JP7279758B2 - テトラヒドロナフタレン誘導体 - Google Patents
テトラヒドロナフタレン誘導体 Download PDFInfo
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- JP7279758B2 JP7279758B2 JP2021153575A JP2021153575A JP7279758B2 JP 7279758 B2 JP7279758 B2 JP 7279758B2 JP 2021153575 A JP2021153575 A JP 2021153575A JP 2021153575 A JP2021153575 A JP 2021153575A JP 7279758 B2 JP7279758 B2 JP 7279758B2
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- Prior art keywords
- group
- tetrahydro
- compound
- acid
- elsd
- Prior art date
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- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 243
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000002837 carbocyclic group Chemical group 0.000 claims description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 claims description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 9
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 208000035217 Ring chromosome 1 syndrome Diseases 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 6
- DVDXHQUQCOAQFA-UHFFFAOYSA-N 1-[8-(2-naphthalen-1-ylethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]azetidine-3-carboxylic acid Chemical compound OC(=O)C1CN(C1)C1CCc2cccc(OCCc3cccc4ccccc34)c2C1 DVDXHQUQCOAQFA-UHFFFAOYSA-N 0.000 claims description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- XIMAYLMGLVYUOJ-UHFFFAOYSA-N 4-[6-(2-naphthalen-1-ylethoxy)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]butanoic acid Chemical compound OC(=O)CCCN1CCc2cccc(OCCc3cccc4ccccc34)c2CC1 XIMAYLMGLVYUOJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 3
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 3
- WABNRGRXPRMIQU-UHFFFAOYSA-N 4-[6-(3-phenylpropoxy)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]butanoic acid Chemical compound C1(=CC=CC=C1)CCCOC1=CC=CC=2CCN(CCC=21)CCCC(=O)O WABNRGRXPRMIQU-UHFFFAOYSA-N 0.000 claims description 3
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 3
- UHPPLJKGPABMEC-UHFFFAOYSA-N 1-[5-(3-phenylpropoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]azetidine-3-carboxylic acid Chemical compound C1CC2=C(CC1N3CC(C3)C(=O)O)C=CC=C2OCCCC4=CC=CC=C4 UHPPLJKGPABMEC-UHFFFAOYSA-N 0.000 claims description 2
- -1 1- methylpentyl Chemical group 0.000 description 168
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- 238000000105 evaporative light scattering detection Methods 0.000 description 85
- 230000014759 maintenance of location Effects 0.000 description 84
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 239000000203 mixture Substances 0.000 description 60
- 239000000243 solution Substances 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- 239000003814 drug Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 229940079593 drug Drugs 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 29
- 238000000034 method Methods 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 102100029802 Sphingosine 1-phosphate receptor 5 Human genes 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 230000000704 physical effect Effects 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 19
- 101710155451 Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 238000010511 deprotection reaction Methods 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- 239000013543 active substance Substances 0.000 description 11
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 10
- 208000035473 Communicable disease Diseases 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 239000003755 preservative agent Substances 0.000 description 10
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 8
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000004770 neurodegeneration Effects 0.000 description 8
- 208000015122 neurodegenerative disease Diseases 0.000 description 8
- DTHHUAXKOMWYBI-UHFFFAOYSA-N oxadiazolidine Chemical compound C1CONN1 DTHHUAXKOMWYBI-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 235000013355 food flavoring agent Nutrition 0.000 description 7
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 7
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 230000002708 enhancing effect Effects 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 230000003449 preventive effect Effects 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 5
- 208000010201 Exanthema Diseases 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 101000653759 Homo sapiens Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 5
- 201000005884 exanthem Diseases 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
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- 201000001441 melanoma Diseases 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- UOCWTLBPYROHEF-UHFFFAOYSA-N methyl azetidine-3-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1CNC1 UOCWTLBPYROHEF-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
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- 239000000843 powder Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
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- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 4
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 4
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 4
- UUZJJNBYJDFQHL-UHFFFAOYSA-N 1,2,3-triazolidine Chemical compound C1CNNN1 UUZJJNBYJDFQHL-UHFFFAOYSA-N 0.000 description 4
- AGSHYIAAUGKFEA-UHFFFAOYSA-N 1,2,5-oxadiazolidine Chemical compound C1CNON1 AGSHYIAAUGKFEA-UHFFFAOYSA-N 0.000 description 4
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- BKWQKVJYXODDAC-UHFFFAOYSA-N 1,2-dihydropyridazine Chemical compound N1NC=CC=C1 BKWQKVJYXODDAC-UHFFFAOYSA-N 0.000 description 4
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 4
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- SCEIUGQQBYRBPP-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-azepine Chemical compound C1CCC=CNC1 SCEIUGQQBYRBPP-UHFFFAOYSA-N 0.000 description 4
- YYVKQFQZKSLYFN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-diazepine Chemical compound C1CNNC=CC1 YYVKQFQZKSLYFN-UHFFFAOYSA-N 0.000 description 4
- GLCYMVDVOVIDBB-UHFFFAOYSA-N 2,3,4,5-tetrahydrooxadiazepine Chemical compound C1CC=CONN1 GLCYMVDVOVIDBB-UHFFFAOYSA-N 0.000 description 4
- ABQOPHYTASMWLA-UHFFFAOYSA-N 2,3,4,5-tetrahydrooxazepine Chemical compound C1CNOC=CC1 ABQOPHYTASMWLA-UHFFFAOYSA-N 0.000 description 4
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 4
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical compound C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 4
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 4
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- BEWVAZNECYSPMT-UHFFFAOYSA-N 2,3-dihydro-1h-azepine Chemical compound C1CC=CC=CN1 BEWVAZNECYSPMT-UHFFFAOYSA-N 0.000 description 4
- QHYXWSXPPUTDRA-UHFFFAOYSA-N 2,3-dihydro-1h-diazepine Chemical compound C1NNC=CC=C1 QHYXWSXPPUTDRA-UHFFFAOYSA-N 0.000 description 4
- PZJFUNZDCRKXPZ-UHFFFAOYSA-N 2,5-dihydro-1h-tetrazole Chemical compound C1NNN=N1 PZJFUNZDCRKXPZ-UHFFFAOYSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 4
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- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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Description
一般式(a)
[1] 一般式(I-1)
Yは、(1)-CH2-、(2)-NH-、(3)-S-、または(4)-O-を表し、
WAは、(1)C1~12アルキレン基、(2)C2~12アルケニレン基、(3)C2~12アルキニレン基、(4)-C1~12アルキレン-O-、(5)-C2~12アルケニレン-O-、(6)-C2~12アルキニレン-O-、(7)-C1~12アルキレン-ring2-、(8)-C2~12アルケニレン-ring2-、または(9)-C2~12アルキニレン-ring2-を表し、基中、アルキレン基、アルケニレン基、アルキニレン基は1~5個のハロゲン原子で置換されていてもよく、
R1は、(1)-L-、(2)-L-ring3-、または(3)-L-NR13-を表し、
R2は、(1)ハロゲン原子、(2)C1~4アルキル基、(3)C1~4ハロアルキル基、(4)C1~4アルコキシ基、または(5)C1~4ハロアルコキシ基を表し、
R3-1は、(1)ハロゲン原子、(2)C1~4アルキル基、(3)C1~4ハロアルキル基、(4)C1~4アルコキシ基、(5)C1~4ハロアルコキシ基、(6)ニトリル基、(7)-S-C1~4アルキル基、(8)-S-C1~4ハロアルキル基、または(9)オキソ基を表し、ここで、R3-1で表されるC1~4アルキル基またはC1~4ハロアルキル基が分枝鎖の場合、同一の炭素原子から分枝したC1~2アルキル基は一緒になってC3~4の飽和炭素環を形成してもよく、
R13は、(1)水素原子、または(2)C1~4アルキル基を表し、
Lは、(1)結合手、または(2)式
Zは、(1)C1~8アルキル基で置換されていてもよいカルボキシル基、(2)C1~8アルキル基で置換されていてもよい水酸基、(3)C1~8アルキル基で置換されていてもよいヒドロキサム酸基、(4)C1~8アルキル基で置換されていてもよいスルホン酸基、(5)C1~8アルキル基で置換されていてもよいボロン酸基、(6)C1~8アルキル基で置換されていてもよいカルバモイル基、(7)C1~8アルキル基で置換されていてもよいスルファモイル基、(8)C1~8アルキル基で置換されていてもよいスルホキシイミン基、または(9)テトラゾリル基を表し、
ring1は、(1)C3~10の炭素環、または(2)3~10員のヘテロ環を表し、
ring2は、(1)C3~7の炭素環、または(2)3~7員のヘテロ環を表し、
ring3は、(1)C1~4アルキル基で置換されていてもよいC3~7の炭素環、または(2)C1~4アルキル基で置換されていてもよい3~7員のヘテロ環を表し、
mは、0~2の整数を表し、
nは、0~2の整数を表し、
pは、0~3の整数を表し、
qは、0~5の整数を表し、
vは、0~1の整数を表し、
pが2以上のとき、複数のR2は同じでも異なってもよく、
qが2以上のとき、複数のR3-1は同じでも異なってもよく、
tが2以上のとき、複数のR11は同じでも異なってもよく、
tが2以上のとき、複数のR12は同じでも異なっていてもよい。]
で示される化合物、またはその薬学的に許容される塩、
[2] 一般式(I)
R3は、(1)ハロゲン原子、(2)C1~4アルキル基、(3)C1~4ハロアルキル基、(4)C1~4アルコキシ基、(5)C1~4ハロアルコキシ基、(6)ニトリル基、(7)-S-C1~4アルキル基、または(8)-S-C1~4ハロアルキル基を表し、ここで、R3で表されるC1~4アルキル基またはC1~4ハロアルキル基が分枝鎖の場合、同一の炭素原子から分枝したC1~2アルキル基は一緒になってC3~4の飽和炭素環を形成してもよく、
qが2以上のとき、複数のR3は同じでも異なっていてもよく、
その他の記号は前記[1]と同じ意味を表す。]
で示される前記[1]記載の化合物、またはその薬学的に許容される塩、
[3] Yが、-CH2-、または-O-である前記[1]または[2]記載の化合物、またはその薬学的に許容される塩、
[4] ring1が、C3~10の炭素環である前記[1]~[3]記載の化合物、またはその薬学的に許容される塩、
[5] ring3が、C1~4アルキル基で置換されていてもよいC3~7の飽和炭素環、またはC1~4アルキル基で置換されていてもよい3~7員の飽和ヘテロ環である前記[1]~[4]記載の化合物、またはその薬学的に許容される塩、
[6] Zが、C1~8アルキル基で置換されていてもよいカルボキシル基である前記[1]~[5]に記載の化合物、またはその薬学的に許容される塩、
[7] 前記[1]記載の一般式(I-1)で示される化合物、またはその薬学的に許容される塩を含有してなる医薬組成物、
[8] S1P5結合および/または調節剤である前記[7]記載の医薬組成物、
[9] S1P5介在性疾患の予防および/または治療剤である前記[7]記載の医薬組成物、
[10] S1P5介在性疾患が、神経変性疾患、自己免疫疾患、感染症または癌である前記[9]記載の医薬組成物、
[11] 神経変性疾患が、統合失調症、ビンスワンガー病、多発性硬化症、視神経脊髄炎、アルツハイマー病、認知障害、筋萎縮性側索硬化症、または脊髄小脳変性症である前記[10]記載の医薬組成物、
[12] 前記[1]記載の一般式(I-1)で示される化合物、またはその薬学的に許容される塩の有効量を哺乳動物に投与することを特徴とする、S1P5介在性疾患の予防および/または治療方法、
[13] S1P5介在性疾患の予防および/または治療のための前記[1]記載の一般式(I-1)で示される化合物、またはその薬学的に許容される塩、および
[14] S1P5介在性疾患の予防および/または治療剤を製造するための前記[1]記載の一般式(I-1)で示される化合物、またはその薬学的に許容される塩の使用等に関する。
本発明において、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
本発明において、C1~2アルキル基としては、メチル、エチル基が挙げられる。
本発明において、C1~6アルキレン基としては、例えば、メチレン、エチレン、プロピレン、ブチレン、ペンチレン、ヘキシレン基が挙げられる。
本発明において、C2~6アルケニレン基としては、例えば、エテニレン、プロペニレン、ブテニレン、ペンテニレン、ヘキセニレン、ブタジエニレン、ペンタジエニレン、ヘキサジエニレン基が挙げられる。
本発明において、C2~6アルキニレン基としては、例えば、エチニレン、プロピニレン、ブチニレン、ペンチニレン、ヘキシニレン、ブタジイニレン、ペンタジイニレン、ヘキサジイニレン基が挙げられる。
本発明において、C3~4の飽和炭素環としては、シクロプロパン、シクロブタン環が挙げられる。
本発明において、WA、またはWの結合の向きは、特に限定されない。
本発明において、R1は、-L-ring3-が好ましい。
本発明において、R1の結合の向きは、特に限定されない。
本発明において、ring1としては、3~7員のヘテロ環も好ましく、チアゾール、イソチアゾール、ピリジン、ピロリジン、テトラヒドロピラン、ピラゾール環がより好ましい。
本発明において、ring3としては、C1~4アルキル基で置換されていてもよい3~7員の飽和ヘテロ環も好ましく、アゼチジン、ピロリジン環がより好ましい。
本発明において、4-[6-(3-フェニルプロポキシ)-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル]ブタン酸、4-{6-[2-(1-ナフチル)エトキシ]-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル}ブタン酸、または1-{8-[2-(1-ナフチル)エトキシ]-1,2,3,4-テトラヒドロ-2-ナフタレニル}-3-アゼチジンカルボン酸がより好ましい。
本発明においては、特に指示しない限り異性体はこれをすべて包含する。例えば、アルキル基には直鎖のものおよび分枝鎖のものが含まれる。さらに、二重結合、環、縮合環における幾何異性体(E体、Z体、シス体、トランス体)、不斉炭素原子の存在等による光学異性体(R、S体、α、β配置、エナンチオマー、ジアステレオマー)、旋光性を有する光学活性体(D、L、d、l体)、クロマトグラフ分離による極性体(高極性体、低極性体)、平衡化合物、回転異性体、これらの任意の割合の混合物、ラセミ混合物は、すべて本発明に含まれる。また、本発明においては、互変異性体による異性体をもすべて包含する。
本発明化合物は、公知の方法、例えば、Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)に記載された方法、または実施例に示す方法等を適宜改良し、組み合わせて用いることで製造することができる。
この保護基の脱保護反応は公知であり、以下の方法で行うことができる。例えば、(1)アルカリ加水分解による脱保護反応、(2)酸性条件下における脱保護反応、(3)加水素分解による脱保護反応、(4)シリル基の脱保護反応、(5)金属を用いる脱保護反応、(6)金属錯体を用いる脱保護反応等が挙げられる。
(1)アルカリ加水分解による脱保護反応は、例えば有機溶媒(例えば、メタノール、テトラヒドロフラン、ジオキサン等)中、アルカリ金属の水酸化物(例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等)、アルカリ土類金属の水酸化物(例えば、水酸化バリウム、水酸化カルシウム等)または炭酸塩(例えば、炭酸ナトリウム、炭酸カリウム等)あるいはその水溶液もしくはこれらの混合物を用いて、0~40℃で行われる。
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明化合物は、S1P5(EDG-8)受容体結合活性を有し、これを調節するため、S1P5介在性疾患の予防および/または治療剤として有用である。S1P5介在性疾患としては、神経変性疾患、自己免疫疾患、感染症、癌等が挙げられる。
1)その化合物の予防および/または治療効果の補完および/または増強、
2)その化合物の動態・吸収改善、投与量の低減、および/または
3)その化合物の副作用の軽減
のために、他の薬物と組み合わせて、併用薬として投与してもよい。
また、本発明化合物と組み合わせる併用薬としては、現在までに見出されているものだけでなく今後見出されるものも含まれる。
また、本発明化合物の癌に対する予防および/または治療効果の補完および/または増強のために、例えば、放射線療法、細胞療法(例えば、キメラ抗原受容体発現T細胞(CAR-T)療法やT細胞受容体(TCR)療法等)等を併用してもよい。
例えば、吸入用液剤の場合には、防腐剤(例えば、塩化ベンザルコニウム、パラベン等)、着色剤、緩衝化剤(例えば、リン酸ナトリウム、酢酸ナトリウム等)、等張化剤(例えば、塩化ナトリウム、濃グリセリン等)、増粘剤(例えば、カルボキシビニルポリマー等)、吸収促進剤等を必要に応じて適宜選択して調製される。
条件A:{カラム:YMC Triart C18(粒子径:1.9 x 10-6 m;カラム長:30 x 2.0 mm I.D.);流速:1.0mL/min;カラム温度:30℃;移動相(A):0.1%トリフルオロ酢酸水溶液;移動相(B):0.1%トリフルオロ酢酸-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]95:5;[0.1分]95:5;[1.2分]5:95;[1.4分]5:95;[1.41分]95:5;[1.5分]95:5;検出器:UV(PDA)、ELSD、MS}、または
条件B{カラム:Waters ACQUITY BEH C18(粒子径:1.7 x 10-6 m;カラム長:30 x 2.1 mm I.D.);流速:1.0mL/min;カラム温度:40℃;移動相(A):0.1%ギ酸水溶液;移動相(B):0.1%ギ酸-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]95:5;[0.1分]95:5;[1.2分]5:95;[1.4分]5:95;[1.41分]95:5;[1.5分]95:5;検出器:UV(PDA)、ELSD、MS}
のいずれかで行った。
本明細書中に用いた化合物名は、一般的にIUPACの規則に準じて命名を行なうコンピュータプログラム、Advanced Chemistry Development社のACD/Name(登録商標)を用いるか、または、IUPAC命名法に準じて命名したものである。
5-ヒドロキシ-3,4-ジヒドロナフタレン-2(1H)-オン(100mg)(CAS登録番号:35697-10-0)の塩化メチレン(5mL)溶液に、メチル アゼチジン-3-カルボキシラート 塩酸塩(111mg)(CAS登録番号:100202-39-9)および水素化トリアセトキシホウ素ナトリウム(260mg)を加え、混合物を室温で16時間撹拌した。反応液を水で希釈し、塩化メチレンで抽出した。有機層を水、飽和食塩水で順次洗浄し、硫酸ナトリウムにて乾燥し、ろ過後濃縮し、以下の物性値を有する標題化合物(110mg)を得た。得られた化合物は精製することなく、次の反応に用いた。
MS (M+H): 262。
実施例1で製造した化合物(110mg)および炭酸カリウム(174mg)のN,N-ジメチルホルムアミド(DMF)(3mL)混合溶液に、(E)-1-(3-クロロプロパ-1-エン-1-イル)-4-(トリフルオロメチル)ベンゼン(111mg)を加え、混合物を70℃で3時間撹拌した。反応液を室温に戻し、水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、硫酸ナトリウムで乾燥し、ろ過後濃縮し、以下の物性値を有する標題化合物(100mg)を得た。得られた化合物は精製することなく、次の反応に用いた。
MS (M+H): 446。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H):416;
1H-NMR (CDCl3):δ 8.10, 7.86, 7.75, 7.56-7.36, 7.02, 6.67, 6.62, 4.30, 3.74, 3.65-3.52, 3.42-3.24, 2.88-2.61, 2.46-2.34, 2.15, 1.89-1.77, 1.50-1.33。
(LC-MS/ELSD):(保持時間:0.94分、条件A);
MS (M+H): 432;
1H-NMR (CD3OD):δ 7.61, 7.14, 6.89 - 6.81, 6.76, 6.63, 4.75, 4.47 - 4.38, 3.69 - 3.62, 3.19, 3.04, 2.80 - 2.70, 2.27 - 2.24, 1.77 - 1.66。
5-ヒドロキシ-3,4-ジヒドロナフタレン-2(1H)-オンまたはその代わりに相当するアルコール化合物、メチル アゼチジン-3-カルボキシラート 塩酸塩またはその代わりに相当するアミン化合物、および(E)-1-(3-クロロプロパ-1-エン-1-イル)-4-(トリフルオロメチル)ベンゼンまたはその代わりに相当するハロゲン化合物を用いて、実施例1→実施例2→実施例3と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
(LC-MS/ELSD):(保持時間:0.94分、条件A);
MS (M+H): 446。
(LC-MS/ELSD):(保持時間:0.86分、条件B);
MS (M+H): 432。
(LC-MS/ELSD):(保持時間:0.86分、条件B);
MS (M+H): 434。
(LC-MS/ELSD):(保持時間:0.86分、条件A);
MS (M+H): 366。
(LC-MS/ELSD):(保持時間:0.88分、条件A);
MS (M+H): 402。
水素化ナトリウム(1.38g)のTHF(40mL)懸濁液に0℃でトリエチルホスホノアセタート(7.73g)のTHF(10mL)溶液を加え、反応混合物を室温で30分撹拌した。4-(トリフルオロメチル)ベンズアルデヒド(CAS登録番号:455-19-6)を加え、室温で1時間撹拌した。反応混合物を10%硫酸水素ナトリウム水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:0→9:1)によって精製することにより、以下の物性値を有する標題化合物(5.92g)を得た。
TLC:Rf 0.78 (ヘキサン:酢酸エチル=8:2);
1H-NMR(CDCl3):δ 7.69, 7.64, 6.51, 4.28, 1.35。
実施例4で製造した化合物(5.91g)のTHF(120mL)溶液に、0℃で水素化ジイソブチルアルミニウムの1Mトルエン溶液(50.8mL)を加え、0℃で30分撹拌した。反応混合物を2N塩酸水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=80:20→55:45)によって精製することにより、以下の物性値を有する標題化合物(4.46g)を得た。
TLC:Rf 0.17 (ヘキサン:酢酸エチル=8:2);
1H-NMR(CDCl3):δ 7.56, 7.47, 6.66, 6.46, 4.37, 1.53。
4-(トリフルオロメチル)フェノール(500mg)(CAS登録番号:402-45-9)のDMF(15mL)溶液に、炭酸カリウム(853mg)および2-ブロモエタノール(771mg)を加え、80℃で16時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=85:15→45:55)によって精製することにより、以下の物性値を有する標題化合物(226mg)を得た。
1H-NMR(CDCl3):δ 7.55, 6.99, 4.15 - 4.10, 4.03 - 3.96, 1.98。
3-フェニル-2-プロピン-1-オール(800mg)(CAS登録番号:1504-58-1)とキノリン(780mg)のエタノール(20mL)溶液にリンドラー触媒(160mg)を加え、水素雰囲気下、室温で1時間撹拌した。反応混合物をセライト(商品名)でろ過後、ろ液を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=90:10→60:40)によって精製することにより、以下の物性値を有する標題化合物(548mg)を得た。
1H-NMR(CDCl3):δ 7.39 - 7.19, 6.58, 5.89, 4.45, 1.47。
ジエチル亜鉛の1Mヘキサン溶液(8.9mL)をジクロロメタン(7.0mL)に希釈し、0℃に冷却した。トリフルオロ酢酸(0.689mL)を加え、0℃で20分撹拌した。さらにジヨードメタン(0.719mL)を加え0℃で20分撹拌した。そこに実施例7で製造した化合物(400mg)のジクロロメタン(3mL)溶液を加え、0℃で30分撹拌し、室温で3時間撹拌した。反応混合物を1N塩酸水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=90:10→60:40)によって精製することにより、以下の物性値を有する標題化合物(57.8mg)を得た。
1H-NMR(CDCl3):δ 7.36, 7.16, 3.48, 3.27, 2.29, 1.51, 1.05, 0.88。
窒素雰囲気下、5-ヒドロキシ-3,4-ジヒドロナフタレン-1(2H)-オン(10.1g)(CAS登録番号:28315-93-7)、臭化ベンジル(12.8g)および炭酸カリウム(10.3g)のDMF(100mL)混合溶液を、室温で4時間撹拌した。混合液を酢酸エチルで希釈し、水を注ぎ、酢酸エチルで抽出した。有機層を、水、5%塩化リチウム水溶液、飽和食塩水で順次洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→60:40)によって精製することにより、以下の物性値を有する標題化合物(13.8g)を得た。
MS (M+H): 253。
実施例9で製造した化合物(7.83g)およびメチルトリフェニルホスホニウムヨージド(13.8g)のTHF(100mL)懸濁液に、カリウム tert-ブトキシド(46.5mL、THFの1M溶液)を0℃で滴下した。反応混合液を室温で1時間撹拌した。混合液に冷水を注ぎ、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順次洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→80:20)によって精製することにより、以下の物性値を有する標題化合物(6.57g)を得た。
1H-NMR (CDCl3): δ 7.45 - 7.25, 7.11, 6.79, 5.46, 5.07, 4.96, 2.84, 2.52 - 2.48, 1.93 - 1.87。
ヨードベンゼン(6.42g)、m-クロロ過安息香酸(7.80g)およびp-トルエンスルホン酸(6.0g)を、順次、1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール/塩化メチレン溶液(1:6、70mL)に加えた。30分間の撹拌後、混合液に水(12mL)および実施例10で製造した化合物(6.57g)を0℃で加えた。反応液を30分間撹拌し、飽和炭酸水素ナトリウム溶液で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→80:20)によって精製することにより、以下の物性値を有する標題化合物(5.5g)を得た。
1H-NMR (CDCl3):δ 7.45 - 7.32, 7.13, 6.89, 6.79, 5.08, 3.73, 3.10 - 3.05, 2.54, 2.01 - 1,92。
実施例11で製造した化合物(1.02g)およびメチル アゼチジン-3-カルボキシラート 塩酸塩(700mg)を用いて、実施例1と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物(820mg)を得た。
MS (M+H): 366。
実施例12で製造した化合物(820mg)および10%パラジウム-炭素(400mg)の酢酸エチル/メタノール(1:1、20mL)の混合溶液に、室温にて16時間水素雰囲気下で撹拌した。反応混合液を、珪藻土を用いてろ過し、ろ液を減圧濃縮し、以下の物性値を有する標題化合物(590mg)を得た。
1H-NMR (CDCl3):δ 6.94, 6.68, 6.61, 3.69, 3.70 - 3.64, 3.58 - 3.53, 3.34 - 2.23, 3.19 - 3.13, 2.76 - 2.63, 2.50 - 2.43, 2.19 - 2.14, 1.96 - 1.94, 1.50 - 1.42, 1.38 - 1.32。
実施例13で製造した化合物(30mg)のTHF(1.0mL)溶液に、実施例5で製造した化合物(26.4mg)およびアゾジカルボニルジピペリジン(55.0mg)およびトリブチルホスフィンを加え、室温で16時間撹拌した。反応混合物を減圧濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=40:60→0:100)によって精製することにより、以下の物性値を有する標題化合物(44.3mg)を得た。
1H-NMR(CDCl3):δ 7.57, 7.50, 7.05, 6.80 - 6.70, 6.51, 4.68, 3.70, 3.70 - 3.59, 3.59 - 3.48, 3.40 - 3.20, 2.80 - 2.60, 2.49, 2.15, 2.02 - 1.85, 1.70 - 1.15。
(LC-MS/ELSD):(保持時間:0.95分、条件A);
MS (M+H): 446。
実施例11で製造した化合物およびメチル アゼチジン-3-カルボキシラート 塩酸塩の代わりに相当するアミン誘導体を用いて、実施例12→実施例13→実施例14→実施例15と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
(LC-MS/ELSD):(保持時間:0.96分、条件A);
MS (M+H): 460。
6-メトキシ-2,3,4,5-テトラヒドロ-1H-3-ベンズアゼピン(1.0g)(CAS登録番号:90047-53-3)のDMF(15mL)溶液に炭酸カリウム(1.56g)およびエチル 4-ブロモブタノアート(1321mg)を加え、室温で16時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=60:40→10:90)によって精製することにより、以下の物性値を有する標題化合物(1.37g)を得た。
1H-NMR(CDCl3):δ 7.07, 6.74, 6.72, 4.13, 3.79, 3.05 - 2.95, 2.94 - 2.86, 2.65 - 2.54, 2.51, 2.37, 1.83, 1.26。
実施例16で製造した化合物(1.37g)のジクロロメタン(23mL)溶液に、0℃でボロントリブロミドの1Mジクロロメタン溶液(9.4mL)を加え、0℃で2時間撹拌した。反応混合物にボロントリブロミドの1Mジクロロメタン溶液(4.7mL)を加え、0℃でさらに2時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=70:30→20:70)によって精製することにより、以下の物性値を有する標題化合物(591mg)を得た。
1H-NMR(CDCl3):δ 6.95, 6.68, 6.62, 4.13, 3.05 - 2.95, 2.95 - 2.85, 2.71 - 2.58, 2.53, 2.35, 1.86, 1.26。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H): 434。
6-メトキシ-2,3,4,5-テトラヒドロ-1H-3-ベンズアゼピン、またはその代わりに相当するジヒドロイソキノリン化合物、エチル4-ブロモブタノアートまたはその代わりに相当するハロゲン化エステル化合物、および以下の(i)~(iv)の化合物群から選択されるいずれか1つの化合物((i)実施例5で製造した化合物、(ii)実施例6で製造した化合物、(iii)実施例8で製造した化合物、(iv)(i)~(iii)の代わりに相当するアルコール化合物)を用いて、実施例16→実施例17→実施例18と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
(LC-MS/ELSD):(保持時間:0.81分、条件B);
MS (M+H): 390。
実施例18(2):4-[8-({(2E)-3-[4-(トリフルオロメチル)フェニル]-2-プロペン-1-イル}オキシ)-3,4-ジヒドロ-2(1H)-イソキノリニル]ブタン酸 トリフルオロ酢酸塩
(LC-MS/ELSD):(保持時間:0.83分、条件B);
MS (M+H): 420。
(LC-MS/ELSD):(保持時間:0.96分、条件A);
MS (M+H): 394。
(LC-MS/ELSD):(保持時間:0.86分、条件A);
MS (M+H): 418。
(LC-MS/ELSD):(保持時間:0.93分、条件A);
MS (M+H): 434。
(LC-MS/ELSD):(保持時間:0.98分、条件A);
MS (M+H): 460。
(LC-MS/ELSD):(保持時間:0.91分、条件A);
MS (M+H): 406。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H): 420。
(LC-MS/ELSD):(保持時間:0.93分、条件A);
MS (M+H): 448。
(LC-MS/ELSD):(保持時間:0.80分、条件B);
MS (M+H): 438;
1H-NMR (CDCl3):δ 7.57, 7.13, 7.01, 6.82, 6.78, 4.41-4.27, 3.30-2.52, 1.92-1.81。
(LC-MS/ELSD):(保持時間:0.79分、条件B);
MS (M+H): 368;
1H-NMR (CD3OD):δ 7.34-7.24, 7.23-7.15, 7.09, 6.76-6.70, 3.94, 3.60-2.50, 2.19-2.04, 1.96-1.86。
(LC-MS/ELSD):(保持時間:0.71分、条件B);
MS (M+H): 370;
1H-NMR (CD3OD):δ 7.35-7.27, 7.13, 7.01-6.89, 6.84, 6.76, 4.31, 3.32-2.70, 2.63-2.56, 1.97-1.85。
(LC-MS/ELSD):(保持時間:0.91分、条件A);
MS (M+H): 396。
(LC-MS/ELSD):(保持時間:0.95分、条件B);
MS (M+H): 374。
(LC-MS/ELSD):(保持時間:0.82分、条件B);
MS (M+H): 432。
(LC-MS/ELSD):(保持時間:0.86分、条件B);
MS (M+H): 394。
(LC-MS/ELSD):(保持時間:0.82分、条件B);
MS (M+H): 380。
MS (M+H): 404;
1H-NMR (CD3OD):δ 8.07, 7.87, 7.79-7.72, 7.56-7.39, 7.04, 6.75-6.66, 4.28, 3.56, 3.30-2.50, 2.00-1.86。
(LC-MS/ELSD):(保持時間:0.83分、条件B);
MS (M+H): 404。
(LC-MS/ELSD):(保持時間:0.90分、条件B);
MS (M+H): 408。
(LC-MS/ELSD):(保持時間:0.85分、条件A);
MS (M+H): 380。
(LC-MS/ELSD):(保持時間:0.81分、条件A);
MS (M+H): 354。
(LC-MS/ELSD):(保持時間:0.90分、条件A);
MS (M+H): 382。
(LC-MS/ELSD):(保持時間:0.94分、条件A);
MS (M+H): 396。
(LC-MS/ELSD):(保持時間:0.83分、条件A);
MS (M+H): 366。
(LC-MS/ELSD):(保持時間:0.88分、条件A);
MS (M+H): 380。
(LC-MS/ELSD):(保持時間:0.83分、条件B);
MS (M+H): 390。
(LC-MS/ELSD):(保持時間:0.77分、条件A);
MS (M+H):306。
(LC-MS/ELSD):(保持時間:0.82分、条件A);
MS (M+H):320。
(LC-MS/ELSD):(保持時間:0.87分、条件A);
MS (M+H):334。
(LC-MS/ELSD):(保持時間:0.93分、条件A);
MS (M+H):348。
MS (M+H):362;
1H-NMR (CD3OD):δ 7.06, 6.80, 6.71, 3.89, 3.75-3.55, 3.18-2.86, 2.84-2.65, 2.37, 2.03-1.88, 1.76-1.62, 1.47-1.34, 1.34-1.13, 0.81。
(LC-MS/ELSD):(保持時間:0.78分、条件A);
MS (M+H):372。
(LC-MS/ELSD):(保持時間:0.91分、条件A);
MS (M+H):347。
(LC-MS/ELSD):(保持時間:0.53分、条件A);
MS (M+H):368。
(LC-MS/ELSD):(保持時間:0.51分、条件A);
MS (M+H):368。
(LC-MS/ELSD):(保持時間:0.83分、条件A);
MS (M+H):331。
(LC-MS/ELSD):(保持時間:0.85分、条件A);
MS (M+H):385;
1H-NMR (CD3OD):δ 7.24, 7.19, 7.02, 6.89, 6.84, 4.01, 3.89-3.62, 3.29-3.18, 3.16-2.75, 2.83, 2.50, 2.18-2.01。
(LC-MS/ELSD):(保持時間:0.63分、条件A);
MS (M+H):374。
(LC-MS/ELSD):(保持時間:0.71分、条件A);
MS (M+H):374。
(LC-MS/ELSD):(保持時間:0.60分、条件A);
MS (M+H):374。
MS (M+H):375;
1H-NMR (CD3OD):δ 7.19, 6.93, 6.84, 4.01, 3.95, 3.87-3.66, 3.44, 3.30-3.18, 3.18-2.96, 2.94-2.77, 2.49, 2.14-1.99, 1.91-1.79, 1.69, 1.65-1.52, 1.51-1.39, 1.29。
(LC-MS/ELSD):(保持時間:0.87分、条件A);
MS (M+H):421;
1H-NMR (CD3OD):δ 7.72, 7.63-7.55, 7.45, 7.19, 6.94, 6.85, 4.33-4.21, 3.82-3.62, 3.29-2.99, 2.98-2.71, 2.49, 2.13-1.97。
(LC-MS/ELSD):(保持時間:0.91分、条件A);
MS (M+H):347。
(LC-MS/ELSD):(保持時間:0.64分、条件A);
MS (M+H):371。
6-メトキシ-2,3,4,5-テトラヒドロ-1H-3-ベンズアゼピン(200mg)のジクロロメタン(5.0mL)溶液に、0℃でボロントリブロミドの1Mジクロロメタン溶液(2.54mL)を加え、0℃で5時間撹拌した。反応混合物を-78℃に冷却し、メタノールを加え、-78℃で15分撹拌した。反応混合物を室温へ昇温し、しばらく撹拌したのちに減圧濃縮した。得られた残さのTHF(5.0mL)懸濁液に、2N水酸化ナトリウム水溶液(1.41mL)、ジ-tert-ブチルジカーボネート(265mg)を加え、室温で6時間撹拌した。反応混合物を1N塩酸水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→75:25)によって精製することにより、以下の物性値を有する標題化合物(286mg)を得た。
1H-NMR(CDCl3):δ 6.97, 6.71, 6.64, 4.91, 3.60 - 3.50, 3.02 - 2.94, 2.93 - 2.86, 1.48。
実施例19で製造した化合物、および実施例5で製造した化合物を用いて、実施例14と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物(286mg)を得た。
1H-NMR(CDCl3):δ 7.58, 7.51, 7.08, 7.83 - 6.71, 6.51, 4.70, 3.62 - 3.48, 3.12 - 3.00, 2.98 - 2.86, 1.47。
実施例20で製造した化合物(190mg)のメタノール(1.0mL)溶液、酢酸エチル(1.0mL)懸濁液に0℃で4N塩酸水溶液(6.0mL)を加え、室温で1.5時間撹拌した。反応混合物を減圧濃縮することにより、以下の物性値を有する標題化合物(157mg)を得た。
1H-NMR(DMSO-d6):δ 9.05, 7.71, 7.14, 6.97, 6.89 - 6.79, 6.69, 4.75, 3.26 - 2.99。
実施例21で製造した化合物、メチル アゼチジン-3-カルボキシラート 塩酸塩の代わりにメチル 3-オキソシクロブタンカルボキシラート(CAS登録番号:695-95-4)を用いて、実施例1と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
(実施例22(1))1H-NMR (CDCl3):δ 7.58, 7.51, 7.06, 6.78, 6.77, 6.73, 6.51, 4.68, 3.68, 3.15-3.00, 2.95-2.85, 2.80-2.67, 2.51-2.28, 2.25-2.11。
(実施例22(2))1H-NMR (CDCl3):δ 7.58, 7.51, 7.07, 6.79, 6.78, 6.74, 6.51, 4.69, 3.71, 3.20-2.82, 2.55-2.18。
実施例23(2):3-[6-({(2E)-3-[4-(トリフルオロメチル)フェニル]-2-プロペン-1-イル}オキシ)-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル]シクロブタンカルボン酸(高極性体)
実施例23(1):(LC-MS/ELSD):(保持時間:0.85分、条件B);
MS (M+H): 446。
実施例23(2):(LC-MS/ELSD):(保持時間:0.86分、条件B);
MS (M+H): 446。
6-メトキシ-2,3,4,5-テトラヒドロ-1H-3-ベンズアゼピン、実施例5で製造した化合物またはその代わりに相当するアルコール化合物、および3-オキソシクロブタンカルボキシラートまたはその代わりに相当する環状ケトン化合物を用いて、実施例19→実施例20→実施例21→実施例22(1)または(2)→実施例23(1)または(2)と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
(LC-MS/ELSD):(保持時間:0.85分、条件B);
MS (M+H): 446。
実施例23(4):rel-(1R,2S)-2-{[6-({(2E)-3-[4-(トリフルオロメチル)フェニル]-2-プロペン-1-イル}オキシ)-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル]メチル}シクロプロパンカルボン酸
(LC-MS/ELSD):(保持時間:0.86分、条件B);
MS (M+H): 446。
(LC-MS/ELSD):(保持時間:0.94分、条件A);
MS (M+H): 460。
(LC-MS/ELSD):(保持時間:0.95分、条件A);
MS (M+H): 460。
(LC-MS/ELSD):(保持時間:0.93分、条件A);
MS (M+H): 460。
(LC-MS/ELSD):(保持時間:0.88分、条件A);
MS (M+H): 416。
(LC-MS/ELSD):(保持時間:0.87分、条件A);
MS (M+H): 416。
実施例19で製造した化合物(132mg)の水(2.0mL)懸濁液にブタノール(0.4mL)およびジソジウム 3,7-ジオキシド-2,4,6,8,9-ペンタオキサ-1,3,5,7-テトラボラビシクロ[3,3,1]ノナン(404mg)を加え、60℃で10分撹拌した。反応混合物に37%ホルムアルデヒド水溶液(1.0mL)を加え、60℃で72時間撹拌した。反応混合物を1N塩酸水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=90:10→50:50)によって精製することにより、以下の物性値を有する標題化合物(80.1mg)を得た。
1H-NMR(CDCl3):δ 7.68,6.78, 6.62, 4.84, 3.58 - 3.48, 3.05 - 2.98, 2.90 - 2.82, 2.23, 1.48。
実施例24で製造した化合物(78mg)のメタノール(3.0mL)溶液にパラジウムプラチナム(ASCA-2(商品名)、15mg)を加え、水素雰囲気下、室温で1時間撹拌した。反応混合物をセライト(商品名)でろ過後、ろ液を減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→75:25)によって精製することにより、以下の物性値を有する標題化合物(71.2mg)を得た。
1H-NMR(CDCl3):δ 6.88, 6.63, 4.65, 3.60 - 3.50, 3.03 - 2.95, 2.91 - 2.82, 2.23, 1.47。
実施例25で製造した化合物、および実施例5で製造した化合物の代わりに3-フェニル-1-プロパノールを用いて、実施例14と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR(CDCl3):δ 7.35 - 7.17, 6.93, 6.79, 3.69, 3.57 - 3.42, 2.94, 2.89 - 2.79, 2.25, 2.14, 1.49。
実施例26で製造した化合物を用いて、実施例21と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR(CD3OD):δ 7.32 - 7.14, 7.02, 6.88, 3.70, 3.29 - 3.21, 3.21 - 3.11, 3.11 - 3.03, 2.85, 2.23, 2.14。
実施例27で製造した化合物、およびエチル 4-ブロモブタノアートを用いて、実施例16と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR(CD3OD):δ 7.34 - 7.15, 6.90, 6.76, 4.13, 3.69, 3.02 - 2.92, 2.92 - 2.78, 2.68 - 2.51, 2.48, 2.35, 2.24, 2.13, 1.84, 1.26。
(LC-MS/ELSD):(保持時間:0.87分、条件A);
MS (M+H): 382。
実施例17で製造した化合物(150mg)のジクロロメタン(1.5mL)溶液に、0℃でジイソプロピルエチルアミン(0.374mL)、およびN,N-ビス(トリフルオロメチルスルホニル)アニリン(580mg)を加え、室温で16時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=85:15→55:45)によって精製することにより、以下の物性値を有する標題化合物(179mg)を得た。
1H-NMR(CDCl3):δ 7.20 - 7.05, 4.14, 3.04 - 2.92, 2.70 - 2.60, 2.51, 2.38, 1.84, 1.27。
実施例30で製造した化合物(40mg)のDMF(0.5mL)溶液に、4-フェニル-1-ブチン(38.2mg)、トリエチルアミン(0.27mL)、ヨウ化銅(1.9mg)、ビス(トリフェニルホスフィン)パラジウムジクロライド(6.9mg)を加え、50℃で16時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=90:10→50:50)、さらにプレパラティブTLC(ヘキサン:酢酸エチル=60:40)により精製することにより、以下の物性値を有する標題化合物(7.5mg)を得た。
1H-NMR(CDCl3):δ 7.37 - 7.18,7.03 - 6.96, 4.14, 3.12 - 3.05, 2.96 - 2.84, 2.72, 2.65 - 2.51, 2.48, 2.36, 1.84, 1.27。
実施例31で製造した化合物を用いて、実施例25と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR(CDCl3):δ 7.29 - 7.23,7.20 - 7.14, 7.03 - 6.90, 4.14, 2.92 - 2.85, 2.66 - 2.57, 2.53, 2.46, 2.35, 1.83, 1.76 - 1.44, 1.26。
(LC-MS/ELSD):(保持時間:0.88分、条件B);
MS (M+H): 366。
2-[1-(ヒドロキシメチル)シクロプロピル]アセトニトリル(1.0g)(CAS登録番号:152922-71-9)のエタノール(10mL)および水(1.0mL)溶液を、水酸化ナトリウム(1.4g)で処理し、得られた混合物を90℃で16時間撹拌した。反応混合物を減圧濃縮することにより、以下の物性値を有する標題化合物(1.2g)を得た。
1H-NMR (DMSO-d6):δ 3.17, 2.04, 3.30 - 0.22, 0.21 - 0.18。
実施例34で製造した化合物(1.2g)のエタノール溶液(10mL)に硫酸(0.5mL)を加え、混合物を90℃で2時間撹拌した。反応混合物を氷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮し、以下の物性値を有する標題化合物(900mg)を得た。
1H-NMR (DMSO-d6):δ 4.52, 4.03, 3.25, 2.32, 1.75, 0.47。
実施例35で製造した化合物(500mg)の塩化メチレン(6mL)溶液に、0℃でテトラブロモメタン(1.2g)およびトリフェニルホスフィン(1.0g)を加え、混合物を室温で2時間撹拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、ろ過後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=100:0→70:30)によって精製することにより、以下の物性値を有する標題化合物(450mg)を得た。
1H-NMR (DMSO-d6):δ 4.07, 3.60, 2.43, 1.18, 0.43 3.60, 2.469 - 0.64。
(LC-MS/ELSD):(保持時間:0.87分、条件B);
MS (M+H): 430。
5-メトキシテトラリン-2-オン(2.00g)のエタノール(60mL)溶液に酢酸ナトリム(2.79g)およびヒドロキシルアミン塩酸塩(2.37g)を加え、70℃で1.5時間撹拌した。反応混合物に水を加え、減圧濃縮でエタノールを減らした。得られた混合物に飽和食塩水を加え、酢酸エチルで2回抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→70:30)によって精製することにより、以下の物性値を有する標題化合物(1.77g)を得た。
1H-NMR(CDCl3):δ 7.16, 6.80, 6.72, 3.83, 3.82, 2.89, 2.52。
塩化チオニル(10mL)とTHF(5.0mL)の混合溶液に、0℃で実施例38で製造した化合物(1.00g)のTHF(1.5mL)懸濁液を加え、0℃で1.5時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで2回抽出した。有機層を飽和炭酸水素ナトリウム溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:80→0:100→酢酸エチル:メタノール=80:20)によって精製することにより、以下の物性値を有する標題化合物(500mg)を得た。
1H-NMR(CDCl3):δ 7.14, 6.83, 6.71, 6.14, 4.38, 3.83, 3.06, 2.82。
水素化リチウムアルミニウム(164mg)のTHF(6.0mL)懸濁液に、80℃で実施例39で製造した化合物(550mg)のTHF(15.0mL)懸濁液を徐々に加え、80℃で15分撹拌した。反応混合物を室温に冷却し、飽和芒硝水とTHFを加え室温で30分撹拌した。反応混合物に硫酸マグネシウムを加え、ろ過した。ろ液を減圧濃縮することにより、以下の物性値を有する標題化合物(433mg)を得た。
1H-NMR(CDCl3):δ 7.07, 6.77, 6.75, 3.93, 3.80, 3.21, 3.04, 1.66。
4-ヒドロキシ-1-インダノン(1.5g)(CAS登録番号:40731-98-4)および臭化ベンジル(1.45mL)のアセトニトリル(40mL)溶液に、炭酸カリウム(3.5g)を加えた。反応混合物を3時間還流した後、ろ過し、真空下で濃縮することにより、以下の物性値を有する標題化合物(2.2g)を得た。
1H-NMR (CDCl3):δ 7.48 - 7.28, 7.09, 5.17, 3.10, 2.73 - 2.65。
実施例41で製造した化合物(2.0g)のメタノール(20mL)およびTHF(20mL)溶液に、0℃で水素化ホウ素ナトリウム(0.64g)を加えた。反応混合物を室温で4時間撹拌し、飽和塩化アンモニウムで反応を停止した。反応混合物を酢酸エチルで抽出し、硫酸マグネシウムで乾燥し、ろ過し、真空下で濃縮することにより、以下の物性値を有する標題化合物(1.8g)を得た。
1H-NMR (CDCl3):δ 7.44 - 7.32, 7.23 - 7.19, 7.04, 6.82, 5.27 - 5.25, 5.11, 3.08 - 3.05, 2.83 - 2.81, 2.52 - 2.48, 2.00 - 1.94, 1.69。
実施例42で製造した化合物(1.0g)のトルエン(40mL)溶液に、p-トルエンスルホン酸(7mg)を加え、混合物を還流下で加熱し、4時間、ディーン・スターク装置を用いて、水を共沸除去した。反応混合物を飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで抽出し、硫酸マグネシウムで乾燥し、ろ過し、真空下で濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→20:80)によって精製することにより、以下の物性値を有する標題化合物(0.6g)を得た。
1H-NMR (CDCl3):δ 7.36 - 7.30, 7.25 - 7.21, 7.07, 6.87 - 6.85, 6.79, 6.58 - 6.56, 5.18, 3.42。
実施例43で製造した化合物(600mg)のアセトン(10mL)溶液に、水(2.5mL)およびN-メチルモルホリン N-オキシド(632mg)を加えた。5分間の撹拌後、四酸化オスモニウム(34mg)のtert-ブチルアルコール(1.0mL)溶液を滴下し、混合物を室温で2時間撹拌した。溶媒を減圧下で除去し、得られた残さを酢酸エチルに溶解し、1Nチオ硫酸ナトリウムおよび飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、ろ過し、濃縮することにより、以下の物性値を有する標題化合物(450mg)を得た。
1H-NMR (CDCl3):δ 7.41 - 7.30, 7.23, 7.06, 6.84, 5.09, 5.02, 4.54 - 4.52, 3.15 - 3.10, 3.00 - 2.95, 2.52, 2.36。
実施例44で製造した化合物(750mg)のトルエン(50mL)溶液にp-トルエンスルホン酸(5mg)を加え、混合物を還流下で加熱し、4時間、ディーン・スターク装置を用いて、水を共沸除去した。反応混合物を室温で4時間撹拌し、飽和炭酸水素ナトリウムで反応を停止し、酢酸エチルで抽出し、硫酸マグネシウムで乾燥し、ろ過し、真空下で濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→20:80)によって精製することにより、以下の物性値を有する標題化合物(400mg)を得た。
ESI-MS m/z 280 [C16H14O2 + H + CH3CN]+。
実施例45で製造した化合物、およびメチル アゼチジン-3-カルボキシラート 塩酸塩を用いて、実施例1と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR (CDCl3):δ 7.40 - 7.31, 7.09, 6.81, 6.70, 5.07, 3.70, 3.61 - 3.58, 3.32 - 3.24, 3.00 - 2.93, 2.75 - 2.71。
実施例46で製造した化合物を用いて、実施例13と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
1H-NMR (CDCl3):δ 7.01, 6.76, 6.56, 3.71, 3.64 - 3.60, 3.35 - 3.27, 3.00 - 2.87, 2.75 - 2.64。
(LC-MS/ELSD):(保持時間:0.78分、条件A);
MS (M+H): 338。
実施例47で製造した化合物、および2-フェニルエタノールの代わりに相当するアルコール誘導体を用いて、実施例47と同様の目的の操作に付すことにより、以下の物性値を有する標題化合物を得た。
(LC-MS/ELSD):(保持時間:0.83分、条件A);
MS (M+H): 352。
(LC-MS/ELSD):(保持時間:0.87分、条件A);
MS (M+H): 366。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H): 448。
実施例2(1)で製造した化合物を、SFC(Supercritical Fluid Chromatography):{カラム:DAICEL CHIRALPAK IB(カラム長:10 x 250 mm);流速:30mL/min;カラム温度:35℃;移動相: 二酸化炭素:メタノール:ジエチルアミン=85:15:0.015;検出器:UVを用いて光学分割し、以下の物性値を有する標題化合物を得た。
1H-NMR (CDCl3):δ 8.10, 7.86, 7.75, 7.56-7.36, 7.02, 6.67, 6.62, 4.30, 3.74, 3.65-3.52, 3.42-3.24, 2.88-2.61, 2.46-2.34, 2.15, 1.89-1.77, 1.50-1.33;
(第一ピーク) 保持時間:4.52分;
(第二ピーク) 保持時間:5.94分。
実施例51(2):(+)-1-{8-[2-(1-ナフチル)エトキシ]-1,2,3,4-テトラヒドロ-2-ナフタレニル}-3-アゼチジンカルボン酸
(LC-MS/ELSD):(保持時間:0.85分、条件B);
MS (M+H): 402。
実施例51(1):[α]D=-52.7 (DMF, c=1.0);
実施例51(2):[α]D=+53.4 (DMF, c=1.0)。
5-ヒドロキシ-3,4-ジヒドロナフタレン-2(1H)-オンの代わりに、8-メトキシ-3,4-ジヒドロナフタレン-2(1H)-オンを用いて、実施例1→実施例17と同様の目的の操作に付し、実施例5で製造した化合物の代わりに1-ヘキサノールを用いて、実施例14→実施例3と同様の目的の操作に付すことにより、以下の物性値を有する表題化合物を得た。
(LC-MS/ELSD):(保持時間:0.88分、条件A);
MS (M+H):332。
1-ヘキサノールの代わりに相当するアルコール化合物を用いて、実施例52と同様の目的の操作に付すことにより、以下の実施例化合物を得た。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H):346。
MS (M+H):360;
1H-NMR (CD3OD):δ 7.10, 6.74, 6.71, 4.36 - 4.18, 4.04 - 3.91, 3.63 - 3.49, 3.45 - 3.34, 3.17, 2.96 - 2.79, 2.41, 2.23 - 2.10, 1.85 - 1.71, 1.70 - 1.58, 1.58 - 1.44, 1.44 - 1.23, 0.90。
(LC-MS/ELSD):(保持時間:1.02分、条件A);
MS (M+H):374;
1H-NMR (CD3OD):δ 7.10, 6.74, 6.71, 4.36 - 4.18, 4.04 - 3.91, 3.63 -D):δ 7.10, 6.74, 6.71, 4.36 - 4.18, 4.04 - 3.91, 3.63 10, 1.85 - 1.71, 1.70 - 1.58, 1.58 - 1.44, 1.44 - 1.23, 0.89。
(LC-MS/ELSD):(保持時間:1.07分、条件A);
MS (M+H):388。
(LC-MS/ELSD):(保持時間:1.12分、条件A);
MS (M+H):402。
(LC-MS/ELSD):(保持時間:0.73分、条件A);
MS (M+H):373
MS (M+H):374;
1H-NMR (CD3OD):δ 7.12, 6.77, 6.74, 4.36 - 4.15, 4.07 - 3.91, 3.58 -D):δ 7.12, 6.77, 6.74, 4.36 - 4.15, 4.07 - 3.91, 3.58 タレニル}-3-アゼチジンカルボン酸.70 - 1.58, 1.58 -, 2.46 1.22。
(LC-MS/ELSD):(保持時間:0.97分、条件A);
MS (M+H):372;
1H-NMR (CD3OD):δ 7.12, 6.76, 6.74, 4.37 - 4.18, 4.07 - 3.91, 3.63 -D):δ 7.12, 6.76, 6.74, 4.37 - 4.18, 4.07 - 3.91, 3.63 カルボン酸-3-アゼチジンカルボン酸.70 - 1.58, 1.58 - 0.89。
メチル 1-(8-ヒドロキシ-1,2,3,4-テトラヒドロナフタレン-2-イル)アゼチジン-3-カルボキシラート(100mg)のDMF(0.5mL)溶液に氷冷下でN-クロロスクシンイミド(51mg)のDMF(0.5mL)溶液を加え、室温で16時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=60:40→20:80)、さらに逆相液体クロマトグラフィー(0.1%トリフルオロ酢酸(TFA)含有水/0.1%TFA含有アセトニトリル)によって精製することにより、以下の物性値を有する標題化合物(10mg)を得た。
1H-NMR (DMSO-d6):δ 10.45-10.20, 9.89, 7.11, 6.69, 4.60 - 4.15, 3.85 - 3.47, 3.09 - 2.95, 2.67 -:δ 10.45-10.2 2.23, 2.20 - 2.03, 1.68 - 1.42。
実施例13で製造した化合物の代わりに実施例53で製造した化合物を用い、実施例5で製造した化合物の代わりに2-(ナフタレン-1-イル)エタノールを用いて、実施例14と同様の目的の操作に付した。得られた化合物(8mg)のメタノール(0.1mL)、ジメトキシエタン(0.1mL)溶液に2N水酸化ナトリウム水溶液(0.05mL)を加え、室温で4時間撹拌した。反応混合物に2N塩酸水溶液(0.05mL)を加え、逆相液体クロマトグラフィー(0.1%TFA含有水/0.1%TFA含有アセトニトリル)によって精製することにより、以下の物性値を有する標題化合物(3.2mg)を得た。
(LC-MS/ELSD):(保持時間:0.92分、条件A);
MS (M+H):435。
ヒトS1P1(EDG-1)またはヒトS1P5遺伝子をそれぞれ過剰発現させたチャイニーズハムスターオーバリー(CHO)細胞膜画分を用いて、膜各分1mg protein/mLを使用し、96穴アッセイプレート内で反応した。各ウェルにバッファー(50mmol/L、Tris pH7.5、5mmol/L、MgCl2、0.5%BSA、Complete EDTA free(1 tablet/50mL))で希釈したビークル(DMSO)溶液または2倍濃度のリガンド溶液100μLとバッファーで希釈した50μLの0.16nmol/L [33P]-S1P(American Radiolabeled Chemicals社製)を加えた後、膜画分溶液(50μL)を加えて室温で60分反応させた。反応後、96穴UNIFILTERを用いて吸引ろ過し、洗浄バッファー(50mmol/L、Tris pH7.5、0.5% BSA)(150mL)で洗浄した後、60℃で45分間乾燥させた。MicroScint(商品名)20(50μL/well)を加えて、プレートをTopSeal-Aでカバーした後、TopCount(Perkin Elmer社製)で放射活性を計測した。
本発明化合物は、[33P]-S1PのS1P5への結合に対して、以下の表に示す阻害活性(IC50値)を示した。さらに、本発明化合物の[33P]-S1PのS1P1の結合活性を表1に示す。なお、表1中に示す記号は、それぞれ、IC50値がA:1~100nM未満、B:100~1000nM未満、C:1μM~3μM、D:>10μM、E:>30μMを表す。その結果、本発明化合物は、いずれもS1P5受容体への結合活性が高いことに加え、S1P1受容体に対してS1P5受容体選択的な結合活性を有することがわかった。
ヒトS1P5(EDG-8)遺伝子を過剰発現させたCHO細胞を、10%FBS(ウシ胎児血清)、ペニシリン/ストレプトマイシン及びジェネティシン(0.25mg/mL)含有のHam’sF12培地(GIBCO BRL社製)で培養した。培養した細胞から培地を除去し、リン酸緩衝生理食塩水で1回洗浄し、バッファー(20mmol/L HEPES、0.1若しくは0.2% BSA、1mmol/L IBMX及び5μmol/L forskolinを含むHank’s balanced salt solution)で希釈したビークル(DMSO)溶液または化合物溶液を、37℃にて30分間処置した。その後、リン酸緩衝生生理食塩液で1回洗浄し、cAMP測定キット(Cisbio Bioassays)を用いて、細胞の溶解及び溶解液中のcyclicAMP濃度を測定した。
製剤例1
以下の各成分を常法により混合した後打錠して、一錠中に10mgの活性成分を含有する錠剤1万錠を得た。
・4-{5-[2-(2-ナフチル)エトキシ]-3,4-ジヒドロ-2(1H)-イソキノリニル}ブタン酸 トリフルオロ酢酸塩…100g
・カルボキシメチルセルロースカルシウム(崩壊剤) … 20g
・ステアリン酸マグネシウム(潤滑剤) … 10g
・微結晶セルロース … 870g
以下の各成分を常法により混合した後、除塵フィルターでろ過し、5mlずつアンプルに充填し、オートクレーブで加熱滅菌して、1アンプル中20mgの活性成分を含有するアンプル1万本を得た。
・1-[5-({(2E)-3-[4-(トリフルオロメチル)フェニル]-2-プロペン-1-イル}オキシ)-1,2,3,4-テトラヒドロ-2-ナフタレニル]-3-ピロリジンカルボン酸…200g
・マンニトール … 20g
・蒸留水 … 50L
Claims (8)
- 一般式(I)
Yは、(1)-CH2-、(2)-NH-、(3)-S-、または(4)-O-を表し、
Wは、(1)C1~6アルキレン基、(2)C2~6アルケニレン基、(3)C2~6アルキニレン基、(4)-C1~6アルキレン-O-、(5)-C2~6アルケニレン-O-、(6)-C2~6アルキニレン-O-、または(7)-C1~6アルキレン-ring2-を表し、
R1は、(1)-L-、(2)-L-ring3-、または(3)-L-NR13-を表し、
R2は、(1)ハロゲン原子、(2)C1~4アルキル基、(3)C1~4ハロアルキル基、(4)C1~4アルコキシ基、または(5)C1~4ハロアルコキシ基を表し、
R 3 は、(1)ハロゲン原子、(2)C1~4アルキル基、(3)C1~4ハロアルキル基、(4)C1~4アルコキシ基、(5)C1~4ハロアルコキシ基、(6)ニトリル基、(7)-S-C1~4アルキル基、または(8)-S-C1~4ハロアルキル基を表し、ここで、R 3 で表されるC1~4アルキル基またはC1~4ハロアルキル基が分枝鎖の場合、同一の炭素原子から分枝したC1~2アルキル基は一緒になってC3~4の飽和炭素環を形成してもよく、
R 13は、(1)水素原子、または(2)C1~4アルキル基を表し、
Lは、(1)結合手、または(2)式
Zは、カルボキシル基を表し、
ring1は、C3~10の炭素環を表し、
ring2は、(1)C3~7の炭素環、または(2)3~7員のヘテロ環を表し、
ring3は、(1)C1~4アルキル基で置換されていてもよいC3~7の炭素環、または(2)C1~4アルキル基で置換されていてもよい3~7員のヘテロ環を表し、
mは、0~2の整数を表し、
nは、0~2の整数を表し、
pは、0~3の整数を表し、
qは、0~5の整数を表し、
pが2以上のとき、複数のR2は同じでも異なってもよく、
qが2以上のとき、複数のR3 は同じでも異なってもよく、
tが2以上のとき、複数のR11は同じでも異なってもよく、
tが2以上のとき、複数のR12は同じでも異なっていてもよい。]
で示される化合物、またはその薬学的に許容される塩。 - Yが、-CH2-、または-O-である請求項1記載の化合物、またはその薬学的に許容される塩。
- ring3が、C1~4アルキル基で置換されていてもよいC3~7の飽和炭素環、またはC1~4アルキル基で置換されていてもよい3~7員の飽和ヘテロ環である請求項1または2に記載の化合物、またはその薬学的に許容される塩。
- ring1が、シクロブタン、シクロヘキサン、ベンゼン、ビシクロ[4.2.0]オクタ-1,3,5-トリエン、インダン、ナフタレン、またはテトラヒドロナフタレン環である請求項1~5のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- ring2が、C3~7の炭素環である請求項1~5のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- (1)4-[6-(3-フェニルプロポキシ)-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル]ブタン酸、
(2)4-{6-[2-(1-ナフチル)エトキシ]-1,2,4,5-テトラヒドロ-3H-3-ベンズアゼピン-3-イル}ブタン酸、
(3)1-{8-[2-(1-ナフチル)エトキシ]-1,2,3,4-テトラヒドロ-2-ナフタレニル}-3-アゼチジンカルボン酸、および
(4)1-[8-(3-フェニルプロポキシ)-1,2,3,4-テトラヒドロ-2-ナフタレニル]-3-アゼチジンカルボン酸からなる群から選択される請求項1記載の化合物、またはその薬学的に許容される塩。
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