Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• This invention relates to imidazo[1 ,2-a]pyridine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
• COX-1 The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2.
• COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors.
• Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow.
• the inducible form, COX-2 is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines.
• a selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1.
• R° represents halogen
• R 1 and R 2 are independently selected from H, halogen, d ⁇ alkyl, C . ⁇ alkyl substituted by one or more fluorine atoms,
• R 3 represents Chalky!.
• pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
• salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
• Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
• halogen is used to represent fluorine, chlorine, bromine or iodine.
• alkyl' as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
• R 1 and R 2 may be at the 5-, 6-, 7- or 8- positions of the pyridine ring of formula (I), as defined hereinbelow:
• R 1 is at the 8- position; and R 2 is at the 7- position or, when R 1 is other than H, the 5-, 6- or 7-position. More preferably, R 1 is at the 8- position; and R 2 is at the 7- position or, when R 1 is C ⁇ _ ⁇ alkyl (e.g. methyl), the 5- or 7- position.
• R 1 is at the 8- position; and R 2 is at the 7- position or, when R 1 is C ⁇ _ ⁇ alkyl (e.g. methyl), the 5- or 7- position.
• R° represents fluorine
• R 1 represents H, chlorine, bromine, d ⁇ alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH 2 F or CF 3 ), C. ⁇ hydroxyalkyl (e.g. CH 2 OH or CH(OH)CH 3 ), SC ⁇ _.alkyl (e.g. SCH 3 ), C(0)H or C(0)C. ,alkyl (e.g. C(0)CH ). More preferably, R 1 represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , SCH 3 , C(0)H or C(0)CH 3 . Most preferably R 1 represents C(0)CH 3 .
• R 2 represents H, chlorine, bromine, or C._.alkyl (e.g. methyl). More preferably, R 2 represents H, bromine or methyl.
• R 3 represents methyl
• R° represents fluorine
• R 1 represents H, chlorine, bromine, (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH 2 F or CF 3 ), C._,hydroxyalkyl (e.g. CH 2 OH or CH(OH)CH 3 ), SC....alkyl (e.g.
• R° represents fluorine
• R 1 represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , SCH 3 , C(O)H or C(0)CH 3
• R 2 represents H, bromine or methyl
• R 3 represents methyl
• R° represents fluorine
• R 1 is at the 8- position and represents H, chlorine, bromine, C. ⁇ alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH 2 F or CF 3 ), C. ⁇ hydroxyalkyl (e.g. CH 2 OH or
• R 2 is at the 7- position or, when R 1 is other than H, the 5-, 6- or 7- position, and represents H, chlorine, bromine, or C ⁇ _,alkyl (e.g. methyl); and R 3 represents methyl.
• R° represents fluorine
• R 1 is at the 8- position and represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , SCH 3 , C(0)H or C(0)CH 3
• R 2 is at the 7- position or, when R 1 is methyl, the 5- or 7- position, and represents H, bromine or methyl
• R 3 represents methyl
• R° represents fluorine
• R 1 is at the 8- position and represents H, chlorine, bromine, C ⁇ alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH 2 F or CF 3 ), C ⁇ hydroxyalkyl (e.g. CH 2 OH or CH(OH)CH 3 ), SC ⁇ alkyl (e.g. SCH 3 ), C(0)H or C(0)C ⁇ alkyl (e.g. C(0)CH 3 );
• R 2 represents H; and R 3 represents methyl.
• R° represents fluorine
• R 1 is at the 8- position and represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , CH(OH)CH 3 , SCH 3 , C(0)H or C(0)CH 3
• R 2 represents H
• R 3 represents methyl
• the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
• Preferred compounds of the invention are:
• a particularly preferred compound of the invention is:
• Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.
• the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain, fever and inflammation of a variety of conditions and diseases.
• conditions and diseases are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
• the compounds of the invention may also be useful for the treatment of other conditions mediated by selective inhibition of COX-2.
• the compounds of the invention may inhibit cellular and neoplastic transformation and metastatic tumour growth and hence be useful in the treatment of certain cancerous diseases, such as colonic cancer.
• Compounds of the invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore may be of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).
• Compounds of the invention also inhibit prostanoid-induced smooth muscle contraction and hence may be of use in the treatment of dysmenorrhoea and premature labour.
• Compounds of the invention inhibit inflammatory processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
• vascular disease migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephro
• Compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
• ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
• Compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea,
• dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea,
• Parkinson's disease and Creutzfeldt-Jakob disease and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated
• a method of treating a human or animal subject suffering from an inflammatory disorder comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
• Suitable agents for adjunctive therapy include pain relievers such as a glycine antagonist, a sodium channel inhibitor (e.g. lamotrigine), a substance P antagonist (e.g. an NKi antagonist), acetaminophen or phenacetin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS or an nNOS inhibitor); an inhibitor of the release, or action, of tumour necrosis factor ⁇ ; an antibody therapy (e.g.
• a stimulant including caffeine; an H 2 -antagonist, such as ranitidine; an antacid, such as aluminium or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan; a diuretic; or a sedating or non-sedating antihistamine.
• a stimulant including caffeine
• an H 2 -antagonist such as ranitidine
• an antacid such as aluminium or magnesium hydroxide
• an antiflatulent such as simethicone
• a decongestant such as phen
• the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
• the compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions.
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
• compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
• the compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
• the pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.
• the pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
• the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
• the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
• formulatory agents such as suspending, stabilising and/or dispersing agents.
• For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
• the active ingredient may be in powder form for reconstitution with a suitable vehicle.
• the compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• the compounds of the invention may also be used in combination with other therapeutic agents.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
• compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
• the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
• a proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05mg/kg to 100mg/kg, e.g. 0.1mg/kg to 50mg/kg, which may be conveniently administered in 1 to 4 doses.
• the precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25mg/kg to 10mg/kg may be suitable for systemic administration.
• R°to R 3 are as defined in formula (I) above unless otherwise stated and Lg represents a leaving group, such as a sulphonate (e.g. methanesulphonate) or a halogen (e.g. bromine).
• compounds of formula (I) may be prepared by reacting a compound of formula (II)
• reaction is conveniently carried out in a solvent, such as a polar solvent (e.g. acetonitrile or isopropanol); at elevated temperature, e.g. reflux; and optionally in the presence of a base, such as an alkali metal bicarbonate or carbonate (e.g. potassium carbonate).
• a solvent such as a polar solvent (e.g. acetonitrile or isopropanol); at elevated temperature, e.g. reflux; and optionally in the presence of a base, such as an alkali metal bicarbonate or carbonate (e.g. potassium carbonate).
• the oxidation is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as OxoneTM) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78°C and ambient temperature.
• a monopersulfate compound such as potassium peroxymonosulfate (known as OxoneTM)
• OxoneTM potassium peroxymonosulfate
• a solvent such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78°C and ambient temperature.
• compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
• compounds of formula (I) wherein R 1 or R 2 represent chlorine, bromine or iodine may be prepared from the corresponding compound of formula (I) wherein R 1 or R 2 represent H, by treatment with an appropriate halogenating agent (i.e. chloro-, bromo- or iodinating agent).
• halogenating agent i.e. chloro-, bromo- or iodinating agent.
• Suitable agents include the corresponding N-halosuccinimdes.
• the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at ambient temperature.
• Compounds of formula (I) wherein R 1 or R 2 represent substituted by one or more fluorine atoms may be prepared from the compound of formula (I) wherein R 1 or R 2 represents the corresponding by treatment with a suitable source of fluorine.
• suitable sources of fluorine include, for example, diethylaminosulphur trifluoride.
• the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.
• Suitable oxidising agents include, for example, manganese (IV) oxide. Conveniently the oxidation is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at elevated temperature (e.g. reflux).
• a solvent such as a halogenated hydrocarbon (e.g. chloroform)
• elevated temperature e.g. reflux
• Compounds of formula (I) wherein R 1 or R 2 represent C . ⁇ hydroxyalkyl, and wherein the hydroxy group is attached to the carbon linked to the pyridine ring, may be prepared by reduction of the compound of formula (I) wherein R 1 or R 2 represent the corresponding aldehyde or ketone.
• Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride. Conveniently the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.
• Another process (D) for preparing compounds of formula (I) thus comprises deprotecting protected derivatives of compounds of formula (I).
• the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups.
• compounds of formula (II) wherein Lg represents a halogen may be prepared from compounds of formula (V) by treatment with a halogenating agent, at reduced temperature and in a solvent, such as a chlorinated hydrocarbon.
• a halogenating agent such as bromine
• the reaction is conveniently effected with a brominating agent, such as bromine in the presence of a strong acid (e.g. hydrobromic acid in acetic acid).
• Compounds of formula (II) wherein Lg represents a sulphonate may be prepared from compounds of formula (V) firstly by oxidation to the corresponding ⁇ -hydroxy . ketone, followed by treatment with a sulphonating agent.
• Suitable oxidising agents include, for example, Pb(OAc) 4 , dimethyldioxirane and those described in F A Davis, J. Org. Chem., 1984, 49(17). 3284.
• Suitable sulphonating agents include sulphonylhalides, such as sulphonylchlorides (e.g. methanesulphonylchloride). The sulphonylation is conveniently effected in the presence of a base, such as an amine (e.g. triethylamine); and in a solvent, such as a halogenated hydrocarbon.
• reaction by treatment with an alkali sulphinate, such as a sodium sulphinate.
• an alkali sulphinate such as a sodium sulphinate.
• the reaction is carried out in a polar solvent, such as dimethyl sulphoxide, and at elevated temperature.
• compounds of the invention are isolated following work-up in the form of the free base.
• Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.
• Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
• microcrystalline cellulose, lactose and cross- linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer.
• the magnesium stearate is sieved through a 250 micron sieve and blended with the active blend.
• the blend is compressed into tablets using suitable punches.
• Compression weight 200.0mg The compound of the invention, lactose and pregelatinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches.
• the compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve).
• the blend is filled into hard gelatine capsules of a suitable size.
• the compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone.
• the wet mass is dried and milled.
• the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules.
• the resultant blend is filled into hard gelatine capsules of a suitable size.
• the hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxybenzoates and the solution is allowed to cool to ambient temperature.
• the saccharin, sodium flavours and sorbitol solution are added to the bulk solution.
• the compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability.
• the solution is made up to volume, filtered and filled into suitable containers.
• Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts.
• Antioxidants and metal chelating salts may also be included.
• the solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessary, to provide 10mg/ml of the compound of formula (I).
• the solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes.
• the ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by heating in an autoclave using one of the acceptable cycles).
• the solution may be packed under an inert atmosphere of nitrogen.
• the solution is filled into ampoules, sealed by fusion of the glass and terminally sterilised.
• sterile formulations are prepared in a similar manner containing 0.5, 2.0 and 5% w/v of the compound of formula (I), so as to provide respectively 5, 20 and 50mg/ml of the compound of formula (I).
• COX-2 24 Hours prior to experiment, COS cells were transferred from the 175cm 2 flasks in which they were grown, onto 24-well cell culture plates using the following procedure.
• the incubation medium being Dulbecco's modified eagles medium (DMEM) to which had been added heat inactivated foetal calf serum (10%v/v), penicillin (100U /ml), streptomycin (100 ⁇ g/ml) and geneticin
• DMEM Dulbecco's modified eagles medium
• the flask was then removed from the incubator and cells resuspended in 10ml of fresh incubation medium.
• the contents of the flask was transferred to a 250ml sterile container and the volume of incubation medium subsequently made up to 100ml.
• 1ml cell suspension was pipetted into each well of 4x24-well cell culture plates. The plates were then placed in an incubator (37°C, 95% air/5% CO 2 ) overnight. If more than 1 flask was used, the cells were combined before being dispensed into the 24-well plates.
• DMEM fetal calf serum
• Test compounds were made up to 250x the required test concentration in DMSO and were added to the wells in a volume of 1 ⁇ l. Plates were then mixed gently by swirling and then placed in an incubator for 1 hour (37°C, 95% air/5% CO2). Following the incubation period, 10 ⁇ l of arachidonic acid (750 ⁇ M) was added to each well to give a final arachidonic acid concentration of 30 ⁇ M. Plates were then incubated for 15 minutes, after which the incubation medium was removed from each well of the plates and stored at -20°C, prior to determination of prostaglandin E 2 (PGE2) levels using enzyme immunoassay.
• PGE2 prostaglandin E 2
• the inhibitory potency of the test compounds was expressed as an IC 50 value, which is defined as the concentration of the compound required to inhibit the PGE2 release from the cells by 50%.
• the selectivity ratio of inhibition of COX-1 versus COX-2 was calculated by comparing respective IC 50 values.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)

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Cited By (57)

Citations (1)

• 1996
  • 1996-04-02 AU AU52766/96A patent/AU5276696A/en not_active Abandoned
  • 1996-04-02 WO PCT/EP1996/001438 patent/WO1996031509A1/en not_active Application Discontinuation
  • 1996-04-02 NZ NZ304886A patent/NZ304886A/en unknown
  • 1996-04-02 EP EP96909164A patent/EP0819127A1/en not_active Withdrawn
  • 1996-04-02 TR TR97/01105T patent/TR199701105T1/xx unknown
  • 1996-04-02 CN CN96194403A patent/CN1186492A/zh active Pending
  • 1996-04-02 HU HU9801602A patent/HUP9801602A3/hu unknown
  • 1996-04-02 JP JP8529971A patent/JPH11501049A/ja active Pending
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  • 1996-04-02 EA EA199700209A patent/EA199700209A1/ru unknown
  • 1996-04-02 CZ CZ973133A patent/CZ313397A3/cs unknown
  • 1996-04-02 KR KR1019970706963A patent/KR19980703559A/ko not_active Application Discontinuation
  • 1996-04-02 CA CA002216809A patent/CA2216809A1/en not_active Abandoned
  • 1996-04-02 SK SK1332-97A patent/SK133297A3/sk unknown
• 1997
  • 1997-09-25 IS IS4570A patent/IS4570A/is unknown
  • 1997-09-30 BG BG101934A patent/BG101934A/xx unknown
  • 1997-10-03 NO NO974595A patent/NO974595L/no unknown

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