-1-[3-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin 2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone ~~ /
N
O
N'/'S
~O
HN
_ /
(3-fluorophenyl isothiocyanate) Yield: 210 mg white solid: MS=488 Example 84 trans-[2-fluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone .~ /
N
O
O N '~S F
HN
i~
(2-fluorophenyl isothiocyanate) Yield: 100 mg product; MS=488 Example 85 trans-1-[4-fluorophenylthioamido]oxycarbonyl-3R-(4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone ~~ /
,, \ N
O
N ( /'S
O
HN
/) F
(4-fluorophenyl isothiocyanate) Yield: 40 mg tan solid; MS=488 Examble 86 trans-1-[2,3,5,6-tetrafluorophenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone \ N
O ~-N S
O ~ F
HN F
i~
F
F
(2,3,5,6-tetrafluorophenyl isothiocyanate) Yield: 20 mg white solid; MS=541.8 Example 87 trans-1-[3-furfurylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone O
\N
o ~
N~S
O
HN
O
(3-furfuryl isothiocyanate) . Yield: 70 mg tan solid; MS=473.9 Example 88 trans-2-naphthylthioamido-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone ~~ /
I
\N
o I

(2-naphthyl isothiocyanate) Yield: 55 mg white solid; MS=520 Examt~le 89 trans-1-[4-trifluoromethylphenylthioamido]-3R-[4S-phenyl-oxazolidin-2-on-3-yl]-4R-[2-(pyridin-3-yl)ethen-1-yl]azetidinone \
.~ /
~ I

wN
o I
N~S
O
HN

(4-trifluoromethylphenyl isothiocyanate) Yield: 30 mg yellow foam; MS=538.0 The biological activity of the compounds of the present invention was evaluated by an initial screening assay which measures the inhibition of the proteolytic activity of PSA
by the compound being tested.

Colorimetric Assav for PSA Inhibitors Compounds were tested to determine the IC50 value (inhibitory concentration 50~) of PSA inhibition following a 2 hour pre-incubation of compound with PSA [prostate-specific antigen-protein concentration 0.72 mg/ml (25.3 uM) in 50 PBS/Glycerol stored at -20°C; molecular weight = 28,433 g/mole;
specific activity of PSA was determined experimentally to be 155 mmol/hr/mg protein using the Beer-Lambert Law]. Two different PBS/BSA Buffers were used: Buffer A which comprised PBS + 0.7 mg BSA/ml used for dilution of PSA and Buffer B which comprised PBS
+ 6.3 mg BSA/ml used in the reaction mixture to prevent non-specific binding of the PSA to the microtiter plate. Both buffers were stored at 4°C. Disposable, non-sterile, polystyrene (not treated), 96 well, flat-bottom, microtiter assay plates from Corning (Catalog #25880-96) were used. A Bio-Tek Instruments, Inc. Microtiter Plate Reader, CERES W900HDi, was used to read the colorimetric changes. Dual wavelengths reading at 405 nm with a reference wavelength of 450 nm were utilized when assessing optical density changes.
The peptide substrate (Me0-Suc-Arg-Pro-Tyr-pNA) was commercially obtained from Pharmacia Hepar [Chromogenix S-2586 [a chromogenic substrate for chymotrypsin; Catalog no. S-2586 (25 mg vials); molecular weight =705.3; stored at room temperature (kept dry) until reconstituted; reconstituted in PBS at 10 mM (7.05 mg/ml) and stored at 4°C as described by the product insert].
The PBS was Gibco BRL Dulbecco's Phosphate-Buffered Saline 1X (D-PBS) (Catalog No. 14040-026) stored at 4°C. The BSA (Bovine Serum Albumin) was obtained from Sigma (Catalog No. #A-7511), stored at 4°C.
PBS/BSA solutions, and the substrate solution (3546 ml PBS/25 mg substrate) were removed from the refrigerator and warmed to 37°C for at least 30 minutes. 1-5 mg of PSA test compound (in the form of a solid or oil) was weighed out and diluted with DMSO to obtain an inhibitor stock solution of 300 uM. Serial dilutions of the inhibitor stock solution were carried out in a 96 well microtiter plate using DMSO to obtain the following inhibitor concentrations in the final reaction mixture. The final concentrations were 100; 33; 10; 3; 1; 0.3;
0.1; 0.03; and 0.01 uM. The outer wells of the plates were not used. The plates consisted of rows A-H and columns 1-12. Well B2 served as an experimental blank in all experiments.
ul of PBS buffer B Was added to all reaction wells including well B2. 10 ul of DMSO was added to well B2 as well as to "no inhibitor control" wells) (B10, C10, D10, E10, F10, G10, H10).
10 10 ul of test compound (final cons. 100; 33; 10; 3; 1; 0.3;
0.1;0.03; 0.01 uM) was added in singlicate, to remaining wells (B1-9, C1-9, D1-9, E1-9, F1-9, G1-9 and H1-9).
10 ul of stock PSA was diluted with 610 ul PBS Buffer A.
10 ul of PBS + 0.7 mg BSA/ml was added to well B2. 10 ul of diluted PSA (40 nM final concentration) was added to all wells containing inhibitor and to the "no inhibitor control" well(s).
The microtiter plate was gently shaken (manually) to ensure adequate mixing of well contents, wells were sealed with parafilm and preincubated for 2 hours at 37°C. Following pre-incubation, 70 ul of substrate stock solution (1 mM final concentration) was added to all wells. Reaction progress, PSA cleavage of g-nitroaniline (g-NA) from the substrate resulting in appearance of yellow color, was monitored for the ensuing 10 minutes. Twenty optical density readings on each well were automatically taken and stored by the instrument.
Following completion of data accumulation, printouts of the reaction profile in all wells were obtained. Reaction velocities (slope in terms of mO.D./minutes) were plotted against inhibitor concentrations to determine the inhibitory concentration at 50~
inhibition (IC50).
The IC50 values were determined using non-linear analysis.
Compounds demonstrating less than 50o inhibition at the highest inhibitor concentration (generally 100 uM) were assigned an IC50 value of ">~~ the highest concentration. Compounds demonstrating greater than 50~ inhibition at the highest inhibitor concentration were modeled with non-linear analysis and assigned an ICSp value.

Colorimetric assav results:
Example # IC50 uM

1 o.2a 2 0.24 3 0.30 4 0.69 5 0.39 6 0.28 7 0.44 8 0.52 0.51 10 0.64 11 0.68 12 1.71 13 1.72 14 1.92 15 1.85 16 2.49 17 3.85 18 3.07 19 4.28 20 9.29 21 0.21 22 17.50 23 18.5 24 19.1 25 23.7 27 0.13 28 0.21 29 0.31 30 0.14 31 0.34 32 0.95 33 13.03 34 0.13 35 1.27 36 0.38 37 1.59 38 1.04 39 >100 40 >100 41 36.61 42 >100 43 49.69 44 22.13 45 1.19 46 2.87 47 4.43 48 4.99 49 6.56 50 1.2 51 0.62 52 1.62 53 0.18 54 0.24 55 11.08 56 0.7 57 15.47 58 0.33 59 0.15 61 20.32 62 27.95 63 5.4 64 >3 0 65 6.68 66 >30 67 12 . 3 68 3.78 69 19.4 70 7.48 71 23.4 72 38.5 73 1.07 74 0.20 75 0.035-0.045 76 8.1 77 2.31 78 10.12 81 .0583 82 .0353 10 83 19.1 84 0.275 0.832 86 20.85 87 >22.6 15 88 >100 89 >100 HPLC Assav Far PSA Inhibitors Compounds were tested to determine the IC50 value 20 (inhibitory concentration 50~) of potential PSA inhibitors following a 2 hour pre-incubation of the potential inhibitor with PSA. The substrate used was a 10 amino acid peptide synthesized on an ABI 433 peptide synthesizer using FMOC
chemistry with HBTU activation. Standard cycles supplied 25 with the instrument were used. The peptide was cleaved from the resin and deprotected using 80~ Trifluoroacetic acid (TFA), 5~ thioanisol, 7.5~ phenol, and 2.5°s ethanedithiol.
Crude peptide was purified by C-18 reversed phase HPLC and characterized by amino acid analysis and electrospray mass 30 spectrometry. The amino acid sequence for the peptide substrate was modeled from the experimentally proposed interaction of PSA with bovine milk casein. The peptide has the following sequence: SGAWYYVPLG [SEQ ID N0:1] (serine-glycine-alanine-tryptophan-tyrosine-tyrosine-valine-proline-35 leucine-giycine) and a molecular weight of 1111.1 g/mol.
The substrate was stored as a lyophilized solid at -20°C

WO 98!25895 PCT/US97/22573 until reconstituted. Prior to the assay, the substrate was reconstituted in phosphate buffer saline (PBS) at 0.1 mg/ml.
The lyophilized substrate and PBS were removed from the freezer and warmed to room temperature for at least 30 minutes before use.
1-5 mg of each compound to be tested (in the form of a solid or oil) was weighed out and diluted (DMSO) to obtain a compound primary stock solution of 300 uM. Serial dilutions (1:10)of each PSA inhibitor test compound primary stock solution were carried out using DMSO to obtain the following additional stock solution concentrations 30, 3, 0.3 uM. The primary stock solution was labelled "A". The remaining stock solutions were labelled "B", "C", and "D"
(corresponding to 30, 3 and 0.3 mM). The final concentrations of the compound to be tested in the reaction vials were 30, 3, 0.3, and 0.03 uM respectively.
The following depicts how the samples were tested, including the volumes of each component utilized. Amounts are in ul. I1 through I8 are the test samples. C1 through C3 are the controls with enzyme and substrate only. S1 is substrate only. P1 is enzyme only.
30ouM 3ouM 3uN! .3uM
A B C D DMSO Substrate PSA Tot.Vol I2 &.6 0 0 0 3.4 80 10 100 I4 0 6.4 0 0 3.4 80 10 100 I6 0 0 6.4 0 3.4 80 10 100 I8 0 0 0 6.4 3.4 80 10 100 80 ul of substrate (with a final concentration of 72 uM) was added to all vials) except P1. 100 ul of stock prostate-specific antigen [PSA-protein concentration 0.72 mg/ml (25.3 uM) in 50% PBS/Glycerol stored at -20 C;
molecular weight 28,433 g/mole; the specific activity of PSA
was determined experimentally to be I55 mmol/hr/mg protein]
was diluted with 620 ul 50% PBS/glycerol. 10 ul of diluted PSA (357 nM final concentration) was added to all HPLC
vials, except S1 to start the reaction. All vials were gently vortexed to ensure adequate mixing, capped, and incubated for 2 hours at 37° C .
The reaction was terminated by adding 100 ul of 0.2%
TFA/water (trifluoroacetic acid/water) to all reaction vials.
HPLC was used to analyze the samples. The analysis was carried out using the following equipment and parameters:
Beckman autosampler model #507; Programmable solvent module model #116; Diode array detector model #168; System Gold software v.7.0; Injection volume:100 ml; Column:Vydac Company, Cat. # 214TP5415 (4.6 mm X 250 mm) for protein and peptide separation C-4 solid phase; Particle size: 5 um;
Pore diameter: 300 A; Detection Parameters: System Gold Diode array scanner (model #168) detection at 210 and 280 nm.
Mobile Phase:
Solvent A = 0.1% TFA in water Solvent B = 0.1% TFA in Acetonitrile Gradient elution as follows:
Time %B
0 minutes 10%
5 minutes 10%
minutes 30%
36 minutes 10%
minutes 10%
35 Elution times:
peak 1 (YVPLG) . 8.5 + 0.3 minutes peak 2 (SGAWY) . 13 ~ 0.3 minutes peak 3 (SGAWYY) . 19 ~ 0.3 minutes Whole substrate peak 4 (SGAWYYVPLG) . 30 ~ 0.3 minutes See Figure 1 for graph.
Data Analysis The initial evaluation of each compound was carried out at final concentrations of 30, 10, 3 and 1 uM inhibitor.
Inhibitors that demonstrated an ICSp estimate < lOUM were re-evaluated in an 8 point concentration response (30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01 uM). The System Gold software integrated all chromatographic peaks and calculated the peak area to be used for statistical analysis. All controls were checked for intra-assay consistency. ~ inhibition was plotted as a function of inhibitor concentration and analyzed by non-linear regression. Compounds demonstrating less than 50% inhibition at the highest inhibitor concentration (generally 30 uM) were assigned an IC50 value of ">" the highest concentration. Compounds demonstrating greater than 50% inhibition at the highest inhibitor concentration were modeled with JMPTN' [SAS Institute, Cary, N.C.] non-linear analysis and assigned an IC50 value.
Compounds that did not inhibit PSA cleavage of the substrate were designated as not active (NA).
HPLC assav results:
Examflle # IC50 uM
2 0.91 7 1.12 21 >30 22 0.45 23 20.10 26 0.70 27 0.84 Several of the compounds of the present invention were tested to determine whether they inhibited other serine proteases. The method used for testing for PSA inhibition is the colorimetric method disclosed above. The method used WO 98!25895 PCT/IJS97/22573 for thrombin and tissue plasminogen activator (t-PA) inhibition is disclosed in "A Family of Arginal Thrombin Inhibitors Related to Efegatran", Seminars in Thrombosis and ( Hemostasis, Vol. 22, No. 2, 1996.
Example # PSA Thrombin t-PA
23 1.2 NA NA
As noted supra, the compounds of the present invention are useful in inhibiting the proteolytic activity of PSA.
Thus, the present invention also provides a method for inhibiting the proteolytic activity of PSA in mammals comprising administering to a mammal in need thereof a PSA
proteoiytic activity-inhibiting dose of a compound of the present invention.
The compounds of the present invention are useful for inhibiting the proteolytic activity of prostate-specific antigen and thereby for use in treating prostatic cancer in mammals. It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
Measurements of the serum concentration of PSA have now found widespread use in monitoring patients with PCa, as well as in diagnosing or predicting the probability of a patient having PCa. In normal males, PSA is present at less than 4 ng/ml. In males, suspicions about the presence of PCa surface once the level of PSA reaches from about 4 to about 10 ng/ml or the change in PSA concentration over time increases. In those males having a level of greater than 10 ng/ml, there is almost certain diagnosis of PCa.
Accordingly, the present compounds can be used to prevent the onset of prostatic cancer, delay the onset of prostatic cancer or decrease the likelihood of the onset of prostatic cancer in males with elevated PSA levels, for example, in males with a family history of the disease.
' 35 Administration of the PSA inhibitors of the present invention alone may provide an effective course of treatment for prostatic cancer. Still another embodiment of the present invention comprises the administration of PSA
inhibitors of the present invention in combination with other known treatments to provide an effective course of treatment for prostatic cancer.
While it is possible to administer a compound employed in the methods of this invention 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 (the compound of the present invention).
Such compositions contain from about 0.2% by weight to about 90.0% by weight of the present compound. These compositions can be administered by a variety of routes including oral, rectal, topical) transdermal, buccally, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable, oral and topical compositions.
Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.a., Remincrton's Pharmaceutical Sciences, (16th ed. 1980).
In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation.
Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, alcohol, 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.
The compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients. Most preferably, a compound of this invention may be admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired.
For topical administration, the compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation.
For oral administration, a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.

WO 98/25895 PCTlUS97122573 The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 500 mg, usually about 1.0 to about 100 mg, more usually about 1.0 to about 50 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 examples, dosages per day normally fall within the range of about 0.01 to about 500 mg/kg of body weight, preferably within the range of about 0.01 to about 30 mg/kg, more preferably within the range of about 0.01 to about 10 mg/kg. In the treatment of adult humans, the range of about 0.1 to about 5 mg/kg/day, in single or divided dose, is especially preferred. However, it will 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 not intended to limit the scope of 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) provided that such larger doses are first divided into several smaller doses for administration throughout the day.
In order to more fully illustrate the operation of the present invention, the following formulation examples are provided. The examples are illustrative only, and are not intended to limit the scope of the invention in any manner.

The formulations may employ as active ingredients (compounds) any of the compounds of the present invention.
Formulation Preparation 1 Hard gelatin capsules containing the following ingredients are prepared:
Quantity Ingredient (ma/capsule) Active Ingredient 10.0 Starch 325.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below:
Quantity Ingredient (ma/tablet) Active Ingredient 100.0 Cellulose, microcrystalline 125.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3 A dry powder inhaler formulation is prepared containing the following components:
Ingredient Weight Active Ingredient 5 Lactose g5 '' 3 5 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

Formulation Preparation 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:

Quantity Ingredient (ma/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 ma Total 120 mg 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°C 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 Preparation 5 Capsules, each containing 40 mg of medicament are made as follows:
Quantity Ingredient (ma/capsule) Active Ingredient 40.0 mg Starch , 109.0 mg Magnesium stearate 1.0 ma Total 150.0 mg 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 Preparation 6 Suppositories, each containing 25 mg of active ingredient are made as follows:
Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg 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 Preparation 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11~) Microcrystalline cellulose (89~) 50.0 mg Sucrose 1.75 g Sodium benzoate 10 . mg Flavor and Color q. v.

Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with ' 35 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 Preparation 8 Capsules, each containing 15 mg of medicament, are made as follows:
Quantity Inaredient 1ma/capsule>
Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 ma Total 425.0 mg 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 Pret~aration 9 An intravenous formulation may be prepared as follows:
Inaredient Ouantity Active Ingredient 250.0 mg Isotonic saline 1000 ml Formulation Preparation 20 A topical formulation may be prepared as follows:
Inaredient Ouantitv Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g 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 Preparation 11 , Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:
Quantity Ingredient Per Tablet Active Ingredient 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 ma Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
When the polymers have gone into solution, the solution is cooled to about 50-55°C 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.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art.
See, e.cr., U.S. Patent 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.

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

Claims (42)

We claim:
1. A compound of the Formula I:
wherein:
R1 is aryl; aryl-(C1-C6 alkylene); where the aryl, or ring of the aryl(C1-C6 alkylene) is optionally substituted with one or two substituents independently selected from halo, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene; phthalimido; or a moiety selected from:
where R4 is hydrogen;

C1-C6 alkyl;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
R5 is:
hydrogen;
C1-C4 alkyl;
C3-C7 cycloalkyl;
C1-C4 alkoxycarbonyl;
phenyl; or naphthyl;
where the phenyl or naphthyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro;
R6 is:
Hydrogen C1-C4 alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, benzylthio and C1-C4 alkylthio;
phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro; or C1-C4 alkoxycarbonyl;
R7 is:
C1-C4 alkoxycarbonyl;
benzyloxycarbonyl;
benzoyl;

where the phenyl ring in benzyloxycarbonyl or benzoyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino, carbamoyl, hydroxy, mono(C1-C4 alkyl)amino, and di(C1-C4 alkyl)amino;
R8 and R9 are independently:
hydrogen;
C1-C5 alkanoyloxy;
benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino and C1-C4 alkoxycarbonyl;
benzyloxy;
diphenylmethoxy; or triphenylmethoxy;
with the proviso that only one of R8 ar R9 can be hydrogen;
R2 is C2-C6 alkenyl;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;

where R10 is carboxy;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
-CH=C(R12)-R11 where R11 is hydrogen or phenyl and R12 is:
nitrile;
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
with the proviso that when R11 is phenyl, R12 is aryl; or C~C-R13;
where R13 is:
aryl; or heterocycle;
where the aryl or heterocycle is optionally substituted with one or two substituents independently selected from the group consisting of halo, n-oxide, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene; and R3 is a heterocycle, CO2R14, or ;
where R14 is C2-C6 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C~ cycloalkyl, substituted C3-C7 cycloalkyl, aryl-(C1-C6 alkyl), aryl, or heterocycle; where the aryl or heterocycle, or the ring of the aryl(C1-C6 alkylene), is optionally substituted with one or two substituents independently selected from the group consisting of halo, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
R15 is aryl or heterocycle-(C1-C6 alkylene); where the aryl or the ring of the heterocycle-(C1-C6 alkylene), is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C6 alkoxy, methoxycarbonyl, phenyl, C1-C6 alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, trifluoromethyl, and hydroxymethylene; and pharmaceutical salts and solvates thereof.
2. The compound of Claim 1, wherein:
R1 is benzyl, phthalimido, or a moiety of the formula:

where R5 is hydrogen, C1-C4 alkyl, or phenyl;
R6 is hydrogen, isopropyl, or phenyl;
R2 is phenyl, C2-C4 alkenyl, -CH2CH2R10, -CH=C(R11)-R12, or -C~C-R13;
where R10 is carboxy or phenyl;
R11 is hydrogen or phenyl;
R12 is cyano, phenyl, naphthyl, furan-2-yl, or furan-3-yl, pyridinyl, pyrimidinyl, or quinolinyl;

where the phenyl group is optionally substituted once with C1-C4 alkyl, C1-C4 alkoxy, or nitro and where the pyridinyl group is optionally substituted once with n-oxide;
R13 is phenyl;
R3 is a heterocycle, CO2R14, or ;
where heterocycle is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinazolinyl, or benzoxazolyl where said heterocycle is optionally substituted 1 or 2 times independently with nitro, trifluoromethyl, C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-C4 alkyl, C1-C4 haloalkyl, C4-C7 cycloalkyl, 2-isopropyl-5-methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally substituted once with halo, C1-C4 alkoxy, carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or furan-3-ylmethyl;
where phenyl is optionally substituted one to four times independently with halo or trifluoromethyl; and pharmaceutical acid addition salts and solvates thereof.
3. The compound of claim 2, which is:

where R3 is a heterocycle, CO2R14, or ;

where heterocycle is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinazolinyl, or benzoxazolyl where said heterocycle is optionally substituted 1 or 2 times independently with nitro, trifluoromethyl, C1-C4 alkoxy, or phenyl;
R14 is C2-C4 alkenyl, C1-C4 alkyl, C1-C4 haloalkyl, C4-C7 cycloalkyl, 2-isopropyl-5-methylcyclohexanyl, benzyl, or phenyl;
where the phenyl group is optionally substituted once with halo, Cl-C4 alkoxy, carbomethoxy, or nitro;
R15 is phenyl, naphthyl, furan-2-ylmethyl, or furan-3-ylmethyl;
where phenyl is optionally substituted one to four times independently with halo or trifluoromethyl; and pharmaceutical acid addition salts and solvates thereof.
4. A compound of the Formula Ib:

where R is naphthyl, benzyl, phenyl or furfuryl;
where the naphthyl, phenyl or aromatic ring of benzyl may be substituted with one to four halo, trifluoromethyl or C1-C6 alkyl groups; or a pharmaceutically salt or solvate thereof.
5. A method for inhibiting the proteolytic activity of prostate-specific antigen comprising administering to a mammal in need of such inhibition a pharmaceutically effective amount of a compound of Claim 1.
6. A method for inhibiting the proteolytic activity of prostate-specific antigen comprising administering to a mammal in need of such inhibition a pharmaceutically effective amount of a compound of Claim 2.
7. A method for inhibiting the proteolytic activity of prostate-specific antigen comprising administering to a mammal in need of such inhibition a pharmaceutically effective amount of a compound of Claim 3.
8. A method for inhibiting the proteolytic activity of prostate-specific antigen comprising administering to a mammal in need of such inhibition a pharmaceutically effective amount of a compound of Claim 4.
9. A method for the treatment of prostatic cancer comprising administering to a mammal in need of such treatment a compound of Claim 1.
10. A method for the treatment of prostatic cancer comprising administering to a mammal in need of such treatment a compound of Claim 2.
11. A method for the treatment of prostatic cancer comprising administering to a mammal in need of such treatment a compound of Claim 3.
12. A method for the treatment of prostatic cancer comprising administering to a mammal in need of such treatment a compound of Claim 4.
13. A method for treating prostatic cancer which comprises administering to a mammal in need thereof, a prostatic specific antigen inhibiting compound.
14. A method for treating benign prostatic hyperplasia which comprises administering to a mammal in need thereof, a prostatic specific antigen inhibiting compound.
15. A method for treating benign prostatic hyperplasia, in a mammal in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 1.
16. A method for treating benign prostatic hyperplasia, in a mammal in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 2.
17. A method for treating benign prostatic hyperplasia, in a mammal in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 3.
18. A method for treating benign prostatic hyperplasia, in a mammal in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 4.
19. A method for treating breast cancer which comprises administering to a mammal in need thereof, a prostatic specific antigen inhibiting compound.
20. A method for treating breast cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 1.
21. A method for treating breast cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 2.
22. A method for treating breast cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 3.
23. A method for treating breast cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 4.
24. A method for treating the metastasis associated with prostatic cancer which comprises administering to a mammal in need thereof, a prostatic specific antigen inhibiting compound.
25. A method for treating the metastasis associated with prostatic cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 1.
26. A method for treating the metastasis associated with prostatic cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 2.
27. A method for treating the metastasis associated with prostatic cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 3.
28. A method for treating the metastasis associated with prostatic cancer, in a patient in need of such treatment, comprising administering to such patient an effective amount of a compound of Claim 4.
29. A pharmaceutical formulation which comprises, in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and the compound of Claim 1.
30. A pharmaceutical formulation which comprises, in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and the compound of Claim 2.
31. A pharmaceutical formulation which comprises, in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and the compound of Claim 3.
32. A pharmaceutical formulation which comprises, in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and the compound of Claim 4.
33. A process for preparing a compound of the formula Ia wherein R16 represents: phenyl, 2-nitrophenyl, 4-nitrophenyl, naphthyl, 3-nitro-1-naphthyl, 4-nitro-2-naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thienyl, 3-furanyl, 3-pyridinyl, 3-pyridin-1-N-oxide, 5-pyrimidinyl, or 3,5-dimethylphenyl; and R17 represents: 1-phenoxycarbonyl, 4-chlorophenoxycarbonyl, 4-fluorophenoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobutyloxycarbonyl, 4-methoxycarbonylphenoxycarbonyl, 4-methoxyphenoxycarbonyl or 1-propylenoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof, which comprises:
functionalizing a 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula IX

where R20 is SnBu3 or B(OH)2, with the electrophile X-R16, wherein X is a leaving group, in the presence of a catalyst, to a compound of the formula XI

;

and acylating the compound of the formula XI to produce the substituted azetidinone of the formula Ia.
34. A compound of the formula IXa
35. A compound of the formula IXc
36. A compound of the formula VI

wherein R18 is a trialkylsilane and R19 is a nitrogen-protecting group.
37. A compound of the formula VII

wherein R19 is a nitrogen-protecting group.
38. A compound of the formula VIII

39. A process for preparing a compound of the formula Ia wherein R16 represents: phenyl, 2-nitrophenyl, 4-nitrophenyl, naphthyl, 3-nitro-1-naphthyl, 4-nitro-2-naphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thienyl, 3-furanyl, 3-pyridinyl, 3-pyridin-1-N-oxide, 5-pyrimidinyl, or 3,5-dimethylphenyl; and R17 represents: 1-phenoxycarbonyl, 4-chlorophenoxycarbonyl, 4-fluorophenoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobutyloxycarbonyl, 4-methoxycarbonylphenoxycarbonyl, 4-methoxyphenoxycarbonyl or 1-propyleneoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof, which comprises:
functionalizing a 3-(4S-phenyl-oxazolidin-2-on-3-yl)-4-ethenylazetidinone of the formula (IX) with the electrophile, X-R16, wherein X is a leaving group, in the presence of a catalyst, to a compound of the formula XI

and acylating the compound of the formula XI to produce the substituted azetidinone of the formula Ia.
40. A compound of the formula IX

41. A compound of the formula VIII

where R19 is a nitrogen-protecting group.
42. A compound of the Formula (vi):

CA002274958A 1996-12-13 1997-12-09 Inhibitors of the enzymatic activity of psa Abandoned CA2274958A1 (en)

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US3317996P 1996-12-13 1996-12-13
US60/033,179 1996-12-13
US4403297P 1997-03-13 1997-03-13
US4053997P 1997-03-13 1997-03-13
US4036297P 1997-03-13 1997-03-13
US4054397P 1997-03-13 1997-03-13
US60/044,032 1997-03-13
US60/040,539 1997-03-13
US60/040,362 1997-03-13
US60/040,543 1997-03-13
US4080597P 1997-03-18 1997-03-18
US4080497P 1997-03-18 1997-03-18
US60/040,804 1997-03-18
US60/040,805 1997-03-18
US4705497P 1997-05-19 1997-05-19
US4705597P 1997-05-19 1997-05-19
US60/047,054 1997-05-19
US60/047,055 1997-05-19
US5072197P 1997-06-25 1997-06-25
US60/050,721 1997-06-25
PCT/US1997/022573 WO1998025895A1 (en) 1996-12-13 1997-12-09 Inhibitors of the enzymatic activity of psa

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