WO1997013750A1 - Azetidinones et leur utilisation therapeutique en tant qu'inhibiteurs des cytokines - Google Patents

Azetidinones et leur utilisation therapeutique en tant qu'inhibiteurs des cytokines Download PDF

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Publication number
WO1997013750A1
WO1997013750A1 PCT/GB1996/002464 GB9602464W WO9713750A1 WO 1997013750 A1 WO1997013750 A1 WO 1997013750A1 GB 9602464 W GB9602464 W GB 9602464W WO 9713750 A1 WO9713750 A1 WO 9713750A1
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WIPO (PCT)
Prior art keywords
alkyl
aryl
azetidinone
cis
acetyl
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PCT/GB1996/002464
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English (en)
Inventor
Hazel Joan Dyke
John Gary Montana
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Chiroscience Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9520634.8A external-priority patent/GB9520634D0/en
Priority claimed from GBGB9520629.8A external-priority patent/GB9520629D0/en
Priority claimed from GBGB9520628.0A external-priority patent/GB9520628D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU72221/96A priority Critical patent/AU7222196A/en
Publication of WO1997013750A1 publication Critical patent/WO1997013750A1/fr

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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
    • 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 relates to novel /S-lactam compounds and their use in treating cytokine-mediated diseases.
  • Interleukin-1 IL-l
  • tumour necrosis factor TNF
  • IL-6 Interleukin-6
  • IL-8 tumour necrosis factor 8
  • IL-l has multiple effects on cells involved in inflammation and wound healing. Subcutaneous injection of IL-l leads to argination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN) . In vitro studies reveal IL-l to be a
  • chemotactic attractant for PMN to activate PMN to metabolize glucose more rapidly to reduce nitroblue tetrazolium and to release their lysozomal enzymes.
  • Endothelial cells are stimulated to proliferate by IL-l to produce thro boxane, to become more adhesive and to release procoagulant activity.
  • IL-l also enhances collagen type IV production by epidermal cells, induces osteoblast proliferation and alkaline phosphatase production and stimulates osteoclasts to resorb bone.
  • macrophages have been reported to be chemotactically attracted to IL-l to produce prostaglandins in response to IL-l and to exhibit a more prolonged and active tumoricidal state.
  • IL-l is also a potent bone resorptive agent capable upon infusion into mice of causing hypercalcemia and increase in bone resorptive surface as revealed by histomorpho etry (Sabatini et al . , PNAS 85:5235-5239, (1988)) .
  • TNF is a cytokine which is produced initially as a cell-associated 28kDa precursor. It is released as an active, 17kDa form (Jue et al . , Biochemistry 29:8371-8377 (1990)), which can mediate a large number of deleterious effects in vivo .
  • TNF When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
  • TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours. Preventing the production or action of TNF is, therefore, predicted to be a potent therapeutic strategy for many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome (Mathison et al . (1988) J. Clin. Invest. 81:1925-1937; Montgomeryhke et al . (1992) J. Exp.
  • disease states in which the cytokine inhibitors may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including toxic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pericarditis, reperfusion injury and vasculitis.
  • Immune-based diseases which may be responsive to cytokine inhibitors inlude but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis.
  • Cytokine inhibitors may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excessive deposition of extracellular matrix. Such diseases include periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, and keloid formation. Cytokine inhibitors may also be useful in treatment of certain tumors which produce
  • R 1 is C,. 6 alkyl-R 5
  • R is hydrogen, C . 6 alkyl or C 1 . 6 alkyl-R 5 , wherein R 1 and R 2 may be the same or different;
  • R 3 is COR 7 or S(O) 0 . 2 R 8 ;
  • R* is COR 9 or S0 2 R 10 ;
  • R 5 is C0 2 H, tetrazolyl, NHS0 2 CF 3 or C0 2 R 6 ;
  • R is C, ⁇ alkyl, C,. 6 alkylaryl or a group that may be removed in vivo (for example by enzymic attack) to provide a carboxylic acid (i.e. an ester prodrug) ;
  • examples of such groups include C 2 . 6 alkenyl, C 6 alkoxy-C ⁇ alkyl, C . 6 alkyl or C, .6 alkylOCO j C, ⁇ alkyl;
  • R 7 is OC,. 6 alkyl, OC ⁇ alkyl-aryl, aryl, C,_ 6 alkyl aryl, * C 6 alkyl, HC ⁇ alkyl, NHC,_ 6 alkyl-aryl, NHaryl or U (C 6 alkyl) 2 ;
  • R 8 is aryl, C,_ 6 alkyl, C ⁇ alkyl-aryl, NHC, ⁇ alkyl, NHC,. 6 alkyl-aryl, NHaryl or N(C 1 . 6 alkyl) 2 ;
  • R and R when R and R is C,_ 6 alkyl or aryl, these groups may each be optionally substituted with OH, NH 2 , C0 2 H, COR 9 , S0 2 R 1 °, tetrazolyl, NHS0 2 CF 3 , NHCOR 9 , NHS0 2 R 10 , NHCOC,. 6 alkyl or NHCOaryl;
  • R 9 is C 1 . 6 alkyl, aryl, C 1 . 6 alkyl-aryl, CF 3 , OC, ⁇ alkyl, OC,_ 6 alkyl-aryl, NHC ⁇ alkyl, NHaryl, HC, ⁇ alkyl-aryl or NfC, ⁇ alkyl) 2 ;
  • R 10 is CF j , C,. 6 alkyl-aryl, C,. 6 alkyl-aryl, NHC 1 . 6 alkyl, NHaryl, N(C 1 . 6 alkyl) 2 or NHC,. 6 alkyl-aryl; and salts, solvates and hydrates thereof.
  • R 7, R 8, R 9 and R 10 may also each be N(C 1-6 alkyl)C, ⁇ alkyl-aryl. It will be readily appreicated that combinations of substituents and/or variables are allowed only if they result in stable compounds. Description of the Invention
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atom.
  • the presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantio ers and diastereomers, and mixtures including racemic mixtures thereof.
  • the - line is used at a potential asymmetric centre to represent the possibility of
  • C, ⁇ alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like.
  • C 2 . 6 alkenyl refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl- 2-propenyl etc.
  • aryl means an optionally substituted phenyl or naphthyl group with the substituent(s) being selected, for example, from halogen, trifluoromethyl, C 1 . 6 alkyl, alkoxy, phenyl and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • C . 6 alkoxy refers to a straight or branched chain alkyl moiety having from one to six carbon atoms and one oxygen atom, including for example, methoxy, ethoxy , propoxy, ethoxymethyl, hexyloxy and the like.
  • Salts of compounds of formula (I) include phar aceutically-acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p- toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • inorganic or organic acids such as hydrochlorides, hydrobromides, hydroiodides, p- toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts may also be formed with bases.
  • Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly preferred compounds according to the invention include: trans ( ⁇ )-l-Acetyl-4-benzoyl-3-[2-(ethoxycarbonyl)ethyl]-2- azetidinone
  • the groups R , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see “Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wutts.
  • a compound of general formula (I) may be prepared by acylation of a compound of general formula (II)
  • Active derivatives of acids of formula (III) include for example acid anhydrides or acid halides, such as acid chlorides.
  • the coupling reaction may be performed using standard conditions for acylation reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, an amide e.g. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at a low temperature e.g. -20 C to ambient temperature, such as 0°C, in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or 4-dimethylaminopyridine.
  • a base e.g. an organic base such as an amine, e.g. triethylamine or 4-dimethylaminopyridine.
  • Acid derivatives of general formula (III) may be commercially available, or readily prepared by methods known by those skilled in the art.
  • the deprotection reaction may be performed using standard conditions for reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, or any alkyl nitrile, such as acetonitrile, optionally in the presence of a cosolvent such as water, in the presence of eerie ammonium nitrate at a low temperature such as -20°C to ambient temperature, preferably 0°C.
  • a solvent for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, or any alkyl nitrile, such as acetonitrile, optionally in the presence of a cosolvent such as water, in the presence of eerie ammonium nitrate at a low temperature such as -20°C to ambient temperature, preferably 0°C.
  • a solvent
  • Cycloaddition reactions of this type may be performed in a solvent, for example an inert organic solvent such as a halogenated hydrocarbon for example dichloromethane, at a temperature ranging from ambient temperature to the boiling point of the solvent, preferably the boiling point of the solvent, in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or a cyclic amine such as N-methylmorpholine.
  • Imines of general formula (V) may be either commercially available or readily prepared from commercially available starting materials using the procedure of W. Hagmann et al . , J. Med. Chem. (1993) 36, 771.
  • Acid chlorides of general formula (VI) may be commercially available or readily prepared by methods known to those skilled in the art, from commercially available starting materials.
  • Isomerisation reactions of this type may be performed in a solvent, such as an inert organic solvent, for example a hydrocarbon such as toluene, at a temperature ranging from ambient temperature to the boiling point of the solvent, preferably 50°C, in the presence of a base, such as an organic base, for example 1,5-diazabicyclo[4.3.0]non- 5-ene.
  • a solvent such as an inert organic solvent, for example a hydrocarbon such as toluene
  • a base such as an organic base, for example 1,5-diazabicyclo[4.3.0]non- 5-ene.
  • Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I) .
  • a compound of formula (I) wherein R contains a C0 2 H group may be prepared by hydrogenation (using palladium on carbon in a suitable solvent, such as an alcohol, e.g. ethanol) of a compound of formula (I) wherein R contains a CO ⁇ R group in which R is a C, ⁇ alkylaryl group (e.g. benzyl) .
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico ⁇ chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
  • the compounds of formula (I) or a pharmaceutically- acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cell, such as but not limited * to monocytes and/or macrophages.
  • Compounds of formula (I) are capable of inhibiting proinfla matory cytokines, such as IL-l, IL-6, IL-8 and TNF and are therefore of use in therapy.
  • IL-l, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
  • the present invention provides a method of treating a cytokine-mediated disease whch comprises administering an effective cytokine-interferring amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compounds of formula (I) or pharmaceutically-acceptable salts thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated IL-l, IL-8 or TNF producton by such mammal's cell, such as, but not limited to, monocytes and/or macrophages.
  • this invention relates to a method of inhibition of the production of IL-l in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula
  • (I) or a pharmaceutically acceptable salt thereof there are many disease states in which excessive or unregulated IL-l production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis,
  • this invention relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft versus host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS) , AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
  • AIDS cachexia secondary to infection or
  • viruses of formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo .
  • the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirecly, by the TNF inhibiting-compounds of formula (I) .
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV) , Influenza adenovirus and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex. Accordingly, in a further aspect, this
  • invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HIV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF-mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to, the lentivirus infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, or the aedi virus, or the retroviruses, such as feline immunodeficiency virus (FIV) , bovine immunodeficiency virus, or canine immunodeficiency virus.
  • the compounds of formula (I) may also be used topically in the treatment of prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine production, such as by IL-l or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjuctivitis; pyresis, pain and other conditions associated with inflammation.
  • cytokine production such as by IL-l or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjuctivitis; pyresis, pain and other conditions associated with inflammation.
  • this invention relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically- acceptable salt thereof.
  • IL-8 IL-8 has the unique property of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutophil infiltration.
  • the compounds of formula (I) are administered in an amount sufficient to inhibit a cytokine, in particular IL- 1, IL-8 or TNF, such that its production is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease stnte.
  • a cytokine in particular IL- 1, IL-8 or TNF
  • Abnormal levels of IL-l, IL-8 or TNF constitute: (i) levels of free (not cell bound) IL-l, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-l, IL-8 or TNF; or (iii) the presence of IL-l, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-l, IL-8 or TNF, respectively, is produced.
  • the compounds of formula (I) are inhibitors of cytokines, specifically IL-l, IL-8 and TNF is based upon the effects of the compounds of formula (I) on the production of the IL-l, IL-8 and TNF in in vitro assays, e.g. as in Example A.
  • IL-l refers to: a) a decrease of excessive in vivo levels of the cytokine (IL-l, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-l,
  • IL-8 or TNF in a human to normal to sub-normal levels
  • a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL- 1, IL-8 or TNF) in a human to normal or sub ⁇ normal levels refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-l, IL-6 or IL-8.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, onokines and lymphokines, regardless of which cells produce them.
  • a onokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin-1 (IL-l), Interleukin-6 (IL-6) , Interleukin-8 (IL-8) , Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor- / 3 (TNF-/?) .
  • the cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HIV-infected human” is a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • TNF-/3 also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • both TNF- ⁇ and TNF-/3 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically indicated otherwise.
  • a compound of formula (I) or a pharmaceutically-acceptable salt thereof in therapy it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to a pharmaceutical composition comprising an effective, non- toxic amount of a compound of formula (I) and a pharmaceutically-acceptable carrier or diluent.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group ⁇ consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the US Patents 4,256,108;4,166,452; and 4,265,874, to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example lecithin, or - condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain a l i pha t i c a l c oho l s , f or examp l e heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally- occurring
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetining, flavouing and colouring agents, may also be present.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occuring gums, for example gum acacia or gum
  • emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example gycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (I) are employed. (For the purposes of this application, topical application shall include mouth washes and gargles. )
  • Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above indicated conditions (about 2.5 mg to about 7 gms per patient per day) .
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • TLC R f 0.25 (1%-MeOH - CH 2 C1 2 ) .
  • Triethylamine 25 ⁇ l was added a suspension of Intermediate 25 (151 mg) in dichlormethane (5 ml) at room temperature under nitrogen.
  • the resultant solution was treated with BOP reagent (217 mg) and then, after stirring for 5 minutes, with N-benzyl methylamine (70 ⁇ l) .
  • the resultant solution was stirred for 2h and then diluted with dichloromethane (30 ml) .
  • the solution was washed with 2 M hydrochloric acid (3 x 8 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and brine ( 1 5 ml ) .
  • Example 6 Using the procedure described for the preparation of Intermediate 11, the title compound was prepared from Example 6 (118 mg) as a white solid (87 mg) .
  • Example 3 From Example 3 (0.6 g) as a white crystalline solid (0.45 g) .
  • Example 16 From Example 16 (0.13 g) as a white powder (20 mg) .
  • the compounds of the invention inhibit the release of IL-13 as indicated in the following in vitro test using THP-1 cells.
  • the effect on the release of other cytokines can also be measured in this assay.
  • THP-1 cells 1 x 10° cells
  • RPMI 1640 medium containing 2mM glutamine and 20 mM 2- mercaptoethanol
  • the compound to be tested is added in a volume of 200 ml.
  • 10 ml of lipopolysaccharide 5 mg/ml is added and the incubation continued for a further 18 hours.
  • Appropriate controls (with and without stimulus, solvent) are also included.
  • the media are harvested by centrifugation at 1000 g for 10 minutes and stored at -20°C until required. The viability of the cells are measured using the MTT assay as previously described (J.A.

Abstract

Composé de la formule (I) dans laquelle R1 représente alkyleC¿1-6?-R?5; R2¿ représente hydrogène, alkyle C¿1-6? ou alkyleC1-6-R?5, R1 et R2¿ pouvant être semblables ou différents; R3 représente COR7 ou S(O)¿0-2?R?8; et R4¿ représente COR9 ou SO¿2R?10.
PCT/GB1996/002464 1995-10-09 1996-10-09 Azetidinones et leur utilisation therapeutique en tant qu'inhibiteurs des cytokines WO1997013750A1 (fr)

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AU72221/96A AU7222196A (en) 1995-10-09 1996-10-09 Azetidinones and their therapeutic use as cytokine inhibitors

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GBGB9520634.8A GB9520634D0 (en) 1995-10-09 1995-10-09 Compounds
GBGB9520629.8A GB9520629D0 (en) 1995-10-09 1995-10-09 Compounds
GB9520628.0 1995-10-09
GB9520634.8 1995-10-09
GBGB9520628.0A GB9520628D0 (en) 1995-10-09 1995-10-09 Compounds
GB9520629.8 1995-10-09

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2000005204A1 (fr) * 1998-07-23 2000-02-03 Shionogi & Co., Ltd. COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT
US6335324B1 (en) 1998-06-25 2002-01-01 Bristol-Myers Squibb Co. Beta lactam compounds and their use as inhibitors of tryptase

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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
US5037819A (en) * 1990-06-04 1991-08-06 Bristol-Myers Squibb Company Azetidin-2-one derivatives as serine protease inhibitors
EP0481671A1 (fr) * 1990-10-15 1992-04-22 Merck & Co. Inc. Azétidinones substituées comme agents anti-inflammatoires et antidégénératifs
GB2266527A (en) * 1992-03-17 1993-11-03 Merck & Co Inc Substituted azetidinones useful in the treatment of leukemia
WO1995002579A1 (fr) * 1993-07-12 1995-01-26 Zeneca Limited Derives d'amide d'azetidinone substitues utilises comme agents anti-inflammatoires et anti-degeneratifs

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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
US5037819A (en) * 1990-06-04 1991-08-06 Bristol-Myers Squibb Company Azetidin-2-one derivatives as serine protease inhibitors
EP0481671A1 (fr) * 1990-10-15 1992-04-22 Merck & Co. Inc. Azétidinones substituées comme agents anti-inflammatoires et antidégénératifs
GB2266527A (en) * 1992-03-17 1993-11-03 Merck & Co Inc Substituted azetidinones useful in the treatment of leukemia
WO1995002579A1 (fr) * 1993-07-12 1995-01-26 Zeneca Limited Derives d'amide d'azetidinone substitues utilises comme agents anti-inflammatoires et anti-degeneratifs

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W. T. HAN ET AL.: "Azetidin-2-one Derivatives as Inhibitors of Thrombin", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 3, no. 8, 1995, pages 1123 - 1143, XP000612953 *

Cited By (2)

* 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
WO2000005204A1 (fr) * 1998-07-23 2000-02-03 Shionogi & Co., Ltd. COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT

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