JPH03109393A - Carboxylic amide derivative - Google Patents
Carboxylic amide derivativeInfo
- Publication number
- JPH03109393A JPH03109393A JP1160171A JP16017189A JPH03109393A JP H03109393 A JPH03109393 A JP H03109393A JP 1160171 A JP1160171 A JP 1160171A JP 16017189 A JP16017189 A JP 16017189A JP H03109393 A JPH03109393 A JP H03109393A
- Authority
- JP
- Japan
- Prior art keywords
- group
- phenyl
- lower alkyl
- substituent
- halogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001408 amides Chemical class 0.000 title 1
- -1 (substituted) phenyl Chemical group 0.000 claims abstract description 214
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004561 phenothiazin-10-yl group Chemical group C1=CC=CC=2SC3=CC=CC=C3N(C12)* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 18
- 239000003795 chemical substances by application Substances 0.000 abstract description 13
- 150000001412 amines Chemical class 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 abstract description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 abstract description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 abstract 1
- 201000005577 familial hyperlipidemia Diseases 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 19
- 238000000034 method Methods 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 235000019441 ethanol Nutrition 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
- 239000000843 powder Substances 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 229940105329 carboxymethylcellulose Drugs 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229940099112 cornstarch Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- DBTMGCOVALSLOR-VPNXCSTESA-N laminarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)C(O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-VPNXCSTESA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000013824 Acidemia Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- FPQWVXMEZDPZIB-UHFFFAOYSA-N N#[C-].CCOP(O)(=O)OCC Chemical compound N#[C-].CCOP(O)(=O)OCC FPQWVXMEZDPZIB-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101150030723 RIR2 gene Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
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- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 239000003205 fragrance Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 229940102223 injectable solution Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 239000010410 layer Substances 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
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- ZFCSVJKNKWZTHU-UHFFFAOYSA-N n-(2-benzoyl-4-bromophenyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1 ZFCSVJKNKWZTHU-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- KRIOVPPHQSLHCZ-UHFFFAOYSA-N phenyl propionaldehyde Natural products CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
- C07F9/650947—Six-membered rings having the nitrogen atoms in the positions 1 and 2 condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/02—Phosphorus compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6544—Six-membered rings
- C07F9/6547—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、新規なカルボン酸アミド誘導体に関する。[Detailed description of the invention] Industrial applications The present invention relates to novel carboxylic acid amide derivatives.
従来の技術
本発明のカルボン酸アミド誘導体は、文献未載の新規化
合物である。BACKGROUND OF THE INVENTION The carboxylic acid amide derivative of the present invention is a novel compound that has not been described in any literature.
発明が解決しようとする問題点
本発明は後記するように医薬品として有用な化合物を提
供することを目的とする。Problems to be Solved by the Invention As described later, an object of the present invention is to provide a compound useful as a pharmaceutical.
問題点を解決するための手段
本発明によれば下記一般式(I)で表わされるカルボン
酸アミド誘導体が提供される。Means for Solving the Problems According to the present invention, a carboxylic acid amide derivative represented by the following general formula (I) is provided.
(I)
〔式中R1及びR2はそれぞれ水素原子、低級アルキル
基、置換基としてハロゲン原子、カルバモイル基、N−
(低級アルキル)カルバモイル基、N−(シクロアルキ
ル)カルバモイル基、フェニル環上にハロゲン原子、低
級アルコキシ基、低級アルキル基を置換基として有する
ことのあるN−(フェニル)カルバモイル基、N−(フ
ェニル低級アルキル)カルバモイル基、低級アルカノイ
ル基、ベンゾイル基、N、N−ジ低級アルキルアミノ基
、フェニルチオ基、低級アルキルチオ基、低級アルキル
スルフィニル基、フェニルスルフィニル基、フェニルピ
ペラジニルカルボニル基、(フェニル低級アルキル)ピ
ペラジニルカルボニル基、ピペリジニルカルボニル基及
びスルファモイル基から選ばれる基の1〜3個を有する
ことのあるフェニル基、低級アルコキシカルボニル低級
アルキル基、置換基としてハロゲン原子、低級アルコキ
シ基及び低級アルコキシカルボニル基から選ばれる基の
1〜3個を有することのあるピリジル基、N〜フェニル
アミノ基、置換基としてハロゲン原子を有することのあ
るナフチル基、ピリミジニル基、置換基として低級アル
キル基を有することのあるイソオキサシリル基又はN−
フタラジニルアミノ基を示すが、或いは互いに結合して
之等が結合している窒素原子と共にインドリン−1−イ
ル基、置換基としてハロゲン原子を有することのある1
、2.3.4−テトラヒドロキノリン−1−イル基、1
.2゜3.4−テトラヒドロイソキノリン−2−イル基
、2位又は3位にフェニル基を有することのある2、3
−ジヒドロ−4H−1,4−ベンゾオキサジン−4−イ
ル基又はベンゼン環上にハロゲン原子を置換基として有
することのあるフェノチアジン−10−イル基を形成す
る基を示す。但し上記R1及びR2は同時に水素原子で
あってはならず、また一方が低級アルキル基の場合、他
方は置換基としてハロゲン原子とベンゾイル基とを有す
るフェニル基を示し、一方が置換基としてハロゲン原子
を有するフェニル基の場合、他方は低級アルコキシカル
ボニル低級アルキル基を示し、更に一方がフェニル基の
場合、他方はN−フェニルアミノ基を示すものとする。(I) [In the formula, R1 and R2 are each a hydrogen atom or a lower alkyl group, and as a substituent a halogen atom, a carbamoyl group, or an N-
(lower alkyl)carbamoyl group, N-(cycloalkyl)carbamoyl group, N-(phenyl)carbamoyl group which may have a halogen atom, lower alkoxy group, or lower alkyl group as a substituent on the phenyl ring, N-(phenyl) lower alkyl) carbamoyl group, lower alkanoyl group, benzoyl group, N,N-di-lower alkylamino group, phenylthio group, lower alkylthio group, lower alkylsulfinyl group, phenylsulfinyl group, phenylpiperazinylcarbonyl group, (phenyl lower alkyl ) Phenyl group, lower alkoxycarbonyl lower alkyl group, which may have 1 to 3 groups selected from piperazinylcarbonyl group, piperidinylcarbonyl group and sulfamoyl group, halogen atom, lower alkoxy group and lower as substituents A pyridyl group that may have 1 to 3 groups selected from alkoxycarbonyl groups, an N-phenylamino group, a naphthyl group that may have a halogen atom as a substituent, a pyrimidinyl group, and a lower alkyl group as a substituent. Sometimes an isoxacylyl group or N-
Indolin-1-yl group, which represents a phthalazinylamino group, or together with the nitrogen atoms to which they are bonded, may have a halogen atom as a substituent.
, 2.3.4-tetrahydroquinolin-1-yl group, 1
.. 2゜3.4-tetrahydroisoquinolin-2-yl group, 2,3 which may have a phenyl group at the 2- or 3-position
-dihydro-4H-1,4-benzoxazin-4-yl group or a group forming a phenothiazin-10-yl group that may have a halogen atom as a substituent on the benzene ring. However, the above R1 and R2 must not be hydrogen atoms at the same time, and if one is a lower alkyl group, the other is a phenyl group having a halogen atom and a benzoyl group as a substituent, and one has a halogen atom as a substituent. In the case of a phenyl group having , the other represents a lower alkoxycarbonyl lower alkyl group, and when one is a phenyl group, the other represents an N-phenylamino group.
R3は低級アルキル基を示す。Xは酸素原子又は硫黄原
子を示す。〕
上記一般式(I)において示される各基としては、具体
的にはそれぞれ以下の各基を例示できる。R3 represents a lower alkyl group. X represents an oxygen atom or a sulfur atom. ] Specific examples of each group shown in the above general formula (I) include the following groups.
低級アルキル基としては、例えばメチル、エチル、プロ
ピル、イソプロピル、ブチル、t−ブチル、ペンチル、
ヘキシル基等を例示できる。Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
Examples include hexyl group.
シクロアルキル基としては、例えばシクロプロピル、シ
クロブチル、シクロペンチル、シクロヘキシル、シクロ
ヘプチル、シクロオクチル基等を例示できる。Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
低級アルコキシ基としては、例えばメトキシ、エトキシ
、プロポキシ、ブトキシ、t−ブトキシ、ペンチルオキ
シ、ヘキシルオキシ基等を例示できる。Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy groups.
フェニル低級アルキル基としては、例えばベンジル、α
−フェネチル、β−フェネチル、3−フェニルプロピル
、4−フェニルブチル、1.1−ジメチル−2−フェニ
ルエチル、5−フェニルペンチル、6−フェニルヘキシ
ル基等を例示できる。Examples of phenyl lower alkyl groups include benzyl, α
Examples include -phenethyl, β-phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl and the like.
N−(低級アルキル)カルバモイル基としては、例えば
N−メチルカルバモイル、N−エチルカルバモイル、N
−プロピルカルバモイル、N−ブチルカルバモイル、N
−(t−ブチルカルバモイル)、N−ペンチルカルバモ
イル、N−へキシルカルバモイル基等を例示できる。Examples of the N-(lower alkyl)carbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N-ethylcarbamoyl, and N-ethylcarbamoyl.
-propylcarbamoyl, N-butylcarbamoyl, N
Examples include -(t-butylcarbamoyl), N-pentylcarbamoyl, and N-hexylcarbamoyl groups.
N−(シクロアルキル)カルバモイル基としては、例え
ばN−シクロプロピルカルバモイル、N−シクロブチル
カルバモイル、N−シクロペンチルカルバモイル、N−
シクロへキシルカルバモイル、N−シクロへブチルカル
バモイル、N−シクロオクチルカルバモイル基等を例示
できる。Examples of the N-(cycloalkyl)carbamoyl group include N-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-
Examples include cyclohexylcarbamoyl, N-cyclohebutylcarbamoyl, and N-cyclooctylcarbamoyl.
フェニル環上にハロゲン原子、低級アルコキシ基、低級
アルキル基を置換基として有することのあるN−(フェ
ニル)カルバモイル基としては、例えばフェニルカルバ
モイル、0−クロロフェニルカルバモイル、m−クロロ
フェニルカルバモイル、N−(p−クロロフェニル)カ
ルバモイル、N−(p−ブロモフェニル)カルバモイル
、N−(p−フルオロフェニル)カルバモイル、N(0
−メトキシフェニル)カルノくモイル、N−(m−メト
キシフェニル)カルバモイル、N(p−メトキシフェニ
ル)カル/くモイル、N−(0−エトキシフェニル)カ
ルノくモイル、N−(m−プロポキシフェニル)カルノ
くモイル、N−(p−ブトキシフェニル)カルバモイル
、N−(0−ペンチルオキシフェニル)カルノくモイル
、N−(m−ヘキシルオキシフェニル)カルノくモイル
、N−(o−メチルフェニル)カルノくモイル、N−(
m−メチルフェニル)カルノ(モイル、N−(p−メチ
ルフェニル)カルバモイル、N−(p−エチルフェニル
)カルバモイル、N−(m−プロピルフェニル)カルバ
モイル、N−(p−ブチルフェニル)カルバモイル、N
−(p−ペンチルフェニル)カルバモイル、N−(p−
へキシルフェニル)カルバモイル基等を例示できる。Examples of the N-(phenyl)carbamoyl group which may have a halogen atom, lower alkoxy group, or lower alkyl group as a substituent on the phenyl ring include phenylcarbamoyl, 0-chlorophenylcarbamoyl, m-chlorophenylcarbamoyl, N-(p -chlorophenyl)carbamoyl, N-(p-bromophenyl)carbamoyl, N-(p-fluorophenyl)carbamoyl, N(0
-methoxyphenyl)carnocumoyl, N-(m-methoxyphenyl)carbamoyl, N(p-methoxyphenyl)car/cumoyl, N-(0-ethoxyphenyl)carnocumoyl, N-(m-propoxyphenyl) Carnocumoyl, N-(p-butoxyphenyl)carbamoyl, N-(0-pentyloxyphenyl)carnocumoyl, N-(m-hexyloxyphenyl)carnocumoyl, N-(o-methylphenyl)carnocumoyl Moyle, N-(
m-methylphenyl)carno(moyl, N-(p-methylphenyl)carbamoyl, N-(p-ethylphenyl)carbamoyl, N-(m-propylphenyl)carbamoyl, N-(p-butylphenyl)carbamoyl, N
-(p-pentylphenyl)carbamoyl, N-(p-
Examples include hexylphenyl)carbamoyl group.
N−(フェニル低級アルキル)カルノくモイル基として
は、例えばN−(ベンジル)カルノくモイル、N−(α
−フェネチル)カルバモイル、N−(β−フェネチル)
カルバモイル、N−(3−フェニルプロピル)カルバモ
イル、N−(4−フェニルブチル)カルバモイル、N−
(1,1−ジメチル−2−フェニルエチル)カルバモイ
ル、N−(5−フェニルペンチル)カルバモイル、N−
(6−フェニルヘキシル)カルバモイル基等を例示でき
る。Examples of the N-(phenyl lower alkyl)carnocumoyl group include N-(benzyl)carnocumoyl, N-(α
-phenethyl)carbamoyl, N-(β-phenethyl)
Carbamoyl, N-(3-phenylpropyl)carbamoyl, N-(4-phenylbutyl)carbamoyl, N-
(1,1-dimethyl-2-phenylethyl)carbamoyl, N-(5-phenylpentyl)carbamoyl, N-
Examples include (6-phenylhexyl)carbamoyl group.
低級アルカノイル基としては、例えばアセチル、プロピ
オニル、ブチリル、イソブチリル、バレリル、イソバレ
リル、ピバロイル、ヘキサノイル基等を例示できる。Examples of lower alkanoyl groups include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl groups.
低級アルコキシカルボニル基としては、例えばメトキシ
カルボニル、エトキシカルボニル、プロポキシカルボニ
ル、イソプロポキシカルボニル、ブトキシカルボニル、
ペンチルオキシカルボニル、ヘキシルオキシカルボニル
基等を例示できる。Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Examples include pentyloxycarbonyl and hexyloxycarbonyl groups.
ハロゲン原子としては、弗素原子、塩素原子、臭素原子
、沃素原子を例示できる。Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
N、N−ジ低級アルキルアミノ基としては、例えばN、
N−ジメチルアミノ、N、N−ジエチルアミノ、N
、N−ジプロピルアミノ、N、N−ジエチルアミノ、N
−メチル−N−エチルアミノ、N−メチル−N−ブチル
アミノ、N−エチル−N−へキシルアミノ基等を例示で
きる。Examples of the N,N-dilower alkylamino group include N,
N-dimethylamino, N, N-diethylamino, N
, N-dipropylamino, N, N-diethylamino, N
Examples include -methyl-N-ethylamino, N-methyl-N-butylamino, and N-ethyl-N-hexylamino groups.
低級アルキルスルフィニル基としては、例えばメチルス
ルフィニル、エチルスルフィニル、プロピルスルフィニ
ル、ブチルスルフィニル、ペンチルスルフィニル、ヘキ
シルスルフィニル基等を例示できる。Examples of lower alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, and hexylsulfinyl groups.
フェニルピペラジニルカルボニル基としては、例えば2
−フェニルピペラジニルカルボニル、3−フェニルピペ
ラジニルカルボニル、4−フェニルピペラジニルカルボ
ニル基等を例示できる。As the phenylpiperazinylcarbonyl group, for example, 2
Examples include -phenylpiperazinylcarbonyl, 3-phenylpiperazinylcarbonyl, and 4-phenylpiperazinylcarbonyl groups.
(フェニル低級アルキル)ピペラジニルカルボニル基と
しては、例えば2−(ベンジル)ピペラジニルカルボニ
ル、3−(ベンジル)ピペラジニルカルボニル、4−(
ベンジル)ピペラジニルカルボニル、4−(α−フェネ
チル)ピペラジニルカルボニル、4−(β−フェネチル
)ピペラジニルカルボニル、4−(4−フェニルブチル
)ピペラジニルカルボニル、4− (6−フェニルヘキ
シル)ピペラジニルカルボニル基等を例示できる。Examples of the (phenyl lower alkyl)piperazinylcarbonyl group include 2-(benzyl)piperazinylcarbonyl, 3-(benzyl)piperazinylcarbonyl, 4-(
benzyl)piperazinylcarbonyl, 4-(α-phenethyl)piperazinylcarbonyl, 4-(β-phenethyl)piperazinylcarbonyl, 4-(4-phenylbutyl)piperazinylcarbonyl, 4-(6-phenyl) Examples include a hexyl)piperazinylcarbonyl group and the like.
低級アルコキシカルボニル低級アルキル基としては、例
えばメトキシカルボニルメチル、エトキシカルボニルメ
チル、2−(エトキシカルボニル)エチル、3−(エト
キシカルボニル)プロピル、4−(エトキシカルボニル
)ブチル、5−(エトキシカルボニル)ペンチル、6−
(エトキシカルボニル)ヘキシル、2−(4−ブトキシ
カルボニル)エチル、6−(ヘキシルオキシカルボニル
)メチル基等を例示できる。Examples of lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, 3-(ethoxycarbonyl)propyl, 4-(ethoxycarbonyl)butyl, 5-(ethoxycarbonyl)pentyl, 6-
Examples include (ethoxycarbonyl)hexyl, 2-(4-butoxycarbonyl)ethyl, and 6-(hexyloxycarbonyl)methyl groups.
置換基としてハロゲン原子を有することのあるナフチル
基にはα−ナフチル、β−ナフチル、2−クロロ−1−
ナフチル、1−クロロ−2−ナフチル、4−クロロ−1
−ナフチル、5−クロロ−1−ナフチル、7−クロロ−
1−ナフチル、2ブロモ−1−ナフチル、4−プロコモ
ー2−ナフチル、8−ブロモ−2−ナフチル、4−フル
オロ−1−ナフチル基等を例示できる。Naphthyl groups that may have a halogen atom as a substituent include α-naphthyl, β-naphthyl, 2-chloro-1-
naphthyl, 1-chloro-2-naphthyl, 4-chloro-1
-naphthyl, 5-chloro-1-naphthyl, 7-chloro-
Examples include 1-naphthyl, 2bromo-1-naphthyl, 4-procomo-2-naphthyl, 8-bromo-2-naphthyl, and 4-fluoro-1-naphthyl.
ピリミジニル基には2−ピリミジニル、4−ピリミジニ
ル、5−ピリミジニル及び6−ピリミジニル基が包含さ
れる。Pyrimidinyl groups include 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 6-pyrimidinyl groups.
N−フタラジニルアミノ基にはN−(1−フタラジニル
)アミノ、N−(5−フタラジニル)アミノ及びN−(
6−フタラジニル)アミノ基が包含される。The N-phthalazinylamino group includes N-(1-phthalazinyl)amino, N-(5-phthalazinyl)amino and N-(
6-phthalazinyl)amino group.
置換基としてハロゲン原子を有することのある1、2.
3.4−テトラヒドロキノリン−1−イル基としては、
例えば1.2,3.4−hテラヒドロキノリン−1−イ
ル、3−クロロ−1,2゜3.4−テトラヒドロキノリ
ン−1−イル、4−クロロ−1,2,3,4−テトラヒ
ドロキノリン−1−イル、5−クロロ−1,2,3,4
−テトラヒドロキノリン−1−イル、6−クロロ−1゜
2.3.4−テトラヒドロキノリン−1−イル、7−ク
ロロ−1,2,3,4−テトラヒドロキノリン−1−イ
ル、8−クロロ−1,2,3,4−テトラヒドロキノリ
ン−1−イル、3−ブロモ−1,2,3,4−テトラヒ
ドロキノリン−1−イル、4−ブロモ−1,2,3,4
−テトラヒドロキノリン−1−イル、5−ブロモ−1,
2,3゜4−テトラヒドロキノリン−1−イル、6−ブ
ロモ−1,2,3,4−テトラヒドロキノリン−1イル
、7−ブロモ−1,2,3,4−テトラヒドロキノリン
−1−イル、8−ブロモ−1,2゜3.4−テトラヒド
ロキノリン−1−イル、5−フルオロ−1,2,3,4
−テトラヒドロキノリン−1−イル、8−フルオロ−1
,2,3,4−テトラヒドロキノリン−1−イル等を例
示できる。1, 2. which may have a halogen atom as a substituent;
3.4-tetrahydroquinolin-1-yl group:
For example, 1.2,3.4-h terahydroquinolin-1-yl, 3-chloro-1,2°3.4-tetrahydroquinolin-1-yl, 4-chloro-1,2,3,4-tetrahydro Quinolin-1-yl, 5-chloro-1,2,3,4
-tetrahydroquinolin-1-yl, 6-chloro-1゜2.3.4-tetrahydroquinolin-1-yl, 7-chloro-1,2,3,4-tetrahydroquinolin-1-yl, 8-chloro- 1,2,3,4-tetrahydroquinolin-1-yl, 3-bromo-1,2,3,4-tetrahydroquinolin-1-yl, 4-bromo-1,2,3,4
-tetrahydroquinolin-1-yl, 5-bromo-1,
2,3゜4-tetrahydroquinolin-1-yl, 6-bromo-1,2,3,4-tetrahydroquinolin-1-yl, 7-bromo-1,2,3,4-tetrahydroquinolin-1-yl, 8-Bromo-1,2゜3.4-tetrahydroquinolin-1-yl, 5-fluoro-1,2,3,4
-tetrahydroquinolin-1-yl, 8-fluoro-1
, 2,3,4-tetrahydroquinolin-1-yl and the like.
置換基として低級アルキル基を有することのあるイソオ
キサシリル基としては、3−イソオキサシリル、4−イ
ソオキサシリル、5−イソオキサシリル基の他、例えば
5−メチル−3−イソオキサシリル、5−メチル−4−
イソオキサシリル、5−プロピル−3−イソオキサシリ
ル、4−へキシル−3−イソオキサシリル、4−メチル
−3−イソオキサシリル、4−エチル−5−イソオキサ
シリル基等を例示できる。Examples of isoxasilyl groups that may have a lower alkyl group as a substituent include 3-isoxasilyl, 4-isoxasilyl, and 5-isoxasilyl groups, as well as 5-methyl-3-isoxasilyl, 5-methyl-4-
Examples include isoxasilyl, 5-propyl-3-isoxasilyl, 4-hexyl-3-isoxasilyl, 4-methyl-3-isoxasilyl, 4-ethyl-5-isoxasilyl group, and the like.
置換基としてハロゲン原子、カルバモイル基、N−(低
級アルキル)カルバモイル基、N−(シクロヘキシル)
カルバモイル基、フェニル環上にハロゲン原子、低級ア
ルコキシ基、低級アルキル基を置換基として有すること
のあるN−(フェニル)カルバモイル基、N−(フェニ
ル低級アルキル)カルバモイル基、低級アルカノイル基
、ベンゾイル基、N、N−ジ低級アルキルアミノ基、フ
ェニルチオ基、低級アルキルチオ基、低級アルキルスル
フィニル基、フェニルスルフィニル基、フェニルピペラ
ジニルカルボニル基、(フェニル低級アルキル)ピペラ
ジニルカルボニル基、ピペリジニルカルボニル基及びス
ルファモイル基から選ばれる基の1〜3個を有すること
のあるフェニル基としては、フェニル基の他、例えば4
−ブロモ−2−カルバモイルフェニル、4−クロロ−3
−力ルバモイルフェニル、3−ブロモ−5−カルバモイ
ルフェニル、3.4−ジブロモ−5−カルバモイルフェ
ニル、4−クロロ−2−(N−ノー1−ルカルバモイル
)フェニル、5−クロロ−2−(N−メチルカルバモイ
ル)フェニル、6−クロロ−2−(N−メチルカルバモ
イル)フェニル、4−ブロモ−2−(N−メチルカルバ
モイル)フェニル、6−ブロモ−2−(N−メチルカル
バモイル)フエニ/Iz、4−10ロー2−(N−シク
ロへキシルカルバモイル)フェニル、4−ブロモ−2−
(N−シクロへキシルカルバモイル)フェニル、4−ク
ロロ−2−(N−(p−クロロフェニル)カルバモイル
)フェニル、4−ブロモ−2−(N−(p−クロロフェ
ニル)カルバモイル)フェニル、4−クロロ−2−(N
−(o−メトキシフェニル)カルバモイル)フェニル、
4−ブロモ−2(N−(o−メトキシフェニル)カルバ
モイル)フェニル、4−クロロ−2−(N−(p−メト
キシフェニル)カルバモイル)フェニル、4−クロロ−
2−(N−(p−メチルフェニル)カルバモイル)フェ
ニル、4−ブロモ−2−(N−(p−メチルフェニル)
カルバモイル)フェニル、4−ブロモ−2−(N−(o
−メチルフェニル)カルバモイル)フェニル、4−クロ
ロ−2−(N−ベンジルカルバモイル)フェニル、4−
ブロモ−2−(N−ベンジルカルバモイル)フェニル、
4−ブロモ−2−(N−(β−フェネチル)カルバモイ
ル)フェニル、4−ブロモ−2−(N−(α−フェネチ
ル)カルバモイル)フェニル、3−ブロモー4−クロロ
−5−カルバモイルフェニル、4−ブロモ−2−アセチ
ルフェニル、3−ブロモ−2−アセチルフェニル、4−
クロロ−2−プロピオニルフェニル、2−ブロモ−4−
バレリルフェニル、2−ブロモ−4−アセチルフェニル
、2−クロロ−5−アセチルフェニル、4−ブロモ−2
−ベンゾイルフェニル、5−ブロモ−3−ベンゾイルフ
ェニル、4−ブロモ−2,6−ジベンシイルフエニ/l
/、4−クロロ−5−ブロモ−2−ベンゾイルフェニル
、2−ジメチルアミノフェニル、3−ジメチルアミノフ
ェニル、4−ジメチルアミノフェニル、2−(フェニル
チオ)フェニル、3−(フェニルチオ)フェニル、4−
(フェニルチオ)フェニル、2.3−ジブロモ−4−(
フェニルチオ)フェニル、2−(メチルチオ)フェニル
、3−(メチルチオ)フェニル、4−(メチルチオ)フ
ェニル、4−(ブチルチオ)フェニル、2−メチルスル
フィニルフェニル、4−メチルスルフィニルフェニル、
3−フェニルスルフィニルフェニル、4−フェニルスル
フィニルフェニル、4−クロロ−2−(4−フェニルピ
ペラジニルカルボニル)フェニル、4−ブロモ−2−(
4−フェニルピペラジニルカルボニル)フェニル、4−
クロロ−2−(4−ベンジルピペラジニルカルボニル)
フェニル、4−ブロモ−2−(4−ベンジルピペラジニ
ルカルボニル)フェニル、4−クロロ−2−(ピペリジ
ニルカルボニル)フェニル、4−ブロモ−2−(ピペリ
ジニルカルボニル)フェニル、2−スルファモイルフェ
ニル、3−スルファモイルフェニル、4−スルファモイ
ルフェニル、2−ベンゾイルフェニル、3−ベンゾイル
フェニル、4−ベンゾイルフェニル、2−アセチルフェ
ニル、3−アセチルフェニル、4−アセチルフェニル、
4−プロピオニルフェニル、3−バレリルフェニル、4
−クロロ−2−ベンゾイルフェニル、3−クロロ−2−
ベンゾイルフェニル、3−クロロ−5−ベンゾイルフェ
ニル基等を例示できる。Substituents include halogen atom, carbamoyl group, N-(lower alkyl)carbamoyl group, N-(cyclohexyl)
Carbamoyl group, N-(phenyl)carbamoyl group which may have a halogen atom, lower alkoxy group, lower alkyl group as a substituent on the phenyl ring, N-(phenyl lower alkyl)carbamoyl group, lower alkanoyl group, benzoyl group, N,N-di-lower alkylamino group, phenylthio group, lower alkylthio group, lower alkylsulfinyl group, phenylsulfinyl group, phenylpiperazinylcarbonyl group, (phenyl lower alkyl)piperazinylcarbonyl group, piperidinylcarbonyl group, and In addition to the phenyl group, examples of the phenyl group that may have 1 to 3 groups selected from sulfamoyl groups include, for example, 4
-bromo-2-carbamoylphenyl, 4-chloro-3
-carbamoylphenyl, 3-bromo-5-carbamoylphenyl, 3,4-dibromo-5-carbamoylphenyl, 4-chloro-2-(N-1-carbamoyl)phenyl, 5-chloro-2-(N -methylcarbamoyl)phenyl, 6-chloro-2-(N-methylcarbamoyl)phenyl, 4-bromo-2-(N-methylcarbamoyl)phenyl, 6-bromo-2-(N-methylcarbamoyl)pheny/Iz, 4-10 rho 2-(N-cyclohexylcarbamoyl)phenyl, 4-bromo-2-
(N-cyclohexylcarbamoyl)phenyl, 4-chloro-2-(N-(p-chlorophenyl)carbamoyl)phenyl, 4-bromo-2-(N-(p-chlorophenyl)carbamoyl)phenyl, 4-chloro- 2-(N
-(o-methoxyphenyl)carbamoyl)phenyl,
4-bromo-2(N-(o-methoxyphenyl)carbamoyl)phenyl, 4-chloro-2-(N-(p-methoxyphenyl)carbamoyl)phenyl, 4-chloro-
2-(N-(p-methylphenyl)carbamoyl)phenyl, 4-bromo-2-(N-(p-methylphenyl)
carbamoyl)phenyl, 4-bromo-2-(N-(o
-methylphenyl)carbamoyl)phenyl, 4-chloro-2-(N-benzylcarbamoyl)phenyl, 4-
Bromo-2-(N-benzylcarbamoyl)phenyl,
4-Bromo-2-(N-(β-phenethyl)carbamoyl)phenyl, 4-bromo-2-(N-(α-phenethyl)carbamoyl)phenyl, 3-bromo4-chloro-5-carbamoylphenyl, 4- Bromo-2-acetylphenyl, 3-bromo-2-acetylphenyl, 4-
Chloro-2-propionylphenyl, 2-bromo-4-
valerylphenyl, 2-bromo-4-acetylphenyl, 2-chloro-5-acetylphenyl, 4-bromo-2
-benzoylphenyl, 5-bromo-3-benzoylphenyl, 4-bromo-2,6-dibensylphenyl/l
/, 4-chloro-5-bromo-2-benzoylphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-(phenylthio)phenyl, 3-(phenylthio)phenyl, 4-
(Phenylthio)phenyl, 2,3-dibromo-4-(
Phenylthio)phenyl, 2-(methylthio)phenyl, 3-(methylthio)phenyl, 4-(methylthio)phenyl, 4-(butylthio)phenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl,
3-phenylsulfinylphenyl, 4-phenylsulfinylphenyl, 4-chloro-2-(4-phenylpiperazinylcarbonyl)phenyl, 4-bromo-2-(
4-phenylpiperazinylcarbonyl)phenyl, 4-
Chloro-2-(4-benzylpiperazinylcarbonyl)
Phenyl, 4-bromo-2-(4-benzylpiperazinylcarbonyl)phenyl, 4-chloro-2-(piperidinylcarbonyl)phenyl, 4-bromo-2-(piperidinylcarbonyl)phenyl, 2-sulfur Famoylphenyl, 3-sulfamoylphenyl, 4-sulfamoylphenyl, 2-benzoylphenyl, 3-benzoylphenyl, 4-benzoylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl,
4-propionylphenyl, 3-valerylphenyl, 4
-chloro-2-benzoylphenyl, 3-chloro-2-
Examples include benzoylphenyl and 3-chloro-5-benzoylphenyl groups.
置換基としてハロゲン原子、低級アルコキシ基及び低級
アルコキシカルボニル基から選ばれる基の1〜3個を有
することのあるピリジル基としては、2−ピリジル、3
−ピリジル、4−ピリジル基の他、6−クロロ−2−ピ
リジル、5−クロロ−2−ピリジル、3−ブロモ−4−
ピリジル、5−ブロモ−2−ピリジル、3−ヨード−2
−ピリジル、4−フルオロ−2−ピリジル、2,6−ジ
プロモー3−ピリジル、2−クロロ−3−ブロモ−4−
ピリジル、2.4.6−1リブロモ−3−ピリジル、2
−メトキシ−5−ピリジル、3−メトキシ−5−ピリジ
ル、4−メトキシ−5−ピリジル、2−メトキシ−4−
ピリジル、2−エトキシ−5−ピリジル、4−ブトキシ
−5−ピリジル、2−へキシルオキシ−5−ピリジル、
5−メトキシカルボニル−2−ピリジル、5−メトキシ
カルボニル−3−ピリジル、5−エトキシカルボニル−
2−ピリジル、5−ペンチルオキシカルボニル−2−ピ
リジル基等を例示できる。Examples of pyridyl groups that may have 1 to 3 substituents selected from halogen atoms, lower alkoxy groups, and lower alkoxycarbonyl groups include 2-pyridyl, 3
-pyridyl, 4-pyridyl group, 6-chloro-2-pyridyl, 5-chloro-2-pyridyl, 3-bromo-4-
Pyridyl, 5-bromo-2-pyridyl, 3-iodo-2
-pyridyl, 4-fluoro-2-pyridyl, 2,6-dipromo-3-pyridyl, 2-chloro-3-bromo-4-
Pyridyl, 2.4.6-1 ribromo-3-pyridyl, 2
-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 4-methoxy-5-pyridyl, 2-methoxy-4-
Pyridyl, 2-ethoxy-5-pyridyl, 4-butoxy-5-pyridyl, 2-hexyloxy-5-pyridyl,
5-methoxycarbonyl-2-pyridyl, 5-methoxycarbonyl-3-pyridyl, 5-ethoxycarbonyl-
Examples include 2-pyridyl and 5-pentyloxycarbonyl-2-pyridyl groups.
上記一般式(I)で表わされるカルボン酸アミド誘導体
は、優れた脂質低下作用を有しており、高脂質血症治療
剤として、高コレステロール血症、高トリグリセリド血
症、高リン脂質血症、高遊離脂肪酸血症等の各種疾患(
高脂質血症)の治療及び予防に有用である。The carboxylic acid amide derivative represented by the above general formula (I) has an excellent lipid-lowering effect and can be used as a therapeutic agent for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperphospholipidemia, Various diseases such as hyperfatty acidemia (
It is useful for the treatment and prevention of hyperlipidemia).
以下、本発明誘導体の製造方法につき詳述すれば、本発
明化合物は種々の方法により製造することができる。そ
の代表的方法としては、下記反応式−1〜−5に示す方
法を例示できる。The method for producing the derivative of the present invention will be described in detail below.The compound of the present invention can be produced by various methods. As representative methods thereof, the methods shown in Reaction Formulas -1 to -5 below can be exemplified.
反応式−1
反応式−3
(n)
(m)
(n)
(III)
反応式−2
スルホン酸ハライド類
(Ia)
P(OR3)2
1
反応式−4
(IV)
(III)
(V)
(VI)
反応式−5
P(OR3)2 (■)
1
(Ia) O
P (OR3)2
1
(Ib) 0
〔上記反応式−1〜−5に示す各一般式中RIR2及び
R3は前記に同じ。Yはハロゲン原子を示す。〕
反応式−1に示す方法によれば、カルボン酸誘導体(n
)とアミン類(III)とを縮合反応させることにより
、本発明化合物(Ia)を得ることができる。Reaction formula-1 Reaction formula-3 (n) (m) (n) (III) Reaction formula-2 Sulfonic acid halides (Ia) P(OR3)2 1 Reaction formula-4 (IV) (III) (V) (VI) Reaction formula-5 P(OR3)2 (■) 1 (Ia) O P (OR3)2 1 (Ib) 0 [In each general formula shown in the above reaction formulas-1 to -5, RIR2 and R3 are the above-mentioned Same as . Y represents a halogen atom. ] According to the method shown in reaction formula-1, carboxylic acid derivative (n
) and amines (III) to undergo a condensation reaction, the compound (Ia) of the present invention can be obtained.
上記縮合反応は、一般に適当な溶媒中、縮合剤の存在下
に実施される。ここで用いられる縮合剤としては、従来
公知の各種のものをいずれも使用できる。その具体例と
しては、例えばN、N’ジシクロへキシルカルボジイミ
ド、1−ヒドロキシベンゾトリアゾール、N−ヒドロキ
シコハク酸イミド、ジエチルリン酸シアニド、ジフェニ
ルリン酸アジド等を例示でき、上記ジエチルリン酸シア
ニドをトリエチルアミンと共に用いるのが特に有利であ
る。また溶媒としては、公知の非プロト、ン性溶媒をい
ずれも用い得、特に好ましいものとしてはN、 N−ジ
メチルホルムアミド(DMF)を例示できる。The above condensation reaction is generally carried out in a suitable solvent in the presence of a condensing agent. As the condensing agent used here, any of various conventionally known condensing agents can be used. Specific examples thereof include N,N' dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-hydroxysuccinimide, diethyl phosphate cyanide, diphenyl phosphate azide, etc. It is particularly advantageous to use them together. Further, as the solvent, any known aprotic or chlorinated solvent can be used, and a particularly preferred example is N,N-dimethylformamide (DMF).
上記反応におけるカルボン酸誘導体(n)とアミン類(
I[)との使用割合は、特に限定されず広範囲から適宜
選択できるが、通常前者に対して後者を等モル量〜過剰
量、好ましくは等モル量程度用いるのがよい。また上記
縮合剤は、カルボン酸誘導体(II)に対して等モル量
〜過剰量、好ましくは少過剰量用いられるのが望ましい
。反応温度条件としては、水冷下〜室温付近の温度が採
用でき、通常的0.5〜2時間程度で反応は完結する。Carboxylic acid derivative (n) and amines (
The ratio of I[) to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually preferable to use the latter in an equimolar amount to an excess amount, preferably in an equimolar amount to the former. Further, the above-mentioned condensing agent is desirably used in an equimolar amount to an excess amount, preferably a slight excess amount, relative to the carboxylic acid derivative (II). As the reaction temperature conditions, temperatures ranging from water cooling to around room temperature can be adopted, and the reaction is usually completed in about 0.5 to 2 hours.
反応式−2に示す方法によれば、カルボン酸塩化物誘導
体(IV)とアミン類(III)とを反応させることに
より、本発明化合物(I a)を得ることができる。According to the method shown in Reaction Formula-2, the compound (Ia) of the present invention can be obtained by reacting the carboxylic acid chloride derivative (IV) with the amine (III).
上記反応は、一般に適当な溶媒中、脱酸剤の存在下に実
施される。ここで用いられる脱酸剤としては、反応に悪
影響を与えない公知の各種のものをいずれも使用できる
。その具体例としては、例えばトリエチルアミン、ジエ
チルアニリン、N−メチルモルホリン、ピリジン、4−
ジメチルアミノピリジン等の第三級アミン類を好ましく
例示できる。また溶媒としては、ベンゼン、トルエン、
キシレン、石油エーテル等の芳香族乃至脂肪族炭化水素
類、ジエチルエーテル、ジメトキシエタン、テトラヒド
ロフラン(THF) 、1.4−ジオキサン等の鎖状乃
至環状エーテル類、アセトン、メチルエチルケトン、ア
セトフェノン等のケトン類、ジクロロメタン、クロロホ
ルム、四塩化炭素、1゜2−ジクロロエタン等のハロゲ
ン化炭化水素類等を例示できる。The above reaction is generally carried out in a suitable solvent in the presence of a deoxidizing agent. As the deoxidizing agent used here, any known deoxidizer that does not adversely affect the reaction can be used. Specific examples include triethylamine, diethylaniline, N-methylmorpholine, pyridine, 4-
Preferable examples include tertiary amines such as dimethylaminopyridine. In addition, as a solvent, benzene, toluene,
Aromatic or aliphatic hydrocarbons such as xylene and petroleum ether, chain or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF), and 1,4-dioxane, ketones such as acetone, methyl ethyl ketone, and acetophenone, Examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1°2-dichloroethane.
上記反応におけるカルボン酸塩化物誘導体(IV)とア
ミン類(nl)との使用割合は、特に限定されないが、
通常後者に対して前者を等モル量〜過剰量用いるのがよ
い。また上記脱酸剤は、通常カルボン酸塩化物誘導体(
IV)に対して等モル量〜少過剰量用いられるのが好適
である。反応は、冷却下、室温下及び加熱下のいずれで
も進行するが、通常室温付近〜溶媒の還流温度範囲の温
度条件を採用して行なわれるのがよく、一般に約0.5
〜10時間程時間路了する。The ratio of the carboxylic acid chloride derivative (IV) and the amines (nl) used in the above reaction is not particularly limited, but
Generally, it is preferable to use an equimolar amount to an excess amount of the former with respect to the latter. In addition, the above deoxidizing agent is usually a carboxylic acid chloride derivative (
It is preferable to use an equimolar amount to a slight excess amount relative to IV). The reaction proceeds either under cooling, at room temperature, or under heating, but it is usually carried out under temperature conditions in the range of around room temperature to the reflux temperature of the solvent, and generally about 0.5
It took about 10 hours.
反応式−3に示す方法によれば、カルボン酸誘導体(I
I)を混合酸無水物として、これとアミン類(III)
とを反応させることにより、本発明化合物(Ia)を得
ることができる。According to the method shown in reaction formula-3, carboxylic acid derivative (I
I) as a mixed acid anhydride, and amines (III)
Compound (Ia) of the present invention can be obtained by reacting with.
上記混合酸無水物を経る反応は、一般に適当な溶媒中で
、混合酸無水物を形成し得るカルボン酸ハライド類又は
スルホン酸ハライド類と脱酸剤との共存下に実施される
。ここで用いられるカルボン酸ハライド類及びスルホン
酸ハライド類としては、通常のもの、例えばクロル炭酸
エチル、クロル炭酸イソブチル、p−トルエンスルホン
酸クロリド、ベンゼンスルホン酸クロリド等を用いるこ
とができ、之等の内ではクロル炭酸エチルが好適である
。脱酸剤としては、反応に悪影響を与えない公知の各種
のものをいずれも使用できる。その具体例としては、ト
リエチルアミン、ジエチルアニリン、N−メチルモルホ
リン、ピリジン等の第三級アミン類を例示できる。また
溶媒としては、ベンゼン、トルエン、キシレン、石油エ
ーテル等の芳香族乃至脂肪族炭化水素類、ジエチルエー
テル、ジメトキシエタン、THF、1.4−ジオキサン
等の鎖状乃至環状エーテル類、アセトン、メチルエチル
ケトン、アセトフェノン等のケトン類、ジクロロメタン
、クロロホルム、四塩化炭素、1゜2−ジクロロエタン
等のハロゲン化炭化水素類等を例示できる。The reaction involving the mixed acid anhydride is generally carried out in a suitable solvent in the presence of a carboxylic acid halide or sulfonic acid halide capable of forming the mixed acid anhydride and a deoxidizing agent. As the carboxylic acid halides and sulfonic acid halides used here, common ones such as ethyl chlorocarbonate, isobutyl chlorocarbonate, p-toluenesulfonic acid chloride, benzenesulfonic acid chloride, etc. can be used. Among them, ethyl chlorocarbonate is preferred. As the deoxidizing agent, any of various known deoxidizing agents that do not adversely affect the reaction can be used. Specific examples include tertiary amines such as triethylamine, diethylaniline, N-methylmorpholine, and pyridine. Examples of solvents include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether, chain and cyclic ethers such as diethyl ether, dimethoxyethane, THF, and 1,4-dioxane, acetone, methyl ethyl ketone, Examples include ketones such as acetophenone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1°2-dichloroethane.
上記反応における化合物(II)とアミン類(III)
との使用割合は、特に限定されないが、通常前者に対し
て後者を等モル量〜過剰量用いるのがよい。Compound (II) and amines (III) in the above reaction
Although the ratio of the latter to the former is not particularly limited, it is usually preferable to use an equimolar amount to an excess amount of the latter to the former.
また上記カルボン酸ハライド類及びスルホン酸ハライド
類と脱酸剤とは、それぞれ化合物(It)に対して等モ
ル量〜少過剰量用いられるのが好適である。反応は、冷
却下、室温下及び加熱下のいずれでも進行するが、通常
室温付近〜溶媒の還流温度範囲の温度条件を採用して行
なわれるのが望ましく、一般に約0.5〜5時間程度で
終了する。The carboxylic acid halides, sulfonic acid halides, and deoxidizing agent are each preferably used in an equimolar amount to a slight excess amount relative to the compound (It). The reaction proceeds either under cooling, at room temperature, or under heating, but it is preferable to carry out the reaction under temperature conditions ranging from around room temperature to the reflux temperature of the solvent, and generally takes about 0.5 to 5 hours. finish.
反応式−4に示す方法によれば、ハロアミド誘導体(V
)と亜リン酸エステル類(VI)との反応により、本発
明化合物(I a)を収得できる。According to the method shown in reaction formula-4, a haloamide derivative (V
) and a phosphite (VI) to obtain the compound (I a) of the present invention.
上記反応は、反応に悪影響を及ぼさない適当な溶媒、例
えば低級アルコール類、芳香族乃至脂肪族炭化水素類、
DMF等の溶媒中で行なうこともできるが、通常無溶媒
で行なわれるのが好ましい。The above reaction can be carried out using a suitable solvent that does not have a negative effect on the reaction, such as lower alcohols, aromatic or aliphatic hydrocarbons,
Although the reaction can be carried out in a solvent such as DMF, it is usually preferable to carry out the reaction without a solvent.
該反応におけるへロアミド誘導体(V)と亜リン酸エス
テル類(VI)との使用割合は、通常前者に対して後者
を過剰量とするのがよく、反応は通常約130〜180
℃、好ましくは約140〜150℃の温度下に実施され
、反応時間は用いる亜リン酸エステル類(VI)の種類
に応じて異なるが、一般に約0.5〜3時間程度である
。The ratio of the heroamide derivative (V) and the phosphite (VI) used in the reaction is usually such that the latter is used in excess of the former, and the reaction is usually carried out at a ratio of about 130 to 180%.
C., preferably about 140 to 150.degree. C., and the reaction time varies depending on the type of phosphite (VI) used, but is generally about 0.5 to 3 hours.
反応式−5に示す方法によれば、カルボン酸アミド誘導
体(Ia)に三硫化ニリン(■)を反応させることによ
り、本発明化合物(Ib)を収得できる。According to the method shown in Reaction Formula-5, the compound (Ib) of the present invention can be obtained by reacting the carboxylic acid amide derivative (Ia) with niline trisulfide (■).
上記反応に供されるカルボン酸アミド誘導体(Ia)は
前記反応式−1〜−4に示す方法により得られるもので
あり、該化合物(Ia)と三硫化ニリン(■)との反応
は適当な溶媒中で行なわれる。ここで溶媒としては、一
般には非プロトン性溶媒、例えばピリジン、トリエチル
アミン、ジメチルアニリン等の三級アミン類、ベンゼン
、トルエン、キシレン等の芳香族炭化水素類、アセトニ
トリル等を有利に使用できる。之等の内で特に好ましい
ものとしてはベンゼンとピリジンとの混合溶媒を例示で
き、該混合溶媒における両者の混合比率は、通常前者を
後者に対して約4〜5倍量とするのがよい。The carboxylic acid amide derivative (Ia) to be subjected to the above reaction is obtained by the method shown in the reaction formulas -1 to -4 above, and the reaction between the compound (Ia) and niline trisulfide (■) is carried out using an appropriate method. It is done in a solvent. As the solvent, generally aprotic solvents such as tertiary amines such as pyridine, triethylamine and dimethylaniline, aromatic hydrocarbons such as benzene, toluene and xylene, and acetonitrile can be advantageously used. Among these, a mixed solvent of benzene and pyridine is particularly preferred, and the mixing ratio of the two in the mixed solvent is usually about 4 to 5 times the amount of the latter.
上記反応における化合物(I a)と三硫化ニリン(■
)との使用割合は、特に限定されず広範囲から適宜選択
できるが、通常前者に対して後者を等モル量〜過剰量、
好ましくは約1.5〜2.5倍モル量とするのがよい。Compound (I a) and niline trisulfide (■
) is not particularly limited and can be appropriately selected from a wide range, but usually the latter is used in an equimolar amount to an excess amount,
The amount is preferably about 1.5 to 2.5 times the molar amount.
反応は通常室温〜溶媒の還流温度、好ましくは約70〜
90℃程度の温度下に実施され、一般に約2〜10時開
路度で終了する。The reaction is usually carried out at room temperature to the reflux temperature of the solvent, preferably about 70 to
The process is carried out at a temperature of about 90° C. and is generally completed at a temperature of about 2 to 10 o'clock.
上記反応式−1〜−5に示す方法により得られる目的の
本発明化合物は、慣用される分離手段により反応系内よ
り単離され得、また精製され得る。The target compounds of the present invention obtained by the methods shown in Reaction Formulas -1 to -5 above can be isolated from the reaction system by conventional separation means and can be purified.
上記単離、精製手段としては、溶媒抽出法、蒸留法、再
結晶法、カラムクロマトグラフィー、プレパラティブ薄
層クロマトグラフィー等を採用することができる。As the above-mentioned isolation and purification means, solvent extraction method, distillation method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. can be employed.
本発明化合物は、通常−船釣な医薬製剤の形態で用いら
れる。製剤は通常使用される充填剤、増量剤、結合剤、
付湿剤、崩壊剤、表面活性剤、滑沢剤等の希釈剤あるい
は賦形剤を用いて調整される。この医薬製剤としては各
種の形態が治療目的に応じて選択でき、その代表的なも
のとして錠剤、乳剤、散剤、液剤、懸濁剤、乳剤、顆粒
剤、カプセル剤、半開、注射剤(液剤、懸濁剤等)等が
挙げられる。錠剤の形態に成形するに際しては、担体と
して例えば乳糖、白糖、塩化ナトリウム、ブドウ糖、尿
素、デンプン、炭酸カルシウム、カオリン、結晶セルロ
ース、ケイ酸等の賦形剤、水、エタノール、プロパツー
ル、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶
液、カルボキシメチルセルロース、セラック、メチルセ
ルロース、リン酸カリウム、ポリビニルピロリドン等の
結合剤、カルボキシメチルセルロースもしくはその塩、
微結晶セルロース、アルギン酸ナトリウム、カンテン末
、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム
、ポリオキシエチレンソルビタン脂肪酸エステル類、ラ
ウリル硫酸ナトリウム、ステアリン酸モノグリセリド、
デンプン、乳糖等の崩壊剤、白糖、ステアリン、カカオ
バター、水素添加油等の崩壊抑制剤、第4級アンモニウ
ム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリ
セリン、デンプン等の保湿剤、デンプン、乳糖、カオリ
ン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製
タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリ
コール等の滑沢剤等を使用できる。さらに錠剤は必要に
応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン
被包錠、腸溶被錠、フィルムコーティング錠あるいは二
重錠、多層錠とすることができる。乳剤の形態に成形す
るに際しては、担体として例えばブドウ糖、乳糖、デン
プン、カカオ脂、硬化植物油、カオリン、タルク等の賦
形剤、アラビアゴム末、トラガント末、ゼラチン、エタ
ノール等の結合剤、ラミナラン、カンテン等の崩壊剤等
を使用できる。半割の形態に成形するに際しては、担体
として例えばポリエチレングリコール、カカオ脂、高級
アルコール、高級アルコールのエステル類、ゼラチン、
半合成グリセライド等を使用できる。カプセル剤は常法
に従い通常本発明化合物を上記で例示した各種の担体と
混合して硬質ゼラチンカプセル、軟質カプセル等に充填
して調整される。注射剤として調整される場合、液剤、
乳剤及び懸濁剤は殺菌され、かつ血液と等張であるのが
好ましく、これらの形態に成形するに際しては、希釈剤
として例えば水、エチルアルコール、マクロゴール、プ
ロピレングリコール、エトキシ化イソステアリルアルコ
ール、ポリオキシ化イソステアリルアルコール、ポリオ
キシエチレンソルビタン脂肪酸エステル類等を使用でき
る。なお、この場合等張性の溶液を調整するに充分な量
の食塩、ブドウ糖あるいはグリセリンを医薬製剤中に含
有せしめてもよく、また通常の溶解補助剤、緩衝剤、無
痛化剤等を添加してもよい。更に必要に応じて着色剤、
保存剤、香料、風味剤、甘味剤等や他の医薬品を医薬製
剤中に含有せしめてもよい。The compounds of the present invention are usually used in the form of pharmaceutical preparations. The formulation contains commonly used fillers, extenders, binders,
It is adjusted using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, semi-open forms, injections (liquids, suspending agents, etc.). When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, carboxymethylcellulose or its salts,
Microcrystalline cellulose, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride,
Disintegrants such as starch and lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, and lactose. Adsorbents such as , kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into an emulsion, carriers such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, laminaran, A disintegrant such as agar can be used. When molding into halved forms, carriers such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin,
Semi-synthetic glycerides etc. can be used. Capsules are prepared by mixing the compound of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods. When prepared as an injectable solution,
Emulsions and suspensions are preferably sterile and isotonic with blood, and when formed into these forms, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, Polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to adjust the isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavors, sweeteners, etc. and other pharmaceutical agents may also be included in the pharmaceutical formulation.
本発明医薬製剤中に含有されるべき本発明化合物の量と
しては、特に限定されず広範囲に適宜選択されるが、通
常医薬製剤中に1〜70重量%とするのがよい。The amount of the compound of the present invention to be contained in the pharmaceutical formulation of the present invention is not particularly limited and may be appropriately selected within a wide range, but it is usually preferably 1 to 70% by weight in the pharmaceutical formulation.
上記医薬製剤の投与方法は特に制限がなく、各種製剤形
態、患者の年齢、性別その他の条件、疾患の程度等に応
じて決定される。例えば錠剤、乳剤、液剤、懸濁剤、乳
剤、顆粒剤及びカプセル剤は経口投与される。注射剤は
単独で又はブドウ糖、アミノ酸等の通常の補液と混合し
て静脈内投与され、更に必要に応じて単独で筋肉内、皮
内、皮下もしくは腹腔内投与される。半割は直腸内投与
される。The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and furthermore, if necessary, are administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Half of the dose is administered rectally.
上記医薬製剤の投与量は、用法、患者の年齢、性別その
他の条件、疾患の程度等により適宜選択されるが、通常
有効成分である本発明化合物の量が1日当り体重1kg
当り約0.05〜80mg程度とするのがよく、該製剤
は1日に1〜4回に分けて投与することができる。The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the compound of the present invention, which is the active ingredient, is 1 kg of body weight per day.
The dosage is preferably about 0.05 to 80 mg per day, and the preparation can be administered in 1 to 4 divided doses per day.
実 施 例
以下、本発明を更に詳しく説明するため本発明化合物の
製造例を実施例として挙げ、次いで薬理試験例を挙げる
。更に本発明化合物を用いて調製された製剤例を挙げる
。EXAMPLES Below, in order to explain the present invention in more detail, production examples of the compounds of the present invention will be given as examples, and then pharmacological test examples will be given. Furthermore, examples of formulations prepared using the compound of the present invention will be given.
実施例 1
4−ジェトキシホスフィノイルメチル安息香酸1.36
g(5ミリモル)と3−アミノ−5−メチルイツオキサ
ゾール0.49g (5ミリモル)とを、乾燥DMF1
53F/に溶解させ、水冷撹拌下、この混合物にジエチ
ルリン酸シアニド1.00g(5,5ミリモル)の乾燥
DMF2zl溶液を滴下した。次いでトリエチルアミン
0.56g(5,5ミリモル)の乾燥DMF3.vA’
溶液を5分間を要して滴下し、水冷下に30分間撹拌し
、更に室温で1時間撹拌した。反応混合物中に水3゜1
1を加え、酢酸エチルで抽出し、有機層を水で2回洗浄
し、芒硝上で乾燥後、溶媒を留去した。残渣をシリカゲ
ルカラムクロマトグラフィーで精製(クロロホルム:酢
酸エチル=1=1より溶出)し、ベンゼン−n−ヘキサ
ンより再結晶して、無色針状晶の4−ジェトキシホスフ
ィノイルメチル−N−(5−メチル−3−イソオキサシ
リル)べンズアミド0.53gを得た。Example 1 4-jethoxyphosphinoylmethylbenzoic acid 1.36
g (5 mmol) and 0.49 g (5 mmol) of 3-amino-5-methylituoxazole in dry DMF1
53 F/, and a solution of 1.00 g (5.5 mmol) of diethyl phosphoric cyanide in 2 zl of dry DMF was added dropwise to this mixture under water-cooling and stirring. Then 0.56 g (5.5 mmol) of triethylamine in 3.5 g (5.5 mmol) of dry DMF. vA'
The solution was added dropwise over 5 minutes, stirred for 30 minutes while cooling with water, and further stirred at room temperature for 1 hour. 3°1 of water in the reaction mixture
1 was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over Glauber's sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with chloroform:ethyl acetate=1=1) and recrystallized from benzene-n-hexane to give colorless needle-like crystals of 4-jethoxyphosphinoylmethyl-N-( 0.53 g of 5-methyl-3-isoxasilyl)benzamide was obtained.
融点151〜152℃
実施例 2〜6
実施例1と同様にして、下記第1表に示す各化合物を得
た。Melting point: 151-152°C Examples 2-6 In the same manner as in Example 1, each compound shown in Table 1 below was obtained.
尚、第1表には前記実施例1で得た化合物も併記する。Note that Table 1 also lists the compounds obtained in Example 1 above.
第
表
尚、上記第1表に示す実施例6の化合物(性状:油状)
の’H−NMR(CDCjf’ 3 、内部標準:TM
S)分析結果(δ値: ppm )は、次の通りであっ
た。Table: Compound of Example 6 shown in Table 1 above (property: oily)
'H-NMR (CDCjf' 3, internal standard: TM
S) The analysis results (δ value: ppm) were as follows.
1.27 (t、J=7.0Hz、6J−D2.7−3
.1 (m、2H)
3.19 (d、J=22.0Hz、2f−I)3.4
−4.0 (m、2H)
3.8−4.2 (m、4H)
4.3−5.0 (m、2H)
7、 1−7. 5 (m、 8I−I)実施例 フ
インドリン1.80g (15ミリモル)とトリエチル
アミン1.82g (18ミリモル)と4−シメチルア
ミノピリジン0.37g (3モリモル)とを乾燥ジク
ロロメタン30y/に溶解させ、これに水冷撹拌下に、
4−ジェトキシホスフィノイルメチルベンゾイル クロ
リド5.21g (15ミリモル)の乾燥ジクロロメタ
ン3011溶液をゆっくり滴下した。室温で10時間撹
拌した後、反応混合物中に水50zIlを加え、クロロ
ホルムで抽出し、芒硝上で乾燥し、溶媒を留去した。残
渣をシリカゲルカラムクロマトグラフィーで精製(クロ
ロホルム:酢酸エチル=1:1で溶出)シ、ベンゼン−
n−へキサンより再結晶して、無色結晶の1−(4−ジ
ェトキシホスフィノイルメチルベンゾイル)インドリン
3.90gを得た。1.27 (t, J=7.0Hz, 6J-D2.7-3
.. 1 (m, 2H) 3.19 (d, J=22.0Hz, 2f-I) 3.4
-4.0 (m, 2H) 3.8-4.2 (m, 4H) 4.3-5.0 (m, 2H) 7, 1-7. 5 (m, 8I-I) Example 1.80 g (15 mmol) of findlin, 1.82 g (18 mmol) of triethylamine, and 0.37 g (3 mmol) of 4-dimethylaminopyridine were dissolved in 30 ml of dry dichloromethane. , and then water-cooled and stirred,
A solution of 5.21 g (15 mmol) of 4-jethoxyphosphinoylmethylbenzoyl chloride in dry dichloromethane 3011 was slowly added dropwise. After stirring at room temperature for 10 hours, 50 zIl of water was added to the reaction mixture, extracted with chloroform, dried over Glauber's sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with chloroform:ethyl acetate = 1:1).
Recrystallization from n-hexane gave 3.90 g of 1-(4-jethoxyphosphinoylmethylbenzoyl)indoline as colorless crystals.
融点93.0〜94.5℃ 実施例 8〜26 実施例7と同様にして、第2表に示す各化合物を得た。Melting point 93.0-94.5℃ Examples 8-26 In the same manner as in Example 7, each compound shown in Table 2 was obtained.
実施例27
1−(4−ジェトキシホスフィノイルメチルベンゾイル
)−1,2,3,4−テトラヒドロキノリン0.77g
(2,0ミリモル)と五硫化ニリン1.0g (4,
6ミリモル)とを、無水ベンゼン2011と脱水ピリジ
ン5xlとの混合溶媒に懸濁させ、7時間加熱還流した
。室温まで放冷後、反応混合物を氷水5011中に注加
し、水層を4N塩酸で酸性にしてクロロホルムで抽出し
、芒硝上で乾燥し、溶媒を留去した。残渣をシリカゲル
カラムクロマトグラフィーで精製(クロロホルム:酢酸
エチル=1=1で溶出)シ、ベンゼン−n−ヘキサンよ
り再結晶して、黄色結晶の1−[(4−ジェトキシホス
フィノイルメチルフェニル)チオカルボニル]−1,2
,3,4−テトラヒドロキノリン0.23gを得た。Example 27 1-(4-jethoxyphosphinoylmethylbenzoyl)-1,2,3,4-tetrahydroquinoline 0.77 g
(2,0 mmol) and 1.0 g of niline pentasulfide (4,
(6 mmol) was suspended in a mixed solvent of 2011 anhydrous benzene and 5xl of dehydrated pyridine, and heated under reflux for 7 hours. After cooling to room temperature, the reaction mixture was poured into ice water 5011, the aqueous layer was acidified with 4N hydrochloric acid, extracted with chloroform, dried over Glauber's sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with chloroform:ethyl acetate=1=1) and recrystallized from benzene-n-hexane to give yellow crystals of 1-[(4-jethoxyphosphinoylmethylphenyl). thiocarbonyl]-1,2
, 0.23 g of 3,4-tetrahydroquinoline was obtained.
融点96〜97℃ 実施例28〜54 実施例7と同様にして、第2表に示す各化合物を得た。Melting point 96-97℃ Examples 28-54 In the same manner as in Example 7, each compound shown in Table 2 was obtained.
尚、第2表には上記実施例7及び実施例27で得られた
各化合物も併記する。Note that Table 2 also lists the compounds obtained in Example 7 and Example 27 above.
第 2
表
薬理試験例 1
7週齢のウィスター系雄性ラットの1群6匹(試験群)
に、0.5%カルボキシメチルセルロース(CMC)で
懸濁させた被検化合物を、ゾンデを用いて強制的に30
0 mg/ 5 yl/ kg/日で2日間経口投与し
た。尚、コントロール群として、0.5%CMCのみを
投与した群を設けた。Table 2 Pharmacological test example 1 Group of 6 male Wistar rats, 7 weeks old (test group)
The test compound suspended in 0.5% carboxymethyl cellulose (CMC) was forcibly suspended for 30 minutes using a sonde.
It was orally administered at 0 mg/5 yl/kg/day for 2 days. A group to which only 0.5% CMC was administered was provided as a control group.
上記最終投与後、20時間絶食させて採血を行ない、血
漿中のHDL−CをHDL−CキットN(日本商事株式
会社製)にて、また中性脂肪をトリグリセライドGテス
トワコー(和光純薬工業株式会社製)にて、それぞれ測
定した。After the final administration, blood was collected after fasting for 20 hours. HDL-C in plasma was measured using HDL-C Kit N (manufactured by Nippon Shoji Co., Ltd.), and triglyceride G Test Wako (Wako Pure Chemical Industries, Ltd.) was used to measure neutral fat. (manufactured by Co., Ltd.), respectively.
得られた各測定値より、1−I D L −Cについて
は下式に従い被検化合物投与群のHD L −Cの上昇
率を算出した。From each of the obtained measured values, the rate of increase in HD L -C of the test compound administration group was calculated for 1-I D L -C according to the following formula.
また中性脂肪については、下式に従い被検化合物投与群
の中性脂肪低下率を算出した。Regarding neutral fat, the neutral fat reduction rate of the test compound administration group was calculated according to the following formula.
上記で得られた試験結果を下記第3表に示す。The test results obtained above are shown in Table 3 below.
第 3 表
製剤例 1 錠剤の調製
有効成分として6−ブロモ−1−(4−ジェトキシホス
フィノイルメチルベンゾイル)−1,2゜3.4−テト
ラヒドロキノリン(以下「化合物A」という)を、1錠
当り250111g含有する錠剤(1000錠)を、次
の処方により調製した。Table 3 Formulation Example 1 Preparation of tablets 6-bromo-1-(4-jethoxyphosphinoylmethylbenzoyl)-1,2°3.4-tetrahydroquinoline (hereinafter referred to as "Compound A") was used as the active ingredient. Tablets (1000 tablets) containing 250111 g per tablet were prepared according to the following formulation.
成 分 量(g)化
合物A 250乳糖(日本薬局
方晶) 33.3コーンスターチ(日
本薬局方晶) 16.4カルボキシメチルセルロー
スカル
シウム(日本薬局方晶) 12.8メチル
セルロース(日本薬局方晶)6.0ステアリン酸マグネ
シウム
(日本薬局方晶)1.5
全 量 320.0即
ち、上記処方に従い、化合物A1乳糖、コーンスターチ
及びカルボキシメチルセルロースを充分に混合し、メチ
ルセルロース水溶液を用いて顆粒化し、24メツシユの
篩に通し、ステアリン酸マグネシウムと混合して錠剤に
プレスした。Ingredients Amount (g) Compound A 250 Lactose (Japanese Pharmacopoeia) 33.3 Corn starch (Japanese Pharmacopoeia) 16.4 Carboxymethyl cellulose calcium (Japanese Pharmacopoeia) 12.8 Methylcellulose (Japanese Pharmacopoeia) 6. 0 Magnesium stearate (Japanese Pharmacopoeia crystal) 1.5 Total amount 320.0 That is, according to the above recipe, compound A1 lactose, cornstarch and carboxymethylcellulose were thoroughly mixed, granulated using an aqueous methylcellulose solution, and sieved through a 24-mesh sieve. and mixed with magnesium stearate and pressed into tablets.
処方例 2 カプセル剤の調製
有効成分として4−ジェトキシホスフィノイルメチル−
N−(2−ベンゾイル−4−ブロモフェニル)ベンズア
ミド(以下「化合物B」という)を、1カプセル当り2
50mg含有する硬質ゼラチンカプセル(1000個)
を、次の処方により調製した。Prescription example 2 Preparation of capsules 4-jethoxyphosphinoylmethyl- as an active ingredient
N-(2-benzoyl-4-bromophenyl)benzamide (hereinafter referred to as "compound B") at 2 ml per capsule.
Hard gelatin capsules (1000 pieces) containing 50mg
was prepared according to the following recipe.
成 分 量(g)化
合物B 250結晶セルロース
(日本薬局方晶)3゜
コーンスターチ(日本薬局方晶)17
タルク(日本薬局方晶) 2ステアリン
酸マグネシウム
(日本薬局方晶) 1全
量 300即ち、上記処方に
従い各成分を細かく粉末にし、均一な混合物となるよう
に充分混和した後、所望の寸法を有する経口投与用ゼラ
チンカプセルに充填して、目的のカプセルを得た。Ingredients Amount (g) Compound B 250 Crystalline Cellulose (Japanese Pharmacopoeia Crystal) 3° Cornstarch (Japanese Pharmacopoeia Crystal) 17 Talc (Japanese Pharmacopoeia Crystal) 2 Magnesium Stearate (Japanese Pharmacopoeia Crystal) 1 Total
Amount: 300 That is, each component was finely powdered according to the above recipe, thoroughly mixed to form a uniform mixture, and then filled into gelatin capsules for oral administration having desired dimensions to obtain the desired capsules.
処方例 3 顆粒剤の調製
有効成分として4−ジェトキシホスフィノイルメチル−
N−(4−アセチル−2−ブロモフェニル)ベンズアミ
ド(以下「化合物C」という)を、1g当り500mg
含有する顆粒剤(1000g)を、次の処方により調製
した。Prescription example 3 Preparation of granules 4-jethoxyphosphinoylmethyl- as an active ingredient
500 mg/g of N-(4-acetyl-2-bromophenyl)benzamide (hereinafter referred to as "Compound C")
Granules (1000 g) containing the following were prepared according to the following formulation.
成 分 量(g)化
合物C500
コーンスターチ(日本薬局方晶) 250乳糖(日本薬
局方晶) 100結晶セルロース(日本薬
局方晶) 100カルボキシメチルセルロースカル
シウム(日本薬局方晶)40
ヒドロキシプロピルセルロース
(日本薬局方晶) 10全
量 ioo。Ingredients Amount (g) Compound C500 Cornstarch (Japanese Pharmacopoeia) 250 Lactose (Japanese Pharmacopoeia) 100 Crystalline Cellulose (Japanese Pharmacopoeia) 100 Carboxymethyl Cellulose Calcium (Japanese Pharmacopoeia) 40 Hydroxypropyl Cellulose (Japanese Pharmacopoeia) Akira) 10 complete
Amount ioo.
即ち、上記処方に従い化合物c1コーンスターチ、乳糖
、結晶セルロース及びカルボキシメチルセルロースカリ
ウムを混合した後、混合物にヒドロキシプロピルセルロ
ース水溶液を加えて混練し、押出し造粒機で造粒し、5
0℃で2時間乾燥して、目的顆粒剤を得た。That is, after mixing compound c1 corn starch, lactose, crystalline cellulose, and carboxymethyl cellulose potassium according to the above recipe, an aqueous hydroxypropyl cellulose solution was added to the mixture, kneaded, and granulated using an extrusion granulator.
It was dried at 0°C for 2 hours to obtain the desired granules.
(以 上)(that's all)
Claims (1)
キル基、置換基としてハロゲン原子、カルバモイル基、
N−(低級アルキル)カルバモイル基、N−(シクロア
ルキル)カルバモイル基、フェニル環上にハロゲン原子
、低級アルコキシ基、低級アルキル基を置換基として有
することのあるN−(フェニル)カルバモイル基、N−
(フェニル低級アルキル)カルバモイル基、低級アルカ
ノイル基、ベンゾイル基、N,N−ジ低級アルキルアミ
ノ基、フェニルチオ基、低級アルキルチオ基、低級アル
キルスルフィニル基、フェニルスルフィニル基、フェニ
ルピペラジニルカルボニル基、(フェニル低級アルキル
)ピペラジニルカルボニル基、ピペリジニルカルボニル
基及びスルファモイル基から選ばれる基の1〜3個を有
することのあるフェニル基、低級アルコキシカルボニル
低級アルキル基、置換基としてハロゲン原子、低級アル
コキシ基及び低級アルコキシカルボニル基から選ばれる
基の1〜3個を有することのあるピリジル基、N−フェ
ニルアミノ基、置換基としてハロゲン原子を有すること
のあるナフチル基、ピリミジニル基、置換基として低級
アルキル基を有することのあるイソオキサゾリル基又は
N−フタラジニルアミノ基を示すか、或いは互いに結合
して之等が結合している窒素原子と共にインドリン−1
−イル基、置換基としてハロゲン原子を有することのあ
る1,2,3,4−テトラヒドロキノリン−1−イル基
、1,2,3,4−テトラヒドロイソキノリン−2−イ
ル基、2位又は3位にフェニル基を有することのある2
,3−ジヒドロ−4H−1,4−ベンゾオキサジン−4
−イル基又はベンゼン環上にハロゲン原子を置換基とし
て有することのあるフェノチアジン−10−イル基を形
成する基を示す。但し上記R^1及びR^2は同時に水
素原子であってはならず、また一方が低級アルキル基の
場合、他方は置換基としてハロゲン原子とベンゾイル基
とを有するフェニル基を示し、一方が置換基としてハロ
ゲン原子を有するフェニル基の場合、他方は低級アルコ
キシカルボニル低級アルキル基を示し、更に一方がフェ
ニル基の場合、他方はN−フェニルアミノ基を示すもの
とする。 R^3は低級アルキル基を示す。 Xは酸素原子又は硫黄原子を示す。〕 で表わされるカルボン酸アミド誘導体。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are a hydrogen atom, a lower alkyl group, and a halogen atom, a carbamoyl group, or a substituent, respectively.
N-(lower alkyl)carbamoyl group, N-(cycloalkyl)carbamoyl group, N-(phenyl)carbamoyl group which may have a halogen atom, lower alkoxy group, or lower alkyl group as a substituent on the phenyl ring, N-
(Phenyl lower alkyl)carbamoyl group, lower alkanoyl group, benzoyl group, N,N-di-lower alkylamino group, phenylthio group, lower alkylthio group, lower alkylsulfinyl group, phenylsulfinyl group, phenylpiperazinylcarbonyl group, (phenyl (lower alkyl) phenyl group which may have 1 to 3 groups selected from piperazinyl carbonyl group, piperidinyl carbonyl group and sulfamoyl group, lower alkoxycarbonyl lower alkyl group, halogen atom, lower alkoxy group as a substituent and a pyridyl group that may have 1 to 3 groups selected from lower alkoxycarbonyl groups, an N-phenylamino group, a naphthyl group that may have a halogen atom as a substituent, a pyrimidinyl group, a lower alkyl group as a substituent. Indoline-1 represents an isoxazolyl group or an N-phthalazinylamino group, which may have a
-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group that may have a halogen atom as a substituent, 1,2,3,4-tetrahydroisoquinolin-2-yl group, 2-position or 3-position 2 which may have a phenyl group in position
,3-dihydro-4H-1,4-benzoxazine-4
-yl group or a group forming a phenothiazin-10-yl group that may have a halogen atom as a substituent on the benzene ring. However, the above R^1 and R^2 must not be hydrogen atoms at the same time, and if one is a lower alkyl group, the other is a phenyl group having a halogen atom and a benzoyl group as a substituent, and one is a substituted In the case of a phenyl group having a halogen atom as a group, the other group represents a lower alkoxycarbonyl lower alkyl group, and when one of the groups is a phenyl group, the other represents an N-phenylamino group. R^3 represents a lower alkyl group. X represents an oxygen atom or a sulfur atom. ] A carboxylic acid amide derivative represented by
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU37078/89A AU606808B2 (en) | 1988-06-29 | 1989-06-27 | Arylcarboxamide substituted by alkylphosphonates, process for preparing the same and a pharmaceutical composition containing the same |
SE8902326A SE469895B (en) | 1988-06-29 | 1989-06-28 | Carboxamide compounds, processes for their preparation and pharmaceutical compositions containing them |
IT8967528A IT1235532B (en) | 1988-06-29 | 1989-06-28 | CARBOXYMIDE COMPOUNDS, PROCEDURES FOR THE PREPARATION OF THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME |
CA000604124A CA1339370C (en) | 1988-06-29 | 1989-06-28 | Carboxamide compounds, processes for preparing the same and a pharmaceutical composition containing the same |
DE3921188A DE3921188C2 (en) | 1988-06-29 | 1989-06-28 | Carboxamide compounds, process for their preparation and pharmaceutical compositions containing them |
NL8901652A NL194239C (en) | 1988-06-29 | 1989-06-29 | Dialkoxyphosphinol methylbenzamide compounds and pharmaceutical preparations containing them. |
CN 89106420 CN1022632C (en) | 1988-06-29 | 1989-06-29 | Carboxamide compounds, process for preparing same and pharmaceutical composition containing same |
CH2429/89A CH678530A5 (en) | 1988-06-29 | 1989-06-29 | |
US07/373,837 US4971957A (en) | 1988-06-29 | 1989-06-29 | Carboxamide compounds, processes for preparing the same and a pharmaceutical composition containing the same |
FR8908722A FR2633624B1 (en) | 1988-06-29 | 1989-06-29 | CARBOXAMIDE, METHODS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME |
ES8902301A ES2017820A6 (en) | 1988-06-29 | 1989-06-29 | Carboxamide compounds, processes for preparing the same and a pharmaceutical composition containing the same |
KR1019890009119A KR950006546B1 (en) | 1988-06-29 | 1989-06-29 | Carboxamide compounds, process for preparing the same and pharmaceutical composition containing the same |
GB8914891A GB2220206B (en) | 1988-06-29 | 1989-06-29 | Carboxamide compounds,processes for preparing the same and a pharmaceutical composition containing the same |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63-163082 | 1988-06-29 | ||
JP16308288 | 1988-06-29 | ||
JP15278489 | 1989-06-15 | ||
JP1-152784 | 1989-06-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH03109393A true JPH03109393A (en) | 1991-05-09 |
JPH0745508B2 JPH0745508B2 (en) | 1995-05-17 |
Family
ID=26481598
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1160171A Expired - Lifetime JPH0745508B2 (en) | 1988-06-29 | 1989-06-21 | Carboxamide derivative |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPH0745508B2 (en) |
KR (1) | KR950006546B1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994018212A1 (en) * | 1993-02-15 | 1994-08-18 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
WO1997024360A1 (en) * | 1995-12-27 | 1997-07-10 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic acid diester derivatives |
JP2009149602A (en) * | 2000-12-07 | 2009-07-09 | Cv Therapeutics Inc | Compound raising abca-1 |
DE212012000278U1 (en) | 2012-06-20 | 2015-01-27 | CosmoCare Ltd. | clothing |
DE202012013149U1 (en) | 2012-06-20 | 2015-08-03 | CosmoCare Ltd. | clothing |
-
1989
- 1989-06-21 JP JP1160171A patent/JPH0745508B2/en not_active Expired - Lifetime
- 1989-06-29 KR KR1019890009119A patent/KR950006546B1/en not_active IP Right Cessation
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994018212A1 (en) * | 1993-02-15 | 1994-08-18 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
KR100296163B1 (en) * | 1993-02-15 | 2001-11-05 | 오츠까 요시미쯔 | Phosphonic acid diester derivative |
WO1997024360A1 (en) * | 1995-12-27 | 1997-07-10 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic acid diester derivatives |
CN1070863C (en) * | 1995-12-27 | 2001-09-12 | 大塚制药工场株式会社 | Phosphonic acid diester derivatives |
JP2009149602A (en) * | 2000-12-07 | 2009-07-09 | Cv Therapeutics Inc | Compound raising abca-1 |
DE212012000278U1 (en) | 2012-06-20 | 2015-01-27 | CosmoCare Ltd. | clothing |
DE202012013149U1 (en) | 2012-06-20 | 2015-08-03 | CosmoCare Ltd. | clothing |
Also Published As
Publication number | Publication date |
---|---|
JPH0745508B2 (en) | 1995-05-17 |
KR910000767A (en) | 1991-01-30 |
KR950006546B1 (en) | 1995-06-16 |
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