WO2000027842A1 - Composes - Google Patents
Composes Download PDFInfo
- Publication number
- WO2000027842A1 WO2000027842A1 PCT/SE1999/001988 SE9901988W WO0027842A1 WO 2000027842 A1 WO2000027842 A1 WO 2000027842A1 SE 9901988 W SE9901988 W SE 9901988W WO 0027842 A1 WO0027842 A1 WO 0027842A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methoxy
- pyridinamine
- piperidinyl
- formula
- compound
- Prior art date
Links
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- 238000000034 method Methods 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 238000011282 treatment Methods 0.000 claims abstract description 27
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- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims abstract description 21
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- 238000011321 prophylaxis Methods 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 24
- -1 trifluoromethoxy, hydroxy, nitro, methanesulphonyl Chemical group 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 11
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- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- 229960003130 interferon gamma Drugs 0.000 description 1
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KVMMIDQDXZOPAB-UHFFFAOYSA-N isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C=NC(C(=O)O)=CC2=C1 KVMMIDQDXZOPAB-UHFFFAOYSA-N 0.000 description 1
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- 229910000836 magnesium aluminium oxide Inorganic materials 0.000 description 1
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- 210000004962 mammalian cell Anatomy 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MHQIMVYNMHGQSF-UHFFFAOYSA-N methylphosphanium;bromide Chemical compound [Br-].[PH3+]C MHQIMVYNMHGQSF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- CKMXAIVXVKGGFM-UHFFFAOYSA-N p-cumic acid Chemical compound CC(C)C1=CC=C(C(O)=O)C=C1 CKMXAIVXVKGGFM-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000004203 pancreatic function Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
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- 208000012672 seasonal affective disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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 compounds of the present invention are clearly distinguished from those of the prior art by virtue of the nature of the particular substituents attached to the 2-aminopyridine ring.
- R represents hydr ⁇ gen or one or more substituents selected independently from Cl to 6
- R independently represent hydrogen or Cl to 4 alkyl; 2 4 or R and R are joined together and represent -[CH2] m -;
- Y represents hydrogen or Cl to 4 alkyl
- 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).
- 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, 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.
- 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.
- Q in formula (I) represents hydrogen, halogen or cyano.
- Particular compounds of the invention include:
- Cl to 6 alkyl denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl and cyclohexyl.
- 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.
- alkylthio are to be interpreted similarly.
- Examples of a five membered aromatic heterocyclic ring containing one to three heteroatoms selected independently from O, S or N, or a six membered aromatic azacyclic ring containing one or two nitrogen atoms include furan, thiophene, pyrrole, thiazole, oxazole, imidazole, triazole, thiadiazole, pyridine, pyrimidine, pyrazine and pyridazine.
- bicyclic aromatic heterocyclic ring system containing one to three heteroatoms independently selected from O, S or N examples include quinoline, isoquinoline, benzofuran, benzothiophene, benzothiazole, indole and benzotriazole.
- R , R , R , R , X, Y and Z are as defined above with an acyl derivative of formula (HI)
- Q and A are as defined above and L represents a leaving group
- R , R , R ' A, Q, X, Y and Z are as defined above;
- R , R , R , A, Q, X, Y and Z are as defined above;
- 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.
- preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
- the preparation of compounds of formula (II) may be achieved by reaction of a compound of formula (IV) with a compound of formula (VET)
- the preparation of compounds of formula (II) may be achieved by reaction of a compound of formula (VI) with a compound of formula (IX) using the methodology of process (c) above.
- Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.
- the compounds of formula (I) may exist in alternative tautomeric forms.
- Compounds of formula (I) are provided in another tautomeric form or as a mixture thereof.
- 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.
- 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 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 of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileit
- 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, glaucoma, 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 cotherapy 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 ADDS-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 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 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 day.
- 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.
- enteral including oral, sublingual or rectal
- intranasal 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, racemate or tautomer thereof.
- the compounds of formula (I), and pharmaceutically acceptable derivatives thereof, may also be advantageously used in combination with a COX-2 inhibitor.
- 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.
- Methyl phosphonium bromide (7.1 g, 0.02 mol) was suspended in tetrahydrofuran (75 ml) and 2M butyl lithium (10 ml in hexane, 0.02 mol) added at 0 °C. After 1 h at room temperature the solution was added dropwise over 30 min. to a solution of l-(4-chlorobenzoyl)-4-piperidone (2.38 g, 0.01 mol) in tetrahydrofuran (75 ml). After 16 h, water was added, followed by extraction with ether three times. The extracts were combined, dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as an oil. MS (+EI) m /z 236/238 (M + ).
- N-ri-(3-FuranylcarbonylV4-piperidinyll-4-methyl-2-pyridinamine A mixture of 4-methyl-N-(4-piperidinyl)-2-pyridinamine (0.19 g, 1 mmol) (Intermediate B), 3-furancarboxylic acid (0.12 g, 1.1 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (0.7 g, 1.5 mmol) and Hunig's base (0.52 ml, 3 mmol) was stirred in dichloromethane for 20 h. The solution was diluted with water, separated and the organic layer dried (magnesium sulphate) and evaporated.
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99971807A EP1124821A1 (fr) | 1998-11-05 | 1999-11-03 | Composes |
JP2000581020A JP2002529463A (ja) | 1998-11-05 | 1999-11-03 | 化合物 |
AU14345/00A AU1434500A (en) | 1998-11-05 | 1999-11-03 | Compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9803773A SE9803773D0 (sv) | 1998-11-05 | 1998-11-05 | Compounds |
SE9803773-2 | 1998-11-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000027842A1 true WO2000027842A1 (fr) | 2000-05-18 |
Family
ID=20413181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1999/001988 WO2000027842A1 (fr) | 1998-11-05 | 1999-11-03 | Composes |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1124821A1 (fr) |
JP (1) | JP2002529463A (fr) |
AU (1) | AU1434500A (fr) |
SE (1) | SE9803773D0 (fr) |
WO (1) | WO2000027842A1 (fr) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001002387A1 (fr) * | 1999-07-05 | 2001-01-11 | Fujisawa Pharmaceutical Co., Ltd. | N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique |
US6887871B2 (en) | 2000-02-23 | 2005-05-03 | Astrazeneca Ab | Use of phenylheteroakylamine derivatives |
US6900243B2 (en) | 2000-02-23 | 2005-05-31 | Astrazeneca Ab | Phenylheteroalkylamine derivatives |
US6953797B2 (en) | 2000-02-23 | 2005-10-11 | Astrazeneca Ab | Use of phenylheteroalkylamine derivatives |
EP1627869A4 (fr) * | 2003-05-20 | 2006-10-18 | Ajinomoto Kk | Derive d'amide |
US7223794B2 (en) | 2001-07-31 | 2007-05-29 | Astrazeneca Ab | Arylheteroalkylamine derivatives and their use as inhibitors of nitric oxide synthase |
CN100340548C (zh) * | 2001-05-08 | 2007-10-03 | 阿斯利康(瑞典)有限公司 | 新型芳杂烷基胺衍生物 |
US7776861B2 (en) | 2003-07-24 | 2010-08-17 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
US7897627B2 (en) * | 2007-12-21 | 2011-03-01 | Hoffmann-La Roche Inc. | Heteroaryl derivatives as orexin receptor antagonists |
US7923450B2 (en) | 2008-01-11 | 2011-04-12 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
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WO1996018617A1 (fr) * | 1994-12-12 | 1996-06-20 | Merck & Co., Inc. | Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote |
WO1996018628A1 (fr) * | 1994-12-13 | 1996-06-20 | Pharmacia & Upjohn Company | Composes de piperadinyle et piperazinyle anti-sida a substitution alkyle |
WO1997024124A1 (fr) * | 1995-12-29 | 1997-07-10 | Smithkline Beecham Corporation | Antagonistes du recepteur de la vitronectine |
WO1997037655A1 (fr) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | ANTAGONISTES DU RECEPTEUR αvβ3 |
EP0870765A1 (fr) * | 1995-05-18 | 1998-10-14 | Zeria Pharmaceutical Co., Ltd. | Derives d'aminothiazole, medicament contenant ces derives et produit intermediaire obtenu durant la production des composes |
-
1998
- 1998-11-05 SE SE9803773A patent/SE9803773D0/xx unknown
-
1999
- 1999-11-03 JP JP2000581020A patent/JP2002529463A/ja active Pending
- 1999-11-03 WO PCT/SE1999/001988 patent/WO2000027842A1/fr not_active Application Discontinuation
- 1999-11-03 EP EP99971807A patent/EP1124821A1/fr not_active Withdrawn
- 1999-11-03 AU AU14345/00A patent/AU1434500A/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1996018617A1 (fr) * | 1994-12-12 | 1996-06-20 | Merck & Co., Inc. | Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote |
WO1996018628A1 (fr) * | 1994-12-13 | 1996-06-20 | Pharmacia & Upjohn Company | Composes de piperadinyle et piperazinyle anti-sida a substitution alkyle |
EP0870765A1 (fr) * | 1995-05-18 | 1998-10-14 | Zeria Pharmaceutical Co., Ltd. | Derives d'aminothiazole, medicament contenant ces derives et produit intermediaire obtenu durant la production des composes |
WO1997024124A1 (fr) * | 1995-12-29 | 1997-07-10 | Smithkline Beecham Corporation | Antagonistes du recepteur de la vitronectine |
WO1997037655A1 (fr) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | ANTAGONISTES DU RECEPTEUR αvβ3 |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001002387A1 (fr) * | 1999-07-05 | 2001-01-11 | Fujisawa Pharmaceutical Co., Ltd. | N-imidazolylmethyl-carboxamides utilises comme inhibiteurs de la production d'oxyde nitrique |
US6887871B2 (en) | 2000-02-23 | 2005-05-03 | Astrazeneca Ab | Use of phenylheteroakylamine derivatives |
US6900243B2 (en) | 2000-02-23 | 2005-05-31 | Astrazeneca Ab | Phenylheteroalkylamine derivatives |
US6953797B2 (en) | 2000-02-23 | 2005-10-11 | Astrazeneca Ab | Use of phenylheteroalkylamine derivatives |
CN100340548C (zh) * | 2001-05-08 | 2007-10-03 | 阿斯利康(瑞典)有限公司 | 新型芳杂烷基胺衍生物 |
WO2002090332A3 (fr) * | 2001-05-08 | 2007-11-01 | Astrazeneca Ab | Nouveaux derives d'aryl heteroalkyl amines |
AU2002306039B2 (en) * | 2001-05-08 | 2008-05-29 | Astrazeneca Ab | Novel arylheteroalkylamine derivatives |
US7223794B2 (en) | 2001-07-31 | 2007-05-29 | Astrazeneca Ab | Arylheteroalkylamine derivatives and their use as inhibitors of nitric oxide synthase |
US8168827B2 (en) | 2003-05-20 | 2012-05-01 | Ajinomoto Co., Inc. | Amide derivative |
EP1627869A4 (fr) * | 2003-05-20 | 2006-10-18 | Ajinomoto Kk | Derive d'amide |
US7572815B2 (en) | 2003-05-20 | 2009-08-11 | Ajinomoto Co., Inc. | Amide derivative |
US7776861B2 (en) | 2003-07-24 | 2010-08-17 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
US8178560B2 (en) | 2003-07-24 | 2012-05-15 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
US8637548B2 (en) | 2003-07-24 | 2014-01-28 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
US9301953B2 (en) | 2003-07-24 | 2016-04-05 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
US7897627B2 (en) * | 2007-12-21 | 2011-03-01 | Hoffmann-La Roche Inc. | Heteroaryl derivatives as orexin receptor antagonists |
US7923450B2 (en) | 2008-01-11 | 2011-04-12 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
Also Published As
Publication number | Publication date |
---|---|
EP1124821A1 (fr) | 2001-08-22 |
SE9803773D0 (sv) | 1998-11-05 |
AU1434500A (en) | 2000-05-29 |
JP2002529463A (ja) | 2002-09-10 |
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