JP5916730B2 - アミド化合物 - Google Patents
アミド化合物 Download PDFInfo
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- JP5916730B2 JP5916730B2 JP2013527433A JP2013527433A JP5916730B2 JP 5916730 B2 JP5916730 B2 JP 5916730B2 JP 2013527433 A JP2013527433 A JP 2013527433A JP 2013527433 A JP2013527433 A JP 2013527433A JP 5916730 B2 JP5916730 B2 JP 5916730B2
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- Prior art keywords
- substituted
- alkyl
- unsubstituted
- aryl
- compound
- Prior art date
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- -1 Amide compounds Chemical class 0.000 title claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- 150000001875 compounds Chemical class 0.000 claims description 95
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 46
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 22
- 230000001575 pathological effect Effects 0.000 claims description 20
- 208000024827 Alzheimer disease Diseases 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 210000000274 microglia Anatomy 0.000 claims description 17
- 150000002825 nitriles Chemical class 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 230000028327 secretion Effects 0.000 claims description 10
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 206010039966 Senile dementia Diseases 0.000 claims description 8
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- HVINEMIENPEMIF-UHFFFAOYSA-N [4-(4-fluorophenyl)piperazin-1-yl]-(4-methyl-6-phenylpyridazin-3-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N(CC1)CCN1C1=CC=C(F)C=C1 HVINEMIENPEMIF-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 208000004296 neuralgia Diseases 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- NYXVPNLKLUWTTL-UHFFFAOYSA-N (4-methyl-6-phenylpyridazin-3-yl)-(2-pyridin-2-ylpiperazin-1-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N1CCNCC1C1=CC=CC=N1 NYXVPNLKLUWTTL-UHFFFAOYSA-N 0.000 claims description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 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
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- MXUPITQAQSEUAQ-UHFFFAOYSA-N (1-cyclohexylpiperazin-2-yl)-(4-methyl-6-phenylpyridazin-3-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)C1CNCCN1C1CCCCC1 MXUPITQAQSEUAQ-UHFFFAOYSA-N 0.000 claims description 3
- CRLIVUKAEJENGH-UHFFFAOYSA-N (4-methyl-6-phenylpyridazin-3-yl)-(1-methylpiperazin-2-yl)methanone Chemical compound CN1CCNCC1C(=O)C1=NN=C(C=2C=CC=CC=2)C=C1C CRLIVUKAEJENGH-UHFFFAOYSA-N 0.000 claims description 3
- UCRCCNKIZFGQTC-UHFFFAOYSA-N (4-methyl-6-phenylpyridazin-3-yl)-(1-propan-2-ylpiperazin-2-yl)methanone Chemical compound CC(C)N1CCNCC1C(=O)C1=NN=C(C=2C=CC=CC=2)C=C1C UCRCCNKIZFGQTC-UHFFFAOYSA-N 0.000 claims description 3
- MPHUCACQKYNGCF-UHFFFAOYSA-N (4-methyl-6-phenylpyridazin-3-yl)-(2-pyrazin-2-ylpiperazin-1-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N1CCNCC1C1=CN=CC=N1 MPHUCACQKYNGCF-UHFFFAOYSA-N 0.000 claims description 3
- LPGIEZJCCXQCAU-UHFFFAOYSA-N (4-methyl-6-phenylpyridazin-3-yl)-(2-pyrimidin-2-ylpiperazin-1-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N1CCNCC1C1=NC=CC=N1 LPGIEZJCCXQCAU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000024777 Prion disease Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- ZJOODRFBAPDHIE-UHFFFAOYSA-N [2-(4-fluoropyrimidin-2-yl)piperazin-1-yl]-(4-methyl-6-phenylpyridazin-3-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N1CCNCC1C1=NC=CC(F)=N1 ZJOODRFBAPDHIE-UHFFFAOYSA-N 0.000 claims description 3
- JMFNMQSOJKSTKE-UHFFFAOYSA-N [4-(2,4-difluorophenyl)piperazin-1-yl]-(4-methyl-6-phenylpyridazin-3-yl)methanone Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1C(=O)N(CC1)CCN1C1=CC=C(F)C=C1F JMFNMQSOJKSTKE-UHFFFAOYSA-N 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 208000034189 Sclerosis Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- 239000007858 starting material Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000000623 heterocyclic group Chemical group 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000001308 synthesis method Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 229940125773 compound 10 Drugs 0.000 description 11
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000002194 synthesizing effect Effects 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 125000004104 aryloxy group Chemical group 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- AVJKDKWRVSSJPK-UHFFFAOYSA-N 1-(4-fluorophenyl)piperazine Chemical compound C1=CC(F)=CC=C1N1CCNCC1 AVJKDKWRVSSJPK-UHFFFAOYSA-N 0.000 description 9
- SOQLWJZRQKFERA-UHFFFAOYSA-N 4-methyl-6-phenylpyridazine-3-carboxylic acid Chemical compound N1=C(C(O)=O)C(C)=CC(C=2C=CC=CC=2)=N1 SOQLWJZRQKFERA-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000002098 pyridazinyl group Chemical group 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000006165 cyclic alkyl group Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 210000001642 activated microglia Anatomy 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 230000006724 microglial activation Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- AXJPMIIGNVFMNW-UHFFFAOYSA-N bis(2-phenylquinazolin-4-yl)methanone Chemical compound N=1C(C=2C=CC=CC=2)=NC2=CC=CC=C2C=1C(=O)C(C1=CC=CC=C1N=1)=NC=1C1=CC=CC=C1 AXJPMIIGNVFMNW-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 210000004748 cultured cell Anatomy 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
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- 239000008103 glucose Substances 0.000 description 4
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- 239000007951 isotonicity adjuster Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- GHCYINBUASKRDG-UHFFFAOYSA-N (5-fluoro-1h-indazol-3-yl)-[4-(4-fluorophenyl)piperazin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1N1CCN(C(=O)C=2C3=CC(F)=CC=C3NN=2)CC1 GHCYINBUASKRDG-UHFFFAOYSA-N 0.000 description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000037259 Amyloid Plaque Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 210000001130 astrocyte Anatomy 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- 229910052731 fluorine Inorganic materials 0.000 description 3
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- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 3
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- 125000003226 pyrazolyl group Chemical group 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- ASQOQJYHIYYTEJ-GBESFXJTSA-N (1r,7s,9as)-7-decyl-2,3,4,6,7,8,9,9a-octahydro-1h-quinolizin-1-ol Chemical compound O[C@@H]1CCCN2C[C@@H](CCCCCCCCCC)CC[C@H]21 ASQOQJYHIYYTEJ-GBESFXJTSA-N 0.000 description 2
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Classifications
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- 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
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Description
ミノザック
式(II)
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルの群から選択され;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロアリール、およびヘテロサイクリックアルキルの群から選択され;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)であり、その置換基は、アルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、アリール、アリールアルキル、およびアリールオキシの群から選択される。
式(A) 式(B) 式(I)
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール基(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリールである。
表示している化学基において、炭素原子の全個数の簡略化した記号(たとえばC4)は、本出願において名前が挙げられたいくつかの化学基を表している。たとえば、C7〜C12アルキルは、以下において定義されるような7〜12個の炭素原子を有するアルキル基を表しており、C4〜C12サイクリックアルキルは、以下において定義されるような4〜12個の炭素原子を有するサイクリックアルキル基を表している。簡略化した記号の中の炭素原子の個数には、その化学基の置換基の中に存在する可能性がある炭素原子は含まれない。
(i)哺乳類において起きる疾患または病的状態の予防、特にその哺乳類が、その病的状態に陥りそうになってはいるが、病的状態であるとはまだ診断されていないとき;
(ii)疾患または病的状態の抑制、すなわちその状態が起きるのを停止させること;または
(iii)疾患または病的状態の寛解、すなわち、疾患または病的状態の後退
一方では、本出願は、式(I)によって表される化合物およびその薬学的に許容される塩に関する:
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、およびヘテロサイクリックアルキルからなる群から選択され;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)である。
式(I)
その置換基が、それぞれ、アリール、アリールアルキル、アルキル、アルコキシ、置換アルキル、ハロゲン、ヒドロキシル、アジル、およびシアノ基からなる群より選択され;
Arは、置換もしくは非置換のヘテロサイクリックアリール基(ベンズピロールは除く)であり、
ここで置換基は、アルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、アリール、アリールアルキル、またはアリールオキシである。
R2、R3、R4、R5が独立して、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arが、置換もしくは非置換のピリダジニル、置換もしくは非置換のキナゾリニル、置換もしくは非置換のピロリル、置換もしくは非置換のチエニル、置換もしくは非置換のインダゾリル、置換もしくは非置換のピラゾリルであって、ここで置換基は、アルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、アリール、アリールアルキル、またはアリールオキシである。
R2、R3、R4、R5がそれぞれ水素であり;そして
Arが、置換もしくは非置換のピリダジニル、置換もしくは非置換のキナゾリニル、置換もしくは非置換のピロリル、置換もしくは非置換のチエニル、置換もしくは非置換のインダゾリル、置換もしくは非置換のピラゾリルであって、ここで置換基は、アルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、アリール、アリールアルキル、またはアリールオキシである。
R2、R3、R4、R5がそれぞれ水素であり;
Arが、置換もしくは非置換のピリダジニルであって、ここで置換基は、アルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、またはアリールである。
R2、R3、R4、R5がそれぞれ、水素であり;Arが置換もしくは非置換のピリダジニルであって、ここで置換基は、メチル、フェニル、メトキシ、トリフルオロメチル、アジル、または塩素である。
(4−(4−フルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(4−(2,4−ジフルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピリミジルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピリジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−(5−フルオロピリミド−2−イル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−(ピリミド−2−イル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−(2−ピリジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(ピロル−2−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(チエン−2−イル)ケトン;
(4−(ピリミド−2−イル)ピペラジニル)(インダゾル−3−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(インダゾル−3−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(5−フルオロインダゾル−3−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(4,7−ジフルオロインダゾル−3−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(5−フルオロインダゾル−3−イル)ケトン;
(4−(2−ピリミジル)ピペラジニル)(5−イソプロピルピラゾル−3−イル)ケトン;
(4−(4−フルオロフェニル)ピペラジニル)(5−イソプロピルピラゾル−3−イル)ケトン;
(2−(4−フルオロピリミジル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピラジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(N−メチルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(N−イソプロピルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(N−シクロヘキシルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(4−(4−ピリジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−(2−ピラジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−メチルピペラジニル)(2−フェニルキナゾリニル)ケトン;
(4−イソプロピルピペラジニル)(2−フェニルキナゾリニル)ケトン;または
(シクロヘキシルピペラジニル)(2−フェニルキナゾリニル)ケトンである。
式(A) 式(B) 式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール(ベンズピロールは除く)であり、そして
R6は、水素またはアルキルである。
は、以下のような方法で合成することができる:
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール基(ベンズピロールは除く)である。いくつかの実施態様においては、R1の置換基が、アリール、アリールアルキル、アルコキシ、ハロゲン化アルキル、ハロゲン、ヒドロキシル、アジル、またはシアノ基である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール基(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール基(ベンズピロールは除く)である。
式(I)
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、またはヘテロサイクリックアルキルであり;そして
Arは、置換もしくは非置換のヘテロサイクリックアリール基であるが、ベンズピロールは除く。
(4−(4−フルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物4)
(4−(2,4−ジフルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物4a)
(2−ピリミジルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物5)
(2−ピリジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物6)
(4−(4−フルオロフェニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物11)
(4−(5−フルオロピリミド−2−イル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物12)
(4−(ピリミド−2−イル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物12a)
(4−(2−ピリジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物13)
(4−(4−フルオロフェニル)ピペラジニル)(ピロル−2−イル)ケトン(化合物14)
(4−(4−フルオロフェニル)ピペラジニル)(チエン−2−イル)ケトン(化合物15)
(4−(ピリミド−2−イル)ピペラジニル)(インダゾル−3−イル)ケトン(化合物17)
(4−(4−フルオロフェニル)ピペラジニル)(インダゾル−3−イル)ケトン(化合物18)
(4−(4−フルオロフェニル)ピペラジニル)(5−フルオロインダゾル−3−イル)ケトン(化合物19)
(4−(4−フルオロフェニル)ピペラジニル)(4,7−ジフルオロインダゾル−3−イル)ケトン(化合物20)
(4−(4−フルオロフェニル)ピペラジニル)(5−クロロインダゾル−3−イル)ケトン(化合物21)
(4−(2−ピリミジル)ピペラジニル)(5−イソプロピルピラゾル−3−イル)ケトン(化合物22)
(4−(4−フルオロフェニル)ピペラジニル)(5−イソプロピルピラゾル−3−イル)ケトン(化合物23)
(2−(4−フルオロピリミジル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物24)
(2−ピラジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物25)
(N−メチルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物26)
(N−イソプロピルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物27)
(N−シクロヘキシルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン(化合物28)
(4−(4−ピリジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物34)
(4−(2−ピラジニル)ピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物35)
(4−メチルピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物36)
(4−イソプロピルピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物37)
(シクロヘキシルピペラジニル)(2−フェニルキナゾリニル)ケトン(化合物38)
[インビトロ活性測定]
本出願の化合物の活性試験では、当分野において公知の方法を使用し、試験のための化合物は、先に実施例において記載された方法を使用して調製する。小膠細胞のIL−Iβ分泌に対する候補化合物の比阻害効率(efficiency of specific inhibition)に従って、適用の可能性を評価する。
1. ラットの小膠細胞BV2およびグリオーム細胞系C6を10%ウシ胎仔血清を用いたDMEM培地の中で培養すると、その第6〜15世代の培養細胞が、化合物活性選択のために適用することが可能である。24ウェルの細胞培養プレートの上に培養細胞を、50,000細胞/ウェルの濃度で接種し、1日間培養した後で、低血清培地(2%ウシ胎仔血清)に移して、さらに16時間培養する。その培地に、300ng/mL(BV2細胞の誘発のため)または1mg/mL(C6細胞の誘発のため)のLPS(サルモネラ・ティフィムチウム(Salmonella tiphimutium))を添加して、培養細胞のIL−1β分泌を誘発する。それと同時に、測定試料(DMSO≦0.1%)を200pM、20nM、2μM、および200μMの濃度で添加し、ブランクに溶媒対照として0.1%DMSOを添加する。
Claims (13)
- 式(I)によって表される化合物およびその薬学的に許容される塩。
R2、R3、R4、R5はそれぞれ、水素、ヒドロキシル、アジル、ニトリル、シアノ基、ハロゲン、アルキル、アルコキシ、シクロアルキル、アリール、アリールアルキル、ヘテロサイクリックアリール、およびヘテロサイクリックアルキルからなる群から選択され;そして
Arは、4−置換−6−置換−ピリダジン−3−イルであり、そして前記置換基がそれぞれ、アルキル、アルコキシ、ハロゲン化アルキル、アジル、アリール、アリールアルキル、およびアリールオキシからなる群より選択される。] - R1が、置換もしくは非置換のC1〜C6アルキル、置換もしくは非置換のC3〜C10サイクリックアルキル、置換もしくは非置換のC6〜C10アリール、または置換もしくは非置換の5〜10員のヘテロサイクリックアリールであるが、前記置換基がそれぞれ、アリール、アリールアルキル、アルキル、アルコキシ、置換アルキル、ハロゲン、ヒドロキシル、アジル、およびシアノ基からなる群より選択される、請求項1に記載の式(I)によって表される化合物およびその薬学的に許容される塩。
- R1が、4−フルオロフェニル、2,4−ビフルオロフェニル、ピリミジン−2−イル、ピリジン−2−イル、5−フルオロピリミジン−2−イル、ピラジン−2−イル、ピリジン−4−イル、メチル、イソプロピル、またはシクロヘキシルである、請求項1または2に記載の式(I)によって表される化合物およびその薬学的に許容される塩。
- R2、R3、R4、R5がそれぞれ水素である、請求項1〜3のいずれかに記載の式(I)によって表される化合物およびその薬学的に許容される塩。
- Arが、4−メチル−6−フェニルピリダジン−3−イルである、請求項1〜4のいずれかに記載の式(I)によって表される化合物およびその薬学的に許容される塩。
- 以下の化合物およびそれらの薬学的に許容される塩から選択される、請求項1〜5のいずれかに記載の式(I)によって表される化合物およびその薬学的に許容される塩。
(4−(4−フルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(4−(2,4−ジフルオロフェニル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピリミジルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピリジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−(4−フルオロピリミジル)ピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(2−ピラジニルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(N−メチルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;
(N−イソプロピルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン;または、
(N−シクロヘキシルピペラジニル)(4−メチル−6−フェニルピリダジニル)ケトン。 - 以下の反応を含む、請求項1〜6のいずれかに記載の化合物およびその薬学的に許容される塩を調製するための方法。
- 前記方法が、N,N−ジシクロヘキシルカルボジイミド(DCC)、N,N−ジイソプロピルカルボジイミド(DIC)、N−エチルカルボンイミドイル−N,N−ジメチルプロパン−1,3−ジアミン(EDC)、または1−エチル−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(EDCI)である、縮合剤の存在下に実施される、請求項7に記載の方法。
- 薬学的に許容されるキャリアならびに請求項1〜6のいずれかに記載の式(I)によって表される化合物またはその薬学的に許容される塩を含む、医薬品組成物。
- 小膠細胞のIL−1βの分泌を抑制するための医薬品組成物の調製における請求項1〜6のいずれかに記載の式(I)によって表される化合物またはその薬学的に許容される塩の使用。
- IL−1βによって媒介される神経炎症性疾患または病的状態を治療および予防するための医薬品組成物の調製における請求項1〜6のいずれかに記載の式(I)によって表される化合物またはその薬学的に許容される塩の使用。
- 前記疾患または病的状態が、老年痴呆(アルツハイマー病)、パーキンソン病、筋萎縮性側索硬化症、自己免疫疾患、プリオン病脳卒中、外傷性脳損傷、脊髄性筋萎縮症、散在性硬化症、てんかん、または神経因性疼痛である、請求項11に記載の使用。
- 前記疾患または病的状態が老年痴呆(アルツハイマー病)である、請求項12に記載の使用。
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