CA2078208A1 - Imidazoles - Google Patents
ImidazolesInfo
- Publication number
- CA2078208A1 CA2078208A1 CA002078208A CA2078208A CA2078208A1 CA 2078208 A1 CA2078208 A1 CA 2078208A1 CA 002078208 A CA002078208 A CA 002078208A CA 2078208 A CA2078208 A CA 2078208A CA 2078208 A1 CA2078208 A1 CA 2078208A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- carbon atoms
- formula
- branched
- straight
- 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.)
- Abandoned
Links
- 150000002460 imidazoles Chemical class 0.000 title claims description 27
- -1 acyl coenzyme-A Chemical compound 0.000 claims abstract description 74
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 claims abstract description 5
- 102000004357 Transferases Human genes 0.000 claims abstract description 4
- 108090000992 Transferases Proteins 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000005516 coenzyme A Substances 0.000 claims abstract description 4
- 229940093530 coenzyme a Drugs 0.000 claims abstract description 4
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 claims abstract description 4
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 109
- 125000004432 carbon atom Chemical group C* 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 230000001668 ameliorated effect Effects 0.000 claims 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 230000007717 exclusion Effects 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 58
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- 239000007787 solid Substances 0.000 description 55
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 54
- 239000000243 solution Substances 0.000 description 53
- 238000000921 elemental analysis Methods 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 235000019341 magnesium sulphate Nutrition 0.000 description 20
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 18
- 239000000725 suspension Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- GMTAWLUJHGIUPU-UHFFFAOYSA-N 4,5-diphenyl-1,3-dihydroimidazole-2-thione Chemical compound N1C(S)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GMTAWLUJHGIUPU-UHFFFAOYSA-N 0.000 description 11
- 101150041968 CDC13 gene Proteins 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 8
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000011521 glass Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 230000006978 adaptation Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- RSDGJSJLAUUDLM-UHFFFAOYSA-N 4-chloro-n-(4,6-dimethylpyridin-2-yl)butanamide Chemical compound CC1=CC(C)=NC(NC(=O)CCCCl)=C1 RSDGJSJLAUUDLM-UHFFFAOYSA-N 0.000 description 4
- ZHHBFCYFYVLXKD-UHFFFAOYSA-N 6-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanylmethyl]-4-hydroxy-4-methyloxan-2-one Chemical compound O1C(=O)CC(C)(O)CC1CSC1=NC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)N1 ZHHBFCYFYVLXKD-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 3
- BHYSFPFZQMMGMF-UHFFFAOYSA-N 3-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]propan-1-amine Chemical compound N1C(SCCCN)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 BHYSFPFZQMMGMF-UHFFFAOYSA-N 0.000 description 3
- FXSJJZADKOGRGZ-UHFFFAOYSA-N 4,5-bis(3-chlorophenyl)-1,3-dihydroimidazole-2-thione Chemical group ClC1=CC=CC(C2=C(NC(=S)N2)C=2C=C(Cl)C=CC=2)=C1 FXSJJZADKOGRGZ-UHFFFAOYSA-N 0.000 description 3
- ACBSEFYLYFANDL-UHFFFAOYSA-N 4-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]-1-morpholin-4-ylbutan-1-one Chemical compound C1COCCN1C(=O)CCCSC(N1)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 ACBSEFYLYFANDL-UHFFFAOYSA-N 0.000 description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- HTLNQGVZXWBKKO-UHFFFAOYSA-N tert-butyl 3-hydroxy-3-methyl-4-(oxiran-2-yl)butanoate Chemical compound CC(C)(C)OC(=O)CC(C)(O)CC1CO1 HTLNQGVZXWBKKO-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical compound SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 description 2
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 2
- OZJQHWJWZWZWLL-UHFFFAOYSA-N 1-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]propan-2-one Chemical compound N1C(SCC(=O)C)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OZJQHWJWZWZWLL-UHFFFAOYSA-N 0.000 description 2
- MMYKTRPLXXWLBC-UHFFFAOYSA-N 1-bromo-2-ethoxyethane Chemical compound CCOCCBr MMYKTRPLXXWLBC-UHFFFAOYSA-N 0.000 description 2
- DPSOBGLGMJUMOF-UHFFFAOYSA-N 2-(3,3-diethoxypropylsulfanyl)-4,5-diphenyl-1h-imidazole Chemical compound N1C(SCCC(OCC)OCC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 DPSOBGLGMJUMOF-UHFFFAOYSA-N 0.000 description 2
- JBXMWRUCWVOOKY-UHFFFAOYSA-N 2-(4-ethoxyhex-5-enylsulfanyl)-4,5-diphenyl-1h-imidazole Chemical compound N1C(SCCCC(OCC)C=C)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 JBXMWRUCWVOOKY-UHFFFAOYSA-N 0.000 description 2
- OTOITCXQTIAIEG-UHFFFAOYSA-N 2-(cyclohexylmethylsulfanyl)-4,5-diphenyl-1h-imidazole Chemical compound C1CCCCC1CSC(N1)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OTOITCXQTIAIEG-UHFFFAOYSA-N 0.000 description 2
- QAFRHFLUQRPXBO-UHFFFAOYSA-N 2-[(3,5-dimethoxyphenyl)methylsulfanyl]-4,5-diphenyl-1h-imidazole Chemical compound COC1=CC(OC)=CC(CSC=2NC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 QAFRHFLUQRPXBO-UHFFFAOYSA-N 0.000 description 2
- GLGPXAYUVYVJFR-UHFFFAOYSA-N 2-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]-n,n-diethylethanamine Chemical compound N1C(SCCN(CC)CC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GLGPXAYUVYVJFR-UHFFFAOYSA-N 0.000 description 2
- OZYPCYKICLAHSK-UHFFFAOYSA-N 2-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]ethanol Chemical compound N1C(SCCO)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OZYPCYKICLAHSK-UHFFFAOYSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 2
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- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-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
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 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
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 208000024042 cholesterol ester storage disease Diseases 0.000 description 1
- 208000013760 cholesteryl ester storage disease Diseases 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- KONIYTHNVWYBMP-UHFFFAOYSA-N ethylcyclohexane Chemical compound [CH2-]C[C+]1CCCCC1 KONIYTHNVWYBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940041476 lactose 100 mg Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- BNRHGFCWOLQSOS-UHFFFAOYSA-N methyl n-cyano-n'-[2-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]ethyl]carbamimidothioate Chemical compound N1C(SCCN=C(NC#N)SC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 BNRHGFCWOLQSOS-UHFFFAOYSA-N 0.000 description 1
- FPHXBFBVGKCPLI-UHFFFAOYSA-N methyl n-cyano-n'-[3-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]propyl]carbamimidothioate Chemical compound N1C(SCCCN=C(NC#N)SC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 FPHXBFBVGKCPLI-UHFFFAOYSA-N 0.000 description 1
- PCXKRWRRKVSNBC-UHFFFAOYSA-N methyl n-cyano-n'-[4-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]butyl]carbamimidothioate Chemical compound N1C(SCCCCN=C(NC#N)SC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 PCXKRWRRKVSNBC-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- IUSXYVRFJVAVOB-UHFFFAOYSA-N n-(2-chloroethyl)-n-propan-2-ylpropan-2-amine;hydron;chloride Chemical compound Cl.CC(C)N(C(C)C)CCCl IUSXYVRFJVAVOB-UHFFFAOYSA-N 0.000 description 1
- ZCLUOYOAEHYVSQ-UHFFFAOYSA-N n-[4-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]butyl]-4,6-dimethylpyridin-2-amine Chemical compound CC1=CC(C)=NC(NCCCCSC=2NC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 ZCLUOYOAEHYVSQ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- XDUHQPOXLUAVEE-BPMMELMSSA-N oleoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCC\C=C/CCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 XDUHQPOXLUAVEE-BPMMELMSSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000009118 salvage therapy Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 230000002455 vasospastic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Obesity (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Imidazole derivates of general formula (II) in which R1 is hydrogen or one or more substituents, k is 0, 1 or 2, Q is a straight or branched alkylene group and Z is hydrogen or a substituent group and pharmaceutically acceptable salts thereof possess useful pharmacological properties as inhibitors of acyl coenzyme-A:
cholesterol-o-acyl transferase and as inhibitors of the binding of thromboxane TXA2 to its receptors, and are useful in therapy.
cholesterol-o-acyl transferase and as inhibitors of the binding of thromboxane TXA2 to its receptors, and are useful in therapy.
Description
- 1 2~782~ `
IMIDAZO:LES
The present invention relates to new therapeutically useful imidazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.
The imidazole derivatives of the present invention are the compounds of the general formula:-A~S()k-Q-Z
wherein A represents a group of general formula II
shown hereinafter in the present specification, wherein the symbols Rl may be the same or different and each represents hydrogen or one or more substituents, for example substituents selected from halogen atoms, and straight- or branched-chain alkyl and alkoxy groups containing from l to about 6 carbon atoms, and trifluoromethyl groups;
k represents 0, l or 2;
Q represents a methylene group or alkylene chain containing from 2 to ahout s carbon atoms, optionally substituted with one or more alkyl groups containing from l to about 4 carbon atoms; and Z represents a hydrogen atom; a hydroxy group;
an alkoxy group optionally substituted by, for example, an alkoxy or alkoxyalkoxy group; an aryl, for example phenyl, group optionally substituted by, for example, WO91/13876 PCT/~91/00408 2~73208 `
one or more alkoxy, e.g. methoxy, groups; a dialkyl-amino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to about 4 carbon atoms; a group of the formula -NHR2, wherein R2 represents an acyl group, for example a straight- or branch~d-chain alkanoyl group containing up to about 6 carbon atoms and which may be substituted, for example, by a carboxy group, or R2 represents a group of the formula -C(SR3)=N-CN wherein R3 represents a straight- or branched-c~ain alkyl group containing from 1 to about 3 carbon a~oms, or R2 represents a 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents selected from, ~or example, amino groups and straight- or branched-chain alkyl groups containing from 1 to about 3 carbon atoms, and preferably attached to the group -NH via a carbon ato~; or Z represents a group of the formula -coR4 wherein R4 represents a straight- or branched-chain alkyl group containing from 1 to about 3 carbon atoms; a group of the formula -CH(OH)R5 -coR5, -CS~5, -CoNHR5 or -CSNHR wherein R
represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents selected from, for example, straight- or branched-chain alkyl groups containing from 1 to ahout 3 carbon atoms; an alkynyl or cycloalkyl group 2~7820.8 . .
containing up to about 6 carbon atoms; a group of the formula -CH(R )OR wherein R represents a straight- or branched-chain alkenyl or alkoxy group containing up to about 6 carbon atoms and R7 represents a straight- or branched-chain alkyl group containing ~rom l to about 4 carbon atoms, optionally substituted by one or more substituents selected from, for example, hydroxy groups; a group of the general formula III shown hereinafter, wherein m is 0 or l, n is 0 or ~ and p is 1, 2 or 3, and the symbols R8 each represent a hydrogen atom, or a methyl group substituted by a straight- or branched-chain alkoxyy or alkanoyloxy group containing up to about 6 carbon atoms; a group of the general formula IV shown hereinafter wherein m is as hereinbefore defined; a group of the general formula V
shown hereinafter wherein R9 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms and Rl0 represents a hydrogen atom or a hydroxy group or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms; or a group of the general formula VI
shown hereinafter wherein R9 is as hereinbefore defined; a group of the general formula VII shown hereinafter wherein R9 and RlO are as hereinbefore defined, the symbols Rll may be the same or different and each represents a hydrogen atom or a 2078208 - 4 ~
hydroxy group and Rl2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms; or a group of the ~ormula -CH(oH)cH2(cR9Rlo)rcH2coRl3 wherein R9 and Rl0 are as hereinbefore defined, r represents 0 or l and Rl3 represents a hydroxy group or a straight- or branched-chain alkoxy or alkylamino group containing from 1 to about 4 carbon atoms; and phar~aceutically acceptable salts thereof.
In this specification alkyl groups and moieties, unless otherwise specified, are straight- or branched-chain and contain from l to about 6 carbon atoms.
(2S,4R,6S)-6-~(4,5-Diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran and (2R,4R,6S)-6-[(4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2~methoxy-3,4,5,6-tetrahydro-2H-pyran are excluded from the scope of this invention.
specially important features of the present invention are, or involve, compounds of general formula I wherein at least one of the symbols has a value selected from the following:-(i) the symbols Rl may be different or, preferably, the same and each represents a - hydrogen or halogen, e.g. chlorine or fluorine, atom or a straight- or branched-chain alkyl group containing from l to 6, preferably from l WO91/13876 PCT/GB9t/00408 5 _ 2~78208 to 4, carbon atoms, c>r a s~raight- or branched-chain alkoxy group containing from 1 to 3 carbon atoms, e.g. methoxy, or a trifluoromethyl gr9uE~;
(ii) k represents 0;
(iii) Z represents a hydrogen atom; a hydroxy group;
an alkoxy, e.g. ethox~, group optionally substituted by, for example, an alkoxyalkoxy, e.g. methoxyethoxy, group; an aryl, for example phenyl, group optionally substituted by, for example, one or more alkoxy, e.g. methoxy, groups; a dialkylamino group wherein the alkyl groups ~ay be the same or dif~erent and each is straight- or branched-chain and contains from 1 to 4, prefarably from 1 to 3, carbon atoms; an ethynyl group, or a cycloalkyl, e.g. cyclohexyl, group, (iv) R2 rapresents an acyl group, for example a straight- or branched chain alkanoyl group containing up to about 6 carbon atoms and which may be substituted, for example, by a carboxy group; or a pyridyl or triazolyl group optionally substituted by one or more, prefPrably o~e or two, substituents selected from amino groups and straight- or branched-chain alkyl, e.g. methyl, groups;
WO91/13876 PCT/GB91~00408 , - 6 -20782~8 (v) R3 represents a methyl group;
(vi~ R represents a methyl group;
(vii) R represents a imidazolyl, morpholinyl or pyridyl group optionally substituted by one or two alkyl, e.g. methyl, groups;
(viii) R6 represen s an allyl group, or an alkoxy group containing from 1 to 3 carbon ato~s, e.`g. methoxy or ethoxy;
(ix1 R7 represents an alkyl group containing from 1 to 3 carbon atoms, e.g. methyl or ethyl, optionally substituted by a hydroxy group;
(x) ~8 represents a hydrogen atom or a hydroxymethyl, methoxymethyl or acetoxymethyl group;
(xi~ R9 represents a hydrogen atom or a methyl group;
(xii) R10 represents a hydrogen atom or a hydroxy or methyl group;
(xiii) R12 represents a hydrogen atom or a methyl group; and/or (xiv) R~3 represents an alkoxy or alkylamino group containing from 1 to 4 carbon atoms;
the other symbols being as hereinbefore defined, and pharmaceuticaIly acceptable salts thereof.
WO91/1387S PCT/~B91/U0408 _ 7 _ 20 782 ~8 ~,, ,,: - ' ;
Particularly important features of the present invention are, or involve, at least one of the following compounds:-A 2-(2-ethoxyethylthio)-4,5-diphenyli~idazole B 2-[(dioxolan-2-yl)methylthio]-4,5-diphenyl-imidazole C 2-benzylthio-4,5-diphenylimidazole D 2-(3,5-dimethoxybenzylthio)-4,5-diphenyl-imidazole E 2-cyclohexylmethylthio-4,5-diphenylimidazole F ~+]-2-[ttetrahydro-2H-pyran-6-yl)methylthio]-4,5-diphenylimidazole G [+]-2-~(tetrahydro-2~I-pyran-6-yl)methylthio]-4(5)-(4-chlorophenyl)-5(4)-phenylimidazole H 2-t2-(l,3-dioxan-2-yl)ethylthio]-4,5-diphenyl-- imidazole I 2-[3-(l,3-dioxan-2-yl)propylthio]-4,5-diphenyl-imida~ole J 2-(2,2-diethoxyethylthio)-4,5-diphenylimidazole K 2-(2,2-dimethoxyethylthio)-4,5-diphenyl-imidazole L 2-(3,3-diethoxypropylthio)-4,5-diphenyl-imidazole M 2-(4-ethoxyhex-5-enylthio)-4,5-diphenyl-imidazole N 2-[4-(2-hydroxyethyl)hept-6-enylthio]-4,5-W091/~3876 PCT/~9~/0040~
. .
~ - 8 diphenylimidazole 0 2-(2-oxoprop-1-yl)thio-4,5-diphenylimidazole P 2-(2-diethylaminoethylthio)-4,5-diphenyl-imidazole Q 2-(2-diisopropylaminoethylthio)-4,5-diphenyl-imidazole R 2-propargylthio-4,~5-diphenylimidazole S [+]-4,5-bis(2-c ~ ophenyl)-2-[(tetrahydro-2H-pyran-2-yl)meth,~ylthio]imidazole T [+~-4(5)-(2-chlorophenyl)-5(4)-phenyl-2-[(tetra-hydro-2H-pyran-2-yl)methylthio]imidazole U [+]-4(5)-(3-chlorophenyl)-5(4)-phenyl-2-[(tetrahydro-2H-pyran-2-yl)methylthio]imidazole V [+]-2-[(1,4-dioxanyl)methylthio]-4,5-diphenyl-imid~zole W [+]-2-[(2,2-di~mathoxymethyl)tetrahydro-2H-pyran-6-yl)methylthio~-4,5-diphenylimidazole X 2-(3-dimethylaminopropylthio)-4,5-diphenyl--imidazole Y 2-(3,6,9-trioxadecylthio)-4,5-diphenylimidazole Z [+]-2-[2,2-di(hydroxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4~5-diphenylimidazole AA [+3-2- r 2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4~5-diphenylimidazole AB 2-(2-hydroxyethylthio)-4,5-diphenylimidazole AC 2-ethylthio-4,S-dîphenylimidazole WO91/l3876 PCT~GB9l/00408 ~ 20782~8`
AD 2-t(1,3-dioxan-2-yl)methylthio]-4,s-diphenyl-imidazole AE 3-cyano-2-methyl-1-[3-(4,5-diphenylimidazol-2-ylthio)propyl]isothiourea AF 2-t2-(5-amino-1 t 2,4-triazol-3-ylamino)ethyl-thio]-4,5-diphenylimidazole dihydrochloride AG 3-cyano-2-methyl-1-[4-(4,s-diphenylimidazol-2-ylthio)butyl]isothiourea AH 2-[4-(S-amino-1;2,4-triazol-3-ylamino)butyl-thio]-4,5-diphenylimidazole AI 2-[3-(5-amino-1,2,4-triazol-3-ylamino)propyl-thio]-4,5-diphenylimidazole AJ 3-cyano-2-methyl-1-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]isothiourea AK N-(4-methylpyrid-2-yl~-4-(4,5-diphenyl-imidazol-2-ylthio)butanamide AL 4,6-dimethyl-2-[4-(4,5-diphenylimidazol-2-yl-thio)butylamino]pyridine AM 2-(3-ace amidopropylthio)-4,5-diphenylimidazole AN 2,6-dimethyl-N-[4-(4,5-diphenylimidazol-2-yl~
thio)butan-l-oyl]morpholine AO N-(4,6-dimethylpyrid-2-yl)-4~(4,5-diphenyl-imidazol-2-ylthio)butanamide AP N-(pyrid-2-yl)-4-(4,5-diphenylimidazol-2-y~thio)butanamide AQ (SR,5S)-4,5-diphenyl-2-[(2-oxotetrahydrofur-5-2078208 - lO -yl)methylthio]imidazole AR (4R,4S)(6R,6S)-6-[(4, s-bis{ 3-chlorophenyl}imid azol-2-yl)thiomethyl]-4 hydroxy-4-methyltetra-hydropyran-2-one AS (4R,4S)(6R,6S)-6-[(4,5-Bis{4-chlorophenyl}-i~idazol-2-yl)thiomethyl]-4-hydroxy-4-methyJ.-tetrahydropyran-2-one AT (4R,4S)~6R,6S)-6-[ ~ -Bis~2-chlorophenyl}-imidazol-2-yl)thi~methyl]-4-hydroxy-4-methyl-tetrahydropyran-2-one AU (4R,4S)(6R,6S)-6-[(4,5-Bis{4-fluorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy 4-methyl-tetrahydropyran-2-one AV (4R,4S)(6R,6S)-6-[(4,5-Bis{4-trifluoromethyl-phenyl}imidazol-2-yl~thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one A~ (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one AX (4R,4S)(6R,6S)-4-Hydroxy-~-[(4,5-bis{4-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one AY (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis~4-isopropylphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one AZ (4R,4Sj(6R,6S)-6-[(4,5-Bis{4-tertbutylphenyl}-W091~13876 PCT/~B91iOOqO8 2 ~ ~`8 ~ o;~
imidazol-2-yl)thiomethyl] 4-hydroxy-4-methyl-tetrahydropyran-2-one BA (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5 bis{2-- methoxyphenyl}i~idazol-2-yl)thiomethyl]-4-methyltetrahydropyrar~-2-one BB (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methoxy-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one BC 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one BD 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one BE 4-hydroxy-6-[~4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran~2-one BF 4-hydroxy-6-[(4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one BG (6R,6S~-6-[(4,5-bis{4-methylphenyl}imidazol-2-yl)thiomethyl]-5t6-dihydro-4-methylpyran~2-one BH (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thio-methyl]-5,6-dihydro-4-methylpyran-2-one BI (6R,6S)-6-~(4,5-Bis{4-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-me~hylpyran-2-one BJ (6R,6S)-6-t(4,5-bis{3-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BK (6R,6S)-6-[(4,5-bis-{2-chlorophenyl}imidaæol-207&2b8 - 12 -2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BL (6R,6S)-6-[(4,5-bis--{4-fluorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BM (5R,5S)-5-[(4,5-bis--{4-methylphenyl}imidazol-2-yl)thiomethyl]tetrahydrofuran-2-one BN (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thio-methyl]-3,4,5,6-tetrahydropyran-2-one BO (6R,6S)-6-t(4,5-dlphenylimidazol-2-yl)thio-methyl]-4,4-di~èthyl-3,4,5,6-tetrahydropyran-2-one ~
BP (4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-3,4,5,6-tetrahydro-pyran-2-one BQ (3R,3S)(5R,5S)-ethyl 6-t(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydroxyhexanoate BR (6R,6S)-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2-oxo-1,4-dioxane BS t-butyl 6-[(4,5-bis-~4-chlorophenyl}imidazol-2-yl)thio]-3,5-dihydroxy-3-methylhexanoate BT (3R,3S~(5R,5S)-ethyl 6-[(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydroxy-3-methylhexanoate BU (2R,2S)-2-[(2-hydroxy-4,4-dimethyl-5-methyl-aminocarbonylpent 1-yl)thio]-4,5-diphenyl-imidazole BV (2R,2S)(6R,6S)-6-~4,5-diphenylimidazol-2-yl)-thiomethyl]-2-hydroxy-3,4,5,6-tetrahydropyran WO91/13876 PCT/~B91/00408 - 13 - .~
20782~8 BW (2R,2S3(4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetra-hydropyran BX (2R,2S)(4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-2~methoxy-4-~ethyl-tetrahydropyran (2-alpha-anomer) BY (2R, 2S) (4R, 4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-2-methoxy-4-methyl-tetrahydropyran (2-beta-anomer) BZ (2S,3R,4R,5S,6S)-2-[(4,5-diphenylimidazol-2-yl~thiomethyl)-6-methoxy-3,4,5-trihydroxyte~ra-hydropyran CA 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-1-~ethylimidazole CB 2-~5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-l-methylimidazole CC 2-[6-(4,S-diphenylimidazo1-2-ylthio)hexanoyl]-1-methylimidazole CD 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-imidazole CE 2-[6-(4,5-diphenylimidazol-2-ylthio)hexanoyl]-imidazole CF 2-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-imidazole CG 2-[4-(4,5-diphenylimidazol-2-ylthio)-1-hydroxy-butyl]-1-methylimidazole 20782~8` - 14 -CH 2-[6-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-hexyl]-l-methylimidazole CI 2-~5-(4,5-diphenylimidazol-2-ylthio~ hydroxy-pentyl]-l-methylimidazole CJ 2-[4-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-butyl]imidazole CX 2-~5-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-- pentyl]imidazole CL 2-[6-(4,5-diphenylimida~ol-2-ylthio)-l-hydroxy-hexyl)imidazole CM 4-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-morpholine CN 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl~-morpholine and Co 4-[6-(4,5-diphenylimidazol-2-ylthio)hexanoyl]-morpholine.
The letters A to CO are allocated to the compounds for easy reference.
As will be apparent to those skilled in the art, many of the compounds of formula I may exist in more than one enantiomeric form. All such compounds, and their mixtures, are within formula I and wlthin the scope of the present invention.
.'` :
- 15 - 2~78208 The compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT; EC 2.3.l.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
They are also inhibitors of the binding o~
thromboxane TxA2 to its receptors. They are therefore of utility in the treatment of conditions such as thrombosis and myocardial infarction, vasospastic disorders, for example associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example a~ter ischaemic injury.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the ~ollowing in-vitro and in-vivo tests which ~re believed to correlate to pharmacological activity in humans and other animals.
In in-vitro tests on human platelet membrane, compounds of the invention produced up to 50 inhibition of the binding of thromboxane TxA2 to its receptors at concentrations down to about 600 nanomolar or less.
WO 91/13876 PCI/GB9]/00408 ..: , `; -- 1 6 --207820~`
In assays performed n-vitro, microsomes, obtained from the livers of rats fed on a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days, were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the i~vention at a concentration of 0.5 or 1 ~g/ml. The degre~iof ACAT inhibition produced was up to 90% or more.~
In in-~iy~ tests, using rats fed on a similar diet to that above and further supplemented by 0.03~
w/w of test compound, the compounds according to the invention inhibited increases in plasma cholesterol concentrations, measured after 3 days, relative to control animals fed on the cholesterol supplemented diet without the drug, by up to 90% or more.
- 17 - 2 0 ~$2 0 Compounds of formula I can be prepared by the application or adaptation of known methods, for example methods illustrated in the following Examples and Reference Examples.
The intermediates and starting materials from which they are prepared can also be prepared by the application or adaptation of known methods.
By the term "known methods" is meant methods known heretofore or described in the literatura.
For example, as a feature o~ the present invention, compounds of formula I, wherein k is O and the other symbols are as hereinbefore defined, are prepared by the reaction of a compound of the general formula:-A-S-H VIII
wherein A is as hereinbefore defined, or a salt thereof, of the general form~la:-A-S M IX
wherein A is as hereinbefore defined and M répresents an alkali metal, with a compound of the general formula:-xl Q z X
.
or a salt thereof, wherein Xl is a group displaceableby a thiolate salt, such as a halogen e.g. a chlorine, bromine or iodine, atom or an alkyl- or aryl-, ~
2078:2~8- - 18 -sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene~ulphonyloxy~ and Q and Z are as hereinbefore defined. The reaction is generally carried out in an inert organic solvent such as tetrahydrofuran, dimethylformamide, a lower alkanol such as methanol or ethanol, at a temperature fro~ ambient to 110C and optionally in the presence~f a proton acceptor, such as an amine (e.g. triet ~`àmine or pyridine) or an alkali metal hydroxide~?carbonate or alkoxide. The salt of formula IX or the compound of formula X can optionally be prepared n situ by the application or adaptation of known methods.
According to a further feature of the invention, compounds of formula I wherein k is 0 and Z represen$s a group of the formula -NH-C(SR3)=N-CN, A, Q and R3 being as hereinbefore defined, are prepared by the reaction of compounds of the general formula:-(R S)-c(sR3)=N-cN XI
wherein R3 is as hereinbefore defined with compounds of the general formula:-A-S-Q~NH XXI
wherein A and ~ are as hereinbefore defined.
According to a further feature of the invention, compounds of formula I wherein k is 0 and Z represents a group of the formula NHR2 wherein R2 represents an acyl group, A and Q being as hereinbefore defined, are WO91~13876 PCT/GB91/00408 - 19 - 20782~
prepared by the acylation by known methods of compounds of formula XII as hereinbefore defined, for example by reaction with the appropriate acid anhydride or acid halide.
According to a further feature of ~he invention, compounds of formula I wherein k is 0 and Z represents a group of the formula -CH(oH)CH2(CR9RlO)rC~2CoRl4 wherein R9, RlO and r are as hereinbefore defined and ~14 represents a straight- or branched-chain alkoxy group containing from l to 4 carbon atoms, A and Q
being as hereinbefore defined, are prepared by the reaction of a compound of formula IX as hereinbefore defined, optionally prepared in situ, with a compound of the general formula~-Rl5C~2(CR9RlO)rcH2coRl4 XIIIwherein R9, RlO, r and ~14 are as hereinbefore defined and Rl5 represents a l,2-epoxyethyl group, in an inert solvent such as methanol.
According to a further feature of the present invention, compounds of general formula I are prepared by the interconversion of other compounds of general formula I.
For example, compounds of formula I wherein k is - 0 and Z represents a group of formula IV wherein m is 0 or Z represents a group of formula V wherein R9 and RlO
are as hereinbefore defined, A and Q being as 207820~ - - 20 -hereinbefore defined, are prepared by the cyclisation of compounds of formula I wherein k is 0 and Z
represents a group of the formula -CH(oH)CH2(CR9RlO)rCH2CoRl4l A, Q, R9, R10, r and R1 being as hereinbefore defined. The cyclisation can be carried out by reaction with a base, e.g. sodium methoxide in methanol, followed by reaction with trifluoroacetic acid.
Conversely, compounds of formula I wherein k is 0 and Z represents a group of the formula -CH(oH)CH2(CR9R1O)rCH2CoR14, A, Q, R9, R10, r and R14 being as hereinbefore defined, are prepared by the hydrolysis and esterification of compounds of formula I
wherein k is 0 and Z represents a group of formula IV
wherein m is 0 or Z represents a group of formula V
wherein R9 and R10 are as hereinbefore defined, A and Q
being as hereinbeforP defined, for example by reaction with a base, e.g. an aqueous solution of an alkali metal hydroxide, e.g. sodium hydroxide, followed by reaction of the resulting salt with the appropriate alkyl halide.
As another example, compounds of general formula I wherein k is 0, Z represents a group of formula III
wherein n is 0, m is 1, and the symbols R8 preferably represent hydrogen atoms, A, Q and p being as WOglJ13876 PCT/GB91/00408 . ~ .
hereinbefore defined, are prepared by the reaction of a compound of the general formulao-A-S-Q-CH(R14)2 XV
wherein A, Q and R14are as hereinbefore defined with a compound of the general formula:-HO-(CH2)p-C(R )2-OH XVI
wherein p and R8 are as hereinbefore d~fined, preferably in the presence of a catalyst such as pyridinium 4-toluenesulphonate, preferably at reflux and preferably in a solvent such as toluene.
As yet another example, compollnds of general formula I wherein k is 0, Z represents a 5-amino-1,2,4-triazol-3-ylamino group, A and Q ~eing as hereinbefore defined, are prepared by the reaction of compounds of formula I wherein k is 0 and Z represents a group of the formula -NH-C(SR3)=N-CN, A, Q and R3 being as hereinbefore defined, with hydrazine, preferably in a solvent such as ethanol or ethoxyethanol, and preferably under reflux.
As yet another example, some compounds of general formula I are prepared by the reduction of other compounds of general ~ormula I.
-: For example, ti~ compounds of general formula I
wherein k is 0, Q represents a group of formula -Q'CH2-, wherein Q' represents a methylene group or alkylene chain containing from 2 to 4 carbon atoms, 2~78208 ` - 22 -op~ionally substituted with one or more alkyl groups containing from l to about 4 carbon atoms, and Z
represents a group of formula -NHR2, A and R~ being as hereinbefore defined, are prepared by the reduction of compounds of general formula I wherein k is 0, Q
represents a group of formula -Q'-, and Z represents a group of formula -CONHR , A, Q' and R5 being as hereinbefore definedr~ ~ and R5 being identical, for example by reactio~~with a metal hydride such as .~ . ., lithium aluminium hydride, in an e~her such as tetrahydrofuran.
(ii) compounds of general formula I wherein k is O and Z represents a group of formula VII wherein Rll and Rl2 represent hydrogen atoms, A, R9 and RlO being as hereinbefore defined, are prep~r d by the reduction of compounds of general formula I wherein k is 0 and Z
represents a group of formula V, A, ~9 and RlO being as hereinbefore defined, for example by reaction with a metal hydride such as di-isobutylaluminium hydride, in an ether such as tetrahydrofuran.
(iii) compounds of general formula I wherein k is O and Z represents a group of formula -CH(oH)R5, A, Q and R5 being as hereinbefore defined,:are prepared by the reduction of compounds of general formula I wherein k is 0 and Z repre~ents a group of formula -coR5l A, Q
and R5 being as hereinbefore defined, for example by - 23 - ?078208 reaction with a metal borohydride such as sodium borohydride in a solvent system such as aqueous ethanol.
As yet another example, some compounds of general formula I are prepared by the elimination of the elements of water from other compounds of general formula I.
For example, compounds of general formula I
wherein k is O and Z represents a group of formula ~I, A, Q and R9 being as hereinbefore defined, are prepared by the elimination of the ele~ents of water from compounds of general formula I wherein k is o and Z
represents a group of formula V wherein R10 represents a hydroxy group, A, Q and R9 being as hereinbefore defined, e.g. by reaction with trifluoroacetic acid.
As a further example, compounds of formula I
wherein k is O and Z represents a group of the formula -CH(OH)CH2(CR9RlO)rCH2CoRl6, wherein Rl6 represents a straight- or branched -chain alkylamino group contain-ing from l to 4 carbon atoms, A, Q, R9, RlO and r being as hereinbefore defined, are prepared from compounds of formula I wherein k is O and Z represents a group of formula v wherein R9 and RlO are as herainbefore defined, A and Q being as hereinbefore defined, for example by reaction with the appropriate alkylamine of formula Rl6NH2, Rl6 being as hereinbefore defined, W~91/13876 PCT/~B91/00408 2 ~7 8 2 0 8 - 24 -preferably at an elevated te!mperature, e.g. at reflux, in a solvent such as ethanol.
As a still further example, compounds of formula I containing one or more lower alkoxy groups are prepared by the alkylation of compounds of formula I
containing one or more hydroxy groups, for example by reaction with the appropriate lower alkanol, preferably in the presence of-a catalyst such as boron trifluoride diethyl etherate.
As a further example, compounds of formula I
wherein k is O and Z represents a group of the formula -CoR5, wherein R5 is as hereinbefore defined, preferably an optionally substituted imidazole group, A
and Q being as hereinbefore defined, are prepared by reaction of corresponding ~ompounds of formula I
wherein Z represents a ~orpholinocarbonyl group with the product of the reaction between lithium diisopropylamide (preferably complexed with mono-tetrahydrofuran) with a compound of formula R5 H
wherein R5 represents a group within the definition of R5 but wherein any free imino groups are temporarily protected, e.g. by dimethylaminomethyl groups.
As yet a f~rther example, compounds of formula I
-- wherein k represents l or 2, A, Q and Z being as hereinbefore defined, are prepared by the oxidation of compounds of formula I wherein A, Q and Z are as hereinbefore defined and p is less than in the desired WO91/13876 PCT/GB91~0040X
2~78208 - 25 - . .
product.
The oxidation may be performed by using a conventional oxidant, such as hydrogen peroxide, sodium metaperiodate, a hypochlorite, an acyl nitrite, sodium perborate, peracids,-such as percarboxylic acids (e.g.
m-chloroperbenzoic acid), potassium permanganate or potassium hydrogen persulphate, or a ruthenium (VIII) compound, in an inert solvent, at or below room temperature.
Suitable solvents may include wa~er, alcohols, water-alcohol mixtures, chlorinated hydrocarbons, such 2S dichloromethane, and organic acids.
As another example, compounds of formula I
containing one or more carboxy grol~ps are prepared by the hydrolysis by known mQthods of compou~ds of formula I containing one or more alkoxycarbonyl groups.
Compounds of general formula I wherein k is l, the other symbols being as hereinbefore defined, may be obtained in a chirally pure form by separation of the enantiomers arising from a non-selective oxidation or by using known enantio-selective oxidising systems.
It is to b8 understood that, where in this specification reference is made to compounds of formula I, it is intended to refer also where the context so permits to their pharmaceutically acceptable salts.
Such salts are prepared from the parent compounds of WO91/13~76 PCT/GB91/00408 20782~8 - 26 -formula I by the application or adaptation of known methods, or are produced by the processes described hereinafter. Parent compounds of formula I can be generated therefrom by the application or adaptation of known methods.
Preferred salts are acid addition salts such as the hydrochIorides or, where the compound of formula I
contains an acidic hydrogen atom, for example when Z
contains a carboxy group, salts formed with alkali metals, e.g. sodium and potassium, or alkaline earth metals, e.g. calcium and magnesium, or with a~monia or with pharmaceutically acceptable amines.
Compounds of formula I can be purified by the usual physical means, for example by crystallisation or chromatography.
The following Examples illustrate the preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates.
In the presentation of the nuclear magnetic resonance ("NMR") spectra chemical shifts were expressed in parts per million relative to tetramethylsilane. Abbreviations have the following significances:- s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, dd =
doublet of doublets, dt = doublet of triplets, and br =
broad si~nal.
- 27 - 2~78~
RL~
k~ (II) Rl~
~()~.
(CH2)n (CH2)p --¦-- R8 ( III) ~(o)~
~ (IV) WO 91/13876 PCI'/GB91/00408 , ~.
8 2 ~ 28 -R9 RlO
~o (V) r ", ~ ~. 1 (VI ) O O
X (VII) Rll~ Rll --\t) \ oR12 .
W091/13876 PCT/GB9l/~0408 .
- 29 - 20782~
Compounds A, B, C, D, E, F, G, H, I, J, K, L, M, N L O ~ P ~ and Q
A A stirred suspension of 4,5-diphenylimidazole-2-thiol (3.2g) and anhydrous potassium carbonate (1.8~) in anhydrous dimethylformamide (50ml) was stirred at room temperature for 15 minutes. Ik was then treated with 2-bromoethyl ethyl ether (2.4g) and the mixture was stirred at room temperature overnight. The mixture was filtered through silica gel and the bright yellow filtrate was evaporated to low bulX. The residue was shaken with ethyl acetate (lOOml) and water (50ml). The layers were separated and the organic layer was washed with water (50ml), dried (magnesium sulphate) and evaporated.
The residue was subjected to flash chromatography eluting with a mixture of ethyl acetate and dichloromethane (1:3 v/v). Crystallisation from cyclohexane gave 2-(2-ethoxyethylthio)-4,5-diphenyl- .
imidazole (2.2g) in the form of a white crystalline solid, m.p. 91-92C.
[Elemental analysis:- C,69.9;H,6.1;N,8.5;S,10.0%;
Calculated:- C,70.34;H,6.21;N,8.64;S,9.88%.
NMR (in C~C13):- 1.23 (3H,t,J = 8Hz), 3.18 (2H,t,J =
6Hz), 3.64 (2H,q,J = 8Hz), 3.83 (2H,t,J = 6Hz), 7.2-7.6 (lO~,m)].
WO 91/13876 PCr/GB91/00408 .''~, i 2~7~ 30-By proceeding in a similar manner, but replacing the 2-bromoethyl ethyl ether used as a starting material by the appropriate quantity of the corresponding halides, and optionally replacing the potassium carbonate by potassium t-butoxide, there were prepared the followln~ compounds:-B 2-t(dioxolan-2-yl)methylthio]-4,5-diphenyl-imidazole, m.p. 139-143C.;
C 2-benzylthio-4,5-diphenylimidazole, m.p. 181-189C.;
D 2-(3,5-dimethoxybenzylthio)-4,5-diphenylimidazole, m.p. 148.5-149.5C.;
E 2-cyclohexylmethylthio-4,5-diphenylimidazole, m.p. 169-171C.;
F [~]-2-t(tetrahydro-2~-pyran-6-yl)methylthio~-4,5-diphenylimidazole, m.p. 143-}45C.;
G [1]-2-[(tetrahydro-2H-pyran-6-yl)methylthio~-4(5)-(4-chlorophenyl)-5(4)-phenylimidazole, m.p. 127-129C.;
H 2-[2-(1,3-dioxan-2-yl)ethylthio)-4,5-diphenyl-imidazole, m.p. }91-193C.;
I 2-[3-(1,3-dioxan-2-yl)propylthio~-4,5-diphenyl-imidazole, m.p. 151C.;
J 2-(2,2-diethoxyethylthio)-4,s-diphenylimidazole, m.p. sO-94c.;
K 2-(2,2-dimethoxyethylthio)-4,5-diphenyl-- 31 - ~ 0 7 8 ~ ~ 8 ~
imidazole, m.p. 162-163C.;
L 2-(3,3-diethoxypropylthio)-4,5-diphenyl-imidazole, m.p. 247-249C.;
M 2-(4-ethoxyhex-5-enylthio)-4,5-diphenyl-imidazole, m.p. 91C.;
N 2-[4-(2-hydroxyethyl)hept-6-enylthio]-4,5-diphenylimidazole, in the form of a colourless gum;
0 2-(2-oxoprop-1-yl)thio-4,5-diphenylimidazole, m.p. 145-147C; and P 2-(2-diethylaminoethylthio)-4,5-diphenyl-imidazole, m.p. 90-92C;
Q ~y again proreeding in a similar manner, but replacing the ~-bromoethyl ethyl ether by 2-diisopropylaminoethyl chloride hydrochloride and the potassium carbonate by potassium t-butoxide, and treating a solution of the free base in ethanol with a solution of hydrogen chloride in e~hanol [prepared by add~ng acetyl chloride (12ml) dropwise to cold ethanol tlOOml;10C) with stirring, maintaining the t~mperature below 30C] there was prepared 2-(2-diisopropylamino-ethylthio)-4,5-diphenylimidazole, m.p.183-185C.
[Elemental analysis:- C,60.8;H,7.1;N,9.jS,7.3;Cl,14.4~, Calculated (C23H29N3S:1.8HC1:0.5H2O):- C,60.8;H,7~05;
N,9.25;S,7.06;Cl,14.05%].
2o78-2~)8 - 32 -Compound R
A stirred suspension of lithium hydroxide hydrate (4.2g) in ethanol (200ml) was treated, portionwise, with 4,5-diphenylimidazole-2-thiol. The mixture was stirred at ambient temperature for 0 minutes and then~.it was treated with propargyl chloride (7.45g), and stirring was continued for a further 3 hours. The reaction mixture was poured into water with stirring, and the resulting solid was filtered off, washed with water and dried. Recrystallisation from a mixture of petroleum ether (b.p.40-60C) and dichloromethane, and then from toluene, gave 2-propargylthio-4,5-diphenylimidazole (16.07g) in the form of a white solid, m.p. 164-166C.
tElemental analysis:- C~74.2;H,4.73;N,9.6;5,10.9%;
Calculated:- C,74.45jH,4.86;N,9.65;S,11.04%3.
Compounds S T and U
S A stirred suspension of 4,5-bis(2-chlorophenyl)-imidazole-2-thiol (2.0g) in anhydrous methanol (20ml) was treated with sodium methoxide (0.41g) and then - stirred at room temperature for 5 minutes. The mixture was then treated with 2-bromomethyltetrahydro-2H-pyran (2.0g) and stirred at reflux for 2 hours.
After cooling to room temperature the mixture was WO9l/13876 PCT/GB91/00408 ~ 33 ~ 2 0782 poured into water (250ml) and the precipitate was filtered off. The product was dissolved in dichloromethane (lOOml) and the solution was dried (magnesium sulphate) and evaporated. Trituration of the residue with diethyl ether gave a white solid, which was crystallised from methanol, to give [+)-4,5-bis(2-chlorophenyl)-2-t(tetrahydro-2H-pyran 2-yl)methylthio]imidazole (1~85g) in the form of a white powder, m.p. 162-4C.
[Elemental analysis:- C,60.2;H,4.82;N,6.82;S,7.5%;
Calculated:- C,60.15;H,4.81;N,6.68;S,7.~5.
NMR (in CDC13):- 1.5-2.0 (6H,m), 3.03 (lH,dd,J = 8Hz, 6Hz), 3.27 (lH,dd,J = 12Hæ, 2Hz), 3.59 (lH,dt,J = 12Hz, 2Hz), 3.72 (lH,m), 4.21 (lH,dt,J = lOHz, 2Hz)].
By proceeding in a similar manner, but replacing the 4,5-bis(2-chlorophenyl)imidazole-2-thiol with the appropriate quantity of the corresponding imidazole-2-thiol, there were prepared:-T [+]-4(5)-(2-chlorophenyl)-5(4)-phenyl-2-[(tetra-hydro-2H-pyran-2-yl)methylthio~imidazole, `m.p. 58-60C.; and U ~*]-4(5)-(3-chlorophenyl)-5(4)-phenyl-2-[(tetrahydro=2H-pyran-2-yl)methylthio]imidazole, m.p.
113-5~.
W091/13876 PCr/GB9l/00408 2~7 82~ 8 _ 34 _ Com~ounds V, W. X and Y
V A stirred suspension of 4,5-diphenylimidazole-2-thiol (4.2g) in anhydrous tetrahydrofuran (60ml) was treated with sodium hydride (80% dispersion in oil, 0.67g) under an argon atmosphere. After stirring at room temperature~or 30 minutes the mixture was treated with t+]-2-iod'omethyl-1,4-dioxane (4.2g). The resulting mixture was stirred at room temperature for 2 days, and then it was poured into water (500ml) and the product was filtered off and dried at 60C.
Crystallisation ~rom a mixture of isopropanol and diethyl ether gave [+]-2-[(1,4-dioxanyl)methyl-thio]-4,5-diphenylimidazole (1.14g), m.p. 144-147C.
[Elemental analysis:- C,68.0;~,5.6s;N,g.2;S,9.0%;
Calculated:- C~68.18;H,5.68;N,7.95;S,9.10%.
NMR (in CDCl3):- 3.04 (lH,dd,J = 14Hz, 8~z), 3.13 (lH,dd,J = 16Hz, 4Hz), 3.52 (lH,t,J - lOHz), 3.6-4.0 (6H,m), 7.2 7.7 (lOH,m).
By proceeding in a similar manner, but replacing the [+]-2-iodomethyl-1,4-dioxane by the appropriate quantity of the corresponding halide, and optionally carrying out the reaction in the presence of triethylamine at temperatures from ambient ~o the reflux temperature, there were prepared:-W [+]-2-[(2,2-di(methoxymethyl)tetrahydro-2H-WO91/l3876 PCT/GB9l/00408 ,~ .20782o8 pyran-6-yl)methylthio]-4,5-diphenylimidazole, m.p.
143-145C.; and X 2-(3-dimethylaminopropylthio)-4l5-diphenyl-imidazole, m.p. 138-140C.
By again pxoceeding in a similar manner, but replacing the t+]-2-iodomethyl-1,4-dioxane by the appropriate quantity of 10-tosyloxy-2,5,8-~rioxadecane and carrying out the reaction at 40-50C for 150 minutes, there was prepared:-Y 2-~3,6,9-trioxadecylthio)-4,5-diphenylimidazole, in the form of a yellow oil.
[Elemental analysis (C22H26N203S:0.5C~30H):-C,64.9;H,S.59;N,6.69;S,7.8%;
Calculated:- C,65.2;H,6.58;N,6.76;S,7.7%].
Compounds Z and AA
Z A stirred suspension of 4,5-diphenylimidazole-2-thiol (2.9g) in anhydrous ~etrahydrofuran (40ml) was treated with sodium hydride (80% dispersion in oil, 0.36g)under an argon atmosphere. The mixture was stirred at room temperature ~or 30 minutes and then it was treated with [+~-2,2-di(acetoxymethyl)-6 iodomethyltetrahydro-2H-pyran (4.9g). The resulting mixture was stirred at room temperature for 24 hours, poured into water (SOOml~, and the product was extracted into diethyl ether (lOOml). The ethereal solution was washed with watler (50ml), dried (magnesium sulphate), and evaporated. The brown gummy residue was subjected to flash chromatography (eluting with a mixture of methanol and dichloromethane; 1:9 v/v) to give crude [+]-2-[2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenylimidazole l4.8g).
A ~ixture o~ this product and potassium hydroxide (lo 68g) in ethanol (25ml) and water (5ml) was stirred at room temperature for 75 minutes. The mixture was then evaporated to low bulX, diluted with water (40ml) and extracted with ethyl acetate (lOOml, then 2x50ml). The resulting organic solution was dried (magnesium sulphate) and evaporated and the residue was crystallised from a mixture of methanol and ethyl acetate, to give [i]-2-[2,2-di(hydroxymethyl)-tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenyl~
imidazole (1.54g), m.p. 176-178C.
[Elemental analysis:- C,67.1;H,6.43jN,6.7,S,7.9%, Calculated:- C, 67.32;~,6.34;N,6.83;S,7.80%.
NMR (in a mixture of CDCl3 and D2O):- 1.2-1.8 (6H,m), 2.79 (lH,dd,J = lOHz, 12Hz), 3.07 (lH,dd,J = 12Hz, 2Hz), 3.49 (2H,m), 3.69 (l~,d,J = lOHz), 3.81 (lH,dt,J
= lOHz, 2Hz), 4.14 (lH,d,J = lOHz), 7.2-7.6 (lOH,m)].
AA A s~lution of [~]-2-[2,2-di(hydroxymethyl)-tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenyl-:.`'' ' ;
_ 37 - ~0~782~8 ,.
imidazole (1.2y) in pyridine (5ml) was treated with acetic anhydride (0.92g) and the mixture was stirred at room temperature overnight. The mixture was treated with a further quantity of acetic anhydride (0.92g) in pyridine (5ml), followed, after one hour, by mathanol (2Oml). Evaporation of the mixture gave a colourless gum. The residue was treated with a mixture of water (20ml) and methanol (20ml) andiit was evaporated again. This procedure was repeated three times, and then th~ residue was dissolved in ethyl acetate (25ml).
This solution was dried (magnesium sulphate) and evaporated to give a pale yellow glass. This was triturated with a mixture diethyl ether and pentane to give [+]-2-[2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenylimidazole ~l.Og) in the form of a stable meringue, m.p. 50-56C.
[Ele~ental analysis:- C,65.7;H,6.25;N,5.80;S,6.4%;
Calculated:- C,65.~9;H,6.07;N,5.67;S,6.48%.
NMR (in CDCl3):- 1.3-1.8 (6H,m), 1.82 (3H,s), 2.07 (3H,s), 2.93 tlH,dd,J = 16Hz, 8Hz), 3.05 (lH,dd,J =
lO~z, 2Hz), 3.95 (2H,m), 4.02 (lH,d,J = 12Hz), 4.11 (lH,d,J = 12Hz), 4.85 (lH,d,J = 12Hz), 7.2-7.6 (lOH,m)]-2~7 8~ 08 3~ _ . EXA~PLE 6 Com~ounds AB and AC
AB A mixture of 4,5-diph,enylimidazole-2-thiol (5.0g) and 2-bromoethanol (2.5g) in ethanol (150ml) was stirred at reflux for 4 hoursO The mixture was filtered hot, cooled t'~5~C., neutralised by treatm2nt with sodium hydrox~de solution (2N) and poured into iced water (1500~13. The resulting cream solid (4.8g) was filtered off and subjected to flash chromatography (eluting with a mixture of dichloromethane and methanol (19:1 v/v) followed by crystallisation from ethanol, to give 2-(2-hydroxy-ethylthio)-4,5-diphenylimidazole (0.7g), in the form of a white crystalline solid, m.p. 168-70C.
[Elemental analysis:- C,68.7;H,5.5;N,9.4;S,10.6~;
Calculated:- C,68.9;H,5.45;N,9.45;S,10.81%.
NMR (in CD3SOCD3):- 3.20 (2H,t,J - 8Hz), 3.68 (2H,t,J =
8Hz), 7.2-7.5 (lOH,m)].
AC By proceeding in a similar manner, but replacing the 2-bromoethanol by bromoethane, there was prepared:-2-ethylthio-4,5-diphenylimidazole, m.p. 190C.
: EXAMPLE 7 Compound AD
A mixture of 2-(2,2-di~thoxyethylthio)-4,5-diphenylimidazole (lO.Og), pyridinium 4-toluene-~ 39 2~78'2b8`"`'`' , sulphonate, polymer-bound (1.6g; approximately 6mmole of active component), and 1,3-propanediol (lO.Og) in toluene (500ml) was stirred at reflux under a Dean and Stark water trap for 24 hours. At periodic intervals of about ~ne hour the fluid collected in the wat~r trap was run off and replaced.in the reaction flask by fresh toluene. After cooli~g to room temperature, the mixture was washed with water (3x250~1), dried (magnesium sulphate) and evaporated. The resulting dark orange oil was subjected to flash chromatography (eluting with mixtures of ethyl acetate and dichloro~ethane; 1:9-4:6 v/v) and crystallised from ethyl acetate, to give 2-[(1,3-dioxan-2-yl)methylthio]-4,5-diphe~ylimidazole, (2.3g) m.p. 153-155C.
[Elemental analysis:- C,68.3;H,5.75;N,7.9;S,9.1%;
Calculated:- C,68.15;H,5.72;N,7.95;S,9.10%.
NMR (in CDCl3):- 1.38 (lH,m), 2.10 (lH,m) 3.11 (2H,d,J
= 6Hz), 3.87 ~2H,dt,J = lOHz, 2Hz), 4.16 (2H,dd,J =
lOHz, 6~z), 4.89 (lH,t,J = 6Hz), 7.2 7.5 (lOH,m)].
Compounds AE AG and AJ
AE A stirred solution of 2-(3-aminopropylthio)-4,5-diphenylimidazole (3036g) in ethanol (150ml) at the ambient temperature was treated with S,S'-dimethyl-N-WO9l/13876 PCT/GB91/00408 20~ 8208 40 _ cyanodithioiminocarbonate (1.76g), and stirred for onehour. The resulting solid was filtered off, washed with diethyl ether and dried, to give -cyano-2-methyl-l-r3-(4,5-diphenylimidazol-2-ylthio)propyl]isothiourea (3.15g) in the form of a colourless solid, m.p.
225-227C. .;
[Elemental analysiso- C,61.8;H,5.3jN,17.1;S,15.6~;
calculated:- C,61.92;H,5.16;N,17.20;S,15.72~.
NMR (in a mixture of CD3SOCD3 and D20):- 1.94 (2H, quin,J = ~Hz), 2.53 (3H,s), 3.13 (2H,t,J = 7Hz~, 3.44 (2H,t,J = 7Hz), 7.1-7.5 (lOH,m)].
A& By proceeding in a similar manner, but replacing the 2-(3-aminopropylthio)-4,5~diphenyli~idazole with the appropriate quantity of 2-(4-aminobut~lthio)-4,5-diphenylimidazole, stirring for a ~otal of 5 hours and, after evaporation of the reaction mixture, subjecting the residue to mplc (using a mixture of dichloromethane and methanol; 19:1 v!Y) as eluent, there was prepared 3-cyano-2-methyl-1-[4-(4,5-diphenylimidazol-2-ylthio)-butyl]isothiourea (4.4g) in the form of a colourless solid, m.p.103-105C. (from isopropanol).
tElemental analysis:- C,62.5;H,5.46;N,16.5;S,15~3%;
Calculated:- C,62.68;H,5.50;N,16.61;S,15.21~.
W091113876 PCT/GB91~00408 - ~1 - 2~7820~
NMR (in a mixture of CD3SOCD~ and D20):- 1.67 (4H,m~, 2.54 (3H,s), 3.13 (2H,t,J= 7Hz), 3.3-3.36 (2H,m), 7.2-7.47 (lOH,m)].
AJ By again proceeding in a si~ilar manner, but replacing the 2-( 3 -aminopropylthio)-4,5-diphenyl-imidazole with 2- (2-aminoethylthio)-4,5-diphenyl-imidazole, there was prapared 3 -cyano-2-methyl-1-[ 2-(4, 5-diphenylimidazol-2-ylthio)-athyl]isothiourea (3. 02g) in the form of a colourless solid, m.p. 215-217C. (~rom ethanol). [Elemental analysis:- C,61.2;H,4.96;N,18.1;S,16.2%; Calculated:-C,61.04;H,4.87;N,17.80;S,16.30%.NMR (in a mixture of CD3SOCD3 and D20):- 2.38 (3H,s), 3~35 (2H,t,J= 7Hz), 3.74 (2H,t,J = 7Hz), 7.1-7.55 (lOH,m)].
Com~ound AF
AF A suspension of 3 cyano-2-methyl-1-[2-(4,5-diphenylimidazol-Z-ylthio)ethyl]isothiourea (1.6g) in ethanol (lOOml) was treated with hydrazine hydrate (0.6ml). The mixture was heated under reflux for 2 hours, and the resulting solution was evaporated.
The residue was dissolved in ethanol (250ml) and was then treatecl with a solution o~ acetyl chloride (5ml) in ethanol (20ml) with ice cooling. After stirring for 10 minutes, the solution was evaporated and the residue was dissolved in methanol (2Oml). The ~ 8 P~/GB91/00408 solution was treated with diethyl ether (60ml) and left to stand for 20 hours. The resulting solid was filtered off and dried, to give 2-[2-(5-amino-1,2,4-triazol-3-ylamino)ethylthio]-4,5-diphenylimidazole dihydrochloride ~1.03g) in the form of a colourless solid, m.p. 223-226C.
[Elemental analysis:- C,49.2;H,4.5;Cl,15.1;N,21.3;
S,7.1:H20,3.2%;
Calculated (for C1gH1gN7S 2HCl H20~ ~
C,48.72jH,4.91;Cl,15.17;N,20094;S,6.84%.
NMR (in D20):- 3.46-3.66 (4H,m), 7.36-7.54 (lOH,m).
Example 10 Compounds AI and AH
AI A suspension of 3-cyano-2-methyl-1-[3-(4,5-diphenylimidazol-2-ylthio~propyl]isothiourea (2.2g) in ethoxyethanol (200ml) was treated with hydrazine hydrate (3.14~1). The mixture was heated under reflux for 6 hours, and the resulting solution was evaporated. The residue was triturated with hot acetonitrile (lOOml), and the resulting solid was collected and dried, giving 2-t3-(5-amino-1,2,4-triazol-3-ylamino)propylthio]-4,5-diphenylimidazole (1.45g) in the form of a colourless solid, m.p. 225-227C.
[Elemental analysis:- C,61.~;H,5.5;N,24.6;5,8.3%;
Calcula~ed:- C,61.36;H,5.41;N,25.04;S,8.19%.
W091/13876 PCT/GB9t/00408 43 207~2~8 .;
NMR (in a mixture of CD3SOCD3 and D20):- 1.87 (2H,quin,J= 7Hz~, 3.1-3.17 (4H,m)j 7.16-7.50 (lOH,m) ] .
AH By proceeding in a similar manner, but substituting ethanol for the ethoxyethanol and 3-cyano-2-methyl-1-[4-(4,5 diphenyli~idazol-2-ylthio)butyl]isothiourea for the 3-cyano-~-methyl-1-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-isothiourea, there was prepared:-2-~4-(5-amino-1,2,4-triazol-3-ylamino)butylthio]-4,5-diphanylimidazole in the form of a colourless solid, m.p.
214-216C. (from isopropanol~.
[Elemental analysis:- C,62.0;H,5.7;N,24.0;S,8.2%;
Calculated: C,62.2;H,5.72,N,24.18;S,7.91~.
NMR (in a mixture of CD3SOCD3 and D20):- 1.57-1.74 ~4H,m), 3.03 (2H,t,J = 7Hz), 3.13 (2H,t,J = 7Hæ), 1.17-7.48 (lO~,m)3.
Compound AM
A suspension of 2-(3-aminopropylthio)-4,5-diphenyl-imidazole (1.55g; prepared as described in Reference Example 1) in acetic anhydride (lOml) was heated at 100C for 3 minutes and then it was allowed to cool to the amblent temperature. The solu~ion was then poured into water t50ml) and the mixture was allowed to stand for 90 minutes. The solution was treated with aqueous sodium hydroxide solution (2N) until it was WO9lJ13876 PCT/GB91/00408 .f--.
~7~ 44 -alkaline, and the mixture was then extracted with dichloromethane (2x30ml). The combined extracts were dried (MgSO4) and evaporated, to give a colourless solid, which was recrystallised from acetonitrile, to give 2-~3-acetamidopropylthio)-4,5-diphenylimidazole tl.08g) in the form of a colourless solid, m~p. 180-181C.
EElemental analysis:- C,68.7;H,6.1;N,12~1;S,8.9%;
Calculated:- C,68.3~;H,6.02;N,11.96;S,9.12%.
NMR (in CDCl3) 1`'88 (2H,quin,J = 7Hz), 3.18 (2H,t,J =
7Hz), 3.44 (2H,q,J = 7Hz), 7.2-7.58 (lOH,m), 7~65 (lH,br.t,J = 7Hz)].
Example 12 Compounds_AO, AK ~AN and AP
AO A stirred suspension of ~,5-diphenylimidazole-2-thiol (3.28g) in dry tetrahydrofuran (lOOml) was treated with a dispersion of sodium hydride on oil (0.6g; 60%) at ambient temperature. After stirring at ambient temperature for 20 minutes. The solution was treated with 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide (4.2g), followed by triethylamine (5ml).
The resulting mixture was heated at reflux f or 20 hours and then diluted with water ~180ml) and diethyl ether (80ml). The organic layer was separated and extracted with dilute hydrochloric acid (lOOml;lN). The acidic aqueous phase was then separated, made alkaline by treatment with aqueous so~ium hydroxide solution (lN) WO9l/13876 PCT/GB91/00408 ~ . .
2;~7;&?0:~`
and then extracted with diethyl ether (2xlSOml). The combined extracts were dried tMgS04) and evaporated, to give a solid residue, which was recrystallised ~rom acetonitrile, to give N-(4~6-dimethylpyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide (2.5g) in the form of a colourless solid, m.p. 186-188C.
[Elemental analysis:- C,70.4;H,5.81;N,12.6;S,6.6%;
Calculated:- C,70.56;H,5.92,N,12.66;S,7.25%.
NMR (in CDC13):- 2.17 (2H,quin,J = 7Hz), 203 (3H,s), 2.35 (3H,s), 2.62 (2H,t,J - 7Hz), 3.1 (2H,t,J = 7Hz), 6.74 tlH,s), 7.23-7.57 (lOH,m), 7.79 (lH,s), 8.22 ~lH,br.s)].
AK By proceeding in a similar manner, but substituting the appropriate quantity of 4-c~loro-N-(4-methylpyrid-2-yl)butanamide for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide, there was prepared:-N-(4-methylpyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide in the form of a colourless solid, m.p. 147-149C.
[Elemental analysis:- C,69.5;H,5.7;N,13.0;S,7.7%;
Calculated:- C,70.09;H,5.61;N,13.08;S,7.~8~.
NMR (in CDC13):- 2.19 (2~,quin,J = 7~z), 2.35 (3H,s), 2.65 (2H,t,J = 7Hz), 3.14 (2H,t,J = 7Hz), 6.86 (lH,d,J
= 6Hz), 7.2-7.63 (lOH,m), 7.97 (lH,s), 8.02 (lH,d,J =
6Hz), 8.49 (lH,br.s)].
` .
207820g AN By proceeding in a similar manner, but substituting the appropriate quantity of N-(4-chlorobutanoyl~-2,6-dimethylmorpholine for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide , there was prepared:-2,6-dimethyl-N-[4-(4,5-diphenylimidazol~2-ylthio)-butan-1-oyl]morphoiine (4.7g) in the for~ of a colourless so~i~d, m.p. 147 149C.
tElemental analysis:- C,68.6j~,6.79;N,9.7;S,7.4%;
Calculated:- C,68.~3;H,6.71;N,9.65;S,7.36%.
AP By proceeding in a similar manner, but substituting the appropriate quantity of 4-chloro-N-(pyrid-2-yl)butanamide for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide, there was prepared:-N-(pyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide (O.8g) in the form o~ a colourless solid, m.p. 167-163C.
tElemental analysis:- C,68.8;H,5.19;M,13.2~;
Calculated:- C,69.54;H,5.35jN,13.52%].
Example 13 ComPoun~d AL
A stirred suspension of lithiu~ aluminium hydride (0.42g) in dry tetrahydrofuran was treated portionwise with N-(4,6-dimethylpyrid-2~yl)-4-(4,5-diphenylimidazol-2ylthio)butanamide t2.44g) at -10C
under an argon atmosphere. The mixture was then . . .
~ 47 ~ 2078208 stirred at the a~bient temperature for 2 hours.
It was then treated with water (0.7ml), followed by aqueous sodium hydroxide solution (2.1ml;15%) and then water (2.lml). After stirring for lO minutes, the mixture was filtered and the filtrate was evaporated, to give a colourless solid. This solid was subjected to flash chromatography on silica gel, using a mixture of dichloromethane and methanol (39:1 v/v) as eluent, to give 4,6-dimethyl-2-[4-(4,5-diphenyl-imida~ol-2-ylthio)butylamino]pyridine (1.64g), in the form of a colourless solid, m.p. 166-168C.
[Elemental analysis:- C,72.7;H,6.6;N,12.9;S,7.5%;
Calculated:- C,72.9;H,6.54;N,13.08;S,7.48%.
NMR (in CDCl3):- 1.73-1.84 (4H,m), 2.18 (3H,s), 2.2 (3H,s), 3.1 (2H,t,J = 7Hz), 3.22 (2H,q,J = 7Hz), 4.63 (lH,br.t,J = 7Hz), 6.0 (lH,s), 6.27 (lH,s), 7.2-7.63 (lOH,m).
Compounds AO to BF
AQ Sodium methoxide (2.16g) was added to a stirred suspension of 4,5-diphenylimidazole-2-thiol ~lO.Og) in anhydrous methanol (250ml). After stirring at room temperature for 30 minutes methyl 4,5-epoxypentanoate (7.7g) was added and the mixture was stirred at room temperature overnight. Evaporation gave a light yellow residue, which was shaken with ethyl acetate WO91/13X76 PCT/~B91/00408 207~208 - 48 -t250ml) and water (2SOml). The layers were separated and the organic layer dried (magnesium sulphate) and evaporated. The residue was boiled with methanol (lOOml) for 15 minutes and then allowed to cool to room temperature. The white insoluble solid was collected by filtration and washed with a little fresh methanol.
The solution was t~r,eated with fresh methanol (lOOml) and lM sodium hy,droxide solution (50ml). After standing at room temperature for 2 hours the clear solution was evaporated to dryness and shaken with ethyl acetate (200ml) and 2M acetic acid solution (150~1). The layers wera separated a~d the organic layer dried (magnasium sulphate) and evaporated. The oily residue was dissolved in dichloromethane (300ml) and treated with trifluoroacetic acid (10~1). After standing at room temperature for 2 hours the solution was washed with 5% sodiu~ hydrogen carbonate solution (5xl50ml), dried (magnesium sulphate) and evaporated. The resulting white foam was subjected to flash chromatography (ethyl acetate-dichloromethane mixture, 1:1 vtv).
Crystallisation from ethyl acetate/hexane gave (5R,5S)-4,5-diphenyl-2-[(2-oxotetrahydrofur-5-yl)methylthio~imidazole,(2.0g) in the form of a dense white solid, m.p. 118-120C.
[Elemental analysis:- C,6B.7;H,5.21;N,7.9;S,9.1%;
Calculated:- C,68.55;H,5.18;N,7.99jS,9.15~.
49 _ 207~208 NMR (in CDC13):- 2.10 (lH,m), 2.3-2.7 (3H,m) 3.32 (lH,m~, 4.83 (lH,m), 7.2-7.5 (lOH,m)].
AR ~y proceeding in a similar manner, but substituting 4,5-bis(3-chlorophenyl)imidazole-2-thiol for the 4,5-diphenylimidazole-2-thiol, and t-butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate for the methyl 4,5-epoxypentanoate, there was prepared:-(4R,4S)(6R,6S)-6-[(4,5-bis{3-chlorophenyl}imidazol~2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one in the form of a white solid, m.p. 178C.
[Elemental analysis:- C,57.~;H,4.32;Cl,15.1;N,5.88;
S,6.73%; Calculated:- C,57.02;~,4.35;Cl,15.3;N,6.05, S,6.9~%. N~R (in CDC13):- 1.35(3H,s), 1.66-1.8(1H,m), 2.14-2.22(1H,m), 2.4-2.78(2H,m), 3.4(2H,d,J = 4Hz), 4.41 (lH.s),4.9-5.1(1H,m)].
By again proceeding in a similar manner, and replacing the 4,5-bis(3-chlorophenyl)imidazole-2-thiol with the appropriate quantity of the corresponding imidazole-2-thiol, there were also prepared:-AS (4R, 4S) (6R, 6S~-6-~(4,5-Bis{4-chlorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one, m.p. 190-1C.
[Elemental analysis:- C,56~8;H,4.3;C1~15.7;N~5~s;S~6~82%;
Calculated:- C,57.02;~,4.35;Cl,15.3;N,6.05;S,6.92%].
AT (4R,4S)(6R,6S)-6-[(4,5-Bis{2-chlorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydro-~97;~2~ - so py~an-2-one, m.p. 100C.
[Elemental analysis:- C,56.8;H,4.36;Cl,15.2;N,6.04;S,7.2%;
Calculated:- C,57.02;H,4.35;Cl,15.3;N,6.05;S,6.92%].
AU (4R,4S)(6R,6S)-6-[(4,5-Bis{4-fluorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one, m.p.~ l74-178C.
[Elemental analysis:- C,61.7;H,4.8;F,8.9;N,6.5;S,7.4%;
Calculated:- C,61.38;H,4.68;F,8.83;N,6.51;S,7.45~].
AV (4R,4S)(6R,6S)-6 [(4,5-Bis{4-trifluoromethyl-phenyl}imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyl-tetrahydropyran-2-one, m.p. 205C.
[Elemental analysis:- C,54.6;H,3.99;N,5.28%;
Calculated:- C,54.3;H,3.80;N,5.28~].
AW (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one, ~.p. 86-88C.
[Elemental analysis:- C,67.90;H,6.40jN,6.50;S,7.30~;
Calculated:- C,68.22;H,6.20;N,6.63;5,7.59%].
AX (4R,4S)(6R,6S) 4-Hydro~y-6-[(4,5-bis{4-methyl-phenyl}i~idazol-2-yl)thiomethyl]-4-methyl~etrahydro-pyran-2-one, m.p. 205-7C.
[Elemental analysis:- C,68.1;H,6.09;N,6.42%;
Calculatedo- C,68.22;~,6.20;N,6.63%].
AY (4R,4S)~6R,6S)-4-Hydroxy-6-[(4,5-bis{4-isopropylphenyl}imidazol-2-yl)thiomethylJ-4-methyltetrahydropyran-2 one, m.p. 89-91C.
.
Sl 2~78208 ...
, [Elemental analysis:- C,69.8;H,7.2;N,5.9;S,6.36~;
Calculated:- C,70.26;H,7.16;N,5.85;S,6.69%.
AZ ~4R,4S)(6R,6S~-6-E(4,5-Bis{4-tertbutylphenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy~-methyltetra-hydropyran-2-one, ~.p. 134-51C.
[Elemental analysis (C30H38N203S:1~4H20~:-C,70.5;H,7.7;N,5.3;S,6.33;H20,1.2%;Calculated:- C,70.48;H,7.59;N,5.48;S,6.2,H20,0~81~].
B~ (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{2-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one, m.p. 108-10C.
[Elemental analysis (C24H26N205S:C4~02):~
C,61.8;H,5.9;N,5.5;S,6.37%;
Calculated:- C,61.99;H,6.27;N,5.17;S,5.90%].
BB (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyl-tetrahydropyran-2-one, m.p. 148C.
[Elemental analysis (C24H26N205S:0-45C4H802):-C,62.2;H,5.74jN,5.79%;
Calculated:- C,62.7;H,6.04;N,5.67;S,6.94%].
BC ~ BD
BC By proceeding in a similar manner, and replacing the 4,5-bis(3-chlorophenyl)imidazole-2-thiol by 4,5-diphenylimidazole-2-thiol in the reaction with t-butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate, there was obtained a product in the form of a mixture of 2 racemates. This mixture was ~riturated with diethyl ether, and the insoluble material recrystallised from a mixture of ethyl acetate and methanol, to give 6-[(4,5-diphenylimidazol-2-y:L)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one, m.p. 201-202.5C.
[Elemental analysis:- C,67.10;H,S.70;N,7.10;S,8.00%;
Calculated:- C,66.98;H,5.62;N,7.10;S,8.13%.
NMR (in CD3SOCD3)~ 1(3H,s), 1.64-2.06(2H,m), 2.3-2.6(2H,m), 3.4-3.5(2H,m), 4.76-4-92(1~,m), 5.06(lH,m)].
BD The washings from the trituration were concentrated, to give a white solid, which was recrystallised from a mixture o~ ethyl acetate and methanol, to give 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one, m.p. 203.5-205C.
[Elemental analysis: C,66.60;H,5.56;N,6.94;S,8.10%;
Calculated:- C,66.98;H,5.62;N,7.10;S,8.13%.
NMR (in CD3SOCD3):- 1.24(3H,s~, 1.7-2.3(2H,m), 2.3-2.7(2H,m), 3.4-3.5(2H,m~, 4.S4-4.7(lH,m), 5.04(1~,s), 7.15-7.6(lOH,m)].
BE ~ BF By proceeding in a similar manner to that described for Compounds BC and BD, but replacing the 4,5-diphenylimidazole-2-thiol by the appropriate quantity of 4,5-bis-(4-methoxyphenyl)imidazole-2-thiol, there were obtained:-_ ~3 _ 2078208 4 hydroxy-6-[(4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one, m.p. 214-215 and 90-115C. [Elemental analyses:-Compound BE:- C,63.3;H,5.82;N,6.11;S,7.1%;
Compound BF:- C,63.8;H,5.94;N,5.94;S,6.9%;
Cal~ulated:- C,63.44; H,5.73;N,6017;S,7.05%~.
Compounds B~ TO BL
BG A suspension of (4R,4S)(6R,6S)-4-hydroxy-6-[(4,5-bis~4-methylphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one (4.7g.) in dichloro-methane (250ml) was treated dropwise with tri~luoroacetic anhydride ~6.3g) with ice-cooling, and left to stand at room temperature for 24 hours. ~he r~sulting solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, and evaporated, to give a gum. This gum was dissolved in tolùene (200ml), and treated with 1,8-diazabicyclo[5.4.0]undec-2-ene (4.~g), and left to stand at room te~perature for 24 hours. The solution was then washed with wa~er, dried over magnesium sulphate, and evaporated to give a white foam. This was recrystallised from a mixture of ethyl acetate and methanol, to give (6R,6S)-6-[(4,5-bis{4-methylphenyl}-imidazol-2-yl~thiomethyl]-5,6-dihydro-4-methylpyran-2-one, (2.1g), m.p. 191C.
20~2~8 - 54 ~
[Elemental analysis:- C,71.2;H,6.12;N,6.85;S, 7.8 %;
Calculated:- C,71.26;H,5.98jN,6.93;S,7~93%.
NMR (in CDCl3):- 1.96(3H,s), 2.3(6H,s), 2.54~2H,d,J =
8Hz), 3 .48(2H,d,J = 6Hz), 4.6-4.8(1H,~), 5.8(1H,d), 7.0-7.2(8H,m).
By proceeding in a similar manner, but replacing compound AX with the appropriate quantity of the corresponding compound from compounds AR to BF, there were also prepared:-BH (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)-thiomethyl]-5,6-dihydro-4-methylpyran-2-oner m.p. 70-71C.
LElemental analysis:- C, 69.7;H,5.69;N,7.3;S,8.6%;
Calculated:- C,70.19jH,5.36;N,7.44;S,8.52%~.
BI (6R,6S)-6-~(4,5-Bis{4-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p~
175-176C. [Elamental analysis:-C,59.1;H,4.04;N,6.3;S,7.3;Cl,15.8~;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;Cl,15.92%~.
BJ (6R,6S)-6-[(4,5-bis{3-chlorophenyl}imidazol-2-yl ? thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p.
132-135C.
[Elemental analysis:-C,59.3;H,4.2;N,6.4;S,7.1;Cl,15.6%;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;C1,15.92%~.
BK (6R,6S)-6-~(4,5-bis-{2-chlorophenyl}imidazol-W091~13876 PCT/GB91/00408 _ 55 _ 20 782 08 2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p..
126-127C.
[Elemental analysis:- C,59.2;H,4.04;N,6.2;Cl,15.9%;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;Cl,15.92%].
BL (6R,6S)-6-[(4,5-bis-{4-fluorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p.
123-126C.
[Elemental analysis:- c~64.5;H~4.6;N~6.9;s~7.a;F~9.3%;
Calculated:- C,64.06;H,4.4;N,6.79;S,7.77;F,9.21%].
Compounds BM TO BO
BM A mixture of 5-(iodomethyl)-2-furanone (2.06g), 4,5-bis-(4-methylphenyl)imidazole-2-thiol (2.2gg), and potassium carbonate (0.5~g), in dry dimethylformamide (40ml~ was stirred at room temperature for 24 hours.
The dimethylformamide was removed by evaporation at reduc~d pressure, and the residue was shaken with water and dichloromethane, the organic layer separated, and the aqueous layer extracted with more dichloromethane.
The combined organic solutions were dried over magnesium sulphate and concentrated, to give a yelIow semi-solid. This was subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane, (3:7v/v), and the foam obtained was recrystallised from diethyl ether to give (5R, 5S) -5-[ (4, 5-bis-{4-methylphenyl}imidazol-2-WO9l/t3876 PCT/GB91/00408 ., -yl)thiomethyl]tetrahydrofuran-2-one, (2.05g), m.p.
128-129C.
[Elemental analysis:- C,69.7;H,5.83;N,7.3;S,8.6%;
Calculated:- C,69.81;H,5086;N,7.40;S,8047%.
NMR (in CDCl3):- 1.96-2.7(4H,m), 2.36(6H,s), 3.3(2H,dd,J = 6Hz,2HZ), 4.72-4.9(1H,m), 6.96-7.5t8R,m)]. ~;
BN By proceeding in a similar manner, but replacing the 4,5-bis-(4-methylphenyl)imidazole-2-thiol by the appropriate quantity of 4,5-diphenylimidazole-2-thiol, and the 5-(iodo~ethyl)-2-furanone by the appropriate quantity of (6R,6S)-6-(iodomethyl)-3,4,5,6-tetrahydropyran-2-one, there was prepared:-(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-3,4,5,6-tetrahydropyran-2-one, with no sharp melting point.
[Elemental analysis:- C,69.00;H,5.52;N,7.7;S,8.70%;
Calculated:- C,69.20;H,5.53;N,7.69;S,8.80].
fiO By again procaeding in a similar manner, but replacing-the ( 6R, 6S) -6- ( iodomethyl)-3,4,5,6-tetrahydropyran-2-one by 4,4-dimethyl-6-iodomethyl-3,4,5,6-tetrahydropyran-2-one there was prepared:-(6R,6S)-6-t(4,5-diphenylimidazol-2-yl)thiomethyl]-4,4-dimethyl-3,4,5,6-tetrahydropyran-2-one, m.p.
130-131C.
tElemental analysis:- C,70.0;H,6.34jN,6.6;S,8.1%;
- 57 - 2 ~ 782 08 Calculated:- C,70.38;H,6.16;N,7.14;S,~.17%.
By again proceeding in a similar manner, but replacing the 5-(iodomethyl)--2-furanone by (4R,4S)(6R,6S)-4-hydroxy-6-iodomethylpyran-2-one, there was obtained, after chromatography:-BP (4R,4S)(6R,6S)-6- E (4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-3 r 4,5,6-tetrahydropyran-2-one, m.p. 191-192C.
[Elemental analysis:- C,66.2;H,5.26;N,7.3;S,8.2%;
Calculated:- ~,66.29;H,5.30;N,7.36;S,8.43~] and BQ (3R,3~)(5R,5S)-ethyl ~-[(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydrox~hexanoate, m.p. 94-95C.
[Elemental analysis:- C,64.4;H,6.02;N,6.48;S,7.5 ~;
Calculated:- C,64.77;H,6.14;N,6.57;S,7.52%].
NMR (in CDC13):- 1.21(3H,t), 1.5-2.1(2H,m~, 2.22-2.6(2H,m), 2.9-3.2~2H,m), 4.16(2H,q), 2.2-2.4(2H,m).
Compound BR
A mixture of 4,5-diphenyli~idazole-2-thiol (3.5g) and anhydrous potassium carbonate (2.9g) in anhydrous dimethylformamide ~60ml) was stirred at room temperature for 30 minutes. It`was then treated with (2R,2S~-2-(iodomethyl)-6-oxo-1,4-dioxane (3.4g) and the resulting mixture stirred at room temperature for 3 days. ~he mixture was poured into water (600ml) and the product collected by filtration and dried at 60~C., to give a cream solid (2.6g). A portion (1.5g) of this solid was dissolved in dichloromethane (60ml) and treated with trifluoroacetic acid (9.48g). After 30 minutes the solution was diluted with fresh dichloromethane (lOOml) and washed with 5~ sodium hydrogen carbonate solution (75ml). The layers were separated and the organic fraction washed with water (50ml), dried ~magnesium sulphate) and evaporated.
Crystallisation from tetrahydrofuran/diethyl ether gave (6R,6S)-[(4,5-diphenylimidazol-2-yl)thio~ethyl]-2-oxo-1,4-dioxane (0.5g) in the form of a white powder, m.p. 194-196C.
[Elemental analysis:-- C,64.8;H,4.91;N,7.7jS,B~8%;
Calculated:- C,65.57;H,4.92;N,7.65;S,8.74~;
NMR (CD3SOCD3):- 3.46 (2H,d,J = 6Hz), 3.76 (lH,dd,J =
12Hz, 6Hz), 4.05 (lH,dd,J = 12Hz, 4Hz), 4.32 (2H,dd,J =
16Hz, 4Hz), 4.87 (lH,m), 7.2-7.5 tlOH,m)].
EXAMP~E_18 Compound B5 Sodium methoxide ~0.34g) was added to a suspension of 4,5-bis-(4-chlorophenyl)imidazole-2-thiol (2.0g) in methanol (50ml), and the mixture was stirred at room temperature for one hour. t-Butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate (1.98g), was added and the mixture was stirred at room ~emperature for 18 hours.
It was then concentrated at reduced pressure and the WO9l/13876 PCT/GB91/00408 _ 59 _ 2078208 res~idue was shaken with ethyl acetate and water. The ethyl acatate layer was separated, dried over magnesium sulphate, and concentrated, to give a semi-solid.
This was triturated with diethyl ether, to give a white solid, which was subjected to chromatography on silica yel eluting with a mixture of dichloromethane and ethyl acetate, to give a gum, which was recrystallised from cyclohexane to give t-butyl 6-[(4,5-bis-~4-chloro phenyl}imidazol-2-yl)thio]-3,5-dihydroxy-3-methyl-hexanoate in the form of one racemate, a white crystalline solid, m.p. 152-153C. ~Elemental analysis:- C,58.3;H,5.68;Cl,13.3;N,5.18;S,5.94%;
Calculated:- C,5801;H,5.63;Cl,13.19;N,5.21;S,5.97%.
NMR (in CDC13):- 1.32(3H,s), 1.46(9H,s), 1.64 (lH,dd,J = 12Hz, 4Hz), 1.9 2.1(1H,m), 2.3-2.7(2H,m), 2.98-3.3(2H,m), 4.3 4.5(1H,m), 4.8-6.4(2H,br.s), 7.1-7.6(8H,m).
Com~ound BT
- 6-[(4,5 Diphenylimidazol-2-yl)thiomethyl]-~-hydroxy-4-methyltetrahydropyran-2-one (4.~2g), was added to a solution of sodium hydroxide (1.0~;10.66ml) and water (70ml), and warmed at 60C for 10 minutes.
Traces of solid were removed by filtration, and the filtrate was co~centrated at reduced pressure to give a glass. This was dissolved in dimethylformamide (40ml), WO91~13876 PCT/GB91/00408 20782~
and treated with ethyl iodicle (2.15g), and the mixture . ¦
was stirred at room temperature for 2 hours. It was then shaken with ethyl acetate and water, the organic layer was separated and washed with water, dried over magnesium sulphate, and concentrated, to give an oil.
This was subjected to chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (l:lv/v), to give (3R,3S)(SR,5S)-ethyl 6-[(4,5-diphenylimidazol-2-yl~thio]-3,5-dihydroxy-3-~ethylhexanoate (2.47g), in the form of a yellow solid with no sharp melting point.
[Elemental analysis:- C,64.9;H,6.4;N,6.2;S,7.1%;
Calculated:- C,64.46;H,6.54;N,6.54;S,7.48~.
MMR (in CDC13):- 1.24(3H,2dt), 1.6(1H~dd,J = lO~z, 3Hz), 1.9-2.1(lH,m), 2.4-2.7(lH,m), 2.9-3.2(2H,m), 4.05-4.24 (3H,m), 4.38-4.58(1H,m), 7.1-7.5(10H,~)].
Com~ound BU
(6R,6S)-6-[(4,5-Diphenylimidazol-2-yl)thio-methyl]-4,4-dimethyl-3,4,5,6-tetrahydropyran-2-one (1.18g) was dissolved in 33% ethanolic methylamine (50ml~, and heated at reflux for 2 hours. It was then concentrated to give a solid, which was recrystallised from ethanol to give (2R,2S)-2-[t2-hydroxy-4,4-dimethyl-5-methylaminocarbonylpent-1-yl)thio~-4,5-diphenylimidazole (0.53g), m.p. 190-191C.
WO 91/13876 P~/GB91/00408 207~208 - 61 - ;
rElemental analysis:- C,68.3;H,7.0;N,9.9;S,8.1%;
Calculated:- C,68.05;H,6.9;N,9.92;S,7.6%.
NNR (in CD3SOCD3) 0.~8(3H,s), 1.0(3H~s), 1.5-1.7(2H,m), 1.98-2.24(2H,m), 2.S-2~7(4H,m), 3.18(2H,m), 3.9-4.05(1H,m), 5.5-5.7(1H,m), 7.2-7.9(10~,m)].
Compounds BV and BW
BV (6R,6S)-6-t(4,5-Diphenylimidazol-2-yl)thio-methyl]-3,4,5,6-tetrahydropyran-2 one, (3.96g), in dry tetrahydrofuran, (55ml), was treated at -78C in an argon atmosphere with di-isobutylaluminium hydride in tetrahydrofuran (1.0~;55ml), and stirred at -78C for 3 hours. It was then poured into a mixture of ice (250g~, water (lOOml) and acetic acid ~50ml), and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulphate. Concentration gave a yellow oil, which was subjected to chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (3:1v/v), and the white solid obtained was recrystallised from a mixture of ethyl acetate and hexane to give (2R,2S)(6R,6S)-6-[(4,5-diphenyl-imidazol-2-yl)thiomethyl]-2-hydroxy-3,4,5,6-tetra-hydropyran (1.15g), m.p.. 172-173C.
[Elemental analysis:- C,68.7;H,6.03;N,7.6 ;S, 8.5%;
Calculated:- C,68.82;H,6.05;N,7.64;S,8.75%~
WO91/13876 PCr/GB9l/00408 .-.
NMR (in a mixture of CDCl3 and CD3SOCD3):-1.2-2.1(6H,m); 2.9-3.3(2H,m), 3.6-3.8(1/4H,m), 4.1-4.3(3/4H,m), 4.7-4.8(1/4H,m), 5.34(3/4H,s), 5.78(3j4H,d,J = 3Hz), 6.46(1/4H~d,J - 6H~), 7.1-7.8(10H,m)].
BW By proceeding i,n a similar manner, but replacing (6R,6S)-6-[(4,5-diphenylimidaæol-2-yl)thiomethyl]-3,4,5,6-tetrahydropyran-2-one by 6-[(4,5-diphenyl-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one there was prepared (2R,2S)~4R,4S)(6R/6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetrahydropyran, m.p. 134-151C.
[Elemental analysisO- C,66.8;H,6.11;N,7.2;S,8.1%;
~alculated:- C,66.64;H,6.10;N97.07;S,8.09~].
Com~ounds BX ~ BY
(2R,2S)(4R,4S)(6~,6S)-6-t(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetrahydropyran (1.9gJ, was dissolved in anhydrous methanol (150ml), boron trifluoride diethyl ethesate (3ml) was addPd, and the solution was left to stand at room temperature for 64 hours. It was then added to excess sodium bicarbonate solution, extracted with ethyl acetate, and the organic extracts were washad with water, dried over magnesium sulphate, and concentrated, ~o give a white . .
solid. This was subjected to chromatography on silica gel eluting with a mixture of ethyl acetate and - cyclohexane (2:1v/v), to give compound BX, (2R,2S~(4~,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy 2-methoxy-4-methyltetra-hydropyran (0.61g), thought to be the 2-alpha-anomer, in the form of a white solid, m.p. 163-166C.
[Elemental analysis:- C,67.1;H,6.41;N,6.61;S,7.6%;
Calculated:- C,67.29;H,6.38;N,6.83;5,7.81%.
NMR (in CD3SOCD3):- 1.16(3H,s), 1.1-1.4(2H,m), 1.5-1.7(2H,m), 3.3(3H,s), 3.2-3.4(2H,m), 3.9-4.1(1H,m), 4.48~1H,s), 4.58(1H,dd,J = 6Hz,2Hz); and compound BY, ~2R,2S) (4R,4S)(~,6S)-6-t(4,5-diphenyl-imidazol-2-yl)thiomethy]-4-hydroxy-2-methoxy-4-methyl-tetrahydropyran, thought to be thP the 2 -beta-anomer, 0.51g, m.p. 4~C.
[Elemental analysis:~ C,67.1jH,6.68;N,6.52;S,7.4%;
Calculated:- C,67.29jH,6.3~;N,6.83;S,7.81%.
NMR (in CD3SOCD3~- 1.08(1H,s), l~25-l.75(4H~m)~
3.3(3H,m), 3.2-3.4(2~,m), 4.0(lH,s), 4.1-4.22(lH,m), 4.8(lH,m), 7~1-7.5(10H,m)3.
Compound BZ
- 4,5--diphenylimidazole-2-thiol (12.99g) was dissolved in dry dimethylformamide (200ml), and then it was treated with potassium carbonate (5.~4g) and methyl .. . .
6-deoxy-6-iodo-A-D-mannopyranoside (~5.66g) and stirred at room temperature for 18 hours. The mixture was then filtered and concentrated at reduced pressure to give an orange oil, which was subjected to chro~atvgraphy on silica gel, eluting with a mixture of ethyl acetate and hexane,(9:lv/v), to give a white solid which was tritùrated with cyclohexane to give (2S,3R,4R,5S,6S)~2-[(4,5-diphenylimidazol-2-yl)thiomethyl]-6-methoxy-3,~,5-trihydroxytetrahydro-pyran (7.0g), m.p. 120-122C.
tElemental analysis:- C,61.2;H,5.~7;N,6.44;S,8.0%;
Calculated:- C,61.66;H,5.65;N,6.54;S,7.48~.
NMR (in CDCl3):- 3.34(3~,m), 3.4-4.1(6H,m), 4.7(1H,s~, 7.2-7.5(10~,m).
- 65 - 2~78208 Compounds CA to CF
CA A solution of 1-methylimidazole (5.0g) in tetrahydrofuran (70ml) was treated with a solution o~
lithium diisopropyla~ide mono-tetrahydrofuran comple~
in cyclohexane (40ml;1.5M~ during lO minutes under nitrogen, keeping the temperature between -60 and -30~C. The solution was then stirred for 30 ~inutes, warming to 10C. The solution was then cooled to -20C and treated with a solution of 4-[4-~4,5-diphenylimidazol-2-ylthio)butanoyl]morpholine (6.15g) in a mixture of tetrahydrofuran (50ml) and 1,4-dioxane (50ml). The solution was stirred at ambient temperature for 6 hours, and then it was trea~ed with dilute hydrochloric acid (lOOml;~N) and the aqueous layer was separated. The organic fraction was extracted with water (lOOml), tha combined aqueous layers were washed with t-butyl methyl ether (lOOml), then basified with aqueous sodium hydroxide solution (120ml;2N) and extracted with t-butyl methyl ether (3x200ml). The ether solution was washed with aqueous sodium chloride solution and concentrated under reduced pressure to leave a solid. The solid was recrystallised from methanol, to give 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-1-methyl-207820~
imidazole (4.0g) in the fo:rm of a white powder, m.pO160-163C.
CB By proceeding in a ;imilar manner to that described above but replac:ing the 4-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]morpholine by 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]
~ , . . .
morpholine there was prepared 2-[5-(4,5-diphenylimid-azol-2-ylthio)pentanoyl~-1-methylimidazole, in the form of a white solid, m.pO 121-123C, after chromatography on silica gel, eluting with ethyl acetate.
CC By proceeding in a similar manner to that described above but replacing the 4-[4-~4,5-diphenyl-imidazol-2-ylthio)butanoyl]morpholine by 4-[6-t4,5-diphenylimidazol-2-ylthio)hexanoyl]morpholine there was prepared 2-[6-(4,5-diphenylimidazol-2-yl-thio~hexanoyl]-1-methylimidazole, in the form of a white solid, m.p. 124-126C, after chromatography on silica gel, eluting with ethyl acetate.
CD By proceeding in a similar manner to that described above but replacing the 1-methylimidaæole by l-[(dimethylamino~methyl]imidazole, there was prepared 2-[4-(4,5-diphenylimidazol=2-ylthio)butanoyl]imidazole, in the form of a white solid, m.p. 186-188C, from acetonitrile.
CE By proceeding in a similar manner to that described above but replacing the l-methylimidazole by WO91/13876 PCTtGB91/00408 - 67 - 207~208 .,, . ~.
1-C(dimethylamino)methyl]imidazole and replacing the 4-t4-(4,5-diphenyli~idazol-2-ylthio~butanoyl]morpholine by 4-~6-(4,5-diphenylimidazol-2~ylthio)hexanoyl]-~orpholine, there was prepared 2-[6-(4,5-diphenylimid-azol-2-ylthio)hexanoyl]imidazole, m.p. ~48-152C, from butan-2-one.
CF By proceeding in a similar manner to that described above but replacing the l-methylimidazole by 1-[~dimethylamino)methyl]imidazole and replacing the 4-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]morpholine by 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-morpholine, there was prepared 2- r 5-~4,5-diphenylimid-azol-2-ylthio~pentanoyl~imidazole, in the form of a white powder, m.p. 188-191C, from butan-2-one.
XA~PLE_25 Compounds CG to CL
CG A suspension of 2-[4-(4,5-diphenylimidazol-2--ylthio~butanoyl]-l-methylimidazole (2.0g) in ethanol was treated with-a solution of sodium borohydride (0.96g) in water (25ml). Tbe mixture was heated at reflux for 1 hour, ~iltered, and treated with acetone (25ml), followed by dilute hydrochloric acid (200ml;
lN). The pH was adjusted to 7 and the mixture was extracted with t-butyl methyl ether (3xl50ml), then dried and concentrated under reduced pressure to leave an oil. Chromatography on silica gel, eluting with a WO9l/13876 PCT/GB91/00408 mixture of ethyl acetate and methanol, gave 2-~4-(4,5-diphenylimidazol-2-ylthio)-1-hydroxybutyl]-l-methylimida~ole (1.32g) in the form of a glass [NMR (CDC13):- 1.78 (2H,m), 2.09 (2H,~), 2.97 (2~,m), 3.58 (3H,s~, 4.83 (lH,dd,J=5Hz & 7Hz), 6.56 ~lH,d, J=2Hz), 6.68 (lH,d,J=2Hz), 7.19-7.27 (6H,m), 7.40-7O45 t4H,m) ] .
C~ By proceeding.in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]-1-methylimidazole by 2-[6-(4,5-diphenylimidazol-2-ylthio~hexanoyl~-1-methylimidazole, there was prepared 2-t6-~4,5-diphenyl-imidazol-2-ylthio)-l-hydroxyhexyl]-l-methylimidazole in the form of a glass. [Elemental analysis:- C,69.4;
H,6.57;N,12.9;S,7.3%; calculated:- C,~9.41;H,6.52;
N,12.95;S,7.41%].
CI By proceeding in a similar manner to that described above but replacing the 2-t4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl~ methylimidazole by 2-[5-(4,5-diphenylimidaæol-2-ylthio)pentanoyl]-1-methylimidazole there was prepared 2-[5-(4,5-diphenyl-imidazol-2--ylthio)-1-hydroxypentyl]-1-methylimidazole in the form of a glass. tElemental analysis:-C,67.3,H,6.27;N,12.6;S,7.4%; calculated for C24H26N4OS~0.5H2O:- C,7.42;H,6.37;N,13.10;S,7.50~].
WO91il3876 PCT/CB91/00408 ~ 69 2078208 CJ By proceeding in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]~l-methylimida2O1e by 2-[4-(4,5-diphenylimidazol-2-ylthio~b~tanoyl3imidazole there was prepared 2-[4-(4,5-diphenylimidazol-2-yl~
thio~ hydroxybutyl]imidazole in the for~ of a glass.
[Elemental analysis:- C,65.1;H,5.71;N,13.4;S,7.6%;
calculated for C22H22N4OS:~2O
S,7.85%. NMR (CDCl3):- 1.56 (lH,m), 1.66 (lH,m), 1.83 (lH,m), 2.00 (lH,m), 2.71 (lX,m), 2.88 (lH,m), 4.92 (lH,bt,wl/2 = 16Hz), fi.64 (2H,s), 7.12-7.22 (6H,m), 7.33-7.40 (4H,m)].
CK By proceeding in a si~ilar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]-1-~ethylimidaæole by 2-~5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]imidazole there was prepared 2-[5-(4,5-diphenylimidazol-2-yl-thio)-l-hydroxypentyl]imidazole in the form of a glassO
[Elemental analysis:- C,62.8;~,5.85;N,12.7;S,7.3%;
calculated ~or C23H24N4OS:2H~O:- C,62.70jH;6.41;
N,12.72;S,7.28~. NMR (CDC13):- 1.52 (2H,m), 1.63 (2H,m), 1.94 (lH,m), 2.08 (lH,m), 2.90 (lH,m), 3.06 (l~,m~, 5.08 (lH,t,J = 6Hz), 6.08 (2H,s), 7.18-7.30 (6H,m), 7.42 (4H,dd,J = 7Hz & 2Hz)].
CL By proceeding in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-~ - 70 -~0~$~$
imidazol-2-ylthio)butanoyl]~ methylimidazole by 2-[6-(4,5-diphenyli~idazol-2-ylthio)hexanoyl]imidazole there was prepared 2-~6-~4,5-diphenylimidazol-2-yl-thio)-l-hydroxyhexyl]imidazole in the ~orm of a glass.
NMR (CDC13):- 1.3~-1.53 (4H,m~, 1.71 (2H,p,J = 7Hz), 1.81 (lH,m), 1.89 (l~,m), 3.08 (2~,m), 4.75 (lH,dd,J -7Hz & 5Hz), 6.90 (2H,s),~7.20-7.32 (6H,m)/ 7.48 (4H,dd, J = 8Hz ~ 2Hz), 7.63 (lH,s)].
Compound_CM
A solution of ~orpholine (6.0g) and pyridine (5.6g) in dimethylformamide (lOml) was added during lO
minutes to a stirred solution o~ 4-chlorobutyryl chloride (9.4g) in dimethylformamide (lOOml). The mixture was stirred at ambient temperature for 2 hours and then it was treated with 4,5-diphenylimidazole-2-thiol (15.0g). The mixture was stirred at 125-135C
for 4 hours. After cooling to room temperature, the mixture was poured into dilute aqueous potassium carbonate solution (1 litre) to give a sticky solid.
This solid was dissolved in dichloromethane (1 litre), was the resulting solution was washed with water (2x500ml) and dried by filtering through anhydrous sodium sulphate. Concentrating under reduced pressure gave a thic~ brown oil, which was partitioned between hydrochloric acid (300ml;1N) and toluene (300ml).
WO 91/13876 PCr/GB91/00408 - 71 - 2~78208 `. ' ' .;
The toluene fraction was extracted with hydrochloric acid (200ml;1N) and the combined acidic solution was adjusted to pH4 by treatment with sodium acetate, and was then extracted with toluene ~3x200ml). This toluene solution was washed with brine, dried over magnesium sulphate and concentrated under reduced pressure to give a solid. The solid was crystallised from a mixture of t-butyl methyl ether (300ml) and ethanol (150ml) by concentrating to about 200ml and cooling overnight, to give 4-[4-(~,5-diphenylimidazol-2-ylthio)butanoyl]~orpholine (10~92~) in the form of colourless crystals, m.p. 168-173C.
Compound CN
A solution of morpholine (13.0g) and pyridine (13.0g) in dimethylformamide (50ml) was added during 10 minutes to a stirred solution of S-chlorovaleryl chloride (22.0g) in dimethylformamide (150ml). The mixture was stirred at ambient temperature for 2 hours then 4,5-diphenylimidazole-2-thiol (37.0g~ was added.
The mixture was stirred at 125-135C for 2 hours.
After cooling to 80C, the mixture was poured into water (500ml) ~nd acidified to pH1 by treatment with dilute hydrochloric acid . The mixture was stirred and the resulting solid was filtered off. The filtrate was adjusted to pH4 by treatment with sodium acetate, WO91/13~76 PCT/~B91/00408 ;~~. I
2~782~8 to~give a sticky solid. I'his solid was dissolved in dichloromethane (1 litre), was washed with water (500ml), and then dried over magnesium sulphate and concentrated under reduced pressure, to give an oil.
The oil was crystallised from t-butyl methyl ether, to give 4-[5-(4,5-diphenyl:imidazol-2-ylthio)pentanoyl]-morpholine (43.8g), in the form o~ a white powder, m.p.
134-136C. ~
Compound Co A solution o~ 6-(4,5-diphenylimidazol-2-ylthio)-hexanoyl chloride [prepared fro~ 6-(4,~-diphenylimid-azol-2-ylthio)hexanoic acid (1105g) and thionyl chloride] in dichloromethane (50ml) was added dropwise to a solution of morpholine (6.0g) in dichloromethane (150ml), keeping the te~perature below 30C. The mixture was stirred at ambient temperature for 2 hours and was then left overnight. The mixture was washed with hydrochloric acid (lOOml;lN), water (lOOml), aqueous potassium hydroxide solution (lOOml;lN) and with brine (2x50ml), and was then dried over magnesium sulphate. Concentrating under reduced pressure gave a gum, which was triturated with diethyl ether to give 4-t6-(4,5-diphenylimidazol-2-ylthio)hexanoyl~morpholine (9.64g) in the form of an off-white solid, m.p.
120-122C.
W091~13876 PCr/GB91/00408 _ 73 _ 2~7820~
.. ., ~, ~ i ., . . ,~, I
The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of for~ula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.
In clinical practice the compounds of the present invention may be administered parenterally, rectally or orally.
Solid compositions for oral administration include co~pressed tablets, pills, powders and granules. In such solid co~positions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also comprise, as is nor~al practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, - perfuming and preserving agents. The compositions according to the inventiOn for oral administration also ;
~8~
include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examp~es of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preser~ing, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I or a pharmaceutically acceptable salt thereof.
WO 91/13876 PCI`/GB91/00408 _ 75 _ 2~7820~
,. .;
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The size and frequency of the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration, the duration of the treatment and the aye, sex, size and condition of the patient. In the adult, the doses are generally from 0.01 to 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from 0.001 to ln, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration.
The following Example illustrates a pharmaceutical composition according to the present invention.
COMPOSITION EXAMPLE
No. 2 size gelatin capsules each containing:-Compound A 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
.
.. - 76 -Capsules can also be made up in a similar manner using any other of the compounds B to CO, or a pharmaceutically acceptable salt thereof.
IMIDAZO:LES
The present invention relates to new therapeutically useful imidazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.
The imidazole derivatives of the present invention are the compounds of the general formula:-A~S()k-Q-Z
wherein A represents a group of general formula II
shown hereinafter in the present specification, wherein the symbols Rl may be the same or different and each represents hydrogen or one or more substituents, for example substituents selected from halogen atoms, and straight- or branched-chain alkyl and alkoxy groups containing from l to about 6 carbon atoms, and trifluoromethyl groups;
k represents 0, l or 2;
Q represents a methylene group or alkylene chain containing from 2 to ahout s carbon atoms, optionally substituted with one or more alkyl groups containing from l to about 4 carbon atoms; and Z represents a hydrogen atom; a hydroxy group;
an alkoxy group optionally substituted by, for example, an alkoxy or alkoxyalkoxy group; an aryl, for example phenyl, group optionally substituted by, for example, WO91/13876 PCT/~91/00408 2~73208 `
one or more alkoxy, e.g. methoxy, groups; a dialkyl-amino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to about 4 carbon atoms; a group of the formula -NHR2, wherein R2 represents an acyl group, for example a straight- or branch~d-chain alkanoyl group containing up to about 6 carbon atoms and which may be substituted, for example, by a carboxy group, or R2 represents a group of the formula -C(SR3)=N-CN wherein R3 represents a straight- or branched-c~ain alkyl group containing from 1 to about 3 carbon a~oms, or R2 represents a 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents selected from, ~or example, amino groups and straight- or branched-chain alkyl groups containing from 1 to about 3 carbon atoms, and preferably attached to the group -NH via a carbon ato~; or Z represents a group of the formula -coR4 wherein R4 represents a straight- or branched-chain alkyl group containing from 1 to about 3 carbon atoms; a group of the formula -CH(OH)R5 -coR5, -CS~5, -CoNHR5 or -CSNHR wherein R
represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents selected from, for example, straight- or branched-chain alkyl groups containing from 1 to ahout 3 carbon atoms; an alkynyl or cycloalkyl group 2~7820.8 . .
containing up to about 6 carbon atoms; a group of the formula -CH(R )OR wherein R represents a straight- or branched-chain alkenyl or alkoxy group containing up to about 6 carbon atoms and R7 represents a straight- or branched-chain alkyl group containing ~rom l to about 4 carbon atoms, optionally substituted by one or more substituents selected from, for example, hydroxy groups; a group of the general formula III shown hereinafter, wherein m is 0 or l, n is 0 or ~ and p is 1, 2 or 3, and the symbols R8 each represent a hydrogen atom, or a methyl group substituted by a straight- or branched-chain alkoxyy or alkanoyloxy group containing up to about 6 carbon atoms; a group of the general formula IV shown hereinafter wherein m is as hereinbefore defined; a group of the general formula V
shown hereinafter wherein R9 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms and Rl0 represents a hydrogen atom or a hydroxy group or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms; or a group of the general formula VI
shown hereinafter wherein R9 is as hereinbefore defined; a group of the general formula VII shown hereinafter wherein R9 and RlO are as hereinbefore defined, the symbols Rll may be the same or different and each represents a hydrogen atom or a 2078208 - 4 ~
hydroxy group and Rl2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from l to about 4 carbon atoms; or a group of the ~ormula -CH(oH)cH2(cR9Rlo)rcH2coRl3 wherein R9 and Rl0 are as hereinbefore defined, r represents 0 or l and Rl3 represents a hydroxy group or a straight- or branched-chain alkoxy or alkylamino group containing from 1 to about 4 carbon atoms; and phar~aceutically acceptable salts thereof.
In this specification alkyl groups and moieties, unless otherwise specified, are straight- or branched-chain and contain from l to about 6 carbon atoms.
(2S,4R,6S)-6-~(4,5-Diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran and (2R,4R,6S)-6-[(4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2~methoxy-3,4,5,6-tetrahydro-2H-pyran are excluded from the scope of this invention.
specially important features of the present invention are, or involve, compounds of general formula I wherein at least one of the symbols has a value selected from the following:-(i) the symbols Rl may be different or, preferably, the same and each represents a - hydrogen or halogen, e.g. chlorine or fluorine, atom or a straight- or branched-chain alkyl group containing from l to 6, preferably from l WO91/13876 PCT/GB9t/00408 5 _ 2~78208 to 4, carbon atoms, c>r a s~raight- or branched-chain alkoxy group containing from 1 to 3 carbon atoms, e.g. methoxy, or a trifluoromethyl gr9uE~;
(ii) k represents 0;
(iii) Z represents a hydrogen atom; a hydroxy group;
an alkoxy, e.g. ethox~, group optionally substituted by, for example, an alkoxyalkoxy, e.g. methoxyethoxy, group; an aryl, for example phenyl, group optionally substituted by, for example, one or more alkoxy, e.g. methoxy, groups; a dialkylamino group wherein the alkyl groups ~ay be the same or dif~erent and each is straight- or branched-chain and contains from 1 to 4, prefarably from 1 to 3, carbon atoms; an ethynyl group, or a cycloalkyl, e.g. cyclohexyl, group, (iv) R2 rapresents an acyl group, for example a straight- or branched chain alkanoyl group containing up to about 6 carbon atoms and which may be substituted, for example, by a carboxy group; or a pyridyl or triazolyl group optionally substituted by one or more, prefPrably o~e or two, substituents selected from amino groups and straight- or branched-chain alkyl, e.g. methyl, groups;
WO91/13876 PCT/GB91~00408 , - 6 -20782~8 (v) R3 represents a methyl group;
(vi~ R represents a methyl group;
(vii) R represents a imidazolyl, morpholinyl or pyridyl group optionally substituted by one or two alkyl, e.g. methyl, groups;
(viii) R6 represen s an allyl group, or an alkoxy group containing from 1 to 3 carbon ato~s, e.`g. methoxy or ethoxy;
(ix1 R7 represents an alkyl group containing from 1 to 3 carbon atoms, e.g. methyl or ethyl, optionally substituted by a hydroxy group;
(x) ~8 represents a hydrogen atom or a hydroxymethyl, methoxymethyl or acetoxymethyl group;
(xi~ R9 represents a hydrogen atom or a methyl group;
(xii) R10 represents a hydrogen atom or a hydroxy or methyl group;
(xiii) R12 represents a hydrogen atom or a methyl group; and/or (xiv) R~3 represents an alkoxy or alkylamino group containing from 1 to 4 carbon atoms;
the other symbols being as hereinbefore defined, and pharmaceuticaIly acceptable salts thereof.
WO91/1387S PCT/~B91/U0408 _ 7 _ 20 782 ~8 ~,, ,,: - ' ;
Particularly important features of the present invention are, or involve, at least one of the following compounds:-A 2-(2-ethoxyethylthio)-4,5-diphenyli~idazole B 2-[(dioxolan-2-yl)methylthio]-4,5-diphenyl-imidazole C 2-benzylthio-4,5-diphenylimidazole D 2-(3,5-dimethoxybenzylthio)-4,5-diphenyl-imidazole E 2-cyclohexylmethylthio-4,5-diphenylimidazole F ~+]-2-[ttetrahydro-2H-pyran-6-yl)methylthio]-4,5-diphenylimidazole G [+]-2-~(tetrahydro-2~I-pyran-6-yl)methylthio]-4(5)-(4-chlorophenyl)-5(4)-phenylimidazole H 2-t2-(l,3-dioxan-2-yl)ethylthio]-4,5-diphenyl-- imidazole I 2-[3-(l,3-dioxan-2-yl)propylthio]-4,5-diphenyl-imida~ole J 2-(2,2-diethoxyethylthio)-4,5-diphenylimidazole K 2-(2,2-dimethoxyethylthio)-4,5-diphenyl-imidazole L 2-(3,3-diethoxypropylthio)-4,5-diphenyl-imidazole M 2-(4-ethoxyhex-5-enylthio)-4,5-diphenyl-imidazole N 2-[4-(2-hydroxyethyl)hept-6-enylthio]-4,5-W091/~3876 PCT/~9~/0040~
. .
~ - 8 diphenylimidazole 0 2-(2-oxoprop-1-yl)thio-4,5-diphenylimidazole P 2-(2-diethylaminoethylthio)-4,5-diphenyl-imidazole Q 2-(2-diisopropylaminoethylthio)-4,5-diphenyl-imidazole R 2-propargylthio-4,~5-diphenylimidazole S [+]-4,5-bis(2-c ~ ophenyl)-2-[(tetrahydro-2H-pyran-2-yl)meth,~ylthio]imidazole T [+~-4(5)-(2-chlorophenyl)-5(4)-phenyl-2-[(tetra-hydro-2H-pyran-2-yl)methylthio]imidazole U [+]-4(5)-(3-chlorophenyl)-5(4)-phenyl-2-[(tetrahydro-2H-pyran-2-yl)methylthio]imidazole V [+]-2-[(1,4-dioxanyl)methylthio]-4,5-diphenyl-imid~zole W [+]-2-[(2,2-di~mathoxymethyl)tetrahydro-2H-pyran-6-yl)methylthio~-4,5-diphenylimidazole X 2-(3-dimethylaminopropylthio)-4,5-diphenyl--imidazole Y 2-(3,6,9-trioxadecylthio)-4,5-diphenylimidazole Z [+]-2-[2,2-di(hydroxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4~5-diphenylimidazole AA [+3-2- r 2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4~5-diphenylimidazole AB 2-(2-hydroxyethylthio)-4,5-diphenylimidazole AC 2-ethylthio-4,S-dîphenylimidazole WO91/l3876 PCT~GB9l/00408 ~ 20782~8`
AD 2-t(1,3-dioxan-2-yl)methylthio]-4,s-diphenyl-imidazole AE 3-cyano-2-methyl-1-[3-(4,5-diphenylimidazol-2-ylthio)propyl]isothiourea AF 2-t2-(5-amino-1 t 2,4-triazol-3-ylamino)ethyl-thio]-4,5-diphenylimidazole dihydrochloride AG 3-cyano-2-methyl-1-[4-(4,s-diphenylimidazol-2-ylthio)butyl]isothiourea AH 2-[4-(S-amino-1;2,4-triazol-3-ylamino)butyl-thio]-4,5-diphenylimidazole AI 2-[3-(5-amino-1,2,4-triazol-3-ylamino)propyl-thio]-4,5-diphenylimidazole AJ 3-cyano-2-methyl-1-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]isothiourea AK N-(4-methylpyrid-2-yl~-4-(4,5-diphenyl-imidazol-2-ylthio)butanamide AL 4,6-dimethyl-2-[4-(4,5-diphenylimidazol-2-yl-thio)butylamino]pyridine AM 2-(3-ace amidopropylthio)-4,5-diphenylimidazole AN 2,6-dimethyl-N-[4-(4,5-diphenylimidazol-2-yl~
thio)butan-l-oyl]morpholine AO N-(4,6-dimethylpyrid-2-yl)-4~(4,5-diphenyl-imidazol-2-ylthio)butanamide AP N-(pyrid-2-yl)-4-(4,5-diphenylimidazol-2-y~thio)butanamide AQ (SR,5S)-4,5-diphenyl-2-[(2-oxotetrahydrofur-5-2078208 - lO -yl)methylthio]imidazole AR (4R,4S)(6R,6S)-6-[(4, s-bis{ 3-chlorophenyl}imid azol-2-yl)thiomethyl]-4 hydroxy-4-methyltetra-hydropyran-2-one AS (4R,4S)(6R,6S)-6-[(4,5-Bis{4-chlorophenyl}-i~idazol-2-yl)thiomethyl]-4-hydroxy-4-methyJ.-tetrahydropyran-2-one AT (4R,4S)~6R,6S)-6-[ ~ -Bis~2-chlorophenyl}-imidazol-2-yl)thi~methyl]-4-hydroxy-4-methyl-tetrahydropyran-2-one AU (4R,4S)(6R,6S)-6-[(4,5-Bis{4-fluorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy 4-methyl-tetrahydropyran-2-one AV (4R,4S)(6R,6S)-6-[(4,5-Bis{4-trifluoromethyl-phenyl}imidazol-2-yl~thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one A~ (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one AX (4R,4S)(6R,6S)-4-Hydroxy-~-[(4,5-bis{4-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one AY (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis~4-isopropylphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one AZ (4R,4Sj(6R,6S)-6-[(4,5-Bis{4-tertbutylphenyl}-W091~13876 PCT/~B91iOOqO8 2 ~ ~`8 ~ o;~
imidazol-2-yl)thiomethyl] 4-hydroxy-4-methyl-tetrahydropyran-2-one BA (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5 bis{2-- methoxyphenyl}i~idazol-2-yl)thiomethyl]-4-methyltetrahydropyrar~-2-one BB (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methoxy-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one BC 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one BD 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one BE 4-hydroxy-6-[~4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran~2-one BF 4-hydroxy-6-[(4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one BG (6R,6S~-6-[(4,5-bis{4-methylphenyl}imidazol-2-yl)thiomethyl]-5t6-dihydro-4-methylpyran~2-one BH (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thio-methyl]-5,6-dihydro-4-methylpyran-2-one BI (6R,6S)-6-~(4,5-Bis{4-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-me~hylpyran-2-one BJ (6R,6S)-6-t(4,5-bis{3-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BK (6R,6S)-6-[(4,5-bis-{2-chlorophenyl}imidaæol-207&2b8 - 12 -2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BL (6R,6S)-6-[(4,5-bis--{4-fluorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one BM (5R,5S)-5-[(4,5-bis--{4-methylphenyl}imidazol-2-yl)thiomethyl]tetrahydrofuran-2-one BN (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thio-methyl]-3,4,5,6-tetrahydropyran-2-one BO (6R,6S)-6-t(4,5-dlphenylimidazol-2-yl)thio-methyl]-4,4-di~èthyl-3,4,5,6-tetrahydropyran-2-one ~
BP (4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-3,4,5,6-tetrahydro-pyran-2-one BQ (3R,3S)(5R,5S)-ethyl 6-t(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydroxyhexanoate BR (6R,6S)-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2-oxo-1,4-dioxane BS t-butyl 6-[(4,5-bis-~4-chlorophenyl}imidazol-2-yl)thio]-3,5-dihydroxy-3-methylhexanoate BT (3R,3S~(5R,5S)-ethyl 6-[(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydroxy-3-methylhexanoate BU (2R,2S)-2-[(2-hydroxy-4,4-dimethyl-5-methyl-aminocarbonylpent 1-yl)thio]-4,5-diphenyl-imidazole BV (2R,2S)(6R,6S)-6-~4,5-diphenylimidazol-2-yl)-thiomethyl]-2-hydroxy-3,4,5,6-tetrahydropyran WO91/13876 PCT/~B91/00408 - 13 - .~
20782~8 BW (2R,2S3(4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetra-hydropyran BX (2R,2S)(4R,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-2~methoxy-4-~ethyl-tetrahydropyran (2-alpha-anomer) BY (2R, 2S) (4R, 4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-2-methoxy-4-methyl-tetrahydropyran (2-beta-anomer) BZ (2S,3R,4R,5S,6S)-2-[(4,5-diphenylimidazol-2-yl~thiomethyl)-6-methoxy-3,4,5-trihydroxyte~ra-hydropyran CA 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-1-~ethylimidazole CB 2-~5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-l-methylimidazole CC 2-[6-(4,S-diphenylimidazo1-2-ylthio)hexanoyl]-1-methylimidazole CD 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-imidazole CE 2-[6-(4,5-diphenylimidazol-2-ylthio)hexanoyl]-imidazole CF 2-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-imidazole CG 2-[4-(4,5-diphenylimidazol-2-ylthio)-1-hydroxy-butyl]-1-methylimidazole 20782~8` - 14 -CH 2-[6-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-hexyl]-l-methylimidazole CI 2-~5-(4,5-diphenylimidazol-2-ylthio~ hydroxy-pentyl]-l-methylimidazole CJ 2-[4-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-butyl]imidazole CX 2-~5-(4,5-diphenylimidazol-2-ylthio)-l-hydroxy-- pentyl]imidazole CL 2-[6-(4,5-diphenylimida~ol-2-ylthio)-l-hydroxy-hexyl)imidazole CM 4-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-morpholine CN 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl~-morpholine and Co 4-[6-(4,5-diphenylimidazol-2-ylthio)hexanoyl]-morpholine.
The letters A to CO are allocated to the compounds for easy reference.
As will be apparent to those skilled in the art, many of the compounds of formula I may exist in more than one enantiomeric form. All such compounds, and their mixtures, are within formula I and wlthin the scope of the present invention.
.'` :
- 15 - 2~78208 The compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT; EC 2.3.l.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
They are also inhibitors of the binding o~
thromboxane TxA2 to its receptors. They are therefore of utility in the treatment of conditions such as thrombosis and myocardial infarction, vasospastic disorders, for example associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example a~ter ischaemic injury.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the ~ollowing in-vitro and in-vivo tests which ~re believed to correlate to pharmacological activity in humans and other animals.
In in-vitro tests on human platelet membrane, compounds of the invention produced up to 50 inhibition of the binding of thromboxane TxA2 to its receptors at concentrations down to about 600 nanomolar or less.
WO 91/13876 PCI/GB9]/00408 ..: , `; -- 1 6 --207820~`
In assays performed n-vitro, microsomes, obtained from the livers of rats fed on a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days, were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the i~vention at a concentration of 0.5 or 1 ~g/ml. The degre~iof ACAT inhibition produced was up to 90% or more.~
In in-~iy~ tests, using rats fed on a similar diet to that above and further supplemented by 0.03~
w/w of test compound, the compounds according to the invention inhibited increases in plasma cholesterol concentrations, measured after 3 days, relative to control animals fed on the cholesterol supplemented diet without the drug, by up to 90% or more.
- 17 - 2 0 ~$2 0 Compounds of formula I can be prepared by the application or adaptation of known methods, for example methods illustrated in the following Examples and Reference Examples.
The intermediates and starting materials from which they are prepared can also be prepared by the application or adaptation of known methods.
By the term "known methods" is meant methods known heretofore or described in the literatura.
For example, as a feature o~ the present invention, compounds of formula I, wherein k is O and the other symbols are as hereinbefore defined, are prepared by the reaction of a compound of the general formula:-A-S-H VIII
wherein A is as hereinbefore defined, or a salt thereof, of the general form~la:-A-S M IX
wherein A is as hereinbefore defined and M répresents an alkali metal, with a compound of the general formula:-xl Q z X
.
or a salt thereof, wherein Xl is a group displaceableby a thiolate salt, such as a halogen e.g. a chlorine, bromine or iodine, atom or an alkyl- or aryl-, ~
2078:2~8- - 18 -sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene~ulphonyloxy~ and Q and Z are as hereinbefore defined. The reaction is generally carried out in an inert organic solvent such as tetrahydrofuran, dimethylformamide, a lower alkanol such as methanol or ethanol, at a temperature fro~ ambient to 110C and optionally in the presence~f a proton acceptor, such as an amine (e.g. triet ~`àmine or pyridine) or an alkali metal hydroxide~?carbonate or alkoxide. The salt of formula IX or the compound of formula X can optionally be prepared n situ by the application or adaptation of known methods.
According to a further feature of the invention, compounds of formula I wherein k is 0 and Z represen$s a group of the formula -NH-C(SR3)=N-CN, A, Q and R3 being as hereinbefore defined, are prepared by the reaction of compounds of the general formula:-(R S)-c(sR3)=N-cN XI
wherein R3 is as hereinbefore defined with compounds of the general formula:-A-S-Q~NH XXI
wherein A and ~ are as hereinbefore defined.
According to a further feature of the invention, compounds of formula I wherein k is 0 and Z represents a group of the formula NHR2 wherein R2 represents an acyl group, A and Q being as hereinbefore defined, are WO91~13876 PCT/GB91/00408 - 19 - 20782~
prepared by the acylation by known methods of compounds of formula XII as hereinbefore defined, for example by reaction with the appropriate acid anhydride or acid halide.
According to a further feature of ~he invention, compounds of formula I wherein k is 0 and Z represents a group of the formula -CH(oH)CH2(CR9RlO)rC~2CoRl4 wherein R9, RlO and r are as hereinbefore defined and ~14 represents a straight- or branched-chain alkoxy group containing from l to 4 carbon atoms, A and Q
being as hereinbefore defined, are prepared by the reaction of a compound of formula IX as hereinbefore defined, optionally prepared in situ, with a compound of the general formula~-Rl5C~2(CR9RlO)rcH2coRl4 XIIIwherein R9, RlO, r and ~14 are as hereinbefore defined and Rl5 represents a l,2-epoxyethyl group, in an inert solvent such as methanol.
According to a further feature of the present invention, compounds of general formula I are prepared by the interconversion of other compounds of general formula I.
For example, compounds of formula I wherein k is - 0 and Z represents a group of formula IV wherein m is 0 or Z represents a group of formula V wherein R9 and RlO
are as hereinbefore defined, A and Q being as 207820~ - - 20 -hereinbefore defined, are prepared by the cyclisation of compounds of formula I wherein k is 0 and Z
represents a group of the formula -CH(oH)CH2(CR9RlO)rCH2CoRl4l A, Q, R9, R10, r and R1 being as hereinbefore defined. The cyclisation can be carried out by reaction with a base, e.g. sodium methoxide in methanol, followed by reaction with trifluoroacetic acid.
Conversely, compounds of formula I wherein k is 0 and Z represents a group of the formula -CH(oH)CH2(CR9R1O)rCH2CoR14, A, Q, R9, R10, r and R14 being as hereinbefore defined, are prepared by the hydrolysis and esterification of compounds of formula I
wherein k is 0 and Z represents a group of formula IV
wherein m is 0 or Z represents a group of formula V
wherein R9 and R10 are as hereinbefore defined, A and Q
being as hereinbeforP defined, for example by reaction with a base, e.g. an aqueous solution of an alkali metal hydroxide, e.g. sodium hydroxide, followed by reaction of the resulting salt with the appropriate alkyl halide.
As another example, compounds of general formula I wherein k is 0, Z represents a group of formula III
wherein n is 0, m is 1, and the symbols R8 preferably represent hydrogen atoms, A, Q and p being as WOglJ13876 PCT/GB91/00408 . ~ .
hereinbefore defined, are prepared by the reaction of a compound of the general formulao-A-S-Q-CH(R14)2 XV
wherein A, Q and R14are as hereinbefore defined with a compound of the general formula:-HO-(CH2)p-C(R )2-OH XVI
wherein p and R8 are as hereinbefore d~fined, preferably in the presence of a catalyst such as pyridinium 4-toluenesulphonate, preferably at reflux and preferably in a solvent such as toluene.
As yet another example, compollnds of general formula I wherein k is 0, Z represents a 5-amino-1,2,4-triazol-3-ylamino group, A and Q ~eing as hereinbefore defined, are prepared by the reaction of compounds of formula I wherein k is 0 and Z represents a group of the formula -NH-C(SR3)=N-CN, A, Q and R3 being as hereinbefore defined, with hydrazine, preferably in a solvent such as ethanol or ethoxyethanol, and preferably under reflux.
As yet another example, some compounds of general formula I are prepared by the reduction of other compounds of general ~ormula I.
-: For example, ti~ compounds of general formula I
wherein k is 0, Q represents a group of formula -Q'CH2-, wherein Q' represents a methylene group or alkylene chain containing from 2 to 4 carbon atoms, 2~78208 ` - 22 -op~ionally substituted with one or more alkyl groups containing from l to about 4 carbon atoms, and Z
represents a group of formula -NHR2, A and R~ being as hereinbefore defined, are prepared by the reduction of compounds of general formula I wherein k is 0, Q
represents a group of formula -Q'-, and Z represents a group of formula -CONHR , A, Q' and R5 being as hereinbefore definedr~ ~ and R5 being identical, for example by reactio~~with a metal hydride such as .~ . ., lithium aluminium hydride, in an e~her such as tetrahydrofuran.
(ii) compounds of general formula I wherein k is O and Z represents a group of formula VII wherein Rll and Rl2 represent hydrogen atoms, A, R9 and RlO being as hereinbefore defined, are prep~r d by the reduction of compounds of general formula I wherein k is 0 and Z
represents a group of formula V, A, ~9 and RlO being as hereinbefore defined, for example by reaction with a metal hydride such as di-isobutylaluminium hydride, in an ether such as tetrahydrofuran.
(iii) compounds of general formula I wherein k is O and Z represents a group of formula -CH(oH)R5, A, Q and R5 being as hereinbefore defined,:are prepared by the reduction of compounds of general formula I wherein k is 0 and Z repre~ents a group of formula -coR5l A, Q
and R5 being as hereinbefore defined, for example by - 23 - ?078208 reaction with a metal borohydride such as sodium borohydride in a solvent system such as aqueous ethanol.
As yet another example, some compounds of general formula I are prepared by the elimination of the elements of water from other compounds of general formula I.
For example, compounds of general formula I
wherein k is O and Z represents a group of formula ~I, A, Q and R9 being as hereinbefore defined, are prepared by the elimination of the ele~ents of water from compounds of general formula I wherein k is o and Z
represents a group of formula V wherein R10 represents a hydroxy group, A, Q and R9 being as hereinbefore defined, e.g. by reaction with trifluoroacetic acid.
As a further example, compounds of formula I
wherein k is O and Z represents a group of the formula -CH(OH)CH2(CR9RlO)rCH2CoRl6, wherein Rl6 represents a straight- or branched -chain alkylamino group contain-ing from l to 4 carbon atoms, A, Q, R9, RlO and r being as hereinbefore defined, are prepared from compounds of formula I wherein k is O and Z represents a group of formula v wherein R9 and RlO are as herainbefore defined, A and Q being as hereinbefore defined, for example by reaction with the appropriate alkylamine of formula Rl6NH2, Rl6 being as hereinbefore defined, W~91/13876 PCT/~B91/00408 2 ~7 8 2 0 8 - 24 -preferably at an elevated te!mperature, e.g. at reflux, in a solvent such as ethanol.
As a still further example, compounds of formula I containing one or more lower alkoxy groups are prepared by the alkylation of compounds of formula I
containing one or more hydroxy groups, for example by reaction with the appropriate lower alkanol, preferably in the presence of-a catalyst such as boron trifluoride diethyl etherate.
As a further example, compounds of formula I
wherein k is O and Z represents a group of the formula -CoR5, wherein R5 is as hereinbefore defined, preferably an optionally substituted imidazole group, A
and Q being as hereinbefore defined, are prepared by reaction of corresponding ~ompounds of formula I
wherein Z represents a ~orpholinocarbonyl group with the product of the reaction between lithium diisopropylamide (preferably complexed with mono-tetrahydrofuran) with a compound of formula R5 H
wherein R5 represents a group within the definition of R5 but wherein any free imino groups are temporarily protected, e.g. by dimethylaminomethyl groups.
As yet a f~rther example, compounds of formula I
-- wherein k represents l or 2, A, Q and Z being as hereinbefore defined, are prepared by the oxidation of compounds of formula I wherein A, Q and Z are as hereinbefore defined and p is less than in the desired WO91/13876 PCT/GB91~0040X
2~78208 - 25 - . .
product.
The oxidation may be performed by using a conventional oxidant, such as hydrogen peroxide, sodium metaperiodate, a hypochlorite, an acyl nitrite, sodium perborate, peracids,-such as percarboxylic acids (e.g.
m-chloroperbenzoic acid), potassium permanganate or potassium hydrogen persulphate, or a ruthenium (VIII) compound, in an inert solvent, at or below room temperature.
Suitable solvents may include wa~er, alcohols, water-alcohol mixtures, chlorinated hydrocarbons, such 2S dichloromethane, and organic acids.
As another example, compounds of formula I
containing one or more carboxy grol~ps are prepared by the hydrolysis by known mQthods of compou~ds of formula I containing one or more alkoxycarbonyl groups.
Compounds of general formula I wherein k is l, the other symbols being as hereinbefore defined, may be obtained in a chirally pure form by separation of the enantiomers arising from a non-selective oxidation or by using known enantio-selective oxidising systems.
It is to b8 understood that, where in this specification reference is made to compounds of formula I, it is intended to refer also where the context so permits to their pharmaceutically acceptable salts.
Such salts are prepared from the parent compounds of WO91/13~76 PCT/GB91/00408 20782~8 - 26 -formula I by the application or adaptation of known methods, or are produced by the processes described hereinafter. Parent compounds of formula I can be generated therefrom by the application or adaptation of known methods.
Preferred salts are acid addition salts such as the hydrochIorides or, where the compound of formula I
contains an acidic hydrogen atom, for example when Z
contains a carboxy group, salts formed with alkali metals, e.g. sodium and potassium, or alkaline earth metals, e.g. calcium and magnesium, or with a~monia or with pharmaceutically acceptable amines.
Compounds of formula I can be purified by the usual physical means, for example by crystallisation or chromatography.
The following Examples illustrate the preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates.
In the presentation of the nuclear magnetic resonance ("NMR") spectra chemical shifts were expressed in parts per million relative to tetramethylsilane. Abbreviations have the following significances:- s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, dd =
doublet of doublets, dt = doublet of triplets, and br =
broad si~nal.
- 27 - 2~78~
RL~
k~ (II) Rl~
~()~.
(CH2)n (CH2)p --¦-- R8 ( III) ~(o)~
~ (IV) WO 91/13876 PCI'/GB91/00408 , ~.
8 2 ~ 28 -R9 RlO
~o (V) r ", ~ ~. 1 (VI ) O O
X (VII) Rll~ Rll --\t) \ oR12 .
W091/13876 PCT/GB9l/~0408 .
- 29 - 20782~
Compounds A, B, C, D, E, F, G, H, I, J, K, L, M, N L O ~ P ~ and Q
A A stirred suspension of 4,5-diphenylimidazole-2-thiol (3.2g) and anhydrous potassium carbonate (1.8~) in anhydrous dimethylformamide (50ml) was stirred at room temperature for 15 minutes. Ik was then treated with 2-bromoethyl ethyl ether (2.4g) and the mixture was stirred at room temperature overnight. The mixture was filtered through silica gel and the bright yellow filtrate was evaporated to low bulX. The residue was shaken with ethyl acetate (lOOml) and water (50ml). The layers were separated and the organic layer was washed with water (50ml), dried (magnesium sulphate) and evaporated.
The residue was subjected to flash chromatography eluting with a mixture of ethyl acetate and dichloromethane (1:3 v/v). Crystallisation from cyclohexane gave 2-(2-ethoxyethylthio)-4,5-diphenyl- .
imidazole (2.2g) in the form of a white crystalline solid, m.p. 91-92C.
[Elemental analysis:- C,69.9;H,6.1;N,8.5;S,10.0%;
Calculated:- C,70.34;H,6.21;N,8.64;S,9.88%.
NMR (in C~C13):- 1.23 (3H,t,J = 8Hz), 3.18 (2H,t,J =
6Hz), 3.64 (2H,q,J = 8Hz), 3.83 (2H,t,J = 6Hz), 7.2-7.6 (lO~,m)].
WO 91/13876 PCr/GB91/00408 .''~, i 2~7~ 30-By proceeding in a similar manner, but replacing the 2-bromoethyl ethyl ether used as a starting material by the appropriate quantity of the corresponding halides, and optionally replacing the potassium carbonate by potassium t-butoxide, there were prepared the followln~ compounds:-B 2-t(dioxolan-2-yl)methylthio]-4,5-diphenyl-imidazole, m.p. 139-143C.;
C 2-benzylthio-4,5-diphenylimidazole, m.p. 181-189C.;
D 2-(3,5-dimethoxybenzylthio)-4,5-diphenylimidazole, m.p. 148.5-149.5C.;
E 2-cyclohexylmethylthio-4,5-diphenylimidazole, m.p. 169-171C.;
F [~]-2-t(tetrahydro-2~-pyran-6-yl)methylthio~-4,5-diphenylimidazole, m.p. 143-}45C.;
G [1]-2-[(tetrahydro-2H-pyran-6-yl)methylthio~-4(5)-(4-chlorophenyl)-5(4)-phenylimidazole, m.p. 127-129C.;
H 2-[2-(1,3-dioxan-2-yl)ethylthio)-4,5-diphenyl-imidazole, m.p. }91-193C.;
I 2-[3-(1,3-dioxan-2-yl)propylthio~-4,5-diphenyl-imidazole, m.p. 151C.;
J 2-(2,2-diethoxyethylthio)-4,s-diphenylimidazole, m.p. sO-94c.;
K 2-(2,2-dimethoxyethylthio)-4,5-diphenyl-- 31 - ~ 0 7 8 ~ ~ 8 ~
imidazole, m.p. 162-163C.;
L 2-(3,3-diethoxypropylthio)-4,5-diphenyl-imidazole, m.p. 247-249C.;
M 2-(4-ethoxyhex-5-enylthio)-4,5-diphenyl-imidazole, m.p. 91C.;
N 2-[4-(2-hydroxyethyl)hept-6-enylthio]-4,5-diphenylimidazole, in the form of a colourless gum;
0 2-(2-oxoprop-1-yl)thio-4,5-diphenylimidazole, m.p. 145-147C; and P 2-(2-diethylaminoethylthio)-4,5-diphenyl-imidazole, m.p. 90-92C;
Q ~y again proreeding in a similar manner, but replacing the ~-bromoethyl ethyl ether by 2-diisopropylaminoethyl chloride hydrochloride and the potassium carbonate by potassium t-butoxide, and treating a solution of the free base in ethanol with a solution of hydrogen chloride in e~hanol [prepared by add~ng acetyl chloride (12ml) dropwise to cold ethanol tlOOml;10C) with stirring, maintaining the t~mperature below 30C] there was prepared 2-(2-diisopropylamino-ethylthio)-4,5-diphenylimidazole, m.p.183-185C.
[Elemental analysis:- C,60.8;H,7.1;N,9.jS,7.3;Cl,14.4~, Calculated (C23H29N3S:1.8HC1:0.5H2O):- C,60.8;H,7~05;
N,9.25;S,7.06;Cl,14.05%].
2o78-2~)8 - 32 -Compound R
A stirred suspension of lithium hydroxide hydrate (4.2g) in ethanol (200ml) was treated, portionwise, with 4,5-diphenylimidazole-2-thiol. The mixture was stirred at ambient temperature for 0 minutes and then~.it was treated with propargyl chloride (7.45g), and stirring was continued for a further 3 hours. The reaction mixture was poured into water with stirring, and the resulting solid was filtered off, washed with water and dried. Recrystallisation from a mixture of petroleum ether (b.p.40-60C) and dichloromethane, and then from toluene, gave 2-propargylthio-4,5-diphenylimidazole (16.07g) in the form of a white solid, m.p. 164-166C.
tElemental analysis:- C~74.2;H,4.73;N,9.6;5,10.9%;
Calculated:- C,74.45jH,4.86;N,9.65;S,11.04%3.
Compounds S T and U
S A stirred suspension of 4,5-bis(2-chlorophenyl)-imidazole-2-thiol (2.0g) in anhydrous methanol (20ml) was treated with sodium methoxide (0.41g) and then - stirred at room temperature for 5 minutes. The mixture was then treated with 2-bromomethyltetrahydro-2H-pyran (2.0g) and stirred at reflux for 2 hours.
After cooling to room temperature the mixture was WO9l/13876 PCT/GB91/00408 ~ 33 ~ 2 0782 poured into water (250ml) and the precipitate was filtered off. The product was dissolved in dichloromethane (lOOml) and the solution was dried (magnesium sulphate) and evaporated. Trituration of the residue with diethyl ether gave a white solid, which was crystallised from methanol, to give [+)-4,5-bis(2-chlorophenyl)-2-t(tetrahydro-2H-pyran 2-yl)methylthio]imidazole (1~85g) in the form of a white powder, m.p. 162-4C.
[Elemental analysis:- C,60.2;H,4.82;N,6.82;S,7.5%;
Calculated:- C,60.15;H,4.81;N,6.68;S,7.~5.
NMR (in CDC13):- 1.5-2.0 (6H,m), 3.03 (lH,dd,J = 8Hz, 6Hz), 3.27 (lH,dd,J = 12Hæ, 2Hz), 3.59 (lH,dt,J = 12Hz, 2Hz), 3.72 (lH,m), 4.21 (lH,dt,J = lOHz, 2Hz)].
By proceeding in a similar manner, but replacing the 4,5-bis(2-chlorophenyl)imidazole-2-thiol with the appropriate quantity of the corresponding imidazole-2-thiol, there were prepared:-T [+]-4(5)-(2-chlorophenyl)-5(4)-phenyl-2-[(tetra-hydro-2H-pyran-2-yl)methylthio~imidazole, `m.p. 58-60C.; and U ~*]-4(5)-(3-chlorophenyl)-5(4)-phenyl-2-[(tetrahydro=2H-pyran-2-yl)methylthio]imidazole, m.p.
113-5~.
W091/13876 PCr/GB9l/00408 2~7 82~ 8 _ 34 _ Com~ounds V, W. X and Y
V A stirred suspension of 4,5-diphenylimidazole-2-thiol (4.2g) in anhydrous tetrahydrofuran (60ml) was treated with sodium hydride (80% dispersion in oil, 0.67g) under an argon atmosphere. After stirring at room temperature~or 30 minutes the mixture was treated with t+]-2-iod'omethyl-1,4-dioxane (4.2g). The resulting mixture was stirred at room temperature for 2 days, and then it was poured into water (500ml) and the product was filtered off and dried at 60C.
Crystallisation ~rom a mixture of isopropanol and diethyl ether gave [+]-2-[(1,4-dioxanyl)methyl-thio]-4,5-diphenylimidazole (1.14g), m.p. 144-147C.
[Elemental analysis:- C,68.0;~,5.6s;N,g.2;S,9.0%;
Calculated:- C~68.18;H,5.68;N,7.95;S,9.10%.
NMR (in CDCl3):- 3.04 (lH,dd,J = 14Hz, 8~z), 3.13 (lH,dd,J = 16Hz, 4Hz), 3.52 (lH,t,J - lOHz), 3.6-4.0 (6H,m), 7.2 7.7 (lOH,m).
By proceeding in a similar manner, but replacing the [+]-2-iodomethyl-1,4-dioxane by the appropriate quantity of the corresponding halide, and optionally carrying out the reaction in the presence of triethylamine at temperatures from ambient ~o the reflux temperature, there were prepared:-W [+]-2-[(2,2-di(methoxymethyl)tetrahydro-2H-WO91/l3876 PCT/GB9l/00408 ,~ .20782o8 pyran-6-yl)methylthio]-4,5-diphenylimidazole, m.p.
143-145C.; and X 2-(3-dimethylaminopropylthio)-4l5-diphenyl-imidazole, m.p. 138-140C.
By again pxoceeding in a similar manner, but replacing the t+]-2-iodomethyl-1,4-dioxane by the appropriate quantity of 10-tosyloxy-2,5,8-~rioxadecane and carrying out the reaction at 40-50C for 150 minutes, there was prepared:-Y 2-~3,6,9-trioxadecylthio)-4,5-diphenylimidazole, in the form of a yellow oil.
[Elemental analysis (C22H26N203S:0.5C~30H):-C,64.9;H,S.59;N,6.69;S,7.8%;
Calculated:- C,65.2;H,6.58;N,6.76;S,7.7%].
Compounds Z and AA
Z A stirred suspension of 4,5-diphenylimidazole-2-thiol (2.9g) in anhydrous ~etrahydrofuran (40ml) was treated with sodium hydride (80% dispersion in oil, 0.36g)under an argon atmosphere. The mixture was stirred at room temperature ~or 30 minutes and then it was treated with [+~-2,2-di(acetoxymethyl)-6 iodomethyltetrahydro-2H-pyran (4.9g). The resulting mixture was stirred at room temperature for 24 hours, poured into water (SOOml~, and the product was extracted into diethyl ether (lOOml). The ethereal solution was washed with watler (50ml), dried (magnesium sulphate), and evaporated. The brown gummy residue was subjected to flash chromatography (eluting with a mixture of methanol and dichloromethane; 1:9 v/v) to give crude [+]-2-[2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenylimidazole l4.8g).
A ~ixture o~ this product and potassium hydroxide (lo 68g) in ethanol (25ml) and water (5ml) was stirred at room temperature for 75 minutes. The mixture was then evaporated to low bulX, diluted with water (40ml) and extracted with ethyl acetate (lOOml, then 2x50ml). The resulting organic solution was dried (magnesium sulphate) and evaporated and the residue was crystallised from a mixture of methanol and ethyl acetate, to give [i]-2-[2,2-di(hydroxymethyl)-tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenyl~
imidazole (1.54g), m.p. 176-178C.
[Elemental analysis:- C,67.1;H,6.43jN,6.7,S,7.9%, Calculated:- C, 67.32;~,6.34;N,6.83;S,7.80%.
NMR (in a mixture of CDCl3 and D2O):- 1.2-1.8 (6H,m), 2.79 (lH,dd,J = lOHz, 12Hz), 3.07 (lH,dd,J = 12Hz, 2Hz), 3.49 (2H,m), 3.69 (l~,d,J = lOHz), 3.81 (lH,dt,J
= lOHz, 2Hz), 4.14 (lH,d,J = lOHz), 7.2-7.6 (lOH,m)].
AA A s~lution of [~]-2-[2,2-di(hydroxymethyl)-tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenyl-:.`'' ' ;
_ 37 - ~0~782~8 ,.
imidazole (1.2y) in pyridine (5ml) was treated with acetic anhydride (0.92g) and the mixture was stirred at room temperature overnight. The mixture was treated with a further quantity of acetic anhydride (0.92g) in pyridine (5ml), followed, after one hour, by mathanol (2Oml). Evaporation of the mixture gave a colourless gum. The residue was treated with a mixture of water (20ml) and methanol (20ml) andiit was evaporated again. This procedure was repeated three times, and then th~ residue was dissolved in ethyl acetate (25ml).
This solution was dried (magnesium sulphate) and evaporated to give a pale yellow glass. This was triturated with a mixture diethyl ether and pentane to give [+]-2-[2,2-di(acetoxymethyl)tetrahydro-2H-pyran-6-ylmethylthio]-4,5-diphenylimidazole ~l.Og) in the form of a stable meringue, m.p. 50-56C.
[Ele~ental analysis:- C,65.7;H,6.25;N,5.80;S,6.4%;
Calculated:- C,65.~9;H,6.07;N,5.67;S,6.48%.
NMR (in CDCl3):- 1.3-1.8 (6H,m), 1.82 (3H,s), 2.07 (3H,s), 2.93 tlH,dd,J = 16Hz, 8Hz), 3.05 (lH,dd,J =
lO~z, 2Hz), 3.95 (2H,m), 4.02 (lH,d,J = 12Hz), 4.11 (lH,d,J = 12Hz), 4.85 (lH,d,J = 12Hz), 7.2-7.6 (lOH,m)]-2~7 8~ 08 3~ _ . EXA~PLE 6 Com~ounds AB and AC
AB A mixture of 4,5-diph,enylimidazole-2-thiol (5.0g) and 2-bromoethanol (2.5g) in ethanol (150ml) was stirred at reflux for 4 hoursO The mixture was filtered hot, cooled t'~5~C., neutralised by treatm2nt with sodium hydrox~de solution (2N) and poured into iced water (1500~13. The resulting cream solid (4.8g) was filtered off and subjected to flash chromatography (eluting with a mixture of dichloromethane and methanol (19:1 v/v) followed by crystallisation from ethanol, to give 2-(2-hydroxy-ethylthio)-4,5-diphenylimidazole (0.7g), in the form of a white crystalline solid, m.p. 168-70C.
[Elemental analysis:- C,68.7;H,5.5;N,9.4;S,10.6~;
Calculated:- C,68.9;H,5.45;N,9.45;S,10.81%.
NMR (in CD3SOCD3):- 3.20 (2H,t,J - 8Hz), 3.68 (2H,t,J =
8Hz), 7.2-7.5 (lOH,m)].
AC By proceeding in a similar manner, but replacing the 2-bromoethanol by bromoethane, there was prepared:-2-ethylthio-4,5-diphenylimidazole, m.p. 190C.
: EXAMPLE 7 Compound AD
A mixture of 2-(2,2-di~thoxyethylthio)-4,5-diphenylimidazole (lO.Og), pyridinium 4-toluene-~ 39 2~78'2b8`"`'`' , sulphonate, polymer-bound (1.6g; approximately 6mmole of active component), and 1,3-propanediol (lO.Og) in toluene (500ml) was stirred at reflux under a Dean and Stark water trap for 24 hours. At periodic intervals of about ~ne hour the fluid collected in the wat~r trap was run off and replaced.in the reaction flask by fresh toluene. After cooli~g to room temperature, the mixture was washed with water (3x250~1), dried (magnesium sulphate) and evaporated. The resulting dark orange oil was subjected to flash chromatography (eluting with mixtures of ethyl acetate and dichloro~ethane; 1:9-4:6 v/v) and crystallised from ethyl acetate, to give 2-[(1,3-dioxan-2-yl)methylthio]-4,5-diphe~ylimidazole, (2.3g) m.p. 153-155C.
[Elemental analysis:- C,68.3;H,5.75;N,7.9;S,9.1%;
Calculated:- C,68.15;H,5.72;N,7.95;S,9.10%.
NMR (in CDCl3):- 1.38 (lH,m), 2.10 (lH,m) 3.11 (2H,d,J
= 6Hz), 3.87 ~2H,dt,J = lOHz, 2Hz), 4.16 (2H,dd,J =
lOHz, 6~z), 4.89 (lH,t,J = 6Hz), 7.2 7.5 (lOH,m)].
Compounds AE AG and AJ
AE A stirred solution of 2-(3-aminopropylthio)-4,5-diphenylimidazole (3036g) in ethanol (150ml) at the ambient temperature was treated with S,S'-dimethyl-N-WO9l/13876 PCT/GB91/00408 20~ 8208 40 _ cyanodithioiminocarbonate (1.76g), and stirred for onehour. The resulting solid was filtered off, washed with diethyl ether and dried, to give -cyano-2-methyl-l-r3-(4,5-diphenylimidazol-2-ylthio)propyl]isothiourea (3.15g) in the form of a colourless solid, m.p.
225-227C. .;
[Elemental analysiso- C,61.8;H,5.3jN,17.1;S,15.6~;
calculated:- C,61.92;H,5.16;N,17.20;S,15.72~.
NMR (in a mixture of CD3SOCD3 and D20):- 1.94 (2H, quin,J = ~Hz), 2.53 (3H,s), 3.13 (2H,t,J = 7Hz~, 3.44 (2H,t,J = 7Hz), 7.1-7.5 (lOH,m)].
A& By proceeding in a similar manner, but replacing the 2-(3-aminopropylthio)-4,5~diphenyli~idazole with the appropriate quantity of 2-(4-aminobut~lthio)-4,5-diphenylimidazole, stirring for a ~otal of 5 hours and, after evaporation of the reaction mixture, subjecting the residue to mplc (using a mixture of dichloromethane and methanol; 19:1 v!Y) as eluent, there was prepared 3-cyano-2-methyl-1-[4-(4,5-diphenylimidazol-2-ylthio)-butyl]isothiourea (4.4g) in the form of a colourless solid, m.p.103-105C. (from isopropanol).
tElemental analysis:- C,62.5;H,5.46;N,16.5;S,15~3%;
Calculated:- C,62.68;H,5.50;N,16.61;S,15.21~.
W091113876 PCT/GB91~00408 - ~1 - 2~7820~
NMR (in a mixture of CD3SOCD~ and D20):- 1.67 (4H,m~, 2.54 (3H,s), 3.13 (2H,t,J= 7Hz), 3.3-3.36 (2H,m), 7.2-7.47 (lOH,m)].
AJ By again proceeding in a si~ilar manner, but replacing the 2-( 3 -aminopropylthio)-4,5-diphenyl-imidazole with 2- (2-aminoethylthio)-4,5-diphenyl-imidazole, there was prapared 3 -cyano-2-methyl-1-[ 2-(4, 5-diphenylimidazol-2-ylthio)-athyl]isothiourea (3. 02g) in the form of a colourless solid, m.p. 215-217C. (~rom ethanol). [Elemental analysis:- C,61.2;H,4.96;N,18.1;S,16.2%; Calculated:-C,61.04;H,4.87;N,17.80;S,16.30%.NMR (in a mixture of CD3SOCD3 and D20):- 2.38 (3H,s), 3~35 (2H,t,J= 7Hz), 3.74 (2H,t,J = 7Hz), 7.1-7.55 (lOH,m)].
Com~ound AF
AF A suspension of 3 cyano-2-methyl-1-[2-(4,5-diphenylimidazol-Z-ylthio)ethyl]isothiourea (1.6g) in ethanol (lOOml) was treated with hydrazine hydrate (0.6ml). The mixture was heated under reflux for 2 hours, and the resulting solution was evaporated.
The residue was dissolved in ethanol (250ml) and was then treatecl with a solution o~ acetyl chloride (5ml) in ethanol (20ml) with ice cooling. After stirring for 10 minutes, the solution was evaporated and the residue was dissolved in methanol (2Oml). The ~ 8 P~/GB91/00408 solution was treated with diethyl ether (60ml) and left to stand for 20 hours. The resulting solid was filtered off and dried, to give 2-[2-(5-amino-1,2,4-triazol-3-ylamino)ethylthio]-4,5-diphenylimidazole dihydrochloride ~1.03g) in the form of a colourless solid, m.p. 223-226C.
[Elemental analysis:- C,49.2;H,4.5;Cl,15.1;N,21.3;
S,7.1:H20,3.2%;
Calculated (for C1gH1gN7S 2HCl H20~ ~
C,48.72jH,4.91;Cl,15.17;N,20094;S,6.84%.
NMR (in D20):- 3.46-3.66 (4H,m), 7.36-7.54 (lOH,m).
Example 10 Compounds AI and AH
AI A suspension of 3-cyano-2-methyl-1-[3-(4,5-diphenylimidazol-2-ylthio~propyl]isothiourea (2.2g) in ethoxyethanol (200ml) was treated with hydrazine hydrate (3.14~1). The mixture was heated under reflux for 6 hours, and the resulting solution was evaporated. The residue was triturated with hot acetonitrile (lOOml), and the resulting solid was collected and dried, giving 2-t3-(5-amino-1,2,4-triazol-3-ylamino)propylthio]-4,5-diphenylimidazole (1.45g) in the form of a colourless solid, m.p. 225-227C.
[Elemental analysis:- C,61.~;H,5.5;N,24.6;5,8.3%;
Calcula~ed:- C,61.36;H,5.41;N,25.04;S,8.19%.
W091/13876 PCT/GB9t/00408 43 207~2~8 .;
NMR (in a mixture of CD3SOCD3 and D20):- 1.87 (2H,quin,J= 7Hz~, 3.1-3.17 (4H,m)j 7.16-7.50 (lOH,m) ] .
AH By proceeding in a similar manner, but substituting ethanol for the ethoxyethanol and 3-cyano-2-methyl-1-[4-(4,5 diphenyli~idazol-2-ylthio)butyl]isothiourea for the 3-cyano-~-methyl-1-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-isothiourea, there was prepared:-2-~4-(5-amino-1,2,4-triazol-3-ylamino)butylthio]-4,5-diphanylimidazole in the form of a colourless solid, m.p.
214-216C. (from isopropanol~.
[Elemental analysis:- C,62.0;H,5.7;N,24.0;S,8.2%;
Calculated: C,62.2;H,5.72,N,24.18;S,7.91~.
NMR (in a mixture of CD3SOCD3 and D20):- 1.57-1.74 ~4H,m), 3.03 (2H,t,J = 7Hz), 3.13 (2H,t,J = 7Hæ), 1.17-7.48 (lO~,m)3.
Compound AM
A suspension of 2-(3-aminopropylthio)-4,5-diphenyl-imidazole (1.55g; prepared as described in Reference Example 1) in acetic anhydride (lOml) was heated at 100C for 3 minutes and then it was allowed to cool to the amblent temperature. The solu~ion was then poured into water t50ml) and the mixture was allowed to stand for 90 minutes. The solution was treated with aqueous sodium hydroxide solution (2N) until it was WO9lJ13876 PCT/GB91/00408 .f--.
~7~ 44 -alkaline, and the mixture was then extracted with dichloromethane (2x30ml). The combined extracts were dried (MgSO4) and evaporated, to give a colourless solid, which was recrystallised from acetonitrile, to give 2-~3-acetamidopropylthio)-4,5-diphenylimidazole tl.08g) in the form of a colourless solid, m~p. 180-181C.
EElemental analysis:- C,68.7;H,6.1;N,12~1;S,8.9%;
Calculated:- C,68.3~;H,6.02;N,11.96;S,9.12%.
NMR (in CDCl3) 1`'88 (2H,quin,J = 7Hz), 3.18 (2H,t,J =
7Hz), 3.44 (2H,q,J = 7Hz), 7.2-7.58 (lOH,m), 7~65 (lH,br.t,J = 7Hz)].
Example 12 Compounds_AO, AK ~AN and AP
AO A stirred suspension of ~,5-diphenylimidazole-2-thiol (3.28g) in dry tetrahydrofuran (lOOml) was treated with a dispersion of sodium hydride on oil (0.6g; 60%) at ambient temperature. After stirring at ambient temperature for 20 minutes. The solution was treated with 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide (4.2g), followed by triethylamine (5ml).
The resulting mixture was heated at reflux f or 20 hours and then diluted with water ~180ml) and diethyl ether (80ml). The organic layer was separated and extracted with dilute hydrochloric acid (lOOml;lN). The acidic aqueous phase was then separated, made alkaline by treatment with aqueous so~ium hydroxide solution (lN) WO9l/13876 PCT/GB91/00408 ~ . .
2;~7;&?0:~`
and then extracted with diethyl ether (2xlSOml). The combined extracts were dried tMgS04) and evaporated, to give a solid residue, which was recrystallised ~rom acetonitrile, to give N-(4~6-dimethylpyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide (2.5g) in the form of a colourless solid, m.p. 186-188C.
[Elemental analysis:- C,70.4;H,5.81;N,12.6;S,6.6%;
Calculated:- C,70.56;H,5.92,N,12.66;S,7.25%.
NMR (in CDC13):- 2.17 (2H,quin,J = 7Hz), 203 (3H,s), 2.35 (3H,s), 2.62 (2H,t,J - 7Hz), 3.1 (2H,t,J = 7Hz), 6.74 tlH,s), 7.23-7.57 (lOH,m), 7.79 (lH,s), 8.22 ~lH,br.s)].
AK By proceeding in a similar manner, but substituting the appropriate quantity of 4-c~loro-N-(4-methylpyrid-2-yl)butanamide for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide, there was prepared:-N-(4-methylpyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide in the form of a colourless solid, m.p. 147-149C.
[Elemental analysis:- C,69.5;H,5.7;N,13.0;S,7.7%;
Calculated:- C,70.09;H,5.61;N,13.08;S,7.~8~.
NMR (in CDC13):- 2.19 (2~,quin,J = 7~z), 2.35 (3H,s), 2.65 (2H,t,J = 7Hz), 3.14 (2H,t,J = 7Hz), 6.86 (lH,d,J
= 6Hz), 7.2-7.63 (lOH,m), 7.97 (lH,s), 8.02 (lH,d,J =
6Hz), 8.49 (lH,br.s)].
` .
207820g AN By proceeding in a similar manner, but substituting the appropriate quantity of N-(4-chlorobutanoyl~-2,6-dimethylmorpholine for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide , there was prepared:-2,6-dimethyl-N-[4-(4,5-diphenylimidazol~2-ylthio)-butan-1-oyl]morphoiine (4.7g) in the for~ of a colourless so~i~d, m.p. 147 149C.
tElemental analysis:- C,68.6j~,6.79;N,9.7;S,7.4%;
Calculated:- C,68.~3;H,6.71;N,9.65;S,7.36%.
AP By proceeding in a similar manner, but substituting the appropriate quantity of 4-chloro-N-(pyrid-2-yl)butanamide for the 4-chloro-N-(4,6-dimethylpyrid-2-yl)butanamide, there was prepared:-N-(pyrid-2-yl)-4-(4,5-diphenylimidazol-2-ylthio)butanamide (O.8g) in the form o~ a colourless solid, m.p. 167-163C.
tElemental analysis:- C,68.8;H,5.19;M,13.2~;
Calculated:- C,69.54;H,5.35jN,13.52%].
Example 13 ComPoun~d AL
A stirred suspension of lithiu~ aluminium hydride (0.42g) in dry tetrahydrofuran was treated portionwise with N-(4,6-dimethylpyrid-2~yl)-4-(4,5-diphenylimidazol-2ylthio)butanamide t2.44g) at -10C
under an argon atmosphere. The mixture was then . . .
~ 47 ~ 2078208 stirred at the a~bient temperature for 2 hours.
It was then treated with water (0.7ml), followed by aqueous sodium hydroxide solution (2.1ml;15%) and then water (2.lml). After stirring for lO minutes, the mixture was filtered and the filtrate was evaporated, to give a colourless solid. This solid was subjected to flash chromatography on silica gel, using a mixture of dichloromethane and methanol (39:1 v/v) as eluent, to give 4,6-dimethyl-2-[4-(4,5-diphenyl-imida~ol-2-ylthio)butylamino]pyridine (1.64g), in the form of a colourless solid, m.p. 166-168C.
[Elemental analysis:- C,72.7;H,6.6;N,12.9;S,7.5%;
Calculated:- C,72.9;H,6.54;N,13.08;S,7.48%.
NMR (in CDCl3):- 1.73-1.84 (4H,m), 2.18 (3H,s), 2.2 (3H,s), 3.1 (2H,t,J = 7Hz), 3.22 (2H,q,J = 7Hz), 4.63 (lH,br.t,J = 7Hz), 6.0 (lH,s), 6.27 (lH,s), 7.2-7.63 (lOH,m).
Compounds AO to BF
AQ Sodium methoxide (2.16g) was added to a stirred suspension of 4,5-diphenylimidazole-2-thiol ~lO.Og) in anhydrous methanol (250ml). After stirring at room temperature for 30 minutes methyl 4,5-epoxypentanoate (7.7g) was added and the mixture was stirred at room temperature overnight. Evaporation gave a light yellow residue, which was shaken with ethyl acetate WO91/13X76 PCT/~B91/00408 207~208 - 48 -t250ml) and water (2SOml). The layers were separated and the organic layer dried (magnesium sulphate) and evaporated. The residue was boiled with methanol (lOOml) for 15 minutes and then allowed to cool to room temperature. The white insoluble solid was collected by filtration and washed with a little fresh methanol.
The solution was t~r,eated with fresh methanol (lOOml) and lM sodium hy,droxide solution (50ml). After standing at room temperature for 2 hours the clear solution was evaporated to dryness and shaken with ethyl acetate (200ml) and 2M acetic acid solution (150~1). The layers wera separated a~d the organic layer dried (magnasium sulphate) and evaporated. The oily residue was dissolved in dichloromethane (300ml) and treated with trifluoroacetic acid (10~1). After standing at room temperature for 2 hours the solution was washed with 5% sodiu~ hydrogen carbonate solution (5xl50ml), dried (magnesium sulphate) and evaporated. The resulting white foam was subjected to flash chromatography (ethyl acetate-dichloromethane mixture, 1:1 vtv).
Crystallisation from ethyl acetate/hexane gave (5R,5S)-4,5-diphenyl-2-[(2-oxotetrahydrofur-5-yl)methylthio~imidazole,(2.0g) in the form of a dense white solid, m.p. 118-120C.
[Elemental analysis:- C,6B.7;H,5.21;N,7.9;S,9.1%;
Calculated:- C,68.55;H,5.18;N,7.99jS,9.15~.
49 _ 207~208 NMR (in CDC13):- 2.10 (lH,m), 2.3-2.7 (3H,m) 3.32 (lH,m~, 4.83 (lH,m), 7.2-7.5 (lOH,m)].
AR ~y proceeding in a similar manner, but substituting 4,5-bis(3-chlorophenyl)imidazole-2-thiol for the 4,5-diphenylimidazole-2-thiol, and t-butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate for the methyl 4,5-epoxypentanoate, there was prepared:-(4R,4S)(6R,6S)-6-[(4,5-bis{3-chlorophenyl}imidazol~2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one in the form of a white solid, m.p. 178C.
[Elemental analysis:- C,57.~;H,4.32;Cl,15.1;N,5.88;
S,6.73%; Calculated:- C,57.02;~,4.35;Cl,15.3;N,6.05, S,6.9~%. N~R (in CDC13):- 1.35(3H,s), 1.66-1.8(1H,m), 2.14-2.22(1H,m), 2.4-2.78(2H,m), 3.4(2H,d,J = 4Hz), 4.41 (lH.s),4.9-5.1(1H,m)].
By again proceeding in a similar manner, and replacing the 4,5-bis(3-chlorophenyl)imidazole-2-thiol with the appropriate quantity of the corresponding imidazole-2-thiol, there were also prepared:-AS (4R, 4S) (6R, 6S~-6-~(4,5-Bis{4-chlorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one, m.p. 190-1C.
[Elemental analysis:- C,56~8;H,4.3;C1~15.7;N~5~s;S~6~82%;
Calculated:- C,57.02;~,4.35;Cl,15.3;N,6.05;S,6.92%].
AT (4R,4S)(6R,6S)-6-[(4,5-Bis{2-chlorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydro-~97;~2~ - so py~an-2-one, m.p. 100C.
[Elemental analysis:- C,56.8;H,4.36;Cl,15.2;N,6.04;S,7.2%;
Calculated:- C,57.02;H,4.35;Cl,15.3;N,6.05;S,6.92%].
AU (4R,4S)(6R,6S)-6-[(4,5-Bis{4-fluorophenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one, m.p.~ l74-178C.
[Elemental analysis:- C,61.7;H,4.8;F,8.9;N,6.5;S,7.4%;
Calculated:- C,61.38;H,4.68;F,8.83;N,6.51;S,7.45~].
AV (4R,4S)(6R,6S)-6 [(4,5-Bis{4-trifluoromethyl-phenyl}imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyl-tetrahydropyran-2-one, m.p. 205C.
[Elemental analysis:- C,54.6;H,3.99;N,5.28%;
Calculated:- C,54.3;H,3.80;N,5.28~].
AW (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methyl-phenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one, ~.p. 86-88C.
[Elemental analysis:- C,67.90;H,6.40jN,6.50;S,7.30~;
Calculated:- C,68.22;H,6.20;N,6.63;5,7.59%].
AX (4R,4S)(6R,6S) 4-Hydro~y-6-[(4,5-bis{4-methyl-phenyl}i~idazol-2-yl)thiomethyl]-4-methyl~etrahydro-pyran-2-one, m.p. 205-7C.
[Elemental analysis:- C,68.1;H,6.09;N,6.42%;
Calculatedo- C,68.22;~,6.20;N,6.63%].
AY (4R,4S)~6R,6S)-4-Hydroxy-6-[(4,5-bis{4-isopropylphenyl}imidazol-2-yl)thiomethylJ-4-methyltetrahydropyran-2 one, m.p. 89-91C.
.
Sl 2~78208 ...
, [Elemental analysis:- C,69.8;H,7.2;N,5.9;S,6.36~;
Calculated:- C,70.26;H,7.16;N,5.85;S,6.69%.
AZ ~4R,4S)(6R,6S~-6-E(4,5-Bis{4-tertbutylphenyl}-imidazol-2-yl)thiomethyl]-4-hydroxy~-methyltetra-hydropyran-2-one, ~.p. 134-51C.
[Elemental analysis (C30H38N203S:1~4H20~:-C,70.5;H,7.7;N,5.3;S,6.33;H20,1.2%;Calculated:- C,70.48;H,7.59;N,5.48;S,6.2,H20,0~81~].
B~ (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{2-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetra-hydropyran-2-one, m.p. 108-10C.
[Elemental analysis (C24H26N205S:C4~02):~
C,61.8;H,5.9;N,5.5;S,6.37%;
Calculated:- C,61.99;H,6.27;N,5.17;S,5.90%].
BB (4R,4S)(6R,6S)-4-Hydroxy-6-[(4,5-bis{3-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyl-tetrahydropyran-2-one, m.p. 148C.
[Elemental analysis (C24H26N205S:0-45C4H802):-C,62.2;H,5.74jN,5.79%;
Calculated:- C,62.7;H,6.04;N,5.67;S,6.94%].
BC ~ BD
BC By proceeding in a similar manner, and replacing the 4,5-bis(3-chlorophenyl)imidazole-2-thiol by 4,5-diphenylimidazole-2-thiol in the reaction with t-butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate, there was obtained a product in the form of a mixture of 2 racemates. This mixture was ~riturated with diethyl ether, and the insoluble material recrystallised from a mixture of ethyl acetate and methanol, to give 6-[(4,5-diphenylimidazol-2-y:L)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one, m.p. 201-202.5C.
[Elemental analysis:- C,67.10;H,S.70;N,7.10;S,8.00%;
Calculated:- C,66.98;H,5.62;N,7.10;S,8.13%.
NMR (in CD3SOCD3)~ 1(3H,s), 1.64-2.06(2H,m), 2.3-2.6(2H,m), 3.4-3.5(2H,m), 4.76-4-92(1~,m), 5.06(lH,m)].
BD The washings from the trituration were concentrated, to give a white solid, which was recrystallised from a mixture o~ ethyl acetate and methanol, to give 6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetrahydropyran-2-one, m.p. 203.5-205C.
[Elemental analysis: C,66.60;H,5.56;N,6.94;S,8.10%;
Calculated:- C,66.98;H,5.62;N,7.10;S,8.13%.
NMR (in CD3SOCD3):- 1.24(3H,s~, 1.7-2.3(2H,m), 2.3-2.7(2H,m), 3.4-3.5(2H,m~, 4.S4-4.7(lH,m), 5.04(1~,s), 7.15-7.6(lOH,m)].
BE ~ BF By proceeding in a similar manner to that described for Compounds BC and BD, but replacing the 4,5-diphenylimidazole-2-thiol by the appropriate quantity of 4,5-bis-(4-methoxyphenyl)imidazole-2-thiol, there were obtained:-_ ~3 _ 2078208 4 hydroxy-6-[(4,5-bis{4-methoxyphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one, m.p. 214-215 and 90-115C. [Elemental analyses:-Compound BE:- C,63.3;H,5.82;N,6.11;S,7.1%;
Compound BF:- C,63.8;H,5.94;N,5.94;S,6.9%;
Cal~ulated:- C,63.44; H,5.73;N,6017;S,7.05%~.
Compounds B~ TO BL
BG A suspension of (4R,4S)(6R,6S)-4-hydroxy-6-[(4,5-bis~4-methylphenyl}imidazol-2-yl)thiomethyl]-4-methyltetrahydropyran-2-one (4.7g.) in dichloro-methane (250ml) was treated dropwise with tri~luoroacetic anhydride ~6.3g) with ice-cooling, and left to stand at room temperature for 24 hours. ~he r~sulting solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, and evaporated, to give a gum. This gum was dissolved in tolùene (200ml), and treated with 1,8-diazabicyclo[5.4.0]undec-2-ene (4.~g), and left to stand at room te~perature for 24 hours. The solution was then washed with wa~er, dried over magnesium sulphate, and evaporated to give a white foam. This was recrystallised from a mixture of ethyl acetate and methanol, to give (6R,6S)-6-[(4,5-bis{4-methylphenyl}-imidazol-2-yl~thiomethyl]-5,6-dihydro-4-methylpyran-2-one, (2.1g), m.p. 191C.
20~2~8 - 54 ~
[Elemental analysis:- C,71.2;H,6.12;N,6.85;S, 7.8 %;
Calculated:- C,71.26;H,5.98jN,6.93;S,7~93%.
NMR (in CDCl3):- 1.96(3H,s), 2.3(6H,s), 2.54~2H,d,J =
8Hz), 3 .48(2H,d,J = 6Hz), 4.6-4.8(1H,~), 5.8(1H,d), 7.0-7.2(8H,m).
By proceeding in a similar manner, but replacing compound AX with the appropriate quantity of the corresponding compound from compounds AR to BF, there were also prepared:-BH (6R,6S)-6-[(4,5-diphenylimidazol-2-yl)-thiomethyl]-5,6-dihydro-4-methylpyran-2-oner m.p. 70-71C.
LElemental analysis:- C, 69.7;H,5.69;N,7.3;S,8.6%;
Calculated:- C,70.19jH,5.36;N,7.44;S,8.52%~.
BI (6R,6S)-6-~(4,5-Bis{4-chlorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p~
175-176C. [Elamental analysis:-C,59.1;H,4.04;N,6.3;S,7.3;Cl,15.8~;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;Cl,15.92%~.
BJ (6R,6S)-6-[(4,5-bis{3-chlorophenyl}imidazol-2-yl ? thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p.
132-135C.
[Elemental analysis:-C,59.3;H,4.2;N,6.4;S,7.1;Cl,15.6%;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;C1,15.92%~.
BK (6R,6S)-6-~(4,5-bis-{2-chlorophenyl}imidazol-W091~13876 PCT/GB91/00408 _ 55 _ 20 782 08 2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p..
126-127C.
[Elemental analysis:- C,59.2;H,4.04;N,6.2;Cl,15.9%;
Calculated:- C,59.33;H,4.07;N,6.29;S,7.20;Cl,15.92%].
BL (6R,6S)-6-[(4,5-bis-{4-fluorophenyl}imidazol-2-yl)thiomethyl]-5,6-dihydro-4-methylpyran-2-one, m.p.
123-126C.
[Elemental analysis:- c~64.5;H~4.6;N~6.9;s~7.a;F~9.3%;
Calculated:- C,64.06;H,4.4;N,6.79;S,7.77;F,9.21%].
Compounds BM TO BO
BM A mixture of 5-(iodomethyl)-2-furanone (2.06g), 4,5-bis-(4-methylphenyl)imidazole-2-thiol (2.2gg), and potassium carbonate (0.5~g), in dry dimethylformamide (40ml~ was stirred at room temperature for 24 hours.
The dimethylformamide was removed by evaporation at reduc~d pressure, and the residue was shaken with water and dichloromethane, the organic layer separated, and the aqueous layer extracted with more dichloromethane.
The combined organic solutions were dried over magnesium sulphate and concentrated, to give a yelIow semi-solid. This was subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane, (3:7v/v), and the foam obtained was recrystallised from diethyl ether to give (5R, 5S) -5-[ (4, 5-bis-{4-methylphenyl}imidazol-2-WO9l/t3876 PCT/GB91/00408 ., -yl)thiomethyl]tetrahydrofuran-2-one, (2.05g), m.p.
128-129C.
[Elemental analysis:- C,69.7;H,5.83;N,7.3;S,8.6%;
Calculated:- C,69.81;H,5086;N,7.40;S,8047%.
NMR (in CDCl3):- 1.96-2.7(4H,m), 2.36(6H,s), 3.3(2H,dd,J = 6Hz,2HZ), 4.72-4.9(1H,m), 6.96-7.5t8R,m)]. ~;
BN By proceeding in a similar manner, but replacing the 4,5-bis-(4-methylphenyl)imidazole-2-thiol by the appropriate quantity of 4,5-diphenylimidazole-2-thiol, and the 5-(iodo~ethyl)-2-furanone by the appropriate quantity of (6R,6S)-6-(iodomethyl)-3,4,5,6-tetrahydropyran-2-one, there was prepared:-(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-3,4,5,6-tetrahydropyran-2-one, with no sharp melting point.
[Elemental analysis:- C,69.00;H,5.52;N,7.7;S,8.70%;
Calculated:- C,69.20;H,5.53;N,7.69;S,8.80].
fiO By again procaeding in a similar manner, but replacing-the ( 6R, 6S) -6- ( iodomethyl)-3,4,5,6-tetrahydropyran-2-one by 4,4-dimethyl-6-iodomethyl-3,4,5,6-tetrahydropyran-2-one there was prepared:-(6R,6S)-6-t(4,5-diphenylimidazol-2-yl)thiomethyl]-4,4-dimethyl-3,4,5,6-tetrahydropyran-2-one, m.p.
130-131C.
tElemental analysis:- C,70.0;H,6.34jN,6.6;S,8.1%;
- 57 - 2 ~ 782 08 Calculated:- C,70.38;H,6.16;N,7.14;S,~.17%.
By again proceeding in a similar manner, but replacing the 5-(iodomethyl)--2-furanone by (4R,4S)(6R,6S)-4-hydroxy-6-iodomethylpyran-2-one, there was obtained, after chromatography:-BP (4R,4S)(6R,6S)-6- E (4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy-3 r 4,5,6-tetrahydropyran-2-one, m.p. 191-192C.
[Elemental analysis:- C,66.2;H,5.26;N,7.3;S,8.2%;
Calculated:- ~,66.29;H,5.30;N,7.36;S,8.43~] and BQ (3R,3~)(5R,5S)-ethyl ~-[(4,5-diphenylimidazol-2-yl)thio]-3,5-dihydrox~hexanoate, m.p. 94-95C.
[Elemental analysis:- C,64.4;H,6.02;N,6.48;S,7.5 ~;
Calculated:- C,64.77;H,6.14;N,6.57;S,7.52%].
NMR (in CDC13):- 1.21(3H,t), 1.5-2.1(2H,m~, 2.22-2.6(2H,m), 2.9-3.2~2H,m), 4.16(2H,q), 2.2-2.4(2H,m).
Compound BR
A mixture of 4,5-diphenyli~idazole-2-thiol (3.5g) and anhydrous potassium carbonate (2.9g) in anhydrous dimethylformamide ~60ml) was stirred at room temperature for 30 minutes. It`was then treated with (2R,2S~-2-(iodomethyl)-6-oxo-1,4-dioxane (3.4g) and the resulting mixture stirred at room temperature for 3 days. ~he mixture was poured into water (600ml) and the product collected by filtration and dried at 60~C., to give a cream solid (2.6g). A portion (1.5g) of this solid was dissolved in dichloromethane (60ml) and treated with trifluoroacetic acid (9.48g). After 30 minutes the solution was diluted with fresh dichloromethane (lOOml) and washed with 5~ sodium hydrogen carbonate solution (75ml). The layers were separated and the organic fraction washed with water (50ml), dried ~magnesium sulphate) and evaporated.
Crystallisation from tetrahydrofuran/diethyl ether gave (6R,6S)-[(4,5-diphenylimidazol-2-yl)thio~ethyl]-2-oxo-1,4-dioxane (0.5g) in the form of a white powder, m.p. 194-196C.
[Elemental analysis:-- C,64.8;H,4.91;N,7.7jS,B~8%;
Calculated:- C,65.57;H,4.92;N,7.65;S,8.74~;
NMR (CD3SOCD3):- 3.46 (2H,d,J = 6Hz), 3.76 (lH,dd,J =
12Hz, 6Hz), 4.05 (lH,dd,J = 12Hz, 4Hz), 4.32 (2H,dd,J =
16Hz, 4Hz), 4.87 (lH,m), 7.2-7.5 tlOH,m)].
EXAMP~E_18 Compound B5 Sodium methoxide ~0.34g) was added to a suspension of 4,5-bis-(4-chlorophenyl)imidazole-2-thiol (2.0g) in methanol (50ml), and the mixture was stirred at room temperature for one hour. t-Butyl 5,6-epoxy-3-hydroxy-3-methylhexanoate (1.98g), was added and the mixture was stirred at room ~emperature for 18 hours.
It was then concentrated at reduced pressure and the WO9l/13876 PCT/GB91/00408 _ 59 _ 2078208 res~idue was shaken with ethyl acetate and water. The ethyl acatate layer was separated, dried over magnesium sulphate, and concentrated, to give a semi-solid.
This was triturated with diethyl ether, to give a white solid, which was subjected to chromatography on silica yel eluting with a mixture of dichloromethane and ethyl acetate, to give a gum, which was recrystallised from cyclohexane to give t-butyl 6-[(4,5-bis-~4-chloro phenyl}imidazol-2-yl)thio]-3,5-dihydroxy-3-methyl-hexanoate in the form of one racemate, a white crystalline solid, m.p. 152-153C. ~Elemental analysis:- C,58.3;H,5.68;Cl,13.3;N,5.18;S,5.94%;
Calculated:- C,5801;H,5.63;Cl,13.19;N,5.21;S,5.97%.
NMR (in CDC13):- 1.32(3H,s), 1.46(9H,s), 1.64 (lH,dd,J = 12Hz, 4Hz), 1.9 2.1(1H,m), 2.3-2.7(2H,m), 2.98-3.3(2H,m), 4.3 4.5(1H,m), 4.8-6.4(2H,br.s), 7.1-7.6(8H,m).
Com~ound BT
- 6-[(4,5 Diphenylimidazol-2-yl)thiomethyl]-~-hydroxy-4-methyltetrahydropyran-2-one (4.~2g), was added to a solution of sodium hydroxide (1.0~;10.66ml) and water (70ml), and warmed at 60C for 10 minutes.
Traces of solid were removed by filtration, and the filtrate was co~centrated at reduced pressure to give a glass. This was dissolved in dimethylformamide (40ml), WO91~13876 PCT/GB91/00408 20782~
and treated with ethyl iodicle (2.15g), and the mixture . ¦
was stirred at room temperature for 2 hours. It was then shaken with ethyl acetate and water, the organic layer was separated and washed with water, dried over magnesium sulphate, and concentrated, to give an oil.
This was subjected to chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (l:lv/v), to give (3R,3S)(SR,5S)-ethyl 6-[(4,5-diphenylimidazol-2-yl~thio]-3,5-dihydroxy-3-~ethylhexanoate (2.47g), in the form of a yellow solid with no sharp melting point.
[Elemental analysis:- C,64.9;H,6.4;N,6.2;S,7.1%;
Calculated:- C,64.46;H,6.54;N,6.54;S,7.48~.
MMR (in CDC13):- 1.24(3H,2dt), 1.6(1H~dd,J = lO~z, 3Hz), 1.9-2.1(lH,m), 2.4-2.7(lH,m), 2.9-3.2(2H,m), 4.05-4.24 (3H,m), 4.38-4.58(1H,m), 7.1-7.5(10H,~)].
Com~ound BU
(6R,6S)-6-[(4,5-Diphenylimidazol-2-yl)thio-methyl]-4,4-dimethyl-3,4,5,6-tetrahydropyran-2-one (1.18g) was dissolved in 33% ethanolic methylamine (50ml~, and heated at reflux for 2 hours. It was then concentrated to give a solid, which was recrystallised from ethanol to give (2R,2S)-2-[t2-hydroxy-4,4-dimethyl-5-methylaminocarbonylpent-1-yl)thio~-4,5-diphenylimidazole (0.53g), m.p. 190-191C.
WO 91/13876 P~/GB91/00408 207~208 - 61 - ;
rElemental analysis:- C,68.3;H,7.0;N,9.9;S,8.1%;
Calculated:- C,68.05;H,6.9;N,9.92;S,7.6%.
NNR (in CD3SOCD3) 0.~8(3H,s), 1.0(3H~s), 1.5-1.7(2H,m), 1.98-2.24(2H,m), 2.S-2~7(4H,m), 3.18(2H,m), 3.9-4.05(1H,m), 5.5-5.7(1H,m), 7.2-7.9(10~,m)].
Compounds BV and BW
BV (6R,6S)-6-t(4,5-Diphenylimidazol-2-yl)thio-methyl]-3,4,5,6-tetrahydropyran-2 one, (3.96g), in dry tetrahydrofuran, (55ml), was treated at -78C in an argon atmosphere with di-isobutylaluminium hydride in tetrahydrofuran (1.0~;55ml), and stirred at -78C for 3 hours. It was then poured into a mixture of ice (250g~, water (lOOml) and acetic acid ~50ml), and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulphate. Concentration gave a yellow oil, which was subjected to chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (3:1v/v), and the white solid obtained was recrystallised from a mixture of ethyl acetate and hexane to give (2R,2S)(6R,6S)-6-[(4,5-diphenyl-imidazol-2-yl)thiomethyl]-2-hydroxy-3,4,5,6-tetra-hydropyran (1.15g), m.p.. 172-173C.
[Elemental analysis:- C,68.7;H,6.03;N,7.6 ;S, 8.5%;
Calculated:- C,68.82;H,6.05;N,7.64;S,8.75%~
WO91/13876 PCr/GB9l/00408 .-.
NMR (in a mixture of CDCl3 and CD3SOCD3):-1.2-2.1(6H,m); 2.9-3.3(2H,m), 3.6-3.8(1/4H,m), 4.1-4.3(3/4H,m), 4.7-4.8(1/4H,m), 5.34(3/4H,s), 5.78(3j4H,d,J = 3Hz), 6.46(1/4H~d,J - 6H~), 7.1-7.8(10H,m)].
BW By proceeding i,n a similar manner, but replacing (6R,6S)-6-[(4,5-diphenylimidaæol-2-yl)thiomethyl]-3,4,5,6-tetrahydropyran-2-one by 6-[(4,5-diphenyl-imidazol-2-yl)thiomethyl]-4-hydroxy-4-methyltetra-hydropyran-2-one there was prepared (2R,2S)~4R,4S)(6R/6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetrahydropyran, m.p. 134-151C.
[Elemental analysisO- C,66.8;H,6.11;N,7.2;S,8.1%;
~alculated:- C,66.64;H,6.10;N97.07;S,8.09~].
Com~ounds BX ~ BY
(2R,2S)(4R,4S)(6~,6S)-6-t(4,5-diphenylimidazol-2-yl)thiomethyl]-2,4-dihydroxy-4-methyltetrahydropyran (1.9gJ, was dissolved in anhydrous methanol (150ml), boron trifluoride diethyl ethesate (3ml) was addPd, and the solution was left to stand at room temperature for 64 hours. It was then added to excess sodium bicarbonate solution, extracted with ethyl acetate, and the organic extracts were washad with water, dried over magnesium sulphate, and concentrated, ~o give a white . .
solid. This was subjected to chromatography on silica gel eluting with a mixture of ethyl acetate and - cyclohexane (2:1v/v), to give compound BX, (2R,2S~(4~,4S)(6R,6S)-6-[(4,5-diphenylimidazol-2-yl)thiomethyl]-4-hydroxy 2-methoxy-4-methyltetra-hydropyran (0.61g), thought to be the 2-alpha-anomer, in the form of a white solid, m.p. 163-166C.
[Elemental analysis:- C,67.1;H,6.41;N,6.61;S,7.6%;
Calculated:- C,67.29;H,6.38;N,6.83;5,7.81%.
NMR (in CD3SOCD3):- 1.16(3H,s), 1.1-1.4(2H,m), 1.5-1.7(2H,m), 3.3(3H,s), 3.2-3.4(2H,m), 3.9-4.1(1H,m), 4.48~1H,s), 4.58(1H,dd,J = 6Hz,2Hz); and compound BY, ~2R,2S) (4R,4S)(~,6S)-6-t(4,5-diphenyl-imidazol-2-yl)thiomethy]-4-hydroxy-2-methoxy-4-methyl-tetrahydropyran, thought to be thP the 2 -beta-anomer, 0.51g, m.p. 4~C.
[Elemental analysis:~ C,67.1jH,6.68;N,6.52;S,7.4%;
Calculated:- C,67.29jH,6.3~;N,6.83;S,7.81%.
NMR (in CD3SOCD3~- 1.08(1H,s), l~25-l.75(4H~m)~
3.3(3H,m), 3.2-3.4(2~,m), 4.0(lH,s), 4.1-4.22(lH,m), 4.8(lH,m), 7~1-7.5(10H,m)3.
Compound BZ
- 4,5--diphenylimidazole-2-thiol (12.99g) was dissolved in dry dimethylformamide (200ml), and then it was treated with potassium carbonate (5.~4g) and methyl .. . .
6-deoxy-6-iodo-A-D-mannopyranoside (~5.66g) and stirred at room temperature for 18 hours. The mixture was then filtered and concentrated at reduced pressure to give an orange oil, which was subjected to chro~atvgraphy on silica gel, eluting with a mixture of ethyl acetate and hexane,(9:lv/v), to give a white solid which was tritùrated with cyclohexane to give (2S,3R,4R,5S,6S)~2-[(4,5-diphenylimidazol-2-yl)thiomethyl]-6-methoxy-3,~,5-trihydroxytetrahydro-pyran (7.0g), m.p. 120-122C.
tElemental analysis:- C,61.2;H,5.~7;N,6.44;S,8.0%;
Calculated:- C,61.66;H,5.65;N,6.54;S,7.48~.
NMR (in CDCl3):- 3.34(3~,m), 3.4-4.1(6H,m), 4.7(1H,s~, 7.2-7.5(10~,m).
- 65 - 2~78208 Compounds CA to CF
CA A solution of 1-methylimidazole (5.0g) in tetrahydrofuran (70ml) was treated with a solution o~
lithium diisopropyla~ide mono-tetrahydrofuran comple~
in cyclohexane (40ml;1.5M~ during lO minutes under nitrogen, keeping the temperature between -60 and -30~C. The solution was then stirred for 30 ~inutes, warming to 10C. The solution was then cooled to -20C and treated with a solution of 4-[4-~4,5-diphenylimidazol-2-ylthio)butanoyl]morpholine (6.15g) in a mixture of tetrahydrofuran (50ml) and 1,4-dioxane (50ml). The solution was stirred at ambient temperature for 6 hours, and then it was trea~ed with dilute hydrochloric acid (lOOml;~N) and the aqueous layer was separated. The organic fraction was extracted with water (lOOml), tha combined aqueous layers were washed with t-butyl methyl ether (lOOml), then basified with aqueous sodium hydroxide solution (120ml;2N) and extracted with t-butyl methyl ether (3x200ml). The ether solution was washed with aqueous sodium chloride solution and concentrated under reduced pressure to leave a solid. The solid was recrystallised from methanol, to give 2-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]-1-methyl-207820~
imidazole (4.0g) in the fo:rm of a white powder, m.pO160-163C.
CB By proceeding in a ;imilar manner to that described above but replac:ing the 4-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]morpholine by 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]
~ , . . .
morpholine there was prepared 2-[5-(4,5-diphenylimid-azol-2-ylthio)pentanoyl~-1-methylimidazole, in the form of a white solid, m.pO 121-123C, after chromatography on silica gel, eluting with ethyl acetate.
CC By proceeding in a similar manner to that described above but replacing the 4-[4-~4,5-diphenyl-imidazol-2-ylthio)butanoyl]morpholine by 4-[6-t4,5-diphenylimidazol-2-ylthio)hexanoyl]morpholine there was prepared 2-[6-(4,5-diphenylimidazol-2-yl-thio~hexanoyl]-1-methylimidazole, in the form of a white solid, m.p. 124-126C, after chromatography on silica gel, eluting with ethyl acetate.
CD By proceeding in a similar manner to that described above but replacing the 1-methylimidaæole by l-[(dimethylamino~methyl]imidazole, there was prepared 2-[4-(4,5-diphenylimidazol=2-ylthio)butanoyl]imidazole, in the form of a white solid, m.p. 186-188C, from acetonitrile.
CE By proceeding in a similar manner to that described above but replacing the l-methylimidazole by WO91/13876 PCTtGB91/00408 - 67 - 207~208 .,, . ~.
1-C(dimethylamino)methyl]imidazole and replacing the 4-t4-(4,5-diphenyli~idazol-2-ylthio~butanoyl]morpholine by 4-~6-(4,5-diphenylimidazol-2~ylthio)hexanoyl]-~orpholine, there was prepared 2-[6-(4,5-diphenylimid-azol-2-ylthio)hexanoyl]imidazole, m.p. ~48-152C, from butan-2-one.
CF By proceeding in a similar manner to that described above but replacing the l-methylimidazole by 1-[~dimethylamino)methyl]imidazole and replacing the 4-[4-(4,5-diphenylimidazol-2-ylthio)butanoyl]morpholine by 4-[5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]-morpholine, there was prepared 2- r 5-~4,5-diphenylimid-azol-2-ylthio~pentanoyl~imidazole, in the form of a white powder, m.p. 188-191C, from butan-2-one.
XA~PLE_25 Compounds CG to CL
CG A suspension of 2-[4-(4,5-diphenylimidazol-2--ylthio~butanoyl]-l-methylimidazole (2.0g) in ethanol was treated with-a solution of sodium borohydride (0.96g) in water (25ml). Tbe mixture was heated at reflux for 1 hour, ~iltered, and treated with acetone (25ml), followed by dilute hydrochloric acid (200ml;
lN). The pH was adjusted to 7 and the mixture was extracted with t-butyl methyl ether (3xl50ml), then dried and concentrated under reduced pressure to leave an oil. Chromatography on silica gel, eluting with a WO9l/13876 PCT/GB91/00408 mixture of ethyl acetate and methanol, gave 2-~4-(4,5-diphenylimidazol-2-ylthio)-1-hydroxybutyl]-l-methylimida~ole (1.32g) in the form of a glass [NMR (CDC13):- 1.78 (2H,m), 2.09 (2H,~), 2.97 (2~,m), 3.58 (3H,s~, 4.83 (lH,dd,J=5Hz & 7Hz), 6.56 ~lH,d, J=2Hz), 6.68 (lH,d,J=2Hz), 7.19-7.27 (6H,m), 7.40-7O45 t4H,m) ] .
C~ By proceeding.in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]-1-methylimidazole by 2-[6-(4,5-diphenylimidazol-2-ylthio~hexanoyl~-1-methylimidazole, there was prepared 2-t6-~4,5-diphenyl-imidazol-2-ylthio)-l-hydroxyhexyl]-l-methylimidazole in the form of a glass. [Elemental analysis:- C,69.4;
H,6.57;N,12.9;S,7.3%; calculated:- C,~9.41;H,6.52;
N,12.95;S,7.41%].
CI By proceeding in a similar manner to that described above but replacing the 2-t4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl~ methylimidazole by 2-[5-(4,5-diphenylimidaæol-2-ylthio)pentanoyl]-1-methylimidazole there was prepared 2-[5-(4,5-diphenyl-imidazol-2--ylthio)-1-hydroxypentyl]-1-methylimidazole in the form of a glass. tElemental analysis:-C,67.3,H,6.27;N,12.6;S,7.4%; calculated for C24H26N4OS~0.5H2O:- C,7.42;H,6.37;N,13.10;S,7.50~].
WO91il3876 PCT/CB91/00408 ~ 69 2078208 CJ By proceeding in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]~l-methylimida2O1e by 2-[4-(4,5-diphenylimidazol-2-ylthio~b~tanoyl3imidazole there was prepared 2-[4-(4,5-diphenylimidazol-2-yl~
thio~ hydroxybutyl]imidazole in the for~ of a glass.
[Elemental analysis:- C,65.1;H,5.71;N,13.4;S,7.6%;
calculated for C22H22N4OS:~2O
S,7.85%. NMR (CDCl3):- 1.56 (lH,m), 1.66 (lH,m), 1.83 (lH,m), 2.00 (lH,m), 2.71 (lX,m), 2.88 (lH,m), 4.92 (lH,bt,wl/2 = 16Hz), fi.64 (2H,s), 7.12-7.22 (6H,m), 7.33-7.40 (4H,m)].
CK By proceeding in a si~ilar manner to that described above but replacing the 2-[4-(4,5-diphenyl-imidazol-2-ylthio)butanoyl]-1-~ethylimidaæole by 2-~5-(4,5-diphenylimidazol-2-ylthio)pentanoyl]imidazole there was prepared 2-[5-(4,5-diphenylimidazol-2-yl-thio)-l-hydroxypentyl]imidazole in the form of a glassO
[Elemental analysis:- C,62.8;~,5.85;N,12.7;S,7.3%;
calculated ~or C23H24N4OS:2H~O:- C,62.70jH;6.41;
N,12.72;S,7.28~. NMR (CDC13):- 1.52 (2H,m), 1.63 (2H,m), 1.94 (lH,m), 2.08 (lH,m), 2.90 (lH,m), 3.06 (l~,m~, 5.08 (lH,t,J = 6Hz), 6.08 (2H,s), 7.18-7.30 (6H,m), 7.42 (4H,dd,J = 7Hz & 2Hz)].
CL By proceeding in a similar manner to that described above but replacing the 2-[4-(4,5-diphenyl-~ - 70 -~0~$~$
imidazol-2-ylthio)butanoyl]~ methylimidazole by 2-[6-(4,5-diphenyli~idazol-2-ylthio)hexanoyl]imidazole there was prepared 2-~6-~4,5-diphenylimidazol-2-yl-thio)-l-hydroxyhexyl]imidazole in the ~orm of a glass.
NMR (CDC13):- 1.3~-1.53 (4H,m~, 1.71 (2H,p,J = 7Hz), 1.81 (lH,m), 1.89 (l~,m), 3.08 (2~,m), 4.75 (lH,dd,J -7Hz & 5Hz), 6.90 (2H,s),~7.20-7.32 (6H,m)/ 7.48 (4H,dd, J = 8Hz ~ 2Hz), 7.63 (lH,s)].
Compound_CM
A solution of ~orpholine (6.0g) and pyridine (5.6g) in dimethylformamide (lOml) was added during lO
minutes to a stirred solution o~ 4-chlorobutyryl chloride (9.4g) in dimethylformamide (lOOml). The mixture was stirred at ambient temperature for 2 hours and then it was treated with 4,5-diphenylimidazole-2-thiol (15.0g). The mixture was stirred at 125-135C
for 4 hours. After cooling to room temperature, the mixture was poured into dilute aqueous potassium carbonate solution (1 litre) to give a sticky solid.
This solid was dissolved in dichloromethane (1 litre), was the resulting solution was washed with water (2x500ml) and dried by filtering through anhydrous sodium sulphate. Concentrating under reduced pressure gave a thic~ brown oil, which was partitioned between hydrochloric acid (300ml;1N) and toluene (300ml).
WO 91/13876 PCr/GB91/00408 - 71 - 2~78208 `. ' ' .;
The toluene fraction was extracted with hydrochloric acid (200ml;1N) and the combined acidic solution was adjusted to pH4 by treatment with sodium acetate, and was then extracted with toluene ~3x200ml). This toluene solution was washed with brine, dried over magnesium sulphate and concentrated under reduced pressure to give a solid. The solid was crystallised from a mixture of t-butyl methyl ether (300ml) and ethanol (150ml) by concentrating to about 200ml and cooling overnight, to give 4-[4-(~,5-diphenylimidazol-2-ylthio)butanoyl]~orpholine (10~92~) in the form of colourless crystals, m.p. 168-173C.
Compound CN
A solution of morpholine (13.0g) and pyridine (13.0g) in dimethylformamide (50ml) was added during 10 minutes to a stirred solution of S-chlorovaleryl chloride (22.0g) in dimethylformamide (150ml). The mixture was stirred at ambient temperature for 2 hours then 4,5-diphenylimidazole-2-thiol (37.0g~ was added.
The mixture was stirred at 125-135C for 2 hours.
After cooling to 80C, the mixture was poured into water (500ml) ~nd acidified to pH1 by treatment with dilute hydrochloric acid . The mixture was stirred and the resulting solid was filtered off. The filtrate was adjusted to pH4 by treatment with sodium acetate, WO91/13~76 PCT/~B91/00408 ;~~. I
2~782~8 to~give a sticky solid. I'his solid was dissolved in dichloromethane (1 litre), was washed with water (500ml), and then dried over magnesium sulphate and concentrated under reduced pressure, to give an oil.
The oil was crystallised from t-butyl methyl ether, to give 4-[5-(4,5-diphenyl:imidazol-2-ylthio)pentanoyl]-morpholine (43.8g), in the form o~ a white powder, m.p.
134-136C. ~
Compound Co A solution o~ 6-(4,5-diphenylimidazol-2-ylthio)-hexanoyl chloride [prepared fro~ 6-(4,~-diphenylimid-azol-2-ylthio)hexanoic acid (1105g) and thionyl chloride] in dichloromethane (50ml) was added dropwise to a solution of morpholine (6.0g) in dichloromethane (150ml), keeping the te~perature below 30C. The mixture was stirred at ambient temperature for 2 hours and was then left overnight. The mixture was washed with hydrochloric acid (lOOml;lN), water (lOOml), aqueous potassium hydroxide solution (lOOml;lN) and with brine (2x50ml), and was then dried over magnesium sulphate. Concentrating under reduced pressure gave a gum, which was triturated with diethyl ether to give 4-t6-(4,5-diphenylimidazol-2-ylthio)hexanoyl~morpholine (9.64g) in the form of an off-white solid, m.p.
120-122C.
W091~13876 PCr/GB91/00408 _ 73 _ 2~7820~
.. ., ~, ~ i ., . . ,~, I
The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of for~ula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.
In clinical practice the compounds of the present invention may be administered parenterally, rectally or orally.
Solid compositions for oral administration include co~pressed tablets, pills, powders and granules. In such solid co~positions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also comprise, as is nor~al practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, - perfuming and preserving agents. The compositions according to the inventiOn for oral administration also ;
~8~
include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examp~es of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preser~ing, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I or a pharmaceutically acceptable salt thereof.
WO 91/13876 PCI`/GB91/00408 _ 75 _ 2~7820~
,. .;
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The size and frequency of the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration, the duration of the treatment and the aye, sex, size and condition of the patient. In the adult, the doses are generally from 0.01 to 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from 0.001 to ln, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration.
The following Example illustrates a pharmaceutical composition according to the present invention.
COMPOSITION EXAMPLE
No. 2 size gelatin capsules each containing:-Compound A 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
.
.. - 76 -Capsules can also be made up in a similar manner using any other of the compounds B to CO, or a pharmaceutically acceptable salt thereof.
Claims (9)
1. An imidazole derivative of the general formula I:
A-S(O)k-Q-Z (I) wherein A represents a group of general formula (II):
(II) wherein the symbols R1 may be the same or different and each represents hydrogen or one or more substituents, k represents 0, 1 or 2;
Q represents a methylene group or alkylene chain containing from 2 to 5 carbon atoms, optionally substituted with one or more alkyl groups containing from 1 to 4 carbon atoms; and Z represents a hydrogen atom; a hydroxy group; an optionally substituted alkoxy group; an optionally substituted aryl group; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 4 carbon atoms; a group of the formula -NHR2, wherein R2 represents an acyl group, a group of the formula -C(SR3)=N-CN wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms, or R2 represents a 5-or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents; or Z represents a group of the formula -COR4 wherein R4 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms; a group of the formula -CH(OH)R5, -COR5, -CSR5, -CONHR5 or -CSNHR5 wherein R5 represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents; an alkynyl or cycloalkyl group containing up to 6 carbon atoms;
a group of the formula -CH(R6)OR7 wherein R6 represents a straight- or branched-chain alkenyl or alkoxy group containing up to 6 carbon atoms and R7 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, optionally substituted by one or more substituents;
or Z represents:
a group of the general formula (III) (III) wherein m is 0 or 1, n is 0 or 1 and p is 1, 2 or 3, and the symbols R8 each represent a hydrogen atom, or a methyl group substituted by a straight- or branched-chain alkoxy or alkanoyloxy group containing up to 6 carbon atoms;
a group of the general formula (IV) (IV) wherein m is as hereinbefore defined;
a group of the general formula (V) (V) wherein R9 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and R10 represents a hydrogen atom, a hydroxy group or a straight or branched-chain alkyl group containing from 1 to 4 carbon atoms;
a group of the general formula (VI) (VI) wherein R9 is as hereinbefore defined;
a group of the general formula (VII) (VII) wherein R9 and R10 are as hereinbefore defined, the symbols R11 may be the same or different and each represents a hydrogen atom or a hydroxy group and R12 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms;
or a group of the formula -CH(OH)CH2(CR9R10)rCH2-COR13 wherein R9 and R10 are as hereinbefore defined, r represents 0 or 1 and R13 represents a hydroxy group or a straight- or branched-chain alkoxy or alkylamino group containing from 1 to 4 carbon atoms, with the exclusion of (2S, 4R, 6S)-6-[4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran and (2R, 4R, 6S)-6-[4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran;
or a pharmaceutically acceptable salt thereof.
A-S(O)k-Q-Z (I) wherein A represents a group of general formula (II):
(II) wherein the symbols R1 may be the same or different and each represents hydrogen or one or more substituents, k represents 0, 1 or 2;
Q represents a methylene group or alkylene chain containing from 2 to 5 carbon atoms, optionally substituted with one or more alkyl groups containing from 1 to 4 carbon atoms; and Z represents a hydrogen atom; a hydroxy group; an optionally substituted alkoxy group; an optionally substituted aryl group; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 4 carbon atoms; a group of the formula -NHR2, wherein R2 represents an acyl group, a group of the formula -C(SR3)=N-CN wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms, or R2 represents a 5-or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents; or Z represents a group of the formula -COR4 wherein R4 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms; a group of the formula -CH(OH)R5, -COR5, -CSR5, -CONHR5 or -CSNHR5 wherein R5 represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents; an alkynyl or cycloalkyl group containing up to 6 carbon atoms;
a group of the formula -CH(R6)OR7 wherein R6 represents a straight- or branched-chain alkenyl or alkoxy group containing up to 6 carbon atoms and R7 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, optionally substituted by one or more substituents;
or Z represents:
a group of the general formula (III) (III) wherein m is 0 or 1, n is 0 or 1 and p is 1, 2 or 3, and the symbols R8 each represent a hydrogen atom, or a methyl group substituted by a straight- or branched-chain alkoxy or alkanoyloxy group containing up to 6 carbon atoms;
a group of the general formula (IV) (IV) wherein m is as hereinbefore defined;
a group of the general formula (V) (V) wherein R9 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and R10 represents a hydrogen atom, a hydroxy group or a straight or branched-chain alkyl group containing from 1 to 4 carbon atoms;
a group of the general formula (VI) (VI) wherein R9 is as hereinbefore defined;
a group of the general formula (VII) (VII) wherein R9 and R10 are as hereinbefore defined, the symbols R11 may be the same or different and each represents a hydrogen atom or a hydroxy group and R12 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms;
or a group of the formula -CH(OH)CH2(CR9R10)rCH2-COR13 wherein R9 and R10 are as hereinbefore defined, r represents 0 or 1 and R13 represents a hydroxy group or a straight- or branched-chain alkoxy or alkylamino group containing from 1 to 4 carbon atoms, with the exclusion of (2S, 4R, 6S)-6-[4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran and (2R, 4R, 6S)-6-[4,5-diphenylimidazol-2-yl)-thiomethyl]-4-hydroxy-2-methoxy-3,4,5,6-tetrahydro-2H-pyran;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, in which, in the group A, the symbols R1 may be the same or different and each represents hydrogen or one or more substituents selected from halogen atoms, and straight- or branched-chain alkyl and alkoxy groups containing from 1 to 6 carbon atoms, and trifluoromethyl groups.
3. A compound according to claim 1 or 2, in which Z represents a hydrogen atom; a hydroxy group; an alkoxy group containing 1 to 6 carbon atoms optionally substituted by an alkoxy or alkoxyalkoxy group containing 1 to 6 carbon atoms in each alkoxy moiety; an aryl group optionally substituted by one or more alkoxy groups containing 1 to 6 carbon atoms; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 4 carbon atoms; a group of the formula -NHR2, wherein R2 represents a straight- or branched-chain alkanoyl group containing up to 6 carbon atoms and which is optionally substituted by a carboxy group, or R2 represents a group of the formula -C(SR3)=N-CN wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms, or R2 represents a 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents selected from amino groups and straight- or branched-chain alkyl groups containing from 1 to 3 carbon atoms; and attached to the group NH via a carbon atoms; or Z represents a group of the formula -COR4 wherein R4 represents a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms; a group of the formula -CH(OH)R5, -COR5, -CSR5, -CONHR5 or CSNHR5 wherein R5 represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents selected from straight- or branched-chain alkyl groups containing from 1 to 3 carbon atoms, and alkynyl or cycloalkyl group containing up to 6 carbon atoms; a group of the formula -CH(R6)OR7 wherein R6 represents a straight- or branched-chain alkenyl or alkoxy group containing up to 6 carbon atoms and R7 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, optionally substituted by one or more substituents selected from hydroxy groups; a group of the general formula (III), (IV), (V), (VI), or (VII) as hereinbefore defined; or a group of the formula -CH(OH)CH2(CR9R10)rCH2COR13 as hereinbefore defined.
4. A compound according to any one of the preceding claims in which:
(i) in the group A, the symbols R1 may be different or the same and each represents a hydrogen, chlorine or fluorine atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a straight-or branched-chain alkoxy group containing from 1 to 3 carbon atoms, or a trifluoromethyl group;
(ii) k represents 0;
(iii) Z represents a hydrogen atom; a hydroxy group; an ethoxy group optionally substituted by a methoxyethoxy group; a phenyl group optionally substituted by one or more alkoxy groups; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 3 carbon atoms; an ethynyl group, or a cyclohexyl group;
(iv) Z represents a group -NHR2, in which R2 represents a straight- or branched chain alkanoyl group containing up to 6 carbon atoms optionally substituted by a carboxy group; a pyridyl or triazolyl group optionally substituted by one or two substituents selected from amino groups and straight- or branched-chain alkyl groups;
(v) Z represents a group -NHC(SR3)=N-CN, wherein R3 represents a methyl group;
(vi) Z represents a group -COR4 wherein R4 represents a methyl group;
(vii) Z represents a group -CH(OH)R5, -COR5, -CSR5, -CONHR5 or -CSNHR5 wherein R5 represents a imidazolyl, morpholinyl or pyridyl group optionally substituted by one or two alkyl groups;
(viii) Z represents a group -CH(R6)OR7, wherein R6 represents an allyl group, or an alkoxy group containing from 1 to 3 carbon atoms;
(ix) Z represents a group -CH(R6)OR7, wherein R7 represents an alkyl group containing from 1 to 3 carbon atoms, optionally substituted by a hydroxy group;
(x) Z represents a group of formula (III), in which R8 represents a hydrogen atom or a hydroxymethyl, methoxymethyl or acetoxymethyl group;
(xi) Z represents a group of formula (V), (VI) or (VII), in which R9 represents a hydrogen atom or a methyl group;
(xii) Z represents a group of formula (V) or (VII) in which R10 represents a hydrogen atom or a hydroxy or methyl group;
(xiii) Z represents a group of formula (VII) in which R12 represents a hydrogen atom or a methyl group; or (xiv) Z represents a group of formula -CH(OH)CH2(CR9R10)rCH2COR13 in which R13 represents an alkoxy or alkylamino group containing from 1 to 4 carbon atoms.
(i) in the group A, the symbols R1 may be different or the same and each represents a hydrogen, chlorine or fluorine atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a straight-or branched-chain alkoxy group containing from 1 to 3 carbon atoms, or a trifluoromethyl group;
(ii) k represents 0;
(iii) Z represents a hydrogen atom; a hydroxy group; an ethoxy group optionally substituted by a methoxyethoxy group; a phenyl group optionally substituted by one or more alkoxy groups; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 3 carbon atoms; an ethynyl group, or a cyclohexyl group;
(iv) Z represents a group -NHR2, in which R2 represents a straight- or branched chain alkanoyl group containing up to 6 carbon atoms optionally substituted by a carboxy group; a pyridyl or triazolyl group optionally substituted by one or two substituents selected from amino groups and straight- or branched-chain alkyl groups;
(v) Z represents a group -NHC(SR3)=N-CN, wherein R3 represents a methyl group;
(vi) Z represents a group -COR4 wherein R4 represents a methyl group;
(vii) Z represents a group -CH(OH)R5, -COR5, -CSR5, -CONHR5 or -CSNHR5 wherein R5 represents a imidazolyl, morpholinyl or pyridyl group optionally substituted by one or two alkyl groups;
(viii) Z represents a group -CH(R6)OR7, wherein R6 represents an allyl group, or an alkoxy group containing from 1 to 3 carbon atoms;
(ix) Z represents a group -CH(R6)OR7, wherein R7 represents an alkyl group containing from 1 to 3 carbon atoms, optionally substituted by a hydroxy group;
(x) Z represents a group of formula (III), in which R8 represents a hydrogen atom or a hydroxymethyl, methoxymethyl or acetoxymethyl group;
(xi) Z represents a group of formula (V), (VI) or (VII), in which R9 represents a hydrogen atom or a methyl group;
(xii) Z represents a group of formula (V) or (VII) in which R10 represents a hydrogen atom or a hydroxy or methyl group;
(xiii) Z represents a group of formula (VII) in which R12 represents a hydrogen atom or a methyl group; or (xiv) Z represents a group of formula -CH(OH)CH2(CR9R10)rCH2COR13 in which R13 represents an alkoxy or alkylamino group containing from 1 to 4 carbon atoms.
5. A compound according to any one of the preceding claims which is hereinbefore identified as any one of compounds A to CO.
6. A process for the preparation of a compound according to any one of the preceding claims which comprises:
a) where k is 0, reacting a compound of the general formula (VIII) A-S-H (VIII) wherein A is as defined in claim 1, or a salt thereof, of the general formula (IX) A-S- M+ (IX) wherein A is as hereinbefore defined in claim 1 and M
represents an alkali metal, with a compound of the general formula (X) X1-Q-Z (X) or a salt thereof, wherein X1 is a group displaceable by a thiolate salt, and Q and Z are as defined in claim 1;
b) where k is 0 and Z represents a group of the formula -NH-C(SR3)=N-CN, as defined in claim 1, reacting a compound of the general formula (XI) (R3S)-C(SR3)=N-CN (XI) wherein R3 is as defined in claim 1 with a compound of the general formula (XII) A-S-Q-NH2 (XII) wherein A and Q are as defined in claim 1;
(c) where k is 0 and Z represents a group of the formula -NHR2 wherein R2 represents an acyl group, acylating a compound of formula (XII) as hereinbefore defined;
(d) where k is 0 and Z represents a group of the formula -CH(OH)CH2(CR9R10)rCH2COR14 wherein R9, R10 and r are as defined in claim 1 and R14 represents a straight- or branched-chain alkoxy group containing from 1 to 4 carbon atoms, reacting a compound of formula (IX) as hereinbefore defined, with a compound of the general formula (XIII) R15CH2(CR9R10)rCH2COR14 (XIII) wherein R9, R10, r are as defined in claim 1, R14 is as hereinbefore defined and R15 represents a 1,2-epoxyethyl group; or (e) converting a compound of general formula (I) to a further compound of general formula (I);
and, if desired, converting the product thus obtained to a pharmaceutically acceptable salt.
a) where k is 0, reacting a compound of the general formula (VIII) A-S-H (VIII) wherein A is as defined in claim 1, or a salt thereof, of the general formula (IX) A-S- M+ (IX) wherein A is as hereinbefore defined in claim 1 and M
represents an alkali metal, with a compound of the general formula (X) X1-Q-Z (X) or a salt thereof, wherein X1 is a group displaceable by a thiolate salt, and Q and Z are as defined in claim 1;
b) where k is 0 and Z represents a group of the formula -NH-C(SR3)=N-CN, as defined in claim 1, reacting a compound of the general formula (XI) (R3S)-C(SR3)=N-CN (XI) wherein R3 is as defined in claim 1 with a compound of the general formula (XII) A-S-Q-NH2 (XII) wherein A and Q are as defined in claim 1;
(c) where k is 0 and Z represents a group of the formula -NHR2 wherein R2 represents an acyl group, acylating a compound of formula (XII) as hereinbefore defined;
(d) where k is 0 and Z represents a group of the formula -CH(OH)CH2(CR9R10)rCH2COR14 wherein R9, R10 and r are as defined in claim 1 and R14 represents a straight- or branched-chain alkoxy group containing from 1 to 4 carbon atoms, reacting a compound of formula (IX) as hereinbefore defined, with a compound of the general formula (XIII) R15CH2(CR9R10)rCH2COR14 (XIII) wherein R9, R10, r are as defined in claim 1, R14 is as hereinbefore defined and R15 represents a 1,2-epoxyethyl group; or (e) converting a compound of general formula (I) to a further compound of general formula (I);
and, if desired, converting the product thus obtained to a pharmaceutically acceptable salt.
7. A pharmaceutical composition which comprises an imidazole derivative of general formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or coating.
8. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase or an inhibitor of the binding of thromboxane TXA2 to its receptors which comprises an amount effective to ameliorate said condition of an imidazole derivative of general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.
9. A method of treatment of a human or animal host suffering from, or subject to, a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase or of an inhibitor of the binding of thromboxane TxA2 to its receptors which comprises the administration to said host of an imidazole derivative of general formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9005966.8 | 1990-03-16 | ||
| GB909005966A GB9005966D0 (en) | 1990-03-16 | 1990-03-16 | New compositions of matter |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2078208A1 true CA2078208A1 (en) | 1991-09-17 |
Family
ID=10672738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078208A Abandoned CA2078208A1 (en) | 1990-03-16 | 1991-03-15 | Imidazoles |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0519996A1 (en) |
| JP (1) | JPH05505398A (en) |
| CA (1) | CA2078208A1 (en) |
| GB (1) | GB9005966D0 (en) |
| WO (1) | WO1991013876A1 (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2933739B2 (en) * | 1990-04-09 | 1999-08-16 | 明治製菓株式会社 | Thiazole or imidazole derivatives and anti-ulcer agents |
| US5212318A (en) * | 1991-03-04 | 1993-05-18 | Eastman Kodak Company | Preparation of omega-substituted alkanamide |
| US5364875A (en) * | 1992-05-11 | 1994-11-15 | The Du Pont Merck Pharmaceutical Company | Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis |
| US5310748A (en) * | 1992-05-11 | 1994-05-10 | The Du Pont Merck Pharmaceutical Company | Imidazoles for the treatment of atherosclerosis |
| US5358946A (en) * | 1992-05-29 | 1994-10-25 | The Du Pont Merck Pharmaceutical Company | Heterocycle-substituted amides, carbamates and ureas as agents for the treatment of atherosclerosis |
| IT1265209B1 (en) * | 1993-11-22 | 1996-10-31 | Pierrel Spa | DIPHENYLIMIDAZOLES USEFUL IN THE TREATMENT OF DYSLIPIDEMIA, ARTERIOSCLEROSIS AND CORONARY DISEASES PROCEDURE FOR THEIR |
| US5491152A (en) * | 1994-03-23 | 1996-02-13 | The Du Pont Merck Pharmaceutical Company | Derivatives of cyclic ethers and sulfides for the treatment of atherosclerosis |
| GB0011120D0 (en) | 2000-05-09 | 2000-06-28 | Avecia Ltd | Process |
| NL1015744C2 (en) | 2000-07-19 | 2002-01-22 | Dsm Nv | Process for the preparation of 2- (6-substituted-1,3-dioxan-4-yl) acetic acid derivatives. |
| AU2006203127B2 (en) * | 2000-07-19 | 2008-06-19 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivatives |
| DE10114775A1 (en) | 2001-03-26 | 2002-10-10 | Gerhard Dannhardt | 2-Mercapto-4,5-diarylimidazole derivatives and their use in pharmacy |
| EP1323717A1 (en) | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| EP1375493A1 (en) | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| DE10238045A1 (en) | 2002-08-20 | 2004-03-04 | Merckle Gmbh Chem.-Pharm. Fabrik | 2-Thio-substituted imidazole derivatives and their use in pharmacy |
| DE10356579A1 (en) * | 2003-12-04 | 2005-07-07 | Merck Patent Gmbh | amine derivatives |
| EP2734513A4 (en) * | 2011-07-19 | 2014-11-26 | Sunshine Lake Pharma Co Ltd | An intermediate of statin drugs and preparation thereof |
| WO2020028150A1 (en) * | 2018-08-01 | 2020-02-06 | Merck Sharp & Dohme Corp. | Inhibitors of histone deacetylase useful for the treatment or prevention of hiv infection |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4182769A (en) * | 1977-02-09 | 1980-01-08 | E. I. Du Pont De Nemours And Company | Anti-inflammatory 1-substituted-4,5-diaryl-2-(substituted-thio) imidazoles and their corresponding sulfoxides and sulfones |
| LU77703A1 (en) * | 1977-07-07 | 1979-03-26 | Ciba Geigy Ag | METHOD FOR PRODUCING BICYCLIC THIA-DIAZA COMPOUNDS |
| DE2823197A1 (en) * | 1978-05-24 | 1979-11-29 | Schering Ag | NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| DE3025484A1 (en) * | 1980-07-03 | 1982-02-04 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| US4882348A (en) * | 1987-12-29 | 1989-11-21 | Smithkline Beckman Corporation | 2-(aminoalkylthio)imidazoles as dopamine-β-hydroxylase inhibitors |
| CA2003283A1 (en) * | 1988-12-05 | 1990-06-05 | C. Anne Higley | Imidazoles for the treatment of atherosclerosis |
| GB8907656D0 (en) * | 1989-04-05 | 1989-05-17 | May & Baker Ltd | New compositions of matter |
| US5021440A (en) * | 1989-07-31 | 1991-06-04 | Merck & Co., Inc. | Imidazole compounds and their use as transglutaminase inhibitors |
-
1990
- 1990-03-16 GB GB909005966A patent/GB9005966D0/en active Pending
-
1991
- 1991-03-15 CA CA002078208A patent/CA2078208A1/en not_active Abandoned
- 1991-03-15 WO PCT/GB1991/000408 patent/WO1991013876A1/en not_active Application Discontinuation
- 1991-03-15 JP JP91505827A patent/JPH05505398A/en active Pending
- 1991-03-15 EP EP91906307A patent/EP0519996A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0519996A1 (en) | 1992-12-30 |
| GB9005966D0 (en) | 1990-05-09 |
| WO1991013876A1 (en) | 1991-09-19 |
| JPH05505398A (en) | 1993-08-12 |
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