JP5544299B2 - フルオロアルキル置換ベンズイミダゾールカンナビノイドアゴニスト - Google Patents
フルオロアルキル置換ベンズイミダゾールカンナビノイドアゴニスト Download PDFInfo
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- JP5544299B2 JP5544299B2 JP2010538679A JP2010538679A JP5544299B2 JP 5544299 B2 JP5544299 B2 JP 5544299B2 JP 2010538679 A JP2010538679 A JP 2010538679A JP 2010538679 A JP2010538679 A JP 2010538679A JP 5544299 B2 JP5544299 B2 JP 5544299B2
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- XWRLQRLQUKZEEU-UHFFFAOYSA-N ethyl(hydroxy)silicon Chemical class CC[Si]O XWRLQRLQUKZEEU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005817 fluorobutyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
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- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BAQAVOSOZGMPRM-UHFFFAOYSA-N sucralose Chemical compound OC1C(O)C(Cl)C(CO)OC1OC1(CCl)C(O)C(O)C(CCl)O1 BAQAVOSOZGMPRM-UHFFFAOYSA-N 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- A61P9/12—Antihypertensives
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Transplantation (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
nは整数0、1又は2であり;
R1はポリハロC3−6アルキルであり;
R2はC1−6アルキルであり;
R3は水素、ハロ、C1−4アルキル、C1−4アルキルオキシ、トリフルオロメチル又はシアノであり;
R4はC1−8アルキル;
C3−8シクロアルキルで置換されたC1−8アルキル;
ポリハロC1−8アルキル;
ハロ、ヒドロキシ、C1−8アルキル、C1−4アルキルオキシ、ポリハロC1−4アルキルオキシ、シアノ、アミノカルボニル、ニトロ、ヘテロシクリル、アリール又はヘテロアリールからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたC1−8アルキル;
ヘテロシクリル;
アリール;又は
ヘテロアリール
であり;
ヘテロシクリルは、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、オキセパニル、テトラヒドロチオフェニル、テトラヒドロチオピラニル、1,3−ジオキサニル、オキサゾリジニル、アゼチジニル、ピロリジニル、ピペリジニル、アゼピニル、ピペラジニル、モルホリニル、テトラヒドロチオピラニル−1−オキシド、テトラヒドロチオピラニル−1,1−ジオキシド、ピロリジノニル、ピペリジノニル、アゼピノニル、ピペラジジノニル、オキサジジリノニル、アゼチジノニル、モルホリノニルから選ばれ、且つ該ヘテロシクリルは場合によりハロ、CN、C1−6アルキル、C1−6ポリハロアルキルあるいはヒドロキシで置換されたC1−6アルキル、C1−4アルキルオキシ、ポリハロC1−4アルキルオキシ、C1−4アルキルオキシC1−6アルキル、ベンジル又はアリールから選ばれる1〜3個の基で置換されていることができ;
アリールは、フェニル;あるいはハロ;ヒドロキシ;C1−4アルキル;ポリハロC1−4アルキル;C1−4アルキルオキシ;ポリハロC1−4アルキルオキシ;シアノ;ニトロ;NR5R6;R7−カルボニル;R7−SO2−;ヒドロキシ、NR5R6、R7−カルボニル又はR7−SO2−で置換されたC1−4アルキルからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたフェニルであり;
ヘテロアリールは、フラニル、チオフェニル、ピロリル、ピラゾリル、イミダゾリル、イソオキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、イソチアゾリル、チアジアゾリル、オキサジアゾリル、ピリジニル、ピリダジニル、ピリミジニル又はピラジニルから選ばれ;
ここでR5及びR6は互いに独立して水素、C1−4アルキル、ポリハロC1−4アルキル、アミノスルホニル又はC1−8アルキルスルホニル;あるいはR7−カルボニルから
選ばれ;
ここでR7はC1−4アルキル、ヒドロキシ、アミノ、モノ−もしくはジ−(C1−4アルキル)アミノ、(ヒドロキシC1−4アルキル)アミノ、(C1−4アルキルオキシC1−4アルキル)アミノ、ジ(C1−4アルキル)アミノC1−4アルキル、ピロリジニル、ピペリジニル、モルホリニル又はN−メチル−ピペラジニルである]
の化合物あるいはその製薬学的に許容され得る酸付加塩又はその溶媒和物に関する。
−ハロはフルオロ、クロロ、ブロモ及びヨードの総称であり;
−C1−4アルキルは、1〜4個の炭素原子を有する直鎖状及び分枝鎖状飽和炭化水素基、例えばメチル、エチル、プロピル、ブチル、1−メチルエチル、2−メチルプロピルなどを定義し;
−C1−6アルキルは、C1−4アルキル及び5もしくは6個の炭素原子を有するその高級同族体、例えば2−メチルブチル、ペンチル、ヘキシルなどを含むものとし;
−C3−6アルキルは、3〜6個の炭素原子を有する直鎖状及び分枝鎖状飽和炭化水素基、例えばプロピル、ブチル、ペンチル、ヘキシル、1−メチルエチル、2−メチルプロピル、2−メチルブチルなどを定義し;
−ポリハロC3−6アルキルは、2〜6個のハロゲン原子で置換されたポリハロ置換C3−6アルキル(上記で定義された)、例えばジフルオロメチル、トリフルオロメチル、トリフルオロエチル、n−トリフルオロブチル又はn−トリフルオロペンチルなどとして定義され;
−C3−6シクロアルキルは、シクロプロピル、シクロブチル、シクロペンチル及びシクロヘキシルの総称であり;
−C3−8シクロアルキルは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル及びシクロオクチルの総称であり;
−C6−8シクロアルキルは、シクロヘキシル、シクロヘプチル及びシクロオクチルの総称である。
ヒドロキシ酢酸、乳酸、ピルビン酸、シュウ酸(すなわちエタン二酸)、マロン酸、コハク酸(すなわちブタン二酸)、マレイン酸、フマル酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、シクラミン酸、サリチル酸、p−アミノサリチル酸、パモ酸などの酸を含む。
a)nが整数0であるか、又はnが整数2であるか;あるいは
b)R1がポリハロC3−6アルキルであるか;あるいは
c)R1がn−トリフルオロブチル又はn−トリフルオロペンチルであるか;あるいは
d)R2がC1−6アルキルである、特にR2がtert−ブチルであるか;あるいは
e)R3が水素であるか;あるいは
f)R4がC3−8シクロアルキルで置換されたC1−8アルキルであるか;あるいは
g)R4がアリールで置換されたC1−8アルキルであり、ここでアリールはフェニルあるいはシアノ、C1−4アルキルオキシ又はR7−カルボニルで置換されたフェニルであり、ここでR7はアミノであるか;あるいは
h)R4がアリールで置換されたCF2であり、ここでアリールはフェニルあるいはシアノ、CONH2又はC1−4アルキルオキシで置換されたフェニルであるか;あるいは
i)R4がアリールであり、ここでアリールはフェニルあるいはシアノ、CONH2又はC1−4アルキルオキシで置換されたフェニルであるか;あるいは
j)R4がヘテロアリールで置換されたC1−8アルキルであり、ここでヘテロアリールはピリジニル又はピラゾリルであるか;
k)R4がヘテロシクリル又はヘテロシクリルで置換されたC1−4アルキルであり、ここでヘテロシクリルはテトラヒドロチオピラニル−1,1−ジオキシド、ピロリジノニル、ピペリジノニル、アゼピノニル、アゼチジノニル、モルホリノニルから選ばれ、且つ該ヘテロシクリルは場合によりハロ、CN、C1−6アルキル、C1−6ポリハロアルキル、ヒドロキシで置換されたC1−6アルキル、C1−4アルキルオキシ、ポリハロC1−4アルキルオキシ又はC1−4アルキルオキシC1−6アルキルから選ばれる1〜3個の基で置換されていることができる。
nが整数0、1又は2であり;
R1がポリハロC3−6アルキルであり;
R2がC1−6アルキルであり;
R3が水素であり;
R4がC3−8シクロアルキルで置換されたC1−8アルキル;
ハロ、C1−8アルキル又はアリールからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたC1−8アルキル;
ヘテロシクリル;
アリール;又は
ヘテロアリール
であり;
ヘテロシクリルがピロリジノニルから選ばれ;
アリールがC1−4アルキルオキシ;シアノ;又はR7−カルボニルから選ばれる1個の置換基で置換されたフェニルであり;
ヘテロアリールがピラゾリル又はピリジニルから選ばれ、
ここでR7はアミノである
立体化学的異性体を含む式(I)の化合物あるいはその製薬学的に許容され得る酸付加塩又はその溶媒和物である。
ホウ酸ナトリウム、過硫酸水素カリウム、mCPBAなどの試薬の添加によりスルホンにさらに酸化することができる。十分な酸化剤が存在すれば、スルホキシドを単離せずに直接、スルフィドをスルホンに転換することができる。
学的に許容され得る塩の治療的に有効な量を投与することを含む。
有する。そのような投薬単位形態物の例は錠剤(刻み付き又はコーティング錠を含む)、カプセル、丸薬、粉剤小包、ウェハース、注入可能な溶液又は懸濁剤、小さじ一杯、大さじ一杯など、ならびに分離されたそれらの複数である。
Cool)、ファンタジー(Fantasy)などが必要であり得る。各風味料は、約0.05%〜1%(重量/容量)の範囲の濃度で、最終的な組成物中に存在することができる。該強い風味料の組み合わせは、有利に用いられる。好ましくは、調剤の環境下で味及び/又は色の変化又は喪失を経ない風味料が用いられる。
量容器中で存在することができる。それらは、油性又は水性ビヒクル中の懸濁剤、溶液又は乳剤のような形態をとることができ、等張化剤、懸濁化剤、安定剤及び/又は分散剤のような調製剤を含有することができる。あるいはまた、活性成分は、使用前に適したビヒクル、例えば発熱物質を含まない無菌水と混合するための粉末形態で存在することができる。
下記に記載する方法において、以下の略語を用いた:「CH2Cl2」はジクロロメタンを示し、「THF」はテトラヒドロフランを示し、「DIPE」はジイソプロピルエーテルを示し、「NaBH3(CN)」はナトリウムシアノトリヒドロボレートを示し、「Cs2CO3」は炭酸セシウムを意味し、「MgSO4」は硫酸マグネシウムを意味し、「NaHCO3」は炭酸一ナトリウム塩を意味し、「NaOH」は水酸化ナトリウムを意味し、「Pd2(dba)3」はトリス[μ−[(1,2−η:4,5−η)−(1E,4E)−1,5−ジフェニル−1,4−ペンタジエン−3−オン]ジパラジウムを意味し、そして「キサントフォス」は(9,9−ジメチル−9H−キサンテン−4,5−ジイル)ビス[ジフェニルホスフィン]を意味し、「DMAP」は4−(ジメチルアミノ)ピリジンを意味し、「CF3COOH」は2,2,2−トリフルオロ酢酸を意味し、「EtOAc」は酢酸エチルを意味し、そして「CHCl3」はトリクロロメタンを意味する。IsoluteTMフィルターは、水及び/又は固体不純物を試料から除去することができる珪藻土の改質された形態を含んでなる短カラムである。
−精製法A
生成物を逆相高−性能液体クロマトグラフィー(Shandon Hyperprep
(R) C18 BDS(Base Deactivated Silica)8μm,250g,内径5cm)により精製した。2つの移動相を用いる勾配を適用した。相A:水中の0.25%NH4HCO3溶液;相B:CH3CN)。
生成物を逆相高−性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(Base Deactivated Silica)8μm,250g,内径5cm)により精製した。3つの移動相を用いる勾配を適用した。相A:水中の0.25%NH4HCO3溶液;相B(場合による):CH3OH;相C:CH3CN)。
実施例A.1
実施例B.1
C.分析部分
C.1 融点
複数の化合物に関し、DSC823e(Mettler−Toledo)を用いて融点(m.p.)を決定した。30℃/分の温度勾配を用いて融点を測定した。報告される値はピーク値である。最高温度は400℃であった。値は、この分析法に通常伴う実験的不確定性と共に得られる。
LCMS一般的方法A
HPLC測定は、脱ガス器を有するクウォーターナリーポンプ、オートサンプラー、カラムオーブン(他に指示しなければ40℃に設定)、ダイオード−アレー検出器(DAD)及び下記のそれぞれの方法において特定されるカラムを含んでなるAlliance HT 2790(Waters)システムを用いて行なわれた。カラムからの流れはMS分光計に分けられた。MS検出器は、エレクトロスプレーイオン化源を用いて形成された。0.1秒の滞留時間を用いて1秒内に100から1000まで走査することにより、質量スペクトルを取得した。毛管針電圧は3kVであり、源温度は140℃に保たれた。ネブライザーガスとして窒素を用いた。Waters−Micromass MassLynx−Openlynxデータシステムを用いてデータ取得を行なった。
LC測定は、バイナリーポンプ、サンプルオルガナイザー、カラムヒーター(55℃に設定)、ダイオードアレー検出器(DAD)及び下記のそれぞれの方法において特定されるカラムを含んでなるAcquity UPLC(Waters)システムを用いて行なわれた。カラムからの流れはMS分光計に分けられた。MS検出器は、エレクトロスプレーイオン化源を用いて形成された。0.02秒の滞留時間を用いて0.18秒内に100から1000まで走査することにより、質量スペクトルを取得した。毛管針電圧は3.5kVであり、源温度は140℃に保たれた。ネブライザーガスとして窒素を用いた。Waters−Micromass MassLynx−Openlynxデータシステムを用いてデータ取得を行なった。
一般的方法Aに加え:逆相HPLCをXterra MS C18カラム(3.5μm,4.6x100mm)上で、1.6ml/分の流量を用いて行なった。3種の移動相(移動相A:95% 25mM酢酸アンモニウム+5%アセトニトリル;移動相B:アセトニトリル;移動相C:メタノール)を用い、6.5分内に100%Aから1%A、49%B及び50%Cにし、1分内に1%A及び99%Bにし、これらの条件を1分間保持し、100%Aを用いて1.5分間再平衡化する勾配条件を実施した。10μlの注入容積を用いた。コーン電圧は、正のイオン化モードの場合に10Vであり、負のイオン化モードの場合に20Vであった。
一般的方法Bに加え:架橋エチルシロキサン/シリカハイブリッド(BEH) C18カラム(1.7μm,2.1x50mm;Waters Acquity)上で、0.8ml/分の流量を用い、逆相UPLC(超性能液体クロマトグラフィー(Ultra Performance Liquid Chromatography))を行なった。
2種の移動相(移動相A:H2O中の0.1%ギ酸/メタノール 95/5;移動相B:メタノール)を用い、1.3分内に95%A及び5%Bから5%A及び95%Bにし、0.2分間保持する勾配条件を実施した。0.5μlの注入容積を用いた。コーン電圧は、正のイオン化モードの場合に10Vであり、負のイオン化モードの場合に20Vであった。
D.1 ヒトCB1及びCB2受容体の活性化に反応するcAMPの阻害
均一時間分解蛍光(HTRF)アッセイを介し、ヒトCB1(hCB1)又はヒトCB2(hCB2)受容体が活性化される時のホルスコリン−活性化cAMP生産を阻害する試験化合物の能力を測定することにより、それらの機能的活性を評価した。
MIX F−12倍地中において80〜90%密集まで生育させた。実験の前に倍地を除去し、細胞をPBS/EDTA(140mM NaCl,1mM Na2−EDTA,8mM Na2HPO4.2H2O,8.5mM KH2PO4,2.7mM KCl,21mM グルコース)で洗浄し、刺激緩衝液(HBSS 1x,IBMX 1mM,Hepes 5mM,MgCl2 10mM,BSA 0.1%,pH7.4)中に再懸濁させた。細胞を、hCB1実験のためにml当たり8.105個の細胞の濃度及びhCB2実験のためにml当たり106個の細胞の濃度まで希釈した。cAMP Dynamic HTRFキット(CIS bio international,France)を用い、製造者の推薦に従ってアッセイを行なった。
CP55490(2%DMSO中)を含有する25μlの刺激緩衝液で満たした。次いで25μlの希釈された細胞を加えた(ウェル当たり20,000個の細胞)。室温における暗所中での30分間のインキュベーションの後、25μlのcAMP−XL665及び25μlの抗−cAMPクリプテート(両方とも1/80の最終的な希釈において)を細胞に加えた。
Claims (9)
- 立体化学的異性体を含む式(I)
nは整数0、1又は2であり;
R1はn−トリフルオロブチル又はn−トリフルオロペンチルであり;
R2はC1-6アルキルであり;
R3は水素であり;
R4 はC 3-8シクロアルキルで置換されたC1-8アルキル;
ハロ、C 1-8アキル及びアリールからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたC1-8アルキル;
ヘテロシクリル;
アリール;又は
ヘテロアリール
であり;
ヘテロシクリルはピロリジニルであり;
アリールはC 1-4アルキルオキシ、シアノ及びR7がアミノであるR7−カルボニルから選ばれる1個の置換基で置換されたフェニルであり;
ヘテロアリールはピラゾリル及びピリジニルから選ばれる]
で表される化合物あるいはその製薬学的に許容され得る酸付加塩。 - R2がtert−ブチルである請求項1に記載の化合物。
- 製薬学的に許容され得る担体及び請求項1〜2のいずれかに記載の化合物の治療的に活性な量を含んでなる製薬学的組成物。
- 請求項1〜2のいずれかに記載の化合物の治療的に活性な量を製薬学的に許容され得る担体と緊密に混合する請求項3に記載の製薬学的組成物の調製方法。
- 薬剤としての使用のための請求項1〜2のいずれかに記載の化合物。
- アテローム性動脈硬化症、高血圧、心筋虚血、慢性痛障害(chronic pain disorders)、痛覚過敏症、神経障害痛(neuropathic pain)、抹消痛、内臓痛、炎症痛、熱性痛覚過敏症、侵害受容痛(nociceptive pain)、線維筋痛、慢性背下部痛、歯痛、炎症、浮腫、膀胱炎、神経炎症性疾患、免疫系障害、自己免疫疾患、多発性硬化症、慢性関節リウマチ、胃腸障害、腸運動障害、過敏性腸症候群(IBS)、炎症性腸疾患(IBD)、クローン病、慢性肝臓障害(肝硬変)、ガン、前立腺ガン、ガン痛、神経膠腫、アレルギー、吐き気、嘔吐、喘息、慢性閉塞性肺疾患、乾癬、てんかん及び骨粗しょう症から選ばれる症状又は疾患の処置に使用するための請求項1〜2のいずかに記載の化合物を有効成分として含んでなる製薬学的製剤。
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WO (1) | WO2009077533A1 (ja) |
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WO2008014199A2 (en) | 2006-07-28 | 2008-01-31 | Boehringer Ingelheim International Gmbh | Sulfonyl compounds which modulate the cb2 receptor |
CN101516839A (zh) | 2006-09-25 | 2009-08-26 | 贝林格尔.英格海姆国际有限公司 | 调节cb2受体的化合物 |
CA2704684A1 (en) | 2007-11-07 | 2009-05-14 | Boehringer Ingelheim International Gmbh | Compounds which modulate the cb2 receptor |
JP5749162B2 (ja) | 2008-07-10 | 2015-07-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Cb2受容体を調節するスルホン化合物 |
EP2342200B1 (en) | 2008-09-25 | 2013-01-23 | Boehringer Ingelheim International GmbH | Compounds which selectively modulate the cb2 receptor |
BRPI1007202A2 (pt) * | 2009-01-22 | 2016-02-23 | Raqualia Pharma Inc | composto de fórmula (i), composição farmacêutica, método para tratamento de condição mediada pela atividade do receptor cb2 em um indivíduo mamífero e uso de composto de fórmula (i) |
US8299103B2 (en) | 2009-06-15 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
EP2443107B1 (en) | 2009-06-16 | 2018-08-08 | Boehringer Ingelheim International GmbH | Azetidine 2 -carboxamide derivatives which modulate the cb2 receptor |
US8541386B2 (en) * | 2009-08-19 | 2013-09-24 | University Of South Florida | Cannabinoid 2 (CB2) receptor gene promoter and unique RNA transcripts in B cells and methods of use |
US8383651B2 (en) | 2009-09-22 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
EP2523936A1 (en) | 2010-01-15 | 2012-11-21 | Boehringer Ingelheim International GmbH | Compounds which modulate the cb2 receptor |
EP2542539B1 (en) | 2010-03-05 | 2014-02-26 | Boehringer Ingelheim International GmbH | Tetrazole compounds which selectively modulate the cb2 receptor |
JP5746764B2 (ja) | 2010-07-22 | 2015-07-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Cb2受容体を調節する化合物 |
EP2803668A1 (en) | 2013-05-17 | 2014-11-19 | Boehringer Ingelheim International Gmbh | Novel (cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
WO2021207466A1 (en) * | 2020-04-09 | 2021-10-14 | Credo Science, Llc | Diagnosing and treating fibromyalgia |
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DE602005011844D1 (de) * | 2004-11-02 | 2009-01-29 | Pfizer | Sulfonylbenzimidazolderivate |
DE602007009807D1 (de) * | 2006-03-06 | 2010-11-25 | Raqualia Pharma Inc | Sulfonylbenzimidazolderivate |
KR20090024789A (ko) * | 2006-07-04 | 2009-03-09 | 얀센 파마슈티카 엔.브이. | 치환 복소환기를 갖는 벤즈이미다졸 카나비노이드 작용제 |
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- 2008-12-16 ES ES08862464.8T patent/ES2574130T3/es active Active
- 2008-12-16 JP JP2010538679A patent/JP5544299B2/ja active Active
- 2008-12-16 US US12/747,931 patent/US20100273831A1/en not_active Abandoned
- 2008-12-16 EP EP08862464.8A patent/EP2234984B1/en active Active
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JP2011506549A (ja) | 2011-03-03 |
ES2574130T3 (es) | 2016-06-15 |
EP2234984A1 (en) | 2010-10-06 |
WO2009077533A1 (en) | 2009-06-25 |
EP2234984B1 (en) | 2016-03-16 |
US20100273831A1 (en) | 2010-10-28 |
CN101896471A (zh) | 2010-11-24 |
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