JPH0352861A - Diurea derivative - Google Patents
Diurea derivativeInfo
- Publication number
- JPH0352861A JPH0352861A JP18704189A JP18704189A JPH0352861A JP H0352861 A JPH0352861 A JP H0352861A JP 18704189 A JP18704189 A JP 18704189A JP 18704189 A JP18704189 A JP 18704189A JP H0352861 A JPH0352861 A JP H0352861A
- Authority
- JP
- Japan
- Prior art keywords
- group
- bis
- nmr
- pyridine
- compound
- 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
- XMKLTEGSALONPH-UHFFFAOYSA-N 1,2,4,5-tetrazinane-3,6-dione Chemical class O=C1NNC(=O)NN1 XMKLTEGSALONPH-UHFFFAOYSA-N 0.000 title claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 45
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 230000002093 peripheral effect Effects 0.000 abstract description 2
- 150000007945 N-acyl ureas Chemical class 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 230000000302 ischemic effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- -1 cyclodecyl group Chemical group 0.000 description 65
- 229910052757 nitrogen Inorganic materials 0.000 description 39
- 229910052739 hydrogen Inorganic materials 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 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 28
- 238000006243 chemical reaction Methods 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000000921 elemental analysis Methods 0.000 description 19
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 235000012000 cholesterol Nutrition 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 7
- 229910052805 deuterium Inorganic materials 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001840 cholesterol esters Chemical class 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-DYCDLGHISA-N Deuterium chloride Chemical group [2H]Cl VEXZGXHMUGYJMC-DYCDLGHISA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001728 carbonyl compounds Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 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
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 2
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 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 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- YIYKUVVECCMODI-UHFFFAOYSA-N 2-methylpropyl hydrogen carbonate hydrochloride Chemical compound Cl.CC(C)COC(O)=O YIYKUVVECCMODI-UHFFFAOYSA-N 0.000 description 1
- BVBROYUJTJCCHU-UHFFFAOYSA-N 2-n,6-n-di(cycloheptyl)pyridine-2,6-dicarboxamide Chemical compound C=1C=CC(C(=O)NC2CCCCCC2)=NC=1C(=O)NC1CCCCCC1 BVBROYUJTJCCHU-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 108010004103 Chylomicrons Proteins 0.000 description 1
- 102220519703 Cytosolic phospholipase A2 gamma_H44N_mutation Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 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
- 239000007868 Raney catalyst Substances 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
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-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
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl 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])* 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- GUBNMFJOJGDCEL-UHFFFAOYSA-N dicyclomine hydrochloride Chemical group [Cl-].C1CCCCC1C1(C(=O)OCC[NH+](CC)CC)CCCCC1 GUBNMFJOJGDCEL-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 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 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- GPPYYOFCUVXNNH-UHFFFAOYSA-N methyl hydrogen carbonate;hydrochloride Chemical compound Cl.COC(O)=O GPPYYOFCUVXNNH-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- MRQBOQFWZXYNHY-UHFFFAOYSA-N n-[[6-[(propan-2-ylamino)methyl]pyridin-2-yl]methyl]propan-2-amine Chemical compound CC(C)NCC1=CC=CC(CNC(C)C)=N1 MRQBOQFWZXYNHY-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 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 1
- XDUHQPOXLUAVEE-BPMMELMSSA-N oleoyl-CoA 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)NCCSC(=O)CCCCCCC\C=C/CCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 XDUHQPOXLUAVEE-BPMMELMSSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- YEXIGDOOPPENOC-UHFFFAOYSA-N phenyl hydrogen carbonate;hydrochloride Chemical compound Cl.OC(=O)OC1=CC=CC=C1 YEXIGDOOPPENOC-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OYBLXLFKRJWZJG-UHFFFAOYSA-N pyridine-2,3-dicarbaldehyde Chemical compound O=CC1=CC=CN=C1C=O OYBLXLFKRJWZJG-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 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
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は医薬として有用ｋ下記一般式（Ｉ）で示される
ジウレア誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a diurea derivative represented by the following general formula (I) that is useful as a medicine.
一般式
Ｋ゛リ
（式中 Ｒｌ及びＲ２は同一又は異ｋっでアルキル基；
シクロアルキル基を，
Ｒ３ ． Ｒ４ ， Ｒ５及びＲ６は同一又は異なって
水素原子；低級アルキル基；シクロアルキル基；未置換
又は置換のフェニル基若しくはピリジル基；未置換又は
置換のアラルキル基を，
ｎ，及又ｎ２は１乃至３の整数を意味する。General formula: (wherein Rl and R2 are the same or different alkyl groups;
a cycloalkyl group, R3. R4, R5 and R6 are the same or different and are hydrogen atom; lower alkyl group; cycloalkyl group; unsubstituted or substituted phenyl group or pyridyl group; unsubstituted or substituted aralkyl group, n, and n2 is 1 to 3 means an integer of
以下同様）
（従来の技術及び発明が解決しようとする課題）血管系
におけるコレステロールの沈着が冠状動脈性心臓病を含
む様々な病気の原因として挙げられる。このうち，アテ
ローム性動脈硬化症は，中間及び大動脈壁の脂質，特に
コレステロールエステルの蓄積及び肥厚に特色のある動
脈硬化症の形態である。(The same applies hereinafter) (Prior Art and Problems to be Solved by the Invention) Cholesterol deposition in the vascular system is cited as a cause of various diseases including coronary heart disease. Among these, atherosclerosis is a form of arteriosclerosis characterized by the accumulation and thickening of lipids, especially cholesterol esters, in the medial and aortic walls.
近年，このコレステロールエステルの生成はアシルーコ
エンザイムＡ コレステロールアシルトランスフエラー
ゼＡｃｙｌ −ＣｏＡ Ｃｈｏｌｅｓｔｅｒｏｌ ａｃ
ｙｌ −ｔｒａｎｓｆｅ−ｒａｓｅ （ Ａ Ｃ Ａ
Ｔ ）により触媒されることが知られできた。即ち，動
脈壁におけるコレステロールエステルの過剰蓄積はＡＣ
ＡＴ酵素の増加と関係している。従って，ＡＣＡＴ酵素
の阻害は，コレステロールのエステル化速度を減じ，動
脈壁におけるコレステロールエステルの多量蓄積に基づ
く粥状病変の形成及び発展を抑制することが期待される
。In recent years, the production of this cholesterol ester has been developed using acyl-coenzyme A cholesterol acyltransferase Acyl-CoA cholesterol ac.
yl-transfe-rase (A C A
It has been known that it is catalyzed by T ). That is, excessive accumulation of cholesterol esters in the arterial wall causes AC
Associated with an increase in AT enzyme. Therefore, inhibition of the ACAT enzyme is expected to reduce the rate of cholesterol esterification and suppress the formation and development of atherosclerotic lesions based on large accumulation of cholesterol esters in the arterial wall.
一方，食物中のコレステロールは遊離のコレステロール
として吸収され，ＡＣＡＴ酵素の作用によりエステル化
されたのち，カイロミクロンの形で血液中に放出される
。従ってＡＣＡＴ酵素の阻害は，食物中コレステロール
の腸内からの吸収を抑制し，されに腸内に放出されたコ
レステロールの再吸収をも抑制することが期待される。On the other hand, dietary cholesterol is absorbed as free cholesterol, esterified by the action of ACAT enzyme, and then released into the blood in the form of chylomicrons. Therefore, inhibition of the ACAT enzyme is expected to suppress the absorption of dietary cholesterol from the intestine, and also to suppress the reabsorption of cholesterol released into the intestine.
本発明者等は，このＡＣＡＴ酵素を阻害することにより
血管壁におけるコレステロールの沈着を防止し，更に腸
管からのコレステロールの吸収を抑制する化合物の創製
を目指し鋭意研究した結果，本発明を完成した。The present inventors completed the present invention as a result of intensive research aimed at creating a compound that inhibits this ACAT enzyme to prevent cholesterol deposition in blood vessel walls and further suppresses the absorption of cholesterol from the intestinal tract.
（課題を解決するための手段）
即ち，本発明は頭記一般式（Ｄで示されるジウレア誘導
体又はその塩に関する。(Means for Solving the Problems) That is, the present invention relates to a diurea derivative represented by the general formula (D) or a salt thereof.
本発明の化合物（Ｉ）は，２個の尿素誘導体がアルキレ
ン基を介してビリジル基に結合しているもので，結合の
態様により，オルトー メタパラジウレア誘導体となる
ことができる。Compound (I) of the present invention has two urea derivatives bonded to a biridyl group via an alkylene group, and depending on the mode of bonding, it can be an ortho-meta-paradiurea derivative.
一般式（Ｉ）の定義に釦いて，「シクロアルキル基」は
，炭素数３乃至１８個からなる環状アルキル基であって
，例えば，シクロプロビル基，シクロブチル基，シクロ
ベンチル基，シクロヘキシル基，シクロヘプチル基，シ
クロオクチル基，シクロノニル基，シクロデシル基，シ
クロドデシル基，シクロトリデシル基，シクロペンタデ
シル基等を挙げることができる。特に好１しいものは炭
素数５乃至１０個のシクロアルキル基である。In the definition of general formula (I), a "cycloalkyl group" is a cyclic alkyl group having 3 to 18 carbon atoms, such as a cycloprobyl group, a cyclobutyl group, a cyclobentyl group, a cyclohexyl group, and a cycloalkyl group. Examples include heptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cyclododecyl group, cyclotridecyl group, and cyclopentadecyl group. Particularly preferred is a cycloalkyl group having 5 to 10 carbon atoms.
「低級アルキル基」は，炭素数が１乃至５個の直鎖状又
は分校状のアルキル基であって，例えば，メチル基，エ
チル基，プロビル基，イソフロピル基，ブチル基，イソ
プチル基，ｓｅｃ一ブチル基， ｔｅｒｔ−プチル基
，ベンチル基（アミル基），インペンチル基． ｔｅ
ｒｔペンチル基，ネオペンチル基，１−メチルプチル基
，２−メチルブチル基，１，２−ジメチルプロピル基等
カ挙げられる。"Lower alkyl group" is a linear or branched alkyl group having 1 to 5 carbon atoms, such as methyl group, ethyl group, probyl group, isofropyl group, butyl group, isobutyl group, Butyl group, tert-butyl group, bentyl group (amyl group), impentyl group. te
Examples include rtpentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, and 1,2-dimethylpropyl group.
「アルキル基」は，炭素数が１乃至１０個のアルキル基
であって，例えば，前記低級アルキル基で示した具体例
に加え，更に，ヘキシル基，インヘキシル基，１−メチ
ルペンチル基，２−メチルベンチル基，３−，，’チル
ペンチル基， １．１−ジメチルプチル基，１，２−
ジメチルプチル基，１，３−ジメチルプチル基，２，２
−ジメチルプチル基，２，３−ジメチルプチル基，１−
エチルフチル基，１，１．２−｝リメチルプロビル基，
１−エチル−１−メチルプロピル基，ヘプチル基，１−
メチルヘキシル基，２−メチルヘキシル基，３−メチル
ヘキシル基，４−メチルヘキシル基，５−メチルヘキシ
ル基，１．１−１メチルペンチル基，１，２−ジメチル
ペンチル基，１，３−ジメチルペンチル基＋ １．４
−シメチルペンチル基，２，２−ジメチルペンチル基，
２，３−ジメチルペンチル基，２，４−ジメチルペンチ
ル基，３．３−ジメチルペンチル基，３，４−ジメチル
ペンチルＬ １−エチルペンチル基，２−エチルペン
チル基， ３ −工ｆルペンチル＆， １，１．２
− ｝ ＩＪ メチルブチル基， １，１．３ −
トリメチルプチル基，１，２．２ − ｝リメチルプ
チル基，２，２．３−｝リメチルプチル基，１−エチル
−１−メチルプチル基，１−エチル−２−メチルブチル
基，１−エチル−３−メチルプチル基，１−プロピルブ
チル基，１−イソブ口ビルブチル基，オクチル基，６−
メチルヘプチル基，ノニル基，７−メチルオクチル基，
デシル基，８−メチルノニル基等の直鎖状又は分枝状の
アルキル基が挙げられる。"Alkyl group" is an alkyl group having 1 to 10 carbon atoms, and includes, for example, hexyl group, inhexyl group, 1-methylpentyl group, 2 -methylbentyl group, 3-,,'tylpentyl group, 1.1-dimethylbutyl group, 1,2-
dimethylbutyl group, 1,3-dimethylbutyl group, 2,2
-dimethylbutyl group, 2,3-dimethylbutyl group, 1-
Ethyl phthyl group, 1,1.2-}rimethylprobyl group,
1-ethyl-1-methylpropyl group, heptyl group, 1-
Methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1.1-1 methylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethyl Pentyl group + 1.4
-dimethylpentyl group, 2,2-dimethylpentyl group,
2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3,4-dimethylpentyl L 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl &, 1,1.2
- } IJ methylbutyl group, 1,1.3 -
Trimethylbutyl group, 1,2.2-}limethylbutyl group, 2,2.3-}limethylbutyl group, 1-ethyl-1-methylbutyl group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group , 1-propylbutyl group, 1-isobutylbutyl group, octyl group, 6-
Methylheptyl group, nonyl group, 7-methyloctyl group,
Straight chain or branched alkyl groups such as decyl group and 8-methylnonyl group are mentioned.
「アラルキル基」は，フェニル基，ナフチル基，ビリジ
ル基等のアリール基で置換された炭素数１乃至１０個の
アルキル基である。代表的なものとしては，ペンジル基
，フエネチル基，フエニルブロビル基，フェニルプチル
基，フエニルベンチル基，フェニルヘキシル基，ナフチ
ルメチル基，ビリジルメチル基，ビリジルエチル基，ピ
リジルブロビル基等を挙げることができる。An "aralkyl group" is an alkyl group having 1 to 10 carbon atoms substituted with an aryl group such as a phenyl group, a naphthyl group, or a biridyl group. Typical examples include penzyl group, phenethyl group, phenylbrobyl group, phenylbutyl group, phenylbentyl group, phenylhexyl group, naphthylmethyl group, pyridylmethyl group, pyridylethyl group, and pyridylbrobyl group.
「ピリジル基」は， ２ −， ３一又は４−ビリ
ジル基である。A "pyridyl group" is a 2-, 3- or 4-pyridyl group.
１た，フェニル基，ビリジル基又はアラルキル基は，未
置換であるか，又は低級アルキル基，ハロゲン原子，ニ
トロ基，アミノ基，モノ若しくはジ低級アルキルアミノ
基，水酸基，又は低級アルコキシ基等で置換されていて
もよい。1. The phenyl group, biridyl group, or aralkyl group is unsubstituted or substituted with a lower alkyl group, halogen atom, nitro group, amino group, mono- or di-lower alkylamino group, hydroxyl group, or lower alkoxy group, etc. may have been done.
この置換基としての低級アルキル基は前記の意味を有す
る。ノ・ロゲン原子は，フツソ原子，塩素原子，臭素原
子，ヨウ素原子を意味する。The lower alkyl group as this substituent has the above meaning. Norogen atom means Fuso atom, chlorine atom, bromine atom, and iodine atom.
モノ若しくはジ低級アルキルアミノ基は，前記の低級ア
ルキル基が１個又は２個置換したアミノ基を意味し，例
えばメチルアミノ基，エチルアミノ基，プロピルアミノ
基，ジメチルアミノ基，ジエチルアミノ基等が挙げられ
る。Mono- or di-lower alkylamino group means an amino group substituted with one or two lower alkyl groups, such as methylamino group, ethylamino group, propylamino group, dimethylamino group, diethylamino group, etc. It will be done.
低級アルコキシ基としてはメトキシ基，エトキシ基，プ
ロポキシ基，イソブロポキシ基，プトキシ基，イソブト
キ７基， ｓｅｃ−プトキシ基，ｔｅｒｔ−ブトキシ
基，ペンチルオキシ基（アミルオキシ基），インペンチ
ルオキシ基， ｔｅｒｔ−ベンチルオキシ基，ネオベ
ンチルオキシ基，２一メチルブトキシ基，１，２−ジメ
チルプロポキン基，１−エチルプロポキシ基が挙げられ
る。Lower alkoxy groups include methoxy group, ethoxy group, propoxy group, isobropoxy group, putoxy group, isobutoxy group, sec-putoxy group, tert-butoxy group, pentyloxy group (amyloxy group), impentyloxy group, tert-bentyloxy group. group, neobentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoquine group, and 1-ethylpropoxy group.
以上のフェニル基，ビリジル基若しくはアラルキル基の
置換基は，同一又は異なるものが１個乃至複数個置換し
てもよい。The above phenyl group, pyridyl group, or aralkyl group may be substituted with one or more of the same or different substituents.
一般式（Ｉ）で示される化合物は塩を形或することもで
き，本発明には，化合物（Ｉ）の塩も含咬れる。そのよ
うな塩としては，塩酸，臭化水素酸，ヨウ化水素酸，硫
酸，硝酸，リン酸等の鉱酸やギ酸，酢酸，シュウ酸，ク
エン酸，コノ・ク酸，フマール酸，マレイン酸，リンゴ
酸，酒石酸，メタンスルホン酸，エタンスルホン酸等の
各種の有機酸との酸付加塩が挙げられる。The compound represented by general formula (I) can also be in the form of a salt, and the salt of compound (I) is also included in the present invention. Such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as formic acid, acetic acid, oxalic acid, citric acid, cono-citric acid, fumaric acid, and maleic acid. , malic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, and other acid addition salts with various organic acids.
（製造法）
本発明により提供さ・れる化合物（Ｉ）は種々の方法に
より製造することができる。以下にその代表的な方法を
例示する。(Production method) Compound (I) provided by the present invention can be produced by various methods. Typical methods are illustrated below.
第１製法
（■）ａＩ［）
Ｒ１
Ｒ２
ＣＩ＆）
（式中，Ｒ’，Ｒ’は同一又は異なって水素原子；低級
アルキ゛ル基；シクロアルキル基，未置換又は置換のフ
エニル基若しくはピリジル基；未置換又は置換のアラル
キル基を意味する。以下同様）本発明化合物中，一般式
（Ｉａ）で示される化合物は，一般式（ｎ）で示される
ジアミノ化合物と，一般式（ＩＬ［）で示される１種又
は２種のインシアナート化合物を反応させることにより
得ることができる。一般式（ＩＩＩ）で示されるイソシ
アナート化合物は一般式（ｎ）で示される化合物に対し
通常２倍モル乃至過剰モルが用いられる。1st production method (■) aI[) R1 R2 CI&) (wherein, R' and R' are the same or different, hydrogen atom; lower alkyl group; cycloalkyl group, unsubstituted or substituted phenyl group or pyridyl group; Among the compounds of the present invention, the compound represented by the general formula (Ia) is a diamino compound represented by the general formula (n) and the diamino compound represented by the general formula (IL[). It can be obtained by reacting one or two incyanate compounds. The isocyanate compound represented by the general formula (III) is usually used in an amount of 2 times to an excess molar amount relative to the compound represented by the general formula (n).
反応はＮ，Ｎ−ジメチルホルムアミド，ピリジン，ベン
ゼン，トルエン，ジオキサ／，テｌ・ラヒドロフラン，
エーテル，クロロホルム，ジクロロメタン，ジクロロエ
タン，ｎ−ヘキサン等の反応に不活性な溶媒中，室温下
乃至加熱下に行われる。The reaction is N,N-dimethylformamide, pyridine, benzene, toluene, dioxa/, terahydrofuran,
The reaction is carried out in a solvent inert to the reaction, such as ether, chloroform, dichloromethane, dichloroethane, n-hexane, etc., at room temperature or under heating.
第２製法
ＲＩ
Ｋ′
ＣＩ）
（式中，Ｙはノ・ロゲン原子を意味する。以下同様）本
発明化合物は一般式（Ｉ［）で示されるアミノ化合物と
一般式（ＩＶ）で示されるノ・ロゲン化合物とを反応さ
せることによっても得ることができる。2nd Production Method RI K' CI) (In the formula, Y means a norogen atom. The same applies hereinafter) The compound of the present invention is produced by combining an amino compound represented by the general formula (I[) and an amino compound represented by the general formula (IV). - It can also be obtained by reacting with a rogen compound.
反応は，一般式（ｎ）で示されるアミノ化合物と２倍乃
至過剰モルのハロゲン化合物（■）とをＮ，Ｎ−ジメチ
ルホルムアミド，ベンゼン，トルエン，ジオキサン，テ
トラヒドロフラン，エーテル，クロロホルム，シクロロ
メタン，シクロロエタン，ｎ−ヘキサン等の不活性溶媒
中で反応させることにより行われる。反応温度は原料化
合物や溶媒の種類により適宜調節されるが，通常，室温
下乃至加温下に設定される。The reaction is carried out by combining the amino compound represented by the general formula (n) and a halogen compound (■) in a molar excess of 2 to 2 times the amount in N,N-dimethylformamide, benzene, toluene, dioxane, tetrahydrofuran, ether, chloroform, cyclomethane, silica, etc. The reaction is carried out in an inert solvent such as chloroethane or n-hexane. The reaction temperature is appropriately adjusted depending on the raw material compound and the type of solvent, but is usually set at room temperature or under elevated temperature.
第３製法
Ｒ′
ＣＩ）
（式中ＪＲ９は低級アルキル基又はフエニル基を意味す
る。以下同様）
本発明化合物（Ｉ）は一般式（■）で示されるアミノ化
合物に，一般式（■）で示される炭酸ノ・ロゲン化合物
を反応させカルバミン酸エステルとしたのち，更に一般
式（ＩＩ）で示される化合物を反応させることによって
も得ることができる。3rd Production Method R' CI) (In the formula, JR9 means a lower alkyl group or a phenyl group. The same applies hereinafter) The compound (I) of the present invention is added to an amino compound represented by the general formula (■). It can also be obtained by reacting the carbonic acid compound shown to form a carbamate ester, and then reacting the compound shown by the general formula (II).
一般式（■）で示される炭酸ハロゲン化物としては，例
えばイソプチル炭酸クロライド，メチル炭酸クロライド
，エチル炭酸フロマイド，フェニル炭酸クロライド等で
ある。１た，反応を促進させるために炭酸カリウム，炭
酸ナトリウム，水酸化ナトリウム，水酸化カリウム，ト
リエチルアミン， Ｎ，Ｎ−ジ、メチルアニリンの如き
塩基の存在下に行なうのが有利な場合がある。Examples of the carbonate halide represented by the general formula (■) include isobutyl carbonate chloride, methyl carbonate chloride, ethyl carbonate furomide, and phenyl carbonate chloride. In addition, in order to accelerate the reaction, it may be advantageous to carry out the reaction in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-di,methylaniline.
反応溶媒としては， Ｎ，Ｎ−ジメチルホルムアミト，
クロロホルム，ベンゼン，トルエン，キシレン，ジオキ
サン，エーテル，テトラヒドロフラン，クロロホルム，
ジクロロメタン，ジクロロエタン等の不活性溶媒であれ
ばいずれでもよい。反応温度は，一般式（ＩＩ）で示さ
れるアミノ化合物と炭酸ハロゲン化合物の反応に釦いて
は冷却下乃至室温下に，１た，ここで得られたカルバミ
ン酸エステルと化合物（ｎ）の反応に釦いては室温下乃
至加温下に設定される。As a reaction solvent, N,N-dimethylformamide,
Chloroform, benzene, toluene, xylene, dioxane, ether, tetrahydrofuran, chloroform,
Any inert solvent such as dichloromethane or dichloroethane may be used. The reaction temperature is one under cooling to room temperature for the reaction between the amino compound represented by the general formula (II) and the halogen carbonate compound, and one under cooling or at room temperature for the reaction between the carbamate ester obtained here and the compound (n). The button is set at room temperature or under heating.
その他の製造法
目的化合物を製造するその他の方法として，一般式（Ｉ
）の化合物にかける置換基を相互に変換する方法がある
。相互変換法の主なものとしては，フエニル基の置換の
うち，
■ アミノ基をモノもしくはジ低級アルキルアミノ基に
変換する方法
■ ニトロ基をアミノ基に変換する方法などである。Other manufacturing methods As other methods for manufacturing the target compound, general formula (I
) There is a method of mutually converting the substituents applied to the compound. Among the substitution methods for phenyl groups, the main interconversion methods include: (1) converting an amino group into a mono- or di-lower alkylamino group; and (2) converting a nitro group into an amino group.
このうち芳香族アミノ基を芳香族（モノもしくはジ）ア
ルキルアミノ基に変換するには通常のアルキル化反応が
用いられるが，特にアルデヒドと反応させイミンとし，
これを還元してアミンを得る還元的アミノ化が好適であ
る。イミンの還元には，バラジウムー炭素，酸化白金等
の触媒を用いる接触還元もしくはシアノ水素化ホウ素ナ
トリウム，シアノ水素化ホウ素リチウム等の金属水素化
物を用いるのが好適である。Among these, ordinary alkylation reactions are used to convert aromatic amino groups into aromatic (mono- or di)alkylamino groups, but in particular, reaction with aldehydes to form imines,
Reductive amination to reduce this to give the amine is preferred. For the reduction of imines, it is preferable to use catalytic reduction using a catalyst such as palladium-carbon or platinum oxide, or a metal hydride such as sodium cyanoborohydride or lithium cyanoborohydride.
芳香族二トロ基を芳香族アミノ基に変換するには，常法
による接触還元が用いられる。触媒としては，パラジウ
ム炭素，ラネーニッケル，白金などが用いられる。A conventional catalytic reduction method is used to convert an aromatic nitro group to an aromatic amino group. Palladium on carbon, Raney nickel, platinum, etc. are used as the catalyst.
筐た目的化合物の製造原料となるジアミノ化合物（Ｉ［
）は以下の様にして製造される。A diamino compound (I[
) is manufactured as follows.
（ＸＩＩＩ）
（式中Ｙは，水素原子又はノ・ロゲン原子をｎｓ ，
ｎ４１’ｔＯ，１又ｉ’ｔ２をｙ Ｒ”，Ｒ”ｌｄ夫々
Ｒ’，Ｒ”の意味するアルキル基からメチレン基の少な
い基を意味する）
一般式（Ｕで示されるフエニレンジアミン誘導体は
（１）一般式（ＩＸ）で示されるカルボニル化合物と一
般式（Ｘ）で示されるアミノ化合物とを反応させたのち
所望により還元するか，あるいは（１１）一般式（ＸＩ
）で示されるジアミン化合物と一般式（ＸＩＩ．）で
示されるカルボニル化合物とを反応させ，その後所望に
より還元するか，あるいは
（ｉｉｉ） 一般式（Ｘ［Ｉ）で示されるアミド化合
物をハロゲン化し，その後還元することによって行なわ
れる。(XIII) (In the formula, Y is a hydrogen atom or a hydrogen atom,
n41'tO, 1 or i't2 is y R", R"ld means a group with less methylene group from the alkyl group meant by R', R" respectively) General formula (Phenyl diamine derivative represented by U is (1) The carbonyl compound represented by the general formula (IX) and the amino compound represented by the general formula (X) are reacted and then reduced as desired; or (11) the carbonyl compound represented by the general formula (XI
) and a carbonyl compound represented by the general formula (XII.), and then optionally reduced, or (iii) halogenating the amide compound represented by the general formula (X[I), This is done by subsequent reduction.
上記反応式中（１）及び（１１）に３いて化合物（ＸＩ
［）と化合物（Ｘ）又は化合物（ＸＩ）と化合物（ＸＩ
Ｉ）との反応温度は水冷下乃至室温下に設定される。In the above reaction formulas (1) and (11), compound (XI
[) and compound (X) or compound (XI) and compound (XI
The reaction temperature with I) is set between water cooling and room temperature.
反応溶媒としてはベンゼン，ヘキサン，トルエン，キシ
レン，ジクロロメタン，クロロホルム， Ｎ，Ｎ−ジ
メチルホルムアミド等が用いられる。尚，反応を促進さ
せるためにトリメチルアミン，トリエチルアミン等の有
機塩基，炭酸ナトリウム，炭酸水素ナトリウム等の無機
塩基を添加してもよい。Benzene, hexane, toluene, xylene, dichloromethane, chloroform, N,N-dimethylformamide, etc. are used as the reaction solvent. In order to accelerate the reaction, organic bases such as trimethylamine and triethylamine, and inorganic bases such as sodium carbonate and sodium bicarbonate may be added.
次ニ還元は，トルエン，ベンゼン，キ７レン，テトラヒ
ドロフラン，ジオキサン，エーテル等の溶媒中，水素化
リチウムアルミニウム，水素化ジイソブチルアルミニウ
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，ボランテトラヒドロフラン錯体，ボラン硫
化ジメチル錯体等で処理することにより行われる。The secondary reduction is performed using lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, boranetetrahydrofuran complex, borane in a solvent such as toluene, benzene, xylene, tetrahydrofuran, dioxane, or ether. This is done by treatment with dimethyl sulfide complex, etc.
反応温度は通常水冷下乃至加温下に設定される。The reaction temperature is usually set between water cooling and heating.
１た上記反応式（ｉ１ｉ）に訃いて，化合物（ＸＩＩＩ
）は，ハロゲン化試薬（例えば，塩化チオニル，三塩化
リン，五塩化リン，オキシ塩化リン，ホスゲン，オキザ
リルクロライド，三臭化リン，五臭化リン，オキシ臭化
リン等）により一旦イミノハライド化合物とし，このも
のを単離・精製するか，ちるいはせずして金属水素化物
（例えば，水素化ホウ素ナトリウム，水素化ホウ素リチ
ウム，水素化ホウ素カリウム等）により還元する。1 Based on the above reaction formula (i1i), the compound (XIII
) can be converted into an iminohalide once using a halogenating reagent (e.g., thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosgene, oxalyl chloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, etc.). This compound is isolated and purified, or reduced with a metal hydride (e.g., sodium borohydride, lithium borohydride, potassium borohydride, etc.) without sieving.
通常単に濃縮，留去等により未反応ハロゲン化試薬の大
半を除去したのち，還元に付される。Usually, most of the unreacted halogenating reagent is simply removed by concentration, distillation, etc., and then reduction is carried out.
反応溶媒としては，■ハロゲン化反応に釦いては，ベン
ゼン，トルエン，キシレン，クロロホルム，四塩化炭素
，テトラヒドロフラン，ジオキサン等の不活性溶媒か又
は，ハロゲン化試薬が反応溶媒を兼ねることもできる。As a reaction solvent, (1) In the halogenation reaction, an inert solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, etc., or a halogenation reagent can also serve as the reaction solvent.
１た，■還元工程に釦いては，メタノール，エタノール
，イソプロパノール，テトラヒドロフラン，アセトニト
リル等である。1) For the reduction step, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, etc. are used.
反応温度は，■ハロゲン化反応では室温下乃至加温下で
あり，■還元工程にかいては，冷却下乃至室温下である
。The reaction temperature is (1) halogenation reaction at room temperature or under heating, and (2) reduction step at cooling or room temperature.
このようにして製造された本発明化合物（Ｔ）は遊離の
ままあるいはその塩として常法にまり造塩あるいは脱塩
し単離精製される。単離，精製は，抽出，結晶化．再結
晶，各種クロマトグラフィー等の通常の化学操作を適用
して行われる。The compound (T) of the present invention thus produced is isolated and purified in its free state or as a salt thereof by salt formation or desalting in a conventional manner. Isolation and purification include extraction and crystallization. This is done by applying normal chemical operations such as recrystallization and various chromatography.
（発明の効果）
本発明化合物（Ｉ）又はその塩は， ＡＣＡＴ酵素を
阻害することにより血管内においては，動脈壁平滑筋細
胞内へのコレステロールエステルの蓄積を抑制する。ま
た，既存の脂質低下剤と比較して，コレステロールの腸
管からの吸収を抑制し，肝臓内におけるコレステロール
の異化***を促進することにより血中コレステロールの
低下のみならず，動脈壁におけるコレステロールエステ
ルの蓄積及び貯蔵を減少させ，アテローム性動脈硬化病
変の形成又は発展を抑制する。(Effects of the Invention) The compound (I) of the present invention or a salt thereof suppresses the accumulation of cholesterol ester in arterial wall smooth muscle cells in blood vessels by inhibiting the ACAT enzyme. In addition, compared to existing lipid-lowering agents, it not only lowers blood cholesterol by suppressing the absorption of cholesterol from the intestinal tract and promoting the catabolism and excretion of cholesterol in the liver, but also the accumulation of cholesterol esters in the arterial walls. and storage, inhibiting the formation or development of atherosclerotic lesions.
また，本発明化合物（Ｉ）又はその塩は，動物実験によ
れば，優れた血液中総コレステロール並びに低比重リポ
蛋白（ＬＤＬ）の低下作用を有しており，脂質低下作用
と同時に動脈硬化症の関連する諸疾患，例えば，脳梗塞
，一過性虚血発作，狭心症，末梢性血栓および閉塞等の
予防．治療に有用である。Furthermore, according to animal experiments, the compound (I) of the present invention or a salt thereof has an excellent effect of lowering blood total cholesterol and low-density lipoprotein (LDL), and has a lipid-lowering effect as well as an ability to reduce arteriosclerosis. Prevention of various diseases related to cerebral infarction, transient ischemic attack, angina pectoris, peripheral thrombosis, and occlusion. Useful for treatment.
本発明化合物の効果は，次の様にして確認されたもので
ある。The effects of the compounds of the present invention were confirmed as follows.
） ＡＣＡＴ酵素阻害活性
０ｏ
実験例 ウサギ肝ミクロソームのアシルーｅｉＡ；コレ
ステロールアシルトランスフ
エラーゼ（ＡＣＡＴ）活性に対する阻害作用
家兎肝ミクロソームをＨｅｉｄｅｒ の方法に従って調
製し，酵素画分とする。) ACAT enzyme inhibitory activity 0o Experimental example Acyl-eiA of rabbit liver microsomes: Inhibitory effect on cholesterol acyltransferase (ACAT) activity Rabbit liver microsomes were prepared according to the method of Heider and used as an enzyme fraction.
０．１５４Ｍリン酸緩衝液（ＰＨ７．４）， ２ｍＭジ
チオスレイトール３６μＭ牛血清アルブミン， １０
１００μｇミクロンーム画分に， Ｓｕｃｋｌｉｎｇ
の方法に従って調製したリポソームを２０％ｖ／ｖとな
るように加える。これに各濃度検体化合物のジメチルス
ルフォキシド溶液を２％ｖ／ｖで加え，３７℃．５分間
加温する。次いで１１４ｃ−オレオイルＣｏＡを含む，
３６μＭオレオイルＣｏＡを加え，３７？Ｃ，１０分間
加温した後，クロロホルム／メタノール（−２／１ ）
混液を添加して反応を停止する。0.154M phosphate buffer (PH7.4), 2mM dithiothreitol 36μM bovine serum albumin, 10
Suckling to 100 μg micron fraction
Add liposomes prepared according to the method of 20% v/v. A dimethyl sulfoxide solution of each concentration of the test compound was added to this at 2% v/v, and the mixture was heated at 37°C. Warm for 5 minutes. Then containing 114c-oleoyl CoA,
Add 36μM oleoyl-CoA, 37? C, after heating for 10 minutes, chloroform/methanol (-2/1)
The reaction is stopped by adding the mixture.
攪拌後．クロロホルム層に抽出されるコレステロールオ
レエイトを薄層クロマトグラフィーにて分離後，放射活
性を測定しＡＣＡＴ活性とした。After stirring. Cholesterol oleate extracted into the chloroform layer was separated by thin layer chromatography, and radioactivity was measured and defined as ACAT activity.
１） Ｊ，Ｇ，Ｈｅｉｄｅｒｅｔ．ａｌ，Ｊ．ｏｆＬ
ｉｐｉｄＲｅｓ，Ｖｏｌ，２４．１１２７−３４（１９
８３）
２） Ｋ，Ｂ，Ｓｕｃｋ１ｉｎｇｅｔ，ａｌ，ＦＥＢ
ＳＬｅｔｔｅｒｓ，Ｖｏｌ，１５１．Ｎｏ，１１１１−
１１６， （１９８３）
１１）脂質低下作用；
生後５週令のスブラグ ドウリー （ Ｓｐｒａｇｕｅ
−ｐｅｗｌｅｙ）の雄性ラットにコレステロール１．
５％と胆汁酸０５％含有食餌を７日間与え，最後の５日
間，メチルセルロース０．５％水溶液に懸濁させた本発
明化合物（Ｉ）を１日１回経ロゾンデによって投与し，
最終投与２時間後にエーテル麻酔下採血し． 血清のｍ
コレステロール及ヒＨＤＬ−コレステロールの量を測定
した。コレステロールの測定は，シーデル，Ｊ等；ジャ
ーナル オブ クリニカル ケ■ストリー アンド ク
リニカル？イオケ■ストリー第１９巻８３８頁１９８１
年（ Ｓｉｅｄｅｌ， Ｊ，， ｅｔ ａｌ ； Ｊ，
Ｃｌｉｎ．Ｃｈｅｍ， Ｃｌｉｎ．Ｂｉｏｃｈｅｍ．
ｌ ９８３８ （１９８１ ））に記載されている方法
で，またＨＤＬ−コレステロールの測定はりピソド第１
１巻６２８頁１９７６年（Ｉｓｈｉｋａｗａ， Ｔ，
Ｔ，， ｅｔ．ａｌ，， Ｌｉｐｉｄｓ １ １６２８
（１９７６））に記載されている方法で行なった。1) J, G, Heideret. al, J. ofL
ipidRes, Vol, 24.1127-34 (19
83) 2) K, B, Suck1inget, al, FEB
SLetters, Vol, 151. No.1111-
116, (1983) 11) Lipid-lowering effect; Sprague-Dawley at 5 weeks old
- pewley) male rats with cholesterol 1.
A diet containing 5% bile acid and 05% bile acid was given for 7 days, and for the last 5 days, the compound (I) of the present invention suspended in a 0.5% methylcellulose aqueous solution was administered once a day by oral transfusion.
Two hours after the final administration, blood was collected under ether anesthesia. serum m
The amounts of cholesterol and human HDL-cholesterol were measured. Cholesterol measurement is as follows: Schiedel, J. et al.; Journal of Clinical Studies ■Story and Clinical? Ioke Story Vol. 19, p. 838, 1981
(Siedel, J, et al; J,
Clin. Chem, Clin. Biochem.
19838 (1981)), and the method for measuring HDL-cholesterol (Piso 1).
Volume 1, 628 pages, 1976 (Ishikawa, T.
T,, etc. al,, Lipids 1 1628
(1976)).
本発明化合物（Ｉ）やその塩を主成分として含有する薬
剤は，当分野において通常用いられている製剤用担体，
賦形剤等を用いて，通常使用されている方法によって調
製することができる。A drug containing the compound (I) of the present invention or a salt thereof as a main component can be prepared using a pharmaceutical carrier commonly used in the art,
It can be prepared by commonly used methods using excipients and the like.
投与は錠剤，丸剤，カプセル剤，顆粒剤，散剤，液剤等
による経口投与，あるいは静注，筋注等の注射剤，坐剤
等による非経口投与のいずれの形態であってもよい。投
与量は症状，投与対象の年令，性別等を考慮して個々の
場合に応じて適宜決定されるが，通常経口投与の場合成
人１日当り５０〜５００ｍｇ程度であり，これを１回で
，あるいは２〜４回に分けて投与する。Administration may be in the form of oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections such as intravenous or intramuscular injections, suppositories, etc. The dosage is determined depending on the individual case, taking into consideration the symptoms, the age and gender of the recipient, etc., but the usual oral administration is about 50 to 500 mg per day for adults; Alternatively, administer in 2 to 4 doses.
（実施例） 以下に実施例を掲記し，本発明を更に詳細に脱明する。(Example) EXAMPLES The present invention will be explained in further detail by way of examples below.
実施例中， ’Ｈ−ＮＭＲは水素核磁気共鳴スペクトル
を， ｍｐは融点を， Ｍａｓｓは質量分析値を，
ＩＲは赤外線吸収スペクトルを意味する。In the examples, 'H-NMR means hydrogen nuclear magnetic resonance spectrum, mp means melting point, Mass means mass spectrometry value,
IR means infrared absorption spectrum.
参考例 １．
２，６−ビス（Ｎ−シクロヘプチルアミノメチ）Ｌ／）
ピリジン
２，６−ビス（Ｎ−シクロへプチルカルバモイル）ピリ
ジン２．７ ４ ｇ （ ７．６ ６ ｍｍｏｌ ）に
５０ｍ７の塩化チオニルを加え，３時間加熱還流した。Reference example 1. 2,6-bis(N-cycloheptylaminomethy) L/)
Pyridine 50 m7 of thionyl chloride was added to 2.74 g (7.66 mmol) of 2,6-bis(N-cycloheptylcarbamoyl)pyridine, and the mixture was heated under reflux for 3 hours.
余剰の塩化チオニルを留去した残渣に１００ｍｌのメタ
ノールを加え，３０分間にわたり激しく攪拌しながら２
．３ ２ ｇ （６．１ ３ｍｍｏｌ ）の水素化ホウ
素ナトリウムを氷水浴で内淵２０〜２５℃に保ち々がら
加えた。反応液を室温で１時間攪拌した後，５ｍｌの濃
塩酸を加えた。メタノールを留去した残渣に４Ｎ水酸化
ナトリウム液を加え， １００ｍＺのクロロホルムで
３回抽出した。抽出族を無水硫酸マグネシウムで乾燥し
，溶媒を留去した残渣をシリカゲル力ラムクロマトグラ
フィーで精製し１．８０ｇ（７１．３％）の粘調液体を
得た。100 ml of methanol was added to the residue after removing excess thionyl chloride, and the mixture was stirred vigorously for 30 minutes.
．． 32 g (6.13 mmol) of sodium borohydride was added while keeping the inner temperature at 20 to 25° C. in an ice water bath. After stirring the reaction solution at room temperature for 1 hour, 5 ml of concentrated hydrochloric acid was added. A 4N sodium hydroxide solution was added to the residue after methanol was distilled off, and the mixture was extracted three times with 100 mZ chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.80 g (71.3%) of a viscous liquid.
’Ｈ−ＮＭＲ （δｐＰｍｌ重クｏｃｙホ／ｌ／ ム中
）１．２〜２．１ （２４Ｌ ｍ）． ３．８（４Ｈ，
ｓ ）， ７．８（ＩＨ， ｄ ）同様にして，以下
の化合物を合成した。'H-NMR (in δpPml heavy volume/l/ml) 1.2-2.1 (24L m). 3.8 (4H,
s), 7.8 (IH, d) The following compounds were synthesized in the same manner as in 7.8 (IH, d).
参考例 ２．
２．６−ビス（Ｎ〜シクロヘキシルアミノメチル）ピリ
ジン
’Ｈ−ＮＭＲ（δｐＰｍ＃重クＦＣＩボルム中）１．２
−２．２（２０Ｈ， ｍ）． ３．９（４Ｈ， ｓ）．
７．６（ＩＨ， ｄｄ）参考例３．
２，６−ビス（Ｎ−シクロベンチルアミノメチルピリジ
ン
’Ｈ−ＮＭＲ（δｐｐ” ｒ重クロロホルム中）１．２
−２．３（１６Ｈ， ｍ）， ３．９（４Ｈ， ｓ），
７．６（ＩＨ， ｄｄ）参考例 ４．
２，６−ビス［Ｎ一（２−プロビル）アミノメチル］ピ
リジン
’Ｈ−ＮＭＲ （δｐｐｍ ＋重クｏｏホルム中）１．
１（１２Ｈ， ｄ）， ３．９（４Ｈ， ｓ）． ７．
６（ＩＨ， ｄｄ）参考例 ５．
３． ５ − ヒス（Ｎ−シクロヘプチルアミノメチル
：ピリジン
Ｈ−ＮＭＲ（δｐｐｍ，重クロロボルム中）１．２−２
．２（２４Ｈ， ｍ）， ３．８（４Ｈ， ｓ）， ８
．４（２Ｈ， ｄ）参考例 ６．
３，５−ビス（Ｎ−シクロヘキシルアミノメチル）ピリ
ジン
’Ｈ−ＮＭＲ（δｐｐｍ，重クｏｏホルム中）１．２−
２．２（２０Ｈ， ｍ）， ３．８（４Ｈ， ｓ），
８．４’（２Ｈ， ｄ）参考例 ７．
３，５−ビス（Ｎ−シクロベンチルアミノメチル）ピリ
ジン
’Ｈ−ＮＭＲ（δｐｐｍ．重クロロホ／ｌ／ム中）１．
２ ２．１（１６Ｈ， ｍ）， ３．８（４Ｈ， ｓ
）， ８．４（２Ｈ， ｄ）参考例 ８，
３，５−ビス［Ｎ−（２−プロビノレ）アミノメチル］
ピリジン
’Ｈ−ＮＭＲ（δＰＩ）ｍ１重クロロホルム中）１．１
（１２Ｈ， ｄ）， ３．８（４Ｈ， ｓ ）． ８．
４（２Ｈ， ｄ）参考例 ９．
３．５−ビス（Ｎ−メチルアミノメチル）ピリジン’Ｈ
−ＮＭＲ（δｐＰ” ｊ重ジメチルスルボキシド中）３
．０（６Ｈ， ｓ）． ４．５（４Ｈ， ｓ）， ８．
５（２Ｈ， ｓ）参考例 １０．
２，６−ビス（Ｎ−メチルアミノメチル）ピリジン２．
６〜ピリジンジアルデヒド２．５ ｇ （１ ８．５ｍ
ｍｏｌ ）と３０％メチルアミンーメタノール溶液８．
３ｇ（ｏ．ｏｇｍｏｌ）の混合物に０．１ｍ７の酢酸を
加え室温下２時間攪拌した。Reference example 2. 2.6-bis(N~cyclohexylaminomethyl)pyridine'H-NMR (δpPm# in heavy FCI volume) 1.2
-2.2 (20H, m). 3.9 (4H, s).
7.6 (IH, dd) Reference example 3. 2,6-bis(N-cyclobentylaminomethylpyridine'H-NMR (δpp'' r in deuterium chloroform) 1.2
-2.3 (16H, m), 3.9 (4H, s),
7.6 (IH, dd) Reference example 4. 2,6-bis[N-(2-propyl)aminomethyl]pyridine'H-NMR (δppm + in deuterium chloride form)1.
1 (12H, d), 3.9 (4H, s). 7.
6 (IH, dd) Reference example 5. 3. 5-His(N-cycloheptylaminomethyl:pyridine H-NMR (δppm, in deuterochloroborum) 1.2-2
．． 2 (24H, m), 3.8 (4H, s), 8
．． 4 (2H, d) Reference example 6. 3,5-bis(N-cyclohexylaminomethyl)pyridine'H-NMR (δppm, in deuterium chloride form) 1.2-
2.2 (20H, m), 3.8 (4H, s),
8.4' (2H, d) Reference example 7. 3,5-bis(N-cyclobentylaminomethyl)pyridine'H-NMR (in δppm. deuterium chloroform/l/m)1.
2 2.1 (16H, m), 3.8 (4H, s
), 8.4(2H, d) Reference example 8, 3,5-bis[N-(2-provinole)aminomethyl]
Pyridine'H-NMR (δPI) m1 in dichloroform) 1.1
(12H, d), 3.8 (4H, s). 8.
4 (2H, d) Reference example 9. 3.5-bis(N-methylaminomethyl)pyridine'H
-NMR (δpP'' in deuterium dimethyl sulfoxide) 3
．． 0 (6H, s). 4.5 (4H, s), 8.
5 (2H, s) Reference example 10. 2,6-bis(N-methylaminomethyl)pyridine2.
6-2.5 g of pyridine dialdehyde (18.5 m
mol) and 30% methylamine-methanol solution8.
0.1 m7 of acetic acid was added to a mixture of 3 g (o.ogmol) and stirred at room temperature for 2 hours.
反応液に５０ｍｌのア七トニトリルを加え２室温下攪拌
しながら水素化ホウ素ナトリウム１．５ ｇ （０．０
４’ｍｏｌ）を４５分間にわたり投入し，同温度で１
時間攪拌した。２ｍ４の濃塩酸を加えた後，溶媒を留去
した。残渣に２５ｍｌの４Ｎ水酸化ナトリウム液を加え
全量２００ｍｌのクロロホルムで抽出し，無水炭酸カリ
ウムで乾燥した。溶媒を留去した残渣をシリカゲルヵラ
ムクロマトグラ７イーで精製し，褐色粘調液体２．３
５ ｇを得た。Add 50 ml of a7tonitrile to the reaction solution and add 1.5 g (0.0 g) of sodium borohydride while stirring at room temperature.
4' mol) was added over 45 minutes, and 1 mol was added at the same temperature.
Stir for hours. After adding 2 m4 of concentrated hydrochloric acid, the solvent was distilled off. 25 ml of 4N sodium hydroxide solution was added to the residue, extracted with a total of 200 ml of chloroform, and dried over anhydrous potassium carbonate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography 7E to obtain a brown viscous liquid 2.3.
5 g was obtained.
Ｈ−ＮＭＲ（δＩ’ ｐ” ＋重クロロホルム中）２．
５（６Ｈ， ３）． ３．８（４Ｈ， ｓ）， ８．７
（２Ｈ， ｄ）実施例１
２．６−ビス［［１−シクロヘチプルー３−（４−Ｎ，
Ｎ−ジメチルアミノフェニル）ウレイド］ピリジン・
三塩酸塩
２，４−ビス（Ｎ−シクロヘプチルアミノメチル）ピリ
ジン６１０ ｍｇ （ １．５２ｍｍｏｌ ）の３０ｍ
ｌ無水塩化メチレン溶液に，室温攪拌下，ｐ一（ジメチ
ルアミノ）フェニルイソシアナート０．５ ９ （Ｏｇ
（ ３．６ ４ ｍｍｏ ｌ ）の塩化メチレン溶液
を３０分間にわたり滴下し室温で１時間攪拌した。溶媒
を留去した残渣をシリカゲルカラムクロマトグラフィで
精製した後，塩酸含有エタノールで塩酸塩とし，無品性
粉末６９０■を得た。H-NMR (δI′ p” + in deuterated chloroform)2.
5 (6H, 3). 3.8 (4H, s), 8.7
(2H, d) Example 1 2.6-bis[[1-cyclohethypuru-3-(4-N,
N-dimethylaminophenyl)ureido]pyridine
30 m of 610 mg (1.52 mmol) of 2,4-bis(N-cycloheptylaminomethyl)pyridine trihydrochloride
l Anhydrous methylene chloride solution was added with 0.59 (Og
(3.64 mmol) of methylene chloride solution was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was purified by silica gel column chromatography and converted into a hydrochloride with ethanol containing hydrochloric acid to obtain 690 lbs of pure powder.
ＩＲ（ａｍ−”， ＫＢｒ錠）１６４８， １６１８．
１５２２’Ｈ−ＮＭＲ（δｐｐｍ，重ジメチルスルホ
キシド中３．１（１２Ｈ， ｄ）， ４．９（４Ｈ，
ｓ）， ８．２０（ＩＨ， ｔ）Ｍａｓｓ（ＦＡＢ）
６５４（Ｍ＋１）同様にして，以下の化合物を合成
した。IR (am-”, KBr tablet) 1648, 1618.
1522'H-NMR (δppm, 3.1 (12H, d), 4.9 (4H,
s), 8.20(IH, t)Mass(FAB)
The following compounds were synthesized in the same manner as 654 (M+1).
）
実施例２
２，６−ビス［［１−シクロへプチル−３ −（２．４
−ジフルオロフエニル）ウレイド］メチルコピリジン・
一塩酸塩・一水和物
融点 １０９−１１２°Ｃ
１Ｈ−ＮＭＲ（δｐｐｍ，重ジメチルスルホキシド中）
１．２−１．９（２４Ｈ， ｍ）， ４．６（４Ｈ，
ｓ）， ８．５（２Ｈ， ｄ）元素分析値 （ Ｃ，，
Ｈ４４Ｎ， Ｏ， Ｃ ＩＦ，として）測定値 Ｃ
： ６ ０．５ ６％ Ｈ ： ６．２ ８％ Ｎ：１
０．１３％理論値 Ｃ ： ６ ０．５ ６％ Ｈ ：
６．３ ９％ Ｎ：１０．０９％実施例３
２，６−ビス［「１
ーメチルフェニル）
一塩酸塩
シクロヘプチル−３−（４
ウレイド］メチル］ピリジン・
融点 １４５−１４６℃
’Ｎ−ＮＭＲ（δｐｐｍ＋重ジメチルスルホキジド中）
２．２（６Ｈ， ｓ）， ４．７（４Ｈ， ｓ）， ８
．０（ＩＨ， ｔ）元素分析値 （ Ｃ，７Ｈ５ＯＮ，
０２Ｃｌとして）実測値 Ｃ ： ７ ０．０ ７％
Ｈ ： ７．９ ８％ Ｎ：１０．８４％計算値 Ｃ
： ７ ０．２ ９％ Ｈ ： ７．９ ２％ Ｎ：
１１．０８％実施例４
２，６−ビス［［１−シクロヘプチル−３−（３ニトロ
フエニル）ウレイド］メチルコピリジン・−塩酸塩
融点 １２２−１２５℃
＋Ｈ−ＮＭＲ（δｐｐｍｔ重ジメチルスルホキシド中）
３．０（６Ｈ， ｄ）， ４．６（４Ｈ， ｓ）， ７
．８（ＩＨ， ｔ）元素分析値 （ ”ｓｓ Ｈ４４
Ｎ７ ０６ Ｃ １として）実測値 Ｃ ： ６ ０．
５ １％ Ｈ ： ６．３ ９％ Ｎ：１４．０３％計
算値 Ｃ ： ６ ０．５ ５％ Ｈ ： ６．３ ９
％ Ｎ：，１４．１２％実施例５
２．６−ビス［［１−シクロへプチル−３−（４メトキ
シフェニル）ウレイド］メチル］ピリジン●一塩酸塩
ＩＲ（ｍ−’，ＫＢｒ錠”）１６４８，１６０４．１５
１４’Ｈ−ＮＭＲ（δｐｐｍ，Ｆｔジメチルスルホキシ
ド中）３．７（６Ｈ， ）， ４．７（４Ｈ． ｓ），
８．０（２Ｈ， ｄ）Ｍａｓｓ（ＦＡＢ） ６２
８（Ｍ＋１）実施例６
３，５−ビス［（１−シクロヘプチル−３−フエニルウ
レイド）メチル］ピリジン
融点 １７２−１７４℃
’Ｈ−ＮＭＲ（δｐｐｍ＋重クＤＯホルム中）４．５（
４Ｈ， ｓ ）， ７．７ （ＩＨ， ｓ ）， ８．
５ （２Ｈ， ｓ）元素分析値 （ Ｃ３５ Ｈ４５
Ｎ５ ｏ２として）測定値 Ｃ ： ７ ３．８ ８％
Ｈ ： ８．０ ８％ Ｎ：１２．２４％理論値 Ｃ
：７４．０４％ Ｈ ： ７．９ ９％ Ｎ：１２．３
３％実施例７
３，５−ビス［［１−シク口へプチル−３〜（４−メチ
ルフエニル）ウレイド］メチルコピリジン融点 １５７
−１５８°Ｃ
’Ｈ−ＮＭＲ（δｐｐｍ１ ！クロロホルム中）２．３
（６Ｈ，ｓ），４．５（４Ｈ，ｓ），７．５（２Ｈ，ｓ
）元素分析値 （ Ｃ３？ Ｈ４Ｑ Ｎ５ ０２として
）測定値 Ｃ ： ７ ４．４ ９％ Ｈ ： ８．２
２％ Ｎ：１１．４８％理論値 Ｃ：７４．５９％
Ｈ ： ８．２ ９％ Ｎ：１１．７５％実施例８
３．５−ビス［（Ｉ−シクロへブチル−３−メチルウレ
イド）メチル］ピリジン
融点 １８７−１８８°Ｃ
’Ｈ−ＮＭＲ（δＰＰｍｌ重クロロホルム中）２．８（
６Ｈ， ｓ）， ４．４（４Ｈ， ｓ）， ８．４（２
Ｈ， ｓ）元素分析値 （ Ｃ２５ Ｈ４１ Ｎ５ ０
ｊｌとして）測定値 Ｃ：６７．４９％ Ｈ：９．２
１％ Ｎ：１５．５１％理論値 Ｃ ： ６ ７．６
９％ Ｈ：９．３２％ Ｎ：１５．７９％実施例９
３，５−ビス［［１−シク口へプチル−３ − （ ２
．４−ジフルオロフエニル）ウレイド］メチル］ピリジ
ン
ＩＲ（ｃｍ−１， ＫＢｒ錠＞ １６４２． １５２１
． １４３３’Ｈ−ＮＭＲ（δｐｐｍｙ重クロロホルム
中）４．５（４Ｈ，ｓ），７．７（４Ｈ，ｓ），８．５
２（２Ｈ，ｓ）Ｍａｓｓ（ＦＡＢ） ６４０（Ｍ
＋１）実施例１０
３．５−ビス［（１−シク口へブチル−３−シクロヘキ
シルウレイド）メチル］ピリジン融点 １８０−１８１
°Ｃ
’Ｈ−ＮＭＲ（δｐｐｍ，重クｏｏホルム中）４．４（
４Ｈ， ｓ）， ７．６（ ＬＨ， ｓ）， ８．４（
２Ｈ， ｓ）元素分析値 （ Ｃ３５ Ｈ５７ Ｎ５
ｏ２として）実測値 Ｃ ： ７ ２．８ ６％ Ｈ
： ９．８ ２％ Ｎ：１１．８３％計算値 Ｃ ：
７ ２．５ ０％ Ｈ ： ９．９ １％ Ｎ：１２．
０８％実施例１１
３，５−ビス［［１−シクロへチプル−３−（４ −Ｎ
，Ｎ−ジメチルアミノフェニル）ウレイド］メチル］ピ
リジン融点 １２２−１２３℃
’Ｈ−ＮＭＲ（δｐＩ）ｍｌ重ジメチルスルホキシド中
）２．９（１２Ｈ， ｓ）， ４．５（４Ｈ， ｓ），
８．５（２Ｉ｛， ｓ）元素分析値 （Ｃ３。Ｈ５５
Ｎ？ ｏ２として）測定値 Ｃ ： ７ １．５ ４
％ Ｈ ： ８．５ ９％ Ｎ：１４．８３％理論値
Ｃ：７１．６３％ Ｈ ： ８．４ ８％ Ｎ ： １
４．９ ９％実施例１２
２，６−ビス［（１−シクロへプチル−３−メチルウレ
イド）メチルコピリジン
ＩＲ（ｃＷＬ−ｌ， ＫＢｒ錠）
’Ｈ−ＮＭＲ（δｐＰｍｌ重クロロホルム中）３．０（
６Ｈ， ！＋）， ４．６（４Ｈ， ｄ）， ７．８（
ＬＨ， ｔ）Ｍａｓｓ（ＦＡＢ） ４４４（Ｍ
＋１）実施例１３
２．６−ビス「（１−シクロへプチル−３−シクロへキ
シルウレイド）メチル］ピリジンＩＲ（ａｒｔ−’．
ＫＢｒ錠） １６４６， １６１６． １５１４’Ｈ
−ＮＭＲ（δｐＩ）ｍｌ重クロロホルム中）４．６（４
Ｈ， ｓ）， ７．３（２Ｈ， ｄ）， ７．７（ＩＨ
， ｔ）Ｍａｓｓ（ＦＡＢ） ． ５８０（Ｍ＋１
）融点 １７９−１８０’Ｃ
’Ｈ−ＮＭＲ（δｐ ｐｍ，重クロロホルム中）４．６
（４Ｈ， Ｓ）， ７．４（２Ｈ， ｄ）， ７．７（
ＩＨ， ｔ）元素分析値 （ Ｃ３１ Ｈ４？ Ｎ５
０２として）実測値 Ｃ ： ７ ２．５ ７％ ｝
Ｉ：７．３０％ Ｎ：１３．３７％計算値 Ｃ ： ７
２．７ ７％ Ｈ ： ７．２ ９％ Ｎ ： １
３．６ ９％実施例１５
２，６−ビス［［１−シクロペンチルー３−（４−ジフ
ルオロフエニル）ウレイドコメチル］リジン
２，
ビ
融点 １４３−１４４°Ｃ
Ｈ−ＮＭＲ（δｐｐｍ，重クロロホルム中）４．６（４
Ｈ， ｓ）， ７．３（２Ｈ， ｄ）， ７．８（ＩＨ
， ｔ）元素分析値 （ Ｃ３１ Ｈ３３ Ｎ５ ｏ２
Ｆ４として）実測値 Ｃ ： ６ ３．４ ４％ Ｉ｛
： ５．７ ７％ Ｎ：１１．８７％計算値 Ｃ ：
６ ３．８ ０％ Ｈ ： ５．７ ０％ Ｎ ：
１ ２．０ ０％実施例１６
３．５−ピス［（１−シクロペンチルー３−フエニルウ
レイド）メチル］ピリジン
融点 １７２−１７３℃
ＩＨ−ＮＭＲ（δｐｐｍ１重クロロホルム中）４．６（
４Ｈ， ｓ）， ７．４（２Ｈ， ｄ）， ７．７（Ｉ
Ｈ， ｔ）元素分析値 （ Ｃｓ＋ Ｈ４？ Ｎ５ ０
２として）実測値 Ｃ ： ７ ２．５ ７％ Ｈ：７
．３０％ Ｎ ： １ ３．３ ７％計算値 Ｃ ：
７ ２．７ ７％ Ｈ ： ７．２ ９％ Ｎ：１３．
６９％実施例１７
３． ５−ビス［［１−シクロペンチルー３ − （
２．４−ジフルオロフェニル）ウレイド］メチル］ヒリ
ジン
融点 １３１−１３２℃
’Ｈ−ＮＭＲ（δｐｐｍ，重クロロホルム中）４．６（
４１， ｓ）， ７．６ （２Ｈ， ｄ）， ８．５
（ ＩＨ， ｔ ）元素分析値 （ Ｃ３１ Ｈ３３
Ｎ５ ０２ Ｆ４として）実測値 Ｃ ： ６ ３．７
３％ Ｈ ： ５．６ ８％ Ｎ：１１．９５％計算
値 、Ｃ ： ６ ３．８ ０％ Ｈ ： ５．７ ０
％ Ｎ：１２．０Ｏ％実施例１８
２．６−ビス［［３−フェニル−１−（２−プロビル）
ウレイド］メチルコピリジン
融点 １８７−１８８°Ｃ
ＬＨ−ＮＭＲ（δＰＩ）ｍ１重クｏｏホルム中）ｔ２（
１２Ｈ， ｄ）， ４．６（４Ｈ， ａ）， ７．８（
ＩＨ， ｔ）元素分析値 （ Ｃ２， Ｈ，， Ｎ，
０２として）実測値 Ｃ ： ７ ０．３ ８％ Ｈ：
７．２８％ Ｎ：１５．１１％計算値 Ｃ ： ７ ０
．５ ６％ Ｈ ： ７．２ ４％ Ｎ：１５．２４％
実施例１９
２．６−ビス［［
ミノフエニル）一
メチルコピリジン
３−（４−Ｎ，Ｎ−ジメチルア
１−（２−プロビル）ウレイド］
融点 １６７−１６９°Ｃ
’Ｈ−ＮＭＲ（δｐｐｍ，重クロロホルム中）１。２（
１２Ｈ”， ｄ）， ４．６（４Ｈ， ｓ）， ７．８
（ＩＨ， ｔ）元素分析値 （ Ｃｓ＋ Ｈ４ｔ Ｎ？
０２として）実測値 Ｃ ： ６ ８．２ ２％ Ｈ
： ７．７ ９％ Ｎ：１７．７５％計算値 Ｃ：６
８．２３％ Ｈ ： ７．９ ４％ Ｎ：１７．９７％
実施例２０
３，５−ビス［［１−（２−プロビル）−３−７エニル
ウレイドコメチルコピリジン
融点 １７７−１７８°Ｃ
’｝Ｉ−ＮＭＲ（δｐｐｍ，重クｏｏホルム中）１．２
（１２Ｈ， ｄ）， ４．５（４Ｈ， ｓ）， ７．７
（ＩＨ， ｔ）元素分析値 （ Ｃ２？ Ｈ３３ Ｎ５
ｏ，として）実測値 Ｃ ： ７ ０．２ ７％ Ｈ
： ７．２ ４％ Ｎ：１５．１９％計算値 Ｃ ：
７ ０．５ ６％ Ｈ ： ７．２ ４％ Ｎ ：
１ ５．２ ４％実施例 ２１
２，６−ビス［［１−メチル−３−（４−Ｎ，Ｎ−ジメ
チルアミノフェニル）ウレイド］メチル］ピリジン・三
塩酸塩
？点 １７３ − １７５℃
ＩＨ−ＮＭＲ（δｐＰ ｍ ’＋重ジメチルスルホキシ
ド中）３．０（６Ｈ， ｄ）， ３．１（１２Ｈ， ｓ
）， ４．８（４Ｈ， ｓ）元素分析値（Ｃ２■Ｎ３，
Ｎ７０，ＣＩ，として）実測値 Ｃ ： ５２．３１％
Ｈ：６．４５％ Ｎ：１５．７６％計算値 Ｃ ： ５
２．５６％Ｈ：６．５３％ Ｎ：１５．８９％実施例
２２
２，６−ビス［（１−メチル−３−フエニルウレイド）
メチル］ピリジン
融点 １５２ − １５３゜Ｃ
ＩＨ−ＮＭＲ（δＰ Ｐ ” ｒ 重クｏｏホＡ／ム中
）３．０（６Ｈ， ｄ）， ４．６（４Ｈ， ｓ），
７．８（ＩＨ， ｔ）元素分析値（ ０２３ Ｎ２ｓ
Ｎ！＋ ０２として）実測値 Ｃ ： ６８．５５％
Ｈ ： ６．２６％ Ｎ：１７．５０％計算値 Ｃ ：
６８．４７％ Ｉ｛ ： ６．２５％ Ｎ：１７．３
６％実施例 ２３
３，５−ビス［［１−シクロへキ７ル−３−（４−Ｎ，
Ｎ−ジメチルアミノフェニル）ウレイド］メチル］ピリ
ジン・三塩酸塩
ＩＲ（Ｃｍ−’， ＫＢｒ錠） １６５４， １５４０
， １．５２０’Ｈ−ＮＭＲ（δｐＰ ” ｒ重ジメチ
ルスルホキシド中）３．１（１２Ｈ， ｓ）， ４．８
（４Ｈ， ３）， ８．８（２Ｈ， ａ）Ｍａｓｓ （
Ｆ Ａ Ｂ ） ６２６ （ Ｍ＋ １ ）実施例
２４
２，６−ビス［［１−シクロへキシル−３−（−Ｎ，Ｎ
−ジメチルアミノフェニル）ウレイド］チル］ピリジン
・三塩酸塩
４
メ
ＩＲ（ｃｍ””， ＫＢｒ錠） １６４８， １５４０
． １５２２ＩＨ−ＮＭＲ（δｐＰ”＋重ジメチルスル
ホキシド中）３．１（１２Ｈ， ｓ）， ４．９（４Ｈ
， ｓ）， ８．２（ＩＨ， ｔ）Ｍａｓｓ（ＦＡＢ）
６２６（Ｍ＋１）実施例 ２５
３，５−ビス［（１−メチル−３
イド）メチル］ピリジン
フェニルウレ
ＩＲ（ａｍ−’， ＫＢｒ錠） １６４０， １５９８
． １５４０ＩＨ−ＮＭＲ（δＰ ｐｍ ｒ重ジメチル
スルホキシド中）３．０ （ ６Ｈ，ｓ ），４．９
（ ４Ｈ， ｓ ）＋ ８．２ （ ＩＨ，ｔ ）Ｍａ
ｓｓ （ ＦＡＢ ） ６２６ （Ｍ＋１ ）実施
例 ２６
２，６−ビス［ ［ ３ − （ ２，４．６ − ｝
リフルオ口フェニルノ−１−（２−プロビル）ウレイド
コメチル］ピリジン・一塩酸塩
２，６−ビス（Ｎ−シクロヘプチルアミノメチル）ピリ
ジン３７０ｆｆｌｇと２．４．６ − トリフルオロフ
エニルカルハミン酸フエニルエステル９４０ ｍｇ ヲ
５０ ｍｌのトルエンに溶かし，１時間加熱還流した。) Example 2 2,6-bis[[1-cycloheptyl-3-(2.4
-difluorophenyl)ureido] methylcopyridine/
Monohydrochloride/monohydrate Melting point 109-112°C 1H-NMR (δppm, in deuterium dimethyl sulfoxide)
1.2-1.9 (24H, m), 4.6 (4H,
s), 8.5 (2H, d) Elemental analysis value (C,,
H44N, O, C IF, as) Measured value C
: 6 0.5 6% H: 6.2 8% N: 1
0.13% theoretical value C: 6 0.5 6% H:
6.3 9% N: 10.09% Example 3 2,6-bis['1-methylphenyl) monohydrochloride cycloheptyl-3-(4 ureido]methyl]pyridine Melting point 145-146°C 'N-NMR ( δppm + in heavy dimethyl sulfoxide)
2.2 (6H, s), 4.7 (4H, s), 8
．． 0(IH, t) elemental analysis value (C,7H5ON,
02Cl) Actual measurement value C: 7 0.0 7%
H: 7.9 8% N: 10.84% Calculated value C
: 7 0.2 9% H: 7.9 2% N:
11.08% Example 4 2,6-bis[[1-cycloheptyl-3-(3nitrophenyl)ureido]methylcopyridine-hydrochloride Melting point 122-125°C +H-NMR (in δppmt deuterium dimethyl sulfoxide)
3.0 (6H, d), 4.6 (4H, s), 7
．． 8 (IH, t) elemental analysis value (”ss H44
N7 06 C 1) Actual measurement value C: 6 0.
5 1% H: 6.3 9% N: 14.03% Calculated value C: 6 0.5 5% H: 6.3 9
% N:, 14.12% Example 5 2.6-bis[[1-cycloheptyl-3-(4methoxyphenyl)ureido]methyl]pyridine Monohydrochloride IR (m-', KBr tablets) 1648, 1604.15
14'H-NMR (δppm, Ft in dimethyl sulfoxide) 3.7 (6H, ), 4.7 (4H.s),
8.0 (2H, d) Mass (FAB) 62
8(M+1) Example 6 3,5-bis[(1-cycloheptyl-3-phenylureido)methyl]pyridine Melting point 172-174°C 'H-NMR (δppm + in heavy DO form) 4.5 (
4H, s), 7.7 (IH, s), 8.
5 (2H, s) Elemental analysis value (C35 H45
N5 o2) Measured value C: 7 3.8 8%
H: 8.0 8% N: 12.24% theoretical value C
: 74.04% H: 7.9 9% N: 12.3
3% Example 7 3,5-bis[[1-cycloheptyl-3-(4-methylphenyl)ureido]methylcopyridine Melting point 157
-158°C 'H-NMR (δppm1! in chloroform) 2.3
(6H, s), 4.5 (4H, s), 7.5 (2H, s
) Elemental analysis value (C3? H4Q N5 02) Measured value C: 7 4.4 9% H: 8.2
2% N: 11.48% theoretical value C: 74.59%
H: 8.2 9% N: 11.75% Example 8 3.5-bis[(I-cyclohebutyl-3-methylureido)methyl]pyridine Melting point 187-188°C 'H-NMR (δPPml weight in chloroform) 2.8(
6H, s), 4.4 (4H, s), 8.4 (2
H, s) Elemental analysis value (C25 H41 N5 0
jl) Measured value C: 67.49% H: 9.2
1% N: 15.51% Theoretical value C: 6 7.6
9% H: 9.32% N: 15.79% Example 9 3,5-bis[[1-cycloheptyl-3-(2
．． 4-difluorophenyl)ureido]methyl]pyridine IR (cm-1, KBr tablets> 1642. 1521
．． 1433'H-NMR (δppmy in deuterochloroform) 4.5 (4H, s), 7.7 (4H, s), 8.5
2(2H,s)Mass(FAB) 640(M
+1) Example 10 3.5-bis[(1-cyclobutyl-3-cyclohexylureido)methyl]pyridine Melting point 180-181
°C 'H-NMR (δppm, in deuterium chloride form) 4.4 (
4H, s), 7.6(LH, s), 8.4(
2H, s) Elemental analysis value (C35 H57 N5
o2) Actual measurement value C: 7 2.8 6% H
: 9.8 2% N: 11.83% Calculated value C:
7 2.5 0% H: 9.9 1% N: 12.
08% Example 11 3,5-bis[[1-cyclohethypur-3-(4-N
, N-dimethylaminophenyl)ureido]methyl]pyridine Melting point 122-123°C 'H-NMR (δpI) in ml dimethyl sulfoxide) 2.9 (12H, s), 4.5 (4H, s),
8.5 (2I{, s) elemental analysis value (C3.H55
N? o2) Measured value C: 7 1.5 4
% H: 8.5 9% N: 14.83% theoretical value
C: 71.63% H: 8.4 8% N: 1
4.9 9% Example 12 2,6-bis[(1-cycloheptyl-3-methylureido)methylcopyridine IR (cWL-l, KBr tablets) 'H-NMR (δpPml in deuterium chloroform)3. 0(
6H, ! +), 4.6 (4H, d), 7.8 (
LH, t)Mass(FAB) 444(M
+1) Example 13 2.6-bis(1-cycloheptyl-3-cyclohexylureido)methyl]pyridine IR(art-'.
KBr tablet) 1646, 1616. 1514'H
-NMR (δpI) in ml deuterated chloroform) 4.6 (4
H, s), 7.3 (2H, d), 7.7 (IH
, t)Mass(FAB). 580 (M+1
) Melting point 179-180'C 'H-NMR (δp pm, in deuterated chloroform) 4.6
(4H, S), 7.4(2H, d), 7.7(
IH, t) Elemental analysis value (C31 H4? N5
02) Actual measurement value C: 7 2.5 7%}
I: 7.30% N: 13.37% Calculated value C: 7
2.7 7% H: 7.2 9% N: 1
3.6 9% Example 15 2,6-bis[[1-cyclopentyl-3-(4-difluorophenyl)ureidocomethyl]lysine 2, bis melting point 143-144°C H-NMR (δppm, dechloroform Medium) 4.6 (4
H, s), 7.3 (2H, d), 7.8 (IH
, t) Elemental analysis value (C31 H33 N5 o2
As F4) Actual measurement value C: 6 3.4 4% I{
: 5.7 7% N: 11.87% Calculated value C:
6 3.8 0% H: 5.7 0% N:
1 2.0 0% Example 16 3.5-pis[(1-cyclopentyl-3-phenylureido)methyl]pyridine Melting point 172-173°C IH-NMR (δppm in monochloroform) 4.6 (
4H, s), 7.4(2H, d), 7.7(I
H, t) Elemental analysis value (Cs+ H4? N5 0
2) Actual measurement value C: 7 2.5 7% H: 7
．． 30% N: 1 3.3 7% calculated value C:
7 2.7 7% H: 7.2 9% N: 13.
69% Example 17 3. 5-bis[[1-cyclopentyl-3-(
2.4-difluorophenyl)ureido]methyl]hyridine Melting point 131-132°C 'H-NMR (δppm, in deuterated chloroform) 4.6 (
41, s), 7.6 (2H, d), 8.5
(IH, t) Elemental analysis value (C31 H33
N5 02 F4) Actual measurement value C: 6 3.7
3% H: 5.6 8% N: 11.95% calculated value, C: 6 3.8 0% H: 5.7 0
% N: 12.0O% Example 18 2.6-bis[[3-phenyl-1-(2-probyl)
[Ureido] Methylcopyridine Melting point 187-188°C LH-NMR (δPI) m1 in dichloromethane form) t2 (
12H, d), 4.6(4H, a), 7.8(
IH, t) Elemental analysis value (C2, H,, N,
02) Actual measurement value C: 7 0.3 8% H:
7.28% N: 15.11% Calculated value C: 7 0
．． 5 6% H: 7.2 4% N: 15.24%
Example 19 2.6-bis[[minophenyl)monomethylcopyridine 3-(4-N,N-dimethylal-1-(2-probyl)ureido] Melting point 167-169°C 'H-NMR (δppm, deuterochloroform middle) 1.2(
12H”, d), 4.6 (4H, s), 7.8
(IH, t) Elemental analysis value (Cs+ H4t N?
02) Actual measurement value C: 6 8.2 2% H
: 7.7 9% N: 17.75% calculated value C: 6
8.23% H: 7.9 4% N: 17.97%
Example 20 3,5-bis[[1-(2-propyl)-3-7enylureidocomethylcopyridine Melting point 177-178°C'}I-NMR (δppm, in dichloromethane form) 1.2
(12H, d), 4.5 (4H, s), 7.7
(IH, t) Elemental analysis value (C2? H33 N5
o) Actual measured value C: 7 0.2 7% H
: 7.2 4% N: 15.19% Calculated value C:
7 0.5 6% H: 7.2 4% N:
1 5.2 4% Example 21 2,6-bis[[1-methyl-3-(4-N,N-dimethylaminophenyl)ureido]methyl]pyridine trihydrochloride? Point 173-175℃ IH-NMR (δpP m'+in deuterated dimethyl sulfoxide) 3.0 (6H, d), 3.1 (12H, s
), 4.8 (4H, s) elemental analysis value (C2■N3,
N70, CI, actual measurement value C: 52.31%
H: 6.45% N: 15.76% Calculated value C: 5
2.56% H: 6.53% N: 15.89% Example
22 2,6-bis[(1-methyl-3-phenylureido)
Methyl]pyridine Melting point 152 - 153°C IH-NMR (δP ''r in heavy gas) 3.0 (6H, d), 4.6 (4H, s),
7.8 (IH, t) elemental analysis value (023 N2s
N! +02) Actual value C: 68.55%
H: 6.26% N: 17.50% calculated value C:
68.47% I{ : 6.25% N: 17.3
6% Example 23 3,5-bis[[1-cyclohexyl-3-(4-N,
N-dimethylaminophenyl)ureido]methyl]pyridine trihydrochloride IR (Cm-', KBr tablets) 1654, 1540
, 1.520'H-NMR (δpP'' in deuterium dimethyl sulfoxide) 3.1 (12H, s), 4.8
(4H, 3), 8.8 (2H, a) Mass (
F A B ) 626 (M+1) Example
24 2,6-bis[[1-cyclohexyl-3-(-N,N
-dimethylaminophenyl)ureido]thyl]pyridine trihydrochloride 4mer IR (cm"", KBr tablets) 1648, 1540
．． 1522IH-NMR (δpP''+ in deuterated dimethyl sulfoxide) 3.1 (12H, s), 4.9 (4H
, s), 8.2(IH, t)Mass(FAB)
626(M+1) Example 25 3,5-bis[(1-methyl-3ido)methyl]pyridinephenylure IR (am-', KBr tablet) 1640, 1598
．． 1540IH-NMR (δP pm r in heavy dimethyl sulfoxide) 3.0 (6H,s), 4.9
(4H, s) + 8.2 (IH, t) Ma
ss (FAB) 626 (M+1) Example 26 2,6-bis [ [ 3 - ( 2,4.6 - }
370 fflg of 2,6-bis(N-cycloheptylaminomethyl)pyridine and phenyl 2.4.6-trifluorophenylcarhamate 940 mg of ester was dissolved in 50 ml of toluene and heated under reflux for 1 hour.
反応液を５０ｍ乙のＩＮ水酸化ナトリウム液で３回，５
０ｍｌの飽和塩化ナトリウム液で洗浄し，無水硫酸マグ
ネシウムで乾燥し，溶媒を留去した残渣に塩酸含有エタ
ノールを処理し得た固体を酢酸エチルから再結晶し，無
色粉末６３０ ｍｇを得た。The reaction solution was diluted with 50 m of IN sodium hydroxide solution 3 times, 5 times.
The solid was washed with 0 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the residue obtained by treating the residue with ethanol containing hydrochloric acid was recrystallized from ethyl acetate to obtain 630 mg of colorless powder.
融点 １２２−１２４゜Ｃ
’Ｈ−ＮＭＲ（δｐｐｍ，重クｏｏホルム中）１．２（
１２Ｈ， ｄ）， ４．７（４Ｈ， ！１）， ８．３
（ＩＨ， ｔ）元素分析値（ Ｃ，７Ｎ２，Ｎ，０２Ｃ
ｌとして）実測値 Ｃ ： ５４．０１％ Ｈ ： ４
，５９％ Ｎ：１１．５４％計算値 Ｃ ： ５３．６
９％ Ｈ：４．６７％ Ｎ：１１．６０％同様にして，
以下の化合物を合成した。Melting point 122-124°C 'H-NMR (δppm, in deuterium chloride form) 1.2 (
12H, d), 4.7 (4H, !1), 8.3
(IH, t) Elemental analysis value (C, 7N2, N, 02C
Actual value C: 54.01% H: 4
,59% N: 11.54% Calculated value C: 53.6
9% H: 4.67% N: 11.60% Similarly,
The following compounds were synthesized.
実施例 ２７
３，５−ビス［ ［ ３−（ ２，４．６ − ｝リフ
ルオ口フヱニル）−１−（２−プロビル）ウレイト］メ
チルコピリジン
融点 １２９ − １３０℃
ＩＨ−ＮＭＲ（δｐｐｍ，重クｏａボルム中）１．２（
１２Ｈ， ｄ）， ４．６（４Ｈ， ｓ）， ７．７（
ＬＨ， ｔ）元素分析値（ Ｃ２？ Ｎ２７ Ｎ５ ０
２ Ｆ６として）実測値 Ｃ：５８．１３％ Ｈ ：
４．９０％ Ｎ：１１．４７％計算値 Ｃ：５７．１４
％ Ｈ ： ４．８０％ Ｎ：１２．３４％実施例 ２
８
２，６−ビス［ ［ ３−（ ２．４．６−トリフルオ
口フェニル）−１−メチルウレイド］メチル］ピリジン
Ｉ Ｒ（ ｃｍ−’， ＫＢｒ錠）
’Ｈ−ＮＭＲ（δｌ’ ｐ” ＋重クｏｏホルム中）３
．０（６Ｈ， ｄ）， ４．６（４Ｈ， ｓ）， ７．
７（ＩＨ，Ｍａｓｓ（ＦＡＢ） ５１２（Ｍ＋１）
ｔ）
実施例
２９
２，６−ビス［［１
−ピリジルメチル）
（ ４
シクロヘプチル−３
ウレイド］メチル］ピリジン
ＩＲ（ｃｍ−’， ＫＢｒ錠） １６４４， １６０４
． １５３２’Ｈ−ＮＭＲ（δｐｐｍ，重クｏｏホ／Ｌ
’ ム中）４．３（４Ｈ， ｓ）， ４．４（４Ｈ，
ｄ）， ６．２（２Ｈ， ｔ），７．７（ＩＨ， ｄｄ
）
Ｍａｓｓ（ＦＡＢ） ５９８（Ｍ＋１）実施例 ３０
２，６−ビス［［１−シクロへプチル−３−（３ービリ
ジルメチル）ウレイド］メチルコピリジンＩＲ（ｃｍ−
’， ＫＢｒ錠） １６３８， １５８０． １５２６
ＩＨ−ＮＭＲ（δｐｐｍ，重クロロホルム中）４．２（
４Ｈ， ｓ）， ４．４（４Ｈ， ｄ）， ６．２（２
Ｈ， ｔ）Ｍａｓｓ（ＦＡＢ） ５９６（Ｍ−１）実
施例 ３１Example 27 3,5-bis[[3-(2,4.6-}refluorophenyl)-1-(2-propyl)ureate]methylcopyridine Melting point 129-130°C IH-NMR (δppm, heavy (in oa volume) 1.2 (
12H, d), 4.6(4H, s), 7.7(
LH, t) Elemental analysis value (C2? N27 N5 0
2 F6) Actual measurement value C: 58.13% H:
4.90% N: 11.47% Calculated value C: 57.14
% H: 4.80% N: 12.34% Example 2
8 2,6-bis[[3-(2.4.6-trifluorophenyl)-1-methylureido]methyl]pyridine I R (cm-', KBr tablet) 'H-NMR (δl'p" + Heavy Kuoo form) 3
．． 0 (6H, d), 4.6 (4H, s), 7.
7 (IH, Mass (FAB) 512 (M+1)
t) Example 29 2,6-bis[[1-pyridylmethyl)(4cycloheptyl-3 ureido]methyl]pyridine IR (cm-', KBr tablet) 1644, 1604
．． 1532'H-NMR (δppm, heavy coo/L
4.3 (4H, s), 4.4 (4H,
d), 6.2 (2H, t), 7.7 (IH, dd
) Mass (FAB) 598 (M+1) Example 30 2,6-bis[[1-cycloheptyl-3-(3-biridylmethyl)ureido]methylcopyridine IR (cm-
', KBr tablet) 1638, 1580. 1526
IH-NMR (δppm, in deuterated chloroform) 4.2 (
4H, s), 4.4 (4H, d), 6.2 (2
H, t) Mass (FAB) 596 (M-1) Example 31
Claims (4)
基；シクロアルキル基を Ｒ＾３、Ｒ＾４、Ｒ＾５及びＲ＾６は同一又は異なって
水素原子；低級アルキル基；シクロアルキル基；未置換
又は置換のフェニル基若しくはピリ ジル基；未置換又は置換のアラルキル基を、ｎ＿１及び
ｎ＿２は１乃至３の整数を意味する。）で示されるジウ
レア誘導体又はその塩。(1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2 are the same or different and are alkyl groups; cycloalkyl groups are R^3, R^4, R ^5 and R^6 are the same or different and represent a hydrogen atom; a lower alkyl group; a cycloalkyl group; an unsubstituted or substituted phenyl group or a pyridyl group; an unsubstituted or substituted aralkyl group; n_1 and n_2 are 1 to 3; means an integer) or a salt thereof.
の置換基が低級アルキル基、ハロゲン原子、ニトロ基、
アミノ基、モノ若しくはジ低級アルキルアミノ基、水酸
基又は低級アルコキシ基である請求項（１）記載のジウ
レア誘導体又はその塩。(2) The substituent of the phenyl group, pyridyl group, or aralkyl group is a lower alkyl group, a halogen atom, a nitro group,
The diurea derivative or salt thereof according to claim 1, which is an amino group, a mono- or di-lower alkylamino group, a hydroxyl group, or a lower alkoxy group.
−Ｎ，Ｎ−ジメチルアミノフェニル）ウレイド］メチル
］ピリジン又はその塩。(3) 2,6-bis[[1-cycloheptyl-3-(4
-N,N-dimethylaminophenyl)ureido]methyl]pyridine or a salt thereof.
４−Ｎ，Ｎ−ジメチルアミノフェニル）ウレイド］メチ
ル］ピリジン又はその塩。(4) 2,6-bis[[(1-cyclohexyl-3-(
4-N,N-dimethylaminophenyl)ureido]methyl]pyridine or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18704189A JPH0352861A (en) | 1989-07-19 | 1989-07-19 | Diurea derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18704189A JPH0352861A (en) | 1989-07-19 | 1989-07-19 | Diurea derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0352861A true JPH0352861A (en) | 1991-03-07 |
Family
ID=16199141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18704189A Pending JPH0352861A (en) | 1989-07-19 | 1989-07-19 | Diurea derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0352861A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005961A1 (en) * | 1996-08-01 | 1998-02-12 | Isis Pharmaceuticals, Inc. | Compounds having a plurality of nitrogenous substituents |
-
1989
- 1989-07-19 JP JP18704189A patent/JPH0352861A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005961A1 (en) * | 1996-08-01 | 1998-02-12 | Isis Pharmaceuticals, Inc. | Compounds having a plurality of nitrogenous substituents |
| US6077954A (en) * | 1996-08-01 | 2000-06-20 | Isis Pharmaceuticals, Inc. | Substituted heterocyclic compounds |
| US6197965B1 (en) | 1996-08-01 | 2001-03-06 | Isis Pharmaceuticals, Inc. | Compounds having a plurality of nitrogenous substituents |
| US6329523B1 (en) | 1996-08-01 | 2001-12-11 | Isis Pharmaceuticals, Inc. | Compounds having a plurality of nitrogenous substitutents |
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