PT100667A

PT100667A - Derivados de benzofurano e composicoes farmaceuticas que os contem

Derivados de benzofurano e composicoes farmaceuticas que os contem Download PDF

Info

Publication number: PT100667A
Authority: PT; Portugal
Prior art keywords: compound; benzofuran; ethyl; crystals; hydroxy
Prior art date: 1991-07-09

Application number

PT10066792A

Other languages

English (en)

Portuguese (pt)

Inventor

Shoichi Chokai

Shinji Ohmachi

Masafumi Taira

Original Assignee

Nippon Shinyaku Co Ltd

Priority date

1991-07-09

Filing date

1992-07-08

Publication date

1993-08-31

1992-07-08 Application filed by Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd

1993-08-31 Publication of PT100667A publication Critical patent/PT100667A/pt

Links

239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
150000001907 coumarones Chemical class 0.000 title claims description 3
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 13
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims abstract description 13
125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 12
150000003839 salts Chemical class 0.000 claims abstract description 11
125000005041 acyloxyalkyl group Chemical group 0.000 claims abstract description 9
229910052736 halogen Inorganic materials 0.000 claims abstract description 9
150000002367 halogens Chemical group 0.000 claims abstract description 9
230000002265 prevention Effects 0.000 claims abstract description 7
206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 6
208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 6
125000002252 acyl group Chemical group 0.000 claims abstract description 5
125000000217 alkyl group Chemical group 0.000 claims abstract description 5
206010008118 cerebral infarction Diseases 0.000 claims abstract description 4
KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 claims abstract description 3
239000001257 hydrogen Substances 0.000 claims abstract description 3
150000002431 hydrogen Chemical group 0.000 claims abstract description 3
208000031225 myocardial ischemia Diseases 0.000 claims abstract description 3
239000000203 mixture Substances 0.000 claims description 43
239000000126 substance Substances 0.000 claims description 22
210000004369 blood Anatomy 0.000 claims description 19
239000008280 blood Substances 0.000 claims description 19
238000002560 therapeutic procedure Methods 0.000 claims description 12
201000010099 disease Diseases 0.000 claims description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
108010033266 Lipoprotein(a) Proteins 0.000 claims description 3
208000037803 restenosis Diseases 0.000 claims description 2
239000004480 active ingredient Substances 0.000 claims 5
102000057248 Lipoprotein(a) Human genes 0.000 claims 1
150000001875 compounds Chemical class 0.000 abstract description 138
208000031481 Pathologic Constriction Diseases 0.000 abstract 1
230000036262 stenosis Effects 0.000 abstract 1
208000037804 stenosis Diseases 0.000 abstract 1
-1 alkyl radicals Chemical class 0.000 description 69
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
239000013078 crystal Substances 0.000 description 42
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
239000000243 solution Substances 0.000 description 32
238000006243 chemical reaction Methods 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
239000002904 solvent Substances 0.000 description 22
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
238000000921 elemental analysis Methods 0.000 description 17
239000003795 chemical substances by application Substances 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
235000019441 ethanol Nutrition 0.000 description 15
238000001914 filtration Methods 0.000 description 15
239000011541 reaction mixture Substances 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
239000000843 powder Substances 0.000 description 13
239000003638 chemical reducing agent Substances 0.000 description 12
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
238000002474 experimental method Methods 0.000 description 12
239000008187 granular material Substances 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
238000003756 stirring Methods 0.000 description 11
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
238000002844 melting Methods 0.000 description 10
230000008018 melting Effects 0.000 description 10
238000000034 method Methods 0.000 description 10
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
201000001320 Atherosclerosis Diseases 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
239000002585 base Substances 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
229910052987 metal hydride Inorganic materials 0.000 description 9
150000004681 metal hydrides Chemical class 0.000 description 9
239000002775 capsule Substances 0.000 description 8
239000005457 ice water Substances 0.000 description 8
150000002632 lipids Chemical class 0.000 description 8
230000035484 reaction time Effects 0.000 description 8
210000002966 serum Anatomy 0.000 description 8
239000012279 sodium borohydride Substances 0.000 description 8
229910000033 sodium borohydride Inorganic materials 0.000 description 8
238000012360 testing method Methods 0.000 description 8
241001465754 Metazoa Species 0.000 description 7
MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 7
150000002148 esters Chemical class 0.000 description 7
239000007788 liquid Substances 0.000 description 7
239000000725 suspension Substances 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
241000282693 Cercopithecidae Species 0.000 description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
230000001476 alcoholic effect Effects 0.000 description 6
XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
239000003054 catalyst Substances 0.000 description 6
238000009903 catalytic hydrogenation reaction Methods 0.000 description 6
235000012000 cholesterol Nutrition 0.000 description 6
239000003814 drug Substances 0.000 description 6
239000003921 oil Substances 0.000 description 6
235000019198 oils Nutrition 0.000 description 6
229910000027 potassium carbonate Inorganic materials 0.000 description 6
238000002360 preparation method Methods 0.000 description 6
230000001603 reducing effect Effects 0.000 description 6
239000007787 solid Substances 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 5
239000002552 dosage form Substances 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
235000019359 magnesium stearate Nutrition 0.000 description 5
238000002156 mixing Methods 0.000 description 5
231100000252 nontoxic Toxicity 0.000 description 5
230000003000 nontoxic effect Effects 0.000 description 5
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
238000006722 reduction reaction Methods 0.000 description 5
UWGRHSSKDKXHOA-UHFFFAOYSA-N 4-[2-hydroxy-2-(5-propan-2-yl-1-benzofuran-2-yl)ethoxy]benzoic acid Chemical compound C=1C2=CC(C(C)C)=CC=C2OC=1C(O)COC1=CC=C(C(O)=O)C=C1 UWGRHSSKDKXHOA-UHFFFAOYSA-N 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
239000004372 Polyvinyl alcohol Substances 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
239000002253 acid Substances 0.000 description 4
239000013543 active substance Substances 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
230000037396 body weight Effects 0.000 description 4
238000001816 cooling Methods 0.000 description 4
229940079593 drug Drugs 0.000 description 4
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
238000006460 hydrolysis reaction Methods 0.000 description 4
230000003287 optical effect Effects 0.000 description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
229920002451 polyvinyl alcohol Polymers 0.000 description 4
238000001953 recrystallisation Methods 0.000 description 4
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
239000006188 syrup Substances 0.000 description 4
235000020357 syrup Nutrition 0.000 description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 3
108010010803 Gelatin Proteins 0.000 description 3
208000031226 Hyperlipidaemia Diseases 0.000 description 3
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 3
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239000002202 Polyethylene glycol Substances 0.000 description 3
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229910052783 alkali metal Inorganic materials 0.000 description 3
229910052784 alkaline earth metal Inorganic materials 0.000 description 3
239000000010 aprotic solvent Substances 0.000 description 3
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QMZGHUOCCDICFD-UHFFFAOYSA-N methyl 4-[2-(5-chloro-1-benzofuran-2-yl)-2-hydroxyethoxy]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OCC(O)C1=CC2=CC(Cl)=CC=C2O1 QMZGHUOCCDICFD-UHFFFAOYSA-N 0.000 description 3
MXNLNXMAMXCEFU-UHFFFAOYSA-N methyl 4-[2-hydroxy-2-(5-propan-2-yl-1-benzofuran-2-yl)ethoxy]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OCC(O)C1=CC2=CC(C(C)C)=CC=C2O1 MXNLNXMAMXCEFU-UHFFFAOYSA-N 0.000 description 3
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239000007858 starting material Substances 0.000 description 3
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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 3
238000005406 washing Methods 0.000 description 3
SVBXODTZYGTZCO-NEPJUHHUSA-N (1r,2s)-2-benzamidocyclohexane-1-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCCC[C@@H]1NC(=O)C1=CC=CC=C1 SVBXODTZYGTZCO-NEPJUHHUSA-N 0.000 description 2
CHJRLLWSWYERGO-UHFFFAOYSA-N 1-(5-tert-butyl-1-benzofuran-2-yl)ethanone Chemical compound CC(C)(C)C1=CC=C2OC(C(=O)C)=CC2=C1 CHJRLLWSWYERGO-UHFFFAOYSA-N 0.000 description 2
125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
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HTDZABJZVNBDQR-UHFFFAOYSA-N 4-[2-(5-tert-butyl-1-benzofuran-2-yl)-2-hydroxyethoxy]benzoic acid Chemical compound C=1C2=CC(C(C)(C)C)=CC=C2OC=1C(O)COC1=CC=C(C(O)=O)C=C1 HTDZABJZVNBDQR-UHFFFAOYSA-N 0.000 description 2
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102100040214 Apolipoprotein(a) Human genes 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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