JP6611799B2 - 新規化合物 - Google Patents

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Publication number

JP6611799B2

JP6611799B2 JP2017516387A JP2017516387A JP6611799B2 JP 6611799 B2 JP6611799 B2 JP 6611799B2 JP 2017516387 A JP2017516387 A JP 2017516387A JP 2017516387 A JP2017516387 A JP 2017516387A JP 6611799 B2 JP6611799 B2 JP 6611799B2

Authority

JP

Japan

Prior art keywords

compound

formula

acid

fluoro

tetrahydro

Prior art date

2014-09-26

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

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• 150000001875 compounds Chemical class 0.000 title claims description 220
• 150000003839 salts Chemical class 0.000 claims description 71
• -1 3- (3- (2-methoxyethoxy) phenyl) butanoic acid maleate Chemical compound 0.000 claims description 55
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
• 239000008194 pharmaceutical composition Substances 0.000 claims description 37
• 201000010099 disease Diseases 0.000 claims description 32
• 238000011282 treatment Methods 0.000 claims description 27
• 239000003814 drug Substances 0.000 claims description 26
• MKIJZIVRJUMEAD-AMGIVPHBSA-N COCCOC1=CC=CC(=C1)[C@@H](CN1CC[C@@](F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O Chemical compound COCCOC1=CC=CC(=C1)[C@@H](CN1CC[C@@](F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O MKIJZIVRJUMEAD-AMGIVPHBSA-N 0.000 claims description 15
• 239000003112 inhibitor Substances 0.000 claims description 13
• 239000013543 active substance Substances 0.000 claims description 12
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 12
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 11
• 230000003176 fibrotic effect Effects 0.000 claims description 10
• 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 9
• 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 9
• 230000015572 biosynthetic process Effects 0.000 claims description 9
• 239000003085 diluting agent Substances 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 238000003786 synthesis reaction Methods 0.000 claims description 8
• 208000035475 disorder Diseases 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• MKIJZIVRJUMEAD-UHFFFAOYSA-N COCCOC1=CC=CC(=C1)C(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O Chemical compound COCCOC1=CC=CC(=C1)C(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O MKIJZIVRJUMEAD-UHFFFAOYSA-N 0.000 claims description 6
• MKIJZIVRJUMEAD-WXVAWEFUSA-N (3R)-4-[(3R)-3-fluoro-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl]-3-[3-(2-methoxyethoxy)phenyl]butanoic acid Chemical compound F[C@]1(CN(CC1)C[C@H](CC(=O)O)C1=CC(=CC=C1)OCCOC)CCC1=NC=2NCCCC=2C=C1 MKIJZIVRJUMEAD-WXVAWEFUSA-N 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 229940044551 receptor antagonist Drugs 0.000 claims description 5
• 239000002464 receptor antagonist Substances 0.000 claims description 5
• 229940124597 therapeutic agent Drugs 0.000 claims description 5
• MKIJZIVRJUMEAD-AJTFRIOCSA-N (3S)-4-[(3R)-3-fluoro-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl]-3-[3-(2-methoxyethoxy)phenyl]butanoic acid Chemical compound F[C@]1(CN(CC1)C[C@@H](CC(=O)O)C1=CC(=CC=C1)OCCOC)CCC1=NC=2NCCCC=2C=C1 MKIJZIVRJUMEAD-AJTFRIOCSA-N 0.000 claims description 3
• MKIJZIVRJUMEAD-CUNXSJBXSA-N COCCOC1=CC=CC(=C1)[C@H](CN1CC[C@@](F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O Chemical compound COCCOC1=CC=CC(=C1)[C@H](CN1CC[C@@](F)(CCC2=CC=C3CCCNC3=N2)C1)CC(O)=O MKIJZIVRJUMEAD-CUNXSJBXSA-N 0.000 claims description 3
• 230000008485 antagonism Effects 0.000 claims description 3
• CPMDPSXJELVGJG-UHFFFAOYSA-N methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate Chemical group OC=1NC2=CC(=CC=C2C=1C(=NC1=CC=C(C=C1)N(C(CN1CCN(CC1)C)=O)C)C1=CC=CC=C1)C(=O)OC CPMDPSXJELVGJG-UHFFFAOYSA-N 0.000 claims description 2
• 229960003073 pirfenidone Drugs 0.000 claims description 2
• ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical group C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 2
• 230000009286 beneficial effect Effects 0.000 claims 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
• 239000000203 mixture Substances 0.000 description 79
• 239000000243 solution Substances 0.000 description 70
• 235000002639 sodium chloride Nutrition 0.000 description 68
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 61
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• 102000006495 integrins Human genes 0.000 description 38
• 108010044426 integrins Proteins 0.000 description 38
• 239000000543 intermediate Substances 0.000 description 37
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
• 239000005557 antagonist Substances 0.000 description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 238000000034 method Methods 0.000 description 21
• 239000007787 solid Substances 0.000 description 21
• 239000002904 solvent Substances 0.000 description 20
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
• 238000004296 chiral HPLC Methods 0.000 description 18
• 235000019441 ethanol Nutrition 0.000 description 17
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 238000006243 chemical reaction Methods 0.000 description 16
• 229910052757 nitrogen Inorganic materials 0.000 description 16
• 230000002829 reductive effect Effects 0.000 description 16
• 238000002560 therapeutic procedure Methods 0.000 description 16
• 239000002253 acid Substances 0.000 description 15
• 235000019439 ethyl acetate Nutrition 0.000 description 15
• 239000011541 reaction mixture Substances 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
• 238000005481 NMR spectroscopy Methods 0.000 description 13
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• 238000001514 detection method Methods 0.000 description 13
• 238000010828 elution Methods 0.000 description 13
• 239000003921 oil Substances 0.000 description 13
• 206010016654 Fibrosis Diseases 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• 239000007788 liquid Substances 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
• 230000004761 fibrosis Effects 0.000 description 11
• 235000019198 oils Nutrition 0.000 description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
• 239000012267 brine Substances 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 239000003446 ligand Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000004480 active ingredient Substances 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 239000006071 cream Substances 0.000 description 9
• 239000012453 solvate Substances 0.000 description 9
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
• GUYYJJSMXQMXCB-LLVKDONJSA-N (4S)-4-[3-(2-methoxyethoxy)phenyl]oxolan-2-one Chemical compound COCCOC=1C=C(C=CC=1)[C@@H]1CC(OC1)=O GUYYJJSMXQMXCB-LLVKDONJSA-N 0.000 description 8
• IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 8
• 238000000576 coating method Methods 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 8
• 208000005069 pulmonary fibrosis Diseases 0.000 description 8
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 7
• UMYZHWLYICNGRQ-UHFFFAOYSA-N ethanol;heptane Chemical compound CCO.CCCCCCC UMYZHWLYICNGRQ-UHFFFAOYSA-N 0.000 description 7
• 229920000642 polymer Polymers 0.000 description 7
• CPXKTNWJMSBHBA-UHFFFAOYSA-N C1CC2=C(NC1)N=C(C=C2)C=CC3(CCN(C3)C(=O)O)F Chemical compound C1CC2=C(NC1)N=C(C=C2)C=CC3(CCN(C3)C(=O)O)F CPXKTNWJMSBHBA-UHFFFAOYSA-N 0.000 description 6
• FIQAEAYSLKCHGP-IAPIXIRKSA-N C[C@@H](NC(=O)C1(F)CCN(C1)C(O)=O)c1ccccc1 Chemical compound C[C@@H](NC(=O)C1(F)CCN(C1)C(O)=O)c1ccccc1 FIQAEAYSLKCHGP-IAPIXIRKSA-N 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
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• 206010028980 Neoplasm Diseases 0.000 description 6
• 235000019502 Orange oil Nutrition 0.000 description 6
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
• 229920002472 Starch Polymers 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• 108010009583 Transforming Growth Factors Proteins 0.000 description 6
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• 238000001914 filtration Methods 0.000 description 6
• 239000000499 gel Substances 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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• 235000019698 starch Nutrition 0.000 description 6
• 239000003826 tablet Substances 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• YVMHYDQOUZWQQA-UHFFFAOYSA-N 3-fluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(F)(C(O)=O)C1 YVMHYDQOUZWQQA-UHFFFAOYSA-N 0.000 description 5
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
• 108010010803 Gelatin Proteins 0.000 description 5
• 229940123038 Integrin antagonist Drugs 0.000 description 5
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
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• OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
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• RWOGZQDBFUFMSJ-RXMQYKEDSA-N [(3R)-3-fluoropyrrolidin-3-yl]methanol Chemical compound F[C@]1(CNCC1)CO RWOGZQDBFUFMSJ-RXMQYKEDSA-N 0.000 description 5
• 230000004913 activation Effects 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 5
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• 238000011065 in-situ storage Methods 0.000 description 5
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 5
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• CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 5
• RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 4
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
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• 238000000113 differential scanning calorimetry Methods 0.000 description 4
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• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
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• 229920006395 saturated elastomer Polymers 0.000 description 4
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
• 230000001225 therapeutic effect Effects 0.000 description 4
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