EP0876355A1 - 2-thioxo-imidazolidin-4-eins derivate und ihre verwendung zur erhöhung der hdl-cholesterolkonzentration - Google Patents
2-thioxo-imidazolidin-4-eins derivate und ihre verwendung zur erhöhung der hdl-cholesterolkonzentrationInfo
- Publication number
- EP0876355A1 EP0876355A1 EP96942118A EP96942118A EP0876355A1 EP 0876355 A1 EP0876355 A1 EP 0876355A1 EP 96942118 A EP96942118 A EP 96942118A EP 96942118 A EP96942118 A EP 96942118A EP 0876355 A1 EP0876355 A1 EP 0876355A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- thioxo
- imidazolidin
- ethyl
- alkyl
- 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.)
- Withdrawn
Links
- 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 title claims abstract description 69
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 27
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical class O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 58
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- 241000124008 Mammalia Species 0.000 claims abstract description 12
- 210000004369 blood Anatomy 0.000 claims abstract description 11
- 239000008280 blood Substances 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 229920001774 Perfluoroether Polymers 0.000 claims abstract description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 137
- -1 fluorophenylmethyl Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 238000010992 reflux Methods 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- XZJRRJZOWDPGQM-UHFFFAOYSA-N 3-(2-chloro-6-methylphenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=C(C)C=CC=C1Cl XZJRRJZOWDPGQM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- LYMYDEGHCJPIGY-UHFFFAOYSA-N 3-(2-chlorophenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=CC=CC=C1Cl LYMYDEGHCJPIGY-UHFFFAOYSA-N 0.000 claims description 2
- KFYLJQOXOLFXFZ-UHFFFAOYSA-N 3-(2-ethyl-6-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound CCC1=CC=CC(C)=C1N1C(=S)N(C)CC1=O KFYLJQOXOLFXFZ-UHFFFAOYSA-N 0.000 claims description 2
- VIUZPNQTARUJED-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=CC=C(C(C)(C)C)C=C1 VIUZPNQTARUJED-UHFFFAOYSA-N 0.000 claims description 2
- ZUYDSOMIFLJINW-UHFFFAOYSA-N 3-(5-chloro-2-methylphenyl)-1-prop-2-ynyl-2-sulfanylideneimidazolidin-4-one Chemical compound CC1=CC=C(Cl)C=C1N1C(=S)N(CC#C)CC1=O ZUYDSOMIFLJINW-UHFFFAOYSA-N 0.000 claims description 2
- JXZCLPIMYFOZOX-UHFFFAOYSA-N 3-[2,6-di(propan-2-yl)phenyl]-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=C(C(C)C)C=CC=C1C(C)C JXZCLPIMYFOZOX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 4
- ATUNXJFMSCHLLW-UHFFFAOYSA-N 3-(5-chloro-2-methylphenyl)-1-propan-2-yl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C(C)C)CC(=O)N1C1=CC(Cl)=CC=C1C ATUNXJFMSCHLLW-UHFFFAOYSA-N 0.000 claims 2
- FOAWJTFHAJDPTI-UHFFFAOYSA-N 1-ethyl-3-[1-(4-fluorophenyl)ethyl]-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C(C)C1=CC=C(F)C=C1 FOAWJTFHAJDPTI-UHFFFAOYSA-N 0.000 claims 1
- LNAMMQSFHJHFPF-UHFFFAOYSA-N 3-(2,3-dihydro-1h-inden-5-yl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=CC=C(CCC2)C2=C1 LNAMMQSFHJHFPF-UHFFFAOYSA-N 0.000 claims 1
- GRQDHYSORYMGNF-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=CC=C(Cl)C=C1Cl GRQDHYSORYMGNF-UHFFFAOYSA-N 0.000 claims 1
- DUYRFNPGJDCDEH-UHFFFAOYSA-N 3-(2,6-dimethylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=C(C)C=CC=C1C DUYRFNPGJDCDEH-UHFFFAOYSA-N 0.000 claims 1
- VRVHDAPELYNQEP-UHFFFAOYSA-N 3-(2,6-dimethylphenyl)-1-propan-2-yl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C(C)C)CC(=O)N1C1=C(C)C=CC=C1C VRVHDAPELYNQEP-UHFFFAOYSA-N 0.000 claims 1
- KKQMIMGLLQIIJM-UHFFFAOYSA-N 3-(2-chloro-6-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=C(C)C=CC=C1Cl KKQMIMGLLQIIJM-UHFFFAOYSA-N 0.000 claims 1
- ZTLQCQKQZSGEDJ-UHFFFAOYSA-N 3-(2-ethyl-6-propan-2-ylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound CCC1=CC=CC(C(C)C)=C1N1C(=S)N(C)CC1=O ZTLQCQKQZSGEDJ-UHFFFAOYSA-N 0.000 claims 1
- YWNIIMXOOLURSG-UHFFFAOYSA-N 3-(3-chloro-2-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=CC=CC(Cl)=C1C YWNIIMXOOLURSG-UHFFFAOYSA-N 0.000 claims 1
- ATRNWDOLZYAEOO-UHFFFAOYSA-N 3-(4-chloro-2-methylphenyl)-1-prop-2-ynyl-2-sulfanylideneimidazolidin-4-one Chemical compound CC1=CC(Cl)=CC=C1N1C(=S)N(CC#C)CC1=O ATRNWDOLZYAEOO-UHFFFAOYSA-N 0.000 claims 1
- OOCSJDWFSDSUBT-UHFFFAOYSA-N 3-(4-fluorophenyl)-1-propan-2-yl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C(C)C)CC(=O)N1C1=CC=C(F)C=C1 OOCSJDWFSDSUBT-UHFFFAOYSA-N 0.000 claims 1
- WFOZHXDSZIJLFK-UHFFFAOYSA-N 3-(5-chloro-2-methylphenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=CC(Cl)=CC=C1C WFOZHXDSZIJLFK-UHFFFAOYSA-N 0.000 claims 1
- FKVLPQQMNPAKDQ-UHFFFAOYSA-N 3-(5-chloro-2-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=CC(Cl)=CC=C1C FKVLPQQMNPAKDQ-UHFFFAOYSA-N 0.000 claims 1
- GNXQPXXHLAYEJD-UHFFFAOYSA-N 3-(5-chloro-2-methylphenyl)-1-phenyl-2-sulfanylideneimidazolidin-4-one Chemical compound CC1=CC=C(Cl)C=C1N1C(=S)N(C=2C=CC=CC=2)CC1=O GNXQPXXHLAYEJD-UHFFFAOYSA-N 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 138
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 96
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 78
- 238000001819 mass spectrum Methods 0.000 description 64
- 239000000203 mixture Substances 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- 229940086542 triethylamine Drugs 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 238000002425 crystallisation Methods 0.000 description 35
- 230000008025 crystallization Effects 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 238000000746 purification Methods 0.000 description 25
- 102000015779 HDL Lipoproteins Human genes 0.000 description 22
- 108010010234 HDL Lipoproteins Proteins 0.000 description 22
- YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 21
- 108010065338 N-ethylglycine Proteins 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- NIDZUMSLERGAON-UHFFFAOYSA-N ethyl 2-(methylamino)acetate;hydron;chloride Chemical compound Cl.CCOC(=O)CNC NIDZUMSLERGAON-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- HEPOIJKOXBKKNJ-UHFFFAOYSA-N 2-(propan-2-ylazaniumyl)acetate Chemical compound CC(C)NCC(O)=O HEPOIJKOXBKKNJ-UHFFFAOYSA-N 0.000 description 9
- 244000144730 Amygdalus persica Species 0.000 description 9
- 235000006040 Prunus persica var persica Nutrition 0.000 description 9
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 8
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 5
- RRWZZMHRVSMLCT-UHFFFAOYSA-N 2-(butylazaniumyl)acetate Chemical compound CCCCNCC(O)=O RRWZZMHRVSMLCT-UHFFFAOYSA-N 0.000 description 4
- VDBDGAPNWNWUSA-UHFFFAOYSA-N 4-chloro-2-isothiocyanato-1-methylbenzene Chemical compound CC1=CC=C(Cl)C=C1N=C=S VDBDGAPNWNWUSA-UHFFFAOYSA-N 0.000 description 4
- 201000001320 Atherosclerosis Diseases 0.000 description 4
- 108010077895 Sarcosine Proteins 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 4
- 208000029078 coronary artery disease Diseases 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229940043230 sarcosine Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- NFIUJHJMCQQYDL-UHFFFAOYSA-N 1-fluoro-4-isothiocyanatobenzene Chemical compound FC1=CC=C(N=C=S)C=C1 NFIUJHJMCQQYDL-UHFFFAOYSA-N 0.000 description 3
- YVWGGGZYGSZDKW-UHFFFAOYSA-N 2-(prop-2-enylazaniumyl)acetate Chemical compound OC(=O)CNCC=C YVWGGGZYGSZDKW-UHFFFAOYSA-N 0.000 description 3
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- BNDZNKDOPHTAFQ-UHFFFAOYSA-N ethyl 2-(prop-2-ynylamino)acetate Chemical compound CCOC(=O)CNCC#C BNDZNKDOPHTAFQ-UHFFFAOYSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 150000002540 isothiocyanates Chemical class 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000464 thioxo group Chemical group S=* 0.000 description 3
- SUCGVQHNGIQXGD-UHFFFAOYSA-N 1,3-dichloro-2-isothiocyanatobenzene Chemical compound ClC1=CC=CC(Cl)=C1N=C=S SUCGVQHNGIQXGD-UHFFFAOYSA-N 0.000 description 2
- MLQPKPCDKLACIG-UHFFFAOYSA-N 1-chloro-2-isothiocyanato-3-methylbenzene Chemical compound CC1=CC=CC(Cl)=C1N=C=S MLQPKPCDKLACIG-UHFFFAOYSA-N 0.000 description 2
- IPCSOFYQRXYMDN-UHFFFAOYSA-N 1-ethyl-2-isothiocyanato-3-methylbenzene Chemical compound CCC1=CC=CC(C)=C1N=C=S IPCSOFYQRXYMDN-UHFFFAOYSA-N 0.000 description 2
- OVAFDUCMHLFDIG-UHFFFAOYSA-N 1-ethyl-2-isothiocyanatobenzene Chemical compound CCC1=CC=CC=C1N=C=S OVAFDUCMHLFDIG-UHFFFAOYSA-N 0.000 description 2
- NSDDRJXKROCWRZ-UHFFFAOYSA-N 1-isothiocyanato-2-methylpropane Chemical compound CC(C)CN=C=S NSDDRJXKROCWRZ-UHFFFAOYSA-N 0.000 description 2
- QQOOMDSEMQHMIR-UHFFFAOYSA-N 1-isothiocyanato-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1N=C=S QQOOMDSEMQHMIR-UHFFFAOYSA-N 0.000 description 2
- HZGOUCYIYIFQHX-UHFFFAOYSA-N 2-isothiocyanato-1,3-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N=C=S HZGOUCYIYIFQHX-UHFFFAOYSA-N 0.000 description 2
- UULUECCNPPJFBU-UHFFFAOYSA-N 2-isothiocyanato-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1N=C=S UULUECCNPPJFBU-UHFFFAOYSA-N 0.000 description 2
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 2
- WGLDKQQXEWPFAR-UHFFFAOYSA-N 4-chloro-2-isothiocyanato-1-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1N=C=S WGLDKQQXEWPFAR-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- GVONPBONFIJAHJ-UHFFFAOYSA-N imidazolidin-4-one Chemical compound O=C1CNCN1 GVONPBONFIJAHJ-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XJRIDJAGAYGJCK-UHFFFAOYSA-N (1-acetyl-5-bromoindol-3-yl) acetate Chemical compound C1=C(Br)C=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 XJRIDJAGAYGJCK-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RQZIODPVCCTBAQ-UHFFFAOYSA-N 1,2-dichloro-3-isothiocyanatobenzene Chemical compound ClC1=CC=CC(N=C=S)=C1Cl RQZIODPVCCTBAQ-UHFFFAOYSA-N 0.000 description 1
- PXVPXJHMTUKENZ-UHFFFAOYSA-N 1-butyl-4-isothiocyanatobenzene Chemical compound CCCCC1=CC=C(N=C=S)C=C1 PXVPXJHMTUKENZ-UHFFFAOYSA-N 0.000 description 1
- ZXEZATIRZLJXFU-UHFFFAOYSA-N 1-chloro-3-isothiocyanato-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1N=C=S ZXEZATIRZLJXFU-UHFFFAOYSA-N 0.000 description 1
- LPVNPJMEWWUFHD-UHFFFAOYSA-N 1-fluoro-4-(isothiocyanatomethyl)benzene Chemical compound FC1=CC=C(CN=C=S)C=C1 LPVNPJMEWWUFHD-UHFFFAOYSA-N 0.000 description 1
- VASTZUGVKHOFPE-UHFFFAOYSA-N 1-isothiocyanato-2,3-dimethylbenzene Chemical compound CC1=CC=CC(N=C=S)=C1C VASTZUGVKHOFPE-UHFFFAOYSA-N 0.000 description 1
- STZONCTUVBZNCF-UHFFFAOYSA-N 1-isothiocyanato-2,4,5-trimethylbenzene Chemical compound CC1=CC(C)=C(N=C=S)C=C1C STZONCTUVBZNCF-UHFFFAOYSA-N 0.000 description 1
- HOHSBFCSOARUBF-UHFFFAOYSA-N 1-isothiocyanato-2,4-dimethylbenzene Chemical compound CC1=CC=C(N=C=S)C(C)=C1 HOHSBFCSOARUBF-UHFFFAOYSA-N 0.000 description 1
- FCEKLQPJGXIQRY-UHFFFAOYSA-N 1-isothiocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1N=C=S FCEKLQPJGXIQRY-UHFFFAOYSA-N 0.000 description 1
- JYKYYPPZLPVIBY-UHFFFAOYSA-N 1-isothiocyanato-2-methylbenzene Chemical compound CC1=CC=CC=C1N=C=S JYKYYPPZLPVIBY-UHFFFAOYSA-N 0.000 description 1
- KGSVNOLLROCJQM-UHFFFAOYSA-N 2-(benzylamino)acetic acid Chemical compound OC(=O)CNCC1=CC=CC=C1 KGSVNOLLROCJQM-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- UIZZXGXTVVWRED-UHFFFAOYSA-N 2-chloro-1-isothiocyanato-4-methylbenzene Chemical compound CC1=CC=C(N=C=S)C(Cl)=C1 UIZZXGXTVVWRED-UHFFFAOYSA-N 0.000 description 1
- PQLHTYDGCDDPNU-UHFFFAOYSA-N 2-chloro-4-isothiocyanato-1-methylbenzene Chemical compound CC1=CC=C(N=C=S)C=C1Cl PQLHTYDGCDDPNU-UHFFFAOYSA-N 0.000 description 1
- RTMXPNYHPHIDHX-UHFFFAOYSA-N 2-isothiocyanatonaphthalene Chemical compound C1=CC=CC2=CC(N=C=S)=CC=C21 RTMXPNYHPHIDHX-UHFFFAOYSA-N 0.000 description 1
- POFQOUVDEVIYTO-UHFFFAOYSA-N 3-(2,5-dimethylphenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=CC(C)=CC=C1C POFQOUVDEVIYTO-UHFFFAOYSA-N 0.000 description 1
- SCCNLEIQXKBXQE-UHFFFAOYSA-N 3-(2,6-dimethylphenyl)-1-ethyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(CC)CC(=O)N1C1=C(C)C=CC=C1C SCCNLEIQXKBXQE-UHFFFAOYSA-N 0.000 description 1
- NWTOUTYJKJXGFG-UHFFFAOYSA-N 3-(2-ethyl-6-methylphenyl)-1-propan-2-yl-2-sulfanylideneimidazolidin-4-one Chemical compound CCC1=CC=CC(C)=C1N1C(=S)N(C(C)C)CC1=O NWTOUTYJKJXGFG-UHFFFAOYSA-N 0.000 description 1
- FHFTWKDDJGZVIF-UHFFFAOYSA-N 3-(2-ethylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound CCC1=CC=CC=C1N1C(=S)N(C)CC1=O FHFTWKDDJGZVIF-UHFFFAOYSA-N 0.000 description 1
- GCELFRKVCJVPJV-UHFFFAOYSA-N 3-(3-chloro-2-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one;3-(5-chloro-2-methylphenyl)-1-methyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1N(C)CC(=O)N1C1=CC(Cl)=CC=C1C.S=C1N(C)CC(=O)N1C1=CC=CC(Cl)=C1C GCELFRKVCJVPJV-UHFFFAOYSA-N 0.000 description 1
- VMSZFBSYWXMXRF-UHFFFAOYSA-N 3-isothiocyanatopyridine Chemical compound S=C=NC1=CC=CN=C1 VMSZFBSYWXMXRF-UHFFFAOYSA-N 0.000 description 1
- ZZRIQDWDJVLELF-UHFFFAOYSA-N 3-phenyl-2-sulfanylideneimidazolidin-4-one Chemical class O=C1CNC(=S)N1C1=CC=CC=C1 ZZRIQDWDJVLELF-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- XTYLRVPBHHRTMS-UHFFFAOYSA-N 4-chloro-1-isothiocyanato-2-methylbenzene Chemical compound CC1=CC(Cl)=CC=C1N=C=S XTYLRVPBHHRTMS-UHFFFAOYSA-N 0.000 description 1
- QVCYTKXGZLOVFA-UHFFFAOYSA-N 4-fluoro-2-isothiocyanato-1-methylbenzene Chemical compound CC1=CC=C(F)C=C1N=C=S QVCYTKXGZLOVFA-UHFFFAOYSA-N 0.000 description 1
- FEPBITJSIHRMRT-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1 FEPBITJSIHRMRT-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- DRZNKOAIZHUADV-UHFFFAOYSA-N 5-isothiocyanato-2,3-dihydro-1h-indene Chemical compound S=C=NC1=CC=C2CCCC2=C1 DRZNKOAIZHUADV-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N 7-chloro-3',4,6-trimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Chemical compound COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000006410 Apoproteins Human genes 0.000 description 1
- 108010083590 Apoproteins Proteins 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010089254 Cholesterol oxidase Proteins 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 108010055297 Sterol Esterase Proteins 0.000 description 1
- 102000000019 Sterol Esterase Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100023038 WD and tetratricopeptide repeats protein 1 Human genes 0.000 description 1
- WDOSFTZMBFYTED-UHFFFAOYSA-N [isothiocyanato(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(N=C=S)C1=CC=CC=C1 WDOSFTZMBFYTED-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000000489 anti-atherogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 235000019416 cholic acid Nutrition 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
- 229960002471 cholic acid Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 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
- 239000006185 dispersion Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- SNGHSMCKPHXUAK-UHFFFAOYSA-N ethyl 2-[n-[(5-chloro-2-methylphenyl)carbamothioyl]anilino]acetate Chemical compound C=1C=CC=CC=1N(CC(=O)OCC)C(=S)NC1=CC(Cl)=CC=C1C SNGHSMCKPHXUAK-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IZJDOKYDEWTZSO-UHFFFAOYSA-N phenethyl isothiocyanate Chemical compound S=C=NCCC1=CC=CC=C1 IZJDOKYDEWTZSO-UHFFFAOYSA-N 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000001008 quinone-imine dye Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 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
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000021195 test diet Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61P9/10—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
Definitions
- the present invention relates to compounds for increasing HDL cholesterol concentration in the blood of a mammal, to their use in this method of treatment, to pharmaceutical compositions containing the compounds and to a process for preparation of the compounds.
- Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke.
- Angiographical studies have shown that elevated levels of some HDL particles appears to be correlated with a decrease in the number of sites of stenosis in the coronary arteries of humans ( Miller et al. Br. Med. J .. 282 (1981 , 1741-1744).
- HDL may protect against the progression of atherosclerosis.
- Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al, Arteriosclerosis. 6 (1986) 434-441). Data of this nature suggests that one antiatherogenic property of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset. J. Lipid Res.. 9 (1968) 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al, Circulation. 66 (Suppl. I) (1982) 102; MacKinnon et al, J. Biol. Chem..
- HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem.. 253 (1978) 1834-1841; Lagocki and Scanu, J. Biol. Chem.. 255 (1980) 3701-3706; Schaefer et al, J. Lipid Res.. 23 (1982) 1259-1273).
- agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary heart disease.
- Z is alkyl, phenylalkyl, phenyl or substituted phenyl, where the substituent is a halogen, alkyl, alkoxy or halogenated alkyl group
- X is phenyl, halophenyl, alkyl, alkenyl, or alkynyl
- Y is S or O.
- EP 0584694 andWO 93/18057 disclose a group of imidazolidin-3-yl benzoyl or alkanoyl amino acid derivatives as inhibitors of cell-cell adhesion for use in inhibition of thrombocyte aggregation, metastasis and osteoclast formation. Chronic administration for prevention of arteriosclerosis and thrombosis is disclosed.
- JP 04,297,461 discloses a group of 2-thiohydantoin compounds of the following formula, said to be useful as anti-bacterial, anti-viral, anti-inflammatory and anti-rheumatic agents:
- R* is lower alkyl, lower alkenyl, phenyl(lower)alkyl or substituted phenyl with 1-3 groups chosen from lower alkyl, lower alkoxy, halogen, lower alkoxycarbonyl or hydroxy;
- R2 is either hydrogen or alkanoyl; and R3 is hydrogen, lower alkyl, phenyl, phenyl (lower) alkyl, or a lower alkylthio, lower alkyl group that can be substituted with one to three phenyl groups that have had a lower alkoxy group.
- EP 0578516 discloses a group of 2-thiohydantoins, said to be useful anti- androgenic agents for treatment of various cancer, of the formula :
- X oxygen or sulfur
- Y is oxygen, sulfur or NH
- Rl and R ⁇ are cyano, nitro, halogen, trifluoromethyl, or a free or esterified carboxylic acid or salt;
- R3 is hydrogen, alkyl, alkenyl, alkynyl, aryl or aryl-alkyl; R and R ⁇ are hydrogen, optionally substituted alkyl, or cycloalkyl.
- US 5,411 ,981 discloses compounds closely related to EP 0578516, supra, where R ⁇ and R ⁇ are both methyl.
- R ⁇ and R ⁇ are hydrogen, chloro, bromo, fluoro or alkyl of 1-2 carbon atoms.
- JP 73 87,030 discloses a group of 3-phenyl-2-thiohydantoin derivatives useful as herbicides.
- US 4,473,393 discloses a group of pesticidal thiohydantoin compositions.
- R is alkyl of 1 to 6 carbon atoms; a substituted or unsubstituted aromatic N, O or S heterocycle having 4 to 6 carbon and one hetero ring members; substituted or unsubstituted aryl of 6 to 10 carbon atoms, arylalkyi of 7 to 12 carbon atoms, benzhydryl or indanyl , in which the substituents are one to three members independendy selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy; and
- Rl is aryl of 6 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms or substituted aryl of 6 to 10 carbon atoms where the substituents are one to three members independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy, for use in the treatment of mammals.
- a preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are two members of the group consisting of alkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, halo, or ortho substituted trimethylene or tetramethylene and R ⁇ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms.
- Another preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are a halo and an alkyl group of 1 to 3 carbon atoms or ortho substituted trimethylene and R ⁇ is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
- Another preferred embodiment of the invention provides a compound of formula I in which R is substituted phenyl where the substituents are chloro or fluoro in the 4- or 5- position and an alkyl group of 1 to 3 carbon atoms and R 1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
- R is substituted phenyl where the substituents are chloro or fluoro in the 4- or 5- position and an alkyl group of 1 to 3 carbon atoms and R 1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
- Rl is alkyl of 1 to 6 carbon atoms and R is alkyl of 1 to 6 carbon atoms, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, l-(fluorophenyl)ethyl, 5-chloro- 2-methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methy lsulfanyl- phenyl, pyridyl or the group of formula II
- R ⁇ , R ⁇ and R ⁇ together are 2-chloro, 4-fluoro, 2,4-chloro or 2,6- chloro, or
- R2 is hydrogen, R ⁇ is a halogen in 3-position and R ⁇ is alkyl of 1 to 6 carbon atoms in
- R ⁇ is alkyl of 1 to 6 carbon atoms and R ⁇ and R ⁇ are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or R ⁇ is a halogen and R ⁇ is hydrogen; or
- Rl is alkenyl of 2 to 6 carbon atoms
- R is is the group of formula II where R ⁇ is alkyl of 1 to 6 carbon atoms and R ⁇ and R ⁇ are, independendy, hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁇ is hydrogen and R ⁇ and R ⁇ taken together are ortho substituted trimethylene or tetramethylene, or R ⁇ is alkyl of 1 to 6 carbon atoms,
- R3 is halogen and R ⁇ is hydrogen, or R ⁇ is hydrogen, R ⁇ is halogen in 3-position and
- R is alkyl of 1 to 6 carbon atoms in 4-position; or when Rl is alkynyl of 2 to 6 carbon atoms, R is a group of formula II where any two of R ⁇ , R3 and R ⁇ are, independently, alkyl of 1 to 6 carbon atoms, halo, perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 carbon atoms, or, taken together, are ortho substituted trimethylene or tetramethylene; or when Rl is aryl of 6 to 10 carbon atoms or arylalkyi of 7 to 12 carbon atoms, R is the group of formula II where R 2 is alkyl of 1 to 6 carbon atoms, R 3 is a halogen and R 4 is hydrogen, or R 2 is hydrogen, R 3 is a halogen in 3-position and R 4 is alkyl of 1 to 6 carbon atoms in 4- position.
- R 1 ' R 2 , R 3 or R 4 is alkyl it is preferably alkyl of 1 to 3 carbon atoms, especially methyl or ethyl, or any two of R 2 , R3 and R 4 when taken together are ortho substituted trimethylene or tetramethylene.
- Rl is alkenyl of 2 to 6 carbon atoms it is preferably allyl
- R 2 or R 3 are halogen they are preferably independendy, chlorine or fluorine, especially in the 2-, 4-, and/or -6 positions.
- R 2 or R 3 are perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 carbon atoms
- Rl is alkynyl of 2 to 6 carbon atoms it is preferably ethynyl, propargyl or butynyl, especially prop-2-ynl.
- R is aryl of 6 to 10 carbon atoms it is preferably, phenyl or naphthyl, the latter being preferably, 2-naphthyl.
- R is aralkyl of 7 to 12 carbon atoms, it is preferably benzyl or phenethyl.
- R is fluorophenylmethyl, it is preferably 4-fluorophenylmethyl.
- R When R is l-(fluorophenyl)ethyl, it is preferably l-(4-fluorophenyl)ethyl. When R is trifluoromethoxyphenyl, it is preferably 4-trifluoro-methoxyphenyl. When R is methylsulfanylphenyl, it is preferably 2-methylsulfanylphenyl. When R is pyridyl, it is preferably 3-pyridyl.
- a preferred use of the compounds of formula I or method of treatment using the compounds is for increasing HDL cholesterol concentration in the blood of a mammal, by administering to said mammal an amount of a substituted 2-thioxo-imidazolidin-4- one as herein defined, sufficient to increase that HDL cholesterol concentration, and this represents further aspects of the present invention.
- the compounds of the invention can be prepared readily according to the following reaction scheme or modification thereof using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
- R is hydrogen or alkyl of 1 to 6 carbon atoms and X is a halogen.
- N-Substituted amino acids (2a) were prepared by reacting the corresponding ⁇ - halo acids (1) with the appropriate amines (excess). The reaction was carried out either neat or in water at ambient temperature for 18 hours. One equivalent of the amine scavenges the hydrohalide formed during the alkylation forming the amine hydrohalide (2b) as a side product.
- the N-alkyl amino acids (2a) were either purified by crystallization from an appropriate solvent, or reacted with the isothiocyanates as crude product mixtures containing the amine hydrohalide salt. Reaction of 2a with isothiocyanates is carried out in chloroform or methylene chloride in the presence of a base such as triethyl amine.
- compositions comprised of uie 2- thioxo imidazolidin-4-one derivatives either alone or in combination with excipients (i.e. pharmaceutically acceptable materials with no pharmacological effects).
- excipients i.e. pharmaceutically acceptable materials with no pharmacological effects.
- Such compositions are useful in the treatment of atherosclerotic conditions such as dyslipoproteinemias and coronary heart disease, in that they increase the blood serum high density lipoprotein concentration of mammals treated with the compounds.
- the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition being treated, the mode of administration and the particular active substance employed.
- the compounds may be administered by any conventional route, in particular enterally, preferably orally in the form of tablets or capsules.
- Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of atherosclerosis and sequelae (angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure stroke, peripheral arterial occlusion, and related disease states). These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
- the carrier may be a solid, liquid or mixture of a solid and a liquid.
- Solid compositions include powders, tablets and capsules.
- a solid carrier can be one or more substances which may also act as a flavoring agent, lubricant, solubilizer, suspending agent, binder, or tablet disintegrant.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
- Encapsulating materials may also be employed with the compounds of this invention, and the term "composition" is intended to include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers.
- Cachets may also be used in the delivery of the anti-atherosclerotic medicament of this invention.
- Sterile liquid compositions include solutions, suspensions, emulsions, syrups and elixirs.
- the compounds of this invention may be dissolved or suspended in the pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
- the liquid carrier is one suitable for parental injection.
- the compounds are sufficiendy soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents , such as propylene glycol or polyethylene glycol.
- suitable organic solvents such as propylene glycol or polyethylene glycol.
- dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, such as arachis oil.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal or subcutaneous injection. In many instances a liquid composition form may be used instead of the preferred solid oral method of administration.
- unit dosage forms of the compounds for standard administration regimens.
- the composition can be subdivided readily into smaller doses at the physicians direction.
- unit dosages may be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.
- the active compound present in these unit dosage forms of the composition may be present in an amount of from about one gram to about fifteen grams or more, for single or multiple daily administration, according to the particular need of the patient.
- the daily dose of active compound will vary depending upon the route of administration, the size, age and sex of the patient, the severity of the disease state, and the response to the therapy as traced by blood analysis and the patients recovery rate.
- the blood levels of HDL and the patients symptomatic relief analysis may be used to determine whether a larger dose is indicated.
- the projected daily dose for both human and veterinary use will be from about 10 to about 200 milligrams/kilogram per day. However, in general, satisfactory results are indicated to be obtained at daily dosages in the range of from 400 milligrams to about 2000 milligrams, conveniendy administered in divided doses two to four times a day.
- the ability of the compounds of this invention to increase blood serum HDL levels was established by the following standard experimental procedure for determination of HDL cholesterol:
- Test substances Male Sprague-Dawley rats weighing 200-225 g are housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25 % cholic acid and 1.0 % cholesterol and water ad libitum for 8 days. Each test substance is administered to a group of six rats fed the same diet with the test diet mixed in as 0.005 - 0.1 % of the total diet. Body weight and food consumption are recorded prior to diet administration and at termination. Typical doses of the test substances are 5 - 100 mg/kg/day. At termination, blood is collected from anesthetized rats and the serum is separated by centrifugation.
- Total serum cholesterol is assayed using the Sigma Diagnostics enzymatic kit for the determination of cholesterol, Sigma Procedure No. 352, modified for use with ninety-six well microtiter plates. After reconstitution with water the reagent contains 300 U/1 cholesterol oxidase, 100 U ⁇ cholesterol esterase, 1000 U/1 horse radish peroxidase, 0.3 mmoles/l 4-aminoantipyrine and 30.0 mmoles/l p-hydroxybenzenesulfonate in a pH 6.5 buffer. In the reaction cholesterol is oxidized to produce hydrogen peroxide which is used to form a quinoneimine dye. The concentration of dye formed is measured spectrophotometrically by absorbance at 490 nm after incubation at 25C for 30 minutes. The concentration of cholesterol was determined for each serum sample relative to a commercial standard from Sigma.
- HDL cholesterol concentrations in serum are determined by separation of lipoprotein classes by fast protein liquid chromatography (FPLC) by a modification of the method of Kieft et al., J. Lipid Res.. 2 (1991) 859-866. 25 ul of serum is injected onto Superose 12 and Superose 6 (Pharmacia), in series, with a column buffer of 0.05 M Tris (2-amino-2-hydroxymethyl-l,3-propanediol) and 0.15 M sodium chloride at a flow rate of 0.5 ml/min. The eluted sample is mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 ml/min.
- FPLC fast protein liquid chromatography
- the combined eluents are mixed and incubated on line through a knitted coil (Applied Biosciences) maintained at a temperature of 45C.
- the eluent is monitored by measuring absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration.
- the relative concentration of each lipoprotein class is calculated as the per cent of total absorbance.
- HDL cholesterol concentration, in serum is calculated as the per cent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration.
- Test compounds were administered at a dose of 100 mg/kg. The duration of treatment was eight days.
- the compounds of the present invention increase HDL cholesterol concentrations as summarized in Table I:
- the title compound was prepared by the procedure described in Example 1 using 13.2 g of 3-chloro-2-methylphenyl-isothiocyanate, 11.0 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the tide compound (15.2 g) as a tan solid, m.p. 122-124° C.
- the tide compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the tide compound (14.5 g) as an off-white solid, m.p. 178-180°
- the tide compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113-
- the tide compound was prepared by the procedure described in Example 1 using 7.7 g of indan-5-yl-isothiocyanate, 6.7 g of sarcosine ethyl ester hydrochloride, 12 g of trieuiyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded uie tide compound (7.9 g) as a tan solid, m.p. 158-160° C. Anal. Calcd. for Cl3 Hi4 N2 O S: C, 63.39; H, 5.73; N.11.37. Found: C, 63.30; H, 5.81; N, 11.31. Mass spectrum (EI, M. + ) m/z 246.
- the tide compound was prepared by the procedure described in Example 1 using 8.3 g of 2,6-diisopropylphenyl-isothiocyanate, 5.8 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl edier/hexane mixture afforded the title compound (6.6 g) as a tan solid, m.p. 174-176° C.
- Mass spectrum (+FAB, [M+H]+) m/z 269/271.
- the tide compound was prepared by d e procedure described in Example 1 using 8.9 g of 2-euiyl-6-meuiylphenyl-isouiiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.5 g of trieuiyl amine, and 250 mL of chloroform. Crystallization from diethyl ether afforded die title compound (7.45 g) as a peach solid, m.p. 106-108° C. Anal. Calcd. for Ci3 Hi6 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.52;
- the tide compound was prepared by the procedure described in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isouiiocyanate, 7.68 g of sarcosine euiyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (7.1 g) as an orange solid (7.1 g), m.p. 142-145°
- the tide compound was prepared by die procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform.
- the tide compound (20.4 g) was obtained as an off-white solid, m.p. 135-137° C.
- the tide compound was prepared by d e procedure described in Example 1 using 14.2 g of 2-isopropylphenyl-isouiiocyanate, 12.29 g of sarcosine ethyl ester hydrochloride, 16.0 g of trieuiyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.9 g) as a peach solid, m.p. 129-131° C.
- the tide compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine etiiyl ester hydrochloride, 14.5 g of trieuiyl amine, and 200 mL of chloroform. Crystallization from diediyl euier afforded the tide compound (16.9 g) as a light peach solid, m.p.
- the tide compound was prepared by die procedure described in Example 16 using 10.2 g of 2,6-dichlorophenyl-isothiocyanate, 7.4 g of N-e ⁇ iyl glycine, 10 g of trieuiyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The tide compound (6.5 g) was obtained as a tan solid, m.p. 170-172° C. Anal. Calcd. for. Cn Hio Cl2 N2 O S: C, 45.69; H, 3.48; N,
- the tide compound was prepared by d e procedure described in Example 16 using 7.65 g of 4-fluorophenyl-isothiocyanate, 9.32 g of N-etivyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The tide compound (6.6 g) was obtained as a pink solid, m.p. 149-151° C. Anal. Calcd. for. C11 H11 F N2 O S: C, 55.45; H, 4.65; N.1 1.76.
- the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluoromethoxyphenyl-isod ⁇ iocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Tide compound (4.6 g) was obtained as a creamy solid, m.p. 116-119° C. Anal. Calcd. for. C12 Hn F3 N2 O2 S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
- the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isod ⁇ iocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128-131° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H, 6.49; N,
- the tide compound was prepared by d e procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Tide compound (4.85 g) was obtained as a white solid, m.p. 73-76° C. Anal. Calcd. for. C12 Hi 3 F N2 O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H.5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
- the tide compound was prepared by d e procedure described in Example 19 using 9.2 g of N-etiryl glycine, 5.7 g of isobutyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Titie compound (2.3 g) was obtained as an oil. Anal. Calcd. for. C9 Hi6 N2 O S: C, 53.97; H, 8.05; N, 13.99.
- the tide compound was prepared by die procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.48 g of 2-chlorophenyl-isouiiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Tide compound (3.85 g) was obtained as an orange solid, m.p. 142-145° C. Anal. Calcd. for. Cn Hn Cl N2 O S: C, 51.87; H, 4.35; N ,
- the tide compound was prepared by die procedure described in Example 19 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved through crystallization from edianol. Title compound (3.6 g) was obtained as a creamy solid, m.p. 105-108°
- the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ediyl glycine, 9.3 g of 2-naphthyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of metiiylene chloride. Purification was achieved dirough crystallization from ethanol. Title compound (4.7 g) was obtained as a light pink solid, m.p. 156-159° C. Anal. Calcd. for. C15 H14 N2 O S: C, 66.64; H, 5.22; N, 10.36
- the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.1 g of 2-chloro-6-methylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the tide compound (5.4 g) as a creamy solid, m.p. 124-126° C. Anal. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M. + ) m/z 268/270.
- the titie compound was prepared by the procedure described in Example 16 using 21.9 g of 2,6-diisopropylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved through crystalUzation from ethanol. The title compound (8.2 g) was obtained as light yellow solid, m.p. 159-161° C. Anal. Calcd. for. C17 H24 N2 O S: C, 67.07; H, 7.94; N ,
- EXAMPLE 30 1 -Ethvl.2-thioxo-3-f2-trifl ⁇ oromethvlnhenvn-imidazolidin.4-one.
- the tide compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded d e titie compound (2.7 g), m.p. 82-85° C. Anal. Calcd. for. Cl2 H F3 N2 O S: C, 50.00; H, 3.85; N.9.72. Found: C, 50.00; H, 3.61; N, 9.61.
- the tide compound was prepared by d e procedure described in Example 28 using 20.5 g of 2-ethyl-6-isopropylphenyl-isouiiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane). CrystalUzation from diethyl ether/hexane afforded pure title compound (7.5 g) as a white solid, m.p. 77-79° C. Anal. Calcd. for. Ci6 H22 N2 O S: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12; H, 7.77; N, 9.69. Mass spectrum (EI, M. + ) m/z 290.
- the tide compound was prepared by the procedure described in Example 28 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20 % etfiyl acetate in hexane). The title compound was obtained (8.6 g) as a light peach solid, m.p. 82-84° C. Anal. Calcd. for. C14 H s N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M. + ) m/z 262.
- the tide compound was prepared by the procedure described in Example 28 using 18.3 g of 2-chloro-4-methylphenyl-isothiocyanate, 18.4 g of N-etivyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the titie compound (5.8 g) as a peach solid, m.p. 126-128° C. Anal. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.50; H, 4.76; N,
- the tide compound was prepared by the procedure described in Example 16 using 18.1 g of l-(4-fluorophenyl)-ethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded die tide compound (8.8 g) as a Ught yellow solid, m.p. 93-95° C. Anal.
- the tide compound was prepared by the procedure described in Example 16 using 20.4 g of 2,3-dichlorophenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (20 % etiiyl acetate in hexane) The tide compound (8.8 g) was obtained as a light peach solid, m.p. 144-146° C. Anal. Calcd. for. Cn Hio Cl2 N2 O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.81; H, 3.40; N, 9.58. Mass spectrum (CI, [M+H]+) m/z 289/291/293.
- the tide compound was prepared by the procedure described in Example 16 using 16.3 g of phenethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (20 % ethyl acetate in hexane) The title compound (15.0 g) was obtained as an off-white solid, m.p. 66-68° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H,
- the tide compound was prepared by tiie procedure described in Example 16 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120-121° C. Anal. Calcd. for. C13 Hi6 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H, 6.44; N, 11.47. Mass spectrum (EI, M. + ) m/z 248.
- EXAMPLE 38 3-f2.4-DimethvlDhenvn-l-ethvl-2-thioxo-imida7.olidin-4.one
- the tide compound was prepared by the procedure described in Example 16 using 16.3 g of 2,4-dimethylphenyl-isothiocyanate, 18.4 g of N-ediyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. CrystalUzation from ethanol afforded the title compound (10.8 g) as a light peach solid, m.p. 161-162° C. Anal. Calcd. for. C13 Hi6 N2 O S: C62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 1 1.17. Mass spectrum (EI, M. + ) m/z 248.
- EXAMPLE 39 3. .->-nimethvlDhenvn-l-ethvl-2-thioxo-imida7 lidin-4-one
- the tide compound was prepared by the procedure described in Example 16 using 16.3 g of 2,5-dimed ⁇ ylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the tide compound (10.6 g) as an off-white solid, m.p. 176-178° C. Anal. Calcd. for.
- the tide compound was prepared by d e procedure described in Example 16 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded d e tide compound (15.3g) as an off-white solid, m.p. 162-164° C. Anal. Calcd. for.
- the tide compound was prepared by d e procedure described in Example 16 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of trieuiyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20 % ethyl acetate in hexane) CrystalUzation from ethanol afforded the tide compound (9.8 g) as a white solid, m.p. 125-127° C. Anal. Calcd. for. Ci4 Hi8 N2 O S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
- the tide compound was prepared by die procedure described in Example 16 using 16.3 g of 2-ed ⁇ ylphenyl-isod ⁇ iocyanate, 18.4 g of N-ethyl glycine, 20.2 g of trieuiyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % etiiyl acetate in hexane) Crystallization from diediyl etiier afforded the title compound (9.12 g) as a white solid, m.p. 71-73° C. Anal. Calcd. for. Ci3 Hi6 N2 O S: C62.87; H, 6.49; N, 11.28. Found: C, 62.81; H,
- the tide compound was prepared by die procedure described in Example 45 using 21.9 g of 2,6-diisopropylphenyl-isoti ⁇ ocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. CrystaUization from etiianol afforded d e tide compound (11.7 g) as a white solid, m.p. 175-177° C. Anal. Calcd. for. Ci8 H26 2 O S: C, 67.88; H, 8.23; N, 8.80. Found: C, 68.03; H, 8.09; N , 8.81. Mass spectrum (+FAB, [M+H] + ) m/z 319. EXAMPLE 4ft
- the tide compound was prepared by d e procedure described in Example 45 using 17.5 g of indan-5-yl-isod iocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of trieuiyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178-180° C. Anal. Calcd. for. C15 Hi8 N2 O S: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass spectrum (EI, M. + ) m/z 21 A.
- the tide compound was prepared by die procedure described in Example 45 using 16.3 g of 2-ethylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of trieuiyl amine, and 300 mL of chloroform. CrystaUization from diediyl ether afforded die tide compound (6.8 g) as a white solid, m.p. 103-105° C. Anal. Calcd. for. C14 Hi8 N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.08; H, 6.92; N, 10.62. Mass spectrum (EI, M. + ) m/z 262.
- the title compound was prepared by the procedure described in Example 45 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded die tide compound (6.8 g) as a light pink solid, m.p. 112-1 14° C. Anal. Calcd. for.
- the tide compound was prepared by d e procedure described in Example 54 using 6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of tried yl amine, and 150 mL of metiiylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). CrystaUization from ethanol afforded die tide compound (3.85 g) as a Ught pink solid, m.p. 97-100° C. Anal. Calcd. for. C14 H ⁇ Cl N2 O S : C, 56.65; H, 5.77; N, 9.44. Found: C, 56.45; H , 5.67; N, 9.33. Mass spectrum (+FAB, [M+H]+) m/z 297.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US765895P | 1995-11-28 | 1995-11-28 | |
US765495P | 1995-11-28 | 1995-11-28 | |
US766695P | 1995-11-28 | 1995-11-28 | |
US766195P | 1995-11-28 | 1995-11-28 | |
US766595P | 1995-11-28 | 1995-11-28 | |
US7666P | 1995-11-28 | ||
US7654P | 1995-11-28 | ||
US08/563,325 US5554607A (en) | 1995-11-28 | 1995-11-28 | Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis |
US7665P | 1995-11-28 | ||
US7661P | 1995-11-28 | ||
US7658P | 1995-11-28 | ||
US563325 | 1995-11-28 | ||
PCT/US1996/019164 WO1997019932A1 (en) | 1995-11-28 | 1996-11-25 | 2-thioxo-imidazolidin-4-one derivatives and their use for increasing hdl cholesterol concentration |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0876355A1 true EP0876355A1 (de) | 1998-11-11 |
Family
ID=27555583
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96942118A Withdrawn EP0876355A1 (de) | 1995-11-28 | 1996-11-25 | 2-thioxo-imidazolidin-4-eins derivate und ihre verwendung zur erhöhung der hdl-cholesterolkonzentration |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0876355A1 (de) |
JP (1) | JP2000501100A (de) |
AU (1) | AU1127697A (de) |
CA (1) | CA2238762A1 (de) |
WO (1) | WO1997019932A1 (de) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6455566B1 (en) | 1997-09-03 | 2002-09-24 | Wyeth | Substituted 1-aryl-3-heteroaryl-thioureas (or isothioureas) as antiatherosclerotic agents |
TW415942B (en) * | 1997-09-03 | 2000-12-21 | American Home Prod | Novel substituted 1-aryl-3-heteroaryl-thioureas and substituted 1-aryl-3-heteroaryl-isothioureas as antiatherosclerotic agents |
CA2339090C (en) * | 1998-08-31 | 2009-11-17 | Sentron Medical, Inc. | Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases |
WO2003024441A1 (fr) | 2001-09-14 | 2003-03-27 | Shionogi & Co., Ltd. | Nouvelle utilisation de composes tricycliques |
FR2845384B1 (fr) * | 2002-10-04 | 2004-12-31 | Fournier Lab Sa | Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique |
FR2845385B1 (fr) * | 2002-10-04 | 2004-12-31 | Fournier Lab Sa | Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique |
AU2003279442A1 (en) * | 2002-10-04 | 2004-04-23 | Laboratoires Fournier S.A. | 2-thiohydantoine derivative compounds and use thereof for the treatment of diabetes |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR956150A (de) * | 1950-01-26 | |||
BE550650A (de) * | 1955-08-30 | |||
IL66242A0 (en) * | 1981-07-23 | 1982-11-30 | Erba Farmitalia | N-imidazolyl derivatives of 1,2,3,4-tetrahydro-naphthalene,indan and 2-substituted-1-chroman,their preparation and pharmaceutical compositions containing them |
JPH0629943B2 (ja) * | 1983-10-31 | 1994-04-20 | 富士写真フイルム株式会社 | 画像形成方法 |
JPH01187543A (ja) * | 1988-01-21 | 1989-07-26 | Mitsubishi Paper Mills Ltd | 写真用分光増感色素 |
FR2694290B1 (fr) * | 1992-07-08 | 1994-09-02 | Roussel Uclaf | Nouvelles phénylimidazolidines éventuellement substituées, leur procédé de préparation, leur application comme médicaments et les compositions pharmaceutiques les renfermant. |
US5554607A (en) * | 1995-11-28 | 1996-09-10 | American Home Products Corporation | Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis |
-
1996
- 1996-11-25 CA CA002238762A patent/CA2238762A1/en not_active Abandoned
- 1996-11-25 JP JP9520724A patent/JP2000501100A/ja active Pending
- 1996-11-25 WO PCT/US1996/019164 patent/WO1997019932A1/en not_active Application Discontinuation
- 1996-11-25 EP EP96942118A patent/EP0876355A1/de not_active Withdrawn
- 1996-11-25 AU AU11276/97A patent/AU1127697A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9719932A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2000501100A (ja) | 2000-02-02 |
AU1127697A (en) | 1997-06-19 |
WO1997019932A1 (en) | 1997-06-05 |
CA2238762A1 (en) | 1997-06-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5554607A (en) | Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis | |
JPH0261477B2 (de) | ||
US5783707A (en) | 2-thioxo-imidazolidin-4-one derivatives | |
JP2593273B2 (ja) | 置換ジアミノフタルイミドおよび同族体 | |
WO1997019931A1 (en) | 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives | |
EP0876355A1 (de) | 2-thioxo-imidazolidin-4-eins derivate und ihre verwendung zur erhöhung der hdl-cholesterolkonzentration | |
EP0211429A1 (de) | 1,5-Benzodiazepinverbindungen | |
US4650797A (en) | Substituted 1,5-benzodiazepine compounds | |
EP0384320A1 (de) | Trisubstituierte Harnstoffverbindungen mit antihyperlipidemischer und antiatherosklerotischer Wirkung | |
US6008362A (en) | Elevation of HDL cholesterol by 2-(-4-chlorol-1-aryl-butylidene)-hydrazinecarbothioamides | |
US4861778A (en) | 2,3-dihydrophthalazine-1,4-diones | |
US5861517A (en) | 2-thioxo-imidazolidin-4-one derivatives | |
US5599829A (en) | 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives for increasing HDL cholesterol levels | |
US5821372A (en) | 2-thioxo-imidazolidin-4-one derivatives | |
US5807864A (en) | 2-thioxo-tetrahydropyrimidin-4-one derivatives | |
US5663363A (en) | 2-thioxo-imidazolidin-4-one derivatives | |
US5877324A (en) | 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives | |
US6160114A (en) | Substituted tetrahydro-1,3,5-triazin-2[1H]-thiones as anti-atherosclerotic agents | |
US5939435A (en) | 2-substituted-1-acyl-1,2-dihydroquinoline derivatives | |
US20030119889A1 (en) | 1,3-Disubstituted-2- thioxo-imidazolidine-4,5-dione derivatives useful in the treatment of atherosclerosis | |
US6049006A (en) | Elevation of HDL cholesterol by N-[2-[(aminothioxomethyl) hydrazono]-2-arylethyl]amides | |
US6034272A (en) | Elevation of HDL cholesterol by N-[4-[(aminothioxomethyl) hydrazono]-4-arylbutyl]amides | |
US6011053A (en) | Substituted indole-1-carbothioic acid amides as novel antiatherosclerotic agents | |
WO1998021190A1 (en) | Substituted tetrahydro-1,3,5-triazin-2[1h]-thiones as anti-atherosclerotic agents | |
US6448255B1 (en) | Imidazo-isoquinolin-5-one derivatives, pyrimido-isoquinolin-6-one derivatives and imidazo-naphthyridin-5-one derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19980423 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 980423;LT PAYMENT 980423;LV PAYMENT 980423;RO PAYMENT 980423;SI PAYMENT 980423 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20010601 |