WO1995002579A1 - Derives d'amide d'azetidinone substitues utilises comme agents anti-inflammatoires et anti-degeneratifs - Google Patents

Derives d'amide d'azetidinone substitues utilises comme agents anti-inflammatoires et anti-degeneratifs Download PDF

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WO1995002579A1
WO1995002579A1 PCT/GB1994/001466 GB9401466W WO9502579A1 WO 1995002579 A1 WO1995002579 A1 WO 1995002579A1 GB 9401466 W GB9401466 W GB 9401466W WO 9502579 A1 WO9502579 A1 WO 9502579A1
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alkyl
formula
hydrogen
ethyl
methyl
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PCT/GB1994/001466
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Graham Charles Crawley
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Zeneca Limited
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    • 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
    • C07D205/09—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 with a sulfur atom directly attached in position 4

Definitions

  • This invention concerns amide derivatives and more particularly azetidinone derivatives which are inhibitors of the production of cytokines, in particular of tumour necrosis factor (TNF).
  • the invention also concerns processes for the manufacture of said amide derivatives and pharmaceutical compositions containing them. Also included in the invention is the use of said amide derivatives in the treatment of various diseases including inflammatory and allergic diseases in which the direct or indirect effects of cytokines are involved and the production of new medicaments for such use.
  • the amide derivatives described hereinafter are inhibitors of the production of TNF which is believed to be formed by the cleavage of a larger precursor or pro-form by the enzyme proTNF Convertase.
  • the amide derivatives of the present invention are inhibitors of TNF production by mechanisms which are believed to include proTNF Convertase inhibition.
  • the term "TNF" is used herein to refer to TNF in general but particularly TNF-alpha.
  • Excessive TNF production is known to give rise via a cascade of processes to a variety of physiological sequelae including the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis.
  • physiologically-active eicosanoids such as the prostaglandins and leukotrienes
  • proteolytic enzymes such as collagenase
  • osteoclast activity leading to the resorption of calcium the stimulation of the release of proteoglycans from, for example, cartilage
  • angiogenesis the stimulation of cell proliferation and to angiogenesis.
  • TNF production precedes and mediates the production of other cytokines such as interleukin-1 (IL-1) and interleukin-2 (IL-2) which are also believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity.
  • IL-1 interleukin-1
  • IL-2 interleukin-2
  • Excessive TNF production has also been implicated in mediating or exacerbating the development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease.
  • various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic
  • Excessive TNF production has also been implicated in mediating complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome. Excessive TNF production has also been implicated in mediating or exacerbating the development of adult respiratory distress syndrome, diseases involving cartilage or muscle resorption, Paget's disease and osteoporosis, pulmonary fibrosis, cirrhosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis.
  • AIDS malignant disease and acquired immune deficiency syndrome
  • TNF is also known to cause the activation of latent AIDS.
  • azetidinone derivatives are effective inhibitors of the production of TNF and this is believed to include inhibition of the enzyme proTNF Convertase; other means of inhibition of TNF production are also contemplated.
  • proTNF Convertase enzyme was identified as PR-3, a protease found in leucocyte granules. PR-3 is believed to act on a 26kD transmembrane precursor of mature active 17kD TNF.
  • Such compounds are of value as therapeutic agents in the treatment of diseases or medical conditions mediated alone or in part by TNF, for example, inflammatory and allergic conditions such as rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, ulcerative colitis and gastritis, skin conditions such as psoriasis, eczema and dermatitis, respiratory conditions such as asthma, bronchitis and allergic rhinitis, cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease, endotoxic shock, septic shock and toxic shock syndrome, adult respiratory distress syndrome, diseases involving cartilage or muscle resorption, Paget's disease, osteoporosis, pulmonary fibrosis, cirrhosis, cachexia, tumour growth and AIDS.
  • inflammatory and allergic conditions such as rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, ulcerative colitis and gastritis
  • skin conditions such as ps
  • X is thio, sulphinyl or sulphonyl; p is the integer 1 or 2; each R , which may be the same or different, is selected from hydrogen, halogeno, carboxy, carbamoyl, cyano, hydroxy, amino, ureido,
  • Y is hydrogen or ( l-4C) alkyl or a group of the formula
  • r is an integer from 0 to 2 and one of the methylene groups when r is the integer 1 or 2 may optionally bear one or two
  • each R which may be the same or different, is selected from hydrogen, halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (2-4C)alkenyl,
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
  • An analogous convention applies to other generic terms.
  • the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting TNF Convertase or other means of inhibiting TNF production.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • inhibitory properties against TNF Convertase and/or TNF production may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Suitable values for the substituents R or R which may be present on the aryl rings in the compound of the formula I or for substituents on (CH-) include, for example:- for halogeno: fluoro, chloro, bromo and iodo; for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl; for (2-4C)alkenyl: vinyl and allyl; for (2-4C)alkynyl: ethynyl and prop-2-ynyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-4C)alkylamino: methylamino, ethylamino, propylamino and butylamino; for di-[(l-4C)alkyl]amino: dimethylamino, diethylamin
  • a suitable value for Y when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • a suitable pharmaceutically-acceptable salt of an amide derivative of the invention is, for example, an acid-addition salt of an amide derivative of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically-acceptable salt of an amide derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methyla ine, dimethylamine, trimethylamine, piperidine, orpholine or tris-(2-hydroxyethyl)amine.
  • novel compounds of the invention include, for example, amide derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein the variable groups
  • each R which may be the same or different, is selected from hydrogen, fluoro, chloro, carboxy, carbamoyl, cyano, hydroxy, amino, ureido, methyl, ethyl, vinyl, allyl, ethynyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, acetamido, N-methylacetamido, acetyl, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, carbamoylmethyl, N-methylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl and methylenedioxy;
  • Y is methyl, ethyl, propyl, isopropyl or butyl;
  • R which may be the same or different, is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy and trifluoromethyl; or
  • r is 1 and the methylene group may optionally bear one or two substituents selected from methyl, ethyl, propyl and isopropyl, q is 1
  • each R which may be the same or different, is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy and trifluoromethyl.
  • a preferred compound of the invention is an amide derivative of the formula I wherein X is thio, sulphinyl or sulphonyl; p is 1 or 2 and each R , which may be the same or different, is selected from hydrogen, fluoro, chloro, carboxy, carbamoyl, cyano, hydroxy, amino, ureido, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, acetamido, N-methylacetamido, acetyi, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, carbamoylmethyl, N-methylcarbamoylmethyl,
  • Y is methyl, ethyl, propyl, isopropyl or butyl, or
  • Y is a group of the formula
  • R which may be the same or different, is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention is an amide derivative of the formula I wherein X is thio; p is 1 and R is selected from hydrogen, fluoro, chloro, carboxy, carbamoyl, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl and carbamoylmethyl;
  • Y is a group of the formula
  • R is 1, q is 1 and R is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.
  • a specific preferred compound of the invention is the following amide derivative of the formula I 1-(N-benzylcarbamoyl)-4-(phenylthio)azetidin-2-one; or a pharmaceutically-acceptable salt thereof.
  • a compound of the invention -.omprising an amide derivative of the formula I, or a pharmaceutically-acceptable salt thereof may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following
  • a suitable base is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, (l-4C)alkanoate, hydroxide or hydride, for example sodium carbonate, potassium carbonate, barium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
  • a suitable base for the reaction is, for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example, one or more of pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, methylene chloride, carbon tetrachloride or a dipolar aprotic solvent such as acetone, N,N-dimethylformamide and dimethylsulphoxide.
  • a suitable inert solvent or diluent for example, one or more of pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, methylene chloride, carbon tetrachloride or a dipolar aprotic solvent such as acetone, N,N-dimethylformamide and dimethylsulphoxide.
  • the reaction is conveniently performed at a temperature in the range, for example, 10 to 150°C, conveniently in the range 20 to 60°C.
  • the starting materials of the formulae II and III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist, (b) For the production of those compounds of the formula I wherein X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X is a thio group.
  • a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , a di-(l-4C)alkyldioxiran (such as dimethyldioxiran) , chromium trioxide or gaseous oxygen in the presence of platinum.
  • a peracid such as 3-chloroperoxybenzoic or peroxyacetic acid
  • an alkali metal peroxysulphate such as potassium peroxymonosulphate
  • a di-(l-4C)alkyldioxiran such as dimethyldioxiran
  • the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
  • the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
  • a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a sulphonyl group is required, it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
  • a pharmaceutically-acceptable salt of a compound of the formula I When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
  • an optically active form of a compound of the formula I it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.
  • the compounds of the formula I are believed to include inhibitors of the enzyme proTNF Convertase; the cell based assays described below measure inhibition of TNF production by mechanisms which are believed to include proTNF convertase inhibition. The effects of this inhibition may be demonstrated using one or more of the procedures set out below:-
  • THP-1 cells [4xl0 5 cells in 160 ⁇ l of RPMI 1640 medium (Gibco Catalogue No. 041-01870) supplemented with penicillin (100 units per ml), streptomycin (100 ⁇ g/ml) and gluta ine (2 mM)] and test compound (20 ⁇ l of various concentrations of test compound in a mixture of DMSO and RPMI medium) were incubated at 37°C for 30 minutes prior to the addition of E. Coli 0111:B4 PS (obtained from Sigma, Catalogue No. L-4130; 20 ⁇ l giving a final concentration of 50 ⁇ g/ml). The cells were incubated for 6 hours.
  • Portions (20 ⁇ l) of the supernatant solution were assayed for TNF using a modification of a sandwich-ELISA procedure as described in Methods in Enzymology, 1980, Vol. 70, 419.
  • the assay involved a sheep IgG anti-human TNF ⁇ antibody as the capture antibody, a rabbit IgG anti-human TNF ⁇ antibody and an affinity chromatography purified sheep anti-rabbit IgG antibody conjugated to horseradish peroxidase (obtained from ICN Inc., Catalogue No. ICN 68-397) as the detecting antibody.
  • Urea peroxide substrate was added and TNF ⁇ levels were calculated based on a standard curve generated using recombinant human TNF ⁇ .
  • the assay detects levels of TNF ⁇ of 50 pg/ml and above.
  • the compound l-(N-benzylcarbamoyl)-4-(phenylthio)azetidin-2-one has an IC of approximately 22 ⁇ M in Test (a) and an IC 5Q of approximately 35 ⁇ M in Test (b). No toxicity was observed for compounds tested of the present invention.
  • a pharmaceutical composition which comprises an amide derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is an amide derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • an amide derivative of the formula I, or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • the invention also includes a method of treating a disease or medical condition mediated alone or in part by tumour necrosis factor (TNF) which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above.
  • TNF tumour necrosis factor
  • the invention also provides the use of such an active ingredient in the production of a new medicament for use in a TNF mediated disease or medical condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating diseases or medical conditions which are due alone or in part to the effects of TNF.
  • a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route -s employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of TNF. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment.
  • a known cyclooxygenase inhibitor such as indomethacin, acetylsalicyclic acid, diclofenac, flurbiprofen and piroxicam
  • a known inhibitor of the enzyme 5-lipoxygenase such as zileuton and the compounds disclosed in European Patent Application No. 0385662
  • a known disease-modifying agent such as methotrexate and penicillamine
  • a known anti-hista ine such as astemizole and terfenadine
  • steroid such as beclomethasone dipropionate and betamethasone
  • beta-adrenergic stimulant such as salbutamol and salmeterol
  • anti-inflammatory such as sodium cromoglycate and nedocromil sodium
  • leukotriene antagonist such as the compounds disclosed in European Patent Application No. 0199543
  • a known anti-hypertensive agent for example a beta-adrenergic blocker, diuretic, vasodilator, inhibitor of angiotensin-converting enzyme, calcium antagonist or an angiotensin antagonist
  • platelet aggregation inhibitor such as aspirin
  • hypolipidaemic agent such as cholestyramine and simvastatin
  • a known antibacterial, antifungal or antiviral agent, an inhibitor of nitric oxide release or an adrenergic stimulant such as adrenaline
  • an adrenergic stimulant such as adrenaline
  • a known oestrogen such as ethinyloestradiol
  • a diphosphonic acid such as disodium etidronate
  • calcitonin may usefully also be administered, whether simultaneously, sequentially or separately, with the composition of the invention.
  • a known antagonist of 5-hydroxytryptamine such as ondansetron
  • a known cytotoxic agent such as methotrexate, 5-fluorouracil and taxol
  • a hormone antagonist such as tamoxifen
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol. acetone, ether or hexane, alone or in admixture; and
  • Benzyl isocyanate (0.07 ml) was added to a stirred mixture of 4-(phenylthio)azetidin-2-one (0.1 g), triethylamine (0.7 ml) and DMF (1.5 ml). The mixture was stirred at ambient temperature for 15 minutes. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO.) and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent. There was thus obtained l-(N-benzylcarbamoyl)-4-(phenylthio)azetidin-2-one (0.094 g, 54%), m.p. 81-83°C;
  • the 4-(4-Tert-butyl-phenylthio)azetidin-2-one used as starting material was obtained as follows.
  • the 4-(4-fluorophenylthio)azetidi ⁇ -2-one used as starting material was obtained as follows. Acetic acid 4-oxo—azetidin-2-yl ester (0.5 g) was dissolved, in ethanol (10 ml) and cooled to 0° in an ice bath, 4-fluorobenzenethiol (0.7 g) added, then NaOH (2.13 ml of 2M solution) whilst keeping the temperature below 5° and the mixture stirred for 2% hours.
  • the 4-o-Tolylsulfanyl-azetidin-2-one used as starting material was obtained as follows. Acetic acid 4-oxo-azetidin-2-yl ester (0.25 g) was dissolved in ethanol (3 ml), cooled to 0°, 2-thiocresol (0.336 g) added, then NaOH (1.06 ml of 2M solution) and the mixture stirred at 0°C for 2h.
  • the 4-(4-Methoxyphenylsulfanyl)-azetidin-2-one used as starting material was obtained as follows. Acetic acid 4-oxo-azetidin-2-yl ester (0.3 g) was dissolved in ethanol (7 ml), cooled to 0°, l-thio-4-methoxy-benzene (0.46 g) added, then base under argon and the mixture was stirred at 0°C for 2h.
  • N[4-(4-oxo-azetidin-2-ylsulfanyl)-phenyl]acetamide (0.21 g) was dissolved in DMF (1.5 ml), triethylamine (0.68 ml) added, then benzylisocyanate (0.14 g) under argon and the mixture stirred overnight at room temperature.
  • N[4-(4-oxo-azetidin-2-ylsulfanyl)-phenyl]acetamide used as starting material was obtained as follows. Acetic acid 4-oxo-azetidin-2-yl ester (0.3 g) was dissolved in ethanol (7 ml), cooled to 0°C, N-(4-mercaptophenyl)acetamide added (0.54 g), then NaOH (1.3 ml of 2M solution) and the mixture stirred at 0° for 2 hours. Ethanol was removed under vacuum, residue washed with 2M NaOH (0.7 ml in 10 ml water), extracted with ethylacetate and solvent removed to give the desired starting material as a yellow solid (0.251 g, 46%).
  • the 4-p-tolylsulfanyl-azetidin-2-one used as starting material was obtained as follows. Acetic acid 4-oxoazetidin-2-yl ester (0.25 g) was dissolved in ethanol (4 ml), 4-thio-cresol (0.26 g) added under argon, then NaOH (1.06 ml of 2M solution) and the mixture stirred at room temperature for 1 hour. Ethanol was removed under vacuum, residue washed in water, extracted into ethyl acetate, dried and solvent removed to give the desired starting material as a white solid (0.374 g, 54.5%). Melting point 98-100°.
  • the 4-(3-chlorophenylsulfanyl)-azetidin-2-one used as starting material was obtained as follows. Acetic acid 4-oxoazetidin-2-yl ester (0.25 g) was dissolved in ethanol (4 ml), 3-chlorobenzenethiol added (0.31 g) under argon, then NaOH (1.06 ml of 2M solution) and the mixture stirred at room temperature for 3 hours. Ethanol was removed, residue washed in water and extracted into ethyl acetate, dried and solvent removed to give the desired starting material (approx. 0.25 g, 60%).
  • the desired products were 2-oxo-4(R)phenylsulfanyl-azetidine-1-[N-(R)- 1-phenylethyl]-carboxamide and 2-oxo-4(S phenylsulfanyl-azetidine-1-[N- (R)-1-phenylethyl]-carboxamide.
  • the top band crystallised in ether to give white crystals (70 mg) with a melting point of 80-82°. Elemental Analysis: required C 66.2, H 5.56, N 8.55; found (top band) C 66.4, H 5.7, N 8.6; found (bottom band) C 66.2, H 5.7, N 8.4.
  • Examples 13 & 14 were repeated in an analogous manner but substituting the isomer of (1-isocyanato-ethyl)benzene (Fluka). A combined yield for the two isomers of 74% was obtained (117 mg of top band, 125 mg of bottom band).
  • the desired two isomers were 2-oxo-4(R)- phenylsulfanyl-azetidine-l-[N-(S)-1-phenylethyl]-carboxamide and 2-oxo-4(S phenylsulfanyl-azetidine-l-[N-(£5)-1-phenylethyl]-carboxamide. Elemental Analysis: required C 66.2, H 5.56, N 8.58, found (top band) C 66.3, H 5.8, N 8.5; found (bottom band) C 66.1, H 5.9, N 8.1.
  • Example 17 required C 66.2, H 5.56, N 8.58, found (top band) C 66.3, H 5.8, N 8.5; found (
  • the starting material 4-(3-methyl-phenylsulfanyl)-azetidin-2- one was obtained in an analogous manner to the corresponding step in Example 8.
  • the following reagents were used: acetic acid 4-oxo-azetidin-2-yl ester (0.5 g); 3-thiocresol (0.64 ml); NaOH (2.12 ml) and ethanol (8 ml).
  • the reagents were mixed for 1 hour, then further portions of NaOH and acetic acid 4-oxo-azetidin-2-yl ester (0.5 g) were added and mixed for a further 30 minutes.
  • the desired starting material was obtained as a gum (0.376 g, 50%). Molecular weight by mass spec. 193.
  • Triethylamine (0.17 ml) and diphenylphosphonylazide (0.34 g) were added under argon to 3-cyanophenylacetic acid (0.2 g) in dichloromethane (0.3 ml); the mixture was stirred at room temperature for 3 hours, then heated to reflux for 2 hours.
  • Example 22 l-(N-benzylcarbamoyl)-4-(phenylthio)azetidin-2-one (97 mg; prepared as described in Example 1) in methanol (2.5 ml) was stirred at room temperature and potassium peroxymonosulphate (300 mg in 1.5 ml water; Tet. Lett. 22 (14), 1981: 1287) added and left overnight. A further 200 mg of potassium peroxymonosulphate was added and the mixture heated in an oil bath at 70° for 5 hours, cooled and diluted in aqueous 2 C0-,/ethyl acetate. The organic layer was separated and the aqueous residue washed twice in ethyl acetate.

Abstract

Composés d'azétidinone d'utilité pharmaceutique en tant qu'inhibiteurs de la production du facteur de necrose tumorale (TNF), de la formule générale (I), dans laquelle Y représente H, alkyle (1-4C) ou (a), et X représente thio, sulfinyle ou sulfonyle.
PCT/GB1994/001466 1993-07-12 1994-07-07 Derives d'amide d'azetidinone substitues utilises comme agents anti-inflammatoires et anti-degeneratifs WO1995002579A1 (fr)

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AU70800/94A AU7080094A (en) 1993-07-12 1994-07-07 Substituted azetidinone amide derivatives as anti-inflammatory and antidegenerative agents

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GB939314350A GB9314350D0 (en) 1993-07-12 1993-07-12 Armide derivatives
GB9314350.1 1993-07-12

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013750A1 (fr) * 1995-10-09 1997-04-17 Chiroscience Limited Azetidinones et leur utilisation therapeutique en tant qu'inhibiteurs des cytokines
WO1997021676A1 (fr) * 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
US5843693A (en) * 1989-08-16 1998-12-01 Chiron Corporation Assay method for screening for inhibitors of proTNF conversion
WO1999018072A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
WO1999018071A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
WO1999018073A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
US5998378A (en) * 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
WO2000005204A1 (fr) * 1998-07-23 2000-02-03 Shionogi & Co., Ltd. COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT
US6586222B1 (en) 1989-08-16 2003-07-01 Chiron Corporation Recombinant PR-3 and compositions thereof
US6599706B1 (en) 1994-03-07 2003-07-29 Chiron Corporation Recombinant PR-3 and assays employing the same
WO2004009113A1 (fr) * 2002-07-24 2004-01-29 Renovo Limited Utilisation d'inhibiteurs de convertase dans le traitement de fibrose et de cicatrisation
US9085750B2 (en) 2011-07-01 2015-07-21 Novozymes A/S Stabilized subtilisin composition
WO2015179293A1 (fr) * 2014-05-18 2015-11-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activateurs et inhibiteurs de petites molécules de lécithine-cholestérol acyltransférase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0199630A1 (fr) * 1985-04-10 1986-10-29 Merck & Co. Inc. Azétidinones substituées, compositions pharmaceutiques les contenant et leur utilisation pour la production de médicaments anti-inflammatoires et antidégénératifs
EP0337549A1 (fr) * 1988-04-11 1989-10-18 Merck & Co. Inc. Azétidinones nouvelles substituées comme agents anti-inflammatoires et anti-dégénératifs
EP0481671A1 (fr) * 1990-10-15 1992-04-22 Merck & Co. Inc. Azétidinones substituées comme agents anti-inflammatoires et antidégénératifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0199630A1 (fr) * 1985-04-10 1986-10-29 Merck & Co. Inc. Azétidinones substituées, compositions pharmaceutiques les contenant et leur utilisation pour la production de médicaments anti-inflammatoires et antidégénératifs
EP0337549A1 (fr) * 1988-04-11 1989-10-18 Merck & Co. Inc. Azétidinones nouvelles substituées comme agents anti-inflammatoires et anti-dégénératifs
EP0481671A1 (fr) * 1990-10-15 1992-04-22 Merck & Co. Inc. Azétidinones substituées comme agents anti-inflammatoires et antidégénératifs

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998378A (en) * 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
US5843693A (en) * 1989-08-16 1998-12-01 Chiron Corporation Assay method for screening for inhibitors of proTNF conversion
US6586222B1 (en) 1989-08-16 2003-07-01 Chiron Corporation Recombinant PR-3 and compositions thereof
US6599706B1 (en) 1994-03-07 2003-07-29 Chiron Corporation Recombinant PR-3 and assays employing the same
WO1997013750A1 (fr) * 1995-10-09 1997-04-17 Chiroscience Limited Azetidinones et leur utilisation therapeutique en tant qu'inhibiteurs des cytokines
WO1997021676A1 (fr) * 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
WO1999018071A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
US6211170B1 (en) 1997-10-07 2001-04-03 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of HCMV infections
US6239125B1 (en) 1997-10-07 2001-05-29 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of HCMV infections
US6242439B1 (en) 1997-10-07 2001-06-05 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of HCMV infections
JP2001519328A (ja) * 1997-10-07 2001-10-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｈｃｍｖ感染症治療のためのアゼチジノン誘導体
WO1999018073A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
WO1999018072A1 (fr) * 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Derives d'azetidinone pour le traitement d'infections hcmv
WO2000005204A1 (fr) * 1998-07-23 2000-02-03 Shionogi & Co., Ltd. COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT
WO2004009113A1 (fr) * 2002-07-24 2004-01-29 Renovo Limited Utilisation d'inhibiteurs de convertase dans le traitement de fibrose et de cicatrisation
US7700562B2 (en) 2002-07-24 2010-04-20 Renovo Limited Use of —furin—“convertase” inhibitors in the treatment of fibrosis and scarring
US9085750B2 (en) 2011-07-01 2015-07-21 Novozymes A/S Stabilized subtilisin composition
WO2015179293A1 (fr) * 2014-05-18 2015-11-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activateurs et inhibiteurs de petites molécules de lécithine-cholestérol acyltransférase

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Publication number Publication date
AU7080094A (en) 1995-02-13
GB9314350D0 (en) 1993-08-25
GB9412605D0 (en) 1994-08-10

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