JPH03157381A - Fluorine substituted allylamine derivative - Google Patents
Fluorine substituted allylamine derivativeInfo
- Publication number
- JPH03157381A JPH03157381A JP29565689A JP29565689A JPH03157381A JP H03157381 A JPH03157381 A JP H03157381A JP 29565689 A JP29565689 A JP 29565689A JP 29565689 A JP29565689 A JP 29565689A JP H03157381 A JPH03157381 A JP H03157381A
- Authority
- JP
- Japan
- Prior art keywords
- group
- ring
- formula
- lower alkyl
- atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 title claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 title claims description 10
- 229910052731 fluorine Inorganic materials 0.000 title claims description 8
- 239000011737 fluorine Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 10
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 8
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims abstract description 6
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 3
- -1 1,2-dithiolanyl group Chemical group 0.000 claims description 71
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 125000004434 sulfur atom Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001924 cycloalkanes Chemical class 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 231100000252 nontoxic Toxicity 0.000 claims description 8
- 230000003000 nontoxic effect Effects 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 4
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical group C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 3
- 125000005072 dihydrothiopyranyl group Chemical group S1C(CCC=C1)* 0.000 claims description 3
- 125000003838 furazanyl group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000005969 isothiazolinyl group Chemical group 0.000 claims description 3
- 125000003971 isoxazolinyl group Chemical group 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 3
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 2
- 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 45
- 238000002360 preparation method Methods 0.000 abstract description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract 1
- 239000005977 Ethylene Substances 0.000 abstract 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 102000005782 Squalene Monooxygenase Human genes 0.000 description 11
- 108020003891 Squalene monooxygenase Proteins 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101001056878 Homo sapiens Squalene monooxygenase Proteins 0.000 description 3
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 239000003529 anticholesteremic agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 239000007788 liquid Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 2
- OOLYZFSILFGXCC-GQCTYLIASA-N (e)-1-bromo-6,6-dimethylhept-2-en-4-yne Chemical compound CC(C)(C)C#C\C=C\CBr OOLYZFSILFGXCC-GQCTYLIASA-N 0.000 description 2
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 108010017796 epoxidase Proteins 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 229940031439 squalene Drugs 0.000 description 2
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- QYIMSPSDBYKPPY-RSKUXYSASA-N (S)-2,3-epoxysqualene Chemical group CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CC[C@@H]1OC1(C)C QYIMSPSDBYKPPY-RSKUXYSASA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZPCJPJQUVRIILS-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)benzene Chemical compound BrCC1=CC=CC(Br)=C1 ZPCJPJQUVRIILS-UHFFFAOYSA-N 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- IYKDLGIJFOZFGY-UHFFFAOYSA-N 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)OCC(F)(F)F IYKDLGIJFOZFGY-UHFFFAOYSA-N 0.000 description 1
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical group N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 1
- FCAJYRVEBULFKS-UHFFFAOYSA-N 2-(oxolan-2-yl)ethanol Chemical compound OCCC1CCCO1 FCAJYRVEBULFKS-UHFFFAOYSA-N 0.000 description 1
- YRRZGBOZBIVMJT-UHFFFAOYSA-N 2-fluoroethanamine;hydron;chloride Chemical compound Cl.NCCF YRRZGBOZBIVMJT-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- PBEJTRAJWCNHRS-UHFFFAOYSA-N 2-phenylmethoxybenzaldehyde Chemical compound O=CC1=CC=CC=C1OCC1=CC=CC=C1 PBEJTRAJWCNHRS-UHFFFAOYSA-N 0.000 description 1
- VLPAVSIRLRIOPD-UHFFFAOYSA-N 3-[(3-bromophenyl)methoxy]benzaldehyde Chemical compound BrC1=CC=CC(COC=2C=C(C=O)C=CC=2)=C1 VLPAVSIRLRIOPD-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000021910 Cerebral Arterial disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000233866 Fungi Species 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- NGEVNHYPVVOXPB-UHFFFAOYSA-N Isopyrocalciferolacetat Natural products C1C(OC(C)=O)CCC2(C)C(CCC3(C(C(C)C=CC(C)C(C)C)CCC33)C)C3=CC=C21 NGEVNHYPVVOXPB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- NGEVNHYPVVOXPB-SPRPGQCRSA-N O-acetyl-ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@@H]2C3=CC=C4C[C@H](CC[C@]4(C)[C@@H]3CC[C@]12C)OC(=O)C NGEVNHYPVVOXPB-SPRPGQCRSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- NGEVNHYPVVOXPB-RZZBNZQCSA-N [(3s,9s,10r,13r,14r,17r)-17-[(e,2r,5r)-5,6-dimethylhept-3-en-2-yl]-10,13-dimethyl-2,3,4,9,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1[C@@H](OC(C)=O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 NGEVNHYPVVOXPB-RZZBNZQCSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 230000002484 anti-cholesterolemic effect Effects 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- KBLGHTAYBGZYEU-UHFFFAOYSA-N benzyl(cyanato)phosphinic acid Chemical compound N#COP(=O)(O)CC1=CC=CC=C1 KBLGHTAYBGZYEU-UHFFFAOYSA-N 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
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 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
- 239000002552 dosage form Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000019622 heart disease Diseases 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
- 150000004678 hydrides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000002808 molecular sieve Substances 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
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 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
- 150000004867 thiadiazoles Chemical group 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- BCAFYQWNCAXPRR-UHFFFAOYSA-N tributyl(thiophen-3-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=1C=CSC=1 BCAFYQWNCAXPRR-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
良果よ二且里分立
本発明は新規な置換アリルアミン誘導体に関し、更に詳
しくは、医薬の分野、特には、哺乳動物のスクアレン・
エポキシダーゼを選択的に阻害し、且つ、高コレステロ
ール血症、高脂血症ひいては動脈硬化症の治療及び予防
の分野で有用な置換アリルアミン誘導体及びその無毒性
塩、並びにその用途に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted allylamine derivatives, and more particularly, to the field of medicine, particularly to mammalian squalene.
The present invention relates to substituted allylamine derivatives and nontoxic salts thereof, which selectively inhibit epoxidase and are useful in the fields of treatment and prevention of hypercholesterolemia, hyperlipidemia, and arteriosclerosis, and uses thereof.
従来ユ挾■
近年、人口の高齢化及び食生活の変化等により、勧誘硬
化症並びにそれに伴う各棟冠及び脳動脈系疾患の発生頻
度の増加が指摘されている。この動脈硬化症の発生には
各種の要因が考えられているが、特には、血中コレステ
ロールの増加が最も主要な危険因子の1つである。事実
、各種の作用機序を有する血中コレステa−ル低下剖が
開発され、既に、その一部は臨床的にも応用されている
[エイジエンツ・ユーズド・ツー・トリート・ハイバー
リビデミイア、ドラッグ・エバリュエイションズ・シッ
クス・エデイジョン(Agents Used to
TreatHyper−1ipide11ia、Dru
g Evaluations 6th、editi
on)903−926(1986)]、また、これらコ
レステロール低下剤の中では、生体内に於けるコレステ
ロールの生合成阻害剤が、その明確な作用機序と切れ味
の鋭さで高い評価を受けている[プロシーディング・ナ
ショナル・アカデミ−・サイエンス(Proc、Nat
l。In recent years, due to the aging of the population and changes in dietary habits, it has been pointed out that the frequency of induced sclerosis and associated coronary and cerebral arterial diseases has increased. Although various factors are thought to be responsible for the occurrence of arteriosclerosis, one of the most important risk factors is an increase in blood cholesterol. In fact, blood cholesterol-lowering treatments with various mechanisms of action have been developed, and some of them have already been applied clinically [Ageents Used-to-Treat Hyperlibidemia, Drugs]・Evaluations Sixth Edition (Agents Used to
TreatHyper-1ipide11ia, Dru
g Evaluations 6th, edition
On) 903-926 (1986)] Among these cholesterol-lowering drugs, in vivo cholesterol biosynthesis inhibitors are highly evaluated for their clear mechanism of action and sharpness. [Proceeding National Academy of Sciences (Proc. Nat.
l.
Acad、Scf、 )、77.3957(1980)
]。Acad, Scf, ), 77.3957 (1980)
].
しかし、現在知られているコレステロール生合成阻害剤
は、コレステロール生合成過程の初期あるいは後期の阻
害剤であるため、コレステロールの合成を阻害すると同
時に生理的に重要な種々の代謝物の生成をも抑制し、ま
た阻害により生じる代謝物自体が他の疾病の原因となる
等の問題点を有する。However, currently known cholesterol biosynthesis inhibitors are inhibitors of early or late stages of the cholesterol biosynthesis process, so they inhibit cholesterol synthesis and at the same time suppress the production of various physiologically important metabolites. However, there are also problems in that the metabolites produced by inhibition themselves may cause other diseases.
本発明者等は、先に、一連の置換アリルアミン誘導体が
哺乳動物のコレステロール生合成系の中期に位置するス
クアレン・エポキシダーゼを選択的に阻害し、その結果
、既存のコレステロール生合成阻害剤とは全く異なる作
用機序を有する新たな高コレステロール血症、高脂血症
ひいては動脈硬化症の治療及び予防剤として有用である
ことを報告した【特願昭63−296840 、欧州特
許公開318860号]、なお、補乳動物のスクアレン
・エポキシダーゼ阻害剤については1本発明者等に係わ
る報告以外にも最近いくつかの報告が見られるが、それ
らは全て選択性や活性が著しく低い[ジャーナル・オブ
・ケミカル・リサーチ・シップセス(J、Chem。The present inventors previously demonstrated that a series of substituted allylamine derivatives selectively inhibited squalene epoxidase, which is located in the middle stage of the cholesterol biosynthesis system in mammals, and as a result, they were found to be different from existing cholesterol biosynthesis inhibitors. reported that it is useful as a new therapeutic and preventive agent for hypercholesterolemia and hyperlipidemia, as well as arteriosclerosis, which has a completely different mechanism of action (Japanese Patent Application No. 63-296840, European Patent Publication No. 318860); There have been several recent reports on squalene epoxidase inhibitors for mammalian mammals in addition to the report by the present inventors, but all of them have extremely low selectivity and activity [Journal of Chemical Research Shipses (J, Chem.
Re5earch(S))、 18−19(1988)
:ジャーナル・オブ・ジ・アメリカン・ケミカル・ソサ
エティ(J、Am、Chem。Re5search (S)), 18-19 (1988)
: Journal of the American Chemical Society (J, Am, Chem.
5OC−)lυユ、 1508−1510(1989)
;ジャーナル・オブ・メデイシナル・ケミストリー(J
、Med、Chem、)、32.2152−2158(
1989);特開昭64−3144号公報]。5OC-) lυyu, 1508-1510 (1989)
; Journal of Medicinal Chemistry (J
, Med, Chem, ), 32.2152-2158 (
1989); JP-A-64-3144].
明が しようとする課題
本発明の主たる目的の1つは、既存の抗コレステロール
剤に比べて、より安全性が高く、且つ、優れたコレステ
ロール生合成阻害作用を有する抗高コレステロール血症
剤、抗高脂血症剤ひいては動脈硬化症の治療及び予彷剤
を提供せんとするものである。One of the main objects of the present invention is to provide an anti-hypercholesterolemic agent and an anti-hypercholesterolemic agent that is safer than existing anti-cholesterol agents and has an excellent cholesterol biosynthesis inhibitory effect. The present invention aims to provide a hyperlipidemic agent and, in turn, a therapeutic and prognostic agent for arteriosclerosis.
課題を 決するための手段
本発明者等は、先に、一連の置換アリルアミン誘導体が
、哺乳動物のスクアレン・エポキシダーゼを選択的に阻
害し、且つ、強力な抗コレステロール作用を有すること
を報告した[特願昭63−296840、欧州特許公開
318860号]、今回、更に鋭意研究を重ねた結果、
下記一般式[!]で表される、窒素原子上にフッ素化ア
ルキル基を有する置換アリルアミン誘導体が、先に報告
した化合物群に比べて更に優れた薬効及び安全性を有す
ることを発見し、本発明を完成した。Means for Solving the Problem The present inventors have previously reported that a series of substituted allylamine derivatives selectively inhibit squalene epoxidase in mammals and have strong anticholesterolemic effects [ Patent Application No. 63-296840, European Patent Publication No. 318860], as a result of further intensive research,
The following general formula [! ] It was discovered that substituted allylamine derivatives having a fluorinated alkyl group on the nitrogen atom have superior medicinal efficacy and safety compared to the previously reported compound group, and the present invention was completed.
即ち、本発明は一般式
[式中、A゛及びA′は同−又は異なってメチン基、窒
素原子、酸素原子又は硫黄原子を示し;Q″及びQ″は
同−又は異なって窒素原子、酸素原子及び硫黄原子から
なる群から選ばれる1個又は2個のへテロ原子を含んで
いてもよく、且つ、隣接する炭素原子及びA’又はA1
と共に5員又は6員の芳香環を形成する基を示し;X及
びYは同−又は異なっていてもよく、各々、酸素原子、
硫黄原子、カルボニル基1式ニーCHRa−(ここで、
)(aは水素原子又は低級アルキル基を示す)で表され
る基又は式ニーNRb−(ここで、Rhは水素原子又は
低級アルキル基を示す)で表される基を示すか、或いは
X及びYの両者が一緒になってビニレン基若しくはエチ
ニレン基を示し;R゛は窒素原子、酸素原子及び硫黄原
子からなる群から選ばれる1個〜4個のへテロ原子を含
む5員又は6員の複素環基を示し;R′はフッ素原子を
有する低級アルキル基を示し、R”及びR′は同−又は
異なって低級アルキル基を示すか、或いは両者が結合し
て隣接する炭素原子と共にシクロアルカンを形成する基
を示し;R6は水素原子、低級アルキル基又は低級アル
コキシ基を示し;R1及びR2は同−又は異なって水素
原子、ハロゲン原子、水酸基、シアノ基、低級アルキル
基又は低級アルコキシ基を示す、但し、X及びYのどち
らか一方が酸素原子、硫黄原子又は式ニーNRb−(こ
二で、Hbは前記の意味を有する)で表される基を示す
場合、他方はカルボニル基又は式ニーCl1Ra−(こ
こで、Raは前記の意味を有する)で表される基を示す
]で表される置換アリルアミン誘導体及びその無毒性塩
、その製造法並びに高コレステロール血症、高脂血症及
び動脈硬化症の処置におけるその用途を提供するもので
ある。That is, the present invention relates to the general formula [wherein A'' and A' are the same or different and represent a methine group, a nitrogen atom, an oxygen atom, or a sulfur atom; Q'' and Q'' are the same or different and represent a nitrogen atom, may contain one or two heteroatoms selected from the group consisting of oxygen atoms and sulfur atoms, and adjacent carbon atoms and A' or A1
X and Y may be the same or different, and each represents an oxygen atom,
A sulfur atom, a carbonyl group 1 CHRa- (where,
) (a represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NRb- (where Rh represents a hydrogen atom or a lower alkyl group), or X and Both Y together represent a vinylene group or an ethynylene group; Represents a heterocyclic group; R' represents a lower alkyl group having a fluorine atom, R'' and R' are the same or different and represent a lower alkyl group, or both combine to form a cycloalkane together with adjacent carbon atoms. R6 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group; R1 and R2 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group or a lower alkoxy group; However, when either X or Y represents an oxygen atom, a sulfur atom, or a group represented by the formula NRb- (where Hb has the above meaning), the other is a carbonyl group or a group represented by the formula Substituted allylamine derivatives represented by Cl1Ra- (wherein Ra has the above meaning) and non-toxic salts thereof, methods for producing the same, and hypercholesterolemia, hyperlipidemia and It provides its use in the treatment of arteriosclerosis.
次に、この明細書の記載において言及される各種用語の
定義及びその具体的な例について説明する。Next, definitions of various terms mentioned in the description of this specification and specific examples thereof will be explained.
[低級]なる語は、この語が付された基又は化合物の炭
素数が6個以下、好ましく4個以下であることを意味す
るのに用いる。従って、低級アルキル基としては、例え
ばメチル基、エチル基、プロピル基、イソプロピル基、
ブチル基、イソブチル基、5ec−ブチル基、tert
−ブチル基、ペンチル基、イソペンチル基、ネオペンチ
ル基、ヘキシル基等の炭素数1〜6個の直鎖又は分岐状
のアルキル基が挙げられ、また、低級アルコキシ基とし
ては、好ましくはメトキシ基、エトキシ基、ブロボキシ
基、イソプロポキシ基、ブトキシ基、イソブトキシ基、
5ee−ブトキシ基又はtert−ブトキシ基等の炭素
数1〜4個の直鎖又は分岐状のアルコキシ基が挙げられ
る。シクロアルカンとは炭素数3〜6個のシクロアルカ
ンを意味し、具体的にはシクロプロパン、シクロブタン
、シクロペンタン又はシクロヘキサンが挙げられる。ハ
ロゲン原子とは、フッ素原子、塩素原子、臭素原子又は
ヨウ素原子を意味する。The term [lower] is used to mean that the group or compound to which this term is attached has 6 or less carbon atoms, preferably 4 or less carbon atoms. Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group,
butyl group, isobutyl group, 5ec-butyl group, tert
- Straight chain or branched alkyl groups having 1 to 6 carbon atoms such as butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, etc. are mentioned, and lower alkoxy groups are preferably methoxy group, ethoxy group, etc. group, broboxy group, isopropoxy group, butoxy group, isobutoxy group,
Examples include straight chain or branched alkoxy groups having 1 to 4 carbon atoms such as 5ee-butoxy group and tert-butoxy group. Cycloalkane means a cycloalkane having 3 to 6 carbon atoms, and specifically includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
次に、前訂一般式[I]で表される本発明の化合物をさ
らに具体的に開示するため、式[+]に於いて用いられ
る各種記号につき、その好適な具体例を挙げて更に詳細
に説明する。Next, in order to more specifically disclose the compound of the present invention represented by the previously revised general formula [I], preferred specific examples of various symbols used in the formula [+] will be given in further detail. Explain.
R“で示されうる窒素原子、酸素原子及び硫黄原子から
なる群から選ばれる1個〜4個のへテロ原子を含む5員
又は6員の複素環基としては、例えばピロリル基、フリ
ル基、チエニル基、オキサシリル基、イソオキサシリル
基、チアゾリル基、インチアゾリル基、イミダゾリル基
、ピラゾリル基、オキサジアゾリル基、チアジアゾリル
基、ドリアゾリル基、テトラゾリル基、フラザニル基、
ピリジル基、ピリダジニル基、ピリミジニル基、ピラジ
ニル基、トリアジニル基等の芳香族複素環基、例えばジ
ヒドロチエニル基、テトラヒドロチエニル基、ピロリニ
ル基、ピロリジニル基、オキサゾリニル基、オキサゾリ
ジニル基、イソオキサゾリニル基、インオキサゾリジニ
ル基、チアゾリニル基、チアゾリジニル基、イソチアゾ
リニル基、イソチアゾリジニル基、1.2−ジチアニル
基、1.3−ジチオラニル基、1.2−ジチオリル基、
1.3−ジチアニル基、ジヒドロチオピラニル基、テト
ラヒドロチオピラニル基、1.4−ジチアニル基、1.
4−ジチイニル基、1.4−オキサチイニル基又はチオ
モルホリニル基等の非芳香族複素環基等が挙げられ、二
のうち、チエニル基、ピロリル基、オキサシリル基。Examples of the 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom that can be represented by R" include a pyrrolyl group, a furyl group, thienyl group, oxasilyl group, isoxasilyl group, thiazolyl group, inthiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, doriazolyl group, tetrazolyl group, furazanyl group,
Aromatic heterocyclic groups such as pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, such as dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, in Oxazolidinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1,2-dithianyl group, 1.3-dithiolanyl group, 1.2-dithiolyl group,
1.3-dithianyl group, dihydrothiopyranyl group, tetrahydrothiopyranyl group, 1.4-dithianyl group, 1.
Examples include non-aromatic heterocyclic groups such as 4-dithienyl group, 1,4-oxathiinyl group, and thiomorpholinyl group, among which are thienyl group, pyrrolyl group, and oxacylyl group.
イソオキサシリル基、チアゾリル基、イソチアゾリル基
、イミダゾリル基、ピリジル基又はジヒドロチエニル基
等が好ましく、更に、特には、3−チエニル基、l−ピ
ロリル基、5−オキサシリル基、4イソオキサシリル基
、5−イソオキサシリル基、4−チアゾリル基、5−チ
アゾリル基、3−イソチアゾリル基、4−インチアゾリ
ル基、5−イソチアゾリル基、3−ピリジル基、2,3
−ジヒドロ−4−チエニル基、2.5−ジヒドロ−3−
チエニル基等が好ましい。An isoxasilyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyridyl group or a dihydrothienyl group are preferred, and more particularly a 3-thienyl group, a l-pyrrolyl group, a 5-oxasilyl group, a 4-isoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-inchazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3
-dihydro-4-thienyl group, 2,5-dihydro-3-
A thienyl group and the like are preferred.
X及びYは、前述のとおり、同−又は異なっていてもよ
く、各々、酸素原子、硫黄原子、カルボニル基、式ニー
C)lRa−(ここで Haは水素原子又は低級アルキ
ル基を示す)で表される基又は式ニーNRb(ここで
Hbは水素原子又は低級アルキル基を示す)で表される
基を示すか、或いはX及びYが一緒になってビニレン基
若しくはエチニレン基を示し、但し、X及びYのどちら
か一方が酸素原子、硫黄原子又は式ニーNRb−で示さ
れる基を示す場合、他方はカルボニル基又は式ニーCH
Ra−で示される基を示すが、式ニーx−y−で示され
る基としては、具体的ニル、式ニー(C1(Ra)、−
、−CHRao−、−0CHRa−−C)l]’1aS
−1−3CHRa−、−CHRaNRb−、−NRbC
HRa−−CHRaCO−1−COCI(I’la−、
−COO−、−0CO−、−〇O5−1−5CD−1−
CONRb−、−NRbCO−、−C)I=C11−1
−CミC−C式中、Ha及びHbは前記の意味を有する
)で表される基を意味し、このうち、特に、エチレン基
、(E)ビニレン基、式ニーCH,O−で表される基、
式ニー0CI−1゜で表される基、式: −C)I 、
S−で表される基、式−5CH,−で表される基、式
ニーCH,Nトで表される基若しくは式ニーN)ICH
t−で表される基が好ましい。As described above, X and Y may be the same or different, and each is an oxygen atom, a sulfur atom, a carbonyl group, or a compound of the formula C)lRa- (where Ha represents a hydrogen atom or a lower alkyl group). The group or formula represented by NRb (where
Hb represents a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or ethynylene group, provided that either X or Y is an oxygen atom, When a sulfur atom or a group of the formula NRb- is represented, the other is a carbonyl group or a group of the formula CH
This refers to a group represented by Ra-, but examples of groups represented by the formula x-y- include specific groups such as nyl, the formula nyl (C1(Ra), -
, -CHRao-, -0CHRa--C)l]'1aS
-1-3CHRa-, -CHRaNRb-, -NRbC
HRa--CHRaCO-1-COCI(I'la-,
-COO-, -0CO-, -〇O5-1-5CD-1-
CONRb-, -NRbCO-, -C)I=C11-1
-CmiC-C In the formula, Ha and Hb have the above-mentioned meanings), and among these, in particular, ethylene group, (E) vinylene group, The group to be
A group represented by the formula: -C)I,
A group represented by S-, a group represented by the formula -5CH, -, a group represented by the formula CH, N, or a group represented by the formula N)ICH
A group represented by t- is preferred.
R’はフッ素原子を有する低級アルキル基を示し、好ま
しいフッ素原子を有する低級アルキル基の例としては、
ジフルオロメチル基、トリフルオロメチル基、1−フル
オロエチル基、2−フルオロエチル基、1.1−ジフル
オロエチル基、1.2−ジフルオロエチル基、2.2−
ジフルオロエチル基、2,2.2−トリフルオロエチル
基、3−フルオロプロピル基、2,2−ジフルオロプロ
ピル基、2−フルオロ−1−メチルエチル基、3,3.
3−トリフルオロ−1−メチルエチル基、4−フルオロ
ブチル基、5−フルオロペンチル基等の1〜3個のフッ
素原子を有する炭素数1〜5個の直鎖又は分岐状の低級
アルキル基を挙げることができる。R' represents a lower alkyl group having a fluorine atom, and examples of preferable lower alkyl groups having a fluorine atom include:
Difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1.1-difluoroethyl group, 1.2-difluoroethyl group, 2.2-
Difluoroethyl group, 2,2.2-trifluoroethyl group, 3-fluoropropyl group, 2,2-difluoropropyl group, 2-fluoro-1-methylethyl group, 3,3.
A linear or branched lower alkyl group having 1 to 5 carbon atoms and having 1 to 3 fluorine atoms such as 3-trifluoro-1-methylethyl group, 4-fluorobutyl group, 5-fluoropentyl group, etc. can be mentioned.
Ro及びRoは同−又は異なって低級アルキル基を示す
か、或いは両者が結合して隣接する炭素原子と共にシク
ロアルカンを形成する基を示し、好ましい低級アルキル
基としては1例えばメチル基、エチル基、プロピル基又
はブチル基等の炭素数1〜4個の直鎖の低級アルキル基
を挙げることができ、また好ましいシクロアルカンとし
ては、例えばシクロプロパン、シクロブタン、シクロペ
ンタン又はシクロヘキサン等の炭素数3〜6個のシクロ
アルカンを挙げることができる。 このうち、特に、R
1及びR4の置換基としては、メチル基、エチル基、プ
ロピル基又は隣接する炭素原子と共にシクロプロパン環
を形成する基が好ましく、更にメチル基が最も好ましい
、R1は水素原子、低級アルキル基又は低級アルコキシ
基を示し、好ましい低級アルキル基としては、例えばメ
チル基、エチル基、プロピル基、イソプロピル基、ブチ
ル基。Ro and Ro are the same or different and represent a lower alkyl group, or a group in which both are bonded together to form a cycloalkane with adjacent carbon atoms, and preferred lower alkyl groups include 1, such as methyl group, ethyl group, Examples include linear lower alkyl groups having 1 to 4 carbon atoms such as propyl or butyl groups, and preferred cycloalkanes include 3 to 6 carbon atoms such as cyclopropane, cyclobutane, cyclopentane or cyclohexane. cycloalkanes can be mentioned. Among these, especially R
The substituents for 1 and R4 are preferably methyl, ethyl, propyl, or groups that form a cyclopropane ring together with adjacent carbon atoms, and most preferably methyl. R1 is a hydrogen atom, a lower alkyl group, or a lower alkyl group. It represents an alkoxy group, and preferred lower alkyl groups include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.
イソブチル基、5ee−ブチル基、tert−ブチル基
又はペンチル基等の炭素数1〜5個の直鎖又は分岐状の
低級アルキル基を挙げることができ、好ましい低級アル
コキシ基としては、メトキシ基、エトキシ基、プロポキ
シ基、イソプロポキシ基、ブトキシ基、インブトキシ基
、5ee−ブトキシ基又はtert−ブトキシ基等の炭
素数1〜4個の直鎖又は分岐状のアルコキシ基が挙げら
れる。このうち、特に、メチル基、エチル基、プロピル
基、イソプロピル基、メトキシ基、エトキシ基、プロポ
キシ基又はイソプロポキシ基が好ましく、更にメチル基
、エチル基又はメトキシ基が最も好ましい。Examples include linear or branched lower alkyl groups having 1 to 5 carbon atoms such as isobutyl group, 5ee-butyl group, tert-butyl group, and pentyl group. Preferred lower alkoxy groups include methoxy group and ethoxy group. Examples include straight-chain or branched alkoxy groups having 1 to 4 carbon atoms, such as a propoxy group, an isopropoxy group, a butoxy group, an inbutoxy group, a 5ee-butoxy group, or a tert-butoxy group. Among these, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, or isopropoxy group is particularly preferred, and methyl group, ethyl group, or methoxy group is most preferred.
環としては、同−又は異なってベンゼン環、ピロール環
、フラン環、チオフェン環、オキサゾール環、インオキ
サゾール環、チアゾール環、イソチアゾール環、イミダ
ゾール環、1,3.4−オキサジアゾール環、1,3.
4−チアジアゾール環、ピリジン環、ピリダジン環、ピ
リミジン環、ピラジン環又はトリアジン環等の窒素原子
、酸素原子及び硫黄原子からなる群から選ばれる1個〜
3個のへテロ原子を含んでいてもよい芳香環であること
が好ましく、ベンゼン環又はチオフェン環が特に好まし
い。Examples of the rings include benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, inoxazole ring, thiazole ring, isothiazole ring, imidazole ring, 1,3.4-oxadiazole ring, 1 ,3.
4-Thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, etc., one or more selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom
An aromatic ring which may contain 3 heteroatoms is preferred, and a benzene ring or a thiophene ring is particularly preferred.
また、該芳香環は、通常無置換の場合が最も好ましいが
、場合により、ハロゲン原子、水酸基、シアノ基、低級
アルキル基又は低級アルコキシ基等の置換基で置換され
ていてもよく、それ等の置換基の例としては1例えば水
酸基、フッ素原子。Further, the aromatic ring is usually most preferably unsubstituted, but in some cases, it may be substituted with a substituent such as a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. Examples of substituents include 1, such as hydroxyl group and fluorine atom.
塩素原子、メチル基、エチル基、メトキシ基等が挙げら
れる。Examples include a chlorine atom, a methyl group, an ethyl group, a methoxy group, and the like.
かくして1本発明により提供される化合物において、好
適な例としては、R1がピロリル基、フリル基、チエニ
ル基、オキサシリル基、インオキサシリル基、チアゾリ
ル基、イソチアゾリル基、イミダゾリル基、ピラゾリル
基、オキサジアゾリル基、チアジアゾリル基、トリアゾ
リル基、テトラゾリル基、フラザニル基、ピリジル基、
ピリダジニル基、ピリミジニル基、ピラジニル基、トリ
アジニル基、ジヒドロチエニル基、テトラヒドロチエニ
ル基、ピロリニル基、ピロリジニル基、オキサゾリニル
基、オキサゾリジニル基、イソオキサゾリニル基、イソ
オキサゾリジニル基、チアゾリニル基、チアゾリジニル
基、イソチアゾリニル基、インチアゾリジニル基、l、
2−ジチオラニル基、l。Thus, in the compound provided by the present invention, preferred examples include R1 being a pyrrolyl group, a furyl group, a thienyl group, an oxasilyl group, an inoxasilyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, or an oxadiazolyl group. , thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group, pyridyl group,
Pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group , isothiazolinyl group, inthiazolidinyl group, l,
2-dithiolanyl group, l.
3−ジチオラニル基、1,2−ジチオリル基、1.3−
ジチオリル基、ジヒドロチオピラニル基、テトラヒドロ
チオピラニル基、1.4−ジチアニル基、1,4−ジチ
アニル基、1.4−オキサチイニル基又はチオモルホリ
ニル基であり;
る5員又は6員の芳香環が同−又は異なってベンゼン環
、ビロール環、フラン環、チオフェン環、オキサゾール
環、イソオキサゾール環、チアゾール環、イソチアゾー
ル環、イミダゾール環、l、3゜4−オキサジアゾール
環、l 、3.4−チアジアゾール環、ピリジン環、ピ
リダジン環、ピリミジン環、ピラジン環又はトリアジン
環であり;X及びYが同一又は異なっていてもよく、各
々、酸素原子、硫黄原子、カルボニル基、式ニーCHR
a−(ここで、Raは水素原子又は低級アルキル基を示
す)で表される基又は式ニーNRb−(ここで Hbは
水素原子又は低級アルキル基を示す)で表される基であ
るか、或いはX及びYの両者が一緒になってビニレン基
若しくはエチニレン基[但し、X及びYのどちらか一方
が酸素原子、硫黄原子又は式ニーNRb−(ここで、)
(bは前記の意味を有する)で表される基を示す場合、
他方はカルボニル基又は式ニーCHRa−(ここで H
aは前記の意味を有する)で表される基である]であり
;R1がフッ素原子を有する低級アルキル基であり;R
’及びR4が同−又は異なって低級アルキル基であるか
、或いは両者が結合して隣接する炭素原子と共にシクロ
アルカンを形成する基であり:R@が水素原子、低級ア
ルキル基又は低級アルコキシ基であり:R°及びR′が
同−又は異なって水素原子、ハロゲン原子、水酸基、シ
アノ基、低級アルキル基又は低級アルコキシ基である前
記一般式[Hの置換アリルアミン誘導体が挙げられる。3-dithiolanyl group, 1,2-dithiolyl group, 1.3-
A 5- or 6-membered aromatic ring that is a dithiolyl group, a dihydrothiopyranyl group, a tetrahydrothiopyranyl group, a 1,4-dithianyl group, a 1,4-dithianyl group, a 1,4-oxathiinyl group, or a thiomorpholinyl group; are the same or different and are benzene ring, virol ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, l, 3°4-oxadiazole ring, l, 3. 4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring;
a- (wherein Ra represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NRb- (wherein Hb represents a hydrogen atom or a lower alkyl group); Or, both X and Y are combined to form a vinylene group or an ethynylene group [provided that one of X and Y is an oxygen atom, a sulfur atom, or a compound of the formula NRb- (herein)
When a group represented by (b has the above meaning),
The other is a carbonyl group or has the formula CHRa- (where H
a is a group represented by the above meaning); R1 is a lower alkyl group having a fluorine atom; R
' and R4 are the same or different lower alkyl groups, or both are bonded together to form a cycloalkane with adjacent carbon atoms: R@ is a hydrogen atom, a lower alkyl group, or a lower alkoxy group; Yes: Examples include substituted allylamine derivatives of the general formula [H] in which R° and R' are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group.
これらの群の中では、式
又はチオフェン環であるものが好ましく、更には、R′
がチエニル基、ピロリル基、オキサシリル基、イソオキ
サシリル基、チアゾリル基、イソチアゾリル基、イミダ
ゾリル基、ピリジル基又はジヒドロチエニル基であり;
式:
芳香環がベンゼン環、ビロール環、フラン環、チオフェ
ン環、オキサゾール環、イソオキサゾール環、チアゾー
ル環、イソチアゾール環、イミダゾール環、1,3.4
−オキサジアゾール環、1..3.4−チアジアゾール
環、ピリジン環、ピリダジン環、ピリミジン環、ピラジ
ン環又はトリアジン環であるものが好ましく、このうち
、特に、R’が3−チエニル基、l−ピロリル基、5−
オキサシリル基、4−インオキサシリル基、5−イソオ
キサシリル基、4−チアゾリル基、5−チアゾリル基、
3−インチアゾリル基、4−イソチアゾリル基、5−イ
ソチアゾリル基、3−ピリジル基、2.3−ジヒドロ−
4−チエニル基又は2,5−ジヒドロ−3−チエニル基
であり:式・で、且つ1式・
ゾリル基、5−チアゾリル基、3−イソチアゾリル基、
4−インチアゾリル基、5−イソチアゾリル基、3−ピ
リジル基、2.3−ジヒドロ−4−チエニル基又は2.
5〜ジヒドロ−3−チエニル基であり:Xがメチレン基
であり、Yがメチレン基、酸素原子、硫黄原子又はイミ
ノ基であるか又はYがメチレン基であり、Xがメチレン
基、酸素原子、硫黄原子又はイミノ基であるか、或いは
X及びYの両者が一緒になってフェン環、オキサゾール
環、イソオキサゾール環、チアゾール環、イソチアゾー
ル環、1,3.4−オキサジアゾール環、1.3.4−
チアジアゾール環、ピリジン環、ピリダジン環、ピリミ
ジン環又はピラジン環であるものが好ましい。Among these groups, those having the formula or thiophene ring are preferred, and furthermore, R′
is a thienyl group, pyrrolyl group, oxasilyl group, isoxasilyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyridyl group or dihydrothienyl group;
Formula: Aromatic ring is benzene ring, virol ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, 1,3.4
-oxadiazole ring, 1. .. 3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring is preferable, and among these, R' is particularly 3-thienyl group, l-pyrrolyl group, 5-
oxasilyl group, 4-ynoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group,
3-inchazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-
A 4-thienyl group or a 2,5-dihydro-3-thienyl group, and a 4-thienyl group or a 2,5-dihydro-3-thienyl group, and a zolyl group, 5-thiazolyl group, 3-isothiazolyl group,
4-inchazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2.3-dihydro-4-thienyl group or 2.
5-dihydro-3-thienyl group: X is a methylene group, Y is a methylene group, oxygen atom, sulfur atom or imino group, or Y is a methylene group, X is a methylene group, an oxygen atom, a sulfur atom or an imino group, or a combination of both X and Y such as a phen ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a 1,3.4-oxadiazole ring, 1. 3.4-
A thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring is preferred.
更に好ましい化合物群としては、R’が3−チエニル基
、1−ピロリル基、5−オキサシリル基、4−イソオキ
サシリル基、5−イソオキサシリル基、4−チする芳香
環がベンゼン環又はチオフェン環で、且つ、フラン環、
チオフェン環、オキサゾール環、イソオキサゾール環、
チアゾール環、イソチアゾール環、1,3.4−オキサ
ジアゾール環、1,3.4−チアジアゾール環、ピリジ
ン環、ピリダジン環、ピリミジン環又はピラジン環であ
り、R1が1〜3個のフッ素原子を有する炭素数1〜5
個の低級アルキル基であり;Hs及びR4が同−又は異
なって低級アルキル基であるか、或いは両者が結合して
隣接する炭素原子と共にシクロアルカンを形成する基で
・あり;R6が水素原子、低級アルキル基又は低級アル
コキシ基であり:R′及びR1が同−又は異なって水素
原子、ハロゲン原子、水酸基、シアノ基、低級アルキル
基又は低級アルコキシ基である化合物である。More preferable compound groups include R' being a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, or 5-isoxasilyl group, and R' being a benzene ring or a thiophene ring. a ring, and a furan ring,
Thiophene ring, oxazole ring, isoxazole ring,
a thiazole ring, isothiazole ring, 1,3.4-oxadiazole ring, 1,3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring, and R1 is 1 to 3 fluorine atoms 1 to 5 carbon atoms
Hs and R4 are the same or different lower alkyl groups, or both are bonded together to form a cycloalkane with adjacent carbon atoms; R6 is a hydrogen atom, It is a lower alkyl group or a lower alkoxy group: A compound in which R' and R1 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group.
このうち、特に、R’が3−チエニル基、1−ピロリル
基、5−オキサシリル基、4−イソオキサシリル基、5
−イソオキサシリル基、4−チアゾリル基、5−チアゾ
リル基:3−イソチアゾリル基、4−イソチアゾリル基
、5−イソチアゾリル基、3−ピリジル基、2,3−ジ
ヒドロ−4−チエニル基、2,5−ジヒドロ−3−チエ
ニル基であり;
れる芳香環がベンゼン環、フラン環、チオフェン環、オ
キサゾール環、イソオキサゾール環、チアゾール環、イ
ソチアゾール環、1,3.4−オキサジアゾール環、1
,3.4−チアジアゾール環、ピリジン環、ピリダジン
環、ピリミジン環又はピラジン環であり、R1が1〜3
個のフッ素原子を有する炭素数1〜3個の低級アルキル
基であり;R゛及びR4がメチル基であり;Rsがメチ
ル基、エチル基又はメトキシ基であり;R6及びR′が
水素原子である化合物が好ましい。Among these, in particular, R' is a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5
-Isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group: 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-4-thienyl group, 2,5 -dihydro-3-thienyl group; the aromatic ring is a benzene ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a 1,3.4-oxadiazole ring, 1
, 3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring, and R1 is 1-3
R′ and R4 are methyl groups; Rs is methyl, ethyl, or methoxy group; R6 and R′ are hydrogen atoms; Certain compounds are preferred.
前記式[IFの置換アリルアミン誘導体は、酸付加塩の
形で存在することができ、そのような酸付加塩としては
、例えば塩酸塩、臭化水素酸塩。The substituted allylamine derivatives of formula [IF can exist in the form of acid addition salts, such as hydrochloride, hydrobromide.
ヨウ化水素酸塩、硫酸塩、硝酸塩、過塩素酸塩若しくは
リン酸塩等の無機酸塩;又は、例えばp−トルエンスル
ホン酸塩、ベンゼンスルホン酸塩、メタンスルホン酸塩
、シュウ酸塩、コハク酸塩、酒石酸塩、クエン酸塩、フ
マル酸塩若しくはマレイン酸塩等の有機酸塩が挙げられ
、特に製薬掌上許容され得る無毒性の塩が好ましい。Inorganic acid salts such as hydroiodides, sulfates, nitrates, perchlorates or phosphates; or, for example, p-toluenesulfonates, benzenesulfonates, methanesulfonates, oxalates, succinates. Examples include organic acid salts such as acid salts, tartrates, citrates, fumarates, and maleates, and pharmaceutically acceptable non-toxic salts are particularly preferred.
次に、本発明に係わる化合物の一般的製造法について説
明する。Next, a general method for producing the compound according to the present invention will be explained.
本発明の式[!]の化合物は1例えば下記の製法A、B
及びCのいずれかの方法を用いて製造することができる
。The formula of the present invention [! ] Compound 1, for example, the following production methods A and B
It can be manufactured using any of the methods of and C.
[製法A]
[製法C]
(以下余白)
[製法B]
[fV]
[V]
c式中、Zは脱離基を示し:またA1、A1、Q゛、Q
l、R’、R”、R′、R4、R1、R’ 及ヒR’
ハ前11a (7) ! 味を有する]
上記製法、A、B及びCはいずれも有機合成化学の分野
でよく知られたアミン類のアルキル化反応であり、従っ
て、それ自体公知の通常の手段を用いて行なうことがで
きる1反応は、通常、いずれの場合も反応に悪影響を及
ぼさない溶媒、例えばベンゼン、トルエン若しくはキシ
レン等の芳香族炭化水素1例えばエチルエーテル、テト
ラヒドロフラン若しくはジオキサン等のエーテル類;例
えば塩化メチレン、クロロホルム若しくはジクロルエタ
ン等のハロゲン化炭化水素;例えばエタノール若しくは
イソプロパツール等のアルコール類;ジメチルホルムア
ミド、アセトニトリル、ジメチルスルホキシド又はそれ
らの混合物を使用して、通常、製法Aの場合、化合物[
I1]及び化合物[l111を、製法Bの場合、化合物
[IV]及び化合物[V]を、また製法Cの場合、化合
物[V[]及び化合物[■]を1等モル比で反応させる
か、いずれか一方を少過剰反応させることにより行なわ
わる。この時採用される反応条件としては、反応温度は
一般に一20〜150℃、好ましくは0−100℃であ
り、また反応時間は通常、5分間〜10日間、好ましく
は1〜24時間とすることができる。またこの反応では
、反応を円滑に進めるために塩基の存在下に行なうこと
が有利であり、その際使用される塩基としては1例えば
水素化ナトリウム、水素化リチウム若しくは水素化カリ
ウム等の水素化アルカリ金属:例えば水酸化ナトリウム
、水酸化カリウム若しくは水酸化カルシウム等のアルカ
リ金属若しくはアルカリ土類金属水酸化物;例えば炭酸
ナトリウム。[Manufacturing method A] [Manufacturing method C] (hereinafter blank) [Manufacturing method B] [fV] [V] In the c formula, Z represents a leaving group: Also, A1, A1, Q゛, Q
l, R', R", R', R4, R1, R' and R'
Hamae 11a (7)! The above production methods A, B, and C are all well-known alkylation reactions of amines in the field of organic synthetic chemistry, and therefore can be carried out using conventional means known per se. 1. The reaction is usually carried out using solvents which do not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene or xylene; 1. ethers such as ethyl ether, tetrahydrofuran or dioxane; such as methylene chloride, chloroform or dichloroethane. In the case of Process A, the compound [
I1] and compound [l111, in the case of production method B, compound [IV] and compound [V], and in the case of production method C, react compound [V[] and compound [■] in a 1 equimolar ratio, or This is carried out by reacting either one in slight excess. Regarding the reaction conditions employed at this time, the reaction temperature is generally -20 to 150°C, preferably 0 to 100°C, and the reaction time is usually 5 minutes to 10 days, preferably 1 to 24 hours. Can be done. In addition, in this reaction, it is advantageous to carry out the reaction in the presence of a base in order to proceed smoothly, and examples of the base used in this case include 1, an alkali hydride such as sodium hydride, lithium hydride, or potassium hydride. Metal: an alkali metal or alkaline earth metal hydroxide such as, for example, sodium hydroxide, potassium hydroxide or calcium hydroxide; for example, sodium carbonate.
炭酸カリウム若しくは炭酸水素ナトリウム等の炭酸アル
カリ金属塩;又は、例えばトリエチルアミン若しくはピ
リジン等の有機アミン類等が挙げられる。これら塩基の
使用量は1通常、各原料化合物に対して等モル又は過剰
量、好ましくは1〜2モルとすることができる。Alkali metal carbonate salts such as potassium carbonate or sodium hydrogen carbonate; or organic amines such as triethylamine or pyridine. The amount of these bases to be used is usually an equimolar amount or an excess amount, preferably 1 to 2 mols, relative to each raw material compound.
以上の工程で得られる本発明の目的化合物口]は1例え
ばカラムクロマトグラフィー、溶媒抽出又は再結晶等を
単独又は適宜組み合せて行なうことにより単離精製する
ことができる。更に、必要により、一般式[I]で表さ
れる本発明化合物の遊離塩基をその酸付加塩に変換した
り、またその逆に酸付加塩をその遊離塩基に変換するこ
とができる1式[I]の化合物の遊離塩基をその酸付加
塩に変換する工程、また、酸付加塩をその遊離塩基に変
換する工程は、それぞれに対応する酸又は塩基を用いて
普通の方法により容易に行なうことができる。The target compound of the present invention obtained in the above steps can be isolated and purified by, for example, column chromatography, solvent extraction, recrystallization, etc. alone or in an appropriate combination. Furthermore, if necessary, the free base of the compound of the present invention represented by the general formula [I] can be converted into its acid addition salt, or vice versa, the acid addition salt can be converted into its free base. The step of converting the free base of the compound of [I] into its acid addition salt, and the step of converting the acid addition salt into its free base, can be easily carried out by a conventional method using the corresponding acid or base. Can be done.
なお、Zで示される脱離基としては、例えば塩素原子、
臭素原子若しくはヨウ素原子等のハロゲン原子、又は例
えばメタンスルホニルオキシ基、p−トルエンスルホニ
ルオキシ基、トリフルオロメタンスルホニルオキシ基若
しくは0−ニトロベンゼンスルホニルオキシ基等の有機
スルホニルオキシ基が挙げられる。Note that the leaving group represented by Z includes, for example, a chlorine atom,
Examples include halogen atoms such as bromine or iodine atoms, or organic sulfonyloxy groups such as methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, or 0-nitrobenzenesulfonyloxy.
上記製法A−Cで用いられる原料化合物CU]〜[■]
は、市販品として購入するか又は本発明者等が先に報告
した製法[特願昭63−296840 、欧州特許公開
318860号コ、或いはそれらに準する方法等により
製造入手することができる。Raw material compound CU used in the above production method A-C] ~ [■]
can be purchased as a commercial product or manufactured and obtained by the manufacturing method previously reported by the present inventors [Japanese Patent Application No. 63-296840, European Patent Publication No. 318860, or a method similar thereto.
一般弐〇同で表される本発明の化合物は、#乳動物のス
クアレン・エポキシダーゼを極めて選択的、且つ、強力
に阻害し、抗高脂血症剤ひいては抗動脈硬化剤としての
用途が期待される有用な化合物である。The compound of the present invention, represented by the general formula #2, highly selectively and strongly inhibits squalene epoxidase in mammals, and is expected to be used as an antihyperlipidemic agent and, ultimately, an antiarteriosclerotic agent. It is a useful compound.
このことを立証するために、以下に薬理試験例を挙げて
説明する。In order to prove this, pharmacological test examples will be given and explained below.
薬理試験例1
スクアレン・エポキシダーゼの阻害作用(1)スクアレ
ン・エポキシダーゼの調製ヒトのスクアレン・エポキシ
ダーゼはジャーナル・オブ・バイオロジカル・ケミスト
リー(J、Biol。Pharmacological test example 1 Inhibitory effect of squalene epoxidase (1) Preparation of squalene epoxidase Human squalene epoxidase was published in the Journal of Biological Chemistry (J, Biol.
Chem、)、第245巻、第1670頁(1970年
);同第250巻、第1572頁(1975年)に記載
の方法に串じて調製する。Chem, Vol. 245, p. 1670 (1970); Vol. 250, p. 1572 (1975).
即ち、ヒユーマンへバトーマ(Hep−02)細胞を5
%二酸化炭素混合空気下37℃で培養する。培養終了後
細胞をかき取り遠心分離により採取する。That is, 5 human batoma (Hep-02) cells were
% carbon dioxide mixed air at 37°C. After the culture is completed, the cells are scraped and collected by centrifugation.
0、IM Tris−HCI緩衝液(pF17.5)に
懸濁しくlXl0”ce11/a+1)ホモジナイズし
、9750Xgで10分間遠心分離する。得られた上清
をさらに105000X、gで1時間遠心分離し、つい
で沈渣を0.IM Tris−HCI緩衝液(p)17
.5)テ洗浄した後、1105000Xテ1時間遠心分
離する。得られたミクロソームを、蛋白量20mg/m
lになるよう0.IM Tris−HCI緩衝液(pF
17.5)に懸濁し、水冷下1%トリトンX−100の
存在下、撹拌して可溶化する。この可溶化処理後、1+
にEDTA及び1mMジチオスレイトールでトリトンx
−ioo濃度を0.125%に希釈し、1105000
Xテ1時間遠心分離する。得、られた上清をスクアレン
・エポキシダーゼ画分として、後記の試験に使用する。0, IM Tris-HCI buffer (pF17.5), homogenized and centrifuged at 9750Xg for 10 minutes.The resulting supernatant was further centrifuged at 105000Xg for 1 hour. , then the precipitate was added to 0.IM Tris-HCI buffer (p) 17
.. 5) After washing, centrifuge at 1105,000X for 1 hour. The obtained microsomes were mixed with a protein content of 20 mg/m
0 so that it becomes l. IM Tris-HCI buffer (pF
17.5) and solubilized by stirring in the presence of 1% Triton X-100 while cooling with water. After this solubilization treatment, 1+
Tritonx with EDTA and 1mM dithiothreitol.
-ioo concentration was diluted to 0.125%, 1105000
Centrifuge for 1 hour. The obtained supernatant is used as a squalene epoxidase fraction in the test described below.
(2)スクアレン・エポキシダーゼ活性の測定法ヒトの
スクアレン・エポキシダーゼ活性の測定は、ジャーナル
・オブ・バイオロジカル・ケミストリー(J、Biol
、Chem、)、第245巻、第1670頁(197
0年)に記載の方法に準じて行なう。(2) Method for measuring squalene epoxidase activity The measurement of human squalene epoxidase activity is described in the Journal of Biological Chemistry (J. Biol.
, Chem, ), Volume 245, Page 1670 (197
This is done according to the method described in Year 0).
即ち、(1)で調製したスクアレン・エポキシダーゼ画
分の0.21111[蛋白量0.4mg、0.1%トリ
トンX−100,20μM Tris−HCI緩衝液(
pH7,5)]、 100μM FAD。That is, 0.21111 of the squalene epoxidase fraction prepared in (1) [protein amount 0.4 mg, 0.1% Triton X-100, 20 μM Tris-HCI buffer (
pH 7,5)], 100 μM FAD.
1 mM NADPHlL iM EDTA及び8μM
’H−スクアレンートウイーン80懸濁液からなる溶液
に試験薬剤のジメチルスルホキシド溶液3μlを加え、
全量を0.31111とし、37℃で60分間振盪反応
させる。10%水酸化カリウム−メタノール溶液0.3
i1を加えて反応を停止させ、75℃で1時間加熱する
1次いで非ケン化物質を石油エーテルで抽出した後、窒
素気流下濃縮乾固する。得られた残渣を少量のエチルエ
ーテルに溶かしてPre−coated Silica
gel TLCにスポットし、ベンゼン−酢酸エチル(
99,5: 0.5)で展開する。なお生成した3■−
スクアレン−2,3−エポキシドのTLCにおける位置
はエルゴステロールアセテートをマーカーとして確認し
、 TLCの゛H−スクアレンー2,3−エポキシド部
分を切り取る。該TLC片はトルエン系シンチレータ−
に浸し、液体シンチレーションカウンターで測定する。1 mM NADPHIL iM EDTA and 8 μM
'Add 3 μl of a dimethyl sulfoxide solution of the test drug to a solution consisting of H-squalate Vienna 80 suspension,
The total amount was adjusted to 0.31111, and the reaction was carried out with shaking at 37° C. for 60 minutes. 10% potassium hydroxide-methanol solution 0.3
The reaction is stopped by adding i1 and heated at 75°C for 1 hour.Non-saponifiable materials are extracted with petroleum ether and concentrated to dryness under a stream of nitrogen. The obtained residue was dissolved in a small amount of ethyl ether to prepare Pre-coated Silica.
Spotted on gel TLC, benzene-ethyl acetate (
99,5: 0.5). Furthermore, the generated 3■-
The position of squalene-2,3-epoxide in TLC is confirmed using ergosterol acetate as a marker, and the ``H-squalene-2,3-epoxide portion of TLC is cut out. The TLC piece is a toluene scintillator.
and measure using a liquid scintillation counter.
これにより1本発明化合物のスクアレン・エポキシダー
ゼに対する50%の阻害濃度(IC,、値)を求め、そ
の結果を次の表に示す。As a result, the 50% inhibitory concentration (IC, value) of one of the compounds of the present invention against squalene epoxidase was determined, and the results are shown in the following table.
表 ヒトスクアレン・エポキシダーゼ阻害作用以上の結
果から明らかな如く、本発明の化合物はスクアレン・エ
ポキシダーゼを強力に阻害して。Table Human squalene epoxidase inhibitory effect As is clear from the above results, the compounds of the present invention strongly inhibit squalene epoxidase.
コレステロールの生合成を阻害することから、コレステ
ロールの生合成機構の先進により惹起される各種疾患、
例えば肥満、高脂血症及び動脈硬化症等の疾患の治療及
び予防に有効である。また本発明化合物のスクアレン・
エポキシダーゼ阻害作用は、真菌等には認められず哺乳
動物に特異的であること、更に毒性も低いことから1本
発明は医薬の分野で極めて有用である。Since it inhibits cholesterol biosynthesis, various diseases caused by advances in the cholesterol biosynthesis mechanism,
For example, it is effective in treating and preventing diseases such as obesity, hyperlipidemia, and arteriosclerosis. In addition, squalene of the compound of the present invention
The epoxidase inhibitory effect is not observed in fungi and is specific to mammals, and furthermore, the toxicity is low, making the present invention extremely useful in the pharmaceutical field.
本発明の式[I]の化合物は、経口又は非経口的に投与
することができ、そしてそのような投与に遺する形態に
製剤化する二とにより、高コレステロール血症、高脂血
症及び動脈硬化症等の治療及び改善に供することができ
る0本発明の化合物を臨床的に用いるにあたり、その投
与形態に合わせ、薬剤学的に許容される添加剤を加えて
各種製剤化の後投与することも可能である。その際の添
加剤としては、製剤分野に於いて通常用いられる各種の
添加剤が使用可能であり、例えばゼラチン、乳糖、白糖
、酸化チタン、デンプン、結晶セルロース、ヒドロキシ
プロピルメチルセルロース、カルボキシメチルセルロー
ス、トウモロコシデンプン。The compounds of formula [I] of the present invention can be administered orally or parenterally, and by being formulated into a form suitable for such administration, hypercholesterolemia, hyperlipidemia and When the compound of the present invention, which can be used for the treatment and improvement of arteriosclerosis, etc., is used clinically, it is administered after being formulated into various formulations by adding pharmaceutically acceptable additives according to the dosage form. It is also possible. As additives in this case, various additives commonly used in the pharmaceutical field can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and corn starch. .
マイクロクリスタリンワックス、白色ワセリン、メタケ
イ酸アルミン酸マグネシウム、無水リン酸カルシウム、
クエン酸、クエン酸三ナトリウム、ヒドロキシプロピル
セルロース、ソルビトール、ソルビタン脂肪酸エステル
、ポリソルベート、ショ糖脂肪酸エステル、ポリオキシ
エチレン硬化ヒマシ油、ポリビニルピロリドン、ステア
リン酸マグネシウム、軽質無水ケイ酸、タルク、植物油
、ベンジルアルコール、アラビアゴム、プロピレングリ
コール、ポリアルキレンゲリコール、シクロデキストリ
ン又はヒドロキシプロピルシクロデキストリン等が挙げ
られる。Microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate,
Citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol , gum arabic, propylene glycol, polyalkylene gelicol, cyclodextrin, or hydroxypropyl cyclodextrin.
これらの添加剤との混合物として製剤化される射影には
、例えば錠剤、カプセル剤、顆粒剤、散剤若しくは坐剤
等の固形製剤、又は、例えばシロップ剤、エリキシル剤
若しくは注射剤等の液体製剤があり、これらは、製剤分
野に於ける通常功方法に従って調製することができる。Projections formulated as mixtures with these excipients include solid preparations, e.g. tablets, capsules, granules, powders or suppositories, or liquid preparations, e.g. syrups, elixirs or injections. These can be prepared according to conventional methods in the pharmaceutical field.
なお、液体製剤にあっては、同時に水又は他の適当な媒
体に溶解又は懸濁させる形であってもよい、また、特に
注射剤の場合、必要に応じて生理食塩水又はブドウ糖液
に溶解又は懸濁させてもよく、更に緩衝剤や保存剤を添
加してもよい。In addition, in the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium, and especially in the case of injections, they may be dissolved in physiological saline or glucose solution as necessary. Alternatively, it may be suspended, and a buffer or preservative may be added.
これらの製剤は、本発明化合物を全薬剤1.0〜100
重量%、好ましくは1.0〜60重量%の割合で含有す
ることができる。これらの製剤は、また、治療上有効な
他の化合物を含んでいてもよい。These preparations contain the compound of the present invention at a total dosage of 1.0 to 100%.
It can be contained in a proportion of 1.0 to 60% by weight, preferably 1.0 to 60% by weight. These formulations may also contain other therapeutically effective compounds.
本発明の化合物を抗高脂血症剤、抗動脈硬化剤又は抗高
コレステロール血症剤として使用する場合、その投与量
及び投与回数は、患者の性別1年齢1体重、症状の程度
及び目的とする治療効果の種類と範囲等により異なるが
、一般に経口投与の場合、成人1日あたり、0.01〜
20謹g/kgを1〜数回に分けて、また非経口投与の
場合は、0.001〜2mg/kgを1〜数回に分けて
投与するのが好ましい。When the compound of the present invention is used as an antihyperlipidemic agent, antiarteriosclerotic agent, or antihypercholesterolemic agent, the dosage and frequency of administration should be determined depending on the patient's sex, age, weight, severity of symptoms, and purpose. Although it varies depending on the type and scope of the therapeutic effect, in general, in the case of oral administration, the dose per day for adults is 0.01~
It is preferable to administer 20 mg/kg in one to several doses, and in the case of parenteral administration, 0.001 to 2 mg/kg in one to several doses.
以下に実施例及び参考例を挙げて本発明をより具体的に
説明するが、もとより本発明はこれらの実施例のみに限
定されるものではない。The present invention will be described in more detail below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.
(以下余白)
実施例1
N−(2−フルオロエチル)−3−[3−(3−チエニ
ル)ベンジルオキシ]ベンジルアミン塩酸塩80mgを
ジメチルホルムアミド10i1に溶解し、(E)−1−
ブロモ−6,6−シメチルー2−ヘプテン−4−イン4
3111gと炭酸ナトリウム30mgを加えて一夜撹拌
する0反応液に水とエチルエーテルを加えて抽出し、有
機層を分取後節和食塩水で洗浄し、無水硫酸ナトリウム
により乾燥する。乾燥剤を濾別後溶媒を留去し、残渣を
中圧液体クロマトグラフィー[カラム:Lobar c
olumn。(Left below) Example 1 80 mg of N-(2-fluoroethyl)-3-[3-(3-thienyl)benzyloxy]benzylamine hydrochloride was dissolved in 10i1 of dimethylformamide, and (E)-1-
Bromo-6,6-dimethyl-2-hepten-4-yne 4
3111 g of sodium carbonate and 30 mg of sodium carbonate are added and stirred overnight. The reaction mixture is extracted with water and ethyl ether. The organic layer is separated, washed with brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar c
olumn.
5ize A、Lichroprep Si 60F(
メルク社製)、溶出溶媒:ヘキサンl酢酸エチル=20
ハ→10/11により精製すれば、無色油状の表題化合
物68mg(収率70%)が得られる。5ize A, Lichroprep Si 60F (
Merck), elution solvent: hexane l ethyl acetate = 20
Purification by Ha→10/11 yields 68 mg (yield 70%) of the title compound as a colorless oil.
IRv neaual:2968,2824.1584
、1491 、1458.1365 。IRvneual:2968,2824.1584
, 1491, 1458.1365.
■ax
1152.1035,963,693
NMR(CDCI、 )δ:1.24(9H,s)、2
.76(2H,dt、J:26.1Hz5.1Hz)、
3.19(2H,dd、J=6.8Hz、1.9Hz)
、3.65(2Hs)、4.48(2H,dt、J=4
6.4Hz、5.1Hz)、5.11(2H,s)5.
65(IH,dt、J=15.8[Iz、1.9Hz)
、6.05(1B、d5に1.5.8Hz、6.8Hz
)、6.85−6.93(2H,i)、7.01−7.
03(IH,w) 、7.22(IH,t、J=8.0
Hz)、7.34−7.45(4H。■ax 1152.1035,963,693 NMR (CDCI, )δ: 1.24 (9H, s), 2
.. 76 (2H, dt, J: 26.1Hz 5.1Hz),
3.19 (2H, dd, J=6.8Hz, 1.9Hz)
, 3.65 (2Hs), 4.48 (2H, dt, J=4
6.4Hz, 5.1Hz), 5.11 (2H, s)5.
65 (IH, dt, J=15.8 [Iz, 1.9Hz)
, 6.05 (1B, 1.5.8Hz on d5, 6.8Hz
), 6.85-6.93 (2H, i), 7.01-7.
03 (IH, w), 7.22 (IH, t, J=8.0
Hz), 7.34-7.45 (4H.
II)、7.47(1B、dd、J=2.6Hz、1.
7Hz)、7.55(II、dc。II), 7.47 (1B, dd, J=2.6Hz, 1.
7Hz), 7.55 (II, dc.
に7.7Hz、1.7Hz)、7.66−7.68(I
I(、Im)実施例2
(E)−N−(2−フルオロエチル)−3−(2−[3
−(3−チエニル)フェニル]エチニル]ベンジルアミ
ン120mg及び(E)−1−ブロモ−6,6−シメチ
ルー2−ヘプテン−4−インl100Il1を用い、実
施例1と同様に処理すれば、表題化合物9smg(収率
65%)が無色油状物として得られる。7.7Hz, 1.7Hz), 7.66-7.68 (I
I(, Im) Example 2 (E)-N-(2-fluoroethyl)-3-(2-[3
-(3-Thienyl)phenyl]ethynyl]benzylamine (120 mg) and (E)-1-bromo-6,6-dimethyl-2-hepten-4-yne (1100111) were treated in the same manner as in Example 1 to produce the title compound. 9 smg (65% yield) are obtained as a colorless oil.
IRv”’ art:2968.1605,1482,
1365,1266.12]8゜a+aX
1029.963,852,774,696NMR(C
DC1,)δ:1.24(9■、s)、2.82(2H
,dt、J:26.1Hz。IRv"' art:2968.1605,1482,
1365,1266.12]8゜a+aX 1029.963,852,774,696NMR(C
DC1,) δ: 1.24 (9■, s), 2.82 (2H
, dt, J: 26.1 Hz.
5.1Hz)、3.23(2H,dd、J:6.3Hz
、1.5Hz)、3.70(28゜s)、4.53(2
H,dt、J=47.6Hz、5.1)1z)、5.6
8(IH,dt。5.1Hz), 3.23 (2H, dd, J: 6.3Hz
, 1.5Hz), 3.70 (28°s), 4.53 (2
H, dt, J=47.6Hz, 5.1)1z), 5.6
8 (IH, dt.
J=15.8Hz、1.5)1z)、6.09(IH,
dt、J=15.8Hz、6.3Hz)、7.16(2
1,s)、7.21−7.26(IH,m)、7.31
(1■1tlJ=7.6Hz)、7.38−7.52(
8H,m)、7.74(In、t、J4.7Hz)
実施例3
(E)−N−(6,6−シメチルー2−ヘプテン−4−
イニル)−3−(3−(3−チエニル)ベンジルオキシ
フベンジルアミン300mgをスルホラン4mlに溶解
し、2,2.2−トリフルオロエチル2−ニトロベンゼ
ンスルホナート400mgを加えて150℃で6時間加
熱撹拌する1反応液に水とエチルエーテルを加えて抽出
し、有機層を分取後飽和食塩水で洗浄し、無水硫酸ナト
リウムにより乾燥する。乾燥剤を濾別後溶媒を留去し、
残渣を中圧液体クロマトグラフィー[カラム:Lo−b
ar coluIIn、5ize B、Lichrop
rep St 60F(メルク社製)、溶出溶媒:ヘキ
サンl酢酸エチル・2011→511]により精製すれ
ば1表題化合物37mg(収率10%)が無色油状物と
して得られる。J=15.8Hz, 1.5)1z), 6.09(IH,
dt, J=15.8Hz, 6.3Hz), 7.16(2
1, s), 7.21-7.26 (IH, m), 7.31
(1■1tlJ=7.6Hz), 7.38-7.52(
8H, m), 7.74 (In, t, J4.7Hz) Example 3 (E)-N-(6,6-dimethyl-2-heptene-4-
300 mg of benzyl)-3-(3-(3-thienyl)benzyloxyfubenzylamine was dissolved in 4 ml of sulfolane, 400 mg of 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate was added, and the mixture was heated at 150°C for 6 hours. Water and ethyl ether are added to the stirred reaction solution for extraction, and the organic layer is separated, washed with saturated brine, and dried over anhydrous sodium sulfate.After filtering off the desiccant, the solvent is distilled off.
The residue was subjected to medium pressure liquid chromatography [column: Lo-b
ar coluIIn, 5ize B, Licrop
Rep St 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate/2011→511] to obtain 37 mg (yield 10%) of the title compound as a colorless oil.
1044.846,693
NMR(CDCI、 )δ:1.24(9H,s)、3
.08(2H,q、J=9.4Hz) 。1044.846,693 NMR (CDCI, )δ: 1.24 (9H, s), 3
.. 08 (2H, q, J=9.4Hz).
3.26(21,d、J=6.6Hz)、3.77(2
H,s)、5.10(21(、s)。3.26 (21, d, J = 6.6 Hz), 3.77 (2
H,s), 5.10(21(,s).
5.64(IH,dt、J=15.9Hz、1.5Hz
)、5.99(IH,dt、J=15.9Hz、6.6
Hz)、6.87−6.93(2H,m)、7.01(
IH,t。5.64 (IH, dt, J=15.9Hz, 1.5Hz
), 5.99 (IH, dt, J=15.9Hz, 6.6
Hz), 6.87-6.93 (2H, m), 7.01 (
IH,t.
J=2.0Hz)、7.23(IH,t、に7.8Hz
)、7.34−7.45(4H。J = 2.0Hz), 7.23 (IH, t, 7.8Hz
), 7.34-7.45 (4H.
m)、7.47(1■、dd、J=2.3Hz、1.7
Hz)、7.56(IH,dt。m), 7.47 (1■, dd, J=2.3Hz, 1.7
Hz), 7.56 (IH, dt.
J=7.7Hz、1.7Hz)、7.66−7.68(
IH,m)実施例4
エニル)フェニル]エチニル]ベンジルアミンの製(E
)、(E)−”N−(6,6−シメチルー2−ヘプテン
−4−イニル)−3−[2−[3−(3−チエニル)フ
ェニル]エチニル]ベンジルアミン240■g及び2,
2.2−トリフルオロエチル2−ニトロベンゼンスルホ
ナート170a+gを用い、実施例3と同様に処理すれ
ば、表題化合物10■g(収率3.5%)が無色油状物
として得られる。J=7.7Hz, 1.7Hz), 7.66-7.68(
IH, m) Example 4 Preparation of enyl)phenyl]ethynyl]benzylamine (E
), (E)-”N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-[3-(3-thienyl)phenyl]ethynyl]benzylamine 240 g and 2,
By treating 170a+g of 2.2-trifluoroethyl 2-nitrobenzenesulfonate in the same manner as in Example 3, 10 g (yield 3.5%) of the title compound is obtained as a colorless oil.
11?vnea’ai1:2974,1368,131
7,1203,1149.1077゜18X
960.831.696
NMR(CDC1,)δ:1.24(9H,s)、3.
12(21(、q、J・9.5Hz)。11? vnea'ai1:2974,1368,131
7,1203,1149.1077°18X 960.831.696 NMR (CDC1,) δ: 1.24 (9H, s), 3.
12(21(,q,J・9.5Hz).
3.31(2[I,d、J=6.6Hz) 、3.82
(2H,s)、5.68(1■、dt。3.31 (2[I, d, J=6.6Hz), 3.82
(2H, s), 5.68 (1■, dt.
J=15.4Hz、1.5)1z)、6.05(LH,
dt、J=15.4Hz、6.6Hz)、7.16(2
■、S)、7.21−7.23(IH,I)、7.33
(11(、t。J=15.4Hz, 1.5)1z), 6.05(LH,
dt, J=15.4Hz, 6.6Hz), 7.16(2
■, S), 7.21-7.23 (IH, I), 7.33
(11(, t.
J=7.6Hz)、7.36−7.51(81,a+)
、7.74(LH,L、J=1.4)1z)
以下に参考例を記載し、上記実施例中で使用された原料
化合物の一般的合成法を説明する。J=7.6Hz), 7.36-7.51(81,a+)
, 7.74 (LH, L, J=1.4)1z) Reference examples are described below to explain the general synthesis method of the raw material compounds used in the above examples.
参考例I
N−2−フルオロエチル−3−(3−(3−チエニルベ
ンジルオキシュベンジルアミン塩酸塩の製造3−ブロモ
ベンジルブロマイド5.Ogをイソプロピルアルコール
70111に溶解し、3−ヒドロキシベンズアルデヒド
2.4gと炭酸カリウム2.0gを加えて4時間加熱還
流する。放冷後エチルエーテルを加えて不溶物を濾別後
溶媒を留去する。残渣にエチルエーテルと水酸化ナトリ
ウム水溶液を加えて抽出し、常法により後処理を行なえ
ば、3−(3−ブロモベンジルオキシ)ベンズアルデヒ
ド5.5g(収率95%)が得られる。Reference Example I Preparation of N-2-fluoroethyl-3-(3-(3-thienylbenzyloxybenzylamine hydrochloride) 5.0 g of 3-bromobenzyl bromide was dissolved in isopropyl alcohol 70111, and 3-hydroxybenzaldehyde 2.0 g was dissolved in isopropyl alcohol 70111. Add 4 g of potassium carbonate and 2.0 g of potassium carbonate and heat under reflux for 4 hours. After cooling, add ethyl ether, filter out insoluble matter, and distill off the solvent. Ethyl ether and aqueous sodium hydroxide solution are added to the residue for extraction. After a conventional post-treatment, 5.5 g (yield: 95%) of 3-(3-bromobenzyloxy)benzaldehyde is obtained.
上記のアルデヒド体3.0gをトルエン50a+1に溶
解し、トリブチル(3−チエニル)スズ4.Og及びテ
トラキス(トリフェニルホスフィン)パラジウム100
mgを加えて6時間加熱還流する。放冷後反応液にフッ
化カリウム水溶液を加えて、不溶物を濾別後トルエンを
加えて抽出する。有機層を分取後学法により後処理すれ
ば、3−[3−(3−チエニル)ベンジルオキシュベン
ズアルデヒド1.2g(収率40%)が得られる。 上
記のチエニル体100mgをテトラヒドロフラン−エタ
ノール(1:1)の混合溶媒20m lに溶解し、2〜
フルオロ工チルアミン塩酸塩90+IIg、炭酸カリウ
ム80a+g及びモレキュラーシーブス3Aを加えて一
晩放置した後、水素化ホウ素ナトリウム1100oを加
えて3時間撹拌する。不溶物を濾別後溶媒を留去し、常
法により後処理すれば、白色結晶の表題化合物a7mg
(収率68%)が得られる。3.0 g of the above aldehyde was dissolved in 50a+1 of toluene, and 4.0 g of tributyl (3-thienyl)tin was dissolved. Og and tetrakis(triphenylphosphine)palladium 100
mg and heated under reflux for 6 hours. After cooling, an aqueous potassium fluoride solution is added to the reaction mixture, and insoluble matter is filtered off, followed by extraction with toluene. If the organic layer is post-treated by a post-preparative method, 1.2 g (yield: 40%) of 3-[3-(3-thienyl)benzyloxybenzaldehyde is obtained. Dissolve 100 mg of the above thienyl compound in 20 ml of a mixed solvent of tetrahydrofuran-ethanol (1:1),
After adding 90+IIg of fluoroengineered tylamine hydrochloride, 80a+g of potassium carbonate and 3A of molecular sieves and standing overnight, 1100o of sodium borohydride was added and stirred for 3 hours. After filtering off the insoluble materials, the solvent is distilled off and after-treatment is carried out in a conventional manner to obtain 7 mg of the title compound as white crystals.
(Yield 68%) is obtained.
参考例2
m−ブロモベンズアルデヒド3.7g及びジエチル3−
シアノベンジルホスホネート5.1g[m−hルニトリ
ルをN−ブロモコハク酸イミドでブロモ化し、次いで亜
リン酸トリエチルを反応させて製造する]をジメチルホ
ルムアミド50I!Iに溶解し、水冷撹拌下、60%油
性水素化ナトリウム1.ogを加えて室温で3時間撹拌
する6反応液に水と酢酸エチルを加えて抽出し、常法に
より後処理を行なった後、シリカゲルクロマトグラフィ
ー[ワコーゲルC−Zoo、100g、溶出溶媒コヘキ
サンl酢酸エチル・100/1→20/l]により精製
すれば、 (E)−3−ブロモ−3′−シアノスチルベ
ン2.9g(収率50%)が得られる。Reference example 2 m-bromobenzaldehyde 3.7g and diethyl 3-
5.1 g of cyanobenzylphosphonate [produced by brominating m-h nitrile with N-bromosuccinimide and then reacting with triethyl phosphite] was dissolved in dimethylformamide 50I! 1. Dissolved in 60% oily sodium hydride under water cooling and stirring. 6 Add water and ethyl acetate to the reaction mixture and stir for 3 hours at room temperature. After post-treatment by a conventional method, silica gel chromatography [Wakogel C-Zoo, 100g, eluent cohexane l acetic acid 2.9 g (yield: 50%) of (E)-3-bromo-3'-cyanostilbene is obtained.
上記で得られたスチルベン2.9g、トリブチル(3−
チエニル)スズ4.0g及びテトラキス(トリフェニル
ホスフィン)パラジウム1001gをトルエン100
mlに溶解し、参考例1と同様な反応を行なえば、(E
)−3−シアノ−3’ −(3−チエニル)スチルベン
1.14(収率38%)が得られる。2.9 g of stilbene obtained above, tributyl (3-
4.0 g of tin (thienyl) and 1001 g of tetrakis(triphenylphosphine) palladium were added to 100 g of toluene.
ml and conduct the same reaction as in Reference Example 1, (E
)-3-cyano-3'-(3-thienyl)stilbene 1.14 (yield 38%) is obtained.
上記のチエニル体1.1gをトルエン20m1に溶解し
、−78℃撹拌下、1M水素化ジイソブチルアルミニウ
ムートルエン溶液3.8mlを滴下する。同温で1時間
反応後、飽和塩化アンモニウム水溶液を加えて常法によ
り後処理すれば、3−[2−[3−チエニル)フェニル
コニテニル]ベンズアルデヒド0.8g(収率69%)
が得られる。1.1 g of the above thienyl compound was dissolved in 20 ml of toluene, and 3.8 ml of 1M diisobutylaluminum hydride-toluene solution was added dropwise while stirring at -78°C. After reacting at the same temperature for 1 hour, adding a saturated ammonium chloride aqueous solution and post-treating in a conventional manner, 0.8 g of 3-[2-[3-thienyl)phenylconitenyl]benzaldehyde (yield 69%)
is obtained.
上記のベンズアルデヒド150IIgをエタノール−テ
トラヒドロフラン(1:1)の混合溶媒20m lに溶
解し、2−フルオロエチルアミン塩酸塩1001I+g
及び28%ナトリウムメトキシド−メタノール溶液20
0μmを加え一夜放置する。水素化ホウ素ナトリウム1
00Jを加えて1時間撹拌した後溶媒を留去し、常法に
より後処理後、中圧液体グロマトグラフィ−[カラム°
Lobar column、5ize B、Lichr
oprep 5i60F(メルク社製)、溶出溶ls:
ヘキサン/酢酸エチル・to/1→511]により精製
すれば、表題化合物120mg(収率62%)が得られ
る。Dissolve 150IIg of the above benzaldehyde in 20ml of a mixed solvent of ethanol-tetrahydrofuran (1:1), and prepare 1001I+g of 2-fluoroethylamine hydrochloride.
and 28% sodium methoxide-methanol solution 20
Add 0 μm and leave overnight. Sodium borohydride 1
After adding 00J and stirring for 1 hour, the solvent was distilled off, and after post-treatment by a conventional method, medium pressure liquid chromatography [column °
Lobar column, 5ize B, Lichr
oprep 5i60F (manufactured by Merck & Co., Ltd.), elution ls:
Hexane/ethyl acetate to/1→511] to obtain 120 mg (yield 62%) of the title compound.
参考例3
公誓童
3−[3−(3−チエニル)ベンジルオキシ]ベンズア
ルデヒド0.55g及び(IE)−6,6−シメチルー
2−へブテン−4−イニルアミン0.26gを参考例1
と同様に反応を行なえば、表題化合物0.55g(収率
71%)が無色油状物として得られる。Reference example 3 Reference example 1
If the reaction is carried out in the same manner as above, 0.55 g (yield 71%) of the title compound is obtained as a colorless oil.
参考例4
3−[2−[3−(3−チエニル)フェニル]エチニル
]ベンズアルデヒド1.14及び6.6−シメチルー2
−へブテン−4−イニルアミン0.52gを参考例2と
同様な反応を行なえば、白色結晶として表題化合物]、
、2g(収率76%)、m −p 、 66−70℃、
を得る。Reference example 4 3-[2-[3-(3-thienyl)phenyl]ethynyl]benzaldehyde 1.14 and 6.6-dimethyl-2
- When 0.52 g of hebuten-4-ynylamine is reacted in the same manner as in Reference Example 2, the title compound is obtained as white crystals],
, 2g (yield 76%), m-p, 66-70°C,
get.
参考例5
0−ニトロベンゼンスルホン酸クロリド4.9g、トリ
フルオロエタノール2.Og及び水2mlの混合溶媒に
、50℃撹拌下、15%水酸化ナトリウム水溶液10m
1を滴下し3時間撹拌する。放冷後学法により後処理を
行なえば表題化合物2.2gH(収率77%)が得られ
る。Reference example 5 0-nitrobenzenesulfonic acid chloride 4.9g, trifluoroethanol 2. Add 10 ml of 15% aqueous sodium hydroxide solution to a mixed solvent of Og and 2 ml of water under stirring at 50°C.
Add 1 dropwise and stir for 3 hours. After cooling, 2.2 gH (yield 77%) of the title compound can be obtained by post-treatment by the chemical method.
只里凹塾果
本発明化合物は、哺乳動物のスクアレン・エポキシダー
ゼを阻害することによりコレステロールの生合成を阻害
し5、血中コレステロール値を低下させる。従って、コ
レステロールの過剰に起因する疾患、例えば肥満、高脂
血症、動脈硬化症並びにそれらに付随する心臓疾患及び
脳疾患等の治療及び予防剤として有効性が期待できる。By inhibiting mammalian squalene epoxidase, the compound of the present invention inhibits cholesterol biosynthesis5 and lowers blood cholesterol levels. Therefore, it can be expected to be effective as a therapeutic and preventive agent for diseases caused by excess cholesterol, such as obesity, hyperlipidemia, arteriosclerosis, and associated heart and brain diseases.
Claims (5)
、窒素原子、酸素原子又は硫黄原子を示し;Q^1及び
Q^2は同一又は異なって窒素原子、酸素原子及び硫黄
原子からなる群から選ばれる1個又は2個のヘテロ原子
を含んでいてもよく、且つ、隣接する炭素原子及びA^
1又はA^8と共に5員又は6員の芳香環を形成する基
を示し;X及びYは同一又は異なっていてもよく、各々
、酸素原子、硫黄原子、カルボニル基、式:−CHR^
a−(ここで、R^aは水素原子又は低級アルキル基を
示す)で表される基又は式:−NR^b−(ここで、R
^bは水素原子又は低級アルキル基を示す)で表される
基を示すか、或いはX及びYの両者が一緒になってビニ
レン基若しくはエチニレン基を示し;R^1は窒素原子
、酸素原子及び硫黄原子からなる群から選ばれる1個〜
4個のヘテロ原子を含む5員又は6員の複素環基を示し
;R^8はフッ素原子を有する低級アルキル基を示し;
R^3及びR^4は同一又は異なって低級アルキル基を
示すか、或いは両者が結合して隣接する炭素原子と共に
シクロアルカンを形成する基を示し;R^8は水素原子
、低級アルキル基又は低級アルコキシ基を示し;R^6
及びR^7は同一又は異なって水素原子、ハロゲン原子
、水酸基、シアノ基、低級アルキル基又は低級アルコキ
シ基を示す、但し、X及びYのどちらか一方が酸素原子
、硫黄原子又は式:−NR^b−(ここで、R^bは前
記の意味を有する)で表される基を示す場合、他方はカ
ルボニル基又は式:−CHR^a−(ここで、R^aは
前記の意味を有する)で表される基を示す]で表される
置換アリルアミン誘導体及びその無毒性塩。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [1] [In the formula, A^1 and A^8 are the same or different and represent a methine group, nitrogen atom, oxygen atom, or sulfur atom; Q^ 1 and Q^2 may be the same or different and may contain one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and adjacent carbon atoms and A^
Indicates a group that forms a 5- or 6-membered aromatic ring with 1 or A^8; X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, and the formula: -CHR^
A group or formula represented by a- (where R^a represents a hydrogen atom or a lower alkyl group): -NR^b- (here, R
^b represents a hydrogen atom or a lower alkyl group), or both X and Y together represent a vinylene group or an ethynylene group; R^1 represents a nitrogen atom, an oxygen atom, or One selected from the group consisting of sulfur atoms ~
represents a 5- or 6-membered heterocyclic group containing 4 heteroatoms; R^8 represents a lower alkyl group having a fluorine atom;
R^3 and R^4 are the same or different and represent a lower alkyl group, or a group in which both combine to form a cycloalkane with adjacent carbon atoms; R^8 is a hydrogen atom, a lower alkyl group, or Represents a lower alkoxy group; R^6
and R^7 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group, provided that either X or Y is an oxygen atom, a sulfur atom, or the formula: -NR When referring to a group represented by ^b- (where R^b has the above meaning), the other is a carbonyl group or the formula: -CHR^a- (where R^a has the above meaning) A substituted allylamine derivative represented by the following formula and a non-toxic salt thereof.
キサゾリル基、イソオキサゾル基、チアゾリル基、イソ
チアゾリル基、イミダゾリル基、ピラゾリル基、オキサ
ジアゾリル基、チアジアゾリル基、トリアゾリル基、テ
トラゾリル基、フラザニル基、ピリジル基、ピリダジニ
ル基、ピリミジニル基、ピラジニル基、トリアジニル基
、ジヒドロチエニル基、テトラヒドロチエニル基、ピロ
リニル基。 ピロリジニル基、オキサゾリニル基、オキサゾリジニル
基、イソオキサゾリニル基、イソオキサゾリジニル基、
チアゾリニル基、チアゾリジニル基、イソチアゾリニル
基、イソチアゾリジニル基、1,2−ジチオラニル基、
1,3−ジチオラニル基、1,2−ジチオリル基、1,
3−ジチオリル基、ジヒドロチオピラニル基、テトラヒ
ドロチオピラニル基、1,4−ジチアニル基、1,4−
ジチイニル基、1,4−オキサチイニル基又はチオモル
ホリニル基であり;式:▲数式、化学式、表等がありま
す▼又は式:▲数式、化学式、表等があります▼で表さ
れる5員 又は6員の芳香環が同一又は異なってベンゼン環、ピロ
ール環、フラン環、チオフェン環、オキサゾール環、イ
ソオキサゾール環、チアゾール環、イソチアゾール環、
イミダゾール環、1,3,4−オキサジアゾール環、1
,3,4−チアジアゾール環、ピリジン環、ピリダジン
環、ピリミジン環、ピラジン環又はトリアジン環である
第1請求項記載の置換アリルアミン誘導体及びその無毒
性塩。(2) R^1 is a pyrrolyl group, furyl group, thienyl group, oxazolyl group, isoxazole group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group. pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolidinyl group,
Thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1,2-dithiolanyl group,
1,3-dithiolanyl group, 1,2-dithiolyl group, 1,
3-dithiolyl group, dihydrothiopyranyl group, tetrahydrothiopyranyl group, 1,4-dithianyl group, 1,4-
Dithiinyl group, 1,4-oxathiinyl group or thiomorpholinyl group; Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. A benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, in which the aromatic rings are the same or different;
imidazole ring, 1,3,4-oxadiazole ring, 1
, 3,4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring, and the non-toxic salt thereof according to claim 1.
換アリルアミン誘導体又はその無毒性塩を含有する高コ
レステロール血症処置剤。(3) A hypercholesterolemia treatment agent containing the substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1.
換アリルアミン誘導体又はその無毒性塩を含有する高脂
血症処置剤。(4) A hyperlipidemia treatment agent containing a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to the first claim.
換アリルアミン誘導体又はその無毒性塩を含有する動脈
硬化症処置剤。(5) An agent for treating arteriosclerosis containing the substituted allylamine derivative represented by the general formula [I] or a non-toxic salt thereof according to claim 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29565689A JPH03157381A (en) | 1989-11-14 | 1989-11-14 | Fluorine substituted allylamine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29565689A JPH03157381A (en) | 1989-11-14 | 1989-11-14 | Fluorine substituted allylamine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03157381A true JPH03157381A (en) | 1991-07-05 |
Family
ID=17823471
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP29565689A Pending JPH03157381A (en) | 1989-11-14 | 1989-11-14 | Fluorine substituted allylamine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03157381A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3190103A1 (en) * | 2016-01-08 | 2017-07-12 | Rijksuniversiteit Groningen | Inhibitors of the pd-1/pd-l1 protein/protein interaction |
-
1989
- 1989-11-14 JP JP29565689A patent/JPH03157381A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3190103A1 (en) * | 2016-01-08 | 2017-07-12 | Rijksuniversiteit Groningen | Inhibitors of the pd-1/pd-l1 protein/protein interaction |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CZ25497A3 (en) | Benzoxazoles and pyridine derivatives usable for treating type ii diabetes | |
NO170883B (en) | PROCEDURE FOR PREPARING 2-AMINO-5-HYDROXY-4-METHYLPYRIMIDINE DERIVATIVES | |
DE69418311T2 (en) | ISOXAZOLIDE INDION DERIVATIVES AND THEIR USE | |
JPH01143856A (en) | 2-aryl substituted heterocyclic compound for antiallergic and anti-inflammatory agent | |
US5202341A (en) | Hydroxystyrene compounds having tyrosine kinase inhibiting activity | |
JP2691679B2 (en) | Oxime derivative and pharmaceuticals containing the same | |
JPH0717589B2 (en) | Novel 1,3-dicarbonyl compound and composition thereof | |
EP1446402B1 (en) | 2-amino-4-heteroarylethyl thiazoline derivatives and their use an inhibitors of inducible no-synthase | |
US4377588A (en) | 4-(Substituted thiazolyl)-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase | |
WO1990005132A1 (en) | Substituted allylamine derivatives, process for their preparation and their use | |
CH646687A5 (en) | DERIVATIVES OF CARBOXYLIC CYCLOHEXANE ACID. | |
JPWO2005021486A1 (en) | Ester derivatives and their pharmaceutical uses | |
KR100281867B1 (en) | 3- (bis-substituted phenylmethylene) oxindole derivatives | |
FI84057B (en) | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA FLUORALLYLAMINDERIVAT. | |
JPH03287584A (en) | Substituted allylamine derivative | |
FR2479815A1 (en) | CYCLOHEXENE DERIVATIVES | |
CA2089349C (en) | New pyrolidine derivatives, process for their preparation and pharmaceutical composition holding same | |
FR2758329A1 (en) | New imidazole-4-butane-boronic acid derivatives | |
EP0929550A1 (en) | $i(N)-(BENZOTHIAZOL-2-YL) PIPERIDINE-1-ETHANAMINE DERIVATIVES, THEIR PREPARATION AND APPLICATION IN THERAPEUTICS | |
CA2108064C (en) | Thiazolidine dione compounds, process for preparing same and pharmaceutical compositions containing same | |
JPH03157381A (en) | Fluorine substituted allylamine derivative | |
WO2005063671A1 (en) | Ether derivatives | |
JPH02169571A (en) | Substituted allylamine derivative | |
JPH08301841A (en) | Squalene-epoxydase activity inhibitor | |
US5843971A (en) | 1, 1-BIS (heteroazolyl) alkane derivatives and their use as neuroprotective agents |