WO2000064904A1 - Derives d'amidine 5,7-bicyclique utiles en tant qu'inhibiteurs de l'oxyde nitrique synthase - Google Patents

Derives d'amidine 5,7-bicyclique utiles en tant qu'inhibiteurs de l'oxyde nitrique synthase Download PDF

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Publication number
WO2000064904A1
WO2000064904A1 PCT/SE2000/000796 SE0000796W WO0064904A1 WO 2000064904 A1 WO2000064904 A1 WO 2000064904A1 SE 0000796 W SE0000796 W SE 0000796W WO 0064904 A1 WO0064904 A1 WO 0064904A1
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dihydro
thieno
ylamine
oxazepin
formula
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PCT/SE2000/000796
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English (en)
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David Cheshire
Stephen Connolly
David Cox
Peter Hamley
Timothy Luker
Antonio Mete
Austen Pimm
Michael Stocks
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU44465/00A priority Critical patent/AU4446500A/en
Publication of WO2000064904A1 publication Critical patent/WO2000064904A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel 5,7-bicyclic amidine 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. Of the 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).
  • ecNOS endothelial enzyme
  • WO 96/33175 discloses compounds of general formula:
  • R 5 O 96/35677 discloses compounds of general formula:
  • the compounds of the present invention are distinguished from those of the prior art by virtue of the nature of the particular substituents attached to the cyclic amidine ring.
  • A, B and D are independently selected from C, N, O and S, at least one of A. B and D being N, O or S, so as to form a 5-membered heterocyclic aromatic ring;
  • X represents CH 2 , NR , O or S(O) m ;
  • R and R ⁇ independently represent hydrogen, halogen. C 1 to 6 alkyl. NOo. OH. OR . CN.
  • R , R . R and R independently represent hydrogen, C 1 to 8 alkyl. C 2 to 8 alkenyl. C 2 to 8 alkynyl, phenyl, or a 5-membered or 6-membered heterocyclic aromatic ring; said phenyl or a 5-membered or 6-membered heterocyclic aromatic ring being optionally substituted by halogen, C 1 to 6 alkyl or C 1 to 6 alkoxy; and said alkyl, alkenyl and alkynyl groups being optionally substituted by halogen, OH.
  • NR 8 R 9 C 1 to 6 alkoxy, aryl, aryloxy, aryl-C 1 to 6-alkoxy. C 1 to 6 alkyl-S(O) m .
  • aryl-S(O) m aryl-C 1 to 6 alkyl-S(O) m , wherein aryl represents phenyl. naphthyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl or a 5-membered or 6-membered heterocyclic aromatic ring optionally substituted by halogen, C 1 to 6 alkyl or C 1 to 6 alkoxy, OH, CN.
  • R 3 4 or R and R can be joined together so as to form a 3 to 7 membered saturated ring a optionally incorporating a nitrogen atom substituted by R or an oxygen atom;
  • R and R can be joined together so as to form a 3 to 7 membered saturated ring
  • R and R may together represent O; 8 9
  • R and R are independently selected from hydrogen.
  • arylaminocarbonyl and 3-arylacryloyl wherein aryl represents phenyl, naphthyl, indolyl or a 5-membered or 6-membered heterocyclic aromatic ring optionally substituted by halogen, C 1 to 6 alkyl or C 1 to 6 alkoxy, OH, CN, NO 2 or NH 2 ;
  • R , R and R independently represent hydrogen or C 1 to 6 alkyl
  • R represents hydrogen or CO 2 R wherein R represents Cl to 6 alkyl, 2.2.2- trichloroethyl or benzyl;
  • n an integer 0, 1 or 2;
  • the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the advantage that they are inhibitors of the enzyme nitric oxide synthase (NOS).
  • NOS nitric oxide synthase
  • the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the advantage that they are inhibitors of the inducible isoform of the 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, racemate or tautomer thereof.
  • Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer 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 of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer 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, racemate or tautomer 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, racemate or tautomer thereof.
  • the compounds of the present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2).
  • COX-2 cyclooxygenase
  • 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 comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof in combination with a COX-2 inhibitor.
  • A represents S
  • B and D each represent carbon.
  • B represents S
  • a and D each represent carbon
  • X in formula (I) represents O or S.
  • Particular compounds of the invention include: 2,3-dihydro-thieno[2,3-f][ l,4]thiazepin-5-ylamine;
  • Cl to 8 alkyl denotes a straight or branched chain alkyl group having from 1 to 8 carbon atoms or a cyclic alkyl group having from 3 to 8 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl and cyclohexyl.
  • C2 to 8 alkenyl denotes a straight or branched chain alkyl group having from 2 to 8 carbon atoms or a cyclic alkyl group having from 3 to 8 carbon atoms, each incorporating at least one carbon-carbon double bond.
  • Examples of such groups include ethenyl, propenyl, butenyl. cyclopentenyl and cyclohexenyl.
  • C2 to 8 alkynyl denotes a straight or branched chain alkyl group having from 2 to 8 carbon atoms and incorporating at least one carbon-carbon triple bond. Examples of such groups include ethynyl, propynyl, and butynyl.
  • Cl to 6 alkoxy denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.
  • Examples of a five or six membered aromatic heterocyclic ring include furan, thiophene. pyrrole, thiazole, oxazole, imidazole, pyridine, pyrimidine, pyrazine and pyridazine.
  • R , R " , R ' R , R ⁇ , R , A. B, D and X are as defined above, with ammonia;
  • R , R " , R ' R , R . R , A, B, D and X are as defined above and R represents methyl or ethyl, with ammonia or ammonium acetate;
  • R , R " , R ' R , R , R , A, B, D and X are as defined above and PG represents a protecting group
  • reaction will take place on mixing the reactants in a suitable organic solvent at a suitable temperature
  • the reaction time will depend inter alia on the solvent used and on the reaction temperature
  • a saturated solution of ammonia in methanol is used as reagent/solvent and the reaction is conducted at approximately 100 °C in a pressurised container
  • the reaction may be performed by combining the reactants in a organic solvent such as methanol or acetonitrile at a suitable temperature, generally between room temperature and the boiling point of the solvent
  • a suitable temperature generally between room temperature and the boiling point of the solvent
  • the reaction time will depend -nter alia on the polarity of the solvent and the temperature of the reaction
  • the reaction may be performed by treating the compound of formula (D)
  • R " represents hydrogen with a reagent such as a dialkyl dicarbonate under conditions that are well known in the art
  • the present invention 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 of the compound in question Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tarta ⁇ c, lactic, pyruvic. acetic succinic, fuma ⁇ c maleic, methanesulphomc and benzenesulphomc acids
  • Salts of compounds ot formula (I) may be formed by reacting the free base, or a salt, enantiomer. racemate or tautomer thereof, with one or more equivalents of the 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
  • Novel intermediates of formulae (LT), (D ) and (TV) form another aspect of the invention
  • the preparation of compounds of formula (H3) may be achieved by reaction of a compound of formula (II) with a compound R-L, wherein R is as defined above and L is a leaving group such as halogen, particularly iodide, or mesylate.
  • the compounds of the 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 enantiome ⁇ c forms Therefore, all enantiomers diastereomers, racemates and mixtures thereof are included withm the scope of the invention
  • the various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC
  • the compounds of formula (I), and their pharmaceutically acceptable salts, enantiomers racemates and tautomers, are useful because they possess pharmacological activity in animals
  • the compounds are active as inhibitors of the enzyme nitric oxide synthase More particularly, they are inhibitors of the inducible isoform of the 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 of the neuronal isoform of the enzyme nitric oxide synthase
  • the compounds and their pharmaceutically acceptable salts, enantiomers racemates and tautomers 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 In particulai.
  • the compounds are indicated for use in the treatment of inflammatory conditions in mammals including man
  • Conditions that may be specifically mentioned are osteoarth ⁇ tis. rheumatoid arthritis, rheumatoid spondy tis, 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 pyresis. pain and pancreatitis
  • conditions of the gastrointestinal tract including inflammatory bowel disease. Crohn's disease atrophic gastritis, gastritis va ⁇ aloforme, ulcerative colitis, coeliac disease, regional lleitis peptic ulceration, irritable bowel syndrome, reflux oesophagitis, damage to the gastrointestinal tract resulting from infections by, for example, Helicobacter pylori, or from treatments with non-steroidal anti-inflammatory drugs: and other conditions associated with inflammation.
  • 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. racemates and tautomers 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 of the 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 for example in cases of cardiac arrest and stroke
  • neurodegenerative disorders including nerve degeneration and/or nerve necrosis in disorders such as ischaemia.
  • 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.
  • Compounds of formula (I) may also be expected to show activity in the prevention and reversal of drug addiction or tolerance to opiates and diazepines. treatment of drug addiction, treatment of migraine and other vascular headaches, neurogenic inflammation, in the treatment of gastrointestinal motihty 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 of the 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 However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per da ⁇
  • 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, subhngual or rectal), intranasal. intravenous, topical or other parenteral routes Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in.
  • 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, racemate or tautomer thereof
  • a process for the preparation of such a pharmaceutical composition which comprises mixing the ingredients
  • the compounds of formula (1). 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 sequential!)
  • Example 1(b) The product From Example 1(b) (0.15 g. 0.75 mmol) was dissolved in methanol ( 10 ml) saturated with ammonia and the resulting solution placed in a stainless steel finger bomb. The bomb was sealed and heated at 100°C for 18 hours. After cooling the solvent was removed and the residue passed down a silica gel column eluted with dichloromethane:methanol (9: 1) to give a white solid which was converted into the hydrochloride salt with 1M hydrochloric acid in diethyl ether (0.08 g). M.p. 202-204 °C.
  • Example 2(c) The product of Example 2(c) (0.47 g, 1.43 mmol) was dissolved in 4M hydrochloric acid in dioxane (5 ml) and stirred for 2 hours at room temperature. The solvent was removed and the residue dissolved in dimethylformamide (4 ml) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate ( 1.33 g, 2.86 mmol) added. The solution was stirred for 15 minutes then N,N-diisopropylethylamine (0.92 g, 7.15 mmo! ) added. The reaction was stirred at room temperature for 18 hours. Water (80 ml) was added and the reaction extracted with ethyl acetate (3 x 25 ml).
  • Example 7(a) The mesylate produced in Example 7(a) (3.1 g) and 3-mercaptothiophene-2-carboxylic acid (1.5 g) were subjected to the procedure described in Example 2(c) to give the product as an oil (0.6 g).
  • Example 7(b) The product from Example 7(b) (0.6 g) was deprotected by the procedure described in Example 2(d) to afford the product as a gum (0.5 g). Mass spectrum: It 324 [M + H] .
  • Example 7(e) The product from Example 7(e) (0.1 g) in acetonitrile (5 ml) was treated with methyl iodide (0.5 ml) and stirred for 3 hr. The solvent was evaporated to leave a yellow gum. This was dissolved in methanol (5 ml), treated with ammonium acetate (0.1 g) and heated at reflux for 40 hrs. The solvent was evaporated and the residue passed down a silica gel column eluted with dichloromethane:methanol ( 10: 1 , v/v and then 5: 1 , v/v). A yellow solid was obtained which was triturated with IM ethereal hydrochloric acid to afford the product as a solid (0.035g). M.p. 175-179 °C.
  • Example 8(c) The product from Example 8(c) was subjected to the procedure described in Example 12(e) to afford the product as a yellow gum.
  • Example 8(d) The product from Example 8(d) was subjected to the procedure described in Example 12(f) to afford the product as a yellow solid.
  • Example 8(e) (0.15 g) was treated with a saturated solution of ammonia in methanol as in Example 2(0 to afford the product as a yellow solid (0.03 g). M.p. 194- 197 °C.
  • Example 9(a) was converted into the required product by the procedures described in Examples 2(e) and 2(f).
  • Example 2 The synthetic sequence described for the preparation of Example 2 was applied to (2RS)-2- amino-pentanol to give the title compound. M.p. 219-220 °C.
  • Example 12(b) The product from Example 12(b) (2.8 g, 8.2 mmol) was dissolved in 4M hydrochloric acid in dioxane (25 ml) and stirred for 2 hr. The solvent was removed under reduced pressure to give the product (2.3 g).
  • Example 12(d) The product from Example 12(d) (1 g, 4.5 mmol) and [2,4-bis(4-methoxyphenyl)-l,3- dithia-2,4-diphosphetane-2,4-disulfide] (1.2 g, 3 mmol) in benzene (50 ml) were heated at reflux for 3 hr. The reaction mixture was absorbed onto silica and passed down a silica gel column eluted with hexane:ethyl acetate (4: 1. v/v) to afford the product as a yellow solid (0.77 g).
  • C 10 H,5N 2 C1OS requires: C, 48.67; H, 6.13; N, 1 1.35; S, 12.99 %. Found: C, 48.86; H. 6.12; N. 1 1.40; S, 12.56 %.
  • Example 14(e) The product from Example 14(e) (0.16 g, 0.63 mmol) was dissolved in acetonitrile (30 ml) and methyl iodide (1.0 ml) added. The solution was stirred for 24 hr at room temperature and then the solvent removed on a rotary evaporator. The residue was dissolved in acetonitrile (20 ml) and ammonium acetate (486 mg, 6.3 mmol) added. The reaction was refluxed for 36 hours. Water (40 ml) was added and the mixture acidified with aqueous 2M hydrochloric acid, extracted with ethyl acetate (3 x 20 ml) and these extracts discarded.
  • the reaction was basified with aqueous 10% sodium hydroxide (pH>12) and extracted with ethyl acetate (3 x 50 ml). Combined extracts were washed with water (2 x 20 ml), dried (anhydrous MgSO ) and evaporated. The residue was dissolved in ethyl acetate and the solution treated with IM hydrochloric acid in diethyl ether. The precipitated solid was filtered off to give the title compound as a white solid (0.09 g). M.p. 260-263 °C.
  • the aqueous layer was basified to p ⁇ 10 with IN aqueous sodium hydroxide and was extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate, filtered and concentrated to afford an oil that was dissolved in acetonitrile (2 ml) and added to a rapidly stirred solution of ethereal hydrogen chloride (1 M, 30 ml). The resulting solid was filtered off to afford the title compound as a white solid (l . lg)
  • Example 34(a) 6-Allyl-5.6-dihvdro-4H-furo[2,3-c]azepin-8-ylamine hydrochloride
  • the product of Example 34(a) was subjected to the procedures described in Example 29 to afford the title product as a white solid, m.p. 165 - 173 °C.
  • Example 34(b) The title product of Example 34(b) (0.180 g, 0.946 mmol) (as the free base) was dissolved in ethanol (20 ml). This solution was added to a slurry of 10% palladium on charcoal (catalytic amount) in ethanol. The reaction mixture was stirred for 60 h at room temperature under a hydrogen atmosphere (4.0 bar). The reaction mixture was filtered and concentrated in vacuo. Anhydrous hydrogen chloride (IM in diethyl ether) was added to the residue and the resulting white precipitate isolated by filtration. The product was washed with diethyl ether and dried in vacuo to yield the title compound (0.070 g), m.p. 147-149 °C. Mass Spectrum: m /e 193 [M + ⁇ ] + .
  • Example 37(a) The compound from Example 37(a) was subjected to the procedures described in Example 12(c to g) to afford the title product as a white solid, m.p. 199 - 199.5 °C. Mass spectrum: It 197 [M + H] 1" .
  • Example 29 6-Allyl-7,8-dihydro-6H-furo[3,2-c]-azepin-4-ylamine hydrochloride (Example 29) was hydrogenated according to the procedure described in Example 35 to afford the title compound as a white solid, m.p. 168 - 169.5 °C.
  • Example 39 Starting with the product of Example 39, the title compound was synthesised via the route described for Example 35. M.p. 186 - 190 °C. Mass spectrum: m /e 209 [M + H] + .
  • the reaction was stirred for 0.5 h at room temperature and then the product from Example 41(b) (3.64 g, 14.4 mmol) was added and the reaction stirred for 72 h.
  • the reaction was poured into water (80 ml) and washed with ethyl acetate (3 x 40 ml).
  • the aqueous portion was acidified with aqueous 2M hydrochloric acid and extracted with ethyl acetate (3 x 80 ml).
  • the combined organic extracts were washed with water (3 x 40 ml), dried (Na 2 SO ) and evaporated in vacuo.
  • Example 41(d)] was subjected to the procedures described in Example 12(e-g) to afford the title product as a white solid, m.p. 186 - 189 °C.
  • Example 43(b) The product of Example 43(b)) (1.61 g, 8.0 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) at 0 °C and sodium borohydride (0.726 g, 19.2 mmol) was added in one portion. The reaction was stirred for 2 hours at 0 °C, then room temperature for 18 h. Water (80 ml) was added followed, cautiously, by aqueous 2M hydrochloric acid. The mixture was stirred for 15 minutes then extracted with diethyl ether (3 x 100 ml).
  • Diastereoisomer 1 M.p. 251 - 255 °C. Mass Spectrum: m /e 21 1 [M + H] + .
  • Diastereoisomer 2 M.p. 217 - 220 °C. Mass Spectrum: m /e 21 1 [M + H] + .
  • Example 44(a) Starting with the product from Example 44(a), the title compound was synthesised via the route described for Example 12. The product was obtained as two diastereomers.
  • Diastereoisomer 1 M.p. 190 - 195 °C. Mass Spectrum: m /e 21 1 [M + H] + .
  • Diastereoisomer 2 M.p. 238 - 240 °C. Mass Spectrum: m /e 21 1 [M + H] + .
  • Example 47(b) was converted into the title compound via the procedures described in Example 12(e-g).
  • Example 47(a) The product of Example 47(a) and copper (I) cyanide were subjected to the reaction conditions described in Example 47(b) to give a light brown oil. This was converted into the title compound via the route described for Example 12(e-g). M.p. 240 - 241 °C. Mass spectrum: It 250 [M + H] + .
  • Example 49(a) The product of Example 49(a) (3.0 g, 15 mmol) was added to a solution of tert-butyldimethylsilyl chloride (2.5 g. 16.5 mmol) in a mixture of dimethylformamide (5 ml) and dichloromethane (50 ml). Imidazole (2.8 g, 41 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 2M hydrochloric acid, water and brine. The organic phase was dried (anhydrous MgSO 4 ) and evaporated onto silica gel.
  • Example 50(a) Starting with the product of Example 50(a), the title compound was synthesised via the route described for Example 12(e-g).
  • Example 51(a) Starting with the product of Example 51(a), the title compound was synthesised via the route described for Examples 12(e-g). M.p. 208 - 210 °C.
  • Example 54(a) was subjected to the procedures described in Example 29(d) to afford the product as a beige solid, m.p. 213 - 216 °C. Mass spectrum: m /e 285 [M + ⁇ ] + .
  • Example 56(a) The product of Example 56(a) was dissolved in 4N hydrogen chloride in 1,4-dioxane (40 ml) and stirred at room temperature for 16 h. The solvents were removed and the residue dissolved in methanol (10 ml). Sodium methoxide (2 ml of a 4.6M solution in methanol) was added and the reaction refluxed for 48 h. After cooling to room temperature the solvents were removed and the residue was purified by chromatography on silica gel eluting with dichloromethane : methanol (100:0 to 90: 10) to afford the sub-titled product as a yellow solid (1.0 g). NMR (DMSO d ⁇ ): 3.32-3.21 (m, 4H), 6.49 (d, IH), 7.01 (bs, IH), 7.42 (d, IH), 7.51 (bs. IH).
  • Example 56(b) was subjected to the procedures described in Example 12(e- g) to afford the title product as a beige solid, m.p. 65 (dec) °C.
  • Example 57(b) The product from Example 57(b) (0.095 g, 0.37 mmol) in ethanol (5 ml) containing 10% palladium on carbon (0.005 g) was subjected to 3 atmospheres of hydrogen for 16 h. The suspension was filtered and evaporated to dryness to leave the title compound as a white solid (0.09 lg, 95%), m.p. 207 - 208 °C.
  • Example 61(a) Starting with the product of Example 61(a), the title compound was prepared using the procedures described in Example 12(e-g).
  • Example 62(f) (0.05 g, 0.19 mmol) in pyridine (3 ml) for 4 h.
  • the resulting mixture was concentrated onto silica and purified by column chromatography eluting with methanol : dichloromethane (1 : 100 to 5: 100) to leave a white solid (6 mg).
  • Mass spectrum m /e 338 [M + H]+.
  • Trimethylsilyl isocyanate (0.15 ml, 1.1 mmol) was added to a solution of the product from Example 62(f) (0.07 g, 0.26 mmol) in dimethylsulphoxide : N-methylpyrrolidone : Hunig's base (2: 10: 1, 6.5 ml) and stirred for 4 h. The resulting mixture was concentrated onto silica and purified by column chromatography eluting with methanol : dichloromethane ( 1 :20 to 1:5) to leave a white solid (0.011 g). Mass spectrum: /e 241 [M + H] + .
  • Example 72 Starting with the product from Example 72 and benzoic acid, the title compound was synthesised according to the procedure described in Example 66.
  • the activity of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, may be screened for nitric oxide synthase inhibiting activity by a procedure based on that of F ⁇ rstermann et al, 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 of the Imperial Cancer Research Fund). J774A-1 cells are cultured in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10% foetal bovine serum, 4 mM L-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
  • 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 phenylmethylsulphonyl fluoride (50 mg/ml).
  • protease inhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor (10 mg/ml), aprotinin (5 mg/ml) and phenylmethylsulphonyl 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) is added to wells of a 96 well filter plate (0.45 ⁇ M pore size) containing 25 ⁇ l of a solution of test compound in 50 mM Tris-HCl.
  • 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-citrulline is separated from labelled L-arginine using Dowex AG-50W.
  • 150 ⁇ l of a 25% aqueous slurry of Dowex 50W (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-citrulline 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 5 o (the concentration of drug substance which gives 50% enzyme inhibition in the assay) and aminoguanidine, which gives an IC 5 o (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 o 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.
  • the human colorectal carcinoma cell line, DLD-1 obtained from the European Collection of Animal Cell Culture - cell line number 90102540
  • 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 5 hours at 37 °C / 5% CO : in RPMI 1640 containing lOO ⁇ M L-arginine and lOO ⁇ M verapamil-HCl in the presence and absence of test compounds.
  • Nitrite accumulation was determined by mixing an equal volume of culture media with Griess reagent (10 mg/ml sulphanilamide, 1 mg N-( 1 -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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Abstract

L'invention concerne des nouveaux composés correspondant à la formule (I), ainsi que des sels de ceux-ci, acceptables sur le plan pharmacologique, de même que des énantiomères et tautomères de ces composés. Dans cette formule, R?1, R2, R3, R4, R5, R6, R12¿, A, B, D et X possèdent les notations données dans la description. Ces composés constituent des inhibiteurs de l'oxyde nitrique synthase, et ils sont notamment utiles dans le traitement ou la prophylaxie de maladies inflammatoires et de la douleur.
PCT/SE2000/000796 1999-04-28 2000-04-26 Derives d'amidine 5,7-bicyclique utiles en tant qu'inhibiteurs de l'oxyde nitrique synthase WO2000064904A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096150A2 (fr) * 2006-02-23 2007-08-30 Novartis Ag Domaine technique
WO2007132841A1 (fr) * 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996014844A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Analogues d'amidines cycliques utilises comme inhibiteurs de la monoxyde d'azote synthetase
WO1996014842A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique
WO1996035677A1 (fr) * 1995-05-10 1996-11-14 G.D. Searle & Co. Inhibiteurs de la synthase d'oxyde nitrique derives des amidines cycliques
WO1997016430A1 (fr) * 1995-11-01 1997-05-09 Merck & Co., Inc. Derives de l'hexahydro-5-imino-1,4-heteroazepine inhibiteurs des synthases de l'oxyde nitrique
WO1997038977A1 (fr) * 1996-04-13 1997-10-23 Astra Pharmaceuticals Ltd. Amino-isoquinolines et derives d'aminothienopyridine et leur utilisation en tant qu'agents anti-inflammatoires
WO1998045294A1 (fr) * 1997-04-09 1998-10-15 Astra Pharmaceuticals Ltd. Composes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996014844A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Analogues d'amidines cycliques utilises comme inhibiteurs de la monoxyde d'azote synthetase
WO1996014842A1 (fr) * 1994-11-15 1996-05-23 Merck & Co., Inc. Heterocycles a substitutions utilises en tant qu'inhibiteurs de la synthetase d'oxyde nitrique
WO1996035677A1 (fr) * 1995-05-10 1996-11-14 G.D. Searle & Co. Inhibiteurs de la synthase d'oxyde nitrique derives des amidines cycliques
WO1997016430A1 (fr) * 1995-11-01 1997-05-09 Merck & Co., Inc. Derives de l'hexahydro-5-imino-1,4-heteroazepine inhibiteurs des synthases de l'oxyde nitrique
WO1997038977A1 (fr) * 1996-04-13 1997-10-23 Astra Pharmaceuticals Ltd. Amino-isoquinolines et derives d'aminothienopyridine et leur utilisation en tant qu'agents anti-inflammatoires
WO1998045294A1 (fr) * 1997-04-09 1998-10-15 Astra Pharmaceuticals Ltd. Composes

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096150A2 (fr) * 2006-02-23 2007-08-30 Novartis Ag Domaine technique
WO2007096150A3 (fr) * 2006-02-23 2007-10-25 Novartis Ag Domaine technique
US8258128B2 (en) 2006-02-23 2012-09-04 Novartis Ag Organic compounds
WO2007132841A1 (fr) * 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
JPWO2007132841A1 (ja) * 2006-05-16 2009-09-24 武田薬品工業株式会社 縮合複素環化合物およびその用途
US8158617B2 (en) 2006-05-16 2012-04-17 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
JP5528699B2 (ja) * 2006-05-16 2014-06-25 武田薬品工業株式会社 縮合複素環化合物およびその用途
US9079907B2 (en) 2006-05-16 2015-07-14 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof

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