ZA200206642B - Pyridinylimidazoles. - Google Patents
Pyridinylimidazoles. Download PDFInfo
- Publication number
- ZA200206642B ZA200206642B ZA200206642A ZA200206642A ZA200206642B ZA 200206642 B ZA200206642 B ZA 200206642B ZA 200206642 A ZA200206642 A ZA 200206642A ZA 200206642 A ZA200206642 A ZA 200206642A ZA 200206642 B ZA200206642 B ZA 200206642B
- Authority
- ZA
- South Africa
- Prior art keywords
- galkyl
- imidazol
- pyridine
- compound according
- pharmaceutically acceptable
- Prior art date
Links
- SZXUTTGMFUSMCE-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)pyridine Chemical class C1=CNC(C=2N=CC=CC=2)=N1 SZXUTTGMFUSMCE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 61
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 19
- 241000124008 Mammalia Species 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- -1 cyano, phenyl Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 230000019491 signal transduction Effects 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 208000025865 Ulcer Diseases 0.000 claims description 5
- 208000027418 Wounds and injury Diseases 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000011159 matrix material Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 231100000397 ulcer Toxicity 0.000 claims description 5
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 206010052428 Wound Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 230000029663 wound healing Effects 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000022873 Ocular disease Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000001771 impaired effect Effects 0.000 claims description 3
- 230000007658 neurological function Effects 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000001228 trophic effect Effects 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 102000005962 receptors Human genes 0.000 description 26
- 108020003175 receptors Proteins 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 11
- 230000001404 mediated effect Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 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 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000005594 diketone group Chemical group 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- FIWOARRMYCTVNH-UHFFFAOYSA-N 2-[2-tert-butyl-4-(4-methoxyphenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(OC)=CC=C1C1=C(C=2N=CC=CC=2)N=C(C(C)(C)C)N1 FIWOARRMYCTVNH-UHFFFAOYSA-N 0.000 description 2
- 108010059616 Activins Proteins 0.000 description 2
- 102000005606 Activins Human genes 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000488 activin Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000036573 scar formation Effects 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 230000037314 wound repair Effects 0.000 description 2
- UBWXUGDQUBIEIZ-UHFFFAOYSA-N (13-methyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl) 3-phenylpropanoate Chemical compound CC12CCC(C3CCC(=O)C=C3CC3)C3C1CCC2OC(=O)CCC1=CC=CC=C1 UBWXUGDQUBIEIZ-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- OPFNZHIUHJBGEW-UHFFFAOYSA-N 1-hydroxyimidazole Chemical compound ON1C=CN=C1 OPFNZHIUHJBGEW-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
- GVGHVFFCFAKXHA-UHFFFAOYSA-N 2-[4-(2-methylphenyl)-2-propyl-1h-imidazol-5-yl]pyridine Chemical compound N1C(CCC)=NC(C=2N=CC=CC=2)=C1C1=CC=CC=C1C GVGHVFFCFAKXHA-UHFFFAOYSA-N 0.000 description 1
- WDVMPTRGIDTUDO-UHFFFAOYSA-N 2-[4-(3,5-dimethylphenyl)-2-ethyl-1h-imidazol-5-yl]pyridine Chemical compound N1C(CC)=NC(C=2N=CC=CC=2)=C1C1=CC(C)=CC(C)=C1 WDVMPTRGIDTUDO-UHFFFAOYSA-N 0.000 description 1
- HZEZYWLWEUSWLV-UHFFFAOYSA-N 2-[4-(3,5-dimethylphenyl)-2-methyl-1h-imidazol-5-yl]pyridine Chemical compound N1C(C)=NC(C=2N=CC=CC=2)=C1C1=CC(C)=CC(C)=C1 HZEZYWLWEUSWLV-UHFFFAOYSA-N 0.000 description 1
- IUQFNIBXZBWEDC-UHFFFAOYSA-N 2-[4-(3,5-dimethylphenyl)-2-propan-2-yl-1h-imidazol-5-yl]pyridine Chemical compound N1C(C(C)C)=NC(C=2N=CC=CC=2)=C1C1=CC(C)=CC(C)=C1 IUQFNIBXZBWEDC-UHFFFAOYSA-N 0.000 description 1
- PYDPHZGDXZMGRI-UHFFFAOYSA-N 2-[4-(3,5-dimethylphenyl)-2-propyl-1h-imidazol-5-yl]pyridine Chemical compound N1C(CCC)=NC(C=2N=CC=CC=2)=C1C1=CC(C)=CC(C)=C1 PYDPHZGDXZMGRI-UHFFFAOYSA-N 0.000 description 1
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 1
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010018366 Glomerulonephritis acute Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 108010004250 Inhibins Proteins 0.000 description 1
- 102000002746 Inhibins Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000034827 Neointima Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010034650 Peritoneal adhesions Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000027032 Renal vascular disease Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GELXFVQAWNTGPQ-UHFFFAOYSA-N [N].C1=CNC=N1 Chemical compound [N].C1=CNC=N1 GELXFVQAWNTGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003905 agrochemical Substances 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
- 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
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940112869 bone morphogenetic protein Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000000893 fibroproliferative effect Effects 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
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000893 inhibin Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 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
- 230000003902 lesion Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 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
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000000491 multivariate analysis Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008692 neointimal formation Effects 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 208000015670 renal artery disease Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 150000003355 serines Chemical group 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007790 solid phase Substances 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
- 241000894007 species Species 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
¢ > ,
PYRIDINYLIMIDAZOLES
This invention relates to pyridyl substituted imidazoles which are inhibitors of the . transforming growth factor, ("TGF")-B signaling pathway, in particular, the phosphorylation of smad2 or smad3 by the type I or activin-like kinase ("ALK")-5 receptor, methods for their . 5S preparation and their use in medicine, specifically in the treatment and prevention of a disease ’ state mediated by this pathway.
TGF-$1 is the prototypic member of a family of cytokines including the TGF-Bs, activins, inhibins, bone morphogenetic proteins and Miillerian-inhibiting substance, that signal through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin like kinase (ALK) receptors and type II receptors.
The ALK receptors are distinguished from the type II receptors in that the ALK receptors (2) lack the serine/threonine rich intracellular tail, (b) possess serine/threonine kinase domains that are very homologous between type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is critical for activation by the type II receptor. Several studies have shown that TGF- signaling requires both the ALK and type II receptors. Specifically, the type II receptor phosphorylates the GS domain of the type I receptor for TGF-B, ALKS, in the presence of TGF-B. The ALKS, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally it is believed that in many species, the type II receptors regulate cell proliferation and the type I receptors regulate matrix production. Therefore, preferred compounds of this invention are selective in that they inhibit the type I receptor and thus matrix production, and not the type II receptor mediated proliferation.
Activation of the TGF-B1 axis and expansion of extracellular matrix are early and persistent contributors to the development and progression of chronic renal disease and vascular disease. Border W.A., Noble N.A., N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. Further,
TGF-B1 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1, components of sclerotic deposits, through the action of smad3 phosphorylation by the TGF-31 receptor ALKS5. Zhang Y., Feng X.H., Derynck R., Nature, Aug. 27, 1998; 394(6696):909-13;
Usui T., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., Miyata K., Kawabata M., Yamashita
H., Invest. Ophthalmol. Vis. Sci., Oct. 1998; 39(11):1981-9.
Progressive fibrosis in the kidney and cardiovascular system is a major cause of suffering and death and an important contributor to the cost of health care. TGF-PB1 has been implicated in many renal fibrotic disorders. Border W.A_, Noble N.A_ N. Engl J. Med., Nov 10, 1994, 331(19):1286-92. TGF-B1 is elevated in acute and chronic glomerulonephritis, Yoshioka K.,
Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., Maki S., Lab. Invest., Feb. 1993; : 68(2):154-63, diabetic nephropathy, Yamamoto, T., Nakamura, T., Noble, N.A_, Ruoslahti, E.,
Border, W.A., (1993) PNAS 90:1814-1818, allograft rejection, HIV nephropathy and . angiotensin-induced nephropathy, Border W.A., Noble N.A., N. Engl. J. Med., Nov. 10, 1994; 40 331(19):1286-92. In these diseases the levels of TGF-f1 expression coincide with the production of extracellular matrix.- Three lines of evidence suggest a causal relationship between TGF-p1 and the production of matrix. First, normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF- :
¥ Y
B1 in vitro. Second, neutralizing anti-bodies against TGF-B1 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-B1 transgenic mice or in vivo transfection of the TGF-B1 gene into normal rat kidneys resulted in the rapid development of glomerulosclerosis.
Kopp I.B., Factor V.M., Mozes M., Nagy P., Sanderson N., Bottinger E.P., Klotman P.E., : 5 Thorgeirsson S.S., Lab Invest, June 1996; 74(6):991-1003. Thus, inhibition of TGF-B1 activity is indicated as a therapeutic intervention in chronic renal disease. . TGF-B1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty, Saltis J., Agrotis A., Bobik A., Clin Exp
Pharmacol Physiol, Mar. 1996; 23(3):193-200. In addition TGF-B1 is a potent stimulator of smooth muscle cell ("SMC") migration in vitro and migration of SMC in the arterial wall is a contributing factor in the pathogenesis of atherosclerosis and restenosis. Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF- receptor
ALKS5 correlated with total cholesterol (P < 0.001) Blann A.D., Wang J.M., Wilson P.B., Kumar
S., Atherosclerosis, Feb. 1996; 120(1-2):221-6. Furthermore, SMC derived from human atherosclerotic lesions have an increased ALK5/TGF-f type II receptor ratio. Because TGF-B1 is over-expressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components
McCaffrey T.A., Consigli S., Du B., Falcone D.J., Sanborn T.A., Spokojny A.M., Bush H.L., Jr.,
J Clin Invest, Dec. 1995; 96(6):2667-75. TGF-B1 was immunoiocalized to non-foamy macrophages in atherosclerotic lesions where active matrix synthesis occurs, suggesting that non- foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-B-dependent mechanism. Therefore, inhibiting the action of TGF-B1 on
ALKS is also indicated in atherosclerosis and restenosis.
TGF-B is also indicated in wound repair. Neutralizing antibodies to TGF-31 have been used in a number of models to illustrate that inhibition of TGF-B1 signaling 1s beneficial in restoring function after injury by limiting excessive scar formation during the healing process.
For example, neutralizing antibodies to TGF-PB1 and TGF-B2 reduced scar formation and improved the cytoarchitecture of the neodermis by reducing the number of monocytes and macrophages as well as decreasing dermal fibronectin and collagen deposition in rats Shah M., J.
Cell Sci., 1995, 108, 985-1002. Moreover, TGF-f antibodies also improve healing of corneal wounds in rabbits Moller-Pedersen T., Curr. Eye Res., 1998, 17, 736-747, and accelerate wound healing of gastric uicers in the rat, Ernst H., Gut, 1996, 39, 172-175. These data strongly suggest that limiting the activity of TGF-B would be beneficial in many tissues and suggest that any disease with chronic elevation of TGF-f would benefit by inhibiting smad2 and smad3 signaling pathways.
TGF- is also implicated in peritoneal adhesions Saed GM. et al, Wound Repair
Regeneration, 1999 Nov-Dec, 7(6), 504-510. Therefore, inhibitors of ALKS would be beneficial in preventing peritoneal and sub-dermal fibrotic adhesions following surgical procedures.
TGFP1-antibodies prevent transplanted renal tumor growth in nude mice through what is 40 thought to be an anti-angiogenic mechanism Ananth S, et al, Journal Of The American Society Of ) Nephrology Abstracts, 9: 433A(Abstract). While the tumor itself is not responsive to TGF-B, the
IES surrounding tissue is responsive and supports tumor growth by neovascularization of the TGF-B
’ h secreting tumor. Thus, antagonism of the TGF-B pathway should prevent metastasis growth and reduce cancer burden.
Bioorg. Med. Chem. Lett., 1995, 5(6), 543 discloses 2-[5-(2-methylphenyl)-2-propyl-1H- imidazol-4-yl]pyridine as an inhibitor of gastric HY/K* ATPase. ’ 5 DE 2221546 discloses the following compounds as antiinflammatory, analgesic or antipyretic agents: . 2-[2-(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1 H-imidazol-4-yl]pyridine, 2-[2~(1,1-dimethylethyl)-5-phenyi- 1 H-imidazol-4-yl]pyridine.
Japanese Patent No. 09124640 discloses the following compounds as agrochemical fungicides: 2-[5-(3,5-dichlorophenyl)-2-methyl- 1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-methyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-ethyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-amino- 1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylpheny!)-2-propyl- 1 H-imidazo}-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-carboxamide-1H-imidazol-4-yl]pyridine.
Surprisingly, it has now been discovered that a class of 2-pyridyl substituted imidazoles of formula (I), function as potent and selective non-peptide inhibitors of ALKS5 kinase and therefore, have utility in the treatment and prevention of various disease states mediated by ALKS kinase mechanisms, such as chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is 2 major component, including, but not limited to lung fibrosis and liver fibrosis, and restenosis.
According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:
R, X
JR
~~ %2
Lon
RJ
@ wherein Rj is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1_galkoxy, C1-galkylthio, C}_galkyl,
C1-ghaloalkyl, O-(CHy)m-Ph, S{(CHy)m-Ph, cyano, phenyl, and COR, wherein R is hydrogen . or Cj_galkyl and m is 0-3; or Rj is phenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, } 35 independently selected from N, O and S, and is optionally substituted by =O;
Ry represents hydrogen, Cj.galkyl, Ci.galkoxy, phenyl, C|.ghaloalkyl, halo, NHp, NH-
C1-6alkyl or NH(CH)p-Ph wherein n is 0-3;
Rg3 represents C_galkyl, -(CH2)p-CN, -(CH2)p-COOH, -(CH2)p-CONHR4R5,
¢ h ~(CH2)pCORy, -(CH2)4(OR6)2, (CH2)pOR4, -(CHp)q-CH=CH-CN, «(CH2)q-CH=CH-CO2H, ~(CH)p-CH=CH-CONHR4R3, -(CH2)pNHCOR7 or -(CH2)pNRgRo,
R4 and Rs are independently hydrogen or C1_galkyl;
Rg is Cy galkyl; ’ 5 R7 is Cj.7alkyl, or optionally substituted aryl, heteroaryl, arylC}_galky! or heteroarylC1.- alkyl; . Rg and Rg are independently selected from hydrogen, C1.galkyl, aryl and arylC1.galkyl; pis 0-4; q is 1-4; one of Xj and X7 is N and the other is NR | o; and
Rj is hydrogen, Cj_galkyl, or C3.7cycloalkyl; provided that the compound is not: i) 2-[5-(2-methylpheny!)-2-propyl-1H-imidazol-4-yl]pyridine, if) 2-[2-(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1H-imidazol-4-yl]pyridine, ii) 2-[2~(1,1-dimethylethyl)-5-phenyl-1H-imidazol-4-yl]pyridine, iv) 2-[5-(3,5-dichlorophenyl)-2-methyl- 1 H-imidazol-4-yljpyridine, v) 2-[5-(3,5-dimethylphenyl)-2-methyl- 1H-imidazol-4-yl]pyridine, vi) 2-[5-(3,5-dimethylphenyl)-2-ethyl- 1H-imidazol-4-yl]pyridine, vii) 2-[5-(3,5-dimethylphenyi)-2-amino- 1 H-imidazol-4-yl]pyridine, : viii) 2-[5-(3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, ix) 2-[5-(3,5-dimethylphenyl)-2-propyl-1H-imidazol-4-yl]pyridine, or
X) 2-[5-(3,5-dimethylphenyl)-2-carboxamide-1H-imidazol-4-yl}pyridine.
As used herein, the double bond indicated by the dotted lines of formula (I), represent the possible tautomeric ring forms of the compounds falling within the scope of this mvention, the double bond being to the unsubstituted nitrogen.
In a preferred group of compounds R is optionally substituted naphthyl or phenyl.
Preferably R; is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, Cj.galkoxy, C}.galkylthio, and phenyl; more preferably Rj is phenyl optionally substituted with one or more substituents selected from the group consisting of halo,
Cji-galkoxy, Ci_galkylthio, and cyano; or Rj is phenyl or pyridyl (notably phenyl) fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently selected from N, O and S, and is optionally substituted by =O; for example R represents benzo[1,3]dioxolyl, 2,3-dihydrobenzo[ 1,4]dioxinyl, benzoxazolyl, benzothiazolyl, quinoxalinyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5}thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridyl, dihydrobenzofuranyl, benzo[1,4]oxazinyi-3-one or benzoxazolyl-2- one.
Preferably Ry is other than hydrogen. When R> is other than hydrogen it is preferably . positioned ortho to the nitrogen of the pyridyl ring.
Preferably R3 is C1. alkyl or (CH2)pNHCOR7 wherein Ry is Cj.7alkyl, or optionally 40 substituted aryl, heteroaryl, arylC1.galkyl or heteroarylCj_galkyl.
Preferably one of Xj and X3 is N and the other is NR, wherein Rj is hydrogen or Cj. galkyl.
R10 is preferably hydrogen. :
¢ A}
The compounds for use in the methods of the invention preferably have a molecular weight of less than 800, more preferably less than 600.
Specific compounds of the invention which may be mentioned include those described in the examples. ) 5 Suitable, pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, . diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably at least 10% of a compound of formula (I) or pharmaceutically = acceptable derivative thereof. : The terms "Cj _galkyl" and "Cy_7alkyl" as used herein whether on its own or as part of a larger group e.g. C1_galkoxy, means a straight or branched chain radical of 1to 6 and 1 to 7 carbon atoms respectively, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl and tert-butyl.
C1-6 haloalkyl groups may contain one or more halo atoms, a particular Cj.¢ haloalkyl group that may be mentioned in CF3.
The terms "halo" or "halogen" are used interchangeably herein to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
The term "C3_jcycloalkyl” as used herein means cyclic radicals of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl and cyclohexyl. . The term "aryl" as used herein means 5- to 14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not 40 limited to pheny! and naphthyl.
The term "ALKS inhibitor” as used herein means a compound, other than inhibitory smads, e.g. smadé6 and smad7, which selectively inhibits the ALKS5 receptor preferentially over p38 or type II receptors. r - 5 -
The term "ALKS mediated disease state" as used herein means any disease state which is mediated (or modulated) by ALKS, for example a disease which is modulated by the inhibition of the phosphorylation of smad 2/3 in the TGF-18 signaling pathway.
The term "ulcers" as used herein includes, but is not limited to, diabetic ulcers, chronic ’ 5 ulcers, gastric ulcers, and duodenal ulcers.
The compounds of formula (I) can be prepared by art-recognized procedures from known . or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
Specifically, compounds of formula (I) where one of X and X3 is NH may be prepared according to Scheme 1. The ketone may be oxidised to a diketone with HBr in DMSO. This diketone can then be condensed with a suitably substituted aldehyde or protected aldehyde derivative and ammonium acetate to give the imidazole according to the method outlined in WO 98/56788. Alternatively the ketone may be treated with sodium nitrite in HCI to afford an o—oximinoketone which can then be condensed with a suitably substituted aldehyde or protected aldehyde derivative and ammonium acetate to give the N-hydroxyimidazole. Treatment of this with triethylphosphite affords the imidazole according to the method outlined in US Pat. 3,656,644.
Schemel
Ri © R, 0] R, N
N nd HBr na R,CHO nal
LN TT = TT H 4 DMSO \ _N NH, OAC \ N
Re RS Rf
NY Ring?® Agen e
NOH
R;
Compounds of formula (I) where one of X} and X7 is NH may also be prepared according to
Scheme 2. A suitable bromide is coupled with trimethylsilylacetylene using palladium catalysis.
The trimethylsilyl group can be removed by treatment with potassium carbonate and the terminal ) acetylene coupled with 6-bromo-2-methylpyridine again using palladium catalysis. The acetylene may then be oxidised to the diketone using palladium chloride in DMSO. Formation of the - imidazole is then carried out with a suitable aldehyde as described in Scheme 1.
Scheme 2
R, 1) Pde, TMS—== oe
RiBr Sm ES 2) K,CO, ' Ros ZN
Ll xX Me ' PdCl,
DMSO
R, N Ry ©
Na ~ N R,CHO EN 0
YP NH,OAc Lyn
RY R
Non-selective alkylation of the imidazole nitrogen (using one of the procedures outlined in N. J. Liverton et al; J. Med. Chem., 1999, 42, 2180-2190) with a compound of formula L-R1¢ wherein L is a leaving group, e.g. halo, sulfonate or triflate, will yield both isomers of the compounds where Xj or Xp is NRjg in which Rj is other than hydrogen, the isomers can be separated by chromatographic methods (Scheme 3).
Scheme 3
R, N hi Vs, =~ N \ UN Rio
R;
R, N + [ >= 7 \ Je
VP ~* y Rs
Ry N =~
Re
Compounds of formula (I) where R3 is -CH;NHCOR?7 may be prepared according to . Scheme 4. The appropriate dione is condensed with (1,3-dioxo-1,3-dihydro-isomdol-2-yI)- acetaldehyde and ammonium acetate to form the imidazole. This product is treated with hydrazine to unmask the free amine which can then be coupled to an appropriate carboxylic acid using standard amide bond formation conditions.
Scheme 4
H O
R,~_.0 aves Ris N or | or M0
ANS 0) —_ a x N N ‘_N Ammonium acetate | _N 0
Hydrazine
Ri~_ _N Rine—N > R, R,CO,H Dam
NN N= BE ——— Hh N NH, =N HOBT =N
R{ Rr
During the synthesis of the compounds of formula (T) labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective
Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).
Further details for the preparation of compounds of formula (I) are found in the examples.
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (T) may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skiiled in the art. .
Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable salts thereof.
The invention further provides the use of a compound of formula (IT), but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by the ALKS5 receptor in mammals.
The invention further provides a method of treatment of a disease mediated by the ALK5 receptor in mammals, comprising administering to a mammal in need of such treatment, a ) therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.
ALKS-mediated disease states, include, but are not limited to, chronic renal disease, acute ) renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function,
Alzheimer's disease, trophic conditions, atherosclerosis, any disease wherein fibrosis is a major component, including, but not limited to peritoneal and sub-dermal adhesion, lung fibrosis and liver fibrosis, and restenosis. :
By the term "treating" is meant either prophylactic or therapeutic therapy.
The invention further provides a method of inhibiting the TGF-f signaling pathway in mammals, for example, inhibiting the phosphorylation of smad2 or smad3 by the type I or activin- like kinase ALKS receptor, which method comprises administering to 2 mammal in need of such : treatment, a therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.
The invention further provides the use of a compound of formula (I,) but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the TGF- signaling pathway in mammals.
The invention further provides a method of inhibiting matrix formation in mammals, for example, by inhibiting the phosphorylation of smad?2 or smad3 by the type I or activin-like kinase
ALKS receptor, which method comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.
The invention further provides the use of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting matrix formation in mammals.
The compounds of formula (I) and pharmaceutically acceptable salts thereof, may be administered in conventional dosage forms prepared by combining a compound of formula (I), but without provisos i) to x), with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I), but without provisos iv) to x), or a oo pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to } assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or 40 ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, } 5 talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well . known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of admmistration. . Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day. i. 40 It will be recognized by one of skill in the art that the optimal quantity and spacing of ) individual dosages of a compound of formula (I), but without provisos i) to x), will be determined - by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by
Claims (10)
1. A compound of formula (T) or a pharmaceutically acceptable salt thereof: . R, X, Dan R, . ~ % LN Rj ty) wherein Ry is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1.galkoxy, C1.galkylthio, C{_galkyl, Cj-ghaloalkyl, O-(CH2)mp-Ph, S-(CH2)m-Ph, cyano, phenyl. and CO2R, wherein R is hydrogen or Cj_galkyl and m is 0-3; or Rj is phenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently selected from N, O and S, and is optionally substituted by =O; Ry represents hydrogen, C;_galkyl. C;_galkoxy, phenyl. C;.ghaloalkyl, halo. NH3. NH- C1-6alkyl or NH(CHj)p-Ph wherein n is 0-3; R3 represents Cj_galkyl, -(CH2)p-CN, «(CH)p-COOH, -(CHp)p-CONHR4Rs3, ~(CH2)pCORy, -(CH2)q(ORé)2, (CH2)pOR4, -(CH2)q-CH=CH-CN, -(CH3)q-CH=CH-CO2H, -(CH2)p-CH=CH-CONHR4R3, -(CH2)pNHCOR7 or (CH2)pNRgR9, R4 and Rs are independently hydrogen or C_galkyl; Rg is Cj-galkyl; oo R7 is Cy.7alkyl, or optionally substituted aryl, heteroaryl, arylC_galkyl or heteroarylC1. alkyl; Rg and Rg are independently selected from hydrogen, C_galkyl, aryl and arylC;_galkyl; pis 0-4; qis 1-4; one of X and X3 is N and the other is NR; and R10 is hydrogen, C1_galkyl, or C3.7cycloalkyl; provided that the compound is not: i) 2-[5-(2-methylphenyi)-2-propyl-1H-imidazol-4-yl]pyridine, it) 2-[2+(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1 H-imidazol-4-yl]pyridine, iif) 2-[2<(1,1-dimethylethyl)-5-phenyl-1H-imidazol-4-yl]pyridine, iv) 2-[5-3,5-dichlorophenyl)-2-methyl- 1 H-imidazol-4-yl]pyridine, v) 2-[5+3,5-dimethylphenyl)-2-methyl- 1H-imidazol-4-yl]pyridine,
. vi) 2-[5~(3,5-dimethylphenyl)-2-ethyi- 1 H-imidazol-4-yl]pyridine, vii) 2-[5<3,5-dimethyliphenyl)-2-amino-1H-imidazol-4-yljpyridine, vili) 2-[5+3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, ix) 2-[5+(3,5-dimethylphenyl)-2-propyl-1H-imidazol-4-yl]pyridine, or x) 2-[5-(3,5-dimethylphenyi)-2-carboxamide- 1 H-imidazol-4-yl]pyridine.
2. A compound according to claim 1 wherein R; is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, Cj.galkoxy, C1_galkylthio, and cyano; or Ry is phenyl or pyridyl! fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently : selected from N, O and S, and is optionally substituted by =O.
3. A compound according to claim 1 or 2 wherein Ry is positioned ortho to the nitrogen of the pyridyl ring.
4. A compound according to any one of the preceding claims wherein R3 is C}_g alkyl or (CH2)pNHCOR?7 wherein R7 is Cj.7alkyl, or optionally substituted aryl, heteroaryl, arylCj. galkyl or heteroarylC1.galkyl.
5. A compound according to any one of the preceding claims wherein R1( is hydrogen.
6. A compound according to claim 1 as definede in any one of Examples | to 71. ora pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound according to any one of the preceding claims, but without provisos iv) to x), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
8. A method of inhibiting the TGF-B signaling pathway in mammals, comprising administering to 2 mammal, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 6, but without provisos 1) to x), or a pharmaceutically acceptable salt thereof.
9. A method for treating a disease selected from chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, and restenosis, comprising administering to 2a mammal in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 6, but without provisos i) to x), or a pharmaceutically acceptable salt thereof.
10. A method for inhibiting matrix formation in mammals, comprising administering to a mammal, a therapeutically effective amount of a compound according to any one of claims 1 to 6, . but without provisos i) to x), or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0004053A GB0004053D0 (en) | 2000-02-21 | 2000-02-21 | Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200206642B true ZA200206642B (en) | 2003-07-14 |
Family
ID=9886102
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200206642A ZA200206642B (en) | 2000-02-21 | 2002-08-20 | Pyridinylimidazoles. |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB0004053D0 (en) |
ZA (1) | ZA200206642B (en) |
-
2000
- 2000-02-21 GB GB0004053A patent/GB0004053D0/en not_active Ceased
-
2002
- 2002-08-20 ZA ZA200206642A patent/ZA200206642B/en unknown
Also Published As
Publication number | Publication date |
---|---|
GB0004053D0 (en) | 2000-04-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1169317B1 (en) | Triarylimidazoles | |
AU2001233918B2 (en) | Pyridinylimidazoles | |
JP4242651B2 (en) | Synthesis of 4-amino-thalidomide enantiomers | |
EP2099453B1 (en) | Combination therapy of substituted oxazolidinones | |
US20040039198A1 (en) | Compounds | |
US20040152738A1 (en) | Pyridyl-substituted triazoles as tgf inhibitors | |
JP2006526660A (en) | VR1 receptor modulators | |
JP6028306B2 (en) | Triheterocyclic derivatives, preparation methods and uses thereof | |
NO329158B1 (en) | Use of an integrin expression inhibitory compound for the preparation of an agent for the prevention, treatment or amelioration of specific diseases. | |
JP2003522733A (en) | Alkenyl and alkynyl compounds as factor Xa inhibitors | |
EP1423115A2 (en) | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs | |
AU2002323063A1 (en) | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs | |
JP2021152056A (en) | Mct4 inhibitors for treating disease | |
JP4217480B2 (en) | New compounds | |
JP2005518352A (en) | Phenyl-substituted triazoles and their use as selective inhibitors of ALK5 kinase | |
EA004735B1 (en) | Sulfonamides and derivatives thereof that modulate the activity of endothelin | |
CA3093138C (en) | Heteroaryl compounds as kinase inhibitor | |
US20040266842A1 (en) | Thiazolyl substituted triazoles as alk5 inhibitors | |
WO2002055077A1 (en) | Use of imidazolyl cyclic acetal derivatives in the manufacture of a medicament for the treatment of diseases mediated by the alk5 receptors | |
EP4225280A1 (en) | A sortilin antagonist for use in the prevention or treatment of hearing loss | |
CN113980001B (en) | Pyrazolol-pyridazinone coupling compound, pharmaceutical composition thereof and application of pyrazolol-pyridazinone coupling compound in medicines | |
ZA200206642B (en) | Pyridinylimidazoles. | |
TW201718548A (en) | Piperazine derivative | |
WO2002040467A1 (en) | Compounds | |
KR20040094464A (en) | Pyridinyl pyrazole derivatives |