WO1998025895A1 - Inhibiteurs de l'activite enzymatique de l'antigene psa - Google Patents

Inhibiteurs de l'activite enzymatique de l'antigene psa Download PDF

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WO1998025895A1
WO1998025895A1 PCT/US1997/022573 US9722573W WO9825895A1 WO 1998025895 A1 WO1998025895 A1 WO 1998025895A1 US 9722573 W US9722573 W US 9722573W WO 9825895 A1 WO9825895 A1 WO 9825895A1
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phenyl
compound
azetidinone
alkyl
ethen
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PCT/US1997/022573
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English (en)
Inventor
Benjamin A. Anderson
Gerald W. Becker
James A. Carty
Nancy K. Harn
Lowell D. Hatfield
Blake L. Neubauer
John R. Rizzo
Tony Y. Zhang
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Eli Lilly And Company
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Priority to AU55970/98A priority Critical patent/AU5597098A/en
Priority to BR9714394-4A priority patent/BR9714394A/pt
Priority to CA002274958A priority patent/CA2274958A1/fr
Priority to JP52690098A priority patent/JP2002514197A/ja
Priority to IL13030097A priority patent/IL130300A0/xx
Priority to EP97952334A priority patent/EP0944594A4/fr
Publication of WO1998025895A1 publication Critical patent/WO1998025895A1/fr

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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

Definitions

  • 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 (Pea), Pea metastasis, benign prostatic hyperplasia (BPH), breast cancer (Be) and Be metastasis.
  • PSA Prostate-Specific Antigen
  • Another aspect of the invention relates to methods for treating Pea, Pea metastasis, BPH, Be and Be metastasis by administering any PSA inhibiting compound.
  • PCa is the second most common cancer in American men. According to Wingo et al . [P.A. ingo, et al .. CA Cancer J. Clin. , 41 (1), 8-30, (1995)], 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.
  • Pea 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) .
  • Be is another devastating disease for which improved therapies are greatly needed. Be 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 Pea, Pea metastasis, BPH, Be and Be 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 . , Urolo ⁇ v,
  • 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 ⁇ i-antichymotrypsin
  • 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 Be. H. Yu, __________ Cancer Research, 55 , 2104-
  • PSA serine protease
  • IGFBPs insulin growth factor binding proteins
  • PSA has been shown to degrade certain IGFBPs and this action has been proposed as contributory to prostatic cellular growth, leading to BPH and Pea.
  • 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 Be cells is consistent with PSA playing a similar role in the treatment of Be as in the treatment of of Pea.
  • the present invention is directed to a compound of the Formula I :
  • R! is aryl; aryl(C ⁇ -C6 alkylene) ; where the aryl or ring of the aryl(C ⁇ -C6 alkylene) is optionally substituted with one or two substituents independently selected from halo, C1-C alkoxy, methoxycarbonyl, phenyl, C1-C alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene; phthalimido; or a moiety selected from:
  • R ⁇ 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, I ⁇ C Q alkoxy, methoxycarbonyl, phenyl, C ⁇ -CQ alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
  • R 5 is: hydrogen; C1-C4 alkyl;
  • R 6 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-
  • R 7 is:
  • 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 R ⁇ or R ⁇ can be hydrogen; R 2 is
  • -CH C(R 12 )-R 1:L
  • R 11 is hydrogen or phenyl and R 12 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, C ⁇ -C alkoxy, methoxycarbonyl, phenyl, C ⁇ -Cg alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene ; with the proviso that when R 11 is phenyl, R 12 is aryl; or -C ⁇ C-R 13 ' ' where 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, C ⁇ -Cg alkoxy, methoxycarbonyl, phenyl, C ] _-Cg
  • R is a heterocycle, CO2R . 1 14 , or
  • R 14 is C2-Cg alkenyl, C ⁇ Cg alkyl, Ci-Cg haloalkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, aryl- (Ci-Cg alkyl), aryl, or heterocycle; where the aryl or heterocycle, or the ring of the aryl(C ⁇ -Cg alkylene) , is optionally substituted with one or two substituents independently selected from the group consisting of halo, C ⁇ -Cg alkoxy, methoxycarbonyl, phenyl, C ] _-Cg alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, and hydroxymethylene;
  • R1 is aryl or heterocycle- (C ] _-Cg alkylene); where the aryl or the ring of the heterocycle- (C ⁇ -Cg alkylene) , is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C ] _-Cg alkoxy, methoxycarbonyl, phenyl, C ] _-Cg alkyl, carboxy, nitro, acetyl, formyl, carboxymethylene, trifluoromethyl, and hydroxymethylene; and pharmaceutical salts and solvates thereof.
  • the present invention also provides a method for inhibiting the proteolytic activity of Prostate-Specific Antigen (PSA) by administering a compound of Formula I.
  • PSA Prostate-Specific Antigen
  • the present invention also provides methods for treating Pc, Pea metastasis BPH, Be and Be 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.
  • aryl 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) .
  • the substituents may be located at any available position on the aryl ring(s) that are sterically feasible and afford a stable structure.
  • the aryl may optionally be substituted with one or two moieties.
  • 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 .
  • substituted C3-C7 cycloalkyl represents a cycloalkyl group of 3 to 7 carbon atoms substituted with one or two moieties chosen from the group consisting of halo and C ⁇ -Cg alkyl.
  • substituted cycloalkyls include 2-isopropylcyclohexyl, 5- methylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4- chlorocyclohexyl, 3-chlorocyclohexyl, 4-iodocyclohexyl, 3- iodocyclohexyl, 3-chlorocyclopentyl, and 3- chlorocycloheptyl .
  • heterocycle 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.
  • heterocycles include: 2-thienyl or 3-thienyl, 2-fury1 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, C1-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.
  • C ⁇ -Cg alkyl represents a branched or linear, monovalent alkyl group having from one to six carbon atoms.
  • Typical C ⁇ -Cg alkyl groups include methyl, ethyl, n-propyl, iso-oropvl , n-butyl, iso-butvl. sec-butyl , Jz-butyl, n-pentyl, isopentyl, n-hexyl, 2- methylpentyl, and the like.
  • Also encompassed within the - li teral Ci-Cg alkyl are more narrow ranges such as C1-C4 alkyl and C2-C5 alkyl.
  • C2 ⁇ Cg alkenyl represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms with one double bond.
  • Typical C2 ⁇ Cg alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-l-propenyl, 1- hexenyl, 2-methyl-2-propenyl, 1-propenyl, 1-butenyl, 2- pentenyl, and the like.
  • C ] _-Cg alkoxy represents a straight or branched -0-(C ⁇ -Cg alkyl) chain. The oxygen atom bonds at the point of attachment to the parent molecule.
  • Typical C ⁇ -Cg alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t.-butoxy, pentoxy and the like.
  • Ci-Cg haloalkyl represents straight or branched alkyl chain having from one to six carbon atoms with one or more halogen atoms bonded thereto.
  • Typical Ci-Cg haloalkyl groups include 3-chlorobutyl, 4- chlorobutyl, 3-iodobutyl, 4-iodobutyl, 3-fluorobutyl, 4- fluorobutyl, and the like.
  • Ci-Cg alkylene represents a straight chain having from one to six carbon atoms with two bonds thereto.
  • Typical Ci-Cg alkylene groups include ethylene, trimethylene, tetramethylene and the like.
  • aryl(C ⁇ -Cg alkylene) represents an aryl(C ⁇ Cg alkylene)- substituent where the alkylene group is linear, such as phenylethylene or the like.
  • the ring of the aryl(C ⁇ -Cg alkylene) may optionally be substituted with one or two moieties.
  • the substituents may be located at any available position on the aryl ring.
  • halo or halogen, as used herein, means fluorine, chlorine, bromine, or iodine.
  • C1-C4 alkoxycarbonyl 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.
  • benzylthio 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 .
  • C1-C4 alkylthio 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.
  • carbamoyl represents the radical NH2CO- .
  • hydroxymethylene represents the radical -CH2OH.
  • n-oxide refers to the radical 0 bonded to an available nitrogen atom.
  • C1-C5 alkanoyloxy 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
  • H E Human Leukocyte Elastase
  • tPA tissue Plasminogen Activator
  • thrombin tissue Plasminogen Activator
  • 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 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 Organic 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, maleic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic , benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like.
  • the preferred pharmaceutically acceptable salts are those formed with hydrochloric acid or acetic acid.
  • R5 is hydrogen, C1-C4 alkyl, or phenyl
  • R ⁇ is hydrogen, isopropyl, or phenyl
  • R ⁇ 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-C alkyl, C1-C4 alkoxy, or nitro and where the pyridinyl group is optionally substituted once with n- oxide;
  • R ⁇ 3 is phenyl; R 3 is a heterocycle, CO2R . or
  • 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, c l ⁇ c 4 alkoxy, or phenyl;
  • R 14 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; R 15 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.
  • R 3 is a heterocycle, C02R- 1 - 4 .
  • 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, C ] _-C4 alkoxy, or phenyl;
  • R 14 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;
  • 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 1981) . Appropriate resolution methods include direct crystallization, entrainment, and crystallization by optically active solvents. Chrisey, L.A. Heterocvcles , 267, 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.
  • trans . isomers are considered to be those isomers in which the R! moiety will be in the opposite or trans-position with regard to the R 2 moiety.
  • cis isomers are considered to be those isomers in which the R ⁇ moiety will be in the same or cis-position with regard to the R 2 moiety.
  • the present invention therefore encompasses both the R and the S configurations with regard to the 3- and 4- positions.
  • 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 al . The Vocabulary of Organic Chemistry, p. 126, (John Wiley and Sons, Inc.) .
  • the R! moiety will be in the cis-position with regard to the
  • the R ⁇ moiety will be in the trans-position with regard to the R 2 moiety, and in the 3R,4R configuration:
  • Racemic mixtures of the trans isomers are also included within the present invention.
  • mixtures of the cis and trans isomers are contemplated.
  • 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 R ⁇ - is 4- substituted oxazolidin-2-on-3-yl, the 4 position on that ring is asymmetric .
  • 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.
  • preparation of the racemic mixtures of the invention are illustrated by disclosure of a single isomer.
  • the preferred starting material is an aldehyde (i) in which R 2 is defined above for Formula I and p_-anisidine (ii) .
  • Reactive moieties within the R 2 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] .
  • an acid chloride (vi) is produced by reacting oxalyl chloride (v) with an acid (iv) in which R 1 is as defined above for Formula I [STEP 2] .
  • Reactive moieties within the R 1 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) are generally described in U.S. Patent No.
  • trans compounds the 1- (methoxy)phenylazetidinone (vii) compounds are epimerized with Li-t.-OBu at the 3 position to give the trans configuration [STEP 4A] .
  • the compound epimerized is a racemic mixture, then a mixture of racemic trans products will be obtained.
  • the 1- (methoxy)phenylazetidinone (vii) compound is subjected to CAN oxidation to remove the p_-methoxyphenyl substituent
  • 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.
  • diastereomeric mixtures may be separated by chromatography or fractional crystallization to provide single diastereomers 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-methylpiperidine and N- methylmorpholine, aromatic amines, such as pyridine and lutidine, and other organic bases such as 1,8- diazabicyclo[5,4, 0]undec-7-ene (DBU) .
  • TAA trimethylamine and triethylamine
  • DMAP dimethylaminopyridine
  • cyclic tertiary amines such as N-methylpiperidine and N- methylmorpholine
  • aromatic amines such as pyridine and lutidine
  • DBU 1,8- diazabicyclo[5,4, 0]undec-7-ene
  • 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, diethy1 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 .
  • solvents such as dioxane, ethyl acetate, ace
  • R 1 is depicted as phenyl oxazolidinone or phthalimido
  • R 2 is depicted as (2-phenyl) ethen-1-yl and (2-pyridine) ethen-1-yl
  • R 3 is depicted as phenyl oxycarbonyl .
  • 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.
  • 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.
  • the aldehydes are prepared according to the procedure disclosed in Angew. Chem.
  • aldehydes are produced by the method depicted below:
  • 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 .
  • a solvent preferably dichloromethane .
  • One equivalent of a primary amine p-anisidine
  • 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.
  • the imines can be prepared as follow:
  • 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.
  • a solvent preferably toluene or benzene
  • 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) .
  • reaction mixture is cooled to room temperature and the organics removed by vacuum.
  • the acid chlorides are produced as follows :
  • 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.
  • epimerization may be carried out as follows :
  • CAN oxidation is known in the art as depicted in J. Org. 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 :
  • 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. More specifically, by way of example, acylation was performed generally as follows:
  • 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 NH4CI, 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.
  • 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 (Cerric Ammonium Nitrate) Oxidation
  • 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 300ml ethyl acetate.
  • the wash was then combined with 1 X 500ml 5% sodium bicarbonate and 3 X 500ml 10% sodium sulfite.
  • the combined organics were slurried with 50g DarcoTM for 30 minutes and then lOOg 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 60ml ethyl acetate and triturated with 250ml ether.
  • 1:1 mixtures of the cis : trans isomers of the present invention may be prepared by combining the steps as follows : Epimerization and Acylation
  • the trans isomer was obtained in the same manner as Example 4.
  • Example 30 The same procedure was used as in Example 30 with the exception that 55mg of the cis isomer was obtained from the silica gel.
  • the reaction mixture was quenched with 20ml of 0.5N hydrochloric acid and extracted with 20 ml of diethyl ether and 30ml of dichloromethane. A solid formed. The solid was dissolved in 50ml of dichloromethane. The combined organic layers were washed with 50 ml of 10% 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 20ml of ice cold Diethyl ether. The white solid was vacuum filtered, washed with 10 mL of diethyl ether, and vacuum dried.
  • the starting aldehyde (i) is prepared according to the procedures detailed in Tet. Lett. , 32 (6), 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 Org . React. , 14, 270 (1965) and Ace. Chem. Res.. 16, 411 (1983).
  • 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 .
  • 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 la
  • R 1 ⁇ represents: phenyl, 2-nitrophenyl, 4- nitrophenyl, naphthyl, 3-nitro-l-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-l-N-oxide, 5-pyrimidinyl, or 3,5- dimethylphenyl; and
  • R-*- 7 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:
  • R--8 is a trialkylsilane
  • 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, p_- anisidine, in the presence of a solvent, preferably methylene chloride or dichloromethane [STEP 1] .
  • 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., Synthesis, 307 (1978).
  • Suitable R 18 groups include, for example, trimethylsilane or other alkylsilanes .
  • 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) .
  • 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 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.
  • 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.
  • 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.
  • 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.
  • N- protected azetidinone (VI) is preferably desilylated and epimerized by employing tetrabutylammonium fluoride (TBAF) at reaction temperatures below -50°C.
  • TBAF tetrabutylammonium fluoride
  • Tetrahydrofuran is a preferred solvent.
  • trans desilylated 4-acetylenic azetidinone intermediate (VII) is partially reduced and N-deprotected to yield the ⁇ -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. Org. Chem., 47, 2765-68 (1982).
  • cerric ammonium nitrate in the presence of acetonitrile, for example, according to the method outlined at J. Org. Chem., 47, 2765-68 (1982).
  • acetonitrile for example, according to the method outlined at J. Org. 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-R ⁇ °, in the presence of a solvent, and is acylated to produce the substituted oxycarbonylazetidinone of the formula I [STEPS 6 and 7] .
  • X-R 16 X is a leaving group such as halogen, sulfonate or the like and R-*-° is as previously defined.
  • 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 . , Svnlett , 839 (1994).
  • R ⁇ 6 groups are preferred: 2-nitro-4- phenyl, 4-nitro-2-phenyl, 3-nitro-l-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 .
  • Acylation is preferably accomplished with an appropriate chloroformate to produce the substituted oxycarbonylazetidinone of the formula la.
  • 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 la.
  • the compounds of formula la 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 anc j acylating (in either order) ; or 2-functionalizing compound VIII with an electrophile, X-R 16 , 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-R 1 ⁇ and acylation (in either order) .
  • the aldehyde Ila (4.89 g) was dissolved in 10 ml methylene chloride. Anhydrous magnesium sulfate (9.43 g) was added, followed by a solution of p-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.
  • 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 10% hydrochloric acid solution (3x) , brine (lx), saturated sodium bicarbonate (2x) and brine (lx) .
  • the organic solution was washed with brine (lx), saturated ammonium chloride (3x) , brine (lx) 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 a silica plug with chloroform to remove residual 1-iodonaphthalene then ethyl acetate to remove the product. Further purification with column chromatography (chloroform, then
  • Example 51 resulted in 0.007 g of the ⁇ -lactam of Example 52 in the cis configuration.
  • reaction mixture was extracted with chloroform (2x) and the organic fraction washed with brine (lx) .
  • the organic solution was dried over sodium sulfate and concentrated by rotary evaporation to the desired ⁇ -lactam. Trituration with chloroform, and a water wash gave 0.007g.
  • 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 la
  • R 1 ⁇ and R ⁇ 7 are as previously defined, which comprises :
  • R ⁇ y is a trialkylsilane
  • R 2 ⁇ is SnBu3 or B(OH)2;
  • the preferred intermediates of the invention have the formulas VI, VII, VIII, IX', IXa and IXc :
  • R 1 ⁇ R17 / R18 ; R 19 anc j R 20 are as previously defined.
  • the desilylated 4-acetylenic azetidinone intermediate (VII) is first N-deprotected to yield the ⁇ -lactam trans 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. Or ⁇ . 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.
  • hydrostannylation of the triple bond may be afforded by thermolysis in the presence of, for example, 2, 2 ' -azobisisobutyronitrile (AIBN) .
  • AIBN 2, 2 ' -azobisisobutyronitrile
  • 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-
  • X is a leaving group such as halogen, sulfonate or the like and R ⁇ -6 i s as previously defined.
  • Functionalization is best accomplished employing a catalyst, such as, tetrakis (triphenylphosphine) palladium(0) , and preferably in the presence of copper (I) iodide dissolved in tetrahydrofuran.
  • R groups are preferred: 2-nitrophenyl, 4-nitrophenyl, 3-nitro-l-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- dimethylpheny1.
  • Acylation is preferably accomplished with an appropriate chloroformate to produce the substituted azetidinone of the formula la.
  • 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 la.
  • the compounds of formula la 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 1 ), followed by functionalizing with an electrophile X-R-L6 anc j 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-R- ⁇ 6 and acylation (in either order) .
  • the azetidinone (Vila) (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.
  • 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 and the aqueous layer was extracted with ethyl acetate.
  • 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 .
  • 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 (0) (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 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 10 mol% tris (dibenzylideneacetone) dipalladium and 80 mol% 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) .
  • 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(O) was replaced with 10 mol% tris (dibenzylideneacetone) dipalladium and 80 mol% 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 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) .
  • azetidinone compound 28 mg was utilized to prepare compound l-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) .
  • 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 ( triphenylphosphme) 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) .
  • 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 lb:
  • R 2 ⁇ i s phenyl, benzyl, naphthyl or furfuryl; where the phenyl, naphthyl or aromatic ring of benzyl may be substituted with one to four halo, trifluoromethyl or
  • R 2 ⁇ is as previously defined.
  • Preparation of the compound of Formula lb 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 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.
  • Buffer A which comprised PBS + 0.7 mg BSA/ml used for dilution of PSA
  • Buffer B which comprised PBS + 6.3 mg BSA/ml used in the reaction mixture to prevent nonspecific 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 UV900HDi, 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 PBS was Gibco BRL Dulbecco's Phosphate-Buffered Saline IX (D- PBS) (Catalog No. 14040-026) stored at 4°C.
  • the BSA Bovine Serum Albumin
  • Sigma Catalog No. #A-7511
  • PBS/BSA solutions, and the substrate solution 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 ⁇ M.
  • 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 .
  • 10 ⁇ l of PBS buffer B was added to all reaction wells including well B2.
  • 10 ⁇ l of DMSO was added to well B2 as well as to "no inhibitor control" well(s) (B10, CIO, D10, E10, F10, G10, H10) .
  • 10 ⁇ l of test compound (final cone. 100; 33; 10; 3; 1; 0.3; 0.1; 0.03; 0.01 uM) was added in singlicate, to remaining wells (Bl-9, Cl-9, Dl-9, El-9, Fl-9, Gl-9 and Hl-9).
  • 10 ⁇ l of stock PSA was diluted with 610 ⁇ l PBS Buffer A. 10 ⁇ l of PBS + 0.7 mg BSA/ml was added to well B2. 10 ⁇ l 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 ⁇ l of substrate stock solution (1 mM final concentration) was added to all wells. Reaction progress, PSA cleavage of p_- nitroaniline (p-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.
  • p_NA p_- nitroaniline
  • reaction velocities slope in terms of mO .D . /minutes . were plotted against inhibitor concentrations to determine the inhibitory concentration at 50% inhibition (IC50) .
  • IC50 values were determined using non-linear analysis. Compounds demonstrating less than 50% inhibition at the highest inhibitor concentration (generally 100 ⁇ M) 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 IC50 value. Colorimetric assay results:

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Abstract

La présente invention concerne des composés azétidinone, certains intermédiaires et procédés permettant d'élaborer de tels composés azétidinone, et des formulations contenant ces composés et intermédiaires. L'invention concerne également l'utilisation de ces azétidinones comme inhibiteurs de l'activité enzymatique de l'antigène PSA (Prostate-Specific Antigen) ainsi qu'un traitement contre le cancer de la prostate (Pca), contre les métastases Pca, contre l'hyperplasie prostatique bénigne (BPH) et contre le cancer du sein (Bc). Un autre aspect de l'invention concerne des procédés nouveaux permettant de traiter le cancer de la prostate (Pca), les métastases Pca, l'hyperplasie prostatique bénigne (BPH) et le cancer du sein (Bc) par administration de n'importe quel composé inhibiteur du PSA.
PCT/US1997/022573 1996-12-13 1997-12-09 Inhibiteurs de l'activite enzymatique de l'antigene psa WO1998025895A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU55970/98A AU5597098A (en) 1996-12-13 1997-12-09 Inhibitors of the enzymatic activity of psa
BR9714394-4A BR9714394A (pt) 1996-12-13 1997-12-09 Inibidores da atividade enzimática de psa
CA002274958A CA2274958A1 (fr) 1996-12-13 1997-12-09 Inhibiteurs de l'activite enzymatique de l'antigene psa
JP52690098A JP2002514197A (ja) 1996-12-13 1997-12-09 Ｐｓａの酵素活性の阻害物質
IL13030097A IL130300A0 (en) 1996-12-13 1997-12-09 Inhibitors of the enzymatic activity of PSA
EP97952334A EP0944594A4 (fr) 1996-12-13 1997-12-09 Inhibiteurs de l'activite enzymatique de l'antigene psa

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US3317996P 1996-12-13 1996-12-13
US60/033,179 1996-12-13
US4053997P 1997-03-13 1997-03-13
US4054397P 1997-03-13 1997-03-13
US4036297P 1997-03-13 1997-03-13
US4403297P 1997-03-13 1997-03-13
US60/044,032 1997-03-13
US60/040,362 1997-03-13
US60/040,543 1997-03-13
US60/040,539 1997-03-13
US4080497P 1997-03-18 1997-03-18
US4080597P 1997-03-18 1997-03-18
US60/040,805 1997-03-18
US60/040,804 1997-03-18
US4705597P 1997-05-19 1997-05-19
US4705497P 1997-05-19 1997-05-19
US60/047,055 1997-05-19
US60/047,054 1997-05-19
US5072197P 1997-06-25 1997-06-25
US60/050,721 1997-06-25

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US6335324B1 (en) 1998-06-25 2002-01-01 Bristol-Myers Squibb Co. Beta lactam compounds and their use as inhibitors of tryptase
WO2005016326A2 (fr) * 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogues de la thalidomide utilises comme inhibiteurs potentiels de l'angiogenese
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
US7678802B2 (en) 2003-03-03 2010-03-16 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US7713983B2 (en) 2003-03-03 2010-05-11 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US7928107B2 (en) 2004-09-02 2011-04-19 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
US8283354B2 (en) 2004-09-02 2012-10-09 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US8853253B2 (en) 2003-09-17 2014-10-07 P2D, Inc. Thalidomide analogs
US9084783B2 (en) 2011-12-02 2015-07-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US11628160B2 (en) 2017-09-15 2023-04-18 Azevan Pharmaceuticals, Inc. Compositions and methods for treating brain injury

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ES2552682T3 (es) 2003-03-10 2015-12-01 Merck Sharp & Dohme Corp. Agentes antibacterianos novedosos
WO2005063704A1 (fr) * 2003-12-25 2005-07-14 Ono Pharmaceutical Co., Ltd. Composes cycliques d'azetidine et medicaments les renfermant
EP2214484A4 (fr) 2007-10-25 2013-01-02 Cempra Pharmaceuticals Inc Procédé pour la préparation d'agents antibactériens macrolides
EP2358379B1 (fr) 2008-10-24 2015-12-16 Cempra Pharmaceuticals, Inc. Biodéfenses utilisant des macrolides contenant du triazole
US9937194B1 (en) 2009-06-12 2018-04-10 Cempra Pharmaceuticals, Inc. Compounds and methods for treating inflammatory diseases
US9480679B2 (en) 2009-09-10 2016-11-01 Cempra Pharmaceuticals, Inc. Methods for treating malaria, tuberculosis and MAC diseases
PL2587919T3 (pl) * 2010-07-01 2018-05-30 Azevan Pharmaceuticals, Inc. Sposoby leczenia zespołu stresu pourazowego
EP2613630A4 (fr) 2010-09-10 2014-01-15 Cempra Pharmaceuticals Inc Fluorocétolides formant des liaisons hydrogène pour traiter les maladies
KR20140139083A (ko) 2012-03-27 2014-12-04 셈프라 파마슈티컬스, 인크. 마크롤라이드계 항생제를 투여하기 위한 비경구 제제
JP6426696B2 (ja) 2013-03-14 2018-11-21 センプラ ファーマシューティカルズ，インコーポレイテッド 呼吸器疾患の治療のための方法および製剤
EP2968384A4 (fr) 2013-03-15 2017-02-15 Cempra Pharmaceuticals, Inc. Procédés convergents de préparation d'agents antibactériens macrolides

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 10 January 1996, Vol. 118, No. 1, RUHLAND et al., "Solid-Supported Combinatorial Synthesis Structurally Diverse beta-Lactams", pages 253-254. *
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6335324B1 (en) 1998-06-25 2002-01-01 Bristol-Myers Squibb Co. Beta lactam compounds and their use as inhibitors of tryptase
US8716315B2 (en) 2001-02-27 2014-05-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
US8252902B2 (en) 2001-10-22 2012-08-28 The Scripps Research Institute Antibody targeting compounds
US7678802B2 (en) 2003-03-03 2010-03-16 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US8343980B2 (en) 2003-03-03 2013-01-01 Vertex Pharmaceuticals Incorporated Quinazoles useful as modulators of ion channels
US7713983B2 (en) 2003-03-03 2010-05-11 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
WO2005016326A2 (fr) * 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogues de la thalidomide utilises comme inhibiteurs potentiels de l'angiogenese
WO2005016326A3 (fr) * 2003-07-11 2005-06-16 Us Gov Health & Human Serv Analogues de la thalidomide utilises comme inhibiteurs potentiels de l'angiogenese
US8546430B2 (en) 2003-09-17 2013-10-01 P2D, Inc. Thalidomide analogs
US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
US8853253B2 (en) 2003-09-17 2014-10-07 P2D, Inc. Thalidomide analogs
US8283354B2 (en) 2004-09-02 2012-10-09 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US7928107B2 (en) 2004-09-02 2011-04-19 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
US9084783B2 (en) 2011-12-02 2015-07-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US9623020B2 (en) 2011-12-02 2017-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US10220028B2 (en) 2011-12-02 2019-03-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US11628160B2 (en) 2017-09-15 2023-04-18 Azevan Pharmaceuticals, Inc. Compositions and methods for treating brain injury

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EP0944594A1 (fr) 1999-09-29
HUP0000288A2 (hu) 2001-01-29
EP0944594A4 (fr) 2000-05-03
BR9714394A (pt) 2000-05-16
CA2274958A1 (fr) 1998-06-18
IL130300A0 (en) 2000-06-01
HUP0000288A3 (en) 2001-04-28
AU5597098A (en) 1998-07-03
JP2002514197A (ja) 2002-05-14
KR20000069431A (ko) 2000-11-25

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