JP6275649B2 - p75受容体アンタゴニストの新規治療用途 - Google Patents
p75受容体アンタゴニストの新規治療用途 Download PDFInfo
- Publication number
- JP6275649B2 JP6275649B2 JP2014548035A JP2014548035A JP6275649B2 JP 6275649 B2 JP6275649 B2 JP 6275649B2 JP 2014548035 A JP2014548035 A JP 2014548035A JP 2014548035 A JP2014548035 A JP 2014548035A JP 6275649 B2 JP6275649 B2 JP 6275649B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- iii
- alkyl group
- bladder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000002464 receptor antagonist Substances 0.000 title claims description 23
- 229940044551 receptor antagonist Drugs 0.000 title claims description 23
- 102100036220 PC4 and SFRS1-interacting protein Human genes 0.000 title claims 4
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 103
- 150000003839 salts Chemical class 0.000 claims description 23
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 22
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 21
- 208000020629 overactive bladder Diseases 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 15
- 230000002265 prevention Effects 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 11
- -1 4-Chloro-3-trifluoromethylphenyl Chemical group 0.000 claims description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
- CVRCENOFWCSYGS-AQDIUKAZSA-N 6-[(3r,5s)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl]pyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.N1([C@H](C)CN(C[C@@H]1C)C=1N=CC(=CC=1)C(O)=O)CC(=O)N(CC1=C2)CCC1=NN2C1=CC=CC=C1 CVRCENOFWCSYGS-AQDIUKAZSA-N 0.000 claims description 3
- GEHLJBYNRPSRFJ-KDURUIRLSA-N 6-[(3s,5r)-4-[2-[4-(1-benzofuran-7-yl)-3,6-dihydro-2h-pyridin-1-yl]-2-oxoethyl]-3,5-dimethylpiperazin-1-yl]pyridine-3-carboxylic acid Chemical compound C([C@@H](N([C@H](C)C1)CC(=O)N2CC=C(CC2)C=2C=3OC=CC=3C=CC=2)C)N1C1=CC=C(C(O)=O)C=N1 GEHLJBYNRPSRFJ-KDURUIRLSA-N 0.000 claims description 3
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 25
- 210000003932 urinary bladder Anatomy 0.000 description 24
- 241000700159 Rattus Species 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 16
- 125000005843 halogen group Chemical group 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 230000036724 intravesical pressure Effects 0.000 description 13
- 230000027939 micturition Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- 230000008602 contraction Effects 0.000 description 8
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 8
- 208000005615 Interstitial Cystitis Diseases 0.000 description 7
- 108010025020 Nerve Growth Factor Proteins 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 7
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 7
- 229940068968 polysorbate 80 Drugs 0.000 description 7
- 229920000053 polysorbate 80 Polymers 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 238000009530 blood pressure measurement Methods 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 125000003709 fluoroalkyl group Chemical group 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 102000007072 Nerve Growth Factors Human genes 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 230000001747 exhibiting effect Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000003202 urodynamic effect Effects 0.000 description 4
- 0 CCCC=*C(C*(C(C)C1)C(*C)=O)=C1P Chemical compound CCCC=*C(C*(C(C)C1)C(*C)=O)=C1P 0.000 description 3
- 206010011796 Cystitis interstitial Diseases 0.000 description 3
- 102000015336 Nerve Growth Factor Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 206010013990 dysuria Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920001774 Perfluoroether Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 210000004126 nerve fiber Anatomy 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 230000001991 pathophysiological effect Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- WMVPUFWFSOVFML-UHFFFAOYSA-N 1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2h-pyridin-1-yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]ethanone Chemical compound N1=CC(F)=CN=C1N1C2CCC1CN(CC(=O)N1CC=C(CC1)C=1C=C(C(Cl)=CC=1)C(F)(F)F)C2 WMVPUFWFSOVFML-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010005060 Bladder obstruction Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000801254 Homo sapiens Tumor necrosis factor receptor superfamily member 16 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021033 Hypomenorrhoea Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000021891 Micturition disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 102100033725 Tumor necrosis factor receptor superfamily member 16 Human genes 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046392 Ureteric cancer Diseases 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 239000006204 intramuscular dosage form Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000006207 intravenous dosage form Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000036453 micturition reflex Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 206010029446 nocturia Diseases 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000006203 subcutaneous dosage form Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 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
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- 229960004847 urologicals Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- 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
- A61K31/435—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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
- 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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
Description
−1〜3は1、2又は3を表し;
−n(I)は1又は2を表し;
−R1(I)はハロゲン原子、(C1−C4)アルキル基、トリフルオロメチル基、(C1−C4)アルコキシ基又はトリフルオロメトキシ基を表し;
−R2(I)は水素原子、ハロゲン原子、(C1−C4)アルキル基、トリフルオロメチル基、(C1−C4)アルコキシ基、トリフルオロメトキシ基、COOR(I)基又はCONH2基を表し;
−R5(I)は式:
R(I)、R6(I)及びR7(I)は相互に独立して(C1−C6)アルキル基を表す。
−「ハロゲン原子」なる用語はフッ素、塩素、臭素又はヨウ素を意味する;
−「アルキル基」なる用語は直鎖又は分岐鎖飽和脂肪族基を意味する。例えば、C1−C4アルキル基が挙げられ、具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル又はtert−ブチルが挙げられる;
−「フルオロアルキル基」なる用語は水素原子の1個以上がフッ素原子で置換えられたアルキル基を意味する;
−「パーフルオロアルキル基」なる用語は全ての水素原子がフッ素原子で置換えられたアルキル基(例えばトリフルオロアルキル基)を意味する;
−「アルコキシ基」なる用語は−O−アルキル基を意味し、ここでアルキル基は上記に定義した通りである。
−R1(II)及びR2(II)は同一でも異なっていてもよく、独立して水素原子、ハロゲン原子、(C1−C4)アルキル基、(C1−C4)フルオロアルキル基、(C1−C2)パーフルオロアルキル基、(C1−C4)アルコキシ基又はトリフルオロメトキシ基であり;
−n(II)は1又は2であり;
−R3(II)は式:
−R(II)、R6(II)及びR7(II)は相互に独立して(C1−C6)アルキル基である。
−「ハロゲン原子」なる用語はフッ素、塩素、臭素又はヨウ素を意味する;
−「アルキル基」なる用語は直鎖又は分岐鎖飽和脂肪族基を意味する。例えば、C1−C4アルキル基が挙げられ、具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル又はtert−ブチルが挙げられる;
−「フルオロアルキル基」なる用語は1個以上の水素原子がフッ素原子で置換えられたアルキル基を意味する;
−「パーフルオロアルキル基」なる用語は全ての水素原子がフッ素原子で置換えられたアルキル基を意味する;
−「アルコキシ基」なる用語は−O−アルキル基を意味し、ここでアルキル基は上記に定義した通りである。
−n(III)は1又は2を表し;
−m(III)は0又は1を表し;
−Y(III)は炭素、窒素、硫黄もしくは酸素原子又は単結合もしくは二重結合を表し;
−X(III)、X1 (III)及びX2 (III)は炭素、窒素、硫黄又は酸素原子を表し、但し、X(III)、X1 (III)及びX2 (III)の少なくとも1つは炭素原子以外のものであり;
−利用可能な位置のいずれか1つに位置するR(III)及びR1(III)は独立して水素原子、ハロゲン原子、(C1−C4)アルキル基、(C1−C4)アルコキシ基、パーフルオロアルキル基、トリフルオロメトキシ基、シアノ基、COOH基、COO(C1−C4)アルキル基、CONR5(III)R6(III)基又はNHCOR5(III)基を表し;
あるいはR1(III)は
−利用可能な位置のいずれか1つに位置するR3(III)及びR4(III)は独立して水素原子、ハロゲン原子、(C1−C4)アルキル基、(C(C1−C4)−C4)アルコキシ基、パーフルオロアルキル基、トリフルオロメトキシ基、シアノ基、COOH基、COO(C1−C4)アルキル基、CONR5(III)R6(III)基又はNHCOR5(III)基を表し;
−W(III)は
−利用可能な位置のいずれか1つに位置するR7(III)及びR8(III)は独立して水素原子、ハロゲン原子、(C1−C4)アルキル基、(C1−C4)アルコキシ基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、COOH基、COO(C1−C4)アルキル基、COO(C1−C4)シクロアルキル基、SO(C1−C4)アルキル基、SO2(C1−C4)アルキル基、CONH2基、CONR5(III)R6(III)基又はNHCOR5(III)基を表し;
あるいはR7(III)及びR8(III)の一方は
−「ハロゲン原子」なる用語はフッ素、塩素、臭素又はヨウ素を意味する;
−「アルキル基」なる用語は直鎖、分岐鎖又は環状飽和脂肪族基を意味する。例えば、C1−C4アルキル基が挙げられ、具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、シクロプロピル又はシクロブチルが挙げられる;
−「フルオロアルキル基」なる用語は1個以上の水素原子がフッ素原子で置換えられたアルキル基を意味する;
−「パーフルオロアルキル基」なる用語は全ての水素原子がフッ素原子で置換えられたアルキル基(例えばトリフルオロメチル等のトリフルオロアルキル基)を意味する;
−「アルコキシ基」なる用語は−O−アルキル基を意味し、ここでアルキル基は上記に定義した通りである;
−「パーフルオロアルコキシ基」なる用語は全ての水素原子がフッ素原子で置換えられたアルコキシ基(例えばトリフルオロメトキシ等のトリフルオロアルコキシ基)を意味する;
−「シクロアルキル基」なる用語は環状アルキル基を意味する。例えば、シクロプロピル、メチルシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等の基が挙げられる;
−「ハロゲン原子」なる用語はフッ素、塩素、臭素を意味する。
−U(IV)は、
−1又は2個の窒素原子を含み、場合により1もしくは2個のハロゲン原子、1もしくは2個の(C1−C4)アルキル基もしくは(C1−C4)アルコキシ基、又は1もしくは2個のパーフルオロアルキル基で置換された芳香族又は飽和6員環を形成し;
−あるいは窒素、酸素又は硫黄原子を含み、場合により1又は2個の(C1−C4)アルキル基で置換された芳香族又は飽和5員環を形成し;
−X(IV)及びX1(IV)は相互に独立してCH又はNを表し;
−利用可能な位置のいずれかに位置するR(IV)及びR1(IV)は独立して水素原子、ハロゲン原子、(C1−C4)アルキル基、(C1−C4)アルコキシ基、パーフルオロアルキル基、トリフルオロメトキシ基、シアノ基、COOH基、COO(C1−C4)アルキル基、CONR3(IV)R4(IV)基又はNHCOR3(IV)基を表し;
−W(IV)は
あるいはR5(IV)及びR6(IV)の一方は
−ハロゲン原子:フッ素、塩素、臭素又はヨウ素;
−アルキル基:飽和直鎖、分岐鎖又は環状脂肪族基。例としては、(C1−C4)アルキル基が挙げられ、具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、シクロプロピル又はシクロブチルが挙げられる;
−フルオロアルキル基:1個以上の水素原子がフッ素原子で置換えられたアルキル基;
−パーフルオロアルキル基:全ての水素原子がフッ素原子で置換えられたアルキル基(例えばトリフルオロアルキル基);
−アルコキシ基:−O−アルキル基であり、ここでアルキル基は上記に定義した通りである;
−パーフルオロアルコキシ基:全ての水素原子がフッ素原子で置換えられたアルコキシ基(例えばトリフルオロアルコキシ基);
−シクロアルキル基:環状アルキル基。例としては、シクロプロピル、メチルシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等の基が挙げられる。
−化合物番号1:1−[4−(4−クロロ−3−トリフルオロメチルフェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−2−[8−(5−フルオロピリミジン−2−イル)−3,8−ジアザビシクロ[3.2.1]オクト−3−イル]エタノン;
−化合物番号2:6−{(3S,5R)−3,5−ジメチル−4−[2−オキソ−2−(2−フェニル−2,4,6,7−テトラヒドロピラゾロ[4,3−c]ピリジン−5−イル)エチル]ピペラジン−1−イル}ニコチン酸塩酸塩;
−化合物番号3:6−{(3S,5R)−4−[2−(4−ベンゾフラン−7−イル−3,6−ジヒドロ−2H−ピリジン−1−イル)−2−オキソエチル]−3,5−ジメチルピペラジン−1−イル}ニコチン酸;
化合物番号4:1−(2−フェニル−2,4,6,7−テトラヒドロピラゾロ[4,3−c]ピリジン−5−イル)−2−(8−ピリジン−3−イル−3,8−ジアザビシクロ[3.2.1]オクト−3−イル)エタノン
から選択されるp75受容体アンタゴニストの使用を提供し、上記化合物は塩基として存在することもできるし、酸付加塩として存在することもできる。
動物準備
雄性成体SHR/NIcoラット(250g;Charles River Italy)を外科処置の7日前に檻に入れ、標準飼料と水を自由に与えた。sanofi社の実験動物の飼育及び処置に関する国際倫理規則及び国際原則(E.E.E Council Directive 86/609,DJL358,1 Cec.12,1987)に従い、AAALACに完全に認証された施設で動物を使用した。
外科処置から1週間後に動物を尿流動態測定のために小動物膀胱内圧測定実験ステーション(MED Associates,St.Albans,Vermont)に収容した。記録の開始前に膀胱を空にし、Tチューブを介してカテーテルを圧力トランスデューサーとマイクロインジェクションポンプに連結した。等張生理食塩水(0.9% NaCl,室温)を毎時10mlの速度で膀胱に注入した。網底動物ケージの下に化学天秤を置き、連続膀胱内圧測定時に排出された尿の量を測定した。1回の充満−排出サイクル中の膀胱内圧、注入体積及び排出体積の同時記録として単一の膀胱内圧曲線を記録する。25〜30分間の初期安定化期間後にMED−CMGソフトウェア(Catamount Research & Development Company)を使用して少なくとも4回の再現可能な排尿サイクルを記録する(基底期間)。
膀胱内圧測定データ解析用の特定のソフトウェアであるSOF−552を使用して膀胱内圧曲線を解析する。
1.収縮間隔(秒)(ICI)−排尿イベント間の時間(排尿間隔)
2.閾値内圧(mmHg)(TP)−排尿直前の膀胱内圧
3.最高膀胱内圧(mmHg)(Max P)−排尿に伴う最高膀胱内圧
4.最低膀胱内圧(mmHg)(Min P)−膀胱充満時の最低膀胱内圧
5.注入体積(μl)(Inf.Vol)−排尿サイクル中の生理食塩水注入体積
6.平均膀胱内圧(mmHg)(Aver P)−膀胱充満時の平均膀胱内圧。
外科処置後の体重減少、20%以上の嗜眠、sanofi社の認証済み術後鎮痛レジメンにより軽減されない痛みもしくは苦痛、又は血尿等の有害事象が生じた場合には、投与前にラットを試験から外した。
群間又は群内変動の影響を制限するために、全データを対照期間(100%)の%として平均値±標準誤差(SEM)で表し、投与群毎に平均した。一元配置分散分析(ANOVA)後にューマン・クールズ検定又はダネット検定を使用した。p<0.05の確率値を有意とみなした。
溶媒:メチルセルロース(0.6% MC)を含有する緩衝液に0.5%ポリソルベート80(PS80)を添加した溶液
化合物番号1(10mg/kg):懸濁液(0.5% PS80+0.6% MC)
化合物番号2(3、10、30mg/kg):懸濁液(0.5% PS80+0.6% MC)
化合物番号3(10mg/kg):懸濁液(0.5% PS80+0.6% MC)
化合物番号4(10mg/kg):懸濁液(0.5% PS80+0.6% MC)。
排尿経路における本発明の化合物の役割を調べるために、各群4〜12匹ずつ5群のラットを使用する:
第1群,溶媒,経口(po)(n=10)
第2群,化合物番号1(10mg/kg po)(n=12)
第3群,化合物番号2(10mg/kg po)(n=6)
第4群,化合物番号3(10mg/kg po)(n=4)
第5群,化合物番号4(10mg/kg po)(n=5)。
第1群,溶媒,po(n=8)
第2群,化合物番号2(3mg/kg po)(n=7)
第3群,化合物番号2(10mg/kg po)(n=6)
第4群,化合物番号2(30mg/kg po)(n=9)。
存在した群間又は群内変動の影響を制限するために、対照値の百分率としてデータを表した。
溶媒では111.7±10.3%、化合物番号1では195.5±15.4%、化合物番号2(10mg/kg po)では199.7±28.5%、化合物番号3(10mg/kg po)では167.2±20.3%、化合物番号4(10mg/kg po)では186.3±26.9%。
溶媒では111.7±10.3%、化合物番号1では194.9±15.3%、化合物番号2(10mg/kg po)では198.9±28.3%、化合物番号3(10mg/kg po)では167.14±20%、化合物番号4(10mg/kg po)では186.2±26.9%。
溶媒では114.3±12.01%、化合物番号2(3mg/kg po)では160.9±21.8%、化合物番号2(10mg/kg po)では199.7±28.5%、化合物番号2(30mg/kg po)では210.5±24.7%。
溶媒では114.3±12%、化合物番号2(3mg/kg po)では160.8±21.7%、化合物番号2(10mg/kg po)では198.9±28.3%、化合物番号2(30mg/kg po)では209.9±24.5%。
上記化合物はこの病態生理学的モデルにおいてICIと膀胱容量を増加させた。これらの化合物は排尿圧パラメータには全く影響を与えず、特異反応であると予想された。従って、これらの化合物は過活動膀胱の治療及び/又は予防に有用であると思われる。
化合物番号2(10mg/kg):懸濁液(0.5% PS80+0.6% MC)。
各群14〜15匹ずつ2群のラットを構成した:
−溶媒対照ラットには溶媒を7日間投与した。
−投与ラットには化合物番号2を用量10mg/kg/2mlで7日間経口投与した。
存在した群間又は群内変動の影響を制限するために、対照値の百分率としてデータを表した。
p75アンタゴニストの慢性投与(1週間)はDO−OABの特徴を示すSHRラットにおける排尿反射に影響を与える。化合物番号2はこの病態生理学的モデルにおいてICIと膀胱容量を増加させた。この化合物は排尿圧パラメータには全く影響を与えず、特異反応であると予想された。従って、この化合物は過活動膀胱の治療及び/又は予防に有用であると思われる。
代表的な1例として、錠剤形態の本発明の化合物の単位用量形態は以下の成分を含有することができる:
p75受容体アンタゴニスト 5.0mg
ラクトース 122.0mg
微結晶性セルロース 36.0mg
カルボキシメチルスターチナトリウム 7.0mg
ポビドン 9mg
ステアリン酸マグネシウム 1.0mg。
Claims (2)
- 過活動膀胱の治療及び/又は予防用のp75受容体アンタゴニストであって、
有効成分として、塩基又は酸付加塩の形態である以下、
−化合物番号1:1−[4−(4−クロロ−3−トリフルオロメチルフェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−2−[8−(5−フルオロピリミジン−2−イル)−3,8−ジアザビシクロ[3.2.1]オクト−3−イル]エタノン;
−化合物番号2:6−{(3S,5R)−3,5−ジメチル−4−[2−オキソ−2−(2−フェニル−2,4,6,7−テトラヒドロピラゾロ[4,3−c]ピリジン−5−イル)エチル]ピペラジン−1−イル}ニコチン酸塩酸塩;
−化合物番号3:6−{(3S,5R)−4−[2−(4−ベンゾフラン−7−イル−3,6−ジヒドロ−2H−ピリジン−1−イル)−2−オキソエチル]−3,5−ジメチルピペラジン−1−イル}ニコチン酸;
から選択される化合物を含む、p75受容体アンタゴニスト。 - 過活動膀胱の治療及び/又は予防用のp75受容体アンタゴニストの製造における、
塩基又は酸付加塩の形態である以下、
−化合物番号1:1−[4−(4−クロロ−3−トリフルオロメチルフェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−2−[8−(5−フルオロピリミジン−2−イル)−3,8−ジアザビシクロ[3.2.1]オクト−3−イル]エタノン;
−化合物番号2:6−{(3S,5R)−3,5−ジメチル−4−[2−オキソ−2−(2−フェニル−2,4,6,7−テトラヒドロピラゾロ[4,3−c]ピリジン−5−イル)エチル]ピペラジン−1−イル}ニコチン酸塩酸塩;
−化合物番号3:6−{(3S,5R)−4−[2−(4−ベンゾフラン−7−イル−3,6−ジヒドロ−2H−ピリジン−1−イル)−2−オキソエチル]−3,5−ジメチルピペラジン−1−イル}ニコチン酸;
から選択される化合物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11306709.4 | 2011-12-20 | ||
EP11306709.4A EP2606894A1 (en) | 2011-12-20 | 2011-12-20 | Novel therapeutic use of p75 receptor antagonists |
PCT/EP2012/076494 WO2013092918A1 (en) | 2011-12-20 | 2012-12-20 | Novel therapeutic use of p75 receptor antagonists |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017189265A Division JP2018030865A (ja) | 2011-12-20 | 2017-09-29 | p75受容体アンタゴニストの新規治療用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015500863A JP2015500863A (ja) | 2015-01-08 |
JP6275649B2 true JP6275649B2 (ja) | 2018-02-07 |
Family
ID=47429839
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014548035A Expired - Fee Related JP6275649B2 (ja) | 2011-12-20 | 2012-12-20 | p75受容体アンタゴニストの新規治療用途 |
JP2017189265A Pending JP2018030865A (ja) | 2011-12-20 | 2017-09-29 | p75受容体アンタゴニストの新規治療用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017189265A Pending JP2018030865A (ja) | 2011-12-20 | 2017-09-29 | p75受容体アンタゴニストの新規治療用途 |
Country Status (24)
Country | Link |
---|---|
US (2) | US20140296513A1 (ja) |
EP (2) | EP2606894A1 (ja) |
JP (2) | JP6275649B2 (ja) |
KR (1) | KR20140103151A (ja) |
CN (1) | CN104144688B (ja) |
AR (1) | AR089344A1 (ja) |
AU (2) | AU2012356922B2 (ja) |
BR (1) | BR112014014933A2 (ja) |
CA (1) | CA2859582A1 (ja) |
CL (1) | CL2014001619A1 (ja) |
CO (1) | CO6990740A2 (ja) |
CR (1) | CR20140298A (ja) |
DO (1) | DOP2014000137A (ja) |
EA (1) | EA028616B1 (ja) |
HK (1) | HK1198580A1 (ja) |
IL (1) | IL233189A0 (ja) |
MA (1) | MA35850B1 (ja) |
MX (1) | MX2014007673A (ja) |
PE (1) | PE20141854A1 (ja) |
PH (1) | PH12014501390A1 (ja) |
SG (1) | SG11201403390QA (ja) |
TN (1) | TN2014000269A1 (ja) |
UY (1) | UY34535A (ja) |
WO (1) | WO2013092918A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7530182B2 (ja) | 2020-02-06 | 2024-08-07 | 株式会社東芝 | 生体適合部材 |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3236243A1 (de) | 1982-09-30 | 1984-04-05 | Merck Patent Gmbh, 6100 Darmstadt | Schwefelhaltige indolderivate |
FR2744448B1 (fr) | 1996-02-02 | 1998-04-24 | Pf Medicament | Nouvelles piperidines derivees d'aryl piperazine, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments |
IL129475A0 (en) | 1996-10-21 | 2000-02-29 | Allelix Biopharma | Neurotrophin antagonist compositions |
JP2003514508A (ja) | 1997-07-01 | 2003-04-15 | ノボ ノルディスク アクティーゼルスカブ | グルカゴン拮抗剤/逆作用剤 |
US6613942B1 (en) | 1997-07-01 | 2003-09-02 | Novo Nordisk A/S | Glucagon antagonists/inverse agonists |
DE19826841A1 (de) | 1998-06-16 | 1999-12-23 | Merck Patent Gmbh | Arylalkanoylpyridazine |
GB9905010D0 (en) | 1999-03-04 | 1999-04-28 | Merck Sharp & Dohme | Therapeutic agents |
WO2000059893A1 (en) | 1999-04-06 | 2000-10-12 | Krenitsky Pharmaceuticals Inc. | Neurotrophic thio substituted pyrimidines |
US6468990B1 (en) | 1999-05-17 | 2002-10-22 | Queen's University At Kingston | Method of inhibiting binding of nerve growth factor to p75 NTR receptor |
FR2803593B1 (fr) | 2000-01-06 | 2002-02-15 | Sanofi Synthelabo | Nouvelles tetrahydropyridines, procede pour leur preparation et compositions pharmaceutiques les contenant |
UA77526C2 (en) | 2002-06-07 | 2006-12-15 | Sanofi Aventis | Substituted derivatives of 1-piperazineacylpiperidine, a method for the preparation thereof and their use in therapy |
FR2862967B1 (fr) | 2003-12-01 | 2006-08-04 | Sanofi Synthelabo | Derives de (4-phenylpiperazin-1-yl)acylpiperidine, leur preparation et leur application en therapeutique |
FR2862968B1 (fr) | 2003-12-01 | 2006-08-04 | Sanofi Synthelabo | Derives de 4-[(arylmethyl)aminomethyl]piperidine, leur preparation et leur application en therapeutique |
CA2575808A1 (en) | 2004-08-02 | 2006-02-16 | Osi Pharmaceuticals, Inc. | Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds |
BRPI0615930A2 (pt) * | 2005-09-15 | 2016-08-23 | Painceptor Pharma Corp | métodos de modular a interação de uma neurotrofina e um receptor de neurotrofina, de tratar dor em um indivíduo, de tratar distúrbio inflamatório em um indivíduo, de tratar um distúrbio neurológico em um indivíduo, e de tratar uma doença ou distúrbio associado aos sistemas geniturinário e/ou gastrointestinal de um indivíduo, e, composto |
AU2009221860A1 (en) | 2008-03-05 | 2009-09-11 | Targacept, Inc. | Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloal kanes |
CL2009000724A1 (es) | 2008-03-24 | 2009-05-29 | Medivation Technologies Inc | Compuestos derivados de 1,2,3,4-tetrahidro-pirido[3,4-b]indol, moduladores del receptor de histamina, serotonina y dopamina; composicion farmaceutica; kit farmaceutico; y uso para tratar un trastorno cognitivo, psicotico, mediado por neurotransmisores y/o neurologico. |
CN101284838B (zh) | 2008-06-06 | 2011-05-04 | 天津药物研究院 | 含噻吩并吡啶的哌嗪类衍生物、其制备方法和用途 |
FR2932482B1 (fr) | 2008-06-13 | 2010-10-08 | Sanofi Aventis | Nouveaux derives de (phenyl-3,6-dihydro-2h-pyridinyl)- (piperazinyl ponte)-1-alcanone et leur utilisation comme inhibiteurs de p75 |
FR2932481B1 (fr) | 2008-06-13 | 2010-10-08 | Sanofi Aventis | Derives de 4-{2-°4-phenyl-3,6-dihydro-2h-pyridin-1-yl!-2- oxo-alkyl}-1-piperazin-2-one, leur preparation et leur application en therapeutique. |
JP2010254641A (ja) * | 2009-04-28 | 2010-11-11 | Astellas Pharma Inc | アゾールカルボキサミド化合物又はその塩 |
FR2953839A1 (fr) | 2009-12-14 | 2011-06-17 | Sanofi Aventis | Nouveaux derives d'(heterocycle-piperidine condensee)-(piperazinyl)-1alcanone ou d'(heterocycle-pyrrolidine condensee)-(piperazinyl)-1alcanone et leur utilisation comme inhibiteurs de p75 |
FR2953836B1 (fr) | 2009-12-14 | 2012-03-16 | Sanofi Aventis | Nouveaux derives (heterocycle-tetrahydro-pyridine)-(piperazinyl)-1-alcanone et (heterocycle-dihydro-pyrrolidine)-(piperazinyl)-1-alcanone et leur utilisation comme inhibiteurs de p75 |
-
2011
- 2011-12-20 EP EP11306709.4A patent/EP2606894A1/en not_active Withdrawn
-
2012
- 2012-12-20 BR BR112014014933A patent/BR112014014933A2/pt not_active IP Right Cessation
- 2012-12-20 UY UY0001034535A patent/UY34535A/es not_active Application Discontinuation
- 2012-12-20 WO PCT/EP2012/076494 patent/WO2013092918A1/en active Application Filing
- 2012-12-20 KR KR1020147019353A patent/KR20140103151A/ko not_active Application Discontinuation
- 2012-12-20 AU AU2012356922A patent/AU2012356922B2/en not_active Ceased
- 2012-12-20 CN CN201280070033.2A patent/CN104144688B/zh not_active Expired - Fee Related
- 2012-12-20 EP EP12806060.5A patent/EP2793889A1/en not_active Withdrawn
- 2012-12-20 MX MX2014007673A patent/MX2014007673A/es unknown
- 2012-12-20 JP JP2014548035A patent/JP6275649B2/ja not_active Expired - Fee Related
- 2012-12-20 PE PE2014001001A patent/PE20141854A1/es not_active Application Discontinuation
- 2012-12-20 SG SG11201403390QA patent/SG11201403390QA/en unknown
- 2012-12-20 AR ARP120104842A patent/AR089344A1/es unknown
- 2012-12-20 EA EA201491226A patent/EA028616B1/ru not_active IP Right Cessation
- 2012-12-20 CA CA2859582A patent/CA2859582A1/en not_active Abandoned
-
2014
- 2014-06-17 TN TNP2014000269A patent/TN2014000269A1/en unknown
- 2014-06-17 IL IL233189A patent/IL233189A0/en unknown
- 2014-06-17 DO DO2014000137A patent/DOP2014000137A/es unknown
- 2014-06-17 US US14/306,882 patent/US20140296513A1/en not_active Abandoned
- 2014-06-18 CL CL2014001619A patent/CL2014001619A1/es unknown
- 2014-06-18 PH PH12014501390A patent/PH12014501390A1/en unknown
- 2014-06-19 CR CR20140298A patent/CR20140298A/es unknown
- 2014-06-27 CO CO14139616A patent/CO6990740A2/es unknown
- 2014-07-07 MA MA37184A patent/MA35850B1/fr unknown
- 2014-12-01 HK HK14112081.9A patent/HK1198580A1/xx unknown
-
2016
- 2016-08-10 US US15/233,227 patent/US9763940B2/en not_active Expired - Fee Related
-
2017
- 2017-09-29 JP JP2017189265A patent/JP2018030865A/ja active Pending
- 2017-10-20 AU AU2017248550A patent/AU2017248550A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6835740B2 (en) | Methods for treating sleep apnea and sleep induced apnea using optically pure (+) norcisapride | |
JP6441267B2 (ja) | 過活動膀胱を治療するためのβ−3アドレナリン受容体アゴニストおよびムスカリン受容体アンタゴニストの組み合わせ | |
ES2393525T3 (es) | Composición farmacéutica para el tratamiento de la vejiga hiperactiva | |
SK282673B6 (sk) | Použitie (+) norcisapridu, farmaceutický prostriedok s obsahom (+) norcisapridu a jeho farmaceutická jednotková dávková forma | |
US6548082B1 (en) | Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron | |
JP6275649B2 (ja) | p75受容体アンタゴニストの新規治療用途 | |
US7064138B2 (en) | Methods for treating irritable bowel syndrome using optically pure (-) norcisapride | |
HRP20010075A2 (en) | Methods and compositions for treating gastro-esophageal reflux disease | |
EP2172201A1 (en) | Pharmaceutical composition for amelioration of lower urinary tract symptom associated with prostatomegaly | |
TW201332997A (zh) | P75受體拮抗劑的新穎醫療用途 | |
OA16932A (en) | Novel therapeutic use of p75 receptor antagonists. | |
WO2009081837A1 (ja) | 下部尿路症状の改善用医薬組成物 | |
NZ626485B2 (en) | Novel therapeutic use of p75 receptor antagonists | |
JP4384388B2 (ja) | 1,2−エタンジオール誘導体またはその塩を含有する切迫性尿失禁の治療薬 | |
WO2018197638A1 (en) | Novel use of (5r)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-d-prolinamide | |
EP1464333A2 (en) | Use of optically pure (-) norcisapride in the treatment of apnea, bulimia, and other disorders | |
EP1468685A2 (en) | Use of optically pure (+)-norcisapride for treating apnea, bulimia and other disorders | |
EP1435238A1 (en) | Methods for treating apnea and apnea disorders using optically pure R (+) ondansetron |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20151120 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20151207 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20151210 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161011 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170110 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170530 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170929 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20171106 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171212 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171226 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180110 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6275649 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |