JP2022116144A - 糖尿病性末梢神経障害の治療のためのhdac阻害剤 - Google Patents
糖尿病性末梢神経障害の治療のためのhdac阻害剤 Download PDFInfo
- Publication number
- JP2022116144A JP2022116144A JP2022084507A JP2022084507A JP2022116144A JP 2022116144 A JP2022116144 A JP 2022116144A JP 2022084507 A JP2022084507 A JP 2022084507A JP 2022084507 A JP2022084507 A JP 2022084507A JP 2022116144 A JP2022116144 A JP 2022116144A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- formula
- hdac6
- 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.)
- Granted
Links
- 208000032131 Diabetic Neuropathies Diseases 0.000 title claims abstract description 41
- 238000011282 treatment Methods 0.000 title claims abstract description 31
- 239000003276 histone deacetylase inhibitor Substances 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 102
- 102100022537 Histone deacetylase 6 Human genes 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 59
- 239000003112 inhibitor Substances 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 claims 12
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 claims 12
- 125000001475 halogen functional group Chemical group 0.000 claims 6
- 229940121372 histone deacetylase inhibitor Drugs 0.000 abstract description 3
- 108010023925 Histone Deacetylase 6 Proteins 0.000 description 50
- 239000000203 mixture Substances 0.000 description 32
- 229940125782 compound 2 Drugs 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 22
- 102000003964 Histone deacetylase Human genes 0.000 description 21
- 108090000353 Histone deacetylase Proteins 0.000 description 21
- 241000700159 Rattus Species 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 206010012601 diabetes mellitus Diseases 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 14
- 229940125904 compound 1 Drugs 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000008103 glucose Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 108090000704 Tubulin Proteins 0.000 description 10
- 102000004243 Tubulin Human genes 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 210000003594 spinal ganglia Anatomy 0.000 description 9
- 230000008335 axon cargo transport Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 210000003497 sciatic nerve Anatomy 0.000 description 8
- 239000002207 metabolite Substances 0.000 description 7
- 210000002569 neuron Anatomy 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 6
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 4
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- 208000000114 Pain Threshold Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000003376 axonal effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 230000007850 degeneration Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 201000001421 hyperglycemia Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000037040 pain threshold Effects 0.000 description 4
- 208000033808 peripheral neuropathy Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 3
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001952 enzyme assay Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000003470 mitochondria Anatomy 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 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 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 241000124008 Mammalia Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- QGZYDVAGYRLSKP-UHFFFAOYSA-N N-[7-(hydroxyamino)-7-oxoheptyl]-2-(N-phenylanilino)-5-pyrimidinecarboxamide Chemical compound N1=CC(C(=O)NCCCCCCC(=O)NO)=CN=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 QGZYDVAGYRLSKP-UHFFFAOYSA-N 0.000 description 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-O S-adenosyl-L-methionine Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H]([NH3+])C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-O 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000031857 establishment of mitochondrion localization Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000010859 live-cell imaging Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000026326 mitochondrial transport Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- -1 organic acid salts Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- KAJZODLWVHKBSI-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)benzonitrile Chemical compound COC1=CC=C(C(F)(F)F)C=C1C#N KAJZODLWVHKBSI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100123577 Caenorhabditis elegans hda-1 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 108091005772 HDAC11 Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102100039385 Histone deacetylase 11 Human genes 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 102100021453 Histone deacetylase 5 Human genes 0.000 description 1
- 102100038715 Histone deacetylase 8 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 description 1
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 description 1
- 101001032118 Homo sapiens Histone deacetylase 8 Proteins 0.000 description 1
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 description 1
- 101001035694 Homo sapiens Polyamine deacetylase HDAC10 Proteins 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000004044 Hypesthesia Diseases 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101000654471 Mus musculus NAD-dependent protein deacetylase sirtuin-1 Proteins 0.000 description 1
- YJGLQGXOWLMXEQ-UHFFFAOYSA-N N-hydroxy-2-[[2-methoxy-5-(trifluoromethyl)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound ONC(=O)C=1C=NC(=NC=1)NCC1=C(C=CC(=C1)C(F)(F)F)OC YJGLQGXOWLMXEQ-UHFFFAOYSA-N 0.000 description 1
- 229910017855 NH 4 F Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000010886 Peripheral nerve injury Diseases 0.000 description 1
- 102100039388 Polyamine deacetylase HDAC10 Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 101150107360 RPD3 gene Proteins 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- VHRZOOAZTLUOJP-UHFFFAOYSA-N amino heptanoate Chemical compound CCCCCCC(=O)ON VHRZOOAZTLUOJP-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000000738 capillary electrophoresis-mass spectrometry Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- YPGQGLBIQNRGSH-UHFFFAOYSA-N ethyl 2-[[2-methoxy-5-(trifluoromethyl)phenyl]methylamino]pyrimidine-5-carboxylate Chemical compound COC1=C(CNC2=NC=C(C=N2)C(=O)OCC)C=C(C=C1)C(F)(F)F YPGQGLBIQNRGSH-UHFFFAOYSA-N 0.000 description 1
- IEMKQRSOAOPKRJ-UHFFFAOYSA-N ethyl 2-chloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1 IEMKQRSOAOPKRJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000007849 functional defect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000006195 histone acetylation Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 208000034783 hypoesthesia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000006680 metabolic alteration Effects 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 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
- 230000007631 mitochondrial deficit Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- LIIWIMDSZVNYHY-UHFFFAOYSA-N n-hydroxy-2-[(1-phenylcyclopropyl)amino]pyrimidine-5-carboxamide Chemical compound N1=CC(C(=O)NO)=CN=C1NC1(C=2C=CC=CC=2)CC1 LIIWIMDSZVNYHY-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent 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
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 208000004371 toothache Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
以下に、本明細書で使用される様々な用語の定義を列挙する。これらの定義は、具体例で制限の断りがない限り、個別又は集団の一部として明細書及び特許請求の範囲全体において使用される用語に適用する。
一つの態様において、本明細書においては、対象に治療有効量のHDAC6阻害剤を投与することを含む、それを必要とする対象における糖尿病性末梢神経障害の治療又は予防のための方法が提供される。
Rxは、H及びC1-6-アルキルから選択される;
Ryは、H及びC1-6-アルキルから選択される;
又は、Rx及びRyは、それぞれが結合する炭素と一緒に、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、シクロヘプチル又はシクロオクチルを形成し;
各RAは、独立してC1-6-アルキル、C1-6-アルコキシ、ハロ、OH又はハロアルキルであり;
mは0、1又は2である。
Rx及びRyは、それぞれが結合する炭素と一緒に、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、シクロヘプチル又はシクロオクチルを形成し;
各RAは、独立してC1-6-アルキル、C1-6-アルコキシ、ハロ、OH又はハロアルキルであり;
mは0、1又は2である。
環Bは、OH、ハロ又はC1-6-アルキルで置換された又は置換されていないアリール又はヘテロアリールであり;
R1は、OH、ハロ又はC1-6-アルキルで置換された又は置換されていないアリール又はヘテロアリールであり;
Rは、H又はC1-6-アルキルである。
HDAC6(ヒストンデアセチラーゼ6)阻害剤は、血液癌及びCNS疾患の動物モデルにおいて有効性を示す。本願においては、糖尿病性末梢神経障害の治療又は予防のために、HDAC6阻害剤の使用が提供される。
また、本願は、対象において、糖尿病性末梢神経障害を治療する又は予防するためのHDAC6阻害剤を提供する。一つの実施形態において、HDAC6阻害剤はHDAC6特異的阻害剤である。
他の態様において、本発明は、本願で提供される任意の化合物又はその薬学的に許容される塩を、薬学的に許容される担体と共に含み、糖尿病性末梢神経障害の治療又は予防に使用するための医薬組成物を提供する。
本出願を通して列挙したすべての文献(引用文献、登録特許、公開特許公報及び同時係属中の特許出願を含む)の全文は、参照することにより組み入れられたものとする。別段の記載がある場合を除き、明細書で使用される技術用語及び科学用語は全て当業者に一般に公知な意味と一致する。
当業者は、単なる日常的な実験によって、明細書に記載した発明の具体的な実施形態の多くの均等物を認識しまたは確認することができるであろう。そのような均等物は以下の特許請求の範囲によって包含されることが意図されている。
MeOH/DCM(6/2ml)中のエチル2-(2-メトキシ-5-(トリフルオロメチル)ベンジルアミノ)ピリミジン-5-カルボキシレート(100mg、0.28mmol)の混合物に対して、NH2OH(0.5ml)を添加し、次いでNaOH溶液(MeoH中で飽和、1ml)を0°Cで滴下した。混合物を0°Cで3時間撹拌した。TLCで反応が完了したと判断された後、混合物を濃縮しMeOHとDCMを除去し、pH6~7付近まで酸性化し、prep-TLCで精製し、所望の生成物である化合物3を白色固体として得た(30mg、31%)。LCMS: m/z = 343 (M+H)+. 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.99 (s, 1H), 8.61 (d, J = 17.4 Hz, 2H), 8.22 (t, J = 6.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 3.91 (s, 3H)。
化合物1、2及び3を、一般的な疼痛DPNのモデルであるストレプトゾトシン誘導性糖尿病ラット(STZラット)において、神経障害の回復能について試験した。両方の化合物が、STZラットにおいて、用量依存的に接触性アロディニアを反転させ、痛覚閾値を正常レベル付近まで回復させた。化合物1の場合、例えば、薬物治療の停止後でさえも痛覚閾値における薬物のプラスの効果がみられ、このことはDPNにおけるHDAC6阻害剤の進行抑制効果を示している。
後根神経節ニューロン(DRGN: dorsal root ganglion neuron)を化合物2で24時間処置し、全細胞抽出物をウエスタンブロットで分析した。化合物2は、用量依存的にチューブリンのアセチル化の増大を誘導した。DRGNにおいて、最も少ないヒストンアセチル化の増大が観察されたのは、1μMまでの化合物2に対する応答においてである。化合物2は、ラットDRGNの全細胞溶解物においてチューブリン高アセチル化を誘導する(図3A)。
処置後4時間の間、1時間ごとにテールフリック試験を実施した。化合物1又は2をテールフリック試験前4日間にわたってラットに投与した(BID群)。あるいは、化合物1又は2を試験の1時間前にラットに単回投与した(QD群)。
代謝ストレスは、糖尿病に関連する多くの病態の根底にある。Freemanら (Freeman, O.J., Unwin, R.D., Dowsey, A.W., Begley, P., Ali, S., Hollywood, K.A., Rustogi, N., Petersen, R.S., Dunn, W.B., Cooper, G.J.S., Gardiner, N.J. (2016) “Metabolic Dysfunction is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy” Diabetes 65) は、ストレプトゾトシンで処置して高血糖を誘導したラットにおいて、坐骨神経における代謝産物の変化が神経因性疼痛の増加と関連することを示した。
Claims (21)
- 対象において、糖尿病性末梢神経障害の治療又は予防において使用するための、HDAC6阻害剤。
- HDAC6特異的阻害剤である、請求項1に記載のHDAC6阻害剤。
- 治療有効量のHDAC6阻害剤を対象に投与することを含み、それを必要とする対象において糖尿病性末梢神経障害を治療又は予防するための方法。
- HDAC6阻害剤が特異的HDAC6阻害剤である、請求項14に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2024045082A JP2024075703A (ja) | 2015-10-27 | 2024-03-21 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562246965P | 2015-10-27 | 2015-10-27 | |
US62/246,965 | 2015-10-27 | ||
US201662281990P | 2016-01-22 | 2016-01-22 | |
US62/281,990 | 2016-01-22 | ||
PCT/US2016/059075 WO2017075192A1 (en) | 2015-10-27 | 2016-10-27 | Hdac inhibitors for the treatment of diabetic peripheral neuropathy |
JP2018521652A JP7080812B2 (ja) | 2015-10-27 | 2016-10-27 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521652A Division JP7080812B2 (ja) | 2015-10-27 | 2016-10-27 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024045082A Division JP2024075703A (ja) | 2015-10-27 | 2024-03-21 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022116144A true JP2022116144A (ja) | 2022-08-09 |
JP7460685B2 JP7460685B2 (ja) | 2024-04-02 |
Family
ID=57286845
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521652A Active JP7080812B2 (ja) | 2015-10-27 | 2016-10-27 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
JP2022084507A Active JP7460685B2 (ja) | 2015-10-27 | 2022-05-24 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
JP2024045082A Pending JP2024075703A (ja) | 2015-10-27 | 2024-03-21 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521652A Active JP7080812B2 (ja) | 2015-10-27 | 2016-10-27 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024045082A Pending JP2024075703A (ja) | 2015-10-27 | 2024-03-21 | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
Country Status (6)
Country | Link |
---|---|
US (3) | US10040769B2 (ja) |
EP (1) | EP3368026A1 (ja) |
JP (3) | JP7080812B2 (ja) |
CA (1) | CA3001879A1 (ja) |
HK (1) | HK1256042A1 (ja) |
WO (1) | WO2017075192A1 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI2526093T1 (sl) * | 2010-01-22 | 2016-10-28 | Acetylon Pharmaceuticals, Inc. | Reverzne amidne spojine kot inhibitorji protein deacetilaze in postopki njihove uporabe |
US9145412B2 (en) | 2012-11-02 | 2015-09-29 | Acetylon Pharmaceuticals, Inc. | Selective HDAC1 and HDAC2 inhibitors |
JP7080812B2 (ja) | 2015-10-27 | 2022-06-06 | アセチロン ファーマシューティカルズ インコーポレイテッド | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
JP7233220B2 (ja) * | 2016-06-09 | 2023-03-06 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | Hdac阻害剤とbet阻害剤の使用方法及びその薬学的組み合わせ |
US20220168300A1 (en) * | 2019-02-12 | 2022-06-02 | Emory University | Methods of Managing Vascular Conditions and Diabetic Peripheral Neuropathies |
KR20220119653A (ko) | 2019-12-20 | 2022-08-30 | 테나야 테라퓨틱스, 인코포레이티드 | 플루오로알킬-옥사디아졸 및 이의 용도 |
MX2023012095A (es) | 2021-04-23 | 2023-12-14 | Tenaya Therapeutics Inc | Inhibidores de hdac6 para el uso en el tratamiento de la miocardiopatía dilatada. |
EP4333841A1 (en) | 2021-05-04 | 2024-03-13 | Tenaya Therapeutics, Inc. | 2-fluoroalkyl-1,3,4-oxadiazol-5-yl-thiazol, hdac6 inhibitors for use in the treatment of metabolic disease and hfpef |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003095949A (ja) * | 2001-09-21 | 2003-04-03 | Taisho Pharmaceut Co Ltd | 糖取り込み促進剤 |
JP2013542994A (ja) * | 2010-11-16 | 2013-11-28 | アセチロン ファーマシューティカルズ インコーポレイテッド | 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0202623A3 (en) * | 1999-07-16 | 2003-03-28 | Warner Lambert Co | Method for treating chronic pain using mek inhibitors |
JP2003096949A (ja) | 2001-09-20 | 2003-04-03 | Nippon Alum Co Ltd | パネル連結装置 |
US8022249B2 (en) * | 2005-04-01 | 2011-09-20 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
US20070066646A1 (en) | 2005-08-02 | 2007-03-22 | Genmedica Therapeutics Sl | Compounds for Inhibiting Copper-Containing Amine Oxidases and Uses Thereof |
SI2526093T1 (sl) | 2010-01-22 | 2016-10-28 | Acetylon Pharmaceuticals, Inc. | Reverzne amidne spojine kot inhibitorji protein deacetilaze in postopki njihove uporabe |
US9464073B2 (en) | 2014-02-26 | 2016-10-11 | Acetylon Pharmaceuticals, Inc. | Pyrimidine hydroxy amide compounds as HDAC6 selective inhibitors |
US20160158231A1 (en) | 2014-12-05 | 2016-06-09 | Vib Vzw | Pyrimidine hydroxy amide compounds for treating peripheral neuropathy |
JP7080812B2 (ja) | 2015-10-27 | 2022-06-06 | アセチロン ファーマシューティカルズ インコーポレイテッド | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 |
-
2016
- 2016-10-27 JP JP2018521652A patent/JP7080812B2/ja active Active
- 2016-10-27 US US15/335,971 patent/US10040769B2/en active Active
- 2016-10-27 EP EP16794838.9A patent/EP3368026A1/en active Pending
- 2016-10-27 WO PCT/US2016/059075 patent/WO2017075192A1/en active Application Filing
- 2016-10-27 CA CA3001879A patent/CA3001879A1/en active Pending
-
2018
- 2018-07-03 US US16/026,651 patent/US10858323B2/en active Active
- 2018-11-26 HK HK18115094.3A patent/HK1256042A1/zh unknown
-
2020
- 2020-11-04 US US17/089,315 patent/US20210155593A1/en active Pending
-
2022
- 2022-05-24 JP JP2022084507A patent/JP7460685B2/ja active Active
-
2024
- 2024-03-21 JP JP2024045082A patent/JP2024075703A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003095949A (ja) * | 2001-09-21 | 2003-04-03 | Taisho Pharmaceut Co Ltd | 糖取り込み促進剤 |
JP2013542994A (ja) * | 2010-11-16 | 2013-11-28 | アセチロン ファーマシューティカルズ インコーポレイテッド | 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法 |
Non-Patent Citations (1)
Title |
---|
EMBO J., (2002), 21, [24], P.6820-6831, JPN6020031262, ISSN: 0005069204 * |
Also Published As
Publication number | Publication date |
---|---|
US10040769B2 (en) | 2018-08-07 |
JP7460685B2 (ja) | 2024-04-02 |
US20170114023A1 (en) | 2017-04-27 |
JP2024075703A (ja) | 2024-06-04 |
HK1256042A1 (zh) | 2019-09-13 |
US10858323B2 (en) | 2020-12-08 |
WO2017075192A1 (en) | 2017-05-04 |
US20210155593A1 (en) | 2021-05-27 |
US20190106392A1 (en) | 2019-04-11 |
JP2018535965A (ja) | 2018-12-06 |
CA3001879A1 (en) | 2017-05-04 |
EP3368026A1 (en) | 2018-09-05 |
JP7080812B2 (ja) | 2022-06-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7460685B2 (ja) | 糖尿病性末梢神経障害の治療のためのhdac阻害剤 | |
US20210069135A1 (en) | Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis | |
JP7542947B2 (ja) | ヒストン脱アセチル化酵素阻害剤及びエポチロンを含む医薬品組み合わせならびにその使用方法 | |
US11872227B2 (en) | Pharmaceutical combinations comprising a histone deacetylase inhibitor and an aurora kinase inhibitor and methods of use thereof | |
ES2925197T3 (es) | Combinaciones farmacéuticas que comprenden un inhibidor de histona desacetilasa y un inhibidor de BCL-2 y métodos de uso de las mismas | |
DE69724127T2 (de) | Substituierte benzyliden-indenyl-formamide, acetamide und propionamide | |
BR112017006690B1 (pt) | Derivado de ?-aminoamida ou um sal aceitável farmaceuticamente do mesmo, método para a preparação de um derivado de ?-aminoamida, uso do inibidor da monoamina-oxidase b (mao-b) e uso do inibidor da produção de ácido g-aminobutírico (gaba) | |
US11547707B2 (en) | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder | |
WO1995021610A1 (es) | Uso de derivados de fenoles 2,4-disubstituidos como inhibidores de la 5-lipoxigenasa | |
US6037345A (en) | Method for inhibiting neoplastic cells and related conditions by exposure to quinazolinedione and pyridopyrimidinedione derivatives | |
JP2022542992A (ja) | カルパイン阻害剤及び神経障害を処置するためのその使用 | |
WO2008006099A2 (en) | Treatment of psychiatric disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220531 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220622 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230529 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230829 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231127 |
|
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: 20240219 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240321 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7460685 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |