CN104245663B - 二环化合物 - Google Patents
二环化合物 Download PDFInfo
- Publication number
- CN104245663B CN104245663B CN201380020122.0A CN201380020122A CN104245663B CN 104245663 B CN104245663 B CN 104245663B CN 201380020122 A CN201380020122 A CN 201380020122A CN 104245663 B CN104245663 B CN 104245663B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- ethyl
- amino
- carboxybutyl
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 bicyclic compound Chemical class 0.000 title claims abstract description 138
- 150000001875 compounds Chemical class 0.000 claims abstract description 210
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 20
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 132
- 125000001424 substituent group Chemical group 0.000 claims description 132
- 125000005843 halogen group Chemical group 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 229920002554 vinyl polymer Polymers 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 8
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- RCHXQAVCJRQZSQ-UHFFFAOYSA-N 1-[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]-2,3-dihydro-1h-indene-5-carboxylic acid Chemical compound C1CC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1=CC=CC=C1 RCHXQAVCJRQZSQ-UHFFFAOYSA-N 0.000 claims description 2
- LANHEKZGKDEWLK-UHFFFAOYSA-N 2-methylideneheptanoic acid Chemical compound CCCCCC(=C)C(O)=O LANHEKZGKDEWLK-UHFFFAOYSA-N 0.000 claims description 2
- HSZQLEMWIOXIRP-UHFFFAOYSA-N 4-[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]-3,4-dihydro-2h-chromene-7-carboxylic acid Chemical compound C1COC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1=CC=CC=C1 HSZQLEMWIOXIRP-UHFFFAOYSA-N 0.000 claims description 2
- SMENEGSIQKKDEL-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[[4-(2-cyclohexylethyl)phenyl]methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1CCCCC1 SMENEGSIQKKDEL-UHFFFAOYSA-N 0.000 claims description 2
- FXCVTMAVALJBSU-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1=CC=CC=C1 FXCVTMAVALJBSU-UHFFFAOYSA-N 0.000 claims description 2
- WJSJHAATGMVFMC-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydroquinoline-2-carboxylic acid Chemical compound C1CCC2=NC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1=CC=CC=C1 WJSJHAATGMVFMC-UHFFFAOYSA-N 0.000 claims description 2
- 108010078321 Guanylate Cyclase Proteins 0.000 claims description 2
- 102000014469 Guanylate cyclase Human genes 0.000 claims description 2
- ZPKAAYYQBUSQMK-UHFFFAOYSA-N 3-[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]-2,3-dihydro-1-benzofuran-6-carboxylic acid Chemical compound C1OC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1CCC1=CC=CC=C1 ZPKAAYYQBUSQMK-UHFFFAOYSA-N 0.000 claims 1
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical compound C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 claims 1
- ONQVXQSXZQEAEZ-UHFFFAOYSA-N 5-[2-[2-[(3-tert-butylphenyl)methoxy]phenyl]ethyl-(4-carboxybutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound CC(C)(C)C1=CC=CC(COC=2C(=CC=CC=2)CCN(CCCCC(O)=O)C2C3=CC=C(C=C3CCC2)C(O)=O)=C1 ONQVXQSXZQEAEZ-UHFFFAOYSA-N 0.000 claims 1
- MZYAQLFFEOQIHJ-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-(2,3-dihydro-1H-inden-5-ylmethoxy)phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound OC(=O)CCCCN(CCc1ccccc1OCc1ccc2CCCc2c1)C1CCCc2cc(ccc12)C(O)=O MZYAQLFFEOQIHJ-UHFFFAOYSA-N 0.000 claims 1
- APHUFAFXRCOWSC-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-(5,6,7,8-tetrahydronaphthalen-1-ylmethoxy)phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC1=CC=CC2=C1CCCC2 APHUFAFXRCOWSC-UHFFFAOYSA-N 0.000 claims 1
- NRFWNGURKREYRV-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[(4-cyclopropylphenyl)methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1C1CC1 NRFWNGURKREYRV-UHFFFAOYSA-N 0.000 claims 1
- SNOGYWUZBUMPHW-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[(4-ethynylphenyl)methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC1=CC=C(C#C)C=C1 SNOGYWUZBUMPHW-UHFFFAOYSA-N 0.000 claims 1
- NQPMDBJUXJCMLD-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[(4-phenylmethoxyphenyl)methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1OCC1=CC=CC=C1 NQPMDBJUXJCMLD-UHFFFAOYSA-N 0.000 claims 1
- IPGZORPHTBCEPB-UHFFFAOYSA-N 5-[4-carboxybutyl-[2-[2-[(4-propan-2-ylphenyl)methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1=CC(C(C)C)=CC=C1COC1=CC=CC=C1CCN(CCCCC(O)=O)C1C2=CC=C(C(O)=O)C=C2CCC1 IPGZORPHTBCEPB-UHFFFAOYSA-N 0.000 claims 1
- WVMGJXQTSPSGSQ-WUKNDPDISA-N 5-[4-carboxybutyl-[2-[2-[[4-[(e)-2-cyclohexylethenyl]phenyl]methoxy]phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CCC2=CC(C(O)=O)=CC=C2C1N(CCCCC(=O)O)CCC1=CC=CC=C1OCC(C=C1)=CC=C1\C=C\C1CCCCC1 WVMGJXQTSPSGSQ-WUKNDPDISA-N 0.000 claims 1
- JOSPZIMMFKAJHG-BVOFGUPTSA-N OC(=O)CCCCN(CCc1ccccc1OC[C@H]1CC[C@H](CCc2ccccc2)CC1)C1CCCc2cc(ccc12)C(O)=O Chemical compound OC(=O)CCCCN(CCc1ccccc1OC[C@H]1CC[C@H](CCc2ccccc2)CC1)C1CCCc2cc(ccc12)C(O)=O JOSPZIMMFKAJHG-BVOFGUPTSA-N 0.000 claims 1
- RDQVJILEPPRTBP-UHFFFAOYSA-N OC(=O)CCCCN(CCc1ccccc1OCc1ccc(SCc2ccccc2)cc1)C1CCCc2cc(ccc12)C(O)=O Chemical compound OC(=O)CCCCN(CCc1ccccc1OCc1ccc(SCc2ccccc2)cc1)C1CCCc2cc(ccc12)C(O)=O RDQVJILEPPRTBP-UHFFFAOYSA-N 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical group C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 143
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 93
- 239000002904 solvent Substances 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- 238000000034 method Methods 0.000 description 54
- 239000002585 base Substances 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- 235000002639 sodium chloride Nutrition 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 29
- 230000001419 dependent effect Effects 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- 238000007670 refining Methods 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 238000012360 testing method Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 239000011780 sodium chloride Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 230000004913 activation Effects 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000463 material Substances 0.000 description 14
- 229910052731 fluorine Inorganic materials 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 239000011737 fluorine 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 8
- 206010020772 Hypertension Diseases 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 208000002815 pulmonary hypertension Diseases 0.000 description 8
- 206010019280 Heart failures Diseases 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000004140 cleaning Methods 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 229910052742 iron Inorganic materials 0.000 description 6
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 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 6
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 5
- 150000002118 epoxides Chemical class 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
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- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- 125000005905 mesyloxy group Chemical group 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
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- QMBOGHRCVUZBIR-UHFFFAOYSA-N methyl 2,3-dihydro-1h-indene-5-carboxylate Chemical compound COC(=O)C1=CC=C2CCCC2=C1 QMBOGHRCVUZBIR-UHFFFAOYSA-N 0.000 description 1
- DZNKOAWEHDKBEP-UHFFFAOYSA-N methyl 2-[6-[bis(2-methoxy-2-oxoethyl)amino]-5-[2-[2-[bis(2-methoxy-2-oxoethyl)amino]-5-methylphenoxy]ethoxy]-1-benzofuran-2-yl]-1,3-oxazole-5-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OC)CC(=O)OC)=CC2=C1OC(C=1OC(=CN=1)C(=O)OC)=C2 DZNKOAWEHDKBEP-UHFFFAOYSA-N 0.000 description 1
- GUOMGDNZNYBSJG-UHFFFAOYSA-N methyl 5-oxo-7,8-dihydro-6h-quinoline-2-carboxylate Chemical compound O=C1CCCC2=NC(C(=O)OC)=CC=C21 GUOMGDNZNYBSJG-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000196 olfactory nerve Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960000529 riociguat Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013515 script Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 230000025102 vascular smooth muscle contraction Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- OXKMPRGWDYRLEQ-UHFFFAOYSA-N zinc argon dicyanide Chemical compound [Ar].[Zn++].[C-]#N.[C-]#N OXKMPRGWDYRLEQ-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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Abstract
本发明提供一种含有由通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物的药品。一种由通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物。(式中,A表示C1‑C3直链状亚烷基,其中,1个亚甲基可被O或S取代;n表示3~5的整数;X1和X2各自独立地表示CH或N;W1和W2各自独立地表示羧基或四唑基;V表示C1‑C8直链状或支链状亚烷基,其中,1个亚甲基可被O或S取代;R表示取代苯基等。)
Description
技术领域
本发明涉及对可溶性鸟苷酸环化酶具有血红素非依赖性活化作用的二环化合物和含有该二环化合物的药品。
背景技术
可溶性鸟苷酸环化酶(sGC)是由三磷酸鸟苷(GTP)产生环磷酸鸟苷(cGMP)的酶,由α亚基与β亚基的二聚体构成。β亚基与血红素结合,通常与血红素配位的铁与第105号氨基酸即组氨酸残基相互作用,形成非活化结构。已知一氧化氮(NO)为生物体内主要的sGC的活化因子,与存在于sGC的β亚基的血红素铁相互作用,解除血红素铁与β亚基的组氨酸残基的相互作用,从而转化成活化型的结构。由活化的sGC产生的cGMP进而将蛋白激酶、离子通道等激活,发挥松弛血管平滑肌、抑制血小板活化、抑制细胞增殖、嗅觉神经传递等各种作用。在病理状态下,由于发生sGC的活性降低和sGC的分解而cGMP系统被抑制,引起血管平滑肌收缩、血小板活化、细胞增殖等,最终可造成高血压症、肺高血压症、心力衰竭、内皮功能障碍、粥样动脉硬化症、末梢血管疾病、心绞痛、血栓症、心肌梗塞、勃起障碍、肾功能障碍等(非专利文献1、2)。
在临床中,为了使sGC活化,广泛使用硝酸甘油等硝酸剂。它们通过供给外源性的NO而使sGC活化,从而体现药理作用。然而,已知硝酸剂除了具有副作用以外还存在耐受现象,这是本药剂的严重缺点。已表明硝酸剂的耐受现象是由参与释放NO的线粒体乙醛脱氢酶的活性降低等与sGC不同的机制引起的(非专利文献3),不通过释放NO而直接使sGC活化的化合物能够避免耐受现象。另外,已表明在衰老、高血压、糖尿病、高血脂症等症状下,由于氧化应激而使血红素铁的氧化、血红素的分解加剧,NO与血红素无法相互作用,因而无法期待使sGC充分活化(非专利文献4)。作为NO以外的sGC激动剂,已知有以利奥西呱(Riociguat)(专利文献1)为代表的依赖于血红素的直接性sGC激动剂。已表明这些化合物不依赖于NO地使sGC活化,但在血红素铁的氧化条件下无法充分发挥sGC活化能力(非专利文献5)。因此,认为与NO、利奥西呱不同而不取决于血红素的氧化状态且具有直接性sGC活化作用的化合物对高血压症、肺高血压症、心力衰竭、内皮功能障碍、粥样动脉硬化症、末梢血管疾病、心绞痛、血栓症、心肌梗塞、勃起障碍、肾功能障碍等各种疾病的治疗或预防有效。
作为不取决于血红素的氧化状态且具有直接性sGC活化作用的化合物,专利文献2中公开了西那西呱(Cinaciguat)及其衍生物,专利文献3中公开了吡唑、三唑衍生物,专利文献4中公开了2,6-二取代吡啶衍生物,专利文献5中公开了杂环衍生物。
现有技术文献
专利文献
专利文献1:国际公开第2003/095451号
专利文献2:国际公开第2001/019780号
专利文献3:国际公开第2009/032249号
专利文献4:国际公开第2009/071504号
专利文献5:国际公开第2009/123316号
非专利文献
非专利文献1:Handbook of Experimental Pharmacology,Springer-Verlag,2009年,191卷,p.309-339
非专利文献2:Handbook of Experimental Pharmacology,Springer-Verlag,2009年,191卷,p.277-308
非专利文献3:The Journal of Clinical Investigation,American Societyfor Clinical Investigation,2004年,113卷,352-354
非专利文献4:The Journal of Clinical Investigation,American Societyfor Clinical Investigation,2006年,116卷,p.2552-2561
非专利文献5:European Respiratory Journal,European RespiratorySociety,2008年,32卷,p.881-891
发明内容
本发明的课题在于提供一种对可溶性鸟苷酸环化酶具有血红素非依赖性活化作用且作为药品有用的新型化合物。
因此,本发明人合成了各种化合物,并以可溶性鸟苷酸环化酶活化作用为指标进行了筛选,结果发现具有在氮原子上结合有二环化合物的结构的化合物的血红素非依赖性高,具有优异的可溶性鸟苷酸环化酶活化作用,作为可溶性鸟苷酸环化酶参与的各种疾病的预防或治疗药有用,从而完成了本发明。
即,本发明提供一种由通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物。
(式中,A表示C1-C3直链状亚烷基,这里1个亚甲基可被O或S取代;
n表示3~5的整数;
X1和X2各自独立地表示CH或N;
W1和W2各自独立地表示羧基或四唑基;
V表示C1-C8直链状或支链状亚烷基,这里1个亚甲基可被O或S取代;
R表示选自下式的基团,
其中,R1、R2、R3、R4和R5表示氢原子、卤素原子、可具有取代基的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、可具有取代基的乙烯基、可具有取代基的乙炔基、芳香环上可具有取代基的芳基、芳香环上可具有取代基的芳氧基、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基,
m表示1或2的整数,
Y1和Y2各自独立地表示亚甲基、O或S,但不同时为S。)
另外,本发明提供一种药品,其含有由上述通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物。
另外,本发明提供一种医药组合物,其含有由上述通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物、以及药学上允许的载体。
另外,本发明提供用于预防或治疗心力衰竭、高血压症、肺高血压症、缺血性心脏病等可溶性鸟苷酸环化酶参与的疾病的、由上述通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物。
另外,本发明提供由上述通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物在制造心力衰竭、高血压症、肺高血压症、缺血性心脏病等可溶性鸟苷酸环化酶参与的疾病的预防或治疗药中的应用。
另外,本发明提供一种心力衰竭、高血压症、肺高血压症、缺血性心脏病等可溶性鸟苷酸环化酶参与的疾病的预防或治疗方法,其特征在于,给予有效量的由上述通式(1)表示的化合物、其药学上允许的盐或它们的溶剂合物。
本发明化合物的血红素非依赖性高,具有优异的可溶性鸟苷酸环化酶活化作用,作为可溶性鸟苷酸环化酶参与的各种疾病的预防或治疗药有用。作为可利用可溶性鸟苷酸环化酶活化作用进行预防或治疗的疾病,可举出心力衰竭、高血压症、肺高血压症或缺血性心脏病等。
具体实施方式
本说明书中,“直链状亚烷基”表示具有规定数量碳原子的直链状的亚烷基。具体而言,可举出亚甲基、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)6-等。
本说明书中,“支链状亚烷基表示“具有规定数量碳原子的支链状的亚烷基。具体而言,可举出-CH(CH3)-、-CH(C2H5)-、-CH(C3H7)-、-CH(C4H9)-、-CH(C5H11)-、-CH2CH(CH3)-、-CH2CH2CH(CH3)-等。
本说明书中,“直链状或支链状亚烷基”的“1个亚甲基可被O或S取代”表示该直链状或支链状亚烷基的任意亚甲基被O或S取代。“直链状亚烷基”是碳原子数为1的亚甲基时,也含有-O-、-S-。具体而言,可举出-CH2O-、-CH2S-、-(CH2)2S-、-(CH2)3O-、-(CH2)3S-、-(CH3)O-、-CH(CH3)O-、-CH(CH3)S-、-CH2CH(CH3)O-、-CH2CH(CH3)S-等。
本说明书中,作为“卤素原子”,可举出氟原子、氯原子、溴原子和碘原子。
本说明书中,“C1-C6烷基”表示碳原子数1~6的直链状的烷基或碳原子数3~6的支链状的烷基。作为C1-C6烷基的例子,可举出甲基、乙基、正丙基、正丁基、异丙基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本说明书中,“C1-C6烷氧基”表示上述“C1-C6烷基”的一个氢原子被氧原子取代的基团。具体而言,为碳原子数1~6的直链状烷氧基或碳原子数3~6的支链烷氧基,作为C1-C6烷氧基的例子,可举出甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、正己氧基等。
本说明书中,“C3-C6环烷基”表示碳原子数3~6的环状的烷基。具体而言,可举出环丙基、环丁基、环戊基、环己基。
本说明书中,“C3-C6环烷氧基”表示上述“C3-C6环烷基”的一个氢原子被氧原子取代的基团。具体而言,可举出环丙氧基、环丁氧基、环戊氧基、环己氧基等。
本说明书中,“卤代C1-C4烷基”表示作为碳原子数1~4的直链状或碳原子数3或4的支链状的烷基的C1-C4烷基的一个以上的氢原子被卤素原子取代的基团。作为卤代C1-C4烷基的例子,可举出氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、溴甲基、二溴甲基、三溴甲基、2-氯乙基、2,2-二氯乙基、2,2,2-三氯乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2-四氟乙基、五氟乙基、2-溴乙基、2,2,2-三溴乙基、3,3,3-三氯丙基、3,3,3-三氟丙基、3,3,3-三溴丙基、4,4,4-三氯丁基、4,4,4-三氟丁基。
本说明书中,“卤代C1-C4烷氧基”表示上述“卤代C1-C4烷基”的一个氢原子被氧原子取代的基团。作为卤代C1-C4烷氧基的例子,可举出氯甲氧基、二氯甲氧基、三氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、2-氯乙氧基、2,2-二氯乙氧基、2,2,2-三氯乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、1,1,2,2-四氟乙氧基、五氟乙氧基、3,3,3-三氯丙氧基、3,3,3-三氟丙氧基、4,4,4-三氯丁氧基、4,4,4-三氟丁氧基等。
本说明书中,“芳基”表示碳原子数6~10的单环式或多环式的芳香族烃基。作为芳基的例子,可举出苯基、萘基,更具体而言,可举出苯基、1-萘基、2-萘基。
本说明书中,“芳氧基”表示上述“芳基”的一个氢原子被氧原子取代的基团。作为芳氧基的例子,可举出苯氧基、萘氧基,更具体而言,可举出苯氧基、1-萘氧基、2-萘氧基。
本说明书中,“可具有取代基”表示无取代,或者在可取代的位置上具有1个以上、优选1~2个、更优选1个相同或不同的取代基。作为该取代基,可举出卤素原子、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基、卤代C1-C4烷基、芳基等。各取代基的定义与上述含义相同,也可以进一步具有取代基。
作为由R1、R2、R3、R4和R5表示的卤素原子,优选为氟原子、氯原子,更优选为氯原子。
由R1、R2、R3、R4和R5表示的可具有取代基的C1-C6烷基具有取代基时,作为该取代基,可举出C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基,其中,优选C3-C6环烷基,特别优选环己基。作为可具有取代基的C1-C6烷基,为甲基、乙基、异丙基、叔丁基、2-甲氧基乙基、2-环丙基乙基、2-环己基乙基,更优选异丙基、叔丁基、2-环己基乙基。
作为由R1、R2、R3、R4和R5表示的C1-C6烷氧基,优选甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基,更优选甲氧基和叔丁氧基。
作为由R1、R2、R3、R4和R5表示的C3-C6环烷基,优选环丙基、环己基,更优选环丙基。
作为由R1、R2、R3、R4和R5表示的C3-C6环烷氧基,可举出环丙氧基、环戊氧基、环己氧基,更优选环己氧基。
作为由R1、R2、R3、R4和R5表示的卤代C1-C4烷基,优选为取代有一个以上氟原子的C1-C4烷基,更优选为取代有1~5个氟原子的C1-C4烷基。具体而言,可举出三氟甲基、2,2,2-三氟乙基、1,1,2,2-四氟乙基、五氟乙基等,更优选为三氟甲基。
作为由R1、R2、R3、R4和R5表示的卤代C1-C4烷氧基,优选为取代有一个以上氟原子的C1-C4烷氧基,更优选为取代有1~5个氟原子的C1-C4烷氧基。具体而言,可举出三氟甲氧基、2,2,2-三氟乙氧基、1,1,2,2-四氟乙氧基、五氟乙氧基等,更优选为三氟甲氧基。
由R1、R2、R3、R4和R5表示的可具有取代基的乙烯基或可具有取代基的乙炔基具有取代基时,作为该取代基,优选C1-C6烷基、C3-C6环烷基或芳基,作为芳基,优选苯基,该芳基可以进一步具有卤素原子、C1-C6烷基或卤代C1-C4烷基等取代基。作为乙烯基,优选无取代或者具有1~2个取代基,特别优选具有一个取代基。作为乙炔基,优选无取代或具有一个取代基。作为可具有取代基的乙烯基或可具有取代基的乙炔基,可举出乙烯基、环己基乙烯基、苯乙烯基、乙炔基、3-甲基-1-丁炔-1-基、环丙基乙炔基、环己基乙炔基、苯基乙炔基等,优选环己基乙烯基、苯乙烯基、环己基乙炔基。
作为由R1、R2、R3、R4和R5表示的芳香环上可具有取代基的芳基或芳香环上可具有取代基的芳氧基的芳香环,优选为苯环。芳香环具有取代基时,作为取代基,优选卤素原子、C1-C6烷基、C1-C6烷氧基、卤代C1-C4烷基。作为可具有取代基的芳基或芳氧基,优选无取代或具有1~2个取代基,更优选在对位具有一个取代基。作为可具有取代基的芳基或芳氧基,具体而言,可举出苯基、4-三氟甲基苯基、4-氯苯基、4-叔丁基苯基、4-甲氧基苯基、苯氧基、4-三氟甲基苯氧基、4-氯苯氧基、4-叔丁基苯氧基、4-甲氧基苯氧基等,优选苯基、4-三氟甲基苯基、4-叔丁基苯基、苯氧基、4-三氟甲基苯氧基、4-叔丁基苯氧基。
作为由R1、R2、R3、R4和R5表示的苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基或苯环上可具有取代基的苯氨基甲基(以下,将苄基到苯氨基甲基统称为苄基等),优选无取代或苯环上具有1~2个取代基,特别优选在对位具有一个取代基。作为该取代基,优选卤素原子、C1-C6烷基、卤代C1-C4烷基,更优选卤代C1-C4烷基,最优选三氟甲基。作为苄基等,优选苯乙基、苄氧基、苄硫基,特别优选苯乙基。作为苯环上可具有取代基的苄基等,具体而言,可举出苄基、苯乙基、苄氧基、苄硫基、苄氨基、苯氧基甲基、苯硫基甲基、苯氨基甲基、4-氟苯乙基、4-氟苄氧基、4-氟苄硫基、(4-三氟甲基)苯乙基、(4-三氟甲基)苄氧基、(4-三氟甲基)苄硫基、4-叔丁基苯乙基、4-叔丁基苄氧基、4-叔丁基苄硫基等,优选苯乙基、苄氧基、苄硫基、苯氧基甲基、苯硫基甲基、苯氨基甲基,更优选苯乙基、苄氧基、苄硫基。
作为由A表示的C1-C3直链状亚烷基,具体而言,可举出亚甲基、-O-、-S-、-CH2CH2-、-CH2O-、-CH2S-、-OCH2-、-SCH2-、-(CH2)3-、-OCH2CH2-、-SCH2CH2-、-CH2OCH2-、-CH2SCH2-、-CH2CH2O-、-CH2CH2S-。其中,优选亚甲基、-O-、-CH2CH2-、-CH2O-、-OCH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2SCH2-、-CH2CH2O-,特别优选-CH2CH2-、-CH2O-。
n最优选为4。
X2最优选为CH。
W1、W2优选为羧基。
作为由V表示的C1-C8直链状或支链状亚烷基,具体而言,可举出亚甲基、-O-、-S-、-CH2CH2-、-CH(CH3)O-、-CH2CH(CH3)-、-CH2CH(CH3)O-、-CH2CH(CH3)S-、-CH2O-、-CH2S-、-OCH2-、-SCH2-。其中,优选-CH2CH2-、-CH(CH3)O-、-CH2O-,特别优选-CH2O-。
由R表示的基团为下式时,
(式中,m为1或2的整数,
Y1和Y2各自独立地为亚甲基、O或S,但是不同时为S)
具体而言,可举出下式所示的基团。
其中,优选选自下式的基团。
作为由R表示基团,
优选选自下式的基团,
特别优选:
作为R1,优选可具有取代基的C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、卤代C1-C4烷基、可具有取代基的乙烯基、可具有取代基的乙炔基、芳香环上可具有取代基的芳基、芳香环上可具有取代基的芳氧基、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基。更优选C1-C6烷基、C3-C6环烷基、可具有取代基的乙烯基、可具有取代基的乙炔基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、或苯环上可具有取代基的苄硫基。作为R1的取代位置,优选间位或对位。其中,作为C1-C6烷基上的取代基,优选C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基。作为乙烯基或乙炔基上的取代基,优选C1-C6烷基、C3-C6环烷基、苯基、卤代苯基、C1-C6烷基苯基、卤代C1-C4烷基苯基。作为芳基,优选苯基,作为芳氧基,优选苯氧基,作为这些芳基或芳氧基上的取代基,优选卤素原子、C1-C6烷基、C1-C6烷氧基、卤代C1-C4烷基。作为苯环上的取代基,优选卤素原子、C1-C6烷基、卤代C1-C4烷基。
作为R2,优选可具有取代基的乙烯基、可具有取代基的乙炔基、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基,更优选可具有取代基的乙烯基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基。最优选苯环上可具有取代基的苯乙基。其中,作为乙烯基或乙炔基上的取代基,优选C1-C6烷基、C3-C6环烷基、苯基、卤代苯基、C1-C6烷基苯基、卤代C1-C4烷基苯基。作为苯环上的取代基,优选卤素原子、C1-C6烷基、卤代C1-C4烷基。
作为R3,优选氢原子、可具有取代基的C1-C6烷基、C1-C6烷氧基、卤代C1-C4烷基。最优选氢原子。R3的取代位置最优选对位。其中,作为C1-C6烷基上的取代基,优选C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基。
作为R4,优选氢原子、可具有取代基的C1-C6烷基、C1-C6烷氧基、卤代C1-C4烷基、芳香环上可具有取代基的芳基、或芳香环上可具有取代基的芳氧基。最优选氢原子。R4的取代位置优选为6位。其中,作为C1-C6烷基上的取代基,优选C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基。作为芳基,优选苯基,作为芳氧基,优选苯氧基,作为这些芳基或芳氧基上的取代基,优选卤素原子、C1-C6烷基、C1-C6烷氧基、卤代C1-C4烷基。
作为R5,优选氢原子、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基,更优选氢原子和苯乙基。R5的取代位置优选为6位。其中,作为苯环上的取代基,优选卤素原子、C1-C6烷基、卤代C1-C4烷基。
通式(1)中,A为亚甲基、-O-、-CH2CH2-、-CH2O-、-OCH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2SCH2-或-CH2CH2O-;
n为3~5的整数;
W1和W2为羧基;
V为-CH2CH2-、-CH(CH3)O-或-CH2O-;
R优选为
这里,R1、R2、Y1、Y2和m与上述相同。
通式(1)中,A为亚甲基、-O-、-CH2CH2-、-CH2O-、-OCH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2SCH2-或-CH2CH2O-;
n为4的整数;
W1和W2为羧基;
V为-CH2CH2-、-CH(CH3)O-或-CH2O-;
R更优选为
其中,R1、R2、Y1、Y2和m与上述相同。
在该优选的方式中,作为R1,优选可具有取代基的C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、卤代C1-C4烷基、可具有取代基的乙烯基、可具有取代基的乙炔基、芳香环上可具有取代基的芳基、芳香环上可具有取代基的芳氧基、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基。更优选C1-C6烷基、C3-C6环烷基、可具有取代基的乙烯基、可具有取代基的乙炔基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、或苯环上可具有取代基的苄硫基。其中,烷基、乙烯基、乙炔基、芳基、芳氧基和苯环上的取代基优选与上述相同。
作为R2,优选可具有取代基的乙烯基、可具有取代基的乙炔基、苯环上可具有取代基的苄基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基、苯环上可具有取代基的苄氨基、苯环上可具有取代基的苯氧基甲基、苯环上可具有取代基的苯硫基甲基、或苯环上可具有取代基的苯氨基甲基,更优选可具有取代基的乙烯基、苯环上可具有取代基的苯乙基、苯环上可具有取代基的苄氧基、苯环上可具有取代基的苄硫基。最优选苯环上可具有取代基的苯乙基。其中,乙烯基、乙炔基和苯环上的取代基优选与上述相同。
在该优选的方式中,R为
时,优选为选自
的基团。
作为本发明的通式(1)的化合物中特别优选的化合物,具体而言,可举出以下化合物。
1-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}茚满-5-羧酸(实施例1)
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例2)
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-6,7,8,9-四氢-5H-苯并环庚烯-2-羧酸(实施例3)
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}色满-7-羧酸(实施例4)
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}硫色满-7-羧酸(实施例5)
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢喹啉-2-羧酸(实施例6)
3-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-2,3-二氢苯并呋喃-6-羧酸(实施例7)
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-异色满-7-羧酸(实施例8)
5-{N-(4-羧基丁基)-N-[2-[2-(2-氯苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例13)
5-{N-[2-[2-(4-苄氧基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例14)
5-{N-[2-[2-(4-苄硫基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例15)
5-{N-(4-羧基丁基)-N-[2-[2-(4-苯氧基甲基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例16)
5-{N-(4-羧基丁基)-N-[2-[2-(4-苯硫基甲基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例17)
5-{N-(4-羧基丁基)-N-[2-[2-(4-乙炔基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例19)
5-{N-(4-羧基丁基)-N-[2-[2-(4-环己基乙炔基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例22)
5-{N-(4-羧基丁基)-N-[2-[2-[4-((E)-2-环己基乙烯基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例23)
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-环己基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例24)
5-{N-(4-羧基丁基)-N-[2-[2-[反-4-(2-苯基乙基)环己基甲氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例26)
5-{N-(4-羧基丁基)-N-[2-[2-[顺-4-(2-苯基乙基)环己基甲氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例27)
5-{N-(4-羧基丁基)-N-[2-[2-(5,6,7,8-四氢化萘-1-基甲氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例29)
5-{N-[2-[2-(3-叔丁基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例41)
5-{N-(4-羧基丁基)-N-[2-[2-(4-环丙基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例42)
5-{N-(4-羧基丁基)-N-[2-[2-(4-异丙基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例43)
5-{N-[2-[2-[(1R)-1-(4-叔丁基苯基)乙氧基]苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例45)
5-{N-(4-羧基丁基)-N-[2-[2-(茚满-5-基甲氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸(实施例46)
在本说明书中,通式(1)的化合物有时产生几何异构体、光学异构体、立体异构体、互变异构体等异构体,但作为本发明的通式(1)的化合物,包括该异构体中的任一者或它们的混合物。
此外,本发明的通式(1)的化合物包括用同位元素(例如2H、3H、14C、35S、125I等)等标记的化合物。
另外,本发明中包括通式(1)的化合物在药学上允许的盐。具体而言,可举出盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐等无机酸,甲酸盐、乙酸盐、三氯乙酸盐、三氟乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、枸橼酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐(4-甲基苯磺酸盐)、天冬氨酸盐或谷氨酸盐等与有机酸的酸加成盐;钠盐、钾盐、镁盐、钙盐、铵盐、铝盐等无机碱,与甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等有机碱的碱加成盐等。
此外,本发明中有时也存在本发明化合物(1)及其药学上允许的盐的水合物、各种溶剂合物和结晶多形,但同样没有限定,任一晶型可以是单一的也可以是晶型混合物,均包含在内。
此外,本发明化合物(1)可以通过药理学上允许的基团而形成前药。作为形成前药的药理学上允许的基团,例如可举出Prog.Med.,5,2157-2161(1985)、“医药品的开发”(广川书店,1990年)第7卷分子设计163-198中记载的基团。
本发明的通式(1)的化合物、其药学上允许的盐或它们的溶剂合物(以下,将这些统称为本发明化合物)可利用基于其基本骨架或其取代基的种类的特征,采用与取代基导入、官能团转化相关的各种原本公知的合成法来制造。
以下,例示本发明化合物的制造方法,但本发明化合物的制造方法不受这些例子的任何限定。
通式(1)的化合物例如可利用下式制造。
(式中,A、n、X1、X2、W1、W2、R和V与上述含义相同。U1和U2分别与W1和W2对应,W1和/或W2为四唑基时U1和/或U2为氰基,W1和/或W2为羧基时U1和/或U2表示CO2R6。Q1和Q2分别与W1和W2对应,W1和/或W2为四唑基时Q1和/或Q2也为四唑基,W1和/或W2为羧基时Q1和/或Q2表示CO2R6。其中,R6表示C1-C6烷基。E表示离去基团或羟基。)
这里,“离去基团”表示在碱的存在下被取代的基团或者具有被活化的氧原子的基团。具体而言,可举出卤素原子;三氯甲氧基等三卤代甲氧基;甲磺酰氧基、乙磺酰氧基等低级烷烃磺酰氧基;三氟甲磺酰氧基、五氟乙磺酰氧基等卤代低级烷烃磺酰氧基;苯磺酰氧基、对甲苯磺酰氧基、对硝基苯磺酰氧基等芳基磺酰氧基。
工序1:对硝基苯磺酰基(Nosyl)保护。
化合物(3)可通过使化合物(2)与硝基苯磺酰基导入剂在碱的存在下或非存在下在溶剂的非存在下或非活性溶剂中进行反应来制造。所使用的硝基苯磺酰基导入剂例如为2-硝基苯磺酰氯、4-硝基苯磺酰氯。硝基苯磺酰基导入剂的使用量相对于化合物(2)通常为1~5当量,优选为1~2当量。所使用的碱例如为碱金属碳酸盐、碱金属碳酸氢盐、碱金属氢氧化物或三乙胺、二异丙基乙胺等有机叔胺。所使用的溶剂例如为苯、甲苯等芳香族烃类,乙腈、丙腈、丁腈等腈类,氯仿、二氯甲烷等卤代烃类,二乙醚、四氢呋喃(以下称为THF)等醚类,水或它们的混合物。反应温度通常为-30℃~40℃,优选为0℃~室温。反应时间通常为0.5~24小时,优选为0.5~3小时。
应予说明,化合物(2)可以被市售或者用公知的方法制造。
工序2:光延反应。
化合物(5)可通过使化合物(3)与化合物(4)在脱水缩合剂的存在下、溶剂的非存在下或非活性溶剂中进行反应来制造。
化合物(4)的使用量相对于化合物(3)通常为1~3当量,优选为1~1.5当量。所使用的脱水缩合剂例如可举出偶氮二羧酸二乙酯、1,1’-偶氮双(N,N-二甲基甲酰胺)等偶氮二羧酸化合物与三苯基膦、三正丁基膦等膦类的组合。脱水缩合剂的使用量相对于化合物(3)通常分别为1~3当量,优选为1~1.5当量。所使用的溶剂例如为苯、甲苯等芳香族烃类,氯仿、二氯甲烷等卤代烃类,二乙醚、THF等醚类,N,N-二甲基甲酰胺(以下称为DMF)、二甲基乙酰胺等酰胺类。反应温度通常为-30℃~40℃,优选为0℃~室温。反应时间通常为1~48小时,优选为1~24小时。
应予说明,化合物(4)可以被市售或者用公知的方法制造。
工序3:对硝基苯磺酰基(Nosyl)去保护反应。
化合物(6)可通过使化合物(5)在碱和去保护试剂的存在下、溶剂的非存在下或非活性溶剂中进行反应来制造。
所使用的去保护试剂例如为正丙胺、吡咯烷等有机伯胺或有机仲胺类;1-十二硫醇、苯硫酚、硫代乙醇酸等硫醇类。去保护试剂的使用量相对于化合物(5)通常为1~5当量,优选为1~2当量。所使用的碱例如为碱金属碳酸盐、碱金属碳酸氢盐、碱金属氢化物、碱金属醇盐、有机叔胺。所使用的溶剂例如为乙腈、丙腈、丁腈等腈类,氯仿、二氯甲烷等卤代烃类,DMF、二甲基乙酰胺等酰胺类或它们的混合物。反应温度通常为-30℃~40℃,优选为0℃~室温。反应时间通常为1~48小时,优选为1~24小时。
工序4:烷基化。
化合物(8)可通过使化合物(6)与化合物(7)在碱和根据需要使用的添加剂的存在下、溶剂的非存在下或非活性溶剂中进行反应来制造。化合物(7)的使用量相对于化合物(6)通常为1~5当量,优选为1~3当量。所使用的碱例如为碱金属碳酸盐、碱金属碳酸氢盐、碱金属氢化物、碱金属醇盐、三乙胺、二异丙基乙胺、吡啶等有机胺。作为所使用的添加剂,例如为碱金属碘化物、四丁基铵盐、冠醚等相转移催化剂。所使用的溶剂例如为苯、甲苯等芳香族烃类,乙腈、丙腈、丁腈等腈类,氯仿、二氯甲烷等卤代烃类,酮类,二乙醚、THF等醚类,甲醇、乙醇、2-丙醇等醇类,DMF、二甲基乙酰胺等酰胺类或它们的混合物。反应温度通常为室温~150℃,优选为室温~100℃。反应时间通常为5~72小时,优选为8~48小时。
工序5:四唑环化。
当化合物(8)中U1和U2中的至少一者为氰基时,化合物(9)可利用将氰基转化成四唑基的公知的方法,例如在叠氮化物的存在下、非活性溶剂中进行反应的方法来制造。
所使用的叠氮化物例如为叠氮化金属盐、三烷基叠氮化锡、叠氮化铵、叠氮化三甲基硅烷。在本工序中,根据需要可适当地使用添加剂。所使用的添加剂例如为氯化铝、季铵盐、镁盐、二烷基氧化锡、氯化锌。所使用的溶剂例如为苯、甲苯等芳香族烃类,氯仿、二氯甲烷等卤代烃类、二乙醚、THF等醚类,DMF、二甲基乙酰胺等酰胺类或它们的混合物。反应温度通常为室温~180℃,优选为50℃~120℃。反应时间通常为5~72小时,优选为8~48小时。
工序6:水解。
当化合物(9)中Q1和Q2中的至少一者为CO2R6时,通式(1)的化合物可通过对化合物(9)进行去酯化反应来制造。
去酯化反应可根据酯基(CO2R6)的种类,按照通常在有机合成化学的领域中公知的方法来进行。例如,可通过在碱存在下进行水解反应来制造通式(1)的化合物。
所使用的碱例如为碱金属碳酸盐、碱金属氢氧化物、碱土金属氢氧化物或碱金属醇盐。所使用的溶剂为二乙醚、THF等醚类,甲醇、乙醇、2-丙醇等醇类,水或它们的混合物。应予说明,在本水解反应中,水为必需。反应温度通常为0℃~150℃,优选为室温~80℃。反应时间通常为1~48小时,优选为3~24小时。
应予说明,通式(1)中W1和W2均为羧基时,工序5可省略。另外,W1和W2均为四唑基时,工序6可省略。另外,可通过对光学活性的化合物(8)和(9)进行去酯化反应来制作光学活性的通式(1)的化合物。此外,对于通式(1)的化合物,也可经由利用手性柱的HPLC拆分来制造光学活性的通式(1)的化合物。
V为-O-、-CH(CH3)O-或-CH2O-时,通式(1)的化合物可通过如下方式制造,即,由下式的化合物(10)利用与上述工序1~4相同的方法得到化合物(11),由化合物(11)利用下式的方法得到化合物(8)。
(式中,R7表示羟基的保护基。)
(式中,A、n、X1、X2、R、U1、U2、E和R7与上述含义相同,其中,V为-O-、-CH(CH3)O-或-CH2O-,G为单键或亚甲基)应予说明,化合物(10)可以被市售或者用公知的方法制造。
工序7:去保护。
化合物(12)可通过对化合物(11)进行去保护反应来制造。
去保护反应可按照通常在有机合成化学的领域中公知的方法来进行(例如,T.W.Greene,P.G.Wuts,Greene’s Protective Groups in Organic Synthesis.FourthEdition,2006年,John Wiley&Sons,Inc.中公开的方法)。
工序8:烷基化反应、光延反应。
当化合物(13)中E为离去基团时,化合物(8)可由化合物(12)和化合物(13)利用与上述工序4相同的方法来制造。
另外,当化合物(13)中E为羟基时,化合物(8)可由化合物(12)和化合物(13)利用与上述工序2相同的方法来制造。
另外,通式(1)的化合物可利用下式的方法得到化合物(6)来制造。
(式中,A、X1、X2、R、V和U1与上述含义相同。)
工序9:氧化反应。
化合物(15)可通过使化合物(14)与氧化剂在非活性溶剂中反应来制造。
所使用的氧化剂例如为1,1,1-三乙酰氧基-1,1-二氢-1,2-苯碘酰-3(1H)-酮(DMP)、1-羟基-1,2-苯碘酰-3(1H)-酮-1-氧化物(IBX)等高原子价碘试剂;铝醇盐与苯醌、二苯甲酮、丙酮、苯甲醛等氢受体的组合;四丙基过钌酸铵(TPAP)或2,2,6,6-四甲基-1-哌啶氧自由基(TEMPO)与次氯酸盐、亚溴酸盐、N-氯代琥珀酰亚胺等共氧化剂的组合;二甲基亚砜(以下称为DMSO)与二环己基碳二亚胺、五氧化磷、乙酸酐、草酰氯等亲电子活化试剂的组合。氧化剂的使用量相对于化合物(14)通常为1~10当量,优选为1~3当量。本工序根据需要例如可添加吡啶或碳酸氢钠等碱。所使用的溶剂例如为苯、甲苯等芳香族烃类,乙腈、丙腈、丁腈等腈类,氯仿、二氯甲烷等卤代烃类,二乙醚、THF等醚类,乙酸乙酯、乙酸丙酯、乙酸丁酯等酯类,DMF、二甲基乙酰胺等酰胺类,DMSO、环丁砜等亚砜类或它们的混合物。反应温度通常为-30℃~100℃,优选为0℃~室温。反应时间通常为0.5~24小时,优选为1~8小时。
工序10:还原胺化。
化合物(6)可通过使化合物(15)与化合物(16)在酸的非存在下或存在下、溶剂的非存在下或非活性溶剂中反应,首先得到Schiff碱,接着使其在还原剂的存在下反应来制造。
化合物(16)的使用量相对于化合物(15)通常为1~3当量,优选为1~1.5当量。作为所使用的酸,例如为盐酸、氢溴酸、磷酸、硫酸等无机酸,甲酸、乙酸、丙酸、甲磺酸、对甲苯磺酸等有机酸。所使用的还原剂例如可举出硼烷-四氢呋喃配合物、硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠等硼氢化物;氢化锂铝等氢化铝化合物;氢。还原剂的使用量相对于化合物(15)通常为1~10当量,优选为1~5当量。所使用的溶剂例如为苯、甲苯等芳香族烃类,氯仿、二氯甲烷等卤代烃类,二乙醚、THF等醚类,乙酸乙酯、乙酸丙酯、乙酸丁酯等酯类,甲醇、乙醇、2-丙醇等醇类或它们的混合物。反应温度通常为-78℃~150℃,优选为0℃~60℃。反应时间通常为5分钟~24小时,优选为30分钟~4小时。
应予说明,化合物(16)可以被市售或者用公知的方法制造。
这样得到的本发明化合物如后述试验例所示,具有血红素非依赖性的优异的sGC活化作用。因此,本发明化合物作为包括人在内的动物中的sGC参与的疾病、特别是sGC活化作用有效的各种疾病的预防治疗用的药品有用。作为该疾病的例子,可举出心力衰竭、高血压症、肺高血压症或缺血性心脏病等。
将本发明化合物用作药品时,可通过经口给药或非经口给药来施用。本发明化合物的给药量考虑成为对象的疾病、症状、给药对象的年龄、体重、性别等,根据各个情况适当地决定。通常,经口给药时,成人(体重约60kg)每1天的本发明化合物的给药量为1~1000mg,优选为3~300mg,进一步优选为10~200mg,可1次给药或者分2~4次给药。另外,静脉内给药时,通常成人1天的给药量为每1kg体重0.01~100mg,优选为0.01~50mg,更优选为0.01~20mg,1天给药1次或分数次给药。
本发明的医药组合物可使用1种以上的本发明化合物和药学上允许的添加剂利用通常的方法来制造。
作为用于经口给药的本发明的医药组合物,可举出片剂、丸剂、胶囊剂、颗粒剂、粉剂、乳剂、溶液剂、混悬剂、糖浆剂或酏剂等。这些通常可作为混合1种以上的本发明化合物与药学上允许的稀释剂、赋形剂、载体等添加剂而成的医药组合物来制造。另外,也可含有黏合剂、崩解剂、润滑剂、溶胀剂、溶胀辅助剂、包衣剂、增塑剂、稳定剂、防腐剂、抗氧化剂、着色剂、溶解辅助剂、悬浮剂、乳化剂、甜味剂、保存剂、缓冲剂、润湿剂等添加剂。
作为用于非经口给药的本发明的医药组合物,可举出注射剂、栓剂、滴眼剂、吸入剂、软膏剂、凝胶剂、膏剂、贴剂等。这些通常可作为混合1种以上的本发明化合物与药学上允许的稀释剂、赋形剂、载体等添加剂而成的医药组合物来制造。另外,还可含有稳定剂、防腐剂、溶解辅助剂、保湿剂、保存剂、抗氧化剂、调味剂、凝胶化剂、中和剂、缓冲剂、等渗剂、表面活性剂、着色剂、缓冲化剂、增稠剂、润湿剂、填充剂、吸收促进剂、悬浮剂、黏合剂等添加剂。
另外,只要不违背本发明的目的,含有本发明化合物的医药组合物中也可以适当地含有利尿药等其他种类的药效成分。
以下,举出实施例对本发明进行具体说明,但本发明不限定于这些实施例。
参考例1 甲氧基甲基2-(2-硝基乙烯基)苯基醚
将2-甲氧基甲氧基苯甲醛(16.4g)悬浮于硝基甲烷(54mL)中,加入乙酸铵(5.95g),在80℃搅拌30分钟。冷却至室温后,在减压下馏去溶剂,将残余物悬浮于水中后,用乙酸乙酯萃取。依次用饱和碳酸氢钠水溶液、饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用二醇基硅胶柱色谱(5%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(11.6g)。
1H-NMR(CDCl3)δ:8.22(1H,d,J=13.6Hz),7.83(1H,d,J=13.6Hz),7.50-7.41(2H,m),7.23(1H,dd,J=8.4,0.9Hz),7.07(1H,ddd,J=8.4,7.5,1.1Hz),5.33(2H,s),3.52(3H,s).
参考例2 2-(2-甲氧基甲氧基苯基)乙胺
将氢化锂铝(6.30g)悬浮于四氢呋喃(以下记为THF)(400mL)中,在冰冷下滴加参考例1(11.6g)的THF(100mL)溶液,加热回流下搅拌30分钟。在冰冷下,一点点地滴加硫酸钠10水合物(21.4g),在室温下搅拌15分钟后进行硅藻土过滤。在减压下馏去溶剂,用硅胶柱色谱(20%甲醇/氯仿)精制残余物,得到作为黄色油状物质的标题化合物(6.73g)。
1H-NMR(CDCl3)δ:7.21-7.15(2H,m),7.09-7.06(1H,m),6.97-6.92(1H,m),5.21(2H,s),3.48(3H,s),2.95(2H,t,J=6.9Hz),2.79(2H,t,J=6.9Hz).
参考例3 3-巯基苯甲酸甲酯
将3-巯基苯甲酸(10.0g)悬浮于甲醇(310mL)中,加入硫酸(0.3mL),在加热回流下搅拌24小时。冷却至室温后,在减压下馏去溶剂,向残余物中加入水。用饱和碳酸氢钠水溶液调整为pH8后,用乙酸乙酯萃取,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(10%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物。
1H-NMR(CDCl3)δ:7.95(1H,dd,J=2.0,1.5Hz),7.82(1H,ddd,J=7.7,1.5,1.3Hz),7.45(1H,ddd,J=7.9,2.0,1.3Hz),7.31(1H,dd,J=7.9,7.7Hz),3.91(3H,s),3.54(1H,s).
参考例4 3-(3-甲氧基羰基苯基硫基)丙酸
将参考例3(10.3g)溶解于丙酮(150mL)中,在冰冷下加入碳酸钾(17.0g)、3-溴丙酸(10.3g),在室温下搅拌2.5小时。在减压下馏去溶剂,将残余物悬浮于水中。用6mol/L盐酸调节为pH1后,用乙酸乙酯萃取。依次用水、饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(50%乙酸乙酯/己烷)精制残余物,得到作为白色粉末的标题化合物(14.5g)。
1H-NMR(CDCl3)δ:8.03(1H,dd,J=1.8,1.7Hz),7.88(1H,ddd,J=7.9,1.7,1.1Hz),7.55(1H,ddd,J=7.7,1.8,1.1Hz),7.38(1H,dd,J=7.9,7.7Hz),3.92(3H,s),3.22(2H,t,J=7.3Hz),2.70(2H,t,J=7.3Hz).
参考例5 4-氧代硫色满-7-羧酸甲酯
将参考例4(2.40g)悬浮于聚磷酸(13mL)中,在70℃搅拌15分钟。冷却至室温后,加入冰和水。用乙酸乙酯萃取,依次用饱和碳酸氢钠水溶液、饱和食盐水清洗有机层后,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(5%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(0.36g)。
1H-NMR(CDCl3)δ:8.16(1H,d,J=8.2Hz),7.96(1H,d,J=1.6Hz),7.78(1H,dd,J=8.2,1.6Hz),3.94(3H,s),3.30-3.25(2H,m),3.04-3.00(2H,m).
参考例6 5,6,7,8-四氢喹啉-5-酮N-氧化物
将5,6,7,8-四氢喹啉-5-酮(7.12g)溶解于二氯甲烷(138mL)中,在冰冷下加入3-氯过氧苯甲酸(14.5g),在相同温度下搅拌4小时。加入饱和碳酸氢钠水溶液,用氯仿稀释后,通过硅藻土过滤将不溶物除去。加入1mol/L氢氧化钠水溶液后,用氯仿萃取,用无水硫酸钠干燥。在减压下馏去溶剂后,将残余物悬浮于二乙醚中并过滤收集,由此得到作为黄色粉末的标题化合物(6.61g)。
1H-NMR(CDCl3)δ:8.44(1H,dd,J=6.4,0.9Hz),7.87(1H,dd,J=8.0,0.9Hz),7.32-7.25(1H,m),3.24(2H,t,J=6.2Hz),2.74-2.65(2H,m),2.28-2.17(2H,m)
参考例7 2-氰基-5,6,7,8-四氢喹啉-5-酮
将参考例6(6.59g)溶解于二氯甲烷(81mL)中,在冰冷下加入三甲基氰硅烷(17.9mL)、N,N-二甲基氨基甲酰氯(8.19mL)后,在室温下搅拌2.3小时,在30℃搅拌4.5小时。冷却至室温后,加入2mol/L氢氧化钠水溶液,剧烈搅拌后,用氯仿萃取。用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(4~30%乙酸乙酯/己烷)精制残余物,得到作为浅黄色粉末的标题化合物(6.07g)。
1H-NMR(CDCl3)δ:8.40(1H,d,J=8.0Hz),7.68(1H,d,J=8.0Hz),3.21(2H,t,J=6.3Hz),2.79-2.72(2H,m),2.31-2.18(2H,m)
参考例8 5-氧代-5,6,7,8-四氢喹啉-2-羧酸
向参考例7(6.05g)中加入浓盐酸(70mL),在加热回流下搅拌14小时。冷却至室温后,在减压下馏去浓盐酸。将残余物用25%甲醇/氯仿溶液溶解后,用饱和食盐水清洗,用无水硫酸钠干燥。在减压下馏去溶剂后,将残余物悬浮于二异丙醚中并过滤收集,得到作为浅黄色粉末的标题化合物(6.38g)。
1H-NMR(CDCl3)δ:8.53(1H,d,J=8.0Hz),8.19(1H,d,J=8.0Hz),3.23(2H,t,J=6.3Hz),2.81-2.75(2H,m),2.32-2.21(2H,m)
参考例9 5-氧代-5,6,7,8-四氢喹啉-2-羧酸甲酯
由参考例8(980mg)并利用与参考例3相同的方法得到作为浅黄色粉末的标题化合物(731mg)。
1H-NMR(CDCl3)δ:8.42(1H,d,J=8.1Hz),8.09(1H,d,J=8.1Hz),4.03(3H,s),3.27(2H,t,J=6.0Hz),2.78-2.72(2H,m),2.30-2.18(2H,m)
参考例10 三氟甲磺酸2,3-二氢-3-氧代苯并呋喃-6-基酯
将2,3-二氢-6-羟基-3-氧代苯并呋喃(2.00g)溶解于二氯甲烷(22mL)中,加入吡啶(5.39mL),在冰冷下滴加三氟甲磺酸酐(2.69mL)。在相同温度下搅拌2小时后,在减压下馏去溶剂。将残余物用乙酸乙酯稀释后,依次用水、饱和食盐水清洗,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(5~20%乙酸乙酯/己烷)精制残余物,用己烷/二异丙醚混合溶液悬浮并过滤收集,由此得到作为黄色粉末的标题化合物(1.84g)。
1H-NMR(CDCl3)δ:7.77(1H,d,J=8.4Hz),7.10(1H,d,J=2.0Hz),7.02(1H,dd,J=8.4,2.0Hz),4.73(2H,s)
参考例11 三氟甲磺酸2,3-二氢-3-羟基苯并呋喃-6-基酯
将参考例10(940mg)溶解于THF(15mL)中,在冰冷下分几次加入硼氢化钠(146mg),在相同温度下搅拌1.5小时。在冰冷下加入饱和氯化铵水溶液后,用乙酸乙酯萃取。用饱和食盐水清洗有机层,用无水硫酸钠干燥后,在减压下馏去溶剂。用硅胶柱色谱(6~35%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(785mg)。
1H-NMR(CDCl3)δ:7.47(1H,d,J=8.2Hz),6.86(1H,dd,J=8.2,2.2Hz),6.80(1H,d,J=2.2Hz),5.40(1H,ddd,J=6.8,6.8,2.8Hz),4.66(1H,dd,J=10.9,6.8Hz),4.53(1H,dd,J=10.9,2.8Hz),2.01(1H,d,J=6.8Hz).
参考例12 2,3-二氢-3-羟基苯并呋喃-6-羧酸甲酯
将参考例11(155mg)溶解于DMF(3.0mL)中,加入甲醇(0.40mL)、三乙胺(0.38mL)、1,3-双(二苯基膦)丙烷(11.2mg)、乙酸钯(II)(6.10mg),在一氧化碳气氛下、在常压、60℃搅拌3小时。冷却至室温后,用水稀释,用二乙醚萃取。依次用水、饱和食盐水清洗有机层,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(33%乙酸乙酯/己烷)精制残余物,得到作为浅红色粉末的标题化合物(75.0mg)。
1H-NMR(CDCl3)δ:7.66(1H,dd,J=7.7,1.5Hz),7.52(1H,d,J=1.5Hz),7.47(1H,d,J=7.7Hz),5.41(1H,ddd,J=6.8,6.8,2.9Hz),4.62(1H,dd,J=10.8,6.8Hz),4.50(1H,dd,J=10.8,2.9Hz),3.91(3H,s),2.05(1H,d,J=6.8Hz)
参考例13 三氟甲磺酸4-氧代异色满-7-基酯
由7-羟基异色满-4-酮(1.00g)并利用与参考例10相同的方法得到作为白色粉末的标题化合物(1.70g)。
1H-NMR(CDCl3)δ:8.16(1H,d,J=8.6Hz),7.32(1H,dd,J=8.6,2.4Hz),7.18(1H,d,J=2.4Hz),4.93(2H,s),4.40(2H,s).
参考例14 4-氧代异色满-7-羧酸甲酯
由参考例13(1.50g)并利用与参考例12相同的方法得到作为白色粉末的标题化合物(588mg)。
1H-NMR(CDCl3)δ:8.13-8.04(2H,m),7.92(1H,s),4.94(2H,s),4.41(2H,s),3.96(3H,s).
参考例15 5-羟基-6,7,8,9-四氢-5H-苯并环庚烯-2-羧酸甲酯
由5-氧代-6,7,8,9-四氢-5H-苯并环庚烯-2-羧酸甲酯(523mg)并利用与参考例11相同的方法得到作为白色粉末的标题化合物(526mg)。
1H-NMR(CDCl3)δ:7.88(1H,dd,J=8.1,1.6Hz),7.77(1H,d,J=1.6Hz),7.56(1H,d,J=8.1Hz),5.01-4.96(1H,m),3.90(3H,s),2.99-2.91(1H,m),2.79-2.71(1H,m),2.08-1.97(2H,m),1.89(1H,d,J=4.0Hz),1.85-1.68(3H,m),1.46-1.33(1H,m).
将使用参考例5、9和14的化合物并利用与参考例15相同的方法制造的参考例16~18的化合物示于表1。
[表1]
参考例19 4-(苯硫基甲基)苯甲醇
将4-(苯硫基甲基)苯甲酸甲酯(1.07g)溶解于THF(14mL)中,在冰冷下每次少量地加入氢化锂铝(200mg),在相同温度下搅拌40分钟。在冰冷下一点点地加入硫酸钠10水合物后,进行硅藻土过滤,在减压下馏去溶剂。将残余物悬浮于己烷中并过滤收集,得到作为白色粉末的标题化合物(910mg)。
1H-NMR(DMSO-D6)δ:7.34-7.12(9H,m),5.10(1H,t,J=5.7Hz),4.44(2H,d,J=5.7Hz),4.21(2H,s)
参考例20 N-[4-(四氢-2H-吡喃-2-基氧基甲基)苄基]-N-苯基-2-硝基苯磺酰胺
将N-苯基-2-硝基苯磺酰胺(1.95g)溶解于DMF(15mL)中,在冰冷下加入碳酸钾(1.16g)、2-(4-氯甲基苄氧基)四氢-2H-吡喃(2.02g)的DMF(3mL)溶液,在40℃搅拌18小时。冷却至室温后,在减压下馏去溶剂,将残余物悬浮于水中,用乙酸乙酯萃取。依次用水、饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(33%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(3.29g)。
1H-NMR(CDCl3)δ:7.66-7.64(2H,m),7.54-7.42(2H,m),7.27-7.17(7H,m),7.12-7.06(2H,m),4.95(2H,s),4.73(1H,d,J=12.1Hz),4.68-4.66(1H,m),4.45(1H,d,J=12.1Hz),3.92-3.85(1H,m),3.54-3.49(1H,m),1.89-1.51(6H,m).
参考例21 N-(4-羟基甲基苄基)-N-苯基-2-硝基苯磺酰胺
将参考例20(3.37g)溶解于甲醇(35mL)中,加入对甲苯磺酸1水合物(133mg),在室温下搅拌30分钟。在减压下馏去溶剂,将残余物溶解于乙酸乙酯中。依次用饱和碳酸氢钠水溶液、饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(50%乙酸乙酯/己烷)精制残余物,得到作为浅黄色粉末的标题化合物(2.57g)。
1H-NMR(CDCl3)δ:7.66-7.65(2H,m),7.54-7.43(2H,m),7.26-7.17(7H,m),7.10-7.06(2H,m),4.95(2H,s),4.64(2H,d,J=5.1Hz),1.63(1H,t,J=5.1Hz).
参考例22 4-(3-甲基-1-丁炔-1-基)苯甲醇
将4-碘苯甲醇(1.00g)溶解于DMF(17mL)中,加入碘化亚酮(97.7mg)、三乙胺(0.89mL)、3-甲基-1-丁炔(1.27mL),在氩气氛下搅拌10分钟。接着,加入双(三苯基膦)二氯化钯(II)(300mg),在氩气氛下、在室温搅拌4.3小时。硅藻土过滤后,用乙酸乙酯清洗,在减压下馏去溶剂。用硅胶柱色谱(6~40%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物。
1H-NMR(CDCl3)δ:7.38(2H,d,J=8.3Hz),7.27(2H,d,J=8.3Hz),4.67(2H,d,J=5.5Hz),2.85-2.70(1H,m),1.66(1H,t,J=5.5Hz),1.26(6H,d,J=7.0Hz).
将使用对应的原料并利用与参考例22相同的方法制造的参考例23~24的化合物示于表2。
[表2]
参考例25 4-((E)-2-环己基乙烯基)苯甲醇
将4-碘苯甲醇(2.34g)溶解于DMF(40mL)中,加入乙烯基环己烷(1.32g)、三乙胺(1.81mL)、双(三苯基膦)二氯化钯(II)(700mg),在80℃搅拌23小时。冷却至室温后,在减压下馏去溶剂,用硅胶柱色谱(8~30%乙酸乙酯/己烷)精制残余物,得到作为黄色固体的标题化合物(672mg)。
1H-NMR(CDCl3)δ:7.34-7.19(4H,m),6.29(1H,d,J=16.0Hz),6.13(1H,dd,J=16.0,6.8Hz),4.67-4.56(3H,m),2.15-2.00(1H,m),1.82-1.51(4H,m),1.37-1.04(6H,m)
参考例26 4-(2-环己基乙基)苯甲醇
将参考例25(283mg)溶解于甲醇(7.0mL)中,加入钯-蚕丝蛋白(57.0mg),在氢气氛下、在常压、室温搅拌45分钟。硅藻土过滤后,用甲醇清洗,在减压下馏去溶剂。用硅胶柱色谱(5~35%乙酸乙酯/己烷)精制残余物,得到作为黄色粉末的标题化合物(206mg)。
1H-NMR(CDCl3)δ:7.27(2H,d,J=8.1Hz),7.17(2H,d,J=8.1Hz),4.66(2H,d,J=5.9Hz),2.66-2.57(2H,m),1.82-1.60(5H,m),1.57-1.44(3H,m),1.32-1.10(4H,m),1.01-0.85(2H,m)
参考例27 反-4-((E)-2-苯基乙烯基)环己烷羧酸甲酯
由反-4-乙烯基环己烷羧酸甲酯(492mg)并利用与参考例25相同的方法得到作为茶色固体的标题化合物(326mg)。
1H-NMR(CDCl3)δ:7.39-7.12(5H,m),6.36(1H,d,J=15.9Hz),6.14(1H,dd,J=15.9,7.0Hz),3.68(3H,s),2.35-2.21(1H,m),2.19-1.99(3H,m),1.97-1.87(2H,m),1.60-1.43(2H,m),1.30-1.14(2H,m)
参考例28 反-4-((E)-2-苯基乙烯基)环己基甲醇
由参考例27(120mg)并利用与参考例19相同的方法得到作为白色粉末的标题化合物(99.0mg)。
1H-NMR(CDCl3)δ:7.38-7.22(4H,m),7.21-7.14(1H,m),6.36(1H,d,J=16.0Hz),6.16(1H,dd,J=16.0,7.0Hz),3.48(2H,d,J=6.2Hz),2.17-2.01(1H,m),1.95-1.79(4H,m),1.64-1.31(2H,m),1.30-1.15(2H,m),1.12-0.96(2H,m)
参考例29 反-4-(2-苯基乙基)环己烷羧酸甲酯
将参考例27(200mg)溶解于甲醇(5.0mL)中,加入5%钯-碳(80.0mg),在氢气氛下、以3个大气压、室温搅拌7.3小时。硅藻土过滤后,用甲醇清洗,在减压下馏去溶剂。将残余物用乙酸乙酯稀释后,用饱和食盐水清洗,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(5%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(192mg)。
1H-NMR(CDCl3)δ:7.31-7.23(2H,m),7.21-7.11(3H,m),3.66(3H,s),2.66-2.58(2H,m),2.25(1H,tt,J=12.3,3.5Hz),2.03-1.93(2H,m),1.92-1.83(2H,m),1.57-1.20(5H,m),0.97(2H,ddd,J=16.3,13.4,3.5Hz)
参考例30 反-4-(2-苯基乙基)环己基甲醇
由参考例29(190mg)并利用与参考例19相同的方法得到作为无色油状物质的标题化合物(166mg)。
1H-NMR(CDCl3)δ:7.31-7.23(2H,m),7.21-7.12(3H,m),3.45(2H,d,J=6.4Hz),2.66-2.59(2H,m),1.91-1.74(4H,m),1.60-1.16(5H,m),1.06-0.82(4H,m).
参考例31 顺-4-((E)-2-苯基乙烯基)环己烷羧酸甲酯
将苄基三苯基溴化(2.94g)溶解于THF(23.0mL)中,在-20℃一点点地加入叔丁醇钾(1.07g),在相同温度下搅拌1小时。接着,用35分钟滴加顺-4-甲酰基环己烷羧酸甲酯(1.00g)的THF(6.0mL)溶液,在相同温度下搅拌1.6小时。升温至室温后,加水搅拌后,用甲苯萃取,依次用水、饱和食盐水清洗有机层。用无水硫酸钠干燥后,在减压下馏去溶剂,用硅胶柱色谱(9%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(268mg)。
1H-NMR(CDCl3)δ:7.37-7.15(5H,m),6.37(1H,d,J=16.6Hz),6.22(1H,dd,J=16.6,6.6Hz),3.69(3H,s),2.62-2.50(1H,m),2.38-2.24(1H,m),2.10-2.00(3H,m),1.76-1.42(5H,m)
参考例32 顺-4-(2-苯基乙基)环己烷羧酸甲酯
由参考例31(268mg)并利用与参考例29相同的方法得到作为无色油状物质的标题化合物(248mg)。
1H-NMR(CDCl3)δ:7.31-7.23(2H,m),7.20-7.13(3H,m),3.68(3H,s),2.64-2.48(3H,m),2.05-1.92(2H,m),1.67-1.23(9H,m)
参考例33 顺-4-(2-苯基乙基)环己基甲醇
由参考例32(248mg)并利用与参考例19相同的方法得到作为无色油状物质的标题化合物(208mg)。
1H-NMR(CDCl3)δ:7.31-7.24(2H,m),7.21-7.14(3H,m),3.54(2H,t,J=5.3Hz),2.64-2.56(2H,m),1.72-1.32(12H,m),1.25-1.18(1H,m)
参考例34 6-硫色满甲醛
将6-溴-硫色满(1.00g)溶解于THF(15.0mL)中,在-78℃滴加2.69mol/L的正丁基锂/己烷溶液(3.24mL),在相同温度下搅拌1小时。在相同温度下加入DMF(0.71mL)后,升温至室温同时搅拌16小时。加入饱和氯化铵水溶液,用乙酸乙酯萃取后,用饱和食盐水清洗有机层。用无水硫酸钠干燥后,在减压下馏去溶剂,用硅胶柱色谱(2~15%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(342mg)。
1H-NMR(CDCl3)δ:9.85(1H,s),7.57-7.48(2H,m),7.21(1H,d,J=8.1Hz),3.12-3.05(2H,m),2.89(2H,t,J=6.1Hz),2.20-2.10(2H,m)
参考例35 6-硫色满甲醇
将参考例34(340mg)溶解于甲醇(10mL)中,在冰冷下分几次加入硼氢化钠(91.2mg),在相同温度下搅拌1小时。在冰冷下加入饱和氯化铵水溶液并搅拌,在减压下馏去溶剂。用乙酸乙酯稀释后,依次用水、饱和食盐水清洗。用无水硫酸钠干燥后,在减压下馏去溶剂,用硅胶柱色谱(6~50%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物。
1H-NMR(CDCl3)δ:7.11-7.01(3H,m),4.58(2H,d,J=5.1Hz),3.06-2.98(2H,m),2.81(2H,t,J=6.1Hz),2.17-2.05(2H,m)
参考例36 1-氧代-6-苯基乙炔基-1,2,3,4-四氢化萘
由三氟甲磺酸5-氧代-5,6,7,8-四氢化萘-2-基酯(1.47g)并利用与参考例22相同的方法得到作为黄色粉末的标题化合物(1.10g)。
1H-NMR(CDCl3)δ:8.01(1H,d,J=7.9Hz),7.56-7.51(2H,m),7.46-7.34(5H,m),2.96(2H,t,J=6.0Hz),2.67(2H,t,J=6.6Hz),2.15(2H,tt,J=6.6,6.0Hz).
参考例37 1-羟基-6-苯基乙炔基-1,2,3,4-四氢化萘
由参考例36(493mg)并利用与参考例11相同的方法得到作为白色粉末的标题化合物(485mg)。
1H-NMR(CDCl3)δ:7.58-7.48(2H,m),7.43-7.29(6H,m),4.79-4.75(1H,m),2.87-2.66(2H,m),2.08-1.73(4H,m),1.59(1H,brs).
参考例38 1-羟基-6-(2-苯基乙基)-1,2,3,4-四氢化萘
由参考例37(482mg)并利用与参考例26相同的方法得到作为无色油状物质的标题化合物(423mg)。
1H-NMR(CDCl3)δ:7.37-7.17(6H,m),7.05(1H,dd,J=7.7,1.6Hz),6.95(1H,d,J=1.6Hz),4.80-4.75(1H,m),2.95-2.64(6H,m),2.01-1.72(4H,m),1.63(1H,d,J=6.2Hz).
参考例39 4-(苯硫基甲基)苄基氯
将参考例19(77.0mg)溶解于二氯甲烷(2.0mL)中,加入亚硫酰氯(30μL),搅拌1.8小时。在减压下馏去溶剂和试剂,得到作为白色无定形的标题化合物的粗产物。
1H-NMR(CDCl3)δ:7.34-7.14(9H,m),4.56(2H,s),4.10(2H,s)
将使用对应的原料并利用与参考例39相同的方法制造的参考例40~46的化合物示于表3。
[表3]
参考例47 2-{2-[(E)-2-[4-((E)-2-苯基乙烯基)苯基]乙烯基]苯基}乙醇
由2-(2-溴苯基)乙醇(3.42g)和4-乙烯基-反-二苯乙烯(4.21g)并利用与参考例25相同的方法得到作为黄色固体的标题化合物(4.80g)。
1H-NMR(DMSO-D6)δ:7.69-7.60(7H,m),7.50(1H,d,J=16.2Hz),7.41-7.35(2H,m),7.29-7.20(6H,m),7.12(1H,d,J=16.2Hz),4.73(1H,t,J=5.7Hz),3.57(2H,td,J=7.0,5.7Hz),2.93(2H,t,J=7.0Hz).
参考例48 2-{2-[2-[4-(2-苯基乙基)苯基]乙基]苯基}乙醇
由参考例47(4.80g)并利用与参考例29相同的方法得到作为无色油状物质的标题化合物(4.56g)。
1H-NMR(DMSO-D6)δ:7.36-7.22(4H,m),7.20-7.08(9H,m),4.69(1H,t,J=5.5Hz),3.55(2H,td,J=7.1,5.5Hz),2.86-2.80(4H,m),2.84(2H,t,J=7.1Hz),2.79-2.74(2H,m),2.75(2H,t,J=6.3Hz).
参考例49 2-{2-[2-[4-(2-苯基乙基)苯基]乙基]苯基}乙醛
将参考例48(496mg)溶解于DMSO(10mL)中,加入IBX(840mg),在室温下搅拌1.5小时。依次加入乙酸乙酯、水,在室温下搅拌1小时。过滤沉淀物,用乙酸乙酯清洗。分液操作后,用饱和食盐水清洗有机层,用无水硫酸钠干燥后,在减压下馏去溶剂。用硅胶柱色谱(10~30%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(422mg)。
1H-NMR(DMSO-D6)δ:9.62(1H,t,J=1.7Hz),7.27-7.22(5H,m),7.20-7.15(4H,m),7.13-7.07(4H,m),3.77(2H,d,J=1.7Hz),2.83(4H,s),2.74-2.72(4H,m).
参考例50 5-[2-(2-{2-[4-(2-苯基乙基)苯基]乙基}苯基)乙基氨基]-5,6,7,8-四氢化萘-2-羧酸甲酯
在氩气氛下,将5-氨基-5,6,7,8-四氢化萘-2-羧酸甲酯盐酸盐(311mg)溶解于二氯甲烷(26mL)中,加入三乙胺(0.18mL),在室温下搅拌5分钟。依次加入参考例49(422mg)、乙酸(0.11mL),在相同温度下搅拌10分钟。接着,在冰冷下加入三乙酰氧基硼氢化钠(681mg),在室温下搅拌2小时。加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(30~70%乙酸乙酯/己烷)精制残余物,得到作为无色油状物质的标题化合物(607mg)。
1H-NMR(DMSO-D6)δ:7.68-7.63(2H,m),7.50(1H,d,J=8.4Hz),7.29-7.08(13H,m),3.80(3H,s),3.73(1H,brs),2.85-2.79(7H,m),2.76-2.75(8H,m),1.93-1.56(4H,m).
参考例51 N-[2-(2-甲氧基甲氧基苯基)乙基]-2-硝基苯磺酰胺
将参考例2(6.72g)溶解于二氯甲烷(186mL)中,在冰冷下加入三乙胺(5.67mL)、2-硝基苯磺酰氯(10.1g),在相同温度下搅拌1小时。在减压下馏去溶剂,将残余物悬浮于乙酸乙酯中后,依次用水、饱和食盐水清洗,用无水硫酸钠干燥。在减压下馏去溶剂,用硅胶柱色谱(20%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(11.0g)。
1H-NMR(CDCl3)δ:8.10-8.05(1H,m),7.83-7.79(1H,m),7.72-7.66(2H,m),7.18-7.12(1H,m),7.04-7.01(2H,m),6.86(1H,ddd,J=8.6,7.5,1.3Hz),5.51(1H,t,J=5.5Hz),5.19(2H,s),3.46(3H,s),3.39(2H,td,J=6.9,5.5Hz),2.87(2H,t,J=6.9Hz).
参考例52 N-{2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基}-2-硝基苯磺酰胺
由2-{2-[4-(2-苯基乙基)苄氧基]苯基}乙胺(1.83g)并利用与参考例51相同的方法得到作为黄色油状物质的标题化合物(2.47g)。
1H-NMR(CDCl3)δ:7.97(1H,dd,J=7.6,1.7Hz),7.76(1H,dd,J=7.3,1.8Hz),7.66-7.55(2H,m),7.37-7.12(10H,m),7.01(1H,dd,J=7.3,1.6Hz),6.86-6.78(2H,m),5.43(1H,t,J=5.7Hz),5.00(2H,s),3.40(2H,td,J=6.8,5.7Hz),2.94(4H,s),2.86(2H,t,J=6.8Hz).
参考例53 1-{N-[2-(2-甲氧基甲氧基苯基)乙基]-(2-硝基苯磺酰胺)}茚满-5-羧酸甲酯
将参考例51(733mg)溶解于甲苯(10mL)中,在冰冷下加入1-羟基茚满-5-羧酸甲酯(577mg)、三正丁基膦(0.75mL)、1,1’-偶氮双(N,N-二甲基甲酰胺)(517mg),在室温下搅拌14.5小时。在减压下馏去溶剂,将残余物再溶解于乙酸乙酯中。依次用水、饱和食盐水清洗后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(20%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物。
1H-NMR(CDCl3)δ:8.19-8.16(1H,m),7.92(1H,s),7.86-7.83(1H,m),7.74-7.66(3H,m),7.29-7.25(1H,m),7.14-7.08(1H,m),6.97-6.93(2H,m),6.85(1H,ddd,J=8.4,7.4,1.1Hz),5.66-5.61(1H,m),5.00(1H,d,J=6.8Hz),4.95(1H,d,J=6.8Hz),3.90(3H,s),3.38-3.19(2H,m),3.27(3H,s),3.13-2.78(3H,m),2.67-2.49(2H,m),2.23-2.11(1H,m).
将使用对应的化合物(4)和参考例51或52的化合物并利用与参考例53相同的方法制造的参考例化合物54~61示于表4和表5。
[表4]
[表5]
参考例62 1-[2-(2-甲氧基甲氧基苯基)乙基氨基]茚满-5-羧酸甲酯
将参考例53(1.08g)溶解于DMF(10mL)中,在冰冷下加入苯硫酚(0.41mL)、碳酸钾(553mg),在室温下搅拌18小时。用水稀释后,用二乙醚萃取,依次用水、饱和食盐水清洗有机层。用无水硫酸钠干燥后,在减压下馏去溶剂,用胺硅胶柱色谱(67%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(638mg)。
1H-NMR(CDCl3)δ:7.88-7.85(2H,m),7.32(1H,d,J=7.7Hz),7.20-7.15(2H,m),7.08(1H,dd,J=8.6,1.1Hz),6.95(1H,ddd,J=8.4,7.5,1.1Hz),5.20(2H,s),4.30(1H,t,J=7.0Hz),3.90(3H,s),3.45(3H,s),3.05-2.77(6H,m),2.49-2.38(1H,m),1.91-1.79(1H,m).
将使用参考例54~61的化合物并利用与参考例62相同的方法制造的参考例63~70的化合物示于表6。应予说明,参考例66、67、68、70以盐酸盐的形式离析。
[表6]
参考例71 1-{N-(4-甲氧基羰基丁基)-N-[2-(2-甲氧基甲氧基苯基)乙基]氨基}茚满-5-羧酸甲酯
将参考例62(636mg)溶解于DMF(9.0mL)中,加入碳酸钾(495mg)、5-溴戊酸甲酯(0.51mL),在95℃加热18.5小时。冷却至室温后,在减压下馏去溶剂后,将残余物悬浮于水中,用乙酸乙酯萃取。依次用水、饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(17%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(568mg)。
1H-NMR(CDCl3)δ:7.84-7.82(2H,m),7.27-7.24(1H,m),7.17-7.07(2H,m),7.01(1H,dd,J=8.2,1.0Hz),6.90(1H,ddd,J=8.4,7.3,1.1Hz),5.07(2H,s),4.57(1H,t,J=8.0Hz),3.90(3H,s),3.66(3H,s),3.35(3H,s),2.97-2.56(6H,m),2.52(2H,t,J=6.9Hz),2.29(2H,t,J=7.2Hz),2.23-2.13(1H,m),2.02-1.89(1H,m),1.74-1.48(4H,m).
将使用参考例50和参考例63~70的化合物并利用与参考例71相同的方法制造的参考例72~81的化合物示于表7和表8。
[表7]
[表8]
参考例82 1-{N-(4-甲氧基羰基丁基)-N-[2-(2-羟基苯基)乙基]氨基}茚满-5-羧酸甲酯
将参考例71(564mg)溶解于THF(5.5mL)、甲醇(0.5mL)中,加入浓盐酸(0.6mL),在室温下搅拌22小时。在减压下馏去溶剂后,用水稀释残余物,在冰冷下用饱和碳酸氢钠水溶液调节为pH8。用乙酸乙酯萃取后,用饱和食盐水清洗有机层,用无水硫酸钠干燥。在减压下馏去溶剂,用硅胶柱色谱(20%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(304mg)。
1H-NMR(CDCl3)δ:12.19(1H,s),7.86-7.81(2H,m),7.53(1H,d,J=8.1Hz),7.14(1H,ddd,J=9.7,8.1,1.9Hz),6.96-6.91(2H,m),6.74(1H,ddd,J=8.4,7.2,1.3Hz),4.76(1H,t,J=7.4Hz),3.89(3H,s),3.62(3H,s),3.04-2.54(7H,m),2.43-2.22(4H,m),2.10-1.98(1H,m),1.61-1.51(4H,m).
将使用参考例72和74的化合物并利用与参考例82相同的方法制造的参考例83和84的化合物示于表9。
[表9]
参考例85 1-{N-(4-甲氧基羰基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}茚满-5-羧酸甲酯
将参考例82(298mg)溶解于乙腈(2.8mL)中,加入4-(2-苯基乙基)苄基氯(194mg)、碳酸钾(145mg),加热回流下搅拌18小时。冷却至室温后,在减压下馏去溶剂,将残余物悬浮于水中,用乙酸乙酯萃取。用饱和食盐水清洗有机层后,用无水硫酸钠干燥,在减压下馏去溶剂。用硅胶柱色谱(17%乙酸乙酯/己烷)精制残余物,得到作为黄色油状物质的标题化合物(393mg)。
1H-NMR(CDCl3)δ:7.81-7.78(2H,m),7.31-7.09(12H,m),6.90-6.85(2H,m),4.97(1H,d,J=13.2Hz),4.93(1H,d,J=13.2Hz),4.51(1H,t,J=8.1Hz),3.88(3H,s),3.64(3H,s),2.94-2.82(6H,m),2.76-2.59(4H,m),2.42(2H,t,J=6.9Hz),2.21(2H,t,J=7.3Hz),2.14-2.06(1H,m),1.97-1.84(1H,m),1.65-1.39(4H,m).
将使用对应的化合物(13)和参考例83或84的化合物并利用与参考例85相同的方法制造的参考例86~108的化合物示于表10~表13。
[表10]
[表11]
[表12]
[表13]
参考例109 5-{N-(4-甲氧基羰基丁基)-N-[2-[2-[反-4-((E)-2-苯基乙烯基)环己基甲氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸甲酯
由参考例83(175mg)和参考例28(95.0mg)并利用与参考例53相同的方法得到作为黄色油状物质的标题化合物(132mg)。
1H-NMR(CDCl3)δ:7.76-7.63(3H,m),7.39-7.23(4H,m),7.23-7.10(2H,m),7.07(1H,dd,J=7.3,1.6Hz),6.84(1H,ddd,J=8.4,7.3,1.1Hz),6.77(1H,dd,J=8.3,1.1Hz),6.37(1H,d,J=16.1Hz),6.17(1H,dd,J=16.1,7.0Hz),4.05-3.95(1H,m),3.89(3H,s),3.73-3.65(2H,m),3.64(3H,s),2.94-2.59(6H,m),2.51(2H,t,J=7.0Hz),2.27(2H,t,J=7.5Hz),2.15-1.95(3H,m),1.95-1.83(3H,m),1.76-1.38(8H,m),1.33-1.03(4H,m).
将使用对应的化合物(13)和参考例83的化合物并利用与参考例109相同的方法制造的参考例110~115的化合物示于表14。
[表14]
参考例116 5-{N-(4-甲氧基羰基丁基)-N-[2-[2-[4-(2-苯基氨基甲基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸甲酯
由参考例96(172mg)并利用与参考例62相同的方法得到作为黄色油状物质的标题化合物。
1H-NMR(CDCl3)δ:7.69-7.60(3H,m),7.35-7.08(8H,m),6.89-6.84(2H,m),6.74-6.64(3H,m),4.94(2H,s),4.33(2H,s),3.97-3.91(1H,m),3.87(3H,s),3.64(3H,s),2.90-2.60(6H,m),2.44(2H,t,J=7.0Hz),2.19(2H,t,J=7.3Hz),2.00-1.91(2H,m),1.63-1.38(7H,m).
参考例117 5-{N-[4-(1H-四唑-5-基)丁基]-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸甲酯
将参考例81(102mg)悬浮于甲苯(5.0mL)中,加入三甲基叠氮化锡(175mg),在加热回流下搅拌44小时。冷却至室温后,在减压下馏去溶剂,将残余物溶解于甲醇(2mL)中,在室温下搅拌15分钟。接着,在减压下馏去溶剂,用硅胶柱色谱(2%甲醇/氯仿)精制残余物,得到作为黄色无定形的标题化合物(84mg)。
1H-NMR(CDCl3)δ:7.70-7.69(3H,m),7.30-7.06(11H,m),6.91-6.83(2H,m),4.92(2H,s),4.26(1H,dd,J=8.8,5.9Hz),4.11(1H,s),3.87(3H,s),2.98-2.69(12H,m),2.54(2H,t,J=6.1Hz),2.02-1.84(2H,m),1.75-1.48(6H,m).
参考例118 三氟甲磺酸8-氧代-5,6,7,8-四氢异喹啉-3-基酯
由5,6,7,8-四氢异喹啉-3,8-二酮(970mg)并利用与参考例10相同的方法得到作为黄色油状物质的标题化合物(1.53g)。
1H-NMR(CDCl3)δ:8.96(1H,s),7.07(1H,s),3.05(2H,t,J=6.1Hz),2.76-2.70(2H,m),2.26-2.16(2H,m).
参考例119 3-氰基-8-氧代-5,6,7,8-四氢异喹啉
将参考例118(1.53g)溶解于DMF(12mL)中,在氩气氛下加入氰化锌(487mg)、四(三苯基膦)钯(0)(299mg),在80℃搅拌3小时。硅藻土过滤后,用乙酸乙酯稀释,用饱和食盐水清洗。用无水硫酸钠干燥,在减压下馏去溶剂后,用硅胶柱色谱(8~16%乙酸乙酯/己烷)精制残余物,悬浮于己烷/二异丙醚混合溶液中并过滤收集,由此得到作为白色粉末的标题化合物(680mg)。
1H-NMR(CDCl3)δ:9.20(1H,s),7.64-7.62(1H,m),3.03(2H,t,J=6.0Hz),2.79-2.72(2H,m),2.28-2.18(2H,m).
参考例120 8-氧代-5,6,7,8-四氢异喹啉-3-羧酸
由参考例119(672mg)并利用与参考例8相同的方法得到作为白色粉末的标题化合物(685mg)。
1H-NMR(CDCl3)δ:9.14(1H,s),8.15(1H,s),3.10(2H,t,J=6.0Hz),2.81-2.73(2H,m),2.29-2.19(2H,m).
参考例121 8-氧代-5,6,7,8-四氢异喹啉-3-羧酸甲酯
将参考例120(540mg)溶解于氯仿(14mL)中,在冰冷下加入二偶氮甲烷/二乙醚溶液直到反应结束。加入乙酸至反应液变成无色后,在减压下馏去溶剂。用硅胶柱色谱(8~80%乙酸乙酯/己烷)精制残余物,得到作为白色粉末的标题化合物(360mg)。
1H-NMR(CDCl3)δ:9.24(1H,s),8.06-8.04(1H,m),4.03(3H,s),3.05(2H,t,J=6.1Hz),2.78-2.70(2H,m),2.27-2.16(2H,m).
参考例122 8-羟基-5,6,7,8-四氢异喹啉-3-羧酸甲酯
由参考例121(432mg)并利用与参考例11相同的方法定量地得到标题化合物(448mg)。
1H-NMR(CDCl3)δ:8.78(1H,s),7.88(1H,s),4.96-4.86(1H,m),4.00(3H,s),2.96-2.70(2H,m),2.15-1.76(5H,m).
将使用对应的化合物(4)和参考例51的化合物并利用与参考例53相同的方法制造的参考例化合物123和124示于表15。
[表15]
将使用参考例123和124的化合物并利用与参考例62相同的方法制造的参考例125和126的化合物示于表16。
[表16]
将使用参考例125和126的化合物并利用与参考例71相同的方法制造的参考例127和128的化合物示于表17。
[表17]
将使用参考例127和128的化合物并利用与参考例82相同的方法制造的参考例129和130的化合物示于表18。
[表18]
将使用对应的化合物(13)和参考例82、参考例83、参考例129或130的化合物并利用与参考例85相同的方法制造的参考例131~139的化合物示于表19~表20。
[表19]
[表20]
将使用对应的化合物(13)和参考例83的化合物并利用与参考例109相同的方法制造的参考例140和141的化合物示于表21。
[表21]
实施例1 1-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}茚满-5-羧酸
将参考例85(391mg)溶解于THF(1.0mL)、甲醇(2.1mL)中,加入2.5mol/L氢氧化钠水溶液(1.0mL),在50℃搅拌1.5小时。冷却至室温后,在减压下馏去溶剂,将残余物再溶解于水中。用2mol/L盐酸调节为pH4后,用氯仿萃取,用无水硫酸钠干燥。在减压下馏去溶剂后,用硅胶柱色谱(10%~20%甲醇/氯仿)精制残余物,得到无色无定形的标题化合物。
1H-NMR(CD3OD)δ:7.92-7.87(2H,m),7.50(1H,d,J=7.9Hz),7.30-7.09(11H,m),7.03(1H,d,J=7.5Hz),6.90(1H,ddd,J=8.2,7.3,0.7Hz),5.11(1H,dd,J=8.2,4.9Hz),4.99(2H,s),3.19-2.82(12H,m),2.41-2.14(4H,m),1.78-1.46(4H,m).
ESI-MS Found:m/z 592(M+H)+
将使用对应的参考例的化合物并利用与实施例1相同的方法制造的实施例2~49的化合物示于表22~表32。
[表22]
[表23]
[表24]
[表25]
[表26]
[表27]
[表28]
[表29]
[表30]
[表31]
[表32]
将使用对应的参考例的光学活化合物并利用与实施例1相同的方法制造的实施例50~69的化合物示于表33~表37。
[表33]
[表34]
[表35]
[表36]
[表37]
通过下述试验例测试本发明化合物对sGC的活化作用。
[试验例1]sGC活化作用的最大化能力
试验中,使用使人sGCα亚基和β亚基、小鼠环核苷酸门控通道(CNGA2)稳定表达的中国仓鼠卵巢细胞(CHO-K1细胞)。
人sGC和小鼠CNGA2稳定表达的CHO-K1细胞在37℃用加入了10%(v/v)胎牛血清(FBS)、青霉素(100U/mL)、链霉素(100μg/mL)、G418(250μg/mL)、博来霉素(250μg/mL)的F-12培养基进行培养。细胞悬浮于培养液中,接种于96孔板后,在37℃培养24小时。用检测缓冲液1(140mmol/L氯化钠、5mmol/L氯化钾、0.5mmol/L氯化镁、0.01mmol/L氯化钙、10mmol/L葡萄糖、0.4mmol/L硫酸镁、10mmol/L乙磺酸4-(2-羟基乙基)哌嗪-1-基酯、125μmol/L磺吡酮,pH7.4)清洗后,加入将荧光Ca2+指示剂即Fura2-AM以5μmol/L的浓度溶解于检测缓冲液1而成的指示剂溶液,在37℃培养60分钟。除去培养液,用检测缓冲液1清洗后,加入试验化合物溶液,在室温下培养10分钟。在荧光测定装置(FlexStation II,Molecular Devices公司)中设置平板,将激发波长设为340nm和380nm,将检测波长设为510nm,以由各激发波长得到的荧光强度比测定细胞内钙浓度。
应予说明,试验化合物溶液如下制备,即,将各试验化合物以成为10mmol/L的方式溶解于DMSO后,以试验浓度成为10μmol/L的方式用检测缓冲液2(140mmol/L氯化钠、5mmol/L氯化钾、0.5mmol/L氯化镁、1mmol/L氯化钙、10mmol/L葡萄糖、0.4mmol/L硫酸镁、10mmol/L乙磺酸4-(2-羟基乙基)哌嗪-1-基酯、125μmol/L磺吡酮、100μmol/L异丁基甲基黄嘌呤、10μmol/L 1H-[1,2,4]-二唑[4,3-a]喹喔啉-1-酮(以下记为ODQ),pH7.4)稀释。对于不含ODQ时的评价,则从检测缓冲液2中除去ODQ,实施相同的评价。对照溶液使用DMSO稀释溶液代替试验化合物溶液。
试验化合物的活性由添加试验化合物溶液时的sGC活性相对于添加对照溶液时的sGC活性的增加率(%)表示,通过用添加试验化合物时的荧光强度比除以对照溶液的荧光强度比,再减去添加对照溶液时的sGC活性(100%)而算出。
将试验结果示于表38和表39。
[表38]
[表39]
16 | 116.2 | 97.5 |
17 | 114.6 | 91.8 |
19 | 88.7 | 88.0 |
22 | 107.6 | 100.2 |
23 | 125.5 | 104.5 |
24 | 134.8 | 114.2 |
26 | 119.4 | 86.9 |
27 | 113.0 | 96.6 |
29 | 140.9 | 133.O |
41 | 109.1 | 140.3 |
42 | 86.7 | 122.5 |
43 | 90.3 | 107.4 |
45 | 95.3 | 121.3 |
46 | 81.3 | 122.7 |
西那西呱 | 53.0 | 86.0 |
在本试验体系中,如果sGc被活化则细胞内cGMP浓度上升,由于与其伴随的cNGA2的开口而引起细胞内ca2+浓度上升。因此,可以测定sGc活化作为细胞内ca2+浓度的变化。ODQ是对血红素结合性的铁原子特异性的氧化剂,在ODQ的存在下血红素的铁原子被氧化,因此不发生血红素依赖性的sGc的活化。因此,在ODQ的非存在下能够评价包括血红素依赖性活化的最大sGc活化作用,并且在ODQ的存在下能够评价血红素非依赖性的sGc活化作用。应予说明,在ODQ的存在下和非存在下,包括作为比较例的西那西呱在内,任一试验化合物均在10μmol/L以上的浓度时sGC活性显示最大值并为恒定,因此将10μmol/L时的活性值作为各试验化合物的sGC活性最大化能力(Emax)。
如表38和表39所示,本发明化合物均在ODQ存在下使sGC活性显著增加,显然是血红素非依赖性的直接性sGC激动剂。另外,本发明化合物与西那西呱相比,在ODQ存在下、非存在下Emax都大,显然具有比西那西呱优异的sGC活化作用。
[试验例2]sGC活化作用的血红素非依赖性
此外,对代表性化合物,利用与试验例1相同的方法测定0.0001、0.001、0.003、0.01、0.03、0.1、1、10μmol/L的试验浓度时的活性。
各试验化合物的sGC活化作用中的血红素非依赖性作用的程度可通过如下方式求出,即,对于由上述制成的浓度-活性曲线求出的EC50,用ODQ存在时的EC50去除不存在ODQ时的EC50。即,该EC50比越小,则有无ODQ存在而引起的sGC活化作用的变化越少,可以说更为血红素非依赖性。
EC50值可通过分别测定0.0001、0.001、0.003、0.01、0.03、0.1、1、10μmol/L的浓度时的受试化合物的活性,采用Assay Explorer(Accelrys公司)利用4参数逻辑斯蒂模型算出。
将试验结果示于表40。
[表40]
如表40所示,本发明化合物的EC50比均比西那西呱低,可知与西那西呱相比,更为血红素非依赖性。
[试验例3]血管松弛作用评价
通过下述试验例对本发明的代表性化合物测试血管松弛作用。试验中,在戊巴比妥(30mg/kg)麻醉下,将大鼠(雄性,SD)从心脏上部放血,摘出腹部大动脉。将腹部大动脉在冰冷Krebs-Henseleit液(KH液)(118mmol/L氯化钠、4.7mmol/L氯化钾、1.2mmol/L硫酸镁、1.2mmol/L磷酸二氢钾、25mmol/L碳酸氢钠、2.5mmol/L氯化钙、10mmol/L葡萄糖,pH7.4)中除去附着于血管周围的结缔组织。其后,制成长度2mm的环形标本,固定于填充有KH液的5mL器官浴中。KH液维持在37℃,通入95%O2和5%CO2混合气体。使标本在静息张力1g下稳定1小时。期间,更换2次KH液。标本的张力介由传感器、放大器记录于多通道记录仪。待标本稳定后,用1μmol/L苯福林(Phe)使其收缩,进行各化合物的累积给药(0.001、0.01、0.03、0.1、0.3、1、3、10、30、100、1000、10000nmol/L)。进行含有1H-1,2,4-二唑-(4,3a)-喹喔啉-1-酮(ODQ)时的评价时,在给予Phe 10分钟前添加10μmol/LODQ,实施相同的评价。
EC50值采用Assay Explorer(Accelrys公司)利用4参数逻辑斯蒂模型算出。应予说明,试验化合物溶液是将各试验化合物以成为最终浓度的1000倍的方式溶解于DMSO中而得到的。
将试验结果示于表41。
[表41]
如表41所示,本发明化合物的EC50比均低于西那西呱,可知与西那西呱相比,更为血红素非依赖性。
产业上的可利用性
本发明的二环化合物、其药学上可允许的盐或它们的溶剂合物由于具有血红素非依赖性的优异的sGC活化作用,所以作为可溶性鸟苷酸环化酶发挥作用的各种疾病,例如心力衰竭、高血压症、肺高血压症或缺血性心脏病等的治疗剂或预防剂使用。
Claims (8)
1.一种由通式(1)表示的化合物或其药学上允许的盐,
式(1)中,A表示C1-C3直链状亚烷基,其中,1个亚甲基可被O或S取代;
n表示3~5的整数;
X1和X2各自独立地表示CH或N;
W1和W2各自独立地表示羧基或四唑基;
V表示C1-C8直链状或支链状亚烷基,其中,1个亚甲基可被O或S取代;
R表示选自下式的基团,
其中,R1、R2、R3、R4和R5表示氢原子、卤素原子、可具有取代基的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、可具有取代基的乙烯基、可具有取代基的乙炔基、在芳香环上可具有取代基的芳基、在芳香环上可具有取代基的芳氧基、在苯环上可具有取代基的苄基、在苯环上可具有取代基的苯乙基、在苯环上可具有取代基的苄氧基、在苯环上可具有取代基的苄硫基、在苯环上可具有取代基的苄氨基、在苯环上可具有取代基的苯氧基甲基、在苯环上可具有取代基的苯硫基甲基、或在苯环上可具有取代基的苯氨基甲基,
m表示1或2的整数,
Y1和Y2各自独立地表示亚甲基、O或S,但不同时为S;
其中,R1、R2、R3、R4和R5中的C1-C6烷基上的取代基为C1-C6烷氧基、C3-C6环烷基或C3-C6环烷氧基,乙烯基或乙炔基上的取代基为C1-C6烷基、C3-C6环烷基、苯基、卤代苯基、C1-C6烷基苯基或卤代C1-C4烷基苯基,芳基或芳氧基上的取代基为卤素原子、C1-C6烷基、C1-C6烷氧基或卤代C1-C4烷基,苯环上的取代基为卤素原子、C1-C6烷基或卤代C1-C4烷基。
2.根据权利要求1所述的化合物或其药学上允许的盐,其中,通式(1)中,A为亚甲基、-O-、-CH2CH2-、-CH2O-、-OCH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2SCH2-或-CH2CH2O-;
n为3~5的整数;
W1和W2为羧基;
V为-CH2CH2-、-CH(CH3)O-或-CH2O-;
R为
其中,R1、R2、Y1、Y2和m与上述相同。
3.根据权利要求1或2所述的化合物或其药学上允许的盐,其中,通式(1)中,A为亚甲基、-O-、-CH2CH2-、-CH2O-、-OCH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2SCH2-或-CH2CH2O-;
n为4的整数;
W1和W2为羧基;
V为-CH2CH2-、-CH(CH3)O-或-CH2O-;
R为
其中,R1、R2、Y1、Y2和m与上述相同。
4.如下的化合物或其药学上允许的盐,所述化合物为:
1-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}茚满-5-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-6,7,8,9-四氢-5H-苯并环庚烯-2-羧酸、
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}色满-7-羧酸、
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}硫色满-7-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢喹啉-2-羧酸、
3-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-2,3-二氢苯并呋喃-6-羧酸、
4-{N-(4-羧基丁基)-N-[2-[2-[4-(2-苯基乙基)苄氧基]苯基]乙基]氨基}-异色满-7-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(2-氯苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-[2-[2-(4-苄氧基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-[2-[2-(4-苄硫基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-苯氧基甲基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-苯硫基甲基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-乙炔基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-环己基乙炔基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[4-((E)-2-环己基乙烯基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[4-(2-环己基乙基)苄氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[反-4-(2-苯基乙基)环己基甲氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-[顺-4-(2-苯基乙基)环己基甲氧基]苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(5,6,7,8-四氢化萘-1-基甲氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-[2-[2-(3-叔丁基苄氧基)苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-环丙基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(4-异丙基苄氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-[2-[2-[(1R)-1-(4-叔丁基苯基)乙氧基]苯基]乙基]-N-(4-羧基丁基)氨基}-5,6,7,8-四氢化萘-2-羧酸、
5-{N-(4-羧基丁基)-N-[2-[2-(茚满-5-基甲氧基)苯基]乙基]氨基}-5,6,7,8-四氢化萘-2-羧酸。
5.一种药品,含有权利要求1~4中任一项所述的化合物或其药学上允许的盐。
6.一种医药组合物,含有权利要求1~4中任一项所述的化合物或其药学上允许的盐、以及药学上允许的载体。
7.权利要求1~4中任一项所述的化合物或其药学上允许的盐,用于预防或治疗可溶性鸟苷酸环化酶参与的疾病。
8.权利要求1~4中任一项所述的化合物或其药学上允许的盐在制造可溶性鸟苷酸环化酶参与的疾病的预防或治疗药中的应用。
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CN105777592B (zh) * | 2016-02-15 | 2017-11-07 | 吴丽清 | 一种药物中间体硝基取代磺酰类化合物的合成方法 |
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