ZA200204241B - Substituted oxazoles and thiazoles derivatives as HPPAR Alpha Activators. - Google Patents
Substituted oxazoles and thiazoles derivatives as HPPAR Alpha Activators. Download PDFInfo
- Publication number
- ZA200204241B ZA200204241B ZA200204241A ZA200204241A ZA200204241B ZA 200204241 B ZA200204241 B ZA 200204241B ZA 200204241 A ZA200204241 A ZA 200204241A ZA 200204241 A ZA200204241 A ZA 200204241A ZA 200204241 B ZA200204241 B ZA 200204241B
- Authority
- ZA
- South Africa
- Prior art keywords
- methyl
- thiazol
- phenoxy
- amino
- propionic acid
- Prior art date
Links
- 239000012190 activator Substances 0.000 title description 3
- 150000002916 oxazoles Chemical class 0.000 title description 2
- 150000003557 thiazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 120
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 84
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 78
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 235000019260 propionic acid Nutrition 0.000 claims description 42
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 28
- -1 4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl Chemical group 0.000 claims description 21
- 101000741788 Homo sapiens Peroxisome proliferator-activated receptor alpha Proteins 0.000 claims description 20
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004494 ethyl ester group Chemical group 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000000556 agonist Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 7
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 206010022489 Insulin Resistance Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- KTDSYSXUSWADOW-UHFFFAOYSA-N 2-methyl-2-[4-[[[4-methyl-2-(4-nitrophenyl)-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]propanoic acid Chemical compound CC=1N=C(C=2C=CC(=CC=2)[N+]([O-])=O)SC=1C(=O)NCC1=CC=C(OC(C)(C)C(O)=O)C=C1 KTDSYSXUSWADOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 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
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 2
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 208000022531 anorexia Diseases 0.000 claims description 2
- 206010061428 decreased appetite Diseases 0.000 claims description 2
- JMMTVCHYBGDKFC-UHFFFAOYSA-N ethyl 2-methyl-2-[4-[[[4-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]propanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C(F)(F)F)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 JMMTVCHYBGDKFC-UHFFFAOYSA-N 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- BNMMYXRWLCJTOX-UHFFFAOYSA-N 2-[4-[[[2-(3,4-dichlorophenyl)-4-methyl-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]-2-methylpropanoic acid Chemical compound CC=1N=C(C=2C=C(Cl)C(Cl)=CC=2)SC=1C(=O)NCC1=CC=C(OC(C)(C)C(O)=O)C=C1 BNMMYXRWLCJTOX-UHFFFAOYSA-N 0.000 claims 1
- KJVQPBVQYNACBX-UHFFFAOYSA-N 2-methyl-2-[4-[[[4-methyl-2-(4-propan-2-ylphenyl)-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]propanoic acid Chemical compound C1=CC(C(C)C)=CC=C1C1=NC(C)=C(C(=O)NCC=2C=CC(OC(C)(C)C(O)=O)=CC=2)S1 KJVQPBVQYNACBX-UHFFFAOYSA-N 0.000 claims 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims 1
- MOKYNPWPMRKARS-UHFFFAOYSA-N ethyl 2-[4-[[[2-(4-tert-butylphenyl)-4-methyl-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]-2-methylpropanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=CC(=CC=2)C(C)(C)C)S1 MOKYNPWPMRKARS-UHFFFAOYSA-N 0.000 claims 1
- GKMLVZXUQRZKOM-UHFFFAOYSA-N ethyl 2-methyl-2-[4-[[[4-methyl-2-(4-nitrophenyl)-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]propanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=CC(=CC=2)[N+]([O-])=O)S1 GKMLVZXUQRZKOM-UHFFFAOYSA-N 0.000 claims 1
- CAMWNGJHYXUURY-UHFFFAOYSA-N ethyl 2-methyl-2-[4-[[[5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbonyl]amino]methyl]phenoxy]propanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)SC(C=2C=C(C=CC=2)C(F)(F)F)=N1 CAMWNGJHYXUURY-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 68
- 238000000034 method Methods 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- 239000000203 mixture Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000009472 formulation Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 10
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 108010028924 PPAR alpha Proteins 0.000 description 6
- 102000023984 PPAR alpha Human genes 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Natural products 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 5
- 239000012467 final product Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 4
- 240000007472 Leucaena leucocephala Species 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 108010016731 PPAR gamma Proteins 0.000 description 3
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- IPRFNMJROWWFBH-UHFFFAOYSA-N 4-(trifluoromethyl)benzenecarbothioamide Chemical compound NC(=S)C1=CC=C(C(F)(F)F)C=C1 IPRFNMJROWWFBH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 2
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical class NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- RDULEYWUGKOCMR-UHFFFAOYSA-N ethyl 2-chloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(C)=O RDULEYWUGKOCMR-UHFFFAOYSA-N 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 102000054223 human PPARA Human genes 0.000 description 2
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 201000009104 prediabetes syndrome Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ILUPZUOBHCUBKB-UHFFFAOYSA-N 2-methyl-2-(4-{[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)amino]methyl}phenoxy)propanoic acid Chemical compound CC=1N=C(C=2C=CC(=CC=2)C(F)(F)F)SC=1C(=O)NCC1=CC=C(OC(C)(C)C(O)=O)C=C1 ILUPZUOBHCUBKB-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 1
- OKPUICCJRDBRJT-UHFFFAOYSA-N 4-chlorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=C(Cl)C=C1 OKPUICCJRDBRJT-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- YKFAFWKDOSYQIP-UHFFFAOYSA-N 4-ethylbenzamide Chemical compound CCC1=CC=C(C(N)=O)C=C1 YKFAFWKDOSYQIP-UHFFFAOYSA-N 0.000 description 1
- VQFOHZWOKJQOGO-UHFFFAOYSA-N 4-fluorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=C(F)C=C1 VQFOHZWOKJQOGO-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- WKWVTPKUHJOVTI-UHFFFAOYSA-N 4-methoxybenzenecarbothioamide Chemical compound COC1=CC=C(C(N)=S)C=C1 WKWVTPKUHJOVTI-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010070901 Diabetic dyslipidaemia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 101710117029 Peroxisome proliferator-activated receptor delta Proteins 0.000 description 1
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- 102000007451 Steroid Receptors Human genes 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000002293 adipogenic effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- IRDLUHRVLVEUHA-UHFFFAOYSA-N diethyl dithiophosphate Chemical compound CCOP(S)(=S)OCC IRDLUHRVLVEUHA-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- XIUNAYZRKKWAKC-UHFFFAOYSA-N ethyl 2-[4-[[[2-(3,4-dichlorophenyl)-4-methyl-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]-2-methylpropanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=C(Cl)C(Cl)=CC=2)S1 XIUNAYZRKKWAKC-UHFFFAOYSA-N 0.000 description 1
- ZLRKQBOLJBSBIP-UHFFFAOYSA-N ethyl 2-[4-[[[2-(4-aminophenyl)-4-methyl-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]-2-methylpropanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=CC(N)=CC=2)S1 ZLRKQBOLJBSBIP-UHFFFAOYSA-N 0.000 description 1
- NTUWKLFQZMAZFB-UHFFFAOYSA-N ethyl 2-[4-[[[2-(4-fluorophenyl)-4-methyl-1,3-thiazole-5-carbonyl]amino]methyl]phenoxy]-2-methylpropanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=CC(F)=CC=2)S1 NTUWKLFQZMAZFB-UHFFFAOYSA-N 0.000 description 1
- DQODBAJIOCUCFL-UHFFFAOYSA-N ethyl 2-methyl-2-[4-[[(4-methyl-2-phenyl-1,3-thiazole-5-carbonyl)amino]methyl]phenoxy]propanoate Chemical compound C1=CC(OC(C)(C)C(=O)OCC)=CC=C1CNC(=O)C1=C(C)N=C(C=2C=CC=CC=2)S1 DQODBAJIOCUCFL-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000004136 fatty acid synthesis Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000004322 lipid homeostasis Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003893 regulation of appetite Effects 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Description
SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS HPPAR ALPHA ACTIVATORS
The present invention relates to certain novel compounds. In particular, the present invention relates to compounds that activate the alpha subtype of _the human peroxisome proliferator activated receptor ("hPPAR alpha"). The present invention also relates to methods for preparing the compounds and h methods for prevention or treatment of PPAR alpha mediated diseases or conditions.
Several independent risk factors have been associated with : ‘cardiovascular disease. These include hypertension, increased fibrinogen i levels, high levels of triglycerides, elevated LDL cholesterol, elevated total i} cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors - ("statins") are useful for treating conditions characterized by high LDL-c levels. : 15 It has been shown that lowering LDL-c is not sufficient for reducing the risk of ) cardiovascular disease in some patients, particularly those with normal LDL-c - levels. This population pool is identified by the independent risk factor of low
HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been successfully addressed by drug therapy (i.e., currently } : there are no drugs on the market that are useful for raising HDL-c >40%). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70). : }
Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerides, uric acid, fibrinogen, small dense LDL-c particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
NIDDM is described as insulin resistance which in turn causes anomalous glucose output and a decrease in glucose uptake by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsulinemia.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-
activated transcription factors. See, for example, Willson, T. M. and Wahli, W.,
Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241.
Three mammalian Peroxisome Proliferator-Activated Receptors have : been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H.
Keller and W. Wahli, Trends Endoodn. Met 291-296, 4 (1993)).
Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Patents 5,847,008 (Doebber et al.) and 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.) and W0O99/04815 (Shimckawa et al.).
Fibrates are a class of drugs which may lower serum triglycerides 20- 50%, lower LDL-c 10-15%, shift the LDL particle size from the more atherogenic ) small dense to normal dense LDL-c, and increase HDL-c 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPAR alpha. See, for example, B. Staels et al., Cur.
Pharm. Des., 1-14, 3 (1), (1997). Activation of PPAR alpha results in transcription of enzymes that increase fatty acid catabolism and decrease de- novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL-c production/secretion. In addition, PPAR alpha activation decreases production of apoC-lll. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of VLDL-c. See, for example, J. Auwerx et al,
Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996). PPAR alpha ligands may be useful for the treatment of dyslipidemia and cardiovascular disorders, see Fruchart, J.C., Duriez, P., and Staels, B., Curr. Opin. Lipidol. (1999), Vol 10, pp 245-257. .
According to a first aspect of the invention there is provided a compound of formula {!) and pharmaceutically acceptable salts, solvates and hydrolysable : esters thereof:
RZ 0
R! (CH,), Y
AN ~ Ee
Nd RZ 0 8 wherein;
X, represents O or S;
R' and R? independently represent H, halogen, -CH, and ~OCH,; n represents 1 or 2;
X, represents NH, NCH, or O;
One of Y and Z is N, and the other is O or S;
R® represents phenyl or pyridyl (wherein the N is in position 2 or 3) and is optionally substituted by one or more halogen, NO,, NH,, CF; OCF, OC, straight or branched alkyl, C, straight or branched alkyl, alkenyl or alkynyl with : the provision that when R® is pyridyl, the N is unsubstituted;
R* represents CF, or CH,
In another aspect, the present invention discloses a method for prevention or treatment of a human PPAR alpha ("hPPAR alpha") mediated disease or condition comprising administration of a therapeutically effective amount of a compound of this invention. hPPAR alpha mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type |i diabetes mellitus, type | diabetes, insulin resistance, hyperlipidemia, and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. Other diseases or conditions include inflammation. In particular, the compounds of this invention are useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia. . In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine. in another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR alpha mediated disease or condition.
In another aspect, the present invention provides a method of treatment of a patient suffering from a hPPAR alpha mediated disease or condition comprising the administration of a therapeutically effective amount of a compound of the invention. :
As used herein, "a compound of the invention” means a compound of . formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolyzable ester thereof. :
While hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyze that are the active compounds. Esters that hydrolyze readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind well but is active in the transient transfection assay presumably due to hydrolysis. Preferred hydrolysable esters are C,; alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred.
Preferably X, represents O.
Preferably one of R' and R? represents H with R' and R? both representing H being more preferred. 5 Preferably n represents 1. : Preferably X, represents NH.
Preferably Z represents N,
Preferably Y represents S.
Preferably R® is phenyl, optionally substituted. Preferably R® is mono or disubstituted. Preferably when R?® is pyridyl the N is in the 2 position. R® . 15 preferably is monosubstituted in the para position and is more preferably phenyl.
A preferred substituent is CF.
Preferably R* represents CH,.
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in Formula (1) is selected from the preferred, more preferred, or most preferred groups for each variable.
Therefore, this invention is intended to include all combinations of preferred, more preferred, and most preferred groups.
Preferably, the compounds of formula {I} are hPPAR alpha agonists, As used herein, by "agonist, or “activating compound”, or “activator”, or the like, is meant those compounds which have a pKi of at least 6.0 to the relevant PPAR, for example hPPAR alpha, in the binding assay described below, and which achieve at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described below at concentrations of 10° M or less. More preferably, the compounds of this invention achieve 50% activation of human PPAR alpha in the transfection assay at concentrations of 107 M or less.
Most preferably, the compounds of formula (I) are selective hPPAR alpha agonists. As used herein, a "selective hPPAR alpha agonist" is a hPPAR alpha : agonist whose EC,, for PPAR alpha is at least 10 fold lower than its EC, for
PPAR gamma and PPAR delta. Such selective compounds may be referred to as "10-fold selective." EC,, is defined in the transfection assay described below and is the concentration at which a compound achieves 50% of its maximum activity. Most preferred compounds are greater than 100-fold selective hPPAR alpha agonists.
Preferred compounds of the invention include: 2-methyi-2-[4-{[(4-methyl-2-[4-trifluoromethyiphenyl]-thiazol-5- ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester
N-methyl-2-methyl-2-{4-{[(4-methyi-2-[4-trifiuoromethyiphenyi}-thiazol-5- ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester 4-methyl-2-[4-trifluoromethylphenyl}-thiazol-5-carboxylic . acid 4-(1- tertbutyloxycarbonyl-1-methylethoxy) benzyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester - 2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl}-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{{(4-methyl-2-[4-nitrophenyi]-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-aminophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-{4-{[(4-methyl-2-[4-aminophenyi}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[3,4-dichlorophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyi-2-[3-fluoro-4-trifluoromethylphenyl}-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-bromophenyl}-thiazol-5- yicarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-ethylphenyl]-thiazol-5- ylcarbonyl)amino]methy!}phenoxylpropionic acid ethyf ester 2-methyl-2-[4-{{(4-methyl-2-phenylthiazol-5-ylcarbonyl)amino}- methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-fluorophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-chlorophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxylpropionic acid ethyl ester 2-methyl-2-[4-{[(4-methyi-2-[4-trifluoromethoxyphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-methoxyphenyl]-thiazol-5- ylcarbonyi)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxylpropionic acid ethyl ester 2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-trifluoromethy!-2-[4-tertbutylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-trifluoromethyl-2-{4-tertbutylphenyl]-thiazol-5- ylcarbonyl)amino]methyllphenoxylpropionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethylphenyl]-oxazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl]-thiazol-5- vicarhonyhaminolmethylinhenoxylpropionic acid ethyl ester 2-methyl-2-[2-methoxy-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[2-methy!-4-{[{4-methyl-2-[4 trifluromethylpheny!]-thiazcl-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-trifluromethylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5- yicarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropyiphenyl]-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid
: 2-methyl-2-[4-{[(5-methyl-2-[4-trifluoromethyiphenyl]-thiazol-4- ylcarbonyl)amino]methyl}phenoxylpropionic acid ethyl ester : 2-methyl-2-{4-{[(5-methyl-2-[4-trifluoromethylphenyl]-thiazol-4- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl}-thiazol-4- yicarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl]}-thiazol-4- ylcarbonyl)amino]methyl}phenoxy]propionic acid
More preferred compounds of the invention include: 2-methyl-2-[4-{[(4-methyl-2-{4-trifluoromethylphenyl}-thiazol-5- ylcarbonyl)amino]ethyl}phenoxylpropionic acid ethyl ester 2-methyl-2-{4-{[(4-methyl-2-[4-trifluoromethylphenyi}-thiazol-5- ylcarbonyl)amino]ethyl}phenoxy]propionic acid
N-methyl-2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl)amino]ethyl}phenoxy]propionic acid ] 2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]-thiazol-5- : ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5- : ylcarbonyl)amino]methyli}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-nitrophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[3,4-dichlorophenyl}-thiazol-5- ylcarbonyl)amino]methyf}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[3-fluoro-4-trifluoromethylphenyl}-thiazol-5- ylearbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-bromophenyl]-thiazol-5- ylcarbonyl)amino]methyli}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-ethylphenyl}-thiazol-5- ~ ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-phenylthiazol-5-ylcarbonyl)amino)- methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-fluorophenyl]}-thiazol-5- ylcarbonyl)amino]methyl}phenoxylpropionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-chlorophenyl}-thiazol-5- ylcarbonyl)amino)methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methy!-2-[4-trifluorcmethoxyphenyll-thiazo!-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-methoxyphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxylpropionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl]-thiazol-5- . yicarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-trifluoromethylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethylphenyl}-oxazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[2-methoxy-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid
A particularly preferred compound of the invention is 2-methyl-2-[4-{[(4- methyl-2-[4-trifluoromethylphenyl]thiazol-5-yl-carbonyl)amino]methyl}phenoxy] propionic acid.
The preferred compound listed above is a selective hPPAR alpha agonist.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the } active ingredient as a pharmaceutical formulation. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically : acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient")
with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, sorbitol), lubricants (for example, magnesium stearate, stearic acid, taic, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made bv moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non- . aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Formulations for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of . the intended recipient; and aqueous and non-aqueous sterile suspensions which } may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried } (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, ) granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol. oo Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly : soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and . will be ultimately at the discretion of the attendant physician or veterinarian. In ] 15 general, however, doses employed for adult human treatment will typically be in ) the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations. }
The compound of formula (|) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators. The compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonylureas and/or PPAR gamma agonists (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). The compounds may also be used in combination with antihypertensive agents such as calcium channel antagonists and ACE inhibitors. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (1) with a further therapeutic agent in the treatment of a hPPAR alpha mediated disease.
When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR alpha mediated disease, the - dose of each compound may differ from that when the compound is used alone.
Appropriate doses will be readily appreciated by those skilled in the art.
Compounds of this invention may be conveniently prepared by a general process wherein a moiety like (A) is coupled to an acid (B) using a peptide coupling reaction or by alkylation of (A) using a suitable non nucleophilic amine with an acid chloride (C). Preferably, R is 1-6 alkyl which can be hydrolyzed off to give an acid of Formula (I), or if readily hydrolyzable, the resulting ester can be administered. rR? a ®) oO—=
A B c
A preferred synthesis of (A) when X, is O and X, is NH (and R'and R?are
H) is:
Br NHBoc
JO Bu oder or CF,COOH NH,
Randle
HO DMF / K,CO, ! 80°C CHC int 0
A
Note that this synthesis is preferably carried out with the amine where the alcohol function is already alkylated with the acid side chain protected by R. For example, when nis1, X,is O, X,is NH, Yis S, Zis N, R'and R?are H, and R® is 4-F,C-phenyl:
NH HO S HOBT [EDC / NE, S , pl + rs >, “DMF rt oy or Arye
A 8B
NH oc NEY, F mpd . SeS pcr, Se ro 7 jon AO
A [od
Some of the intermediates of type A are commercially available while others can be synthesized by techniques apparent to a person skilled in the art.
The synthesis of intermediates of type B and C are illustrated below. :
Compounds of the invention may be made by an alternative method in which compounds of formuia (D) are reacted with ethyl 2-bromo-Z metnyi propionate to produce the ethyl ester of the compound of formula (I) which may be hydrolysed to produce the free acid. 0)
Y 3 n Xx; oy"
HO
D
Compounds of formula (D) may be prepared from the reaction between compounds of formula (B) and compounds of formula (E) with HOBT / EDC /
NEt, when X, is NH or NCH, or DIC / DMAP / NEt, when X, is O.
HO
E
The invention is further illustrated by the following examples which should not be construed as constituting a limitation thereto. i 10
HO
Tw
Intermediate 1 : y The procedure was as described in Stout, D. M. J. Med. Chem. 1983, - 26(6), 808-13. To 4-methoxybenzyl amine (25g, 0.18 mol; Aldrich) was added . 16 46% HBr in H,0 (106ml, 0.9 mol; Aldrich). The reaction was refluxed overnight, then the reaction cooled to 0°C and neutralized to pH7 slowly with KOH,,,. The reaction was allowed to stir for ~30 min, then the solid filtered and dried. The solid was redissolved in hot MeOH, filtered and the solution cooled to afford 19g (85%) intermediate 1. 'H NMR (DMSO-d): & 8.0 (bs, 1H), 7.2 (d, 2H), 6.75 (d, 2H), 3.85 (s, 2H), 3.50 (bs, 2H).
C—O
A solution of ethyl 2-chloroacetoacetate (35.3g, 29.7mL, 0.21 mol) and 4- (trifluoromethyl)thiobenzamide (44g, 0.21 mol) in EtOH (300mL) was refluxed overnight. After cooling to room temperature the solvent was removed in vacuo.
The final product (intermediate 2) was recrystallized from a minimum of MeOH to afford 40g (59%) of final product as a white solid. '"H NMR (CDCl,): & 8.10 (d, 2H), 7.70 (d, 2H), 4.40 (q, 2H), 2.80 (s, 3H), 1.4 (t, 3H).
I
HO” S
Ter
Intermediate 3: N
To intermediate 2 (1.84g, 5.8 mmol) in THF was added 1N LiOH (6mL, 6 mmol) and the reaction stirred at rt. After ~3h, the reaction was neutralized with 1N HCI, extracted 3 x 100 mL EtOAc, dried over Na,SO,, filtered and the solvent removed under vacuum to afford 1.5g (89%) intermediate 3 as a white solid. 'H
NMR (DMSO-d,): &§ 13.55 (bs, 1H), 8.25 (d, 2H), 7.95 (d, 2H), 2.75 (s, 3H). 0}
Intermediate 4: HO N
To intermediate 3 (1g, 7 mmol) in CH,CI/DMF (1:1) was added HOBT (565mg, 4.2 mmol; Aldrich), EDC (800mg, 4.2 mmol; Aldrich) and intermediate 1 (860mg, 7 mmol). The reaction was stirred at rt for 18h. The solvent was removed in vacuo, treated with H,O and extracted 3x 100mL CH,Cl,. The organic phases combined and washed with 1N HCI, dried over Na,SO,, filtered and evaporated to afford a mixture (N-substituted and N,O-substituted). The mixture was dissolved in MeOH and treated with 1N NaOH. The reaction was stirred 18h at 50°C. The sclvent was removed in vacuc, and the residue was dissolved in CH,Cl,, washed with H,0, and dried over Na,SO,. The solvent was evaporated and the residue chromatographed (CH,Cl,/MeOH: 99/1) to afford 610mg (47%) of intermediate 4 as a white solid. 'H NMR (DMSO-d;): & 9.30 (s, 1H), 8.80 (t, 1H), 8.20 (d, 2H), 6.70 (d, 2H), 4.35 (d, 2H), 2.6 (s, 3H).
General procedure 1 for the preparation of substituted thiobenzamides
To a solution of P,S,, (0.2 mmol) in toluene (100mL) was added NaHCO, (2 mmol) and the mixture heated to reflux for ca. 30min. The substituted
. benzamide (1 mmol) was added and the reaction stirred at 80°C for 1h. The reaction was then evaporated to dryness, treated with brine (100mL) and extracted with CH,Cl, (2 X 50mL). The organic phase dried, filtered, and evaporated to afford the final product. intermediate 5:
The title compound was prepared as described in general procedure 1 to afford an orange solid (49%). 'H NMR (CDCl,): 57.7 (d, 2H), 7.4 (bs, 1H), 7.3 (d, 2H), 7.0 (bs, 1H), 1.2 (s, 9H). : S
Intermediate 6:
So The title compound was prepared as described in general procedure 1 to afford an orange solid (26%). ) Mp: 150°C
General procedure 2 for the preparation of substituted thiobenzamides
To the substituted benzonitrile (1 mmol) in DMF (30mL) is added dropwise DMF (21mL) saturated with HCl, during 1 min. Thioacetamide (2 mmol) is then added and the reaction heated to 100°C for 1h. HCl, is bubbled in for ca. 1 min and the stirring continued at 100°C for another 18h. The reaction cooled to rt, treated with ice and extracted with Et,O (3 x 250mL). The organic phase was washed with H,O (3 x 300mL), dried over Na,SO,, filtered, and evaporated to dryness. The residue was washed with a mixture of isopropyl ether/pentane (1:3) to afford the final product.
wey,
Intermediate 7: NO,
The title compound was prepared as described in general procedure 2 to afford an orange solid (83%). 'H NMR (DMSO-d): & 10.1 (bs, 1H), 8.7 (bs, 1H), 8.1 (d, 2H), 7.9 (d, 2H).
Ss
Cape
Intermediate 8: Cl : The title compound was prepared as described in general procedure 2 to afford a yellow solid (45%). : MS m/z 207 (M+1) s w NO
Intermediate 9: CF,
The title compound was prepared as described in generai procedure 2 to afford an orange solid (84%). 'H NMR (DMSO-d,): & 10.5 (bs, 1H), 10.05 (bs, : 1H), 8.1 (m, 3H). : s
WNL intermediate 10: Br
To 4-bromobenzonitrile (1 mmol) was added the diethyldithiophosphate (1.2 equiv.). To the suspension was added H,O (ca. 100mL) and the reaction heated to 80°C for ca. 2h. The reaction cooled to rt and extracted with Et,0 (3 x 100mL). The oganic phase was washed with sat. NaHCO,, dried over NaSO, and evaporated to dryness leaving a yellow solid. The solid was rinsed with isopropyl ether and collected by filtration to afford the title compound as a yellow solid (65%).
MS m/z 214
Intermediate 11:
To the 4-ethylbenzamide (1 mmol) in toluene heated to reflux, was added
Laweson's reagent (1 equiv.). After the addidition was complete, the reaction was refluxed for 2h. The reaction cooled to rt, treated with Et,O, washed with
H.O and the organic phase dried over Na,SO,. The solution filtered, evaporated to dryness and the residue chromatographed with CH,Cl,/MeOH (98:2) to afford 3g of the title compound as a yellow solid (55%). 'H NMR (DMSO-d): 5 9.8 (bs, 1H), 9.4 (bs, 1H), 7.8 (d, 2H), 7.2 (d, 2H), 2.6 (q, 2H), 1.2 (t, 3H).
General procedure 3 for the preparation of 2-substituted phenyl-4- methyi-1,3-thiazole-5-caboxylic acid ethyl esters
To a solution of the substituted thiobenzamide (1 mmol) in EtOH (1 00 mL) was added ethyl 2-chloroacetoacetate (1.1 mmol) and the mixture heated to reflux overnight. The reaction is cooled to room temperature and the solvent evaporated. The solid is crystallized from Et,O or hexane to afford the final : product. . “No oot
Intermediate 12: N
Intermediate 5 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (95%). 'H NMR (CDCl): 3 8.0 (d, 2H), 7.55 (d, 2H), 4.45 (q, 2H), 3.85 (s, 3H), 2.5 (t, 3H), 1.45 (s, 9H). “No oc
Intermediate 13: ~~ N 7
Intermediate 6 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (97%). 'H NMR (CDCl,): & 7.85 (d, 2H), 7.25 (d, 2H), 4.30 (q, 2H),-2.90 (st, 1H), 2.70 (s, 3H), 1.30 (t, 3H), 1.20 (d, 6H).
0] lye
Intermediate 14: N
Intermediate 7 was reacted as described in general procedure 3 to afford the title compound as an yellow solid (74%). 'H NMR (CDCl): & 8.25 (d, 2H), 8.05 (d, 2H), 4.30 (q, 2H), 2.70 (s, 3H), 1.30 (t, 3H). 2 cl } ~~ — -
Intermediate 15: N
Intermediate 8 was reacted as described in general procedure 3 to afford the title compound as an pale yellow solid (77%). 'H NMR (CDCl): § 8.0 (d, 1H), 7.70 (dd, 1H), 7.40 (d, 1H), 4.30 (q, 2H), 2.70 (s, 3H), 1.3 (s, 3H). : 10 . 2 F
No s x (hen,
Intermediate 16: N
Intermediate 9 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (40%). ‘H NMR (DMSO-dg): 6 7.85 (m, 3H), 4.30 (q, 2H), 2.65 (s, 3H), 1.3 (s, 3H). ge) ~~ B /=\ : / Br
Intermediate 17: A 'aYs intermediate 10 was reacted as described in general procedure 2 to afford the title compound as an off-white solid (61%). ‘H NMR (CDCl): 57.70 (d, 2H), 7.55 (d, 2H), 4.25 (q, 2H), 2.70 (s, 3H), 1.30 (s, 3H). o ~elype
Lo
Intermediate 11 was reacted as described in general procedure 3 to : afford the title compound as a pale green solid (35%). '"H NMR (CDCl,): 67.70
Co 22 (d, 2H), 7.15 (d, 2H), 4.15 (q, 2H), 2.50 (s, 3H), 2.50 (q, 2H), 1.15 (t, 3H), 1.05 (t, 3H).
No s pa
Intermediate 19: N
The thiobenzamide (Aldrich) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (28%). 'H NMR (CDCl). 58.35 (d, 2H), 7.60 (m, 3H), 4.45 (q, 2H), 3.05 (s, 3H), 1.30 (t, 3H). : “0 s ~~
Intermediate 20: N
The 4-fluorothiobenzamide (Maybridge) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (100%). 'H
NMR (CDCl,): 87.75 (dd, 2H), 6.95 (t, 2H), 4.15 (q, 2H), 2.60 (s, 3H), 1.20 (t, 3H). “No s
Intermediate 21: N
The 4-chlorothiobenzamide (Lancaster) was reacted as described in general procedure 3 to afford the title compound as an pale orange solid (54%). 'H NMR (CDCl,): 57.60 (d, 2H), 7.10 (d, 2H), 4.15 (q, 2H), 2.55 (s, 3H), 1.20 (t, 3H). “No s
Joo"
Intermediate 22: N
The d4-trifluoromethoxythiobenzamide (Interchim) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (100%). 'H NMR (CDCl): 87.90 (d, 2H), 7.15 (d, 2H), 4.25 (q, 2H), 2.65 (s, 3H), 1.30 (t, 3H).
0 pe (ome
Intermediate 23: N
The 4-methoxythiobenzamide (Lancaster) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (52%). 'H
NMR (DMSO-d;): &7.8 (d, 2H), 6.95 (d, 2H), 4.15 (q, 2H), 3.70 (s, 3H), 2.50 (s, 3H), 1.15 (t, 3H).
General procedure 4 for the preparation of 2-substituted phenyl-4- methyl-1,3-thiazole-5-caboxylic acids
To a solution of the substituted thiazole ester (1 mmol) in EtOH (100 mL) was added (1.5 equiv.) NaOH (1N) and the mixture heated to 40°C overnight.
The reaction is cooled to room temperature and the solution acidified with HCI (1N). The precipitate is collected washed with H,O and dried under vaccum to afford the final product. :
Ji a Van
Intermediate 24: N
Intermediate 12 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (64%). ‘H NMR (CDCl): 6 7.70 (d, 2H), 7.30 (d, 2H), 2.60 (t, 3H), 1.15 (s, 9H). 0
I
HO” NS
TO
Intermediate 25: N
Intermediate 13 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (100%). 'H NMR (CDCL): & 7.75 (d, 2H), 7.15 (d, 2H), 2.85 (st, 1H), 2.65 (s, 3H), 1.15 (d, 6H).
HO
Ae
Intermediate 14 was reacted as described in general procedure 4 to afford the title compound as a beige solid (99%). ‘H NMR (DMSO-d): 5 8.15 (d, 2H), 8.05 (d, 2H), 2.50 (s, 3H). [>]
HO S intermediate 27: N
Intermediate 15 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (91%). 'H NMR (DMSO-d,): & 3 8.35 (d, 1H), 8.05 (dd, 1H), 7.90 (d, 1H), 2.80 (s, 3H). : 10 i F
HO cS
Intermediate 16 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (82%). 'H NMR (DMSO-d;): $ 8.05 (m, 3H), 2.75 (s, 3H).
HO 8
A J)
Intermediate29: ~~ MN TT
Intermediate 17 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (87%). 'H NMR (DMSO-d): 87.70 (d, 2H), 7.45 (d, 2H), 2.45 (s, 3H).
HO S$ > —
Intermediate 18 was reacted as described in general procedure 4 to afford the titte compound as a pale green solid (79%). '"H NMR (DMSO-d,): 58.05 (d, 2H), 7.50 (d, 2H), 2.75 (q, 2H), 2.75 (s, 3H), 1.30 (t, 3H). lo} 50)
Ppa
Intermediate 31: N
Intermediate 19 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (93%).
Mp 215°C o
HO S$
Lo)
Intermediate 32: ~~ N
Intermediate 20 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (85%). '"H NMR (DMSO-d,): 68.0 (dd, 2H), 7.30 (t, 2H), 2.60 (s, 3H). 0 fl
HO S
Intermediate 33: ~~ N —
Intermediate 21 was reacted as described in general procedure 4 to afford the title compound as an pale orange solid (92%). 'H NMR (DMSO-d): 87.95 (d, 2H), 7.55 (d, 2H), 2.60 (s, 3H). : v
HO S, oe
Intermediate 34: ~~ N
Intermediate 22 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (66%).
MS m/z 304 (M+1)
yp — ome
Intermediate 35: N
Intermediate 23 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (98%). 'H NMR (DMSO-d): 57.95 (d, 2H), 7.10 (d, 2H), 3.90 (s, 3H), 2.70 (s, 3H). ~~ =,
Intermediate 36: N
Intermediate 17 (1 mmol) was diluted in a mixture of MeCN/dioxane (100mL) then Cul (0.05 equiv.) and 1,1,3,3-tertamethylguanidine (10 equiv.) was added and the reaction stirred 15min under a N, atmosphere. The reaction purged under vaccum and then trimethylsilylacétylene (1.1 equiv.) and
Pd(PPh,),Cl, (0.1 equiv.) added and the reaction stirred at 80°C for 2h. The solvent evaporated, the residue dissolved in CH,Cl,, washed with sat. NH,Cl, then NH,OH and finally brine. The organic layer dried over Na,SO,, filtered and evaporated. The crude product was chromatographed eluting with CH,CI, to afford the title compound as a beige solid (100%). - MS m/z 344 (M+1) “No
Nao
Intermediate 37: N :
To intermediate 36 (1 mmol) in THF was added Bu,NF and the reaction stirred at rt for 2h. The THF was evaporated, the residue dissolved in CH,Cl,, washed with sat. NH,Cl, then NH,OH and finally brine. The organic layer dried over Na,SO,, filtered and evaporated. The crude product was chromatographed eluting with CH,Cl, to afford the title compound as white solid (44%).
MS m/z 272 (M+1)
HO Ss > — =
Intermediate 37 was reacted as described in general procedure 4 to afford the title compound as a pale yellow solid (79%).
MS m/z 244 (M+1) 0 “ore /=\
Intermediate 39: 3
To the 4-trifluoromethylthiobenzamide (1equiv., Lancaster) in DMF (150mL) was added ethyl 2-chloro-4,4 4-trifluoroacetoacetate (1.5 equiv.,
Lancaster) and the reaction stirred at 100°C for 18h. The reaction is cooled, concentrated and the residue chromatographed eluting with CH,Cl,. The yellow oil that is collected is titrated with hexane to afford the title compound as a white : solid (13%).
MS m/z 369 lo]
HO $
X cr
Intermediate 40: FC " i5 intermediate 39 was reacted as described in generai procedure 4 to afford the title compound as a white solid (94%). '"H NMR (DMSO-d,): 58.1 (d, 2H), 7.7 (d, 2H). 0]
No Ss praoss
Intermediate 41: FC "
To intermediate 5 (1equiv.) in EtOH (25mL) was added ethyl 2-chloro- 4.4 4-trifluoroacetoacetate (1 equiv., Lancaster) and the reaction stirred at reflux for 91h. The reaction is cooled, concentrated, the residue dissolved in pentane and filtered. The solvent removed under vaccum to afford the title compound as a brown oil containing 2 compounds which was used without further purification.
Claims (26)
1. A compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof R? 0 RY (CH) Y, aes ce HO, ]* vA (() X, wherein; X, represents O or S; R' and R? independently represent H, halogen, -CH, and -OCHj; n represents 1 or 2; X, represents NH, NCH, or O, : : 15 One of Y and Z is N, and the other is O or S; R® represents phenyl or pyridyl (wherein the N is in position 2 or 3) and is optionally substituted by one or more halogen, NO,, NH,, CF,, OCF,, OC,. : . gstraight or branched alkyl, C,; straight or branched alkyl, alkenyl or alkynyl with the provision that when R?® is pyridyl, the N is unsubstituted; R* represents CF, or CH,
2. A compound of formula (I) which is a hPPAR alpha agonist.
3. A compound according to claim 2 which is a selective hPPAR alpha agonist.
4. A compound according to claims 1-3 wherein X, represents O.
5. A compound according to claims 1-4 wherein one of R' and R? is H.
6. A compound according to claim 5 wherein R' and R? both represent H.
7. A compound according to any of claims 1-6 wherein n represents 1.
8. A compound according to any of claims 1-7 wherein X, represents NH.
9. A compound according to claims 1-8 wherein Z represents N.
10. A compound according to claims 1-9 wherein Y represents S.
11. A compound according to any of claims 1-10 wherein R® is monosubstituted.
12. A compound according to claim 11 where R® is monosubstituted with CF.
13. A compound according to claim 11 or 12 wherein R® is monosubstituted in the para position.
14. A compound according to any previous claim wherein R® is phenyl.
15 A compound according to any preceding claim wherein R* is CH,. ) 2M0N
16. A compound selected from: 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl)aminolethyl}phenoxylpropionic acid ethyl ester N-methyl-2-maethyl-2.14.1114_methyl-2-T4-trifluoromethylphenyll-thiazol-5- ylcarbonyl)amino)ethyl}phenoxy]propionic acid ethyl ester 4-methyl-2-[4-trifluoromethylphenyl}-thiazol-5-carboxylic acid 4-(1- tertbutyloxycarbonyl-1-methylethioxy) benzyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl}-thiazol-5- yicarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-nitrophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-aminophenyl]-thiazol-5- ylcarbonyl)aminojmethyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-{4-aminophenyl]-thiazol-5- ylcarbonyl)amino)methyl}phenoxy]propionic acid 2-methyl-2-{4-{[(4-methyl-2-[3,4-dichlorophenyi]-thiazol-5- ylcarbonyl)aminojmethyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[3-fluoro-4-trifluoromethylphenyi}-thiazol-5- ylcarbonyl)amino]methyl}phenoxylpropionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-bromophenyI}-thiazoi-5- ylcarbonyl)aminojmethyl}phenoxy]propionic acid ethyl ester 2-methyi-2-[4-{[(4-methyi-2-[4-ethylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxyjpropionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-phenyithiazol-5-yicarbonyl)amino]- methyl}phenoxy]propionic acid ethyl ester 2-methyi-2-[4-{[(4-methyl-2-[4-fluocrophenyl}-thiazol-5- yicarbonyl)amino)methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-chlorophenyli]-thiazol-5- ylcarbonyl)aminojmethyl}phenoxy}propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethoxyphenyl]-thiazol-5- yicarbonyf)aminojmethyli}phenoxy]propionic acid ethyl ester
. 2-methyl-2-[4-{[(4-methyl-2-[4-methoxyphenyl]-thiazol-5- ylcarbonyl)amino)methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl]-thiazol-5- ) ylcarbonyl)amino)methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester : 2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-tertbutylphenyl}-thiazol-5- : ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-tertbutylphenyl]-thiazol-5- ylcarbonyl)amino)methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethylphenyi}-oxazol-5- ylcarbonyl)amino]jmethyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[2-methoxy-4-{[(4-methyl-2-{4-trifluromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5- yicarbonyl)aminojmethyl}phenoxy]propionic acid ethyi ester : 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5- yicarbonyi)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropylphenyi]-thiazol-5- vlcarbonyllaminolmethyllphenoxylpropionic acid 2-methyl-2-[4-{[(5-methyl-2-[4-trifluoromethylphenyl]-thiazol-4- yicarbonyl)amino]methyl}phenoxyjpropionic acid ethyl ester 2-methyl-2-[4-{[(5-methyl-2-[4-trifluoromethylphenyl]-thiazol-4- ylcarbonyljamino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl]-thiazol-4- ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester 2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl]-thiazol-4- : ylcarbonyl)amino]methyl}phenoxy]propionic acid
17. A compound selected from: ’ 2-methyi-2-{4-{[(4-methyi-2-{4-trifluoromethyiphenyi}-thiazoi-5- ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester : 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5- ylcarbonyl)amino]ethyi}phenoxy]propionic acid . N-methyl 2 methyl 2-[4-{[{4-methy!-2-[4-triflucromethylphenyl}-thiazol-5- ylcarbonyi)amino]ethyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]-thiazol-5- yicarbonyljaminojmethyl}phenoxyjpropionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-nitrophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[3,4-dichlorophenyl]-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[3-fluoro-4-trifluoromethylphenyi}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4{[(4-methyl-2-[4-bromophenyl]-thiazol-5- yicarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-ethylphenyl]-thiazol-5- -yicarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2{4-{[(4-methyl-2-phenylithiazol-5-ylcarbonyl)amino]- methyl}phenoxy]propionic acid ~~ 2-methyl-2-{4-{[(4-methyl-2-[4-fluorophenyi}-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid 2-methyl-2-{4-{[(4-methyl-2-{4-chlorophenyi}-thiazo}-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-{4-{[(4-methyl-2-[4-trifluoromethoxyphenyi}-thiazol-5- ylcarbonyl)amino]methyi}phenoxy]propionic acid 2-methyl-2{4-{[(4-methyl-2{4-methoxyphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyi-2-{4-{[(4-trifluoromethyi-2-[4-trifluoromethylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid : 2-methyl-2-[4-{[(4-methyl-2-{4-trifluromethylphenyl]-oxazol-5- ylcarbonyl)amino]lmethyl}phenoxylpropionic acid . 2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid 2-methyl-2-[2-methoxy-4-{[(4-methyl-2-{4-trifluromethylphenyl}-thiazol-5- ylcarbonyl)amino]methyl}phenoxy]propionic acid
18. 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]thiazol-5-ylcarbonyl)- : amino]methyl}phenoxy]propionic acid.
19. A compound according to any of claims 1-17 for use in therapy.
20. A pharmaceutical composition comprising a compound according to any of claims 1-17.
21. A pharmaceutical composition according to claim 20 further comprising a pharmaceutically acceptable diluent or carrier.
22. Use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment of a hPPAR alpha disease or condition.
23. Use according to claim 22 wherein the hPPAR alpha mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, inflammation, anorexia bulimia and anorexia nervosa.
24. A compound according to claim 1, substantially as herein described and exemplified and/or described with reference to the examples.
25. A pharmaceutical composition according to claim 20, substantially as herein described and exemplified and/or described with reference to the examples.
26. Use according to claim 22, substantially as herein described and exemplified and/or described with reference to the examples. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9928561.1A GB9928561D0 (en) | 1999-12-02 | 1999-12-02 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200204241B true ZA200204241B (en) | 2003-07-02 |
Family
ID=10865619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200204241A ZA200204241B (en) | 1999-12-02 | 2002-07-28 | Substituted oxazoles and thiazoles derivatives as HPPAR Alpha Activators. |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB9928561D0 (en) |
| ZA (1) | ZA200204241B (en) |
-
1999
- 1999-12-02 GB GBGB9928561.1A patent/GB9928561D0/en not_active Ceased
-
2002
- 2002-07-28 ZA ZA200204241A patent/ZA200204241B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9928561D0 (en) | 2000-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1244642B1 (en) | Substituted oxazoles and thiazoles derivatives as hppar alpha activators | |
| EP1392665B1 (en) | Thiazole or oxazole derivatives which are useful in the treatment of cardiovascular and related diseases | |
| AU765347B2 (en) | Thiazole and oxazole derivatives and their pharmaceutical use | |
| AU2002312954A1 (en) | Thiazole or oxazole derivatives which are useful in the treatment of cardiovascular and related diseases | |
| US20040147571A1 (en) | Substituted oxazoles and thiazoles as hppar alpha agonists | |
| AU2002317765B2 (en) | Oxazol/ thiazol-derivatives activators of the hPPAR-alpha receptor | |
| AU2002317765A1 (en) | Oxazol/ thiazol-derivatives activators of the hPPAR-alpha receptor | |
| US7244849B2 (en) | Process for preparing a thiazole PPAR-ligand and polymorphs thereof | |
| ZA200204241B (en) | Substituted oxazoles and thiazoles derivatives as HPPAR Alpha Activators. | |
| US20070167628A1 (en) | Thiazole-2-carboxamide derivatives for use as hippar agonists in the treatment of i.a. dyslipidemia |