JPH03294256A - 1-phenylalkyl-3-phenylurea derivative - Google Patents
1-phenylalkyl-3-phenylurea derivativeInfo
- Publication number
- JPH03294256A JPH03294256A JP18584590A JP18584590A JPH03294256A JP H03294256 A JPH03294256 A JP H03294256A JP 18584590 A JP18584590 A JP 18584590A JP 18584590 A JP18584590 A JP 18584590A JP H03294256 A JPH03294256 A JP H03294256A
- Authority
- JP
- Japan
- Prior art keywords
- group
- cjt
- formula
- derivative
- present
- 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
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 28
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 9
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- 210000004369 blood Anatomy 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 4
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical class O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 abstract description 2
- 108010054082 Sterol O-acyltransferase Proteins 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 239000005515 coenzyme Substances 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 230000001603 reducing effect Effects 0.000 abstract description 2
- RILGRCOXLIHGMP-UHFFFAOYSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[2-(3-methylphenyl)hexyl]urea Chemical compound C=1C=CC(C)=CC=1C(CCCC)CNC(=O)NC1=C(C(C)C)C=CC=C1C(C)C RILGRCOXLIHGMP-UHFFFAOYSA-N 0.000 abstract 1
- 201000005577 familial hyperlipidemia Diseases 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- -1 5ec-butyl group Chemical group 0.000 description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 150000001448 anilines Chemical class 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 239000012048 reactive intermediate Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BSWZUQPMLVBGBZ-UHFFFAOYSA-N 2-(2,3-dimethoxyphenyl)heptan-1-amine Chemical compound CCCCCC(CN)C1=CC=CC(OC)=C1OC BSWZUQPMLVBGBZ-UHFFFAOYSA-N 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940105631 nembutal Drugs 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- ZRMQFQKJCGGOKY-UHFFFAOYSA-N 2-(3-methylphenyl)hexan-1-amine Chemical compound CCCCC(CN)C1=CC=CC(C)=C1 ZRMQFQKJCGGOKY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
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- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
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- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 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 1
- 239000011230 binding agent Substances 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 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
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- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
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- 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
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
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- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- YSBUANSGDLZTKV-UHFFFAOYSA-N n-phenylcarbamoyl chloride Chemical compound ClC(=O)NC1=CC=CC=C1 YSBUANSGDLZTKV-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は強力な脂質低下作用を有する高脂血症治療薬、
およびアテローム性動脈硬化症の治療薬として有用な１
−フェニルアルキル−３−フェニル尿素誘導体に関する
。Detailed Description of the Invention (Industrial Field of Application) The present invention provides a therapeutic agent for hyperlipidemia having a strong lipid-lowering effect;
and 1 useful as a treatment for atherosclerosis.
-Relating to phenylalkyl-3-phenylurea derivatives.
（従来の技術及び発明が解決しようとする問題点）脂質
代謝異常による高脂血症は動脈硬化の原因と考えられ、
また虚血性心疾患や、脳梗塞などの危険因子と考えられ
ている。最近、脂質代謝とくにコレステロール代謝にお
いて、酵素アシル補酵素コレステロールアシルトランス
フェラーゼ（ＡＣＡＴ）が、コレステロール代謝に重要
な役割を果していることが明らかにされ、酵素ＡＣＡＴ
の阻害活性をもつ化合物は、腸管におけるコレステロー
ル吸収を阻害し、血中におけるコレステロールを低下さ
せ、また、動脈壁におけるコレステロールエステルの沈
着を阻害するなど高脂血症治療薬、さらにはアテローム
性動脈硬化症の治療薬として有用であることが報告され
ている（特開昭６３−３１６７６１号、特開平１−９３
５６９号、同２−６４５５号、同２−６４５６号及び同
２−６４５６号各公報）。(Prior art and problems to be solved by the invention) Hyperlipidemia caused by abnormal lipid metabolism is thought to be a cause of arteriosclerosis.
It is also considered to be a risk factor for ischemic heart disease and cerebral infarction. Recently, it has been revealed that the enzyme acyl coenzyme cholesterol acyltransferase (ACAT) plays an important role in cholesterol metabolism, especially in cholesterol metabolism.
Compounds with inhibitory activity inhibit cholesterol absorption in the intestinal tract, lower cholesterol in the blood, and inhibit the deposition of cholesterol esters in arterial walls. It has been reported that it is useful as a therapeutic agent for the disease (Japanese Patent Application Laid-open No. 63-316761, Japanese Patent Application Laid-Open No. 1-93
No. 569, No. 2-6455, No. 2-6456, and No. 2-6456).
（問題点を解決するための手段）
本発明者らは、これら先行技術の上にさらに優れた脂質
低下作用を示す化合物を探索した結果、新規でかつ有用
な尿素誘導体を見い出し、本発明を完成することに至っ
た。(Means for Solving the Problems) As a result of searching for compounds that exhibit superior lipid-lowering effects on top of these prior art, the present inventors discovered a novel and useful urea derivative, and completed the present invention. I came to the conclusion.
即ち、本発明の要旨は
下記一般式（１）
（）
（式中、Ｒ１は炭素数１−８のアルキル基、炭素数１−
５のアルコキシ基またはハロゲン原子を表わし、Ｒ１は
炭素数１−１５のアルキル基を表わし、Ｒ３及びＲ４は
それぞれ独立して炭素数１＝５のアルキル基を表わし、
ｍは１−３の整数を表わし、ｎは０または１を表わす、
）で示される１−フェニルアルキル−３−フェニル尿素
誘導体に存する。That is, the gist of the present invention is the following general formula (1) () (wherein R1 is an alkyl group having 1-8 carbon atoms,
5 represents an alkoxy group or a halogen atom, R1 represents an alkyl group having 1 to 15 carbon atoms, R3 and R4 each independently represent an alkyl group having 1=5 carbon atoms,
m represents an integer of 1-3, n represents 0 or 1,
) is a 1-phenylalkyl-3-phenylurea derivative represented by
以下、本発明につき詳細に説明する。Hereinafter, the present invention will be explained in detail.
本発明の化合物は前記一般式（１）で表わされる。式中
Ｒ１における炭素数１〜８のアルキル基としてはメチル
基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−
ブチル基、イソブチル基、５ｅｃ−ブチル基、ｔｅｒｔ
−ブチル基、ｎ−ペンチル基、５ｅｃ−ペンチル基、ネ
オペンチル基、ｎ−ヘキシル基、イソヘキシル基、ｎ−
ヘプチル基、ｎ−オクチル基等が挙げられ、炭素数１〜
５のアルコキシ基としては、メトキシ基、エトキシ基、
ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基
、５ｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ｎ−ペ
ントキシ基、５ｅｃ−ペントキシ基、ネオペントキシ基
等が挙げられ、ハロゲン原子としては、フッ素原子、塩
素原子、臭素原子、ヨウ素原子等が挙げられる。The compound of the present invention is represented by the above general formula (1). In the formula, the alkyl group having 1 to 8 carbon atoms in R1 includes methyl group, ethyl group, n-propyl group, isopropyl group, n-
butyl group, isobutyl group, 5ec-butyl group, tert
-butyl group, n-pentyl group, 5ec-pentyl group, neopentyl group, n-hexyl group, isohexyl group, n-
Examples include heptyl group, n-octyl group, etc., and have 1 to 1 carbon atoms.
As the alkoxy group in 5, methoxy group, ethoxy group,
Examples include n-propoxy group, isopropoxy group, n-butoxy group, 5ec-butoxy group, tert-butoxy group, n-pentoxy group, 5ec-pentoxy group, neopentoxy group, and examples of the halogen atom include fluorine atom, chlorine Atom, bromine atom, iodine atom, etc.
式中、Ｒ２における炭素数１〜１５のアルキル基として
はメチル基、エチル基、ｎ−プロピル基、イソプロピル
基、ｎ−ブチル基、イソブチル基、ｎ−ペンチル基、ネ
オペンチル基、ヘキシル基、ヘプチル基、オクチル基、
ノニル基、デシル基、ウンデシル基、ドデシル基、トリ
デシル基、テトラデシル基、ペンタデシル基等が挙げら
れる。In the formula, the alkyl group having 1 to 15 carbon atoms in R2 is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, neopentyl group, hexyl group, heptyl group. , octyl group,
Examples include nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, and the like.
式中Ｒ３及びＲ４における炭素数１〜５のアルキル基と
してはメチル基、エチル基、ｎ−プロピル基、イソプロ
ピル基、ｎ−ブチル基、イソブチル基、５ｅｃ−ブチル
基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、５ｅｃ−ペ
ンチル基、ネオペンチル基等が挙げられる。In the formula, the alkyl group having 1 to 5 carbon atoms in R3 and R4 is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, 5ec-butyl group, tert-butyl group, n- Examples include pentyl group, 5ec-pentyl group, neopentyl group, and the like.
本発明においては、Ｒ２がＣａ Ｃ６の直鎖アルキル
基を表わす化合物が好ましく、またこのときＲ３および
Ｒ４が同一のＣ、Ｃ’ｓのアルキル基を表わすことが更
に好ましい。In the present invention, compounds in which R2 represents a Ca C6 linear alkyl group are preferred, and in this case, it is more preferred that R3 and R4 represent the same C, C's alkyl group.
前記（１）式で示される本発明化合物を以下に例示する
が、本発明化合物はその分子中に不斉炭素を有するため
、ラセミ体は言うまでもなく、その光学異性体をも本願
発明に包含される。The compounds of the present invention represented by the above formula (1) are exemplified below, but since the compounds of the present invention have an asymmetric carbon in their molecules, not only racemates but also their optical isomers are included in the present invention. Ru.
（Ｒ’）。(R').
２ ３ ４ −ＣＨ３ ２−ＣＨ。2 3 4 -CH3 2-CH.
２−ＣＨ。2-CH.
２−ＣＨ。2-CH.
−ＣＨ３ −ＣＨｆｆ ２−ＣＨ。-CH3 -CHff 2-CH.
−ＣＨ３ ２−ＣＨ。-CH3 2-CH.
−ＣＨ３ ２−Ｃ，Ｈ。-CH3 2-C,H.
２−Ｃ，Ｈ。2-C,H.
２−Ｃ，Ｈｓ −ＣＺＨ５ ｎ−ＣＪｗ ｎ−Ｃ，）Ｉ９ ｎ−Ｃ５）１．。2-C,Hs -CZH5 n-CJw n-C,)I9 n-C5)1. .
−ＣｓＨｚ −ｉ−Ｃ，）１．。-CsHz -i-C,)1. .
１−Ｃ３Ｈ１。1-C3H1.
−ｎ−Ｃ６Ｈ，２ −ｎ−ＣＪ＋！ １−Ｃｄ（＋３ −４−Ｃ６Ｈ＋３ ｎ−ＣｄＬ −ｎ−ＣＪ＊ −ｎ−ＣＪ、。-n-C6H,2 -n-CJ+! 1-Cd(+3 -4-C6H+3 n-CdL -n-CJ* -n-CJ,.
ｎ−Ｃ３Ｈ，。n-C3H,.
ＣｚＨｓ １−ＣＪｔ ＣｚＨｓ −ｉ−Ｃ３Ｈ７ ＣｚＨｓ −ｉ−Ｃ３４１７ ＣｚＨｓ −ＣＪ７ ”ＣｚＨｓ −ｉ−ＣｚＨｙ Ｃ２Ｈ５ １−Ｃｄｈ ＣｚＨｓ １−ＣＪｔ ＣＪ。CzHs 1-CJt CzHs -i-C3H7 CzHs -i-C3417 CzHs -CJ7 “CzHs -i-CzHy C2H5 1-Cdh CzHs 1-CJt C.J.
−ＣｚＨｔ Ｃ，）Ｉ。-CzHt C,)I.
−ＣＪ７ Ｃ２）１゜ １−Ｃ３Ｈ。-CJ7 C2) 1° 1-C3H.
ＣｚＨｓ −ＣＪｔ Ｃ，Ｈ。CzHs -CJt C,H.
−１−ＣｚＨｖ ＣｚＨｓ １−ＣＪｔ ＣＪｗ ｉ−Ｃ，Ｈ。-1-CzHv CzHs 1-CJt CJw i-C,H.
２−Ｃ２Ｈ５ ２−Ｃ，ＨＳ ２−ｃ、Ｈ。2-C2H5 2-C,HS 2-c, H.
−ＣＪｓ −ＣＪｓ −ＣｚＨｓ ２−ｎ−Ｃ，Ｈ。-CJs -CJs -CzHs 2-n-C,H.
２−ｎ−Ｃ３Ｈｔ ２−ｎ−Ｃ，Ｈ。2-n-C3Ht 2-n-C,H.
２−ｉ−Ｃ３Ｈｖ ２−ｉ−ＣＪｔ ２−ｎ−Ｃ４Ｈｑ ３−Ｃ０゜ ３−ＣＨ。2-i-C3Hv 2-i-CJt 2-n-C4Hq 3-C0゜ 3-CH.
３−ＣＨ。3-CH.
３−Ｃ）Ｉ。3-C)I.
−ＣＨｘ ３−Ｃ）！。-CHx 3-C)! .
−１−ＣｓＨ＋＋ −１−ＣｓＨ＋ｔ −ｎ−ＣＪｔｓ −ｎ−Ｃ，ＨＩ３ −１−ＣＪＩ：１ −ｉ−ＣｔｈＨ＋３ −ｎ−ＣａＨ＊ −ｎ−ＣｓＨ１＋ −１−Ｃ５Ｈ，１ ｎ−ＣＪｗ −ｎ−ＣｓＨ＋ｔ −ＣＪｑ ｎ−ＣＪｖ −ｎ−ＣａＨｑ −ｎ−ＣＪロ ーｎ−Ｃ５Ｈ＋ｒ −ｎ−ＣＪＩコ ｎ−ＣＪｔｌ ｃｚｕｓ −ｉ−Ｃ，Ｈ。-1-CsH++ -1-CsH+t -n-CJts -n-C, HI3 -1-CJI:1 -i-CthH+3 -n-CaH* -n-CsH1+ -1-C5H,1 n-CJw -n-CsH+t -CJq n-CJv -n-CaHq -n-CJro -n-C5H+r -n-CJI Co. n-CJtl czus -i-C,H.
−Ｃ，Ｂ。-C,B.
−１−Ｃ３Ｈフ −Ｃ，Ｈ。-1-C3H -C,H.
−１−ＣｓＨｙ １−ＣＪ７ −ｉ−ＣゴＨ１ −ＣｓＨｔ −ｉ−Ｃ３Ｈ７ −ｉ−Ｃ□Ｈ１ −ｉ−Ｃ：＋１ｂ −Ｃ，Ｉ（Ｓ −ＣｘＨｒ ｇＨｓ −ｉ−Ｃ３Ｈｙ ｚＨｓ ｉ−Ｃ，Ｈ。-1-CsHy 1-CJ7 -i-CgoH1 -CsHt -i-C3H7 -i-C□H1 -i-C:+1b -C,I(S -CxHr gHs -i-C3Hy zHs i-C,H.
−Ｃ，Ｈ。-C,H.
１−ＣＪｔ ＣＪｓ ｉ−Ｃｓ８丁 ｚａｓ −１−ＣｓＨ） １−ＣＪｔ −１−ＣｓＨフ −１−Ｃ，Ｈフ −１−ＣｓＨｙ −ｉ−Ｃ３Ｆ！。1-CJt CJs i-Cs 8 guns zas -1-CsH) 1-CJt -1-CsH -1-C,H -1-CsHy -i-C3F! .
−１−Ｃｓｔｂ ＣＪｓ １−ＣＪｔ ＣＪｓ ｉ−Ｃ，Ｉｆ。-1-Cstb CJs 1-CJt CJs i-C, If.
ＣｚＨｓ −ｉ−Ｃｓｔｌｔ −ＣＨ３ −ＣＪｓ ３−Ｃ，Ｈｓ −ＣｚＨｓ ３−ＣＪＩ５ ３−ｎ−Ｃ３Ｈ。CzHs -i-Cstlt -CH3 -CJs 3-C,Hs -CzHs 3-CJI5 3-n-C3H.
３−ｉ−Ｃ，Ｈ。3-i-C,H.
３−ｎ−ＣＪｑ ３−ｎ−ＣＪｔｌ ４−ＣＨ。3-n-CJq 3-n-CJtl 4-CH.
−ＣＨｆｆ −ＣＪｓ ４−ｎ−ＣＪ。-CHff -CJs 4-n-CJ.
４−ｉ−ＣＪｙ ４−ｎ−ＣＪ９ ４−ｎ−ＣｓＨｔ１ ４−ｎ−ＣＪＩ１ ２．３−ｄｔｃＨｓ −ｉ−ＣＪ＋３ ｎ−ＣＪｗ −ｎ、ｃＪ＊ ｎ−ＣＪ、。4-i-CJy 4-n-CJ9 4-n-CsHt1 4-n-CJI1 2.3-dtcHs -i-CJ+3 n-CJw -n, cJ* n-CJ,.
−１−ＣＪＩＩ −ＣＪｗ −ｒ＋−ＣＪ＊ −ｎ−ＣＪ＊ ｎ−ＣａＬ ｎ−Ｃｄｂ −ｎ−ＣｓＨ＋１ ｎ−ＣＪｗ −ｎ−ＣａＨｑ −ｎ−ＣａＨ＊ −ｎ−ＣＪ＊ −ｎ−Ｃ４Ｈｗ −ｎ−Ｃ，Ｈ＠ ｎ−Ｃ４Ｈ＊ −１−ＣｓＨｙ ＣＪｉ −ｉ−Ｃ３Ｈ丁 −１−ＣＪｉ −１−Ｃ３Ｈ７ １−ＣＪ７ −に−Ｃｘｌｈ −ｉ−ＣｆｆＨ１ １−Ｃｄｂ −１−Ｃ３Ｂｙ １−ＣＪｙ １−ＣＪｔ −ｉ−ＣｓＨｔ ｉ−Ｃ，Ｈ７ ｉ−ｃｄｌ？ ｔ−ＣＪｔ −ｉ−Ｃ，）１７ ｃｚｏｓ −ｉ−ＣＪフ ＣｔＨｓ −ｉ−ＣｓＨｙ −ｉ−Ｃ工Ｈ７ −ｉ−Ｃ２１１７ −ｉ−ＣｓＨｙ −５−ＣｓＨｔ −ｉ−Ｃ，Ｈ。-1-CJII -CJw -r+-CJ* -n-CJ* n-CaL n-Cdb -n-CsH+1 n-CJw -n-CaHq -n-CaH* -n-CJ* -n-C4Hw -n-C,H@ n-C4H* -1-CsHy CJi -i-C3H-cho -1-CJi -1-C3H7 1-CJ7 -to-Cxlh -i-CffH1 1-Cdb -1-C3By 1-CJy 1-CJt -i-CsHt i-C, H7 i-cdl? t-CJt -i-C,)17 czos -i-CJfu CtHs -i-CsHy -i-C engineering H7 -i-C2117 -i-CsHy -5-CsHt -i-C,H.
−ｔ−ＣツＨ１ １−Ｃｄｂ −ｉ−Ｃ１ｔ１７ −ｉ−Ｃ３Ｈ２ −ｉ−ＣｚＥｔ 、ｔ−ＣＪｔ −ｉ−ＣＪ。-t-CtsuH1 1-Cdb -i-C1t17 -i-C3H2 -i-CzEt ,t-CJt -i-CJ.
−１−ＣｓＨ？ −１−ＣＪ。-1-CsH? -1-CJ.
−Ｃａｔ’ｓ ２．３−ｄｉＣＨ３ ２，３−ｄｉｃＨｆｆ ２．３−ｄｉｃＨ３ ２＝３−ｄｉＣＨｓ ２．３−ｄｉｃＨｚ ３．４−ｄｉｃｅｓ ２．３．４−ｔｒｉｃＨｘ ２．３．４−ｔｒｉｃＨｘ ２．３．４−ｔｒｉＣＨ３ ２，３＋４−ｔｒｔｃＨｚ ２−ＯＣＨ。-Cat's 2.3-diCH3 2,3-dicHff 2.3-dicH3 2=3-diCHs 2.3-dicHz 3.4-dices 2.3.4-tricHx 2.3.4-tricHx 2.3.4-triCH3 2,3+4-trtcHz 2-OCH.
２−ＯＣＲ。2-OCR.
−０ＣＩｈ ２−ＯＣＩ（。-0CIh 2-OCI (.
２−ＯＣＨ３ −０ＣＲｘ ３−ＯＣＲ。2-OCH3 -0CRx 3-OCR.
３−ＯＣＲ。3-OCR.
−ＣａＨｑ −ｎ−ＣｓＨ＋＋ −ｎ−Ｃ５Ｈ目 １−Ｃ３Ｈ１１ −ｉ−Ｃ５Ｈ１゜ −ｎ−Ｃ４Ｈ＊ ｎ−ＣＪｗ −ＣａＨｑ −ｎ−Ｃ５１（１゜ −ＣｓＨｚ −ｎ−ＣａＨｔｒ −ＣＪｑ −Ｃ５Ｈｚ ｎ−Ｃ５Ｈ■ １−ＣｄＬ ３ −ｎ−ＣＪ＋５ −ｎ−ＣＪ＊ −ｎ−ＣａＨ＊ １−ＣＪｔ −Ｃ，ＨＳ ｉ−Ｃ＋Ｈ７ −Ｃ，Ｈｓ −ｉ−Ｃ３Ｈ。-CaHq -n-CsH++ -n-C5H 1-C3H11 -i-C5H1゜ -n-C4H* n-CJw -CaHq -n-C51 (1゜ -CsHz -n-CaHtr -CJq -C5Hz n-C5H■ 1-CdL 3 -n-CJ+5 -n-CJ* -n-CaH* 1-CJt -C,HS i-C+H7 -C,Hs -i-C3H.
ｉ−Ｃ，Ｈ７ ＣＪｓ −ＣＪｔ −Ｃ，ＨＳ １−ＣＪｔ ｔＨｓ −ｉ−Ｃ３Ｈｔ ＣＪｉ ｉ−ＣＪ。i-C, H7 CJs -CJt -C,HS 1-CJt tHs -i-C3Ht CJi i-CJ.
ＣＪｓ −ｉ−ＣｘＨｔ −Ｃ！Ｈ。CJs -i-CxHt -C! H.
ｉ−ｃ、ｌ（。i-c, l(.
−ＣＪｔ ＣＪｉ −１−ＣＪｉ ＣＪｉ １−ＣＪｔ −４−Ｃ３Ｈ１ ＣｚＨｓ −Ｃ３Ｈｔ ｚＨｓ −Ｃ３Ｈ７ ＣＪｓ １−ＣＪｉ ＣＪｓ −ｉ−ＣｓＨｔ ＣｚＨｓ −ｉ−Ｃ３Ｈ＋ ＣＪｓ −ｉ−ＣゴＨ丁 （Ｒ’）ｍ ｎ ２ ３ ４ ３−ＯＣＨ３０ ３−ＯＣＨ３０ ３−ＱＣ）１． ０ ３−ＯＣｌｆｆｆｏ ３−ＯＣＨ，０ ４−ＯＣＨ３０ ４−ＯＣＲ，０ ２，３−ｄｉＣＬ ０ ２．３ＪｉＣＨｚ Ｏ ２，３−ｄｉｃｕ３ ０ ２．３−ｔｈｃＩｈ Ｏ ２，３−ｄｉＣＪ ０ ２．３−ｄｉＣＨｓ ０ ２．３−ｄｉｃＨｓ Ｏ ２，３−ｄｉＣＬ ０ ２．３−ｄｉｃＨｚ Ｏ ２，３−ｄｉｃＨｘ ０ ２．３−ｄｉＯｃＨｘ ０ −ｎ−Ｃ３Ｈ，。-CJt CJi -1-CJi CJi 1-CJt -4-C3H1 CzHs -C3Ht zHs -C3H7 CJs 1-CJi CJs -i-CsHt CzHs -i-C3H+ CJs -i-C Go H-cho (R’)m n 2 3 4 3-OCH30 3-OCH30 3-QC)1. 0 3-OClfffo 3-OCH,0 4-OCH30 4-OCR,0 2,3-diCL 0 2.3 JiCHz O 2,3-dicu3 0 2.3-thcIh O 2,3-diCJ 0 2.3-diCHs 0 2.3-dicHs O 2,3-diCL 0 2.3-dicHz O 2,3-dicHx 0 2.3-diOcHx 0 -n-C3H,.
ｎ−Ｃ５Ｈ＋＋ −ｎ−ＣＪ＋３ −ｎ−Ｃ，Ｈ，３ −ｉ−Ｃｄｌ＋３ −ｎ−Ｃ，Ｈ。n-C5H++ -n-CJ+3 -n-C,H,3 -i-Cdl+3 -n-C,H.
ｎ−Ｃ３Ｈ，。n-C3H,.
ＣＭ。CM.
−Ｃ，Ｈ５ ｎ−ＣＪｔ −ｎ−Ｃ，Ｈ〒 −ＣＪｔ −ｎ−ＣＪ＊ −ＣａＨｑ ｎ−ＣＪｑ −ｎ−ＣＪ＊ ｎ−ＣＪｗ ｎ−Ｃ，Ｆｉｑ −Ｃ，Ｈ。-C, H5 n-CJt -n-C,H〒 -CJt -n-CJ* -CaHq n-CJq -n-CJ* n-CJw n-C, Fiq -C,H.
−１−Ｃ，Ｈ。-1-C,H.
−Ｃ，Ｕ。-C,U.
１−ＣＪ７ −ｉ−Ｃ３Ｈ７ −ＣｓＨｔ ｉ−ｃｆｆＨｔ ＣＨｚ −Ｃ３Ｈｔ Ｃ！Ｈ５ ｉ−Ｃ，Ｈ。1-CJ7 -i-C3H7 -CsHt i-cffHt Hz -C3Ht C! H5 i-C,H.
１−Ｃｄｂ −ＣＨ＋ ＣＪｓ −Ｃ１Ｈ。1-Cdb -CH+ CJs -C1H.
ｃｚｏｓ ＣｔＨｓ ｎ−Ｃ３Ｌ −Ｃ，ＨＳ １−ＣＪｔ −Ｃ，ＨＳ −ｉ−Ｃ３Ｈ７ ｉ−ＣＪ。czos CtHs n-C3L -C,HS 1-CJt -C,HS -i-C3H7 i-CJ.
−ＣＪｔ ｉ−ＣＪ。-CJt i-CJ.
ＣＩ（。CI(.
−Ｃ３Ｈｔ −Ｃ，Ｈ。-C3Ht -C,H.
−１−Ｃ３）１７ １−ＣＪ７ ＣＬ ＣＪｓ ｎ−Ｃ３Ｌ −ｉｎ−Ｃ３Ｌ −ｉ−ＣｓＨｙ−ｓ ｅｃ−Ｃ４Ｈフ ２．３−ｄｉＯｃＨｉ ０ ２．３−ｄｉＯｃＨｓ ０ ２．３−ｄｔＯｃＨｓ ０ ２．３−ｄｉＯｃｌｌｓ Ｏ ２，３−ｄｉＯｃＨｘ Ｏ ２＋３−ｄｉＯｃＨｓ Ｏ ２，３−ｄｉＯｃＨｓ Ｏ ２，３−ｄｉＯｃＨ３０ ２，３−ｄｉＯｃ）Ｉｓ ０ ２．３−ｄｉＯｃＨｓ Ｏ ２，３−ｄｉＯｃＴｏ Ｏ ２，３−ｄｉＯｃＬ ０ ２＋３−ｄｉＯｃＨｓ ０ ２Ｉ３−ｄｉＯｃＨｓ Ｏ ２，３−ｄｉＯｃ）Ｉｓ Ｏ ３，４−ｄｉＯｃＨｓ ０ ３１４−ｄｉＯｃＨｓ ０ ３．４−ｄｉＯｃＨｓ ０ −ｎ−ＣＪ＊ −ｎ−ＣＪＩ。-1-C3)17 1-CJ7 C.L. CJs n-C3L -in-C3L -i-CsHy-s ec-C4H fu 2.3-diOcHi 0 2.3-diOcHs 0 2.3-dtOcHs 0 2.3-diOclls O 2,3-diOcHx O 2+3-diOcHs O 2,3-diOcHs O 2,3-diOcH30 2,3-diOc)Is 0 2.3-diOcHs O 2,3-diOcTo O 2,3-diOcL 0 2+3-diOcHs 0 2I3-diOcHs O 2,3-diOc)IsO 3,4-diOcHs 0 314-diOcHs 0 3.4-diOcHs 0 -n-CJ* -n-CJI.
ｎ−Ｃ５Ｈ＋＋ ５ｅｃｃｓｔｌｚ −ｉ−Ｃ５Ｈ，。n-C5H++ 5eccstlz -i-C5H,.
−ｎ−ＣＪ＋３ −ＣＪＩｓ ｎ−ＣｓＨ＋ｔ ｎ−ＣＪ＋ｗ −ｎ−ｃｌ。Ｌ＋ ｎ−Ｃ１＋Ｌｓ −ｎ−ｃｌＪＺｓ −ｎ−ｃ＋Ｊｚｔ ｎ−ＣＩ４８！４ −ｎ−Ｃｌ５Ｂ！＋ −ｎ−ＣａＨ＊ −ｎ−ＣＪ＊ −ｎ−ＣｓＨ＋ｒ １−ＣＪｔ ｃｚｔｉｓ １−ＣＪｔ １−ＣＪｔ ｔ−ＣＪｔ ＣＪｓ −ｔ−Ｃ，Ｈ。-n-CJ+3 -CJIs n-CsH+t n-CJ+w -n-cl. L+ n-C1+Ls -n-clJZs -n-c+Jzt n-CI48!4 -n-Cl5B! + -n-CaH* -n-CJ* -n-CsH+r 1-CJt cztis 1-CJt 1-CJt t-CJt CJs -t-C,H.
１−ＣＪｔ −ｉ−Ｃ３Ｈ７ １−ＣＪｔ −ｉ−Ｃ３Ｈ７ ｉ−Ｃ−＋Ｌ ｉ−ｃ！）Ｉ？ １−ＣＪｔ −Ｃ３Ｈ７ Ｃ，Ｈ。1-CJt -i-C3H7 1-CJt -i-C3H7 i-C-+L i-c! )I? 1-CJt -C3H7 C,H.
１−Ｃ３Ｌ −Ｃ，ＨＳ −ＣＪ７ −Ｃ，Ｈ。1-C3L -C,HS -CJ7 -C,H.
−１−Ｃ３）１７ −１−ＣＪｔ １−ＣＪ７ ＣＪｓ １−ＣＪｔ −ｉ−Ｃ：＋Ｌ −１−ＣｓＨ７ １−ＣＪｔ １−ＣＪｔ ｉ−Ｃ３ｔ１７ −ｔ−ＣＪ。-1-C3)17 -1-CJt 1-CJ7 CJs 1-CJt -i-C:+L -1-CsH7 1-CJt 1-CJt i-C3t17 -t-CJ.
１−ＣｓＬ −ｉ−ＣｚＨｔ ＣｚＨｓ １−ＣＪｔ −Ｃ，Ｈ５ （Ｒ’）。1-CsL -i-CzHt CzHs 1-CJt -C, H5 (R').
２ Ｒゴ ４ ３．４−ｄｉＯｃＨｚ ３．４−ｄｉＯｃＨｘ ３．４−ｄｉＯｃＨｚ ３．４−ｄｉＯｃＨｓ ３．４−ｄｉＯｃＨｚ ３、４−ｄｉＯｃＨｚ ３．４−ｄｉＯｃＨｚ −Ｆ −Ｆ −Ｆ −Ｆ −Ｆ −Ｆ −Ｃｆ −Ｃｆ ２−ＣＩ。2 R Go 4 3.4-diOcHz 3.4-diOcHx 3.4-diOcHz 3.4-diOcHs 3.4-diOcHz 3,4-diOcHz 3.4-diOcHz -F -F -F -F -F -F -Cf -Cf 2-CI.
−ＣＩ２ −Ｃｆ ｎ−Ｃ５Ｈ，。-CI2 -Cf n-C5H,.
−１−ＣｓＨ＋＋ −１−Ｃ５Ｈ，。-1-CsH++ -1-C5H,.
ｎ−ＣｈＨｒｓ ｎ−Ｃ，Ｈ，。n-ChHrs n-C,H,.
１−ＣＪ（＋ｚ −ｉ−ＣａＨ＋３ ｎ−ＣＪｑ −ｎ−ＣｓＨ＋＋ −ＣＪｑ ｎ−Ｃ５ＨＩＨ −ＣＪｗ −ｎ−ＣｓＨロ ーｎ−ＣａＨｑ −ｎ−Ｃ４Ｈｇ ｎ−Ｃ５Ｈ，。1-CJ(+z -i-CaH+3 n-CJq -n-CsH++ -CJq n-C5HIH -CJw -n-CsHro -n-CaHq -n-C4Hg n-C5H,.
−ｎ−Ｃ，Ｈ目 −ｎ−ＣＪ＋３ １−ＣＪｔ −Ｃ１Ｈ。-n-C, H-th -n-CJ+3 1-CJt -C1H.
−ＣＪ７ −Ｃ，Ｈｓ ｉ−Ｃ，Ｈ。-CJ7 -C,Hs i-C,H.
Ｃ，Ｈ。C,H.
１−ＣＪ７ −ｉ−Ｃ：＋Ｈ１ −ｉ−Ｃ，Ｈ。1-CJ7 -i-C:+H1 -i-C,H.
１−ＣＪｔ −ＣＪ７ １−ＣＪ７ ｉ−Ｃ，Ｈ７ Ｃ，Ｈ。1-CJt -CJ7 1-CJ7 i-C, H7 C,H.
ｉ−Ｃ，Ｈ。i-C,H.
−Ｃ，Ｈ５ −ｉ−Ｃ，Ｈ。-C, H5 -i-C,H.
−ＣＪｔ −ｉ−Ｃ：＋Ｉｂ ｚｌｌＳ −ｉ−Ｃ，Ｈ。-CJt -i-C:+Ib zllS -i-C,H.
Ｃ２Ｈ５ １−Ｃ：）ｍｙ Ｃ，Ｈ。C2H5 1-C:)my C,H.
−１−ＣｓＨｔ １−ＣＪｔ ｉ−Ｃ，Ｈ。-1-CsHt 1-CJt i-C,H.
−１−Ｃ：＋Ｉｂ −１−ＣｓＨｔ −ＣＪｔ １−Ｃ３Ｌ Ｃ，Ｈ８ −ＣＪｚ −Ｃｚ）Ｉｓ ｔ−ＣＪｔ −ＣＪｔ （Ｒ’）。-1-C: +Ib -1-CsHt -CJt 1-C3L C, H8 -CJz -Cz)Is t-CJt -CJt (R').
２ ３ ４ ３＝Ｃ１ ３−Ｃ！ ３−Ｃ！ −Ｃｆ ３−Ｃ！ −Ｃ４ −Ｃｆ ４−Ｃｊ！ −Ｂｒ −Ｂｒ −Ｂｒ −Ｂｒ −Ｂｒ −Ｂｒ −１ −Ｔ ４ −１ −ｎ−Ｃ，Ｈｑ −ｎ−Ｃ，Ｈ９ −ｎ−ＣｓＨ＋ ＋ −ｎ−ＣｓＨ＋ｒ −ｎ−ＣＪＩｓ −ｎ−ＣＪ＋ｚ −ｎ−Ｃ，Ｈ。2 3 4 3=C1 3-C! 3-C! -Cf 3-C! -C4 -Cf 4-Cj! -Br -Br -Br -Br -Br -Br -1 -T 4 -1 -n-C, Hq -n-C, H9 -n-CsH+ + -n-CsH+r -n-CJIs -n-CJ+z -n-C,H.
ｎ−Ｃ５Ｈロ ーｎ−ＣａＨｑ −ｎ−Ｃ５Ｈ１ −ＣｄＬ −ｎ−Ｃ５Ｈ，。n-C5H ro -n-CaHq -n-C5H1 -CdL -n-C5H,.
−ｎ−Ｃ４Ｈｗ −ｎ−ＣｓＨ＋＋ −ＣＪｑ −ｎ−ＣＪ１１ ｎ−ＣＪｗ −ｎ−ＣｓＨｚ −Ｃ２Ｈ。-n-C4Hw -n-CsH++ -CJq -n-CJ11 n-CJw -n-CsHz -C2H.
ｉ−Ｃ，Ｈ。i-C,H.
−Ｃ，Ｈ。-C,H.
−ｉ−Ｃ３Ｈｗ ｔＨｓ １−ＣＪｔ ｉ−Ｃ３Ｈ。-i-C3Hw tHs 1-CJt i-C3H.
−ＣＪ７ １−ＣＪｔ −ｉ−Ｃ３Ｈ７ １−ＣＪｔ −ｉ−Ｃ，Ｈ。-CJ7 1-CJt -i-C3H7 1-CJt -i-C,H.
１−ＣＪｔ ｉ−ｃｆｆ）１７ −ＣＪｔ −ｉ−Ｃ，Ｈ。1-CJt i-cff)17 -CJt -i-C,H.
−１−ＣＪ。-1-CJ.
−１−Ｃ，Ｈ。-1-C,H.
−Ｃ，Ｈｓ １−ＣＪｔ Ｃ，Ｈ５ １−ＣＪｔ Ｃ，Ｈ５ −ＣＪｔ −ＣＪ７ −ＣＪｙ １−ＣＪｔ １−ＣＪｔ −ＣＪｔ −ｉ−ＣｚＨｔ １−ＣＪ７ −Ｃ１Ｈ７ １−ＣＪ７ −ｉ−ＣｓＨｔ −Ｃｄｂ −ｃｌＬ （Ｒ’）。-C,Hs 1-CJt C, H5 1-CJt C, H5 -CJt -CJ7 -CJy 1-CJt 1-CJt -CJt -i-CzHt 1-CJ7 -C1H7 1-CJ7 -i-CsHt -Cdb -clL (R').
ｚ ３ ４ −１ −Ｉ −Ｃ１ｈ −ＣＨ３ −ＣＨｆｆ −Ｃ２ −Ｃ１ −Ｃ１ −ｎ−Ｃ，）Ｉｇ −ｎ−ＣｓＨ＋ Ｉ ｎ−ＣＪｗ −ｎ−Ｃ，Ｈ。z 3 4 -1 -I -C1h -CH3 -CHff -C2 -C1 -C1 -n-C,)Ig -n-CsH+ I n-CJw -n-C,H.
ｎ−Ｃ，）Ｉ。n-C,)I.
−Ｃ４Ｈｑ −ｎ−Ｃ，Ｈｑ −ＣｄＬ −ＣＪ７ −ＣＪ７ １−ＣＪ７ １−ＣＪｔ １−ＣＪｔ １−ＣＪ７ −ＣＪｔ −ｉ、−ＣＪｔ −ＣＪｔ −ＣＪｔ −ＣＪ７ −Ｃｄｈ −ＣＪｔ −ｉ−Ｃ：＋ｌｈ −ＣＪｔ −ＣＪｔ 次に本発明の化合物の製造法について説明する。-C4Hq -n-C, Hq -CdL -CJ7 -CJ7 1-CJ7 1-CJt 1-CJt 1-CJ7 -CJt -i, -CJt -CJt -CJt -CJ7 -Cdh -CJt -i-C:+lh -CJt -CJt Next, a method for producing the compound of the present invention will be explained.
（ｎ）（Ｉ［［）
（式中、Ｒ’＋Ｒ”＋Ｒ’＋Ｒ’＋ｍ及びｎは既に定義
した通りである。）
フェニルアルキルアミン誘導体（ＩＩ）とフェニルイソ
シアナート誘導体（Ｉ［［）をヘンゼン、トルエン、キ
シレン、ヘキサン、ヘプタン、ジエチルエーテル、テト
ラヒドロフラン（ＴＨＦ）、ジオキサン、Ｎ、Ｎ−ジメ
チルホルムアミド等の反応に関与しない溶媒中、０°Ｃ
〜１５０°Ｃの温度範囲で縮合させることにより、本発
明の化合物（Ｉ）が得られる。(n)(I[[) (In the formula, R'+R"+R'+R'+m and n are as defined above.) Phenylalkylamine derivative (II) and phenyl isocyanate derivative (I[[) In a solvent that does not participate in the reaction, such as henzene, toluene, xylene, hexane, heptane, diethyl ether, tetrahydrofuran (THF), dioxane, N,N-dimethylformamide, etc., at 0°C.
Compound (I) of the present invention is obtained by condensation in a temperature range of ~150°C.
（Ｂ） Ｒ”
（式中、Ｒ’＋Ｒ”＋Ｒ’、Ｒ’＋ｍ及びｎは既に定義
した通りである。）
フェニルアルキルイソシアナート誘導体（ＩＶ）とアニ
リン誘導体（Ｖ）を上記Ａ法と同様の条件で反応させる
ことにより、本発明の化合物（１）が得られる。(B) R'' (In the formula, R'+R''+R', R'+m and n are as defined above.) Phenylalkylisocyanate derivative (IV) and aniline derivative (V) in the same manner as in method A above. Compound (1) of the present invention can be obtained by reacting under the following conditions.
（Ｖｌ）
（式中、Ｒ’、Ｒ”、Ｒ’、Ｒ’、ｍ及びｎは既に定義
した通りである。）
本性は基本的には前記Ｂ法と同様であるが、フェニルア
ルキルイソシアナート誘１体（ＩＶ） をフェニルアル
キルカルボン酸誘導体（ＶＩ）から生成させ、次いでア
ニリン誘導体（Ｖ）と縮合させることにより、本発明の
化合物（Ｉ）が得られる。(Vl) (In the formula, R', R'', R', R', m and n are as defined above.) The nature is basically the same as in method B above, but phenylalkyl isocyanate Compound (I) of the present invention can be obtained by producing compound (IV) from phenylalkylcarboxylic acid derivative (VI) and then condensing it with aniline derivative (V).
フェニルアルキルカルボン酸誘導体（ＶＩ）をフェニル
アルキルイソシアナート誘導体（ＩＶ）に変換する方法
としては、例えばトリエチルアミン等の反応に関与しな
い有機アミンとアジ化ジフェニルホスホリル（ＤＰＰＡ
）の存在下、ベンゼン、トルエン、キシレン等の不活性
溶媒中、室温から１５０°Ｃの温度範囲で反応させる方
法等が挙げられる９
（■） （■）
（式中、Ｒ３及びＲ４は既に定義した通りである。）安
息香酸誘導体（■）をフェニルイソシアナート誘導体（
ＩＩＩ）へ上記Ｃ法と同様の方法により変１１、次いで
フェニルアルキルアミン誘導体（ＩＩ）と縮合して本発
明の化合物（Ｉ）を得る方法である。As a method for converting a phenylalkyl carboxylic acid derivative (VI) into a phenylalkyl isocyanate derivative (IV), for example, an organic amine that does not participate in the reaction such as triethylamine and diphenylphosphoryl azide (DPPA) are used.
) in an inert solvent such as benzene, toluene, xylene, etc. at a temperature range from room temperature to 150 °C9 (■) (■) (wherein R3 and R4 are already defined ) The benzoic acid derivative (■) is mixed with the phenyl isocyanate derivative (
In this method, compound (I) of the present invention is obtained by condensing compound (III) with compound (11) and phenylalkylamine derivative (II) in the same manner as the above-mentioned method C.
（ＩＩ）
（式中、Ｒ’、Ｒ”、Ｒ３，Ｒ’ ｍ及びｎは既に定義
した通りであり、Ｘはハロゲン原子、アリールオキシ基
、アルキルチオ基等の脱離基を表わす。）フェニルアル
キル誘導体（Ｉｆ）を反応性中間体（■）に変換したの
ち、アニリン誘導体（Ｖ ）と反応させて本発明の化合
物（Ｉ）を得る方法である。上記反応性中間体（■）と
しては例えばフェニルアルキルアミン誘導体（ＩＩ）と
ホスゲンを反応させて得られるフェニルアルキルカルバ
モイルクロリド（式中のＸが塩素原子）や、フェニルア
ルキルアミン誘導体（ＩＩ）とクロロギ酸アリールを反
応させて得られるフェニルアルキルカルバモイルアリー
ルエステル（式中のＸがアリールオキシ基）等が挙げら
れる。(II) (In the formula, R', R'', R3, R' m and n are as defined above, and X represents a leaving group such as a halogen atom, aryloxy group, alkylthio group, etc.) Phenylalkyl This is a method of converting the derivative (If) into a reactive intermediate (■) and then reacting it with an aniline derivative (V) to obtain the compound (I) of the present invention.The reactive intermediate (■) is, for example, Phenylalkylcarbamoyl chloride (X in the formula is a chlorine atom) obtained by reacting phenylalkylamine derivative (II) with phosgene, and phenylalkylcarbamoyl obtained by reacting phenylalkylamine derivative (II) with aryl chloroformate. Examples include aryl esters (X in the formula is an aryloxy group).
（Ｖ） （ＩＸ） （式中、Ｒ’、Ｒ’及びＸは既に定義した通りである。(V) (IX) (In the formula, R', R' and X are as defined above.
）
アニリン誘導体（Ｖ）を反応性中間体（ＩＸ）に変換し
たのち、フェニルアルキルアミン誘導体（Ｉｔ）と反応
させることにより、本発明の化合物（１）を得る方法で
ある。) This is a method for obtaining the compound (1) of the present invention by converting the aniline derivative (V) into a reactive intermediate (IX) and then reacting it with a phenylalkylamine derivative (It).
上記反応性中間体（ＩＸ）としては、例えばアニリン誘
導体（Ｖ）とホスゲンを反応させて得られるフェニルカ
ルバモイルクロリド（式中のＸが塩素原子）や、アニリ
ン誘導体（Ｖ）とクロロギ酸アリールを反応させて得ら
れるフェニルカルバモイルアリールエステル（式中のＸ
がアリールオキシ基）等が挙げられる。Examples of the reactive intermediate (IX) include phenylcarbamoyl chloride (in the formula, X is a chlorine atom) obtained by reacting the aniline derivative (V) with phosgene, or reacting the aniline derivative (V) with an aryl chloroformate. phenylcarbamoyl aryl ester obtained by
is an aryloxy group).
本発明の化合物は、高脂血症治療薬およびアテローム性
動朦硬化症の治療薬として、好ましくは経口投与によっ
て人に投与される。経口投与のための割型としては、綻
剖、顆粒剤、粉荊、カプセル剤等の形体が用いられ、こ
れらは本発明の化合物に通常の添加剤、たとえばブドウ
糖、乳糖、コーンスターチあるいはマンニトール等の賦
形剤、ヒドロキシプロピルセルロース（ＲＰＣ）、カル
ボキシメチルセルロース（ＣＭＣ）等の結合剤、デンプ
ン、ゼラチン末等の崩壊剤、タルク、ステアリン酸マグ
ネシウム等の滑沢剤等を加えて製造することができる。The compounds of the present invention are administered to humans, preferably by oral administration, as a therapeutic agent for hyperlipidemia and atherosclerosis. For oral administration, forms such as slits, granules, powders, and capsules are used, which contain the compounds of the present invention with conventional excipients, such as glucose, lactose, corn starch, or mannitol. It can be manufactured by adding excipients, binders such as hydroxypropyl cellulose (RPC) and carboxymethyl cellulose (CMC), disintegrants such as starch and gelatin powder, and lubricants such as talc and magnesium stearate.
本発明の化合物の投与量は、経口投与の場合、成人に対
して１日に１■から１１０００ＩＩ程度の使用量で投与
される。しかしながら使用される特定の使用量は、患者
の必要性、治療される病気の程度及び使用される化合物
の活性度によって変化することができる。In the case of oral administration, the dosage of the compound of the present invention is about 1 to 11,000 II per day for adults. However, the specific dosage employed can vary depending on the needs of the patient, the extent of the disease being treated and the activity of the compound used.
（実施例）
以下、本発明を実施例により更に詳細に説明するが、本
発明の要旨を越えない限り本発明はこれら実施例により
何ら制限を受けるものではない。(Examples) Hereinafter, the present invention will be explained in more detail by Examples, but the present invention is not limited in any way by these Examples unless the gist of the present invention is exceeded.
実施例１
１− （２−（３−メチルフェニル）ヘキシル）−３−
（２，６−ジイツブロピルフエニル）尿素の合成
２−（３−メチルフェニル）ヘキシルアミン１．８１
ｇ （９，５ｇｍｏＩりをヘキサン２０ｓｊ！に加え、
氷冷下０．５２モル濃度の２．６−ジイツブロビルフエ
ニルイソシアナートのヘキサン溶液１８Ｉ１１を滴下し
た。この混合物を一晩攪拌し、析出した結晶を濾取して
、１− （２−（３−メチルフェニル）へキシル）３−
（２，６−ジイツブロビルフエニル）尿素 １．８７ｇ
（収率５ｏ％）を得た。Example 1 1-(2-(3-methylphenyl)hexyl)-3-
Synthesis of (2,6-diitubropylphenyl)urea 2-(3-methylphenyl)hexylamine 1.81
g (add 9.5 gmol to 20 sj of hexane,
A hexane solution 18I11 of 2,6-ditubylphenyl isocyanate having a concentration of 0.52 molar was added dropwise under ice cooling. This mixture was stirred overnight, and the precipitated crystals were collected by filtration and 1-(2-(3-methylphenyl)hexyl)3-
(2,6-diitubrobylphenyl)urea 1.87g
(Yield 5o%) was obtained.
融点：１７３−１７４℃
Ｉ Ｒ（ＫＢ、 ） ｃ＋ｓ−’：３３４０，２
９７０，１６３５，１５７５゜１４６０．１２５０．７
０Ｏ
ＮＭＲ（ＣＤ（１３）δ
：０．８０ （ｔ、３Ｈ）。Melting point: 173-174°C IR (KB, ) c+s-': 3340,2
970,1635,1575°1460.1250.7
0O NMR (CD(13)δ: 0.80 (t, 3H).
０．９６−１．２５ （ｍ、 １６Ｈ） 。0.96-1.25 (m, 16H).
１．５０−１．６８ （ｍ、２Ｈ）。1.50-1.68 (m, 2H).
２．２１ （ｓ、３Ｈ）、２．５３ （ｍ、ＩＨ）。2.21 (s, 3H), 2.53 (m, IH).
３．０２−３．１２ （ｍ、 ３ Ｈ） 。3.02-3.12 (m, 3H).
３．５６ （ｍ、 ＩＨ） 、 ３．９３ （
ｂｒ、ｓ、 ＩＨ） 。3.56 (m, IH), 3.93 (
br, s, IH).
５．６５ （ｓ、ＩＨ）、６．７１ （ｍ、２Ｈ）
。5.65 (s, IH), 6.71 (m, 2H)
.
６．９０ （ｄ、ＩＨ）。6.90 (d, IH).
６．９９−７．１０ （ｍ、３Ｈ）。6.99-7.10 (m, 3H).
７．２７ （ｔ、ＩＨ）
実施例２〜４９
実施例１と同様の方法により表１−１．表ｉ−２、表１
−３の化合物を合成した。7.27 (t, IH) Examples 2 to 49 Table 1-1. Table i-2, Table 1
-3 compound was synthesized.
なお、実施例１の方法で、反応混合物より結晶が析出し
ない場合には、シリカゲルカラムクロマトグラフィー（
溶出液、ｎ−ヘキサン：酢酸エチル＝４ ： １）で精
製して目的の化合物を得た。In addition, if crystals do not precipitate from the reaction mixture using the method of Example 1, silica gel column chromatography (
The eluate was purified with n-hexane:ethyl acetate=4:1) to obtain the target compound.
また、表中のＭｅはメチル基、Ｅｔはエチル基、Ｐｒは
プロピル基、Ｂｕはブチル基、Ｐｅｎはペンチル基、Ｈ
ｅにはヘキシル基、Ｈｅｐはヘプチル基、Ｏｃｔはオク
チル基をそれぞれ表わす。In addition, in the table, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, Bu is a butyl group, Pen is a pentyl group, H
e represents a hexyl group, Hep represents a heptyl group, and Oct represents an octyl group.
実施例５０
（＋）−１−（２−（２，３〜ジメトキシフエニル）へ
ブチル）−３−（２，６−ジイツブロピルフエニル）尿
素の合成
（＋）−２−（２，３−ジメトキシフェニル）へブチル
アミン０．６５ ｇ （２，６ｍｍｏｊりに０．５０２
Ｍの２．６−ジイツプロビルフエニルイソシアナートの
トルエン溶液５．２ｍｊ！を室温で滴下し、−晩攪拌し
た後、反応液を濃縮し、得られた残金をメタノールで結
晶化した。この結晶をヘキサンで懸洗して、（＋）−１
−（２−（２，３−ジメトキシフェニル）へブチル）３
−（２，６−ジイツプロビルフエニル）尿素０．５１２
ｇ（収率４３゜５％）を得た。Example 50 Synthesis of (+)-1-(2-(2,3-dimethoxyphenyl)hebutyl)-3-(2,6-diitubropylphenyl)urea (+)-2-(2 ,3-dimethoxyphenyl)hebutylamine 0.65 g (0.502 g per 2,6 mmoj)
5.2mj of toluene solution of M's 2.6-diituprobylphenyl isocyanate! was added dropwise at room temperature, and after stirring overnight, the reaction solution was concentrated, and the resulting residue was crystallized from methanol. This crystal was suspended washed with hexane, and (+)-1
-(2-(2,3-dimethoxyphenyl)hebutyl)3
-(2,6-diitupropylphenyl)urea 0.512
g (yield 43.5%) was obtained.
融点１１３−１１５°Ｃ
ＩＲ（ＫＢ、 ）ｃｍ−’
：３４１０，３２１０，２９５０，１６４０゜１５５０
．１４７０，１２７０．１０６０゜０Ｏ
ＮＭＲ（ＣＤＣｊ２３ ）δ
：０．８０ （ｔ、３Ｈ）。Melting point 113-115°C IR (KB, ) cm-': 3410, 3210, 2950, 1640° 1550
．． 1470,1270.1060°0O NMR (CDCj23) δ: 0.80 (t, 3H).
１．０８−１．２４ （ｍ、 １６Ｈ） 。1.08-1.24 (m, 16H).
１．５０−１．６１ （ｍ、 ２Ｈ） 。1.50-1.61 (m, 2H).
３．０９−３．２７（ｍ ４Ｈ）。3.09-3.27 (m 4H).
３．４０−３．５７ （ｍ、、 Ｉ Ｈ）３．５６
（Ｓ、３Ｈ）、３．８０ （ｓ、３Ｈ）。3.40-3.57 (m,, I H) 3.56
(S, 3H), 3.80 (s, 3H).
４．２４ （ｂｓ、 ＩＨ）、５．５５ （ｓ、
ＩＨ）。4.24 (bs, IH), 5.55 (s,
IH).
６．５９ （ｄ、 ＩＨ）、６．７１ （ｄ、
ＩＨ）。6.59 (d, IH), 6.71 (d,
IH).
６．９０ （ｔ、 ＩＨ）、７．１３ （ｄ、
２Ｈ）７．２９ （ｔ、 １）（）
旋光度：〔α〕。＝±０．６４
（Ｃ＝２．６７、メタノール）
実施例５１
（−）−１−（２−（２，３−ジメトキシフェニル）ヘ
プチル）−３−（２，６−ジイツブロピルフエニル）尿
素の合成
実施例５０における（＋）−２−（２，３−ジメトキシ
フェニル）ヘプチルアミンを（−）−２−（２，３−ジ
メトキシフェニル）へブチルアミンに換えて、同様の方
法で合成した。収率６４％融点：１１５−１１６°Ｃ
ＩＲ（ＫＢ、 ）ｃｍ”’
： ３４ｔｏ、 ３２１０． ２９５０． １６４０
゜１５５０、 １４７０． １２７０． １０６０゜
０Ｏ
Ｎ Ｍ Ｒ（ＣＤ Ｃｆ ３ ） δ：ｏ、ｓｏ
（ｔ、３Ｈ）。6.90 (t, IH), 7.13 (d,
2H) 7.29 (t, 1) () Optical rotation: [α]. =±0.64 (C=2.67, methanol) Example 51 (−)-1-(2-(2,3-dimethoxyphenyl)heptyl)-3-(2,6-diitubropylphenyl ) Synthesis of urea Synthesize in the same manner as in Example 50, replacing (+)-2-(2,3-dimethoxyphenyl)heptylamine with (-)-2-(2,3-dimethoxyphenyl)heptylamine. did. Yield 64% Melting point: 115-116°C IR (KB, ) cm'': 34to, 3210. 2950. 1640
゜1550, 1470. 1270. 1060°
0O N M R (CD Cf 3 ) δ: o, so
(t, 3H).
１．０８−１．２４ （ｍ、 １６ Ｈ） 。1.08-1.24 (m, 16 H).
１．５０−４．６１ （ｍ、 ２Ｈ） 。1.50-4.61 (m, 2H).
３．０９−３．２７ （ｍ、 ４ Ｈ） 。3.09-3.27 (m, 4H).
３．４０−３．５７ （ｍ、 Ｉ Ｈ） 。3.40-3.57 (m, IH).
３．５６ （ｓ、 ３Ｈ）、３．８０ （ｓ、３
Ｈ）。3.56 (s, 3H), 3.80 (s, 3
H).
４．２４ （ｂｓ、ＩＨ）、５．５５ （ｓ、
ＩＨ）。4.24 (bs, IH), 5.55 (s,
IH).
６．５９ （ｄ、 ＬＨ）、６．７１ （ｄ、
ＩＨ）。6.59 (d, LH), 6.71 (d,
IH).
６．９０ （ｔ、 ＬＨ）、７．１３ （ｄ、２
Ｈ）。6.90 (t, LH), 7.13 (d, 2
H).
７．２９ （ｔ、 ＩＨ）
旋光度： 〔α〕。＝−０，８３
（Ｃ＝２．６４．メタノール）
試験例１
本発明の化合物が有する血中コレステロール低下作用を
以下の方法により測定した。7.29 (t, IH) Optical rotation: [α]. =-0,83 (C=2.64.methanol) Test Example 1 The blood cholesterol lowering effect of the compound of the present invention was measured by the following method.
雄のゴールデンハムスター（体重８０〜１００ｇ）を無
作為に群に分割し、正常の食餌（実験動物用固形飼料Ｍ
Ｆ−１マウス・ラット・ハムスター飼育用オリエンタル
酵母工業株式会社）で３日間飼育した。その後、前記の
食餌に１％コレステロールおよび０．５％コール酸を含
む食餌（オリエンタル酵母工業株式会社）に変え自由に
与えた。Male golden hamsters (weighing 80-100 g) were randomly divided into groups and fed a normal diet (laboratory animal chow M).
F-1 mice, rats, and hamsters (Oriental Yeast Industry Co., Ltd.) were used for breeding for 3 days. Thereafter, the above diet was changed to a diet containing 1% cholesterol and 0.5% cholic acid (Oriental Yeast Industry Co., Ltd.) and fed ad libitum.
同時に１日１回決まった時間に示された用量（０，１〜
１０＋＋ｇ／ｌ ０ ｍｌ水／ｋｇ）に調整した被験薬
を強制経口投与した。対照群には水を体重１ｋｇあたり
１０ｍｆ強制経口投与した。５日後、被験薬を投与した
３時間後にネンブタール麻酔下（ネンブタール注射液ダ
イナボット）腹部大静脈より血液を採取し、遠心操作に
より血清を分離した。血清中のコレステロール濃度は血
中コレステロール測定キット（デタミナーＴＣ５協和メ
ディクス）にて求め、結果を対照と比較した血清コレス
テロール濃度の抑制パーセントとして下記表２に表わし
た。At the same time, once a day at a fixed time, the indicated dose (0,1~
The test drug adjusted to 10++ g/l (0 ml water/kg) was orally administered by force. To the control group, water was orally administered by force at 10 mf/kg body weight. Five days later, 3 hours after administering the test drug, blood was collected from the abdominal vena cava under Nembutal anesthesia (Nembutal injection Dynabot), and serum was separated by centrifugation. Cholesterol concentration in serum was determined using a blood cholesterol measurement kit (Determiner TC5 Kyowa Medics), and the results are shown in Table 2 below as percentage inhibition of serum cholesterol concentration compared to the control.
表
１）１−（３，３−ジメチル−２−フェニルブチル）−
３−（２，６−ジイツブロピルフエニル）尿素（特開平
２−６４５６号公報記載の化合物）
２） ＩＣ）＋＋ｇ／ｋｇ
試験例２
本発明の化合物のＡＣＡＴ阻害作用を以下の方法により
測定した。Table 1) 1-(3,3-dimethyl-2-phenylbutyl)-
3-(2,6-diitubropylphenyl)urea (compound described in JP-A-2-6456) 2) IC)++g/kg Test Example 2 The ACAT inhibitory effect of the compound of the present invention was tested by the following method. It was measured.
ＡＣＡＴの活性の測定はハムスター肝臓ミクロゾームを
含有する組織試料中で、放射標識オレイン酸コエンザイ
ムＡから形成された放射標識コレステロールオリエート
の量を測定することにより求めた。したがって、ＡＣＡ
Ｔを阻止する本発明の化合物の活性は、被験薬を加えな
い対照群のコレステロールオリエート生成量を各濃度（
μＭ）の被験薬を加えたものが何パーセント低下させた
かを求め、それよりＩＣ，。値、即ち酵素の５０％表出
を阻止するのに必要な被験化合物の濃度で表わし、その
結果を下記表３に示す。Measurements of ACAT activity were determined by measuring the amount of radiolabeled cholesterol oleate formed from radiolabeled oleate coenzyme A in tissue samples containing hamster liver microsomes. Therefore, the A.C.A.
The activity of the compounds of the present invention to inhibit T is determined by reducing the amount of cholesterol oleate produced in the control group to which no test drug was added at each concentration (
Determine the percent reduction caused by adding the test drug (μM), and then calculate the IC. The results are shown in Table 3 below.
表３
（発明の効果）
上記試験例からも明らかなように、本発明の化合物は、
ＡＣＡＴ阻害による血中コレステロール低下作用を有し
ているため、高脂血症治療薬またはアテローム性動脈硬
化症の治療薬としての用途が期待される。Table 3 (Effect of the invention) As is clear from the above test examples, the compound of the present invention has the following properties:
Since it has a blood cholesterol lowering effect by inhibiting ACAT, it is expected to be used as a therapeutic agent for hyperlipidemia or atherosclerosis.
Claims (1)
−５のアルコキシ基またはハロゲン原子を表わし、Ｒ＾
２は炭素数１−１５のアルキル基を表わし、Ｒ＾３及び
Ｒ＾４はそれぞれ独立して炭素数１−５のアルキル基を
表わし、ｍは１−３の整数を表わし、ｎは０または１を
表わす。）で示される１−フェニルアルキル−３−フェ
ニル尿素誘導体。(1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) (In the formula, R^1 is an alkyl group with 1-8 carbon atoms, 1 carbon number
-5 represents an alkoxy group or a halogen atom, R^
2 represents an alkyl group having 1 to 15 carbon atoms, R^3 and R^4 each independently represent an alkyl group having 1 to 5 carbon atoms, m represents an integer of 1 to 3, and n is 0 or Represents 1. ) A 1-phenylalkyl-3-phenylurea derivative represented by:
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18584590A JPH03294256A (en) | 1989-08-04 | 1990-07-13 | 1-phenylalkyl-3-phenylurea derivative |
| CA002022346A CA2022346A1 (en) | 1989-08-04 | 1990-07-31 | 1-phenylalkyl-3-phenylurea derivatives |
| AU60013/90A AU629376B2 (en) | 1989-08-04 | 1990-07-31 | 1-phenylalkyl-3-phenylurea derivatives |
| EP90114966A EP0415123B1 (en) | 1989-08-04 | 1990-08-03 | 1-Phenylalkyl-3-phenylurea derivatives |
| US07/562,337 US5126483A (en) | 1989-08-04 | 1990-08-03 | 1-phenylalkyl-3-phenylurea derivatives |
| ES90114966T ES2064557T3 (en) | 1989-08-04 | 1990-08-03 | DERIVATIVES OF 1-FENILALQUIL-3-FENILUREA. |
| AT90114966T ATE115121T1 (en) | 1989-08-04 | 1990-08-03 | 1-PHENYLALKYL-PHENYLUREA DERIVATIVES. |
| DK90114966.6T DK0415123T3 (en) | 1989-08-04 | 1990-08-03 | 1-phenylalkyl-3-phenylurea |
| DE69014775T DE69014775T2 (en) | 1989-08-04 | 1990-08-03 | 1-phenylalkylphenylurea derivatives. |
| GR940404117T GR3015275T3 (en) | 1989-08-04 | 1995-03-03 | 1-Phenylalkyl-3-phenylurea derivatives. |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-202422 | 1989-08-04 | ||
| JP20242289 | 1989-08-04 | ||
| JP2-50065 | 1990-03-01 | ||
| JP18584590A JPH03294256A (en) | 1989-08-04 | 1990-07-13 | 1-phenylalkyl-3-phenylurea derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03294256A true JPH03294256A (en) | 1991-12-25 |
Family
ID=16457249
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18584590A Pending JPH03294256A (en) | 1989-08-04 | 1990-07-13 | 1-phenylalkyl-3-phenylurea derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH03294256A (en) |
| ZA (1) | ZA906023B (en) |
-
1990
- 1990-07-13 JP JP18584590A patent/JPH03294256A/en active Pending
- 1990-07-31 ZA ZA906023A patent/ZA906023B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA906023B (en) | 1991-05-29 |
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