JPS62181244A - 4(4(4-chlorophenyl)butoxy)phenylmethylamine derivative, acid addition salt and production thereof - Google Patents
4(4(4-chlorophenyl)butoxy)phenylmethylamine derivative, acid addition salt and production thereofInfo
- Publication number
- JPS62181244A JPS62181244A JP2344586A JP2344586A JPS62181244A JP S62181244 A JPS62181244 A JP S62181244A JP 2344586 A JP2344586 A JP 2344586A JP 2344586 A JP2344586 A JP 2344586A JP S62181244 A JPS62181244 A JP S62181244A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- chlorophenyl
- general formula
- halogen
- butoxy
- 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.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 7
- 239000002253 acid Substances 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title claims 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- -1 4-(4-chlorophenyl)butyl halide Chemical class 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 13
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 abstract description 5
- QXSAKPUBHTZHKW-UHFFFAOYSA-N 4-hydroxybenzamide Chemical class NC(=O)C1=CC=C(O)C=C1 QXSAKPUBHTZHKW-UHFFFAOYSA-N 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 201000005577 familial hyperlipidemia Diseases 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 230000001603 reducing effect Effects 0.000 abstract 1
- 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 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 235000012000 cholesterol Nutrition 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 206010003210 Arteriosclerosis Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 241001465754 Metazoa Species 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 class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical class OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VAOFYKUGDPBCRA-UHFFFAOYSA-N [4-[(4-chlorophenyl)methoxy]phenyl]methyl pyridine-3-carboxylate Chemical compound C1=CC(Cl)=CC=C1COC(C=C1)=CC=C1COC(=O)C1=CC=CN=C1 VAOFYKUGDPBCRA-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- RLUXVCZBKDVAFS-UHFFFAOYSA-N anisole;methanol Chemical compound OC.COC1=CC=CC=C1 RLUXVCZBKDVAFS-UHFFFAOYSA-N 0.000 description 1
- 230000000489 anti-atherogenic effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- SFIHQZFZMWZOJV-HZJYTTRNSA-N linoleamide Chemical class CCCCC\C=C/C\C=C/CCCCCCCC(N)=O SFIHQZFZMWZOJV-HZJYTTRNSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000031142 liver development Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、高脂血症及び動脈硬化症の治療ないし予防に
極めて有用な４−［４−’（４−クロロフェニル〉ブト
キシ］フェニルメヂルアミン誘導体とその酸付加塩及び
その製造法並びにそのｆｒ規化合物を有効成分とする脂
質低下剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides 4-[4-'(4-chlorophenyl>butoxy]phenylmedium) which is extremely useful for the treatment or prevention of hyperlipidemia and arteriosclerosis. The present invention relates to a lipid-lowering agent containing the FR compound as an active ingredient.
（従来の技術）
従来よりコレステロールヤトリグリセライドなどの脂質
代謝異常が動脈硬化症の一因となっていると考えられて
おり、脂質代謝異常を改善させる薬剤としてニコチン酸
及びその誘導体、クロフィブレート及びその部分構造で
あるフェニルアルキルエーテルを有する化合物等が繁用
されている。近年にはリノール酸アミド誘導体のメリナ
ミド、ビスフェノール誘導体のプロブコール、イオン交
換樹脂であるコレスチラミンなどが臨床の場に供される
ようになった。(Prior art) It has been believed that abnormalities in lipid metabolism such as cholesterol and glycerides are a contributing factor to arteriosclerosis, and nicotinic acid and its derivatives, clofibrate and Compounds having phenyl alkyl ether as a partial structure thereof are frequently used. In recent years, melinamide, a linoleic acid amide derivative, probucol, a bisphenol derivative, and cholestyramine, an ion exchange resin, have come into clinical use.
特に最近は、動脈硬化性因子である低比重リポ蛋白コレ
ステロール（ＬＤＬ−Ｃｈ）と抗動脈硬化性因子である
高比重リボ蛋白コレステロール（ＨＤＬ−Ｃｈ）が注目
されている。これらにより、血清中のコレステロールや
トリグリセライド等を低下させるだけでなく、ＬＤＬ−
ｃｈ値を低下させ、ＨＤ Ｌ −ｃ ｈ １ｍを増加さ
せることにより、これらの比で表わされる動脈硬化指数
を改善することも重要になってきた。しかし、現在臨床
におる薬剤は、これらのすべてを満足するものではなく
、さらにはクロフィブレート及びその誘導体においては
、動物実験において肝癌発生が報告されるなど安全性に
問題が提起されている。よって、脂質代謝異常を改善す
る効果がざらに強く、より安全性の高い薬剤の開発が望
まれている。Particularly recently, low-density lipoprotein cholesterol (LDL-Ch), which is an arteriosclerotic factor, and high-density riboprotein cholesterol (HDL-Ch), which is an anti-arteriosclerotic factor, have attracted attention. These not only lower serum cholesterol and triglycerides, but also reduce LDL-
It has also become important to improve the arteriosclerosis index expressed by the ratio of these by lowering the ch value and increasing HD L -ch 1m. However, the drugs currently in clinical use do not satisfy all of these requirements, and safety problems have been raised with clofibrate and its derivatives, such as the occurrence of liver cancer in animal experiments. Therefore, it is desired to develop a drug that is more effective in improving lipid metabolism abnormalities and has higher safety.
（問題点を解決するための手段）
上記問題点を解決すべく、発明者らは、既に特許権の確
立しているニコチン酸４−（４−−クロロベンジルオキ
シ）ベンジルエステル（特許第９８７２３７＠）及びこ
れと関連して特許出願がなされているニコチ°ン酸４−
（４−一置換フェニルアルキルオキシ）フェニルアルキ
ルエステルＩ’ｉ（特開昭５７−１０２８６６ ＠）な
どの一連の脂質低下剤研究を継続する中で、４− ［４
−（４−クロロフェニル）ブトキシ］フェニルメチルア
ミン誘導体が血清中コレステロールを低下させるのはも
ちろんの事、動脈硬化指数を著しく改善するとともに血
清中のトリグリセライドをも低下させるなどの優れた脂
質低下作用を有することを見出し本発明を完成するに至
った。(Means for Solving the Problems) In order to solve the above problems, the inventors developed nicotinic acid 4-(4-chlorobenzyloxy)benzyl ester (Patent No. 987237@ ) and nicotinic acid 4-, for which a patent application has been filed in connection with this.
While continuing research on a series of lipid-lowering agents such as (4-monosubstituted phenylalkyloxy)phenylalkyl ester I'i (JP-A-57-102866 @), 4-[4
-(4-chlorophenyl)butoxy]phenylmethylamine derivatives not only lower serum cholesterol, but also have excellent lipid-lowering effects, such as significantly improving arteriosclerosis index and lowering serum triglycerides. This discovery led to the completion of the present invention.
本発明は下記一般式（Ｉ）
［式中、Ｒ１、Ｒ２は同−又は相異なるもので、水素、
ハロゲン、低級アルキル基、低級アルコキシ基を示す。The present invention relates to the following general formula (I) [wherein R1 and R2 are the same or different, hydrogen,
Indicates halogen, lower alkyl group, and lower alkoxy group.
］
で表わされる化合物及びその酸付加塩に関するものであ
る。] This relates to a compound represented by these and its acid addition salt.
本発明化合物は次の方法により製造することができる。The compound of the present invention can be produced by the following method.
方法１：
（Ｉ）
［式中、Ｒ１、Ｒ２、Ｘは前記に同じ］すなわら、一般
式（ＩＩ）で示される４−ヒドロキシベンズアミド誘導
体と一般式（ＩＩＩ）で示される４−（４−クロロフェ
ニル）ブチルハライドとを塩基の存在下適当な溶媒中に
て０〜２００℃の温度範囲内で反応させた後、これを還
元することにより一般式（Ｉ＞で示される本発明化合物
を得ることができる。Method 1: (I) [In the formula, R1, R2, and -chlorophenyl)butyl halide in a suitable solvent in the presence of a base within a temperature range of 0 to 200°C, and then reduced to obtain the compound of the present invention represented by the general formula (I>) be able to.
塩基としては、水酸化ナトリウム、水酸化カリウム、炭
酸ナトリウム、炭酸カリウム、水素化ナトリウム等が挙
げられ、適当な溶媒としては、メタノール、エタノール
、デトラヒドロフラン、ベンゼン、し・ルエン、塩化メ
チレン、クロロホルム、ジオキサン、ジメチルホルムア
ミド、ジメチルスルホキシド等が挙げられる。Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, etc., and suitable solvents include methanol, ethanol, detrahydrofuran, benzene, diluene, methylene chloride, Examples include chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, and the like.
還元は、無水ベンゼン、無水エーテル、無水テトラヒド
ロフラン等の溶媒中で水素化アルミニウムリヂウム、水
素化ビス（２−メトキシエトキシ）アルミニウムナトリ
ウム等の金属水素化物を反応させることにより行なうこ
とができる。The reduction can be carried out by reacting a metal hydride such as aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as anhydrous benzene, anhydrous ether or anhydrous tetrahydrofuran.
方法：２
すなわち一般式（ＩＶ）で示される４−ヒドロキシベン
ゾニトリル誘導体と一般式（ＩＩＩ）で示される４−（
４−クロロフェニル）ブチルハライドとを塩基の存在下
適当な溶媒中にてＯ〜２００ ’Ｃの温度範囲内で反応
させた後、これを還元することにより一般式（Ｉ＞で示
される本発明化合物を得ることができる。Method: 2 That is, a 4-hydroxybenzonitrile derivative represented by the general formula (IV) and a 4-( represented by the general formula (III))
4-chlorophenyl)butyl halide in a suitable solvent in the presence of a base within a temperature range of 0 to 200'C, and then the reaction is reduced to produce the compound of the present invention represented by the general formula (I>). can be obtained.
本方法においては、方法１記載の塩基、還元剤及び）ｄ
媒を用いて実施することが可能である還元はまた、方法
１記載の方法の他に、メタノール、エタノール、ジメチ
ルホルムアミド等の溶媒中でラネーニッケル触媒の存在
下に水素添加する方法を用いて実施することも可能であ
る。In this method, the base according to method 1, the reducing agent and) d
The reduction, which can be carried out using a solvent, is also carried out using, in addition to the method described in Method 1, the method of hydrogenation in the presence of a Raney nickel catalyst in a solvent such as methanol, ethanol, dimethylformamide, etc. It is also possible.
方法３：
（Ｖ）
［式中、Ｒ＋ 、Ｒ２、Ｘは前記に同じ］すなわち、一
般式（Ｖｌで示される４−［４−（４−クロロフェニル
）ブトキシ］ベンジルハライド誘導体を無溶媒又は含水
系でもよいメタノール、エタノール、ジメチルホルムア
ミド等の溶媒中にてＯ〜２００ ’Ｃの温度範囲内でフ
タルイミドのナトリウム、カリウム等のアルカリ金属塩
と反応させるか又は水酸化ナトリウム、水酸化カリウム
、炭酸ナトリウム、炭酸カリウム等の塩基の存在下にフ
タルイミドと反応させることにより一般式（Ｖｌ ）て
示されるＮ−［４−［４−（４−クロロフェニル）ブト
キシ］フェニルメチル］フタルイミド誘導体を得、次い
でこの化合物（Ｖｌ＞を常法により加水分解するか、又
はメタノール、エタノール、ジメチルホルムアミド等の
溶媒中にてヒドラジンを反応させて一般式（Ｉ）で示さ
れる本発明化合物を）ｑることができる。Method 3: (V) [In the formula, R+, R2, and Phthalimide may be reacted with an alkali metal salt such as sodium or potassium in a solvent such as methanol, ethanol, or dimethylformamide within a temperature range of O to 200'C, or may be reacted with an alkali metal salt such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc. By reacting with phthalimide in the presence of a base such as potassium carbonate, an N-[4-[4-(4-chlorophenyl)butoxy]phenylmethyl]phthalimide derivative represented by the general formula (Vl) is obtained, and then this compound ( The compound of the present invention represented by the general formula (I) can be obtained by hydrolyzing Vl> by a conventional method or by reacting it with hydrazine in a solvent such as methanol, ethanol, dimethylformamide, etc.
ただし、一般式（ｎ）〜（Ｖ）で示される化合物は文献
既知であるか又は既知化合物の合成法と同様の方法にて
合成される。However, the compounds represented by general formulas (n) to (V) are known in the literature or can be synthesized by a method similar to the synthesis method of known compounds.
また、一般式（Ｉ）で示される本発明化合物は、薬理的
に許容される酸付加塩に変換できる。Furthermore, the compound of the present invention represented by general formula (I) can be converted into a pharmacologically acceptable acid addition salt.
そのような酸付加塩としては、塩酸、マレイン酸、フマ
ール酸等の無機駿又は有機酸の塩があげられる。Examples of such acid addition salts include salts of inorganic or organic acids such as hydrochloric acid, maleic acid, and fumaric acid.
つぎに、本発明化合物の薬理作用について以下の実験を
行なった。Next, the following experiments were conducted regarding the pharmacological effects of the compounds of the present invention.
実験１．正常ラットの血清脂質および肝脂質に対する作
用
体１１７０〜１９０３のウィスター糸紐ラットに０．５
％カルポキシメヂルセルロース（ＣＭＣ）溶液に懸濁し
た実施例２の化合物を６．２５．１２．５．２５，０１
５０．０ｍｇ／ Ｋｌ １日１回５日間経口投与した後
、血清および肝脂質を測定した。Experiment 1. Effects on normal rat serum and liver lipids 1170-1903 in Wistar cord rats
The compound of Example 2 suspended in 6.25.12.5.25.01% carboxymethylcellulose (CMC) solution
After oral administration of 50.0 mg/Kl once a day for 5 days, serum and liver lipids were measured.
結果は正常ラット群の値に対する割合（％）で示した。The results were expressed as a percentage (%) of the value of the normal rat group.
（表１）
実験２．高コレステロール食ラットの血清脂質および肝
脂質に対する作用
体重９０〜１１０３のウィスター糸紐ラットに１％コレ
ステロール０．２％コール酸および２．５％オリーブ油
を混合した高コレステロール飼料を与えるとともに０．
５％ＣＭＣ溶液に懸濁した実施例２の化合物を６．２５
及び２５、ＯＩＩｔｇ／ＫｇＩ日１回５日間経口投与し
た後、血清および肝脂質を測定した。結果は
高コレステロール食を与えてＣＭＣ溶液を投与した対照
群の値に対する抑制率で示した（表２）。(Table 1) Experiment 2. Effect on serum lipids and liver lipids in rats fed a high cholesterol diet Wistar cord rats weighing 90 to 1,103 mm were fed a high cholesterol diet containing 1% cholesterol, 0.2% cholic acid, and 2.5% olive oil, and 0.2% cholesterol was fed to the rats.
6.25% of the compound of Example 2 suspended in a 5% CMC solution.
and 25, serum and liver lipids were measured after oral administration of OIItg/KgI once a day for 5 days. The results were shown as inhibition rates relative to the values of a control group fed a high cholesterol diet and administered CMC solution (Table 2).
実験３．フルクトース食ラットの高トリグリセライド血
症および脂肪肝発症に対する
作用
体重２７０〜４５０９のｒクイスター系雄ラットに７０
％フルクトースを含む半合成飼料を与えるとともに、０
．５％ＣＭＣ溶液に懸濁した実施例２の化合物を２５ｍ
Ｆｌ／Ｋｇ１日２回（午前９時と午後５時）計５回経口
投与した後、血清および肝トリグリセライドを測定した
。結果はフルクトース食を与えてＣＭＣ溶液を投与した
対照群の値に対する抑制率で示したく表３）。Experiment 3. Effect on hypertriglyceridemia and fatty liver development in fructose-fed rats.
In addition to feeding semi-synthetic feed containing % fructose,
．． The compound of Example 2 suspended in 5% CMC solution was
After oral administration of Fl/Kg twice a day (9 a.m. and 5 p.m.) for a total of five times, serum and liver triglycerides were measured. The results are shown in Table 3) as an inhibition rate relative to the value of a control group fed a fructose diet and administered CMC solution.
以上の実験から本発明化合物は正常ラットおよび高コレ
ステロール食ラットにおいて動脈硬化性の低比重リボ蛋
白コレステロールを低下させるか又は上昇を抑制させる
とともに抗動脈硬化性の高比重リボ蛋白コレステロール
を上昇させるか又は低下を抑制させて動脈硬化指数を著
しく改善する作用を示した。ざらに正常ラットの血清お
よび肝臓中のトリグリセライドを低下させるとともにフ
ルクトース食による内因性高トリグリセライド血症を予
防し、脂肪肝の発症を抑制する作用を示した。From the above experiments, it was found that the compound of the present invention lowers or suppresses the increase in atherosclerotic low-density riboprotein cholesterol in normal rats and rats fed a high-cholesterol diet, and also increases or suppresses the increase in anti-atherogenic high-density riboprotein cholesterol. It showed the effect of suppressing the decrease in the arterial stiffness index and significantly improving the arterial stiffness index. It showed the effect of lowering triglycerides in the serum and liver of normal rats, preventing endogenous hypertriglyceridemia caused by a fructose diet, and suppressing the development of fatty liver.
本発明化合物の急性毒性をマウス（ＩＣＲ，ｄｄｙ系）
およびラット（ＷｉＳｔａｒ系）で検討したところ、そ
れぞれ１９／に３および２’Ｊ／Ｋｌの経口投与でなん
ら異常を示さず又死亡個体もなかったことから低毒性で
あることが判明した。The acute toxicity of the compound of the present invention was measured in mice (ICR, ddy system).
When examined in rats (WiStar series), no abnormalities were observed after oral administration of 3 and 2'J/Kl on 19/1, and no animals died, indicating low toxicity.
（実施例） 次に実施例を示して、本発明を更に詳しく説明する。(Example) Next, the present invention will be explained in more detail by showing examples.
実施例１゜
Ｎ−［４−［４−（４−クロロフェニル）ブトキシ］フ
ェニルメチル］フタルイミド４− ［４−（４−クロロ
フェニル）ブトキシ１ベンＵンメタノール１５．９ｇ
（０，０５５ｍｏｌ）を乾燥ベンゼン１６０ ｍｌに溶
かし、水冷撹拌下に塩化チオニル９．８９ （０，０８
２ｍｏｌ＞を滴下する。滴下後１時間３０分加熱還流す
る。冷後反応液を氷水におけ、有機層を飽和炭酸水素ナ
トリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナ
トリウムで乾燥する。減圧下に溶媒を除き淡黄色油状物
１６．９９を得る。Example 1 15.9 g of N-[4-[4-(4-chlorophenyl)butoxy]phenylmethyl]phthalimide 4-[4-(4-chlorophenyl)butoxy 1ben-methanol
(0,055 mol) was dissolved in 160 ml of dry benzene, and 9.89 mol of thionyl chloride (0,08
2 mol> is added dropwise. After dropping, the mixture was heated under reflux for 1 hour and 30 minutes. After cooling, the reaction mixture was placed in ice water, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 16.99% of a pale yellow oil.
得られた淡黄色油状物とフタルイミド１２．１９（０，
０８２ｍｏｌ ＞及び無水炭酸カリウム１１．３９（０
，０８２ｍｏｌ ）をジメチルホルムアミド１フ０威に
加え、１時間３０分、７０’Ｃにて撹拌する。冷後、不
溶物を濾別し、ａ、償液の溶媒を減圧下に除き、氷水を
加えて結晶化させる。クロロホルムを加えて結晶を溶か
し、有機層を０．２Ｎ水酸化ナトリウム水溶液で２回、
水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾
燥する。減圧下に溶媒を除き結晶化させた後、エタノー
ルより２回再結晶し、無色針状晶１９．８９ （収率８
６％）を得る。融点１１５〜１１６°Ｃ元素分析値 Ｃ
２５Ｈ２２Ｃ、ｅ Ｎ ０３として計算値（％） Ｃ：
７１．５１ 、 Ｈ： ５．２８゜Ｎ：３．３４
実験値（％） Ｃ： ７１．４１ 、 ｌ−１： ５．
１１゜Ｎ：３．２Ｂ
実施例２
４− ［４−（４−クロロフェニル）ブトキシ］フェニ
ルメチルアミン・塩酸塩
Ｎ−［４−［４−（４−クロロフェニル）ブトキシ］フ
ェニルメチル］フタルイミド２１．１Ｌ；Ｊ（０，０５
０ｍｏｌ ）をエタノール５３０ｍ１に加え、ざらに８
０％ヒドラジン水和物６．１ ｄ （０，１０ｍ０Ｉ
”）を加えて撹拌下に２時間加熱還流する。冷１多、減
圧下に溶媒を除去し、エーテルと０．２ Ｎ水酸化ナト
リウム水溶液を加えて残渣を溶かす。有機層を分離し、
水層をエーテルにて抽出し、有機層を合わせて０．２Ｎ
水酸化ナトリウム水溶液・水・飽和食塩水で順次洗浄後
無水硫酸ナトリウムで乾燥する。硫酸ナトリウムを濾別
し、濾液を激しく撹拌しながら塩化水素飽和エーテル溶
液を加え塩酸塩とする。１時間撹拌した後、結晶を濾取
する。エーテルでよく洗浄し、乾燥した後エタノールよ
り再結晶し、無色針状晶１３．０９ （収率７９％）を
得る。融点１４８〜１４９℃。The resulting pale yellow oil and phthalimide 12.19 (0,
082 mol > and anhydrous potassium carbonate 11.39 (0
, 082 mol) was added to 1 ml of dimethylformamide, and the mixture was stirred at 70'C for 1 hour and 30 minutes. After cooling, insoluble matter is filtered off, a. The solvent of the compensation solution is removed under reduced pressure, and ice water is added to crystallize. Add chloroform to dissolve the crystals, and dilute the organic layer twice with 0.2N aqueous sodium hydroxide solution.
After sequentially washing with water and saturated saline, drying with anhydrous sodium sulfate. After removing the solvent under reduced pressure and crystallizing it, it was recrystallized twice from ethanol to give colorless needle crystals of 19.89 g (yield: 8
6%). Melting point 115-116°C Elemental analysis value C
Calculated value (%) as 25H22C, e N 03 C:
71.51, H: 5.28°N: 3.34 Experimental value (%) C: 71.41, l-1: 5.
11°N: 3.2B Example 2 4-[4-(4-chlorophenyl)butoxy]phenylmethylamine hydrochloride N-[4-[4-(4-chlorophenyl)butoxy]phenylmethyl]phthalimide 21.1L ;J(0,05
Add 0 mol) to 530 ml of ethanol, add 8
0% hydrazine hydrate 6.1 d (0,10m0I
) and heat under reflux for 2 hours with stirring. After cooling, remove the solvent under reduced pressure, add ether and 0.2 N aqueous sodium hydroxide solution to dissolve the residue. Separate the organic layer,
The aqueous layer was extracted with ether, the organic layers were combined, and 0.2N
Wash sequentially with an aqueous sodium hydroxide solution, water, and saturated saline, and then dry with anhydrous sodium sulfate. Sodium sulfate is filtered off, and a saturated ethereal solution of hydrogen chloride is added to the filtrate with vigorous stirring to obtain a hydrochloride. After stirring for 1 hour, the crystals are collected by filtration. After thorough washing with ether and drying, the crystals are recrystallized from ethanol to obtain colorless needle crystals (13.09% yield: 79%). Melting point: 148-149°C.
元素分析値 Ｃａｒ Ｈｚｔ Ｃ柔ｚＮＯとして計算値
（％） Ｃ： ６２．５８ 、 Ｈ： ６．４９゜Ｎ：
４．２９
実験値（％） Ｃ： ８２．５６ 、 ｌ−１： ６．
５８゜Ｎ：４．２２
実施例３
Ｎ−［４−［４−（４−クロロフェニル）ブトキシ］−
３−メトキシフェニルメチル］フタルイミド
４− ［４−（４−クロロフェニル）ブトキシ］−３−
メトキシベンゼンメタノールを原料として、実施例１の
方法に従い、目的物を得る。Elemental analysis value Car Hzt Calculated value as C soft zNO (%) C: 62.58, H: 6.49°N:
4.29 Experimental value (%) C: 82.56, l-1: 6.
58°N: 4.22 Example 3 N-[4-[4-(4-chlorophenyl)butoxy]-
3-methoxyphenylmethyl]phthalimide 4- [4-(4-chlorophenyl)butoxy]-3-
Using methoxybenzene methanol as a raw material, the desired product is obtained according to the method of Example 1.
収率８９％。融点１１８〜１１９℃。Yield 89%. Melting point 118-119°C.
元素分析値 Ｃｚｅ−Ｈ２４Ｃ、ｅ Ｎ Ｏａ、 トＬ
／ テ計算値（％） Ｃ： ６９．４１ 、 Ｈ： ５
．３８゜Ｎ：３．１１
実験値（％） Ｃ： ６９．３７ 、 ｌ−１： ５．
３４゜Ｎ：３．０４
実施例４
４− ［４−（４−クロロフェニル）ブトキシ］−３−
メトキシフェニルメチルアミン・塩酸塩Ｎ−［４−［４
−（４−クロロフェニル）ブトキシ］−３−メトキシフ
ェニルメチル］フタルイミドを原料として、実施例２の
方法に従い、目的物を１ｑる。収率６６％。Elemental analysis value Cze-H24C, e N Oa, To L
/ Te calculation value (%) C: 69.41, H: 5
．． 38°N: 3.11 Experimental value (%) C: 69.37, l-1: 5.
34°N: 3.04 Example 4 4-[4-(4-chlorophenyl)butoxy]-3-
Methoxyphenylmethylamine hydrochloride N-[4-[4
Using -(4-chlorophenyl)butoxy]-3-methoxyphenylmethyl]phthalimide as a raw material, 1 q of the desired product is prepared according to the method of Example 2. Yield 66%.
融点１７４．５〜１７６℃
元素分析値 ＣＩＢ Ｈ２ｇＣ，ｅ２ ＮＯ２として計
算値（％） Ｃ： ６０．６８ 、 Ｈ： ６．５１゜
Ｎ：３．９３
実験値（％） Ｃ： ８０．７３ 、 Ｈ： ６．５４
゜Ｎ：３．８９Melting point 174.5-176℃ Elemental analysis value CIB H2gC,e2 Calculated value as NO2 (%) C: 60.68, H: 6.51°N: 3.93 Experimental value (%) C: 80.73, H : 6.54
°N: 3.89
Claims (5)
素、ハロゲン、低級アルキル基、低級アルコキシ基を示
す。］ で表される化合物及びその酸付加塩(1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 and R_2 are the same or different and represent hydrogen, halogen, lower alkyl group, or lower alkoxy group. ] Compounds represented by and acid addition salts thereof
素、ハロゲン、低級アルキル基、低級アルコキシ基を示
す。］ で表される化合物と 一般式（III） ▲数式、化学式、表等があります▼（III） ［式中、Ｘはハロゲンを示す］ で表わされる化合物とを反応させた後還元することを特
徴とする特許請求の範囲第１項記載の化合物の製造法(2) General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R_1 and R_2 are the same or different and represent hydrogen, halogen, lower alkyl group, or lower alkoxy group. ] The compound represented by general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) A method for producing a compound according to claim 1, which is
素、ハロゲン、低級アルキル基、低級アルコキシ基を示
す。］ で表わされる化合物と一般式（III） ▲数式、化学式、表等があります▼（III） ［式中、Ｘはハロゲンを示す］ で表わされる化合物とを反応させた後還元することを特
徴とする特許請求の範囲第１項記載の化合物の製造法(3) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, R_1 and R_2 are the same or different and represent hydrogen, halogen, lower alkyl group, or lower alkoxy group. ] The compound represented by the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, A method for producing a compound according to claim 1
水素、ハロゲン、低級アルキル基、低級アルコキシ基を
示し、Ｘはハロゲンを示すで表わされる化合物をフタル
イミドと反応させることにより 一般式（VI） ▲数式、化学式、表等があります▼（VI） （III）［式中、Ｒ＿１、Ｒ＿２は同一又は相異なるも
ので、水素、ハロゲン、低級アルキル基、低級アルコキ
シ基を示す］ で表わされる化合物を得、次いで加水分解するか又はヒ
ドラジンと反応させることを特徴とする特許請求の範囲
第１項記載の化合物の製造法(4) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R_1 and R_2 are the same or different,
By reacting a compound represented by hydrogen, halogen, lower alkyl group, or lower alkoxy group, where X is a halogen, with phthalimide, the general formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (III ) [wherein R_1 and R_2 are the same or different and represent hydrogen, halogen, a lower alkyl group, or a lower alkoxy group] and then hydrolyzed or reacted with hydrazine. A method for producing a compound according to claim 1, which is
一種以上を有効成分とする脂質低下剤(5) A lipid-lowering agent containing at least one of the compounds described in claim 1 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2344586A JPS62181244A (en) | 1986-02-05 | 1986-02-05 | 4(4(4-chlorophenyl)butoxy)phenylmethylamine derivative, acid addition salt and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2344586A JPS62181244A (en) | 1986-02-05 | 1986-02-05 | 4(4(4-chlorophenyl)butoxy)phenylmethylamine derivative, acid addition salt and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62181244A true JPS62181244A (en) | 1987-08-08 |
Family
ID=12110699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2344586A Pending JPS62181244A (en) | 1986-02-05 | 1986-02-05 | 4(4(4-chlorophenyl)butoxy)phenylmethylamine derivative, acid addition salt and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62181244A (en) |
-
1986
- 1986-02-05 JP JP2344586A patent/JPS62181244A/en active Pending
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