JPWO2014156196A1 - 2型糖尿病治療剤 - Google Patents
2型糖尿病治療剤 Download PDFInfo
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- JPWO2014156196A1 JPWO2014156196A1 JP2015508096A JP2015508096A JPWO2014156196A1 JP WO2014156196 A1 JPWO2014156196 A1 JP WO2014156196A1 JP 2015508096 A JP2015508096 A JP 2015508096A JP 2015508096 A JP2015508096 A JP 2015508096A JP WO2014156196 A1 JPWO2014156196 A1 JP WO2014156196A1
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- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XDJCYKMWJCYQJM-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCO XDJCYKMWJCYQJM-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 150000003549 thiazolines Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
Description
(1)以下の一般式(I)で表される化合物;
R1は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R2は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜10のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜10のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜10のアルキニル基、置換若しくは非置換の炭素数3〜10の脂環式基、置換若しくは非置換の炭素数6〜10のアリール基、置換又は非置換の炭素数1〜10のアルコキシ基、置換又は非置換の炭素数1〜11のアシル基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、置換又は非置換の炭素数1〜10のスルホニル基、並びに置換又は非置換の炭素数1〜10のスルフィド基のいずれか一つから選ばれる基であり、
R3は水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の炭素数6〜10のアリール基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R4は水素、置換若しくは非置換の炭素数6〜10のアリール基、及び置換若しくは非置換の炭素数6〜10のアリールオキシ基のいずれか一つから選ばれる基であるか、R5及び結合した炭素と一緒にカルボニル基となってもよく、
R5は水素又はR4及び結合した炭素と一緒にカルボニル基となってもよく、
R6は水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数6〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であり、
R7は、水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R8は、水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の炭素数1〜4の直鎖又は分枝のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数6〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であるか、R9及び結合した炭素と一緒にカルボニル基となってもよく、
R9は水素、又はR8及び結合した炭素と一緒にカルボニル基となってもよく、
R10は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数5〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であり、
R11は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、及び置換若しくは非置換の炭素数3〜6の脂環式基のいずれか一つから選ばれる基であり、
また、R10とR11は、これらが結合した窒素原子と共に、置換若しくは非置換の含窒素複素環を構成していてもよい。]や、
一般式(II)で表される化合物;
R21は水素、置換若しくは非置換の直鎖又は分枝の炭素数6〜10のアリール基、及び置換若しくは非置換の直鎖又は分枝の炭素数6〜10の重水素化アリール基のいずれか一つから選ばれる基であり、
R22は置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基のいずれか一つから選ばれる基であり、
R23は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基のいずれか一つから選ばれる基であり、
Xはメチレン又は重水素化メチレンである。]、
及び、一般式(III)で表される化合物;
R31は置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基、置換若しくは非置換の5〜6員環の複素環基、置換若しくは非置換の炭素数6〜10の芳香族基、置換若しくは非置換の炭素数2〜10の含窒素芳香族基、スルホン酸基、及びスルホニル基のいずれか一つから選ばれる基であり、
R32は水素、ヒドロキシメチル基、及び炭素上の水素が重水素に置換されたヒドロキシメチル基のいずれか一つから選ばれる基であり、
R33は置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜6の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の炭直鎖又は分枝の素数2〜6の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6の重水素化アルキニル基、及び置換若しくは非置換の炭素数3〜6の脂環式基のいずれか一つから選ばれる基であり、
R34は水素、ヒドロキシメチル基又は炭素上の水素が重水素に置換されたヒドロキシメチル基であり、
R35は水素、水酸基、置換若しくは非置換の5〜6員環の含窒素複素環基、及び置換若しくは非置換の炭素数2〜10の含窒素芳香族基のいずれか一つから選ばれる基であり、
R36は水素、水酸基、及びハロゲンのいずれか一つから選ばれる基であり、Yはメチレン、重水素化メチレン、及びヒドロキシメチレンのいずれか一つから選ばれる。]、
並びに、それらの医薬的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む、2型糖尿病治療剤に関する。
(2)化合物が、以下の式(I−1)〜(I−6)、式(II−1)、式(II−2)、及び式(III−1)で表される化合物、並びにそれらの医薬的に許容される塩であることを特徴とする上記(1)記載の2型糖尿病治療剤。
(4)医薬的に許容される塩が、塩酸、硝酸、メタンスルホン酸、酢酸、レブリン酸、乳酸、フルビプロフェン、ケトプロフェン、フマル酸、マレイン酸のいずれか一つから選ばれる酸との塩である上記(3)記載の2型糖尿病治療剤や、
(5)2型糖尿病が、Cdkal1遺伝子が変異することによりインスリン分泌能が低下した2型糖尿病である上記(1)〜(4)のいずれか記載の2型糖尿病治療剤や、
(6)プロインスリンからインスリンへの変換を活性化することを特徴とする上記(1)〜(5)のいずれか記載の2型糖尿病治療剤に関する。
R42は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R43は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R44は水素、カルボキシル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、及び置換若しくは非置換の炭素数6〜10のアリール基のいずれか一つから選ばれる基であり、
R45は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R46は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の炭素数5〜10のアリール基、並びに置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、及び置換若しくは非置換の炭素数5〜10のアリール基からなるアリールアルキル基のいずれか一つから選ばれる基であり、
また、R45とR46は、これらが結合した窒素原子と共に、置換若しくは非置換の含窒素複素環を構成していてもよい。]や、
(8)一般式(IV)で表される化合物が、以下の式(IV−1)〜(IV−4)であることを特徴とする上記(7)に記載の化合物、
また、前記R4は、R5及び結合した炭素と一緒にカルボニル基となってもよい。
また、前記R8は、R9及び結合した炭素と一緒にカルボニル基となってもよい。
また、前記R10は、R11及び結合した窒素原子と一緒に置換若しくは非置換の含窒素複素環となってもよい。
また、前記R10は、R11及び結合した窒素原子と一緒に置換若しくは非置換の含窒素複素環となってもよい。
また、前記R45は、R46及び結合した窒素原子と一緒に置換若しくは非置換の含窒素複素環となってもよい。
また、前記R46は、R45及び結合した窒素原子と一緒に置換若しくは非置換の含窒素複素環となってもよい。
本願明細書に記載されている化合物は、公知の方法で調製することもでき、又市販品を用いることもできる。化合物(I−1)〜(I−61)、(II−1)、(II−2)、及び(III−1)は、ナミキ商事(東京、日本)から購入した。
以下に、新規化合物である化合物(IV−1)〜(IV−4)の合成例を示す。
化合物(IV−1)の合成
1H NMR(300MHz,CDCl3)δ2.24−2.33(m,5H),2.50−2.61(m,10H),2.82−2.92(m,2H),3.16−3.26(m,2H),7.44−7.62(m,3H),7.94−8.03(m,2H)
MS(TOF Mass):m/z calcd for C19H28N2O(M+1)301.22;found:301.23.
化合物(IV−2)の合成
1H NMR(300MHz,CDCl3)δ1.59−1.63(m,5H),1.76−1.86(m,4H),2.03(t,J=12Hz,2H),2.27(s,3H),2.47−2.62(m,11H),2.80(t,J=12Hz,3H),2.90(t,15Hz,3H),3.19(t,J=13Hz,2H),7.47(t,J=8.0Hz,2H),7.57(t,J=7.2Hz,1H),7.96(d,J=7.3Hz,2H)
MS(TOF Mass):m/z calcd for C24H38N4O(M+1)399.31;found:399.31.
化合物(IV−3)の合成
1H NMR(300MHz,CDCl3)δ2.12−2.15(m,10H),2.81−2.83(m,2H),3.30(s,3H),3.45−3.50(m,2H),7.31−7.48(m,2H)
MS(TOF Mass):m/z calcd for C16H24N2O2(M+1)277.19;found:277.18.
化合物(IV−4)の合成
1H NMR(300MHz,CDCl3)δ2.41−2.55(m,10H),2.82−2.88(m,2H),3.16−3.22(m,2H),4.21(s,1H),6.92−7.01(m,4H),7.31−7.38(m,2H),7.42−7.58(m,4H),7.92−7.98(m,2H)
MS(TOF Mass):m/z calcd for C26H26F2N2O(M+1)421.20;found:421.23.
(1)プラスミドpACYCDuet-1-Pheの作製
作製したプラスミドpACYCDuet-1-Phe(配列番号1)のベクターマップを図1左に示す。NNNには、フェニルアラニンコドンであるTTTを設計した。正常の読み枠に従って翻訳すると、TTTの直後に終止コドンであるTAAが出現し、Firefly luciferaseが翻訳されない。一方、TTTにおいて誤翻訳が生じTをひとつ読み飛ばすと、終止コドンを回避し、Firefly luciferaseが正しく翻訳されるようになる。すなわち、翻訳の正確性が高いほど、Firefly luciferaseの蛍光強度は下がることとなる。
一方、対照として、同プラスミドにRenilla luciferaseもクローニングした。
得られたpACYCDuet-1-Pheは、ABI Prism 310 genetic analysis(Applied Biosystems社製)を用いて塩基配列を確認した。
pACYCDuet-1-Pheを導入した大腸菌を培地100mLを用いて、37℃、一晩培養した。OD550=0.4〜1に達していることを確認した後、培地を1mLずつ分注し、低分子化合物を最終濃度10μMになるように添加した。1時間振とう培養した後、大腸菌を回収し、10mM Tris−HCl(pH7.4)、1mM 塩化マグネシウム、0.1mg/mL lysozyme(和光純薬社製)に懸濁し溶解した。
Firefly luciferase及びRenilla luciferaseの活性は、Dual-Lucifierase Reporter Assay System(Promega社製)を用いて測定した。溶解した大腸菌液5μLに対して、Firefly luciferase用測定液を50μL加え測定した後、Renilla luciferase用測定液を50μL加え測定した。対照として、DMSOのみを添加した大腸菌溶解液を用意した。
下記式を用いて、Firefly luciferaseの発光強度をRenilla luciferaseに対して補正した。これら一連の実験手法を図解したのが図1である。
相対翻訳精度=相対発光強度(DMSOのみ添加時)/相対発光強度(化合物添加時)
(1)ランゲルハンス島の調整
文献(Gotoh M., et al. Transplantion, 1987, 43(5), p725-730)に従い、膵臓β細胞特異的Cdkal1欠損マウス(非特許文献11参照)よりランゲルハンス島を単離した。マウスをエーテル麻酔下で開胸し、總胆管を剥離してコラゲナーゼ溶液(320U/mL、シグマ社製)をゆっくり注入し、膨らんだ膵臓を摘出した。コラゲナーゼを含んだ膵臓を37℃のウォーターバスにて30分間消化した後、ピペットで分散し、Ficoll溶液(Amersham Pharmacia社製)の濃度勾配を用いてランゲルハンス島を単離した。ランゲルハンス島を、95%O2および5%CO2の混合ガスで飽和させたリンガー液(119mM 塩化ナトリウム、4.74mM 塩化カリウム、1.19mM リン酸二水素一ナトリウム、25mM 炭酸水素ナトリウム、10mM HEPES、2.54mM 塩化カルシウム、1.19mM 塩化マグネシウム、0.2% BSA)中、37℃に保ちながら30分インキュベーションした。
一次スクリーニングにて陽性を示した低分子化合物をそれぞれDMSOに溶解し、終濃度10mMとなるように、グルコースを含むリンガー液に添加したリンガー液を準備した。対照として、DMSOのみを添加したリンガー液を準備した。
単離したマウスランゲルハンス島をまず、低濃度(2.8mM)グルコースリンガー液で30分培養した。その後リンガー液を、低分子化合物を含む低濃度グルコースリンガー液と交換した。30分後リンガー液を回収し、続いて、低分子化合物を含む高濃度(16.7mM)グルコースリンガー液を加えた。30分後、リンガー液を回収した。リンガー液中に放出されたインスリン量は、インスリン検出キット(レビス インスリン−マウス(Sタイプ)、シバヤギ社製)を用いて、該キットのプロトコールにしたがって検出した。
膵臓β細胞特異的Cdkal1欠損マウス、及び野生型マウスを一晩絶食させた後、1mg/kgとなるようにエペリゾンを経腹注射した。対照として、膵臓β細胞特異的Cdkal1欠損マウス、及び野生型マウスに生理食塩水を経腹注射した個体をそれぞれ用意した。30分後、全てのマウスに対し、グルコースを1g/kgとなるように経腹注射した。グルコース投与直後から15分置きに5μLずつ採血を行い、Accu-Check AVIVA Nano(Roche社製)を用いてマウス血中の血糖値を測定した。検定は、repeated measure of two-way ANOVAにより行った。
膵臓β細胞特異的Cdkal1欠損マウスに対し、1日1回、14日間に渡り、1mg/kgとなるように、上記スクリーニングにて陽性を示した低分子化合物を経腹注射した。対照として、DMSOを含む生理食塩水を注射したCdkal1欠損マウスを用意した。最後に低分子化合物を投与してから36時間後に、全てのマウスに対し、グルコースを1g/kgとなるように経腹注射した。グルコース投与直後から15分置きに5μLずつ尾静脈から採血を行い、Accu-Check AVIVA Nano(Roche社製)を用いてマウス血中の血糖値を測定した。検定は、repeated measure of two-way ANOVAにより行った。
Claims (8)
- 以下の一般式一般式(I);
[式中、
R1は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R2は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜10のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜10のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜10のアルキニル基、置換若しくは非置換の炭素数3〜10の脂環式基、置換若しくは非置換の炭素数6〜10のアリール基、置換又は非置換の炭素数1〜10のアルコキシ基、置換又は非置換の炭素数1〜11のアシル基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、置換又は非置換の炭素数1〜10のスルホニル基、並びに置換又は非置換の炭素数1〜10のスルフィド基のいずれか一つから選ばれる基であり、
R3は水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の炭素数6〜10のアリール基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R4は水素、置換若しくは非置換の炭素数6〜10のアリール基、及び置換若しくは非置換の炭素数6〜10のアリールオキシ基のいずれか一つから選ばれる基であるか、R5及び結合した炭素と一緒にカルボニル基となってもよく、
R5は水素又はR4及び結合した炭素と一緒にカルボニル基となってもよく、
R6は水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数6〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であり、
R7は、水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R8は、水素、ハロゲン、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の炭素数1〜4の直鎖又は分枝のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数6〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であるか、R9及び結合した炭素と一緒にカルボニル基となってもよく、
R9は水素、又はR8及び結合した炭素と一緒にカルボニル基となってもよく、
R10は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の炭素数3〜6の脂環式基、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニルオキシカルボニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニルオキシカルボニル基、置換若しくは非置換の炭素数5〜10のアリール基、カルボキシル基、及びそのエステル誘導体又はアミド誘導体、並びにシアノ基、アミノ基のいずれか一つから選ばれる基であり、
R11は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、及び置換若しくは非置換の炭素数3〜6の脂環式基のいずれか一つから選ばれる基であり、
また、R10とR11は、これらが結合した窒素原子と共に、置換若しくは非置換の含窒素複素環を構成していてもよい。]、
一般式(II);
[式中、
R21は水素、置換又は非置換の炭素数6〜10のアリール基、及び置換又は非置換の炭素数6〜10の重水素化アリール基のいずれか一つから選ばれる基であり、
R22は置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基のいずれか一つから選ばれる基であり、
R23は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基のいずれか一つから選ばれる基であり、
Xはメチレン又は重水素化メチレンである。]、
及び、一般式(III);
[式中、
R31は置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4の重水素化アルキニル基、置換若しくは非置換の5〜6員環の複素環基、置換若しくは非置換の炭素数6〜10の芳香族基、置換若しくは非置換の炭素数2〜10の含窒素芳香族基、スルホン酸基、及びスルホニル基のいずれか一つから選ばれる基であり、
R32は水素、ヒドロキシメチル基、及び炭素上の水素が重水素に置換されたヒドロキシメチル基のいずれか一つから選ばれる基であり、
R33は置換若しくは非置換の直鎖又は分枝の炭素数1〜6のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜6の重水素化アルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルケニル基、置換若しくは非置換の炭直鎖又は分枝の素数2〜6の重水素化アルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6のアルキニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜6の重水素化アルキニル基、及び置換若しくは非置換の炭素数3〜6の脂環式基のいずれか一つから選ばれる基であり、
R34は水素、ヒドロキシメチル基又は炭素上の水素が重水素に置換されたヒドロキシメチル基であり、
R35は水素、水酸基、置換若しくは非置換の5〜6員環の含窒素複素環基、及び置換若しくは非置換の炭素数2〜10の含窒素芳香族基のいずれか一つから選ばれる基であり、
R36は水素、水酸基、及びハロゲンのいずれか一つから選ばれる基であり、Yはメチレン、重水素化メチレン、及びヒドロキシメチレンのいずれか一つから選ばれる。]
で表される化合物、並びに、それらの医薬的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む、2型糖尿病治療剤。 - 化合物が、以下の式(I−1)〜(I−6)、式(II−1)、式(II−2)及び式(III−1)で表される化合物、並びにそれらの医薬的に許容される塩であることを特徴とする請求項1記載の2型糖尿病治療剤。
- 医薬的に許容される塩が、塩酸、硝酸、硫酸、炭素数1〜10のスルホン酸、置換若しくは非置換の炭素数1〜6のアルキルカルボン酸、及び置換若しくは非置換の炭素数4〜8のジカルボン酸のいずれか一つから選ばれる酸との塩である請求項1又は2記載の2型糖尿病治療剤。
- 医薬的に許容される塩が、塩酸、硝酸、メタンスルホン酸、酢酸、レブリン酸、乳酸、フルビプロフェン、ケトプロフェン、シュウ酸、フマル酸、及びマレイン酸のいずれか一つから選ばれる酸との塩である請求項3記載の2型糖尿病治療剤。
- 2型糖尿病が、Cdkal1遺伝子が変異することによりインスリン分泌能が低下した2型糖尿病である請求項1〜4のいずれか記載の2型糖尿病治療剤。
- プロインスリンからインスリンへの変換を活性化することを特徴とする請求項1〜5のいずれか記載の2型糖尿病治療剤。
- 以下の一般式(IV)で表されることを特徴とする化合物。
[式中、
R41は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R42は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R43は水素、ハロゲン、水酸基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルコキシ基のいずれか一つから選ばれる基であり、
R44は水素、カルボキシル基、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、及び置換若しくは非置換の炭素数6〜10のアリール基のいずれか一つから選ばれる基であり、
R45は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、及び置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基のいずれか一つから選ばれる基であり、
R46は水素、置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルケニル基、置換若しくは非置換の直鎖又は分枝の炭素数2〜4のアルキニル基、置換若しくは非置換の炭素数5〜10のアリール基、並びに置換若しくは非置換の直鎖又は分枝の炭素数1〜4のアルキル基及び置換若しくは非置換の炭素数5〜10のアリール基からなるアリールアルキル基のいずれか一つから選ばれる基であり、
また、R45とR46は、これらが結合した窒素原子と共に、置換若しくは非置換の含窒素複素環を構成していてもよい。] - 一般式(IV)で表される化合物が、以下の式(IV−1)〜(IV−4)であることを特徴とする請求項7に記載の化合物。
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Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3041344A (en) * | 1960-12-01 | 1962-06-26 | Res Lab Dr C Janssen | 1-(aroylalkyl)-4-piperidinecarboxamides |
GB1097572A (en) * | 1965-03-09 | 1968-01-03 | Mauvernay Roland Yves | Novel piperazines for pharmaceutical use |
JPS4836182A (ja) * | 1971-09-13 | 1973-05-28 | ||
JPS5052078A (ja) * | 1973-09-11 | 1975-05-09 | ||
WO1990013539A1 (en) * | 1989-04-28 | 1990-11-15 | Meiji Seika Kaisha, Ltd. | New n-substituted piperazine derivatives and drug for improving functional disorder of brain |
JPH04506057A (ja) * | 1989-02-14 | 1992-10-22 | アンスティテュ ナシオナル ドゥ ラ サントゥ エ ドゥ ラ ルシェルシェ メディカル(イーエヌエスエーエールエム) | 黒色腫の診断および治療薬 |
JPH10502669A (ja) * | 1994-11-17 | 1998-03-10 | マレキュラー ジェリアトリクス コーポレイション | アルツハイマー病の予防治療のための置換アリール−モルホリノー、チオモルホリノーまたはピペラジノ−プロパノン類の利用 |
JPH115771A (ja) * | 1997-06-16 | 1999-01-12 | Kuraray Co Ltd | アミン誘導体の製造方法 |
WO2001079188A1 (en) * | 2000-04-17 | 2001-10-25 | Cipla Limited | Antihistaminic compounds |
JP2007505088A (ja) * | 2003-09-12 | 2007-03-08 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | 糖尿病の治療のためのスルホンアミド誘導体 |
JP2008542210A (ja) * | 2005-05-27 | 2008-11-27 | 中国科学院上海薬物研究所 | 非ステロイド型男性ホルモン受容体作用剤、その調製方法、薬学組成物及び用途 |
WO2009051119A1 (ja) * | 2007-10-16 | 2009-04-23 | Daiichi Sankyo Company, Limited | ピリミジルインドリン化合物 |
JP2010529022A (ja) * | 2007-05-29 | 2010-08-26 | ヴェロサイエンス・エルエルシー | メタボリックシンドローム、2型糖尿病、肥満又は糖尿病前症の治療的処置方法 |
JP2011506438A (ja) * | 2007-12-11 | 2011-03-03 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 11β−ヒドロキシステロイドデヒドロゲナーゼ1型の環状尿素阻害剤 |
WO2011058994A1 (ja) * | 2009-11-11 | 2011-05-19 | 国立大学法人熊本大学 | 2型糖尿病モデル非ヒト動物 |
WO2014068007A1 (en) * | 2012-10-30 | 2014-05-08 | Pharnext | Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3995047A (en) * | 1973-12-14 | 1976-11-30 | Eisai Co., Ltd. | Propiophenone derivatives in the treatment of pathological muscular conditions |
US4931473A (en) * | 1989-02-15 | 1990-06-05 | Richardson-Vicks Inc. | Anesthetic oral compositions |
JP3150268B2 (ja) * | 1994-05-17 | 2001-03-26 | キヤノン株式会社 | 液晶素子及びそれを用いた液晶装置 |
DE102006031813B4 (de) * | 2006-07-07 | 2011-04-28 | Christian-Albrechts-Universität Zu Kiel | Verwendung basischer Acetophenone als Hemmstoffe von NO-Synthasen |
WO2008065682A2 (en) * | 2006-11-30 | 2008-06-05 | Decode Genetics Ehf. | Genetic susceptibility variants of type 2 diabetes mellitus |
CN101768149B (zh) * | 2008-12-30 | 2013-10-30 | 成都地奥制药集团有限公司 | 一类β-氨基酮(醇)衍生物及其用途 |
-
2014
- 2014-03-28 WO PCT/JP2014/001853 patent/WO2014156196A1/ja active Application Filing
- 2014-03-28 CN CN201480018572.0A patent/CN105188692A/zh active Pending
- 2014-03-28 JP JP2015508096A patent/JP6540505B2/ja active Active
- 2014-03-28 US US14/780,052 patent/US20160060235A1/en not_active Abandoned
Patent Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3041344A (en) * | 1960-12-01 | 1962-06-26 | Res Lab Dr C Janssen | 1-(aroylalkyl)-4-piperidinecarboxamides |
GB1097572A (en) * | 1965-03-09 | 1968-01-03 | Mauvernay Roland Yves | Novel piperazines for pharmaceutical use |
JPS4836182A (ja) * | 1971-09-13 | 1973-05-28 | ||
JPS5052078A (ja) * | 1973-09-11 | 1975-05-09 | ||
JPH04506057A (ja) * | 1989-02-14 | 1992-10-22 | アンスティテュ ナシオナル ドゥ ラ サントゥ エ ドゥ ラ ルシェルシェ メディカル(イーエヌエスエーエールエム) | 黒色腫の診断および治療薬 |
WO1990013539A1 (en) * | 1989-04-28 | 1990-11-15 | Meiji Seika Kaisha, Ltd. | New n-substituted piperazine derivatives and drug for improving functional disorder of brain |
JPH10502669A (ja) * | 1994-11-17 | 1998-03-10 | マレキュラー ジェリアトリクス コーポレイション | アルツハイマー病の予防治療のための置換アリール−モルホリノー、チオモルホリノーまたはピペラジノ−プロパノン類の利用 |
JPH115771A (ja) * | 1997-06-16 | 1999-01-12 | Kuraray Co Ltd | アミン誘導体の製造方法 |
WO2001079188A1 (en) * | 2000-04-17 | 2001-10-25 | Cipla Limited | Antihistaminic compounds |
JP2007505088A (ja) * | 2003-09-12 | 2007-03-08 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | 糖尿病の治療のためのスルホンアミド誘導体 |
JP2008542210A (ja) * | 2005-05-27 | 2008-11-27 | 中国科学院上海薬物研究所 | 非ステロイド型男性ホルモン受容体作用剤、その調製方法、薬学組成物及び用途 |
JP2010529022A (ja) * | 2007-05-29 | 2010-08-26 | ヴェロサイエンス・エルエルシー | メタボリックシンドローム、2型糖尿病、肥満又は糖尿病前症の治療的処置方法 |
WO2009051119A1 (ja) * | 2007-10-16 | 2009-04-23 | Daiichi Sankyo Company, Limited | ピリミジルインドリン化合物 |
JP2011506438A (ja) * | 2007-12-11 | 2011-03-03 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 11β−ヒドロキシステロイドデヒドロゲナーゼ1型の環状尿素阻害剤 |
WO2011058994A1 (ja) * | 2009-11-11 | 2011-05-19 | 国立大学法人熊本大学 | 2型糖尿病モデル非ヒト動物 |
WO2014068007A1 (en) * | 2012-10-30 | 2014-05-08 | Pharnext | Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level |
Non-Patent Citations (17)
Title |
---|
ARCHIV DER PHARMAZIE, vol. 309, no. 1, JPN6018030022, 1976, pages 2 - 11, ISSN: 0003995931 * |
ARCHIV DER PHARMAZIE, vol. 321, no. 8, JPN6014024337, 1988, pages 443 - 445, ISSN: 0003995950 * |
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 7, JPN6014053170, 2012, pages 2434 - 2439, ISSN: 0003995951 * |
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 18, JPN6018030031, 2010, pages 4844 - 4854, ISSN: 0003995936 * |
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 51, no. 2, JPN6018030029, 1978, pages 561 - 562, ISSN: 0003995934 * |
CHMEM. PHARM. BULL., vol. 27, no. 10, JPN6018030035, 1979, pages 2450 - 2455, ISSN: 0003995935 * |
DATABESE REGISTRY (STN) [ON LINE], 2009.05.12, REGISTRY NO.1146080-18-3, RETRIEVED ON 2014-12-09, JPN7014003596, ISSN: 0003995954 * |
DATABESE REGISTRY (STN) [ON LINE], 2011.03.09, REGISTRY NO.1267643-16-2, RETRIEVED ON 2014-12-09, JPN7014003595, ISSN: 0003995953 * |
DATABESE REGISTRY (STN) [ON LINE], vol. Registry No.749902-28-1, JPN7018002652, 23 September 2004 (2004-09-23), pages 2018 - 07, ISSN: 0003995938 * |
DATABESE REGISTRY (STN) [ON LINE], vol. Registry No.801986-36-7, JPN7018002651, 22 December 2004 (2004-12-22), pages 2018 - 07, ISSN: 0003995937 * |
INTERNATIONAL JOURNAL OF OBESITY, vol. 21, no. 2, JPN6014024332, 1997, pages 97 - 102, ISSN: 0003995947 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 9, JPN6014024334, 2008, pages 2795 - 2806, ISSN: 0003995948 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 8, no. 6, JPN6014024335, 1965, pages 851 - 855, ISSN: 0003995949 * |
TETRAHEDRON LETTERS, vol. 54, JPN6018030027, 17 March 2013 (2013-03-17), pages 2669 - 2673, ISSN: 0003995933 * |
TETRAHEDRON, vol. 49, no. 35, JPN6018030025, 1993, pages 7691 - 7700, ISSN: 0003995932 * |
YAKUGAKU ZASSHI, vol. 93, no. 4, JPN6014053171, 1973, pages 508 - 518, ISSN: 0003995952 * |
化学通報, vol. 72, no. 1, JPN6018030019, 2009, pages 86 - 89, ISSN: 0003995930 * |
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CN105188692A (zh) | 2015-12-23 |
US20160060235A1 (en) | 2016-03-03 |
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