WO2002012187A1 - Nouvelles phenylheteroazetidines utiles comme inhibiteurs de la synthase d'oxyde nitrique - Google Patents

Nouvelles phenylheteroazetidines utiles comme inhibiteurs de la synthase d'oxyde nitrique Download PDF

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WO2002012187A1
WO2002012187A1 PCT/SE2001/001688 SE0101688W WO0212187A1 WO 2002012187 A1 WO2002012187 A1 WO 2002012187A1 SE 0101688 W SE0101688 W SE 0101688W WO 0212187 A1 WO0212187 A1 WO 0212187A1
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formula
chloro
compound
azetidin
benzonitrile
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David Cheshire
Timothy Luker
Antonio Mete
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel phenylheteroazetidine derivatives, processes for their preparation, compositions containing them and their use in therapy.
  • Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes - constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Ofthe constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221 - 230).
  • R represents Cl to 5 alkyl, C2 to 4 alkenyl, C2 to 4 alkynyl, C3 to 6 cycloalkyl or a 4 to 8 membered saturated heterocyclic ring incorporating one or two heteroatoms independently . selected from O, S and N; any of said groups being optionally further substituted by one or more substituents selected independently from Cl to 4 alkyl, Cl to 4 alkoxy, Cl to 4 alkylthio, C3 to 6 cycloalkyl, halogen and phenyl; said phenyl group being optionally further substituted by one or more substituents selected independently from halogen, Cl to 4 alkoxy,
  • R represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally substituted by one or more substituents selected independently from halogen, Cl to 4 alkyl, Cl to 4 alkoxy, OH, CN, NO2 or NR R ; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms; 2 R represents H, Cl to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally
  • R , R , R and R independently represent H or Cl to 4 alkyl; said alkyl group being
  • 19 20 21 optionally substituted by OH, SR , NR R or C2 to 4 alkenyl;
  • R , R and R independently represent H, Cl to 4 alkyl, Cl to 4 alkoxy, halogen, CF3,
  • n an integer 0, 1 or 2;
  • W represents N or CH
  • 22 X represents O, S(O) n or NR ;
  • n an integer 0, 1 or 2;
  • Y represents -CO- or a bond
  • R , R , R , R , R , R , R , R , R , R and R independently represent H or Cl to 4 alkyl
  • the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors ofthe enzyme nitric oxide synthase (NOS).
  • the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors ofthe inducible isoform ofthe enzyme nitric oxide synthase (iNOS).
  • the invention further provides a process for the preparation of compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
  • Another aspect ofthe invention provides the use of a compound of formula (1) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition . of nitric oxide synthase activity is beneficial.
  • a more particular aspect ofthe invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
  • a method of treating,, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
  • a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
  • the compounds ofthe present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor ofthe inducible isoform of cyclooxygenase (COX-2).
  • a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders.
  • a method of treating, or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof in combination with a COX-2 inhibitor.
  • X represents O or S.
  • R , R , R and R each represent H.
  • R does not represent H.
  • R does not represent H. o
  • R represents H or fluoro
  • R and R are independently selected from halogen, CN or
  • R represents a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N, it is preferred that R represents furyl, thienyl, thiazolyl, isothiazolyl or pyridyl.
  • Particular compounds ofthe invention include:
  • Cl to 4 alkyl denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • Cl to 5 alkyl is to be interpreted analogously.
  • C3 to 6 cycloalkyl denotes a cycloalkyl group having from 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.
  • C2 to 4 alkenyl referred to herein denotes a straight or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl, propenyl and butenyl.
  • C2 to 4 alkynyl denotes a straight or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon triple bond. Examples of such groups include ethynyl, propynyl, and butynyl.
  • Cl to 4 alkoxy denotes a straight or branched chain alkoxy group having from 1 to 4 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.
  • halogen referred to herein denotes fluoro, chloro, bromo and iodo.
  • Examples of a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or N include pyrrolidine, piperidine, piperazine, morpholine and perhydroazepine.
  • Examples of a 4 to 8 membered saturated heterocyclic ring incorporating one or two heteroatoms independently selected from O, S or N include azetidine, pyrrolidine, piperidine, tetrahydrofuran, morpholine, piperazine, thiomorpholine and perhydroazepine.
  • Examples of a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N include furan, thiophene, pyridine, thiazole, imidazole, oxazole, triazole, oxadiazole, thiadiazole and pyrimidine.
  • Examples of a five or six membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N include pyrrolidine, tetrahydrofuran, piperidine, morpholine and piperazine.
  • Examples of a "Cl to 4 alkyl or Cl to 4 alkoxy optionally further substituted by one or more fluorine atoms" include CF 3 , CF 3 CF 2 , CF 3 CH 2 , CH 2 FCH 2 , CH 3 CF 2 , CF 3 CH 2 CH 2 , OCF 3 and OCH2CF3.
  • R 7 , R 8 , R 9 and W are as defined in formula (I) and L 1 represents a leaving group, with a compound of formula (III)
  • R , R , R , R , R and Y are as defined in formula (I), and L 2 represents a leaving group;
  • R,R ,R,R ,R ,R ,R ,W, X and Y are as defined in formula (I), with an amide, thioamide, urea, thiourea or guanidine;
  • reaction is performed by treating a nucleophile of formula (III) with an electrophile of formula (II) in an inert solvent.
  • Suitable leaving groups L include trifluorosulfonate and halides, particularly fluoride.
  • the reaction is generally performed in the presence of a non-nucleophilic base such as sodium hydride.
  • Suitable organic solvents are those such as N-methyl-2-pyrrolidinone, tetrahydrofuran, N,N-dimethylformamide and dimethylsulfoxide.
  • the reaction is generally conducted at a temperature between 0 °C and the boiling point ofthe solvent.
  • reaction will take place using an appropriate palladium source such as palladium(II) acetate in the presence of a suitable phosphine ligand such as BINAP.
  • an appropriate palladium source such as palladium(II) acetate
  • a suitable phosphine ligand such as BINAP.
  • reaction is performed by treating a nucleophile of formula (IN) with an
  • Suitable leaving groups L include sulfonate, trifluorosulfonate, tosylate and halides selected from the group chloride, bromide or iodide.
  • the reaction is generally performed in the presence of a non- nucleophilic base such as sodium hydride or a metal carbonate, especially an alkali metal carbonate, a metal oxide or hydroxide, or a tertiary amine.
  • Suitable organic solvents are those such as acetonitrile, dioxane, ⁇ , ⁇ -dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, dimethylsulfoxide, sulfolane and Cl to 4 alcohols.
  • the reaction is generally conducted at a temperature between 0 °C and the boiling point ofthe solvent.
  • the reaction is performed by treating an electrophile of formula (VI) with a nucleophile in an inert solvent, if necessary followed by a second dehydration step.
  • Suitable nucleophiles include particularly amides, thioamides, ureas, thioureas or guanidines.
  • Suitable organic solvents are those such as acetonitrile, toluene, water, dioxane, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, dimethylsulfoxide, sulfolane and Cl to 4 alcohols.
  • the reaction is generally conducted at a temperature between 0 °C and the boiling point ofthe solvent.
  • Suitable dehydration agents • include organic or mineral acid, thionyl chloride and aryl or alkyl sulfonyl halides; particularly thionyl chloride. It will be apparent to a person skilled in the art that in the above processes it may be desirable or necessary to protect an amine or other potentially reactive group. Suitable protecting groups and details of processes for adding and removing such groups may be found by reference to the standard text "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts. In one preferred embodiment, amine groups are protected as diphenylmethyl (benzhydryl) derivatives or as carbamate derivatives, for example, as t-buryloxycarbamates.
  • the present mvention includes compounds of formula (I) in the form of salts, in particular acid addition salts.
  • Suitable salts include those formed with both organic and inorganic acids.
  • Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification ofthe compound in question.
  • preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
  • Salts of compounds of formula (I) may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents ofthe appropriate acid.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying.
  • the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
  • R , R , R , R and Y are as defined in formula (I), with an organometallic derivative, R 1 — M, wherein R is as defined in formula (I) and M represents a metallic residue such as lithium or magnesium-halide.
  • the compounds ofthe invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.
  • the compounds of formula (I) may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope ofthe invention.
  • the various optical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, for example, fractional crystallisation, or HPLC.
  • Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.
  • the compounds of formula (I), and their pharmaceutically acceptable salts, enantiomers and racemates, are useful because they possess pharmacological activity in animals.
  • the compounds are active as inhibitors ofthe enzyme nitric oxide synthase. More particularly, they are inhibitors ofthe inducible isoform ofthe enzyme nitric oxide synthase and as such are predicted to be useful in therapy, for example, as anti-inflammatory agents. They may also have utility as inhibitors ofthe neuronal isoform ofthe enzyme nitric oxide synthase.
  • the compounds and their pharmaceutically acceptable salts, enantiomers and racemates are indicated for use in the treatment or prophylaxis of diseases or conditions in which synthesis or oversynthesis of nitric oxide synthase forms a contributory part.
  • the compounds are indicated for use in the treatment of inflammatory conditions in mammals including man.
  • Conditions that may be specifically mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints; eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including uveitis, glaucoma and conjunctivitis; lung disorders in which inflammation is involved, for example, asthma, bronchitis, chronic obstructive pulmonary disease, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome; bacteraemia, endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis, pain, meningitis and pancreatitis; conditions ofthe gastrointestinal tract including inflammatory bowel disease, Crohn's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac
  • the compounds will also be useful in the treatment and alleviation of acute pain or persistent inflammatory pain or neuropathic pain or pain of a central origin.
  • the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates may also be useful in the treatment or prophylaxis of diseases or conditions in addition to those mentioned above.
  • the compounds may be useful in the treatment of atherosclerosis, cystic fibrosis, hypotension associated with septic and/or toxic shock, in the treatment of dysfunction ofthe immune system, as an adjuvant to short-term immunosuppression in organ transplant therapy, in the control of onset of diabetes, in the maintenance of pancreatic function in diabetes, in the treatment of vascular complications associated with diabetes and in co-therapy with cytokines, for example TNF or interleukins.
  • cytokines for example TNF or interleukins.
  • the compounds of formula (I) may also be useful in the treatment of hypoxia, for example in cases of cardiac arrest and stroke, neurodegenerative disorders including nerve degeneration and or nerve necrosis in disorders such as ischaemia, hypoxia, hypoglycaemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia, for example pre-senile dementia, Alzheimer's disease and AIDS-related dementia, Sydenham's chorea, Parkinson's disease, Tourette's Syndrome, Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Korsakoffs disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, pain, autism, seasonal affective disorder, jet-lag, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.
  • PMS Premenstrual Syndrome
  • Compounds of formula (I). may also be expected to show activity in the prevention and reversal of drug addiction or tolerance such as tolerance to opiates and diazepines, treatment of drug addiction, treatment of migraine and other vascular headaches, neurogenic inflammation, in the treatment of gastrointestinal motility disorders, cancer and in the induction of labour.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history ofthe disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired.
  • the compounds of formula (I), and pharmaceutically acceptable derivatives thereof may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
  • the compounds of formula (I), and pharmaceutically acceptable derivatives thereof, may also be advantageously used in combination with a COX-2 inhibitor. Particularly preferred
  • COX-2 inhibitors are Celecoxib and MK-966.
  • the NOS inhibitor and the COX-2 inhibitor may either be formulated together within the same pharmaceutical composition for administration in a single dosage unit, or each component may be individually formulated such that separate dosages may be administered either simultaneously or sequentially.
  • Example 1 The invention is illustrated, but in no way limited, by the following examples: Example 1
  • Example lb The product from Example lb (0.24 g) was dissolved in 4M hydrogen chloride in dioxane and stood for 2 h. The crystals were filtered off and the. liquor stood for a further 16 h. The solvent was removed in vacuo and the residue was washed with diethyl ether to afford a further crop of crystals. The combined crops of crystals were dried to give the title compound (0.17 g) as a white solid. M.p. 217 - 219 °C.
  • Example 4c White solid. M.p. 197 (dec.) °C.
  • Example 1 la Prepared from the product from Example 1 la and 4-chloro-2,5-difluoro-benzonitrile according to the procedure described in Example lb using N,N-dimethylformamide as solvent. Cream solid.
  • Example 13a The product from Example 13a (900 mg) and 2-chloro-6-methyl-3-pyridinecarbonitrile (536 mg) were dissolved in dimethylformamide (60 ml) and caesium carbonate (2.29 g) added. The reaction was heated to 60 °C and stirred for 24 h. The reaction was cooled to room temperature and water added. The mixture was extracted with ethyl acetate (3 x 80 ml) and the combined extracts were washed with water (3 x 25 ml), dried (magnesium sulphate) and evaporated in vacuo. The residue was purified by chromatography (silica, 25% ethyl acetate in hexane as eluent) to give the sub-title compound. Yellow oil, (581 mg, 44%) MS APCI +ve m /z 273 ([M+H-Boc] + ).
  • Example 14b Prepared from the product from Example 14b according to the procedure described in 0 Example lc. Yellow solid. M.p. 178 - 179 °C.
  • Example 17a The product from Example 17a (0.50 g) and triethylamine (0.65 ml) were dissolved in dichloromethane (5 ml) and cooled to 0 °C. Methanesulfonyl chloride (0.36 ml) was added dropwise and the solution stirred for 2 h. The reaction was poured into saturated aqueous sodium bicarbonate and the organic layer separated. The organic layer was washed with water, dried (sodium sulfate) and the solvent removed in vacuo. The crude mesylate was dissolved in acetonitrile (10 ml).
  • Ci 4 Hi 2 Cl 2 N 2 O 4 S 2 requires: C 41.3, H 3.0, N 6.9% found: C 41.1, H 2.8, N 7.0 %
  • Example 18a Prepared from the product from Example 18a and 2,5-dichloro-benzenethiol according to the procedure described in Example 17b. Brown solid. M.p. 165 - 170 °C.
  • Example lc The product from Example lc (40 mg), potassium carbonate (102 mg) and 2-bromoethylamine hydrobromide (153 mg) were dissolved in ethanol (1 ml) and the reaction heated at 50 °C for 12 h. After cooling to room temperature, the reaction was poured into IM aqueous potassium hydroxide / dichloromethane and the organic layer separated. The organic layer was dried (sodium sulfate) and the solvent removed in vacuo. The residue was dissolved in ethanol and a solution of oxalic acid (10 mg) in ethanol added. The solution was diluted with ethyl acetate and the resulting white solid was filtered off and dried. M.p. 185 - 188 °C.
  • Example 20a Prepared from the product from Example 20a and 4-chloro-2,5-difluoro-benzomtrile according to the procedure described in Example lb. Yellow oil.
  • reaction mixture was then stirred at room temperature for 16 h then diluted with dichloromethane (10 ml).
  • the 5 resulting solution was washed with 2M aqueous hydrochloric acid, 10% aqueous sodium bicarbonate solution and brine, dried (magnesium sulfate) and the solvents were removed in vacuo.
  • the resulting colourless oil was used without further purification.
  • Example 24a The product from Example 24a was dissolved in ethanol (8 ml). Concentrated hydrochloric acid (0.5 ml) was added and the solution heated at 80 °C for 2 h. After cooling to room temperature, the volatiles were removed in vacuo. Potassium carbonate (0.44 g) and 2,4-dichloro-benzonitrile (0.23 g) were added and the reaction heated at 80 °C for 48 h. After cooling to room temperature the reaction was poured into ethyl acetate and water and the organic layer separated. The organic layer was washed with IM aqueous sodium hydroxide solution, dried (magnesium sulfate) and the solvents were removed in vacuo.
  • Example 25b Prepared from the product from Example 25b according to the procedure described in Example 4c. Purification by RPHPLC and formation ofthe hydrochloride salt afforded the title product as a white solid. M.p. 219 - 220 °C.
  • Example 24a Prepared from the product from Example 24a and 2-chloro-6-(trifluoromethyl)-3- pyridinecarbonitrile according to the procedure described in Example 24b.
  • the final compound was purified by column chromatography (0 to 7M ammonia in methanol on SCX resin) followed by RPHPLC to give the title compound as a white solid. M.p. 163 - 165 °C . l
  • the activity of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof, may be screened for nitric oxide synthase inhibiting activity by a procedure based on that of F ⁇ rstermann et ah, Eur. J. Pharm., 1992, 225, 161-165.
  • Nitric oxide synthase converts 3 H-L-arginine into 3 H-L-citrulline which can be separated by cation exchange chromatography and quantified by liquid scintillation counting.
  • Enzyme is prepared, after induction, from the cultured murine macrophage cell line J774A-1 (obtained from the laboratories ofthe Imperial Cancer Research Fund). J774A-1 cells are cultured in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10%) foetal bovine serum, 4 mM -glutamine and antibiotics (100 units/ml penicillin G, 100 mg/ml streptomycin & 0.25 mg/ml amphotericin B). Cells are routinely grown in 225 cm 3 flasks containing 35 ml medium kept at 37 °C and in a humidified atmosphere containing 5% CO 2 .
  • DMEM Dulbeccos Modified Eagles Medium
  • antibiotics 100 units/ml penicillin G, 100 mg/ml streptomycin & 0.25 mg/ml amphotericin B.
  • Nitric oxide synthase is produced by cells in response to interferon-g (IFNg) and lipopolysaccharide (LPS).
  • IFNg interferon-g
  • LPS lipopolysaccharide
  • the medium from confluent culture flasks is removed and replaced with 25 ml (per flask) of fresh medium containing 1 mg/ml LPS and 10 units/ml IFNg.
  • harvesting of cells is accomplished by scraping the cell sheet from the flask surface into the culture medium.
  • Cells are collected by centrifugation (1000 g for 10 minutes) and lysate prepared by adding to the cell pellet a solution containing 50 mM Tris-HCl (pH 7.5 at 20 °C), 10% (v/v) glycerol, 0.1% (v/v) Triton-X-100, 0.1 mM dithiothreitol and a cocktail of protease inhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor (10 mg/ml), aprotinin (5 mg/ml) and phenyhnethylsulphonyl fluoride (50 mg/ml).
  • protease inhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor (10 mg/ml), aprotinin (5 mg/ml) and phenyhnethylsulphonyl fluoride (50 mg/ml).
  • substrate cocktail 50 mM Tris-HCl (pH 7.5 at 20 °C), 400 ⁇ M NADPH, 20 ⁇ M flavin adenine dinucleotide, 20 ⁇ M flavin mononucleotide, 4 ⁇ M tetrahydrobiopterin, 12 ⁇ M L-arginine and 0.025 mCi L-[ 3 H] arginine
  • substrate cocktail 50 mM Tris-HCl (pH 7.5 at 20 °C), 400 ⁇ M NADPH, 20 ⁇ M flavin adenine dinucleotide, 20 ⁇ M flavin mononucleotide, 4 ⁇ M tetrahydrobiopterin, 12 ⁇ M L-arginine and 0.025 mCi L-[ 3 H] arginine
  • the reaction is started by adding 50 ⁇ l of cell lysate (prepared as above) and after incubation for 1 hour at room temperature is terminated by addition of 50 ⁇ l of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA.
  • Labelled L-citruUine is separated from labelled L-arginine using Dowex AG-50W.
  • 150 ⁇ l of a 25% aqueous slurry of Dowex 50 W (Na + form) is added to the assay after which the whole is filtered into 96 well plates.
  • 75 ⁇ l of filtrate is sampled and added to wells of 96 well plates containing solid scintillant. After allowing the samples to dry the L-citruUine is quantified by scintillation counting.
  • basal activity is 300 dpm per 75 ⁇ l sample which is increased to 1900 dpm in the reagent controls.
  • Compound activity is expressed as IC 50 (the concentration of drug substance which gives 50% enzyme inhibition in the assay) and aminoguanidine, which gives an IC 50 (50%> inhibitory concentration) of 10 ⁇ M, is tested as a standard to verify the procedure.
  • Compounds are tested at a range of concentrations and from the inhibitions obtained IC 50 values are calculated.
  • Compounds that inhibit the enzyme by at least 25% at 100 ⁇ M are classed as being active and are subjected to at least one retest.
  • Compounds also show activity against the human form of induced nitric oxide synthase as can be demonstrated in the following assay.
  • the human colorectal carcinoma cell line, DLD-1 obtained from the European Collection of Animal Cell Culture - cell line number 90102540
  • RPMI 1640 supplemented with 10%(v/v) foetal bovine serum, and 2mM L-glutamine, at 37 °C in 5% CO 2 .
  • Nitric oxide synthase was induced in cells by addition of medium containing human recombinant gamma-IFN (1000 units/ml), TNF-alpha (200 U/ml), IL-6 (200 U/ml) and
  • IL-1-beta 250 U/ml. After incubation for 18 hours at 37 °C, the medium was removed and the cells washed with warm phosphate buffered saline. Cells were incubated for a further
  • Nitrite accumulation was determined by mixing an equal volume of culture media with Griess reagent (10 mg/ml sulphanilamide, 1 mg N-(l-naphthyl)ethylenediamine in 1 ml 2.5% (v/v) phosphoric acid). Inhibition in the presence of compounds was calculated relative to the nitrite levels produced by untreated cells. IC 50 values were estimated from a semi-log plot of % inhibition versus concentration of compound.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés de la formule (I) où R?1, R2, R3, R4, R5, R6, R7, R8, R9¿, W, X et Y ont la signification donnée dans la description, et leurs sels pharmaceutiquement compatibles ainsi que leurs énantiomères et racémates. L'invention concerne également leurs procédés de préparation, les compositions les contenant et leur utilisation en thérapie. Ces composés, inhibiteurs de la synthase d'oxyde nitrique, sont particulièrement adaptés au traitement ou à la prévention de maladies et douleurs inflammatoires.
PCT/SE2001/001688 2000-08-04 2001-07-31 Nouvelles phenylheteroazetidines utiles comme inhibiteurs de la synthase d'oxyde nitrique Ceased WO2002012187A1 (fr)

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GB0019006A GB0019006D0 (en) 2000-08-04 2000-08-04 Novel compounds
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WO2003088959A3 (fr) * 2002-04-18 2003-12-31 Pharmacia Corp Monotherapie pour le traitement de la maladie de parkinson avec des inhibiteurs de la cyclooxygenase-2 (cox 2)
WO2003088958A3 (fr) * 2002-04-18 2004-08-19 Pharmacia Corp Therapie combinatoire pour le traitement de la maladie de parkinson a l'aide d'un ou de plusieurs inhibiteurs de cyclooxygenase-2 (cox 2)
WO2006102283A3 (fr) * 2005-03-22 2007-11-01 Azevan Pharmaceuticals Inc Acides beta-lactamylalcanoiques destines au traitement des troubles premenstruels
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
JP2009102325A (ja) * 2002-03-15 2009-05-14 Novartis Ag Ｃｃｒ−３レセプターアンタゴニストとしてのアゼチジン誘導体
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
US8048874B2 (en) 2005-07-19 2011-11-01 Azevan Pharmaceuticals, Inc. Beta-lactamyl phenylalanine, cysteine, and serine vasopressin antagonists
AU2013206201B2 (en) * 2005-03-22 2016-06-16 Azevan Pharmaceuticals, Inc. Beta-lactamylalkanoic acids for treating premenstrual disorders
US9376424B2 (en) 2010-07-01 2016-06-28 Azevan Pharmaceuticals, Inc. Methods for treating post traumatic stress disorder
US9802925B2 (en) 2014-03-28 2017-10-31 Azevan Pharmaceuticals, Inc. Compositions and methods for treating neurodegenerative diseases
US11628160B2 (en) 2017-09-15 2023-04-18 Azevan Pharmaceuticals, Inc. Compositions and methods for treating brain injury
CN116444411A (zh) * 2022-01-05 2023-07-18 华中师范大学 一种氮杂环丁烷化合物的制备方法

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009102325A (ja) * 2002-03-15 2009-05-14 Novartis Ag Ｃｃｒ−３レセプターアンタゴニストとしてのアゼチジン誘導体
WO2003088959A3 (fr) * 2002-04-18 2003-12-31 Pharmacia Corp Monotherapie pour le traitement de la maladie de parkinson avec des inhibiteurs de la cyclooxygenase-2 (cox 2)
WO2003088958A3 (fr) * 2002-04-18 2004-08-19 Pharmacia Corp Therapie combinatoire pour le traitement de la maladie de parkinson a l'aide d'un ou de plusieurs inhibiteurs de cyclooxygenase-2 (cox 2)
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
US7906503B2 (en) 2003-06-11 2011-03-15 Merck Sharp & Dohme Corp. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
WO2006102283A3 (fr) * 2005-03-22 2007-11-01 Azevan Pharmaceuticals Inc Acides beta-lactamylalcanoiques destines au traitement des troubles premenstruels
US9597314B2 (en) 2005-03-22 2017-03-21 Azevan Pharmaceuticals, Inc. Beta-lactamylalkanoic acids for treating premenstrual disorders
AU2013206201B2 (en) * 2005-03-22 2016-06-16 Azevan Pharmaceuticals, Inc. Beta-lactamylalkanoic acids for treating premenstrual disorders
US8426400B2 (en) 2005-07-19 2013-04-23 Azevan Pharmaceuticals, Inc. β-lactamyl phenylalanine, cysteine, and serine vasopressin antagonists
US8048874B2 (en) 2005-07-19 2011-11-01 Azevan Pharmaceuticals, Inc. Beta-lactamyl phenylalanine, cysteine, and serine vasopressin antagonists
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
US9376424B2 (en) 2010-07-01 2016-06-28 Azevan Pharmaceuticals, Inc. Methods for treating post traumatic stress disorder
US9987265B2 (en) 2010-07-01 2018-06-05 Azevan Pharmaceuticals, Inc. Methods for treating post traumatic stress disorder
US10953001B2 (en) 2010-07-01 2021-03-23 Azevan Pharmaceuticals, Inc. Methods for treating post traumatic stress disorder
US9802925B2 (en) 2014-03-28 2017-10-31 Azevan Pharmaceuticals, Inc. Compositions and methods for treating neurodegenerative diseases
US10364236B2 (en) 2014-03-28 2019-07-30 Azevan Pharmaceuticals, Inc. Compositions and methods for treating neurodegenerative diseases
US11319306B2 (en) 2014-03-28 2022-05-03 Azevan Pharmaceuticals, Inc. Compositions and methods for treating neurodegenerative diseases
US11628160B2 (en) 2017-09-15 2023-04-18 Azevan Pharmaceuticals, Inc. Compositions and methods for treating brain injury
CN116444411A (zh) * 2022-01-05 2023-07-18 华中师范大学 一种氮杂环丁烷化合物的制备方法

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