WO2006068199A1 - 代謝的に安定な3-オキシ-1,2,4-トリアゾール誘導体 - Google Patents
代謝的に安定な3-オキシ-1,2,4-トリアゾール誘導体 Download PDFInfo
- Publication number
- WO2006068199A1 WO2006068199A1 PCT/JP2005/023526 JP2005023526W WO2006068199A1 WO 2006068199 A1 WO2006068199 A1 WO 2006068199A1 JP 2005023526 W JP2005023526 W JP 2005023526W WO 2006068199 A1 WO2006068199 A1 WO 2006068199A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- atom
- sulfur
- atoms
- oxygen atom
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to the use of substituted 3-oxy-1,2,4-triazole derivatives in the medical field and 11- ⁇ -hydroxysteroid dehydrogenase 'type 1 enzyme (hereinafter referred to as 11 ⁇ -HSD1).
- 11 ⁇ -HSD1 11- ⁇ -hydroxysteroid dehydrogenase 'type 1 enzyme
- Obesity is an important factor in Syndrome X and most type 2 diabetes, and it appears that the network plays a central role.
- Abdominal obesity is closely related to glucose hypersensitivity, hyperinsulinism, hyperglyceridemia, and other so-called syndrome X factors such as increased blood pressure, decreased HDL levels, and increased VLDL levels (Montague & O'Rahill y, Diabetes 49: 883-888, 2000).
- preadipocytes stromal cells
- 11 ⁇ -HSD1 inhibition may have a positive effect on recognition and dementia, possibility of using immunoregulatory function, possibility of intraocular pressure adjustment, application to osteoporosis (Patent Document 1). It is also suggested that 11 ⁇ -HSD1 inhibitory drugs can be applied to dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscle atrophy, and neurodegenerative diseases (patents) Reference 2).
- Patent Document 2 describes the chemical formula or structural formula of many 3-thio-1,2,4 triazole derivatives, and on the basis of this, 11 ⁇ -for a very wide range of 1,2,4-triazole derivatives. Attempts have been made to disclose utility as HSD1 inhibitors. However, specific chemical formulas and structural formulas have not been disclosed at all for specific compounds, especially 3 oxy 1,2,4-triazole derivatives!
- Non-Patent Literature l Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692
- Non-Patent Document 2 Kotelevtsev, Y. et al. (1997) Proc. Natl. Acad. Sci. USA 94: 14924-1492
- Non-Patent Document 3 Montague & O'Rahilly, Diabetes 49: 883-888, 2000
- Non-Patent Document 4 Bujalska, I.J., S. Kumar, and P.M.Stewart (1997) Lancet 349: 1210-
- Non-patent literature 5 Halleux, C.M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105
- Non-patent literature 6 Walker, B.R. et al. (1998) Hypertension 31: 891-895
- Non-Patent Document 7 Fraser, et al. (1999) Hypertension 33: 1364-1368
- Non-Patent Document 8 Woods, S.C. et al. (1998) Science, 280: 1378-1383
- Non-Patent Document 9 Davani, B. et al. (2000) J. Biol. Chem. November 10, 2000; 275 (45): 348
- Non-Patent Document 10 Billaudel, B. and B.C.J.Sutter (1979) Horm. Metab. Res. 11: 555-5 60
- a pharmaceutical composition comprising the derivative or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
- the present inventors have intensively studied paying attention to the 3-oxy 1,2,4-triazole derivative represented by the formula (I), and the 3-oxy compound group has an excellent 11 ⁇ -HSD1 inhibitory action.
- the present inventors have found that the metabolic stability is significantly superior to that of 3thio-1,2,4-triazole derivatives.
- the compound group in which the oxygen atom in formula (I) is converted to a sulfur atom is metabolized very quickly and extensively in human serum or in human liver microsomes, making it a practical drug for humans. While there is great concern about whether it is possible, the compound of the present invention has a remarkable stability in human serum, and is expected to have high potential as a medicine.
- the present invention is a pharmaceutical composition shown in the following embodiment, or a novel compound or a pharmaceutical use thereof.
- R 1 e a linear or branched aliphatic hydrocarbon group represented by R 4 R 5 N- (CO) C n 1-6
- R 4 and R 5 are independently a hydrogen atom, a straight or branched aliphatic carbon represented by C
- a hydride group or a force R 4 R 5 N-that is Q 1 may further contain 1 to 4 heteroatoms optionally selected from nitrogen atom, oxygen atom, sulfur atom, saturated or partially unsaturated Represents a 3- to 10-membered heterocyclic group,
- CO is a carbonyl group
- m and n are each independently an integer 0 or 1
- Q 1 is
- Q 1 may be further substituted with 1 to 4 groups arbitrarily selected from the substituent group A.
- R may be substituted with a hydroxyl group or a C alkoxy group.
- R 2 b C linear or branched aliphatic hydrocarbon group substituted by Q 2
- Q 2 may be further substituted with 1 to 4 groups arbitrarily selected from Substituent Group B R 3 is
- R 3 a C Linear or branched aliphatic hydrocarbon group
- R 3 c C 3 linear or branched aliphatic hydrocarbon group substituted by Q 3 — Y—
- Q 3 may be further substituted with 1 to 4 substituent groups C with any group selected.
- Y is a force that is a single bond, an oxygen atom, NR 6 , CONR 6 , NR 6 CO, NR 6 SO or SO N zz
- z is an integer 1 or 2
- R 6 is hydrogen atom, C alkyl group, C aryl group, nitrogen atom, oxygen atom, sulfur source
- heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from children, C aryl C alkyl group, nitrogen atom, oxygen atom, sulfur atom
- Substituent groups A, B, C are independently
- Halogen atom hydroxyl group, C alkoxy group, C aryloxy group, amino group, C
- a di-substituted 5 or 10-membered heteroarylamino group containing 1 to 4 heteroatoms arbitrarily selected from an aminosulfifer group, nitrogen atom, oxygen atom and sulfur atom Sulfonyl group, nitrogen atom, oxygen atom, sulfur atom containing 1 to 4 hetero atoms arbitrarily selected from 5 to 10-membered heteroarylaminosulfier group, nitrogen atom 'oxygen atom' arbitrarily selected from sulfur atoms 1 to 4 heteroatoms containing 5 to 5: L0 membered heteroloxy group, 1 to 4 heteroatoms optionally containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom
- L0 1 to 3 1 to 6 (which also has an alkyl group), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient,
- a pharmaceutical composition for administration to a patient in need is provided.
- Non-patent document 10 Known diseases [patent document 1] to [non-patent document 10] Specifically, diabetes, glaucoma, cognitive impairment, immune disorder, depression, dyslipidemia, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, neurodegeneration Disease, Cushing's syndrome, Addison's disease, tuberculosis, psoriasis, diabetic complications [eg retinopathy, nephropathy, neuropathy, osteopenia, cataract, macrovascular disorder, diabetic hyperosmotic coma, infection (eg Osteoporosis, urinary tract infection, respiratory infection, digestive tract infection, lower limb infection, skin soft tissue infection), hearing loss, xerostomia, diabetic gangrene, cerebrovascular disorder, peripheral blood circulation disorder], obesity , Cachexia (e.g., cancer cachexia, diabetic cachexia, tuberculosis cachexia, endocrine cachexia, hematological cachexia, infectious cachexia or acquired immunodefic
- R 1 of the compound of formula (I) is
- R 4 R 5 N is optionally selected from nitrogen, oxygen, and sulfur atoms Including 14 tero atoms, which may be a saturated or partially unsaturated 3- to LO-membered heterocyclic group, CO is a carbo group, and mn each independently represents an integer 0 or A composition representing 1.
- R may be substituted with a hydroxyl group or a C alkoxy group.
- R 3 c C linear or branched aliphatic hydrocarbon group substituted with Q 3 Y— or C
- compositions that are 10 alicyclic hydrocarbon groups
- R 1 of the compound of formula (I) is
- R 1 e) R 4 R 5 N- (CO) — C is a linear or branched aliphatic hydrocarbon group, R 4 R 5 is independently a hydrogen atom, C
- R 4 R 5 N further includes 14 terror atoms optionally selected from nitrogen atom, oxygen atom, sulfur atom, So, saturated or partially unsaturated 3 to: L represents a 0-membered heterocyclic group, CO is a carbo group, and mn independently represents an integer 0 or 1.
- R may be substituted with a hydroxyl group or a C alkoxy group.
- R 2 b C linear or branched aliphatic hydrocarbon group substituted by Q 2
- compositions that are 3-10 alicyclic hydrocarbon groups
- R 1 of the compound of formula (I) is
- R 1 e) R 4 R 5 N- (CO) C is a linear or branched aliphatic hydrocarbon group
- R 4 and R 5 are independently a hydrogen atom, a C linear or branched aliphatic hydrocarbon group or
- LO member represents a heterocyclic group, CO is a carbo group, and m and n each independently represent an integer 0 or 1.
- R 2 is also selected as R 2 a) or R) force
- R 2 a) is substituted with a hydroxyl group or the same alkoxy group, and may be a C straight chain or
- R 2 b is a C linear or branched aliphatic hydrocarbon group substituted by Q 2
- Q 2 is Q 2 2 and R 3 is selected from R 3 b) or R 3 c)
- R 3 b is Q 3 or
- R 3 c) is a C linear or branched aliphatic hydrocarbon group substituted by Q 3 — Y— or
- Q 3 3) A cyclic group consisting of a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur nuclear power,
- R 2 a) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-hydroxyethyl group, 3 hydroxypropyl group, 2-methoxyethyl group, 3-methoxypropyl group or cyclopropyl group,
- Q 3 in R 3 b) or R 3 c) is a phenol group, adamantyl group, noradamantyl group, cyclohexyl group or bicyclooctyl group,
- Y is a force that is a single bond, an oxygen atom, NR 6 , CONR 6 , NR 6 CO, NR 6 SO or SO N zz
- z is an integer 1 or 2
- R 6 is hydrogen atom, C alkyl group, C aryl group, nitrogen atom, oxygen atom, sulfur source
- heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from children, C aryl C alkyl group, nitrogen atom, oxygen atom, sulfur atom
- Substituent groups A, B and C are independently
- Alkyl group strength Mono- or di-substituted with a selected group may be used.
- Substituent group C includes C 3 alicyclic hydrocarbon when Q 3 is a bicyclooctyl group.
- a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms optionally selected from
- Hetero atoms selected from elemental atoms, oxygen atoms, sulfur atoms 1 to 4 containing 5 10-membered heteroarylsulfo-lamino groups, hydroxyl groups 'halogen atoms' C alkoxy groups
- the "C linear or branched aliphatic hydrocarbon group” is a saturated hydrocarbon having 16 carbon atoms.
- C Alkynyl group etc. are mentioned.
- Examples of the “c alkyl group” include a methyl group
- Tyl propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, isopentyl, neopentyl, tert pentyl, 1 methylbutyl, 2-methylbutyl, 1, 2— Dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl group, 1,3 dimethylbutyl group, 2,3 dimethylbutyl group, 3,3 dimethylbutyl group, 1 butylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethyl Examples include a propyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group.
- Examples of the "C alkenyl group” include a vinyl group, an aryl group, a propenyl group, and an isopropyl group. -L group, 2-methylaryl group, butenyl group, pentenyl group, hexyl group and the like.
- C alkyl group examples include an ethur group, a 1 propyl group, and a 2-propyl group.
- C aryl group represents a monocyclic or condensed aromatic ring group, such as a phenyl group,
- Examples include ⁇ and ⁇ naphthyl groups.
- C alicyclic hydrocarbon group includes saturated or partially unsaturated carbon atoms of 3 to 10 carbon atoms.
- a saturated monocyclic, condensed cyclic or bridged cyclic alicyclic hydrocarbon group such as a cycloalkyl group.
- a cyclopropyl group such as a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a bicyclooctyl group, a noradamantyl group, and an adamantyl group.
- Examples of the “5- to 10-membered heteroaryl group containing 1 to 4 hetero atoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom” include a pyrrolyl group, a furyl group, a enyl group, and oxazolyl Group, imidazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, birazinyl group, thiadiazyl group, quinolyl group and the like.
- a 3 to 10-membered alicyclic hydrocarbon group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom (saturated or partially unsaturated) Is a monocyclic or condensed, saturated or partially unsaturated 3- to 10-membered heterocyclic group, preferably having 1 or 2 heteroatoms, such as an azetidinyl group, oxalyl Group, oxetanyl group, pyrrolidyl group, tetrahydrofuryl group, thiolanyl group, virazolyl group, virazolidyl group, piperidyl group, tetrahydrobiranyl group, morpholinyl group, piperazine group, tetrahydroquinolyl group, A decahydroquinolyl group etc. are mentioned.
- Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
- C alkoxy group examples include methoxy group, ethoxy group, propoxy group, isopropyl group.
- the “C aryloxy group” includes a monocyclic or condensed aromatic oxy group
- Examples thereof include a phenoxy group, an ⁇ or ⁇ naphthyloxy group, and the like.
- C alkylsulfol group examples include a methanesulfol group, an ethanesulfol group, and the like.
- Examples of the "5- or 6-membered heteroaryloxy group containing 1 or 2 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom” include a pyrrolyloxy group, a furyloxy group, a cheniloxy group, Oxazolyloxy group, imidazolyloxy group, isoxazolyloxy group, thiazolyloxy group, isothiazolyloxy group, virazolyloxy group, tetrazolyloxy group, pyridyloxy group, pyridazinyloxy group, pyrimidyl-loxy group, pyrazoloxy group And thiadiazinyloxy group.
- C alkyl carbonyl group examples include a acetyl group, a propiol group, a butyryl group, and the like.
- Group derived from an aliphatic saturated carboxylic acid having 2 to 6 carbon atoms such as thiol group, valeryl group, isovaleryl group, bivaloyl group, force propyl group, etc.
- groups derived from aliphatic unsaturated carboxylic acids having 3 to 6 carbon atoms such as thiol group, valeryl group, isovaleryl group, bivaloyl group, force propyl group, etc.
- groups derived from aliphatic unsaturated carboxylic acids having 3 to 6 carbon atoms such as thiol group, valeryl group, isovaleryl group, bivaloyl group, force propyl group, etc.
- C alkoxy carbonyl group examples include a methoxy carbo yl group, an ethoxy carbo ol group, and the like.
- Examples thereof include a ball group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbon group, a sec butoxycarbon group, a tert-butoxycarbonyl group, and a pentoxycarbonyl group.
- R 4 R 5 N may further contain 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Saturated or partially unsaturated 3 to: LO Examples of the “membered heterocyclic group” include 1-piperidinyl group, 1-piperazyl group, 1 morpholinyl group and the like.
- C aryl C alkyl group examples include benzyl group, phenethyl group, ⁇ Or j8-naphthylmethyl group.
- amino group examples include a dimethylamino group, an N-ferro-N-methylamino group, and the like.
- Examples of “converted! /, May! /, Aminocarbonyl group” include, for example, a dimethylaminocarbo ol group, an N-phenyl N-methylaminocarbo ol group and the like.
- Examples of the “5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom” include 2 pyridylmethyl group, 2
- Examples of the “5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom” include 2 pyridylmethyl groups, 2
- Examples thereof include a methylaminosulfol group and ⁇ , ⁇ dimethylaminosulfol group.
- Examples thereof include a phenol aminosulfol group and a naphthylaminosulfol group.
- C-aryl group which may be mono- or di-substituted by a aryl group
- Examples thereof include a phenol aminosulfier group and an ⁇ -naphthylaminosulfur group.
- Examples of the “5- to 10-membered heteroarylaminosulfonyl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom” include 2 pyridylaminosulfonyl group, 2— And furylaminosulfo group.
- Examples of the “5- to 10-membered heteroarylaminocarbonyl group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom” include, for example, a 2-pyridylamino force group , 2-furylaminocarbo group and the like.
- C aryl C alkoxy group examples include a phenylmethyloxy group, a phenyl group, and the like.
- Examples include a rubutyloxy group.
- Examples of the “c alkylcarbonyl group” include acetyl group and valeryl group.
- Examples of the “c arylcarbonyl group” include a benzoyl group.
- C aryl C alkylcarbonyl group examples include 2-oxo-2-phenol.
- Examples thereof include a ruetyl group such as a 3-oxo-3-phenylpropyl group.
- C arylaminocarbol group examples include N-phenylaminocarbol.
- N—methyl N—C arylaminocarboxyl group examples include N—
- C alkyl carbolumino group examples include a methyl carbolumino group and a buty
- C alkoxy carbonyl group examples include a methoxy carbo yl group and a butoxy carbo yl group.
- c aryloxy group examples include, for example, a phenyl group
- C alkylsulfo-lamino group examples include methanesulfo-lamino group and butane.
- Examples include a sulfonylamino group.
- C arylsulfo-lumino group examples include a phenol sulfo-lumino group, ⁇
- Examples of the “5- to 10-membered heteroarylsulfo-lumino group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom” include, for example, a 2-pyridylsulfo-lamino group, 2- And furylsulfo-ramino group.
- ⁇ 6 L0 1 3 1 6 alkyl group '' for example, a methyl group, a hydroxyethyl group, a 1 halogenoethyl group, a methoxychetyl group, a acetylmethyl group, an N-methylaminomethyl group, a carboxymethyl group, a methoxycarboromethyl group, Examples thereof include a benzoylmethyl group, a methanesulfonylmethyl group, a trifluoromethanesulfonylmethyl group, a methanesulfurmethyl group, a phenylsulfomethyl group, and a methylthioethyl group.
- R 1 is preferably
- R 1 e R 4 R 5 N- (CO) — C linear or branched aliphatic hydrocarbon group, R 4 R 5 n 1 2
- R 4 R 5 N may further contain 14 hetero atoms optionally selected from nitrogen atom, oxygen atom, sulfur nuclear energy Good 3 ⁇ : L0-membered alicyclic hydrocarbon group, CO is a force sulfonyl group, mn each independently represents an integer 0 or 1
- R 2 is preferably R 2 a) and is substituted with a hydroxyl group or a C alkoxy group
- R 3 is preferably R 3 b), R 3 c), and is a C straight chain substituted by Q 3 , Q 3 — Y— or
- R 1 is 4-halogenophenyl group, 4-halogenobenzyl group, 4-halologenethyl group, 2- (1-piperidyl) ethyl group, 2 cyclohexylethyl group, 2- (4 morpholinyl) ethyl) 2- (4-methyl-1-piperadyl) ethyl, 2-oxo-2— (4-logenophenyl) ethyl, 2-oxo-2- (2-pyridyl) ethyl, 2-oxo 2- (2 Furyl) ethyl group, N— (4 logenophenol) —N-methylaminocarboromethyl group, N— (2-pyridyl) N-methylaminocarboromethyl group, N— (2—cell) — N-methylaminocarboromethyl group, 2-oxo-2- (1-piperidyl) ethyl group, 2-oxo 2- (4 morpholyl) ethyl group, 2-oxoxo
- R 2 represents a methyl group, an ethyl group, a cyclopropyl group, a 3-hydroxypropyl group, and a 3- Methoxypropyl group is a group of choice
- R 3 is 1-adamantyl group, 3 noradamantyl group, bicyclo [2, 2, 2] octane 1-yl group, cyclohexyl group, 4 logenobenzyl group, N— (4 logenophenol) aminomethyl group, 3-halogenoadamantane 1-yl group, 3 hydroxyadamantane 1-yl group, 3 aminoadamantane 1-yl group, 4-halogenobicyclo [2, 2, 2] otatan 1-yl group, 4-methoxycarbobibicyclo [2 , 2, 2] octane 1-yl group, 4 pentylbicyclo [2, 2, 2] octane 1-yl group, 4 (propoxy) methylbicyclo [2, 2, 2] octane-1-yl group, 4 [2- (ethanesulfo- L) ethyl] bicyclo [2,2,2] octane-1-yl group, 4-methylcyclohexyl
- a pharmaceutical composition comprising the compound of embodiment 10, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
- a pharmaceutical composition for administration to a patient in need is provided.
- Aspect 1 characterized by containing as an active ingredient a compound defined by any one of formulas (I) of claim 10, a pharmaceutically acceptable salt thereof or a solvate thereof, and has diabetes, obesity, glaucoma, osteoporosis Cognitive impairment, immune disorder, depression, dyslipidemia, hypertension, heart
- a compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, the following treatment for diseases Or a pharmaceutical composition intended to prevent or reduce side effects caused by treatment with a darcocorticoid receptor agonist by being used in combination with a darcocorticoid receptor agonist, and the disease is Cushing's disease Symptoms ⁇ Allergic immune diseases ⁇ Respiratory system diseases; Infectious visceral diseases; Immune, connective tissue and joint diseases; Endocrine diseases; Hematological diseases; Vomiting due to cancer and chemotherapy; Muscle and neuromuscular cell diseases; Surgery and transplantation Preoperative or postoperative treatment; brain tumor, vomiting, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, medullary disease or saccular aneurysm The. Examples of such side effects include osteoporosis, aseptic osteonecrosis, Cushing-like facial appearance, psychiatric symptoms, insulin
- a compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and the prevention of the following diseases Or a pharmaceutical composition intended to be used in combination with a darcocorticoid agonist for the purpose of treatment, wherein the disease is Cushing's disease, Cushing's syndrome, asthma, athletic dermatitis, cystic fibrosis, emphysema, Bronchitis, hypersensitivity, pneumonia, eosinophilic pneumonia, pulmonary fibrosis, Crohn's disease, ulcerative colitis, reactive arthritis, rheumatoid arthritis, schilaren syndrome, systemic lupus erythematosus, lupus nephritis, Hahn-Hossien line Purpura, gener granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyo
- Embodiments 1-10 The carriers, excipients, and diluents that are acceptable for use in the pharmaceutical product are collectively administered as the first administration, and the darcocorticoid receptor agonist, the carrier that is acceptable for use in the pharmaceutical product, A kit contained in the same container, in which the form and diluent are combined into a second dose.
- a compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and the prevention of the following diseases
- ACE angiotensin converting enzyme
- aspects of the pharmaceutical composition according to aspects 1 to 20 of the present invention are, in other words,
- a method for preventing or treating the target disease or symptom or a combination therapy characterized by using a compound of formula (I) as defined in each embodiment, or the darco It is a method for reducing or preventing side effects in corticoid agonist therapy.
- the compound (I) of the present invention may form an acid addition salt.
- a salt with a base may be formed.
- the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, a base such as an alkali metal such as sodium, potassium, magnesium, calcium, or aluminum or an alkaline earth metal.
- mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,
- Organic carboxylic acids such as formic acid, malic acid, tartaric acid, citrate, and mandelic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, Acid addition salts with acidic amino acids such as aspartic acid and glutamic acid; salts with organic bases such as methylamine, ethylamine, triethylamine, ethanolamine, pyridine, lysine, arginine, ornithine, ammonia And salt.
- the salt of the compound of the present invention may include a mono salt, a di salt, or a tri salt.
- the compound of the present invention can simultaneously form both an acid addition salt and a base salt, depending on the side chain substituent.
- the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers and optical isomers, and isolated isomers. Isolation and purification of powerful isomers can be achieved by those skilled in the art using conventional techniques through resolution or asymmetric synthesis using column chromatography once the preferential crystals are obtained.
- the present invention includes various pharmaceutically acceptable solvates and crystal polymorphs of Compound (I).
- the present invention is not limited to the compounds described in the examples below, but 3-oxy-1,2,4-triazole compounds represented by the formula (I) or pharmaceutically acceptable salts thereof. Is included. It also includes pharmacologically acceptable solvates. Although it does not specifically limit as a solvate, Specifically, a hydrate, alcohol solvate (For example, methanol solvate, ethanol solvate, propanolate solvate, etc.), ether solvate (ethyl ether solvate, THF solvate, etc.) ), Esterates (such as ethyl acetate), and acetates.
- the compound represented by the general formula (I), a salt thereof or a solvate thereof can be produced, for example, by the following method (Reaction Formula 1).
- the compound represented by the formula (I) is a compound represented by the formula (III) that is commercially available or known in the literature, or that can be easily obtained by the production method described later. It can be produced by reacting with the compound represented by the formula (IV) after conversion to the compound represented.
- Compound Power Represented by Formula (I) Conversion to the compound represented by Formula (III) can be carried out by the following methods depending on the types of A and X, respectively.
- the compound represented by the formula ( ⁇ ) is reacted with a halogenating agent typified by salt ⁇ thionyl, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent that does not participate in the reaction.
- the compound represented by the formula (III) can be produced by reacting for a time during which the reaction sufficiently proceeds within the temperature range at which the compound is refluxed.
- Preferred reaction solvents are aromatic hydrocarbon solvents such as toluene and benzene, halogenated solvents such as chloroform, methylene chloride, and 1,2-dichloroethane.
- the reaction temperature is from room temperature to the reaction mixture. The return temperature is preferred.
- Halogenating agent typified by chlorine, bromine, sulfuryl chloride, sulfuryl bromide and the like in a solvent that does not participate in the reaction of the compound represented by the formula ( ⁇ ) and a temperature range at which the reaction mixture is refluxed at -20 ° C.
- the compound represented by the formula ( ⁇ ) can be produced by reacting for a time during which the reaction proceeds sufficiently.
- Solvents that do not participate in the reaction include water, polar solvents such as methanol, aromatic hydrocarbon solvents such as toluene and benzene, chloroform, and chloride.
- the reaction temperature at which halogen-based solvents such as tylene and 1,2-dichloroethane are preferred is preferably 0 ° C to 50 ° C.
- the reaction can be carried out in the presence of a nitrate represented by potassium nitrate, and in this case, acetonitryl is preferred as the solvent.
- a solvent that does not participate in the reaction of the compound represented by the formula ( ⁇ ) preferably in a polar solvent such as N, N dimethylformamide, 1,3 dimethyl-2-imidazolidinone, potassium carbonate, cesium carbonate, sodium hydroxide Alkyl halides, sulfuric acid alkyl esters, etc. in the presence of inorganic bases such as potassium hydroxide, sodium hydride, organic bases such as triethinoleamine, pyridine, N, N dianolenorea-phosphorus, lithium diisopropylamide, etc.
- a polar solvent such as N, N dimethylformamide, 1,3 dimethyl-2-imidazolidinone, potassium carbonate, cesium carbonate, sodium hydroxide Alkyl halides, sulfuric acid alkyl esters, etc.
- inorganic bases such as potassium hydroxide, sodium hydride, organic bases such as triethinoleamine, pyridine, N, N dianolenorea-phosphorus, lithium di
- solvent preferably Is peroxygenated in polar solvents such as water and alcohol, halogenated solvents such as chloroform, methylene chloride and 1,2-dichloroethane.
- a compound represented by the formula ( ⁇ ) can be produced by acidification with a peracid compound such as hydrogen, peracetic acid, 3-chloroperbenzoic acid and the like.
- the production of the compound represented by the formula (I) does not involve the compound represented by the formula (III) in the reaction! It can be carried out by reacting with a compound represented by the formula (IV) in a solvent in the presence of a base.
- Solvents not involved in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as water, methanol, N, N dimethylformamide, 1,3 dimethyl-2-imidazolidinone, dimethyl sulfoxide, triethylamine, pyridine
- Use basic solvents such as chloroform, chloroform, methylene chloride, halogen solvents such as 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran and 1,4 dioxane, or a mixture of these.
- the base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride, or triethylamine, pyridine, N, N Dialkylaline, Lithium diisopropyla Come out is possible to use an organic base of the earth or other.
- Solvent and base combinations include N, N dimethylformamide, 1, 3 dimethyl
- a polar solvent such as chill-2-imidazolidinone and an inorganic base typified by sodium hydride are preferred.
- the reaction can be carried out at a temperature of -78 ° C at a temperature at which the solvent is refluxed. However, if the reaction is difficult to proceed, it can also be carried out at a temperature higher than the boiling point in the sealed tube.
- the reaction time is the time for which the reaction proceeds sufficiently.
- This reaction is carried out by converting the compound represented by formula (IV) into the corresponding metal alkoxide and then reacting with the compound represented by formula (III) in the absence of a base according to the above conditions. Can be done.
- R 2 and R 3 have a reactive substituent (for example, a hydroxyl group, an amino group, a carboxyl group, etc.), the protecting group can be removed after carrying out the reaction by appropriately protecting these groups.
- a reactive substituent for example, a hydroxyl group, an amino group, a carboxyl group, etc.
- Such protecting group introduction / removal methods are based on the group to be protected or the type of protecting group as appropriate. For example, (Protective Groups in Organic Synthesis, 3rd edition, 1999, John This can be done by the method described in the review of [Willie and Sons].
- R 2 and R 3 can be converted to other functional groups according to a known method or a similar method.
- the functional group has a lower alkoxy carbo group
- the compound represented by the formula ( ⁇ ) used as a starting material for (Reaction Scheme 1) is a known method in the literature or Accordingly, it can be produced, for example, according to the following (Scheme 2).
- the compound represented by the formula (IX) is obtained by reacting a hydrazine represented by the formula (V) or a hydrate thereof with a carboxylic acid represented by the formula (V III) or an active compound thereof. ) And then reacting with the compound represented by the formula (VI).
- the compound ( ⁇ ) in which A is a sulfur atom can also be produced according to a method known in the literature or according thereto, for example, according to the following (Scheme 3).
- a compound represented by the formula (XI) is reacted with carbon dioxide and then alkylated with methyl iodide to obtain a compound represented by the formula ( ⁇ ), and then represented by the formula (V).
- the compound represented by the formula ( ⁇ ′) can be produced by reacting with hydrazine or its hydrate.
- R 3 may be substituted bicyclo [2.
- the reaction was started by adding a mixed solution of a test drug (specimen, compound of the present invention), cortisone and NADPH to a well in which an 11 ⁇ -HSD1 enzyme solution was previously added.
- a test drug specimen, compound of the present invention
- cortisone and NADPH an 11 ⁇ -HSD1 enzyme solution was previously added.
- the enzyme a homogenate of Cos-1 cells in which human 11 ⁇ -HSD1 was forcibly overexpressed using a vector for mammalian cells was used.
- a well containing no specimen was used as a control group, and a well containing neither specimen nor enzyme was used as an enzyme blank.
- the reaction solution in each well was diluted 30-fold with the reaction stop solution, and the concentration of cortisol in the diluted solution was measured using a kit based on the HTRF method of Cisbio.
- the inhibitory activity (%) was calculated by linearly regressing the cortisol concentration of each well, assuming that the cortisol concentration of the control group was 0% inhibition and the cortisol concentration of the enzyme blank group was 100% inhibition.
- IC value shows a value where the inhibitory activity is around 50%, 2 or 3
- the IC value for 11 ⁇ -HSD1 of the compound of the present invention is usually between l- ⁇ and ⁇ .
- R 1 As a general substituent for R 1 , (1) a simple aralkyl group (2) an aromatic group ( 3) Select an aliphatic hydrocarbon group substituted with a heterocyclic group, and representative examples are 4-halogenobenzyl group, 4-halogenophenethyl group, 4-halogenophenyl group, 2- (piperidine). — 1—yl) ethyl group was selected.
- R 3 (1) Simple aliphatic cyclic hydrocarbon group (2) bulky ⁇ cyclic hydrocarbon group (3) Select an aromatic group, a cycloalkyl Representative substituents each A xyl group, adamantyl group, 4-no, and logenophenyl group were selected.
- the compound of the present invention having the basic skeleton of the formula (I) of aspect 1 is more metabolically stable in human liver microsomes than the compound in which a sulfur atom is inserted instead of an oxygen atom. It will be readily appreciated by those skilled in the art that In particular, those skilled in the art will be able to combine R 1 with R R′d, R 2 with R 2 a, R and R 3 with R3 ⁇ 4 and R 3 c (combinations of compounds 7 to 8). In the compound of the formula (I) described in Embodiment 10, an improvement in stability is easily inferred.
- test compound is administered orally to a mammal at a predetermined time from 1 to 24 hours.
- Tritium-labeled cortisone is administered intravenously, and blood is collected after several minutes.
- Steroids are extracted from the separated serum and measured by HPLC.
- 3 H-cortisone and its metabolite 3 H-cortisol are measured in animals receiving the drug or in control animals receiving the vehicle. The inhibition rate of change is obtained from these values.
- test compound is vehicle (5% hydroxypropyl mono- ⁇ cyclodex Trizin vZv HO) for oral administration, typically 10 mg at the desired concentration
- ICR mice (Charles River) are orally tested in groups of 3 animals at a dose of 0.5 mL per animal.
- Blood is serum separated in a separation tube within 30 minutes at room temperature. At the end of the incubation, the serum is centrifuged for 10 minutes at 3000Xg and 4 ° C.
- an organic solvent is first extracted. 0. Transfer 2 mL of serum to a clean microcentrifuge tube, add 1. OmL of ethyl acetate and infiltrate vigorously for 1 min. Quickly centrifuge to precipitate the aqueous phase and obtain the supernatant of the organic layer. 0. Transfer 85 mL of organic layer to a fresh microcentrifuge tube and dry. Suspend the dried material in 0.250 mL DMSO containing high concentrations of cortisone and cortisol for HPLC use.
- test drugs are orally administered daily for 3 to 28 days in a pathological model, blood is collected, blood glucose, serum lipids, serum insulin, etc. are measured, or after overnight fasting, oral dalcose After loading, glucose tolerance is measured by collecting blood over time and measuring blood glucose, or measuring body weight every day by measuring body weight gain, or autopsy after completion of continuous injection, Experiments such as measuring the lipid content in the liver can be conducted to examine anti-diabetic, anti-hypertensive, anti-hyperlipidemic, anti-obesity, and body fat reduction effects.
- Pathological models include, for example, spontaneously diabetic, obese or hypertensive mice and rats, such as spontaneously type 2 obese diabetic model mice, such as db / db mice, ob / ob Means mouse or KK-Ay mouse drug-induced diabetes, obese or hypertensive mice and rats, special diet (high fat diet, high sucrose diet, etc.)-Induced diabetes, obese or hypertensive mice and rats.
- spontaneously diabetic, obese or hypertensive mice and rats such as spontaneously type 2 obese diabetic model mice, such as db / db mice, ob / ob Means mouse or KK-Ay mouse drug-induced diabetes, obese or hypertensive mice and rats, special diet (high fat diet, high sucrose diet, etc.)-Induced diabetes, obese or hypertensive mice and rats.
- Such a test can be carried out, for example, with reference to the method described in Endocrinology 144 (11): 4755-4762, 2003,
- compositions for oral administration capsules, pills, tablets, powders, granules and the like are used.
- Such solid compositions are made by combining one or more active substance forces with at least one inert carrier.
- excipients eg lactose, sucrose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, metasilicic acid
- binders eg crystal cell mouths, sugars
- Dextrin hydroxypropyl cell mouthpiece, hydroxypropyl pill methyl cell mouthpiece, polybulurpyrrolidone, macrogol
- lubricant eg magnesium stearate, calcium stearate, talc
- disintegrant eg corn starch
- stabilizers eg sugar alcohols such as lactose
- solubilizers and solubilizers eg cholesterol, triethanolamine, glutamic acid
- coloring agents eg flavoring agents, preservatives, tonicity agents, dispersants, anti-oxidation agents (eg Asukorubin acid, heptyl hydroxy ⁇ - Seo - le), buffering agents, preservatives (
- benzyl alcohol - may include le). If necessary, tablets, pills, granules, etc. may be subjected to enteric film coating for gastric soluble sputum such as sucrose, gelatin, hydroxypropyl methylcellulose mouth sphthalate.
- gastric soluble sputum such as sucrose, gelatin, hydroxypropyl methylcellulose mouth sphthalate.
- Injections for parenteral administration include sterile aqueous or non-aqueous solubilizers, suspensions, and emulsions.
- carriers for aqueous solutions and suspensions include distilled water for injection and physiological saline.
- carriers for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (TM).
- Such a composition may further contain additives such as the above-mentioned isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilizers. These are for example membra It is sterilized by filtration with a water filter, blending of a bactericide or ultraviolet irradiation. They can also be used as injectables which are prepared as sterile solid compositions and dissolved, emulsified or suspended when used. When the solubility of the compound of the present invention is low, solubilization treatment may be performed.
- additives such as the above-mentioned isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilizers. These are for example membra It is sterilized by filtration with a water filter, blending of a bactericide or ultraviolet irradiation. They can also be used as injectable
- the treatment may be a known method applicable to pharmaceutical preparations, for example, a method of adding a surfactant (polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, sucrose fatty acid esters, etc.), or a drug.
- Soluble agents such as polymers (water soluble polymers such as polyethylene glycol (PEG), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid
- a method of forming a solid dispersion with a polymer an enteric polymer such as Eudragit L, S (TM); manufactured by Rohm and Haas).
- the desired dose may conveniently be expressed as a single dose or as divided doses administered at appropriate intervals (eg, 2, 3, 4 or more sub-doses per day).
- This sub-dose itself can be further divided (eg, into a number of discretely spaced administrations; eg, by multiple inhalations from an injector, or by applying multiple drops to the eye).
- the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the patient's symptoms, body weight, age, sex, etc., and is generally 0.001 to 50 mg orally per day for an adult.
- Zkg preferably 0.01 to 25 mgZkg, more preferably 0.05 to 5 mgZkg.
- the above ingredients are weighed and compressed into tablets by conventional methods to make lOOmg tablets.
- the above ingredients are weighed and tableted by a conventional method to give a 200 mg tablet, which is then coated with cellulose acetate phthalate to form an enteric solvent.
- the above ingredients are weighed and compressed into a 300 mg tablet by a conventional method.
- Magnesium stearate 4.5g Weigh each of the above ingredients and mix evenly. Enclose the mixed powder in a No. 1 hard capsule in an amount of 250 mg.
- NMR nuclear magnetic resonance spectrum
- LCZMS Liquid chromatography Z mass spectrometry
- Step 1 Dissolve the compound obtained in Step 1 (3.5 g) in methylene chloride (200 ml), slowly add 3-benzoate perbenzoic acid (containing 35% water; 6.3 g) under ice water cooling, and stir overnight at room temperature. did. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue and filtered to obtain the title compound (2.3 g).
- Example 1 using 3- (adamantane-1-yl) -4-methyl-5 (methylthio) -4 ⁇ -1,2,4-triazole (1.9 g) and 3-chloroperbenzoic acid (containing 35% water; 4.2 g) In the same manner as in Step 2, the title compound (1.7 g) was obtained.
- step 1 The compound obtained in step 1 (0.50 g) and phosphorus pentachloride (0.55 g) were charged with salt and phosphoryl (0.94 ml) and heated at 140 to 150 ° C. for 4 hours.
- the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate.
- the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
- the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
- the residue was purified by column chromatography (elution
- the title compound (0.34 g) was obtained by purification with a medium; ethyl acetate: hexane 1: 1 to ethyl acetate).
- Example 1 using 3- (adamantane-1-yl) -4-ethyl-5-methylthio-4) -1,2,4-triazole (6.7 g) and 3-cloperbenzoic acid (containing 35% water; 14 g) In the same manner as in Step 2, the title compound (4.5 g) was obtained.
- Example 3 Example j
- Example 5 Example 6
- Example 7 Example 3 ⁇ 4 Example 9 Example ⁇
- the following compounds are also synthesized in the same manner as in the above examples.
- the compounds can be synthesized by any combination of the following RR 2 and R 3 forces, and the combinations shown in the table are preferred.
- U1 represented as R 1 represents a 4-fluorophenyl group
- V3 represented as R 2 represents a cyclopropyl group
- W4 represented as R 3 represents a cyclohexyl group. .
- the title compound (0.92 g) was prepared in the same manner as in Step 2 of Example 1, using the compound (0.95 g) obtained in Step 2 and m-cloperbenzoic acid (containing 35% water; 1.5 g). was gotten.
- Example 20 Using the compound obtained in Step 3 (0.10 g), 2, 6 dimethylphenol (1. lg) and potassium carbonate (72 mg), in the same manner as in Step 2 of Example 19, Title compound (68 mg) was obtained.
- Example No. 1-1 means the compound obtained by “Step 1 of Example 1”. Note that in each example, for example, step 1 and step 2, the product of step 1 is an intermediate of step 2 and is not included in the compound of formula (I). .
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-372363 | 2004-12-22 | ||
JP2004372363 | 2004-12-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006068199A1 true WO2006068199A1 (ja) | 2006-06-29 |
Family
ID=36601796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/023526 WO2006068199A1 (ja) | 2004-12-22 | 2005-12-21 | 代謝的に安定な3-オキシ-1,2,4-トリアゾール誘導体 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2006068199A1 (ja) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007128761A2 (de) | 2006-05-04 | 2007-11-15 | Boehringer Ingelheim International Gmbh | Verwendungen von dpp iv inhibitoren |
JP2010518085A (ja) * | 2007-02-08 | 2010-05-27 | シンタ ファーマシューティカルズ コーポレーション | 癌などの増殖障害の治療に有用なトリアゾール化合物 |
WO2010093845A1 (en) * | 2009-02-12 | 2010-08-19 | Exelixis, Inc. | Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity |
KR20110025688A (ko) | 2008-07-03 | 2011-03-10 | 아스텔라스세이야쿠 가부시키가이샤 | 트리아졸 유도체 또는 그의 염 |
WO2012174164A2 (en) * | 2011-06-15 | 2012-12-20 | Metabolex, Inc. | Agonists of gpr131 and uses thereof |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9593109B2 (en) | 2011-08-26 | 2017-03-14 | Cymabay Therapeutics, Inc. | Bicyclic agonists of GPR131 and uses thereof |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US10647661B2 (en) | 2017-07-11 | 2020-05-12 | Vertex Pharmaceuticals Incorporated | Carboxamides as modulators of sodium channels |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5436252A (en) * | 1986-12-19 | 1995-07-25 | Merrell Dow Pharmaceuticals Inc. | 5-aryl-3H-1,2,4-triazol-3-ones and their use in the treatment of neurodegenerative disorders |
WO2002078670A1 (en) * | 2001-03-02 | 2002-10-10 | Neuron Therapeutics, Inc. | Neuroprotectants formulations and methods |
JP2004513166A (ja) * | 2000-11-10 | 2004-04-30 | イーライ・リリー・アンド・カンパニー | ペルオキシソーム増殖因子活性化受容体アルファアゴニスト |
WO2004089367A1 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Pharmaceutical use of substituted 1,2,4-triazoles |
-
2005
- 2005-12-21 WO PCT/JP2005/023526 patent/WO2006068199A1/ja not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5436252A (en) * | 1986-12-19 | 1995-07-25 | Merrell Dow Pharmaceuticals Inc. | 5-aryl-3H-1,2,4-triazol-3-ones and their use in the treatment of neurodegenerative disorders |
JP2004513166A (ja) * | 2000-11-10 | 2004-04-30 | イーライ・リリー・アンド・カンパニー | ペルオキシソーム増殖因子活性化受容体アルファアゴニスト |
WO2002078670A1 (en) * | 2001-03-02 | 2002-10-10 | Neuron Therapeutics, Inc. | Neuroprotectants formulations and methods |
WO2004089367A1 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Pharmaceutical use of substituted 1,2,4-triazoles |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2351568A2 (de) | 2006-05-04 | 2011-08-03 | Boehringer Ingelheim International GmbH | Verwendungen von dpp iv Inhibitoren |
WO2007128761A2 (de) | 2006-05-04 | 2007-11-15 | Boehringer Ingelheim International Gmbh | Verwendungen von dpp iv inhibitoren |
JP2010518085A (ja) * | 2007-02-08 | 2010-05-27 | シンタ ファーマシューティカルズ コーポレーション | 癌などの増殖障害の治療に有用なトリアゾール化合物 |
US8748424B2 (en) | 2007-02-08 | 2014-06-10 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate Hsp90 activity |
US8377923B2 (en) | 2008-07-03 | 2013-02-19 | Astellas Pharma Inc. | Triazole derivative or salt thereof |
KR20110025688A (ko) | 2008-07-03 | 2011-03-10 | 아스텔라스세이야쿠 가부시키가이샤 | 트리아졸 유도체 또는 그의 염 |
CN102395567A (zh) * | 2009-02-12 | 2012-03-28 | 埃克塞利希斯股份有限公司 | 在治疗糖尿病和肥胖症中用作的tgr5激动剂的三唑和咪唑衍生物 |
JP2012517479A (ja) * | 2009-02-12 | 2012-08-02 | エグゼリクシス, インコーポレイテッド | 糖尿病および肥満の処置においてtgr5アゴニストとして使用するためのトリアゾールおよびイミダゾール誘導体 |
WO2010093845A1 (en) * | 2009-02-12 | 2010-08-19 | Exelixis, Inc. | Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity |
US8785488B2 (en) | 2009-02-12 | 2014-07-22 | Exelixis Patent Company Llc | Triazole and imidazole derivatives for use as TGR5 agonists in the treatment of diabetes and obesity |
WO2012174164A2 (en) * | 2011-06-15 | 2012-12-20 | Metabolex, Inc. | Agonists of gpr131 and uses thereof |
WO2012174164A3 (en) * | 2011-06-15 | 2013-04-25 | Metabolex, Inc. | Agonists of gpr131 and uses thereof |
US9593109B2 (en) | 2011-08-26 | 2017-03-14 | Cymabay Therapeutics, Inc. | Bicyclic agonists of GPR131 and uses thereof |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US10568871B2 (en) | 2012-12-20 | 2020-02-25 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
US11666557B2 (en) | 2012-12-20 | 2023-06-06 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US10647661B2 (en) | 2017-07-11 | 2020-05-12 | Vertex Pharmaceuticals Incorporated | Carboxamides as modulators of sodium channels |
US11603351B2 (en) | 2017-07-11 | 2023-03-14 | Vertex Pharmaceuticals Incorporated | Carboxamides as modulators of sodium channels |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2006068199A1 (ja) | 代謝的に安定な3-オキシ-1,2,4-トリアゾール誘導体 | |
JPWO2006080533A1 (ja) | 3−アミノ−1,2,4−トリアゾール誘導体 | |
WO2007007688A1 (ja) | 3,5-ジアミノ-1,2,4-トリアゾール誘導体 | |
TWI415845B (zh) | 用於治療與5-ht2a血清素受體相關聯病症之作為5-ht2a血清素受體之調節劑的吡唑衍生物 | |
EP0501892B1 (fr) | Dérivés hétérocycliques diazotés N-substitués par un groupement biphénylméthyle, leur préparation, les compositions pharmaceutiques en contenant | |
EP0636608A1 (fr) | Dérivés du 1-benzènesulfonyl-1,3-dihydro-indol-2-one, leur préparation, les compositions pharmaceutiques en contenant | |
US20040266755A1 (en) | Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl) homopiperazine | |
EA022134B1 (ru) | 4-амино-4-оксобутаноил-пептиды как ингибиторы репликации вирусов | |
WO2007072782A1 (ja) | カルボン酸誘導体又はその塩 | |
HUE026408T2 (en) | Dabigatran etexylate bis-mesylate salt, solid forms and process for their preparation | |
US11970495B2 (en) | Indolizine derivatives and their application in medicine | |
CN111836795A (zh) | 作为抗炎剂、免疫调节剂和抗增殖剂的新型钙盐多晶型物 | |
JP4814789B2 (ja) | 6−ヒドロキシベンズブロマロン又はその塩からなる医薬組成物 | |
JP2022521081A (ja) | Hbv感染若しくはhbv誘導性疾患の治療において有用なアミド誘導体 | |
EP1567150B1 (fr) | Derives d indole-3-carboxamide, leur preparation et leur application en therapeutique | |
WO2018157801A1 (zh) | 氰基取代的稠合双环衍生物及其制备方法和用途 | |
WO2019096089A1 (zh) | 吲哚嗪衍生物及其在医药上的应用 | |
JP2017514901A (ja) | 6−クロロ置換イミダゾ[1,2−a]ピリジンカルボキサミドおよびその使用 | |
JP7357634B2 (ja) | Urat-1阻害剤の新規塩型 | |
JPH0649034A (ja) | プロペノイル−イミダゾール誘導体 | |
CA3181902A1 (en) | Methods for treating or preventing chronic kidney disease | |
WO2007088895A1 (ja) | 3-アリールアミノ-1,2,4-トリアゾール誘導体 | |
JP2017514898A (ja) | 心血管疾患の治療のためのn−(2−アミノ−5−フルオロ−2−メチルペンチル)−8−[(2,6−ジフルオロベンジル)オキシ]−2−メチルイミダゾ[1,2−a]ピリジン−3−カルボキサミドの、並びにジ−及びトリフルオロ誘導体のエナンチオマー | |
CN114222732B (zh) | 一种尿酸促排剂及其合成方法和其在医药上的应用 | |
RU2809040C2 (ru) | АГОНИСТ РЕЦЕПТОРОВ THRβ И СПОСОБ ЕГО ПОЛУЧЕНИЯ И ПРИМЕНЕНИЕ |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 05820346 Country of ref document: EP Kind code of ref document: A1 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 5820346 Country of ref document: EP |