NZ624022B2 - Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid - Google Patents
Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid Download PDFInfo
- Publication number
- NZ624022B2 NZ624022B2 NZ624022A NZ62402212A NZ624022B2 NZ 624022 B2 NZ624022 B2 NZ 624022B2 NZ 624022 A NZ624022 A NZ 624022A NZ 62402212 A NZ62402212 A NZ 62402212A NZ 624022 B2 NZ624022 B2 NZ 624022B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- acid
- salt
- phd
- hif
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 67
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 title claims abstract description 34
- FQKGMOOXMBVYKA-UHFFFAOYSA-N 1-(5,6-dichloro-1H-benzimidazol-2-yl)pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1C1=NC2=CC(Cl)=C(Cl)C=C2N1 FQKGMOOXMBVYKA-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 229940100615 Topical Ointment Drugs 0.000 claims abstract 3
- -1 dihydrate meglumine salt Chemical class 0.000 claims description 25
- 238000009472 formulation Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 150000004683 dihydrates Chemical class 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 61
- 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 61
- 201000010099 disease Diseases 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 15
- 230000001404 mediated Effects 0.000 abstract description 5
- 239000011780 sodium chloride Substances 0.000 description 49
- 230000002401 inhibitory effect Effects 0.000 description 46
- 150000003839 salts Chemical class 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000002253 acid Substances 0.000 description 26
- 210000004027 cells Anatomy 0.000 description 26
- 206010021143 Hypoxia Diseases 0.000 description 22
- 230000001146 hypoxic Effects 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 22
- 210000001519 tissues Anatomy 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- 210000000130 stem cell Anatomy 0.000 description 19
- 230000001965 increased Effects 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 208000007502 Anemia Diseases 0.000 description 17
- 239000000651 prodrug Substances 0.000 description 17
- 229940002612 prodrugs Drugs 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 229940079593 drugs Drugs 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 11
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 200000000019 wound Diseases 0.000 description 11
- 206010061255 Ischaemia Diseases 0.000 description 10
- 230000033115 angiogenesis Effects 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 230000000302 ischemic Effects 0.000 description 10
- 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 9
- 206010012601 Diabetes mellitus Diseases 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 239000001923 methylcellulose Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 8
- 230000035876 healing Effects 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 159000000001 potassium salts Chemical class 0.000 description 8
- 210000004369 Blood Anatomy 0.000 description 7
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 7
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000003384 small molecules Chemical class 0.000 description 7
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 6
- 102100014691 CXCL12 Human genes 0.000 description 6
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 6
- 102100019027 EGLN1 Human genes 0.000 description 6
- 101700036086 EGLN1 Proteins 0.000 description 6
- 101700003847 MSN1 Proteins 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 6
- 210000003491 Skin Anatomy 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 235000010981 methylcellulose Nutrition 0.000 description 6
- 235000020824 obesity Nutrition 0.000 description 6
- 210000000056 organs Anatomy 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- 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](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 210000000988 Bone and Bones Anatomy 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940044476 Poloxamer 407 Drugs 0.000 description 5
- 102220420181 RPS19BP1 K15M Human genes 0.000 description 5
- 229940032147 Starch Drugs 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 230000001419 dependent Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 229920001992 poloxamer 407 Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 230000001105 regulatory Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000001225 therapeutic Effects 0.000 description 5
- 230000000699 topical Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 210000004204 Blood Vessels Anatomy 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 102000003951 Erythropoietin Human genes 0.000 description 4
- 108090000394 Erythropoietin Proteins 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 206010022114 Injury Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 230000036740 Metabolism Effects 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 102100012897 PGF Human genes 0.000 description 4
- 101710014083 PGF Proteins 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 102100015249 VEGFA Human genes 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 201000009910 diseases by infectious agent Diseases 0.000 description 4
- 230000003511 endothelial Effects 0.000 description 4
- 229940105423 erythropoietin Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 102000018511 hepcidin family Human genes 0.000 description 4
- 108060003558 hepcidin family Proteins 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000035786 metabolism Effects 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- SUQYOUJCBGMSLV-UHFFFAOYSA-N 2,5,6-trichloro-1H-benzimidazole Chemical compound ClC1=C(Cl)C=C2NC(Cl)=NC2=C1 SUQYOUJCBGMSLV-UHFFFAOYSA-N 0.000 description 3
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 206010002383 Angina pectoris Diseases 0.000 description 3
- 102000009088 Angiopoietin-1 Human genes 0.000 description 3
- 108010048154 Angiopoietin-1 Proteins 0.000 description 3
- 210000004556 Brain Anatomy 0.000 description 3
- 206010007554 Cardiac failure Diseases 0.000 description 3
- 229960000958 Deferoxamine Drugs 0.000 description 3
- 210000004207 Dermis Anatomy 0.000 description 3
- 101700074107 EFH1 Proteins 0.000 description 3
- 102100009701 EGLN2 Human genes 0.000 description 3
- 101700051198 EGLN2 Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010019280 Heart failure Diseases 0.000 description 3
- 241000229754 Iva xanthiifolia Species 0.000 description 3
- 229960003194 Meglumine Drugs 0.000 description 3
- 208000008466 Metabolic Disease Diseases 0.000 description 3
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 3
- 208000003067 Myocardial Ischemia Diseases 0.000 description 3
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 3
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 3
- 229940083542 Sodium Drugs 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000002491 angiogenic Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 230000000051 modifying Effects 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 101700056794 phd1 Proteins 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000001023 pro-angiogenic Effects 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- HQBYAESCKCDTDJ-UHFFFAOYSA-N 5,6-dichloro-1,3-dihydrobenzimidazol-2-one Chemical compound ClC1=C(Cl)C=C2NC(O)=NC2=C1 HQBYAESCKCDTDJ-UHFFFAOYSA-N 0.000 description 2
- 102100007747 ANGPT2 Human genes 0.000 description 2
- 108010048036 Angiopoietin-2 Proteins 0.000 description 2
- 101710039834 BHLHE40 Proteins 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 102100002212 CXCR4 Human genes 0.000 description 2
- 101710003734 CXCR4 Proteins 0.000 description 2
- 229960003563 Calcium Carbonate Drugs 0.000 description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L Cobalt(II) chloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 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
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102100009704 EGLN3 Human genes 0.000 description 2
- 101700053907 EGLN3 Proteins 0.000 description 2
- 102100003042 HIF1A Human genes 0.000 description 2
- 101700000053 HIF1A Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- 102000020344 Insulin-Like Growth Factor Binding Proteins Human genes 0.000 description 2
- 108091022066 Insulin-Like Growth Factor Binding Proteins Proteins 0.000 description 2
- 210000003734 Kidney Anatomy 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N Lauric acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N Leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 208000010125 Myocardial Infarction Diseases 0.000 description 2
- 210000004165 Myocardium Anatomy 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 210000001331 Nose Anatomy 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N Palmitic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 210000002381 Plasma Anatomy 0.000 description 2
- 229960000502 Poloxamer Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010038444 Renal failure chronic Diseases 0.000 description 2
- 208000007056 Sickle Cell Anemia Diseases 0.000 description 2
- 229960004274 Stearic acid Drugs 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 229960005137 Succinic Acid Drugs 0.000 description 2
- 206010043391 Thalassaemia beta Diseases 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N Trappsol Cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium 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 2
- 229940035504 Tromethamine Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000027746 artery morphogenesis Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 201000000522 chronic kidney disease Diseases 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 201000008739 coronary artery disease Diseases 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000034659 glycolysis Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229940098895 maleic acid Drugs 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000002669 organ and tissue protective Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 210000001539 phagocyte Anatomy 0.000 description 2
- 230000000090 phagocyte Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002633 protecting Effects 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000002336 sorption--desorption measurement Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 201000006704 ulcerative colitis Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (E)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1H-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-M 2,3-dinitrobenzoate Chemical class [O-]C(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-M 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-M 2-(dimethylamino)acetate Chemical class CN(C)CC([O-])=O FFDGPVCHZBVARC-UHFFFAOYSA-M 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-M 2-chlorobenzoate Chemical class [O-]C(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-M 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 1
- IWFHBRFJOHTIPU-UHFFFAOYSA-N 4,5-dichlorobenzene-1,2-diamine Chemical compound NC1=CC(Cl)=C(Cl)C=C1N IWFHBRFJOHTIPU-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical class OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 1
- GHTBLRRXEUHKTI-UHFFFAOYSA-N 6-oxo-1H-pyrimidine-2-carboxamide Chemical class NC(=O)C1=NC=CC(O)=N1 GHTBLRRXEUHKTI-UHFFFAOYSA-N 0.000 description 1
- 102100010854 ADM Human genes 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- 102100001080 APOA4 Human genes 0.000 description 1
- 210000000579 Abdominal Fat Anatomy 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- ULCUCJFASIJEOE-NPECTJMMSA-N Adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 description 1
- 108090000953 Adrenomedullin Proteins 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 229940063655 Aluminum stearate Drugs 0.000 description 1
- 208000009094 Anemia, Hemolytic, Autoimmune Diseases 0.000 description 1
- 208000008231 Anemia, Refractory, with Excess of Blasts Diseases 0.000 description 1
- 206010002967 Aplastic anaemia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 210000001367 Arteries Anatomy 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000000601 Blood Cells Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 210000001217 Buttocks Anatomy 0.000 description 1
- 101700029237 CENPX Proteins 0.000 description 1
- QGGBSTHOOFGSPQ-UHFFFAOYSA-N CN(S(=O)(=O)C1(N=C2C(=N1)C=C(C(=C2)Cl)Cl)Cl)C Chemical compound CN(S(=O)(=O)C1(N=C2C(=N1)C=C(C(=C2)Cl)Cl)Cl)C QGGBSTHOOFGSPQ-UHFFFAOYSA-N 0.000 description 1
- 102100006077 CP Human genes 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- POIUWJQBRNEFGX-XAMSXPGMSA-N Cathelicidin Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C1=CC=CC=C1 POIUWJQBRNEFGX-XAMSXPGMSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108010075016 Ceruloplasmin Proteins 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
- 229960001231 Choline Drugs 0.000 description 1
- 210000001612 Chondrocytes Anatomy 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 206010053138 Congenital aplastic anaemia Diseases 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- 206010011703 Cyanosis Diseases 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N Cyclamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-Galacturonic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102100001224 DELEC1 Human genes 0.000 description 1
- 101710011667 DELEC1 Proteins 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Chemical class CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 201000004449 Diamond-Blackfan anemia Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 208000002173 Dizziness Diseases 0.000 description 1
- 208000000718 Duodenal Ulcer Diseases 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 229940012017 Ethylenediamine Drugs 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- 210000001508 Eye Anatomy 0.000 description 1
- 206010016256 Fatigue Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000004811 Felty's syndrome Diseases 0.000 description 1
- 208000001034 Frostbite Diseases 0.000 description 1
- 229960002598 Fumaric acid Drugs 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 229940097043 Glucuronic Acid Drugs 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 229940074045 Glyceryl Distearate Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018651 Graft versus host disease Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 229940093912 Gynecological Sulfonamides Drugs 0.000 description 1
- 101700039936 HMOX1 Proteins 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N Hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229960002591 Hydroxyproline Drugs 0.000 description 1
- 241000282619 Hylobates lar Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 210000000936 Intestines Anatomy 0.000 description 1
- 210000001596 Intra-Abdominal Fat Anatomy 0.000 description 1
- 229940045996 Isethionic Acid Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N Isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 210000002510 Keratinocytes Anatomy 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229960000448 Lactic acid Drugs 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 229910013596 LiOH—H2O Inorganic materials 0.000 description 1
- 241000735235 Ligustrum vulgare Species 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 206010025482 Malaise Diseases 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 210000003470 Mitochondria Anatomy 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 210000002200 Mouth Mucosa Anatomy 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 206010028537 Myelofibrosis Diseases 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N N,N-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 108010049175 N-substituted Glycines Proteins 0.000 description 1
- 101700031271 NAA25 Proteins 0.000 description 1
- 101710045273 NANOS2 Proteins 0.000 description 1
- 101700049309 NOS2 Proteins 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 102000007399 Nuclear hormone receptors Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptors Proteins 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-M O-methylsalicylate Chemical class COC1=CC=CC=C1C([O-])=O ILUJQPXNXACGAN-UHFFFAOYSA-M 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 102100006798 P4HTM Human genes 0.000 description 1
- 101700020543 P4HTM Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 206010033546 Pallor Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 208000000733 Paroxysmal Hemoglobinuria Diseases 0.000 description 1
- 229940049954 Penicillin Drugs 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034636 Peripheral vascular disease Diseases 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 230000036823 Plasma Levels Effects 0.000 description 1
- 208000009901 Polycystic Kidney Disease Diseases 0.000 description 1
- 208000008601 Polycythemia Diseases 0.000 description 1
- 229940068918 Polyethylene Glycol 400 Drugs 0.000 description 1
- 229960003975 Potassium Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229940095574 Propionic acid Drugs 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
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 229940107700 Pyruvic Acid Drugs 0.000 description 1
- 102100018787 RPS19 Human genes 0.000 description 1
- 101710007829 RPS19 Proteins 0.000 description 1
- 208000003782 Raynaud Disease Diseases 0.000 description 1
- 206010037912 Raynaud's phenomenon Diseases 0.000 description 1
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 1
- 101700061430 SAT19 Proteins 0.000 description 1
- 101700071021 SETD2 Proteins 0.000 description 1
- 102100000940 SETD2 Human genes 0.000 description 1
- 210000003296 Saliva Anatomy 0.000 description 1
- 208000005682 Shwachman syndrome Diseases 0.000 description 1
- 201000004283 Shwachman-Diamond syndrome Diseases 0.000 description 1
- 206010040661 Sideroblastic anaemia Diseases 0.000 description 1
- CXQXSVUQTKDNFP-UHFFFAOYSA-N Simethicone Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 108020004459 Small Interfering RNA Proteins 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940091252 Sodium supplements Drugs 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 102100008904 TFRC Human genes 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- 101700081234 TTR Proteins 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 206010068760 Ulcers Diseases 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 159000000021 acetate salts Chemical group 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 230000003044 adaptive Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000010210 aluminium Nutrition 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
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 108010073614 apolipoprotein A-IV Proteins 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 235000020127 ayran Nutrition 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical class OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000024881 catalytic activity Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 230000018747 cellular response to hypoxia Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- CRBHXDCYXIISFC-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000003750 conditioning Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001086 cytosolic Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical class OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N dodecane-1-sulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- MSPOSRHJXMILNK-UHFFFAOYSA-N ethyl 1H-pyrazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=NN1 MSPOSRHJXMILNK-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 201000001066 hemolytic-uremic syndrome Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical class CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-L hex-2-ynedioate Chemical class [O-]C(=O)CCC#CC([O-])=O KKLGDUSGQMHBPB-UHFFFAOYSA-L 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000000640 hydroxylating Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 101700024280 ine Proteins 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 230000002530 ischemic preconditioning Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical class CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 239000010807 litter Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000394 mitotic Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical class C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000000422 nocturnal Effects 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000008008 oral excipient Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical class OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004078 physical exercise Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000026341 positive regulation of angiogenesis Effects 0.000 description 1
- 230000019260 positive regulation of glycolysis Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001235 proline group Chemical group [H]N1[C@@](C(=O)[*])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical class CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical class [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000005229 pyrazolopyridines Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229910052904 quartz Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000020874 response to hypoxia Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical class OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical class [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 230000001743 silencing Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RHLFTMGPBSLHRS-UHFFFAOYSA-M sodium;2-phenylbutanoate Chemical class [Na+].CCC(C([O-])=O)C1=CC=CC=C1 RHLFTMGPBSLHRS-UHFFFAOYSA-M 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008229 sterile water for irrigation Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical class [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementation Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 200000000020 tissue injury Diseases 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 238000004642 transportation engineering Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 201000011528 vascular disease Diseases 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- 101700060864 ybgC Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Provided is a meglumine salt of 1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid (compound (1)) and formulations thereof, such as a topical ointment. The compound may be used in the treatment of diseases and conditions mediated by prolyl hydroxylase activity.
Description
PRD3240WOPCT
MEGLUMINE SALT FORMULATIONS OF 1-(5,6-DICHLORO-1HBENZO
[D]IMIDAZOLYL)-1H-PYRAZOLECARBOXYLIC ACID
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of US provisional patent application serial
number 61/551,395, filed on October 25, 2011.
FIELD OF THE INVENTION
The present invention is directed to the meglumine salt of 1-(5,6-dichloro-1H-
benzo[d]imidazolyl)-1H-pyrazolecarboxylic acid and d methods of
manufacture.
OUND
A family of highly conserved oxygen, iron, and 2-oxoglutarate-dependent
prolyl hydroxylase (PHD) enzymes mediate the cells response to hypoxia via post-
translational modification of hypoxia-inducible factors (HIF) (Ivan et al., 2001,
Science, 292:464-68; la et al., 2001, Science, 292:468-72). Under normoxic
conditions, PHD catalyzes the hydroxylation of two conserved proline residues within
HIF. As the affinity of PHD for oxygen is within the physiological range of oxygen
and oxygen is a ary co-factor for modifying hydroxylated HIF, PHD is
inactivated when oxygen tension is reduced. In this way, HIF is y degraded
under normoxic conditions but accumulates in cells under hypoxic conditions or
when PHD is inhibited.
Four isotypes of PHD have been described: PHD1, PHD2, PHD3, and PHD4
(Epstein et al., 2001, Cell, 107:43-54; Kaelin, 2005, Annu Rev Biochem., 74:115-28;
Schmid et al., 2004, J Cell Mol Med., 8:423-31). The different es are
ubiquitously expressed but are differentially regulated and have ct physiological
roles in the cellular response to hypoxia. There is evidence that the various isotypes
have different selectivity for the three ent HIF-α sub-types (Epstein et al.,
supra). In terms of cellular localization, PHD1 is prim arily nuclear, PHD2 is primarily
asmic, and PHD3 appears to be both cytoplasmic and nuclear (Metzen E, et al.
0WOPCT
2003, J Cell Sci., 116(7):1319–26). PHD2 appears to be the inant HIF-α
prolyl hydroxylase under normoxic conditions (Ivan et al., 2002. Proc Natl Acad Sci.
USA, 99(21):13459–64; Berra et al., 2003, EMBO J., 2–90). The three
isotypes have a high degree of amino-acid homology and the active site of the
enzyme is highly conserved.
Targeted disruption of the PHD enzyme activity by small molecules has
potential utility in the treatment of disorders of oxygen sensing and distribution.
Examples include but are not limited to: anemia; sickle cell anemia; peripheral
vascular disease; coronary artery disease; heart failure; protection of tissue from
ischemia in ions such as myocardial ischemia, myocardial infarction and
stroke; preservation of organs for transplant; treatment of tissue ischemia by
regulating and/or restoring blood flow, oxygen delivery and/or energy ation;
acceleration of wound healing particularly in diabetic and aged ts; treatment of
burns; treatment of infection; bone healing, and bone . In addition, targeted
disruption of PHD is expected to have utility in ng metabolic disorders such as
diabetes, obesity, ulcerative colitis, inflammatory bowel disease and related
disorders such as Crohn’s disease. (Recent Patents on Inflammation & Allergy Drug
Discovery, 2009, 3:1-16).
HIF has been shown to be the primary transcriptional factor that leads to
increased erythropoietin tion under ions of hypoxia (Wang et al., 1993,
supra). While treatment with recombinant human erythrop oietin has been
trated to be an effective method of treating anemia, small molecule mediated
PHD inhibition can be expected to offer advantages over treatment with
opoietin. Specifically, the function of other HIF gene products is necessary for
hematopoesis and regulation of these factors increases the efficiency of
hematopoesis. Examples of HIF target gene products that are critical for
hematopoesis include: transferrin (Rolfs et al., 1997, J Biol Chem., 272(32):20055-
62), transferrin receptor (Lok et al., 1999, J Biol Chem., 274(34):24147-52; Tacchini
et al., 1999, J Biol Chem., 274(34):24142-46) and ceruloplasmin (Mukhopadhyay et
al., 2000, J Biol Chem., 275(28):21048-54). Hepcidin expression is also suppressed
PRD3240WOPCT
by HIF (Peyssonnaux et al., 2007, J Clin Invest., 117(7):1926-32) and small
molecule inhibitors of PHD have been shown to reduce hepcidin tion (Braliou
et al., 2008, J Hepatol., 48:801-10). Hepcidin is a negative regulator of the
availability of the iron that is necessary for hematopoesis, so a ion in hepcidin
production is expected to be beneficial to the treatment of anemia. PHD inhibition
may also be useful when used in conjunction with other treatments for anemia
including iron supplementation and/or exogenous erythropoietin. Studies of
mutations in the PHD2 gene occurring naturally in the human population provide
further evidence for the use of PHD inhibitors to treat anemia. Two recent reports
have shown that patients with dysfunctional mutations in the PHD2 gene display
increased erythrocytosis and ed blood obin (Percy et al., 2007, PNAS,
103(3):654-59; Al-Sheikh et al., 2008, Blood Cells Mol Dis., -65). In addition,
a small molecule PHD inhibitor has been evaluated in healthy volunteers and
patients with chronic kidney disease (U.S. Pat. App. No. /0276477,
December 7, 2006). Plasma erythropoietin was increased in a dose-dependent
fashion and blood hemoglobin concentrations were increased in the chronic kidney
disease patients.
Overall accumulation of HIF under hypoxic ions governs an adaptive
up-regulation of glycolysis, a reduction in oxidative phosphorylation resulting in a
reduction in the production of hydrogen peroxide and superoxide, optimization of
ive phosphorylation protecting cells against ischemic damage. Thus, PHD
inhibitors are expected to be useful in organ and tissue transplant preservation
(Bernhardt et al., 2007, Methods Enzymol., 435:221-45). While benefit may be
achieved by administering PHD inhibitors before harvesting organs for lant,
administration of an inhibitor to the organ/tissue after harvest, either in storage (e.g.,
cardioplegia solution) or post-transplant, may also be of eutic benefit.
PHD tors are expected to be effective in preserving tissue from al
ischemia and/or hypoxia. This includes ischemia/hypoxia associated with inter alia:
angina, myocardial ischemia, stroke, ischemia of skeletal muscle. ly,
ischemic pre-conditioning has been demonstrated to be a HIF-dependent
PRD3240WOPCT
phenomenon (Cai et al., 2008, vasc Res., 77(3):463-70). While the concept of
pre-conditioning is best known for its protective effects in the heart, it also applies to
other tissues including but not limited to: liver, skeletal , liver, lung, kidney,
intestine and brain (Pasupathy et al., 2005, Eur J Vasc sc Surg., 29:106-15;
Mallick et al., 2004, Dig Dis Sci., 49(9):1359-77). Experimental evidence for the
tissue tive effects of PHD inhibition and elevation of HIF have been obtained in
a number of animal models including: germ-line knock out of PHD1 which conferred
protection of the skeletal muscle from ischemic insult (Aragonés et al., 2008, Nat
Genet., 40(2):170-80), silencing of PHD2 through the use of siRNA which protected
the heart from ischemic insult (Natarajan et al., 2006, Circ Res., 98(1):133-40),
inhibition of PHD by administering carbon monoxide which protected the
myocardium from ic injury (Chin et al., 2007, Proc Natl Acad Sci. U.S.A.,
104(12):5109-14), a in the brain which increased the tolerance to ischemia
(Bernaudin et al., 2002, J Cereb Blood Flow Metab., 22(4):393-403). In addition,
small molecule inhibitors of PHD t the brain in experimental stroke models
(Siddiq et al., 2005, J Biol Chem., ):41732-43). Moreover, HIF up-regulation
has also been shown to protect the heart of diabetic mice, where outcomes are
generally worse (Natarajan et al., 2008, J Cardiovasc Pharmacol., 51(2):178-187).
The tissue protective effects may also be observed in Buerger's disease, Raynaud's
disease, and acrocyanosis.
The reduced ce on aerobic metabolism via the Kreb’s cycle in the
mitochondria and an increased reliance on anaerobic glycolysis produced by PHD
inhibition may have beneficial effects in normoxic tissues. It is important to note that
PHD inhibition has also been shown to e HIF under normoxic conditions.
Thus, PHD inhibition produces a hypoxia associated with the hypoxic
response being initiated through HIF but with tissue oxygenation remaining normal.
The alteration of metabolism produced by PHD inhibition can also be expected to
provide a treatment paradigm for diabetes, obesity and related disorders, including
co-morbidities.
PRD3240WOPCT
Globally, the collection of gene expression changes produced by PHD
inhibition reduce the amount of energy generated per unit of glucose and will
ate the body to burn more fat to maintain energy balance. The mechanisms
for the increase in ysis are discussed above. Other observations link the
hypoxic response to effects that are expected to be beneficial for the treatment of
diabetes and obesity. Hypoxia and hypoxia mimetics such as desferrioxamine have
been shown to prevent adipocyte differentiation (Lin et al., 2006, J Biol Chem.,
281(41):30678-83; re et al., 2004, J Biol Chem., 279(39):40462-69). Inhibition
of PHD activity during the initial stages of adipogenesis inhibits the formation of new
adipocytes (Floyd et al., 2007, J Cell Biochem., 101:1545-57). Hypoxia, cobalt
chloride and desferrioxamine elevated HIF and inhibited PPAR gamma 2 nuclear
hormone receptor transcription (Yun et al., 2002, Dev Cell., 2:331-41). As PPAR
gamma 2 is an important signal for adipocyte differentiation, PHD inhibition can be
expected to inhibit adipocyte differentiation. These effects were shown to be
mediated by the HIF-regulated gene DEC1/Stra13 (Yun et al., supra).
Small molecular inhibitors of PHD have been demonstrated to have beneficial
effects in animal models of diabetes and obesity (Intl. Pat. App. Pub. No.
WO2004/052284, June 24, 2004; WO2004/052285, June 24, 2004). Among the
effects demonstrated for PHD inhibitors in mouse diet-induced obesity, db/db mouse
and Zucker fa/fa rat models were ng of: blood glucose tration, fat mass
in both abdominal and visceral fat pads, hemoglobin A1c, plasma triglycerides, body
weight as well as changes in established disease bio-markers such as increases in
the levels of adrenomedullin and leptin. Leptin is a known HIF target gene t
(Grosfeld et al., 2002, J Biol Chem., 277(45):42953-57). Gene products involved in
the metabolism in fat cells were demonstrated to be regulated by PHD inhibition in a
HIF-dependent fashion (Intl. Pat. App. Pub. No. WO2004/052285, supra). These
e apolipoprotein A-IV, acyl CoA thioesterase, ine acetyl transferase, and
insulin-like growth factor binding protein (IGFBP)-1.
PHD tors are expected to be therapeutically useful as stimulants of
ogenesis, angiogenesis, and arteriogenesis. These processes establish or
PRD3240WOPCT
restore blood flow and oxygenation to the tissues under ischemia and/or hypoxia
conditions (Semenza et al., 2007, J Cell Biochem., 102:840-47; Semenza, 2007, Exp
Physiol., 92(6):988-91). It has been shown that physical exercise increases HIF-1
and ar endothelial growth factor in experimental animal models and in humans
(Gustafsson et al. 2001, Front Biosci., 6:D75-89) and consequently the number of
blood vessels in skeletal . VEGF is a nown HIF target gene t
that is a key driver of angiogenesis (Liu et al., supra). PHD inhibition offers a
potential advantage over other angiogenic therapies in that it stimulates a controlled
sion of multiple angiogenic growth factors in a HIF-dependent fashion
including but not limited to: placental growth factor (PLGF), angiopoietin-1
(ANGPT1), angiopoietin-2 (ANGPT2), platelet-derived growth factor beta (PDGFB)
(Carmeliet, 2004, J Intern Med., 8-61; Kelly et al., 2003, Circ Res., 93:1074-
81) and stromal cell derived factor 1 (SDF-1) (Ceradini et al., 2004, Nat Med.,
(8):858-64). Expression of angiopoietin-1 during angiogenesis produces leakageresistant
blood vessels, in contrast to the s produced by administration of
VEGF alone (Thurston et al., 1999, Science, 286:2511-14; Thurston et al., 2000, Nat
Med., 6(4):460-3; Elson et al., 2001, Genes Dev., 15(19):2520-32). Stromal cell
derived factor 1 (SDF-1) has been shown to be critical to the process of recruiting
elial progenitor cells to the sites of tissue injury. SDF-1 expression increased
the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to
ischemic tissue. Furthermore tion of SDF-1 in ischemic tissue or de of
CXCR4 on circulating cells ts progenitor cell recruitment to sites of injury
(Ceradini et al., 2004, supra; Ceradini et al., 2005, Trends Cardiovasc Med.,
(2):57-63). Importantly, the tment of endothelial progenitor cells to sites of
injury is reduced in aged mice and this is corrected by interventions that increase
HIF at the wound site (Chang et al., 2007, Circulation, 116(24):2818-29). PHD
inhibition offers the advantage not only of increasing the expression of a number of
angiogenic factions but also a co-ordination in their expression throughout the
angiogenesis process and tment of endothelial progenitor cells to ischemic
tissue.
PRD3240WOPCT
PHD inhibitors are useful in pro-angiogenic therapies, too. Adenovirusmediated
over-expression of HIF has been demonstrated to induce enesis in
non-ischemic tissue of an adult animal (Kelly et al., 2003, Circ Res., 93(11):1074-81)
providing evidence that therapies that elevate HIF, such as PHD inhibition, will
induce angiogenesis. Placental growth factor (PLGF), also a HIF target gene, has
been show to play a critical role in angiogenesis in ischemic tissue (Carmeliet, 2004,
J Intern Med., 255(5):538-61; Luttun et al., 2002, Ann N Y Acad Sci., 979:80-93).
The potent giogenic s of ies that elevate HIF have been
demonstrated, via HIF over-expression, in skeletal muscle (Pajusola et al., 2005,
FASEB J., 19(10):1365-7; Vincent et al., 2000, Circulation, 102:2255-61) and in the
myocardium (Shyu et al., 2002, Cardiovasc Res., 54:576-83). The recruitment of
endothelial progenitor cells to the ischemic dium by the HIF target gene SDF-
1 has also been demonstrated (Abbott et al., 2004, Circulation, 110(21):3300-05).
Thus, PHD inhibitors will likely be effective in ating angiogenesis in the setting
of tissue ischemia, particularly muscle ischemia. Therapeutic angiogenesis
produced by PHD inhibitors will likely lead to restoring blood flow to tissues and
therefore meliorate such diseases as but not limited to angina is, myocardial
ischemia and infarction, peripheral ischemic disease, claudication, gastric and
duodenal ulcers, ulcerative colitis, and matory bowel e.
PHD and HIF play a central role in tissue repair and regeneration including
healing of wounds and ulcers. Recent studies have demonstrated that an increased
sion of all three PHDs at wound sites in aged mice with a resulting reduction
in HIF accumulation (Chang et al., supra). Thus, elevation of HIF in aged mice by
administering desferrioxamine increased the degree of wound healing back to levels
observed in young mice. Similarly, in a diabetic mouse model, HIF elevation was
suppressed compared to non-diabetic litter mates (Mace et al., 2007, Wound Repair
Regen., 15(5):636-45). l administration of cobalt chloride, a hypoxia mimetic,
or over-expression of a murine HIF that lacks the oxygen-dependent degradation
domain and thus provides for a constitutively active form of HIF, resulted in
increased HIF at the wound site, increased expression of HIF target genes such as
VEGF, Nos2, and Hmox1 and accelerated wound healing. The beneficial effect of
PRD3240WOPCT
PHD inhibition is not restricted to the skin and small molecule inhibitors of PHD have
recently been trated to provide benefit in a mouse model of s (Robinson
et al., 2008, Gastroenterology, 134(1):145-55).
In summary, PHD inhibition resulting in accumulation of HIF likely acts by at
least four isms to contribute to accelerated and more complete healing of
wounds: 1) protection of tissue jeopardized by hypoxia and/or ischemia, 2)
stimulation of angiogenesis to establish or restore appropriate blood flow to the site,
3) recruitment of endothelial progenitor cells to wound sites, 4) stimulation of the
release of growth factors that specifically stimulate healing and regeneration.
As PDGF is a HIF gene target (Schultz et al., 2006, Am J Physiol Heart Circ
Physiol., 290(6):H2528-34; Yoshida et al., 2006, J Neurooncol., 76(1):13-21), PHD
inhibition likely increases the expression of endogenous PDGF and produces a
similar or more cial effect to those produced with PDGF alone. Studies in
animals have shown that topical application of PDGF results in increased wound
DNA, protein, and hydroxyproline amounts; formation of thicker granulation and
epidermal tissue; and increased cellular repopulation of wound sites. PDGF exerts a
local effect on enhancing the ion of new connective . The effectiveness
of PHD inhibition is likely greater than that produced by PDGF due to the additional
tissue protective and pro-angiogenic effects mediated by HIF.
The beneficial effects of inhibition of PHD extends not only to accelerated
wound g in the skin and colon but also to the healing of other tissue damage
including but not limited to gastrointestinal , skin graft ements, burns,
c wounds and frost bite.
Stem cells and progenitor cells are found in hypoxic niches within the body
and hypoxia regulates their differentiation and cell fate (Simon et al., 2008, Nat Rev
Mol Cell Biol., 9:285-96). Thus, PHD inhibitors may be useful to maintain stem cells
and progenitor cells in a pluripotent state and to drive differentiation to desired cell
types. Stem cells may be useful in culturing and expanding stem cell populations
PRD3240WOPCT
and may hold cells in a pluripotent state while hormones and other factors are
administered to the cells to nce the entiation and cell fate.
A further use of PHD inhibitors in the area of stem cell and progenitor cell
therapeutics relates to the use of PHD inhibitors to condition these cells to withstand
the process of implantation into the body and to generate an appropriate response to
the body to make the stem cell and progenitor cell implantation viable (Hu et al.,
2008, J Thorac Cardiovasc Surg., 135(4):799-808). More specifically PHD inhibitors
may facilitate the integration of stem cells and draw in an appropriate blood supply to
sustain the stem cells once they are ated. This blood vessel formation will also
on to carry hormones and other factors released from these cells to the rest of
the body.
PHD inhibitors may also be useful in the treatment of infection (Peyssonnaux
et al., 2005, J Invest Dermatol., 115(7):1806-15; Peyssonnaux et al., 2008 J Invest
Dermatol., 2008 Aug;128(8):1964-8). HIF elevation has been demonstrated to
increase the innate immune response to infection in phagocytes and in
keratinocytes. Phagocytes in which HIF is elevated show increased bacteriacidal
activity, increased nitric oxide production and increased expressed of the antibacterial
peptide cathelicidin. These effects may also be useful in treating infection
from burns.
HIF has also been shown to be involved in bone growth and healing (Pfander
D et al., 2003 J Cell Sci., 116(Pt 9):1819-26., Wang et al., 2007 J Clin .,
17(6):1616-26.) and may therefore be used to heal or prevent fractures. HIF
stimulates of glycolysis to provide energy to allow the synthesis of extracellular
matrix of the epiphyseal chondrocytes under a hypoxic environment. HIF also plays
a role in driving the release of VEGF and angiogenesis in bone healing process.
The growth of blood vessels into growing or healing bone can be the rate ng
step in the process.
PRD3240WOPCT
Small molecules inhibitors of PHD have been bed in the ture,
which include, but are not limited to, imidazo[1,2-a]pyridine derivatives (Warshakoon
et al., 2006, Bioorg Med Chem Lett., 16(21):5598-601), substituted pyridine
derivatives (Warshakoon et al., 2006, Bioorg Med Chem Lett., 16(21):5616-20),
pyrazolopyridines (Warshakoon et al., 2006, Bioorg Med Chem Lett., 16(21):5687-
90), bicyclic heteroaromatic N-substituted glycine tives (Intl. Pat. App. Pub. No.
WO2007/103905, September 13, 2007), ine based compounds (Intl. Pat. App.
Pub. No. WO2007/070359, June 21, 2007), pyrimidinetrione tituted glycine
derivatives (Intl. Pat. App. Pub. No. WO2007/150011, December 27, 2007),
substituted aryl or heteroaryl amide compounds (U.S. Pat. App. Pub. No. US
2007/0299086, December 27, 2007) and substituted 4-hydroxypyrimidine
carboxamides (Intl. Pat. App. Pub. No. WO2009/117269, September 24, 2009).
SUMMARY OF THE INVENTION
The invention is directed to the general and preferred embodiments defined, as
set forth herein. red and exemplary features of the invention will be apparent
from the detailed description below and with reference to the drawing figures.
In its many embodiments, the t invention relates to a novel salt of an
inhibitor of prolyl hydroxylase (PHD) enzymes. A method of treatment, prevention,
inhibition or amelioration of one or more diseases disorders ated with PHD
enzymes is also described herein.
More particularly, the present invention relates to the meglumine salt of a
compound of the following formula:
and related methods of preparation or manufacture of the compound.
PRD3240WOPCT
In another embodiment, the present invention relates to the hydrated form of
the meglumine salt of compound (1).
In a particular embodiment, the invention relates to the compound (I) in the
form of the dihydrate ine salt.
Additional embodiments and advantages of the invention will become apparent
from the detailed discussion, schemes, es, and claims below.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the pH-dependency of saturation of compound (1) in on.
Figure 2 shows PXRD data of the ine salt of compound (1).
Figure 3 shows DSC, TGA and x-ray data of the meglumine salt of compound
(1).
Figure 4 shows: (A) the single crystal structure of the meglumine salt of
compound (1); and (B) the experimental and stimulated powder pattern of a single
crystal for the meglumine salt of compound (1).
Figure 5 shows the percentage stimulation of HIF1-α upon exposure of
formulations of the meglumine salt of compound (1).
Figure 6 shows plasma levels (systemic burden) in wounded mice after topical
application of formulations of the meglumine salt of compound (1).
Figure 7 shows the correlation of the flux of compound (1) across skin (human
dermis) and an artificial membrane using a Franz ion cell upon application of a
ation of meglumine salt of compound (1).
PRD3240WOPCT
Figure 8 shows no to very low irritation caused by application of a formulation
of the meglumine salt of nd (1) as tested in a HET-CAM assay.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a novel salt of a compound of the ing formula:
that is a inhibitor of prolyl hydroxylase (PHD) s, and compositions thereof for
the treatment, amelioration or inhibition of disorders and diseases related to the
modulation of a prolyl hydroxylase enzyme. Also bed herein are methods of
making such a compound, pharmaceutical compositions, pharmaceutically
acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active
metabolites thereof.
A) Terms
The present invention is best understood by reference to the following
definitions, the drawings and exemplary disclosure ed herein.
The terms “comprising”, ining”, and “including,” are used herein in
their open, non-limiting sense.
“Administering” or “administration” means ing a drug to a patient in a
manner that is pharmacologically useful.
“Composition” means a product containing a compound of the present
invention (such as a product comprising the specified ingredients in the specified
amounts, as well as any product which s, directly or indirectly, from such
combinations of the specified ingredients in the specified amounts).
PRD3240WOPCT
“Compound” or “drug” means a compound of Formula (1) or
ceutically acceptable forms thereof.
“Forms” means various s and mixtures of one or more compounds of
Formula (1) and salts or hydrates thereof. The term “isomer” refers to compounds
that have the same composition and lar weight but differ in physical and/or
chemical properties. Such substances have the same number and kind of atoms but
differ in structure. The structural ence may be in constitution (geometric
isomers) or in an ability to rotate the plane of polarized light (stereoisomers). The
term “stereoisomer” refers to isomers of identical constitution that differ in the
arrangement of their atoms in space. Enantiomers and diastereomers are
stereoisomers wherein an asymmetrically tuted carbon atom acts as a chiral
center. The term “chiral” refers to a molecule that is not superposable on its mirror
image, implying the absence of an axis and a plane or center of symmetry.
The term "hypoxia" or "hypoxic disorder" refers to a condition where there is
an insufficient level of oxygen provided in the blood or to tissues and organs.
Hypoxic disorders can occur through a variety of mechanisms including where there
is an icient capacity of the blood to carry oxygen (i.e. anemia), where there is
an uate flow of blood to the tissue and/or organ caused by either heart failure
or blockage of blood s and/or arteries (i.e. ia), where there is reduced
barometric pressure (i.e. elevation sickness at high altitudes), or where dysfunctional
cells are unable to properly make use of oxygen (i.e. hystotoxic conditions).
Accordingly, one of skill in the art would readily appreciate the present invention to
be useful in the treatment of a variety of hypoxic conditions including anemia, heart
failure, coronary artery disease, oembolism, stroke, angina and the like.
“Patient” or “subject” means an animal, preferably a mammal, more
preferably a human, in need of therapeutic intervention.
“Pharmaceutically acceptable” means molecular entities and compositions
that are of sufficient purity and quality for use in the formulation of a composition or
PRD3240WOPCT
medicament of the present ion. Since both human use (clinical and over-thecounter
) and veterinary use are equally included within the scope of the present
invention, a formulation would include a composition or medicament for either human
or veterinary use.
“Pharmaceutically acceptable excipient” refers to a substance that is nontoxic
, biologically tolerable, and otherwise biologically suitable for administration to a
subject, such as an inert substance, added to a pharmacological ition or
otherwise used as a e, carrier, or diluent to facilitate administration of an agent
and that is ible ith. Examples of excipients include calcium carbonate,
calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin,
vegetable oils, and polyethylene glycols.
“Pharmaceutically acceptable salt” means an acid or base salt of the
compounds of the invention that is of sufficient purity and quality for use in the
formulation of a composition or medicament of the present invention and are
tolerated and sufficiently non-toxic to be used in a pharmaceutical preparation.
Suitable pharmaceutically acceptable salts include acid addition salts which may, for
example, be formed by reacting the drug compound with a le pharmaceutically
acceptable acid such as hydrochloric acid, sulfuric acid, c acid, maleic acid,
succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid.
The term tes” means those compounds that are formed from the
interaction or xation of such compounds with one or more solvent molecule,
either in solution or in solid or crystalline form. The term “hydrates” mean solvates,
wherein the solvent is water.
“Therapeutically ive amount” means that amount of nd that
elicits the biological or medicinal response in a tissue , animal or human, that
is being sought by a researcher, veterinarian, medical doctor, or other clinician,
which includes therapeutic alleviation of the symptoms of the disease or disorder
PRD3240WOPCT
being treated.
The term "treating" as used herein, unless otherwise indicated, means
reversing, alleviating, inhibiting the progress of, lessening the severity of, or
preventing the disorder or condition to which such term applies, or one or more
symptoms of such disorder or condition. The term "treatment", as used ,
unless otherwise ted, refers to the act of treating.
B) Compounds
The present invention relates to novel salts of compound of Formula (1). In
ular, the invention relates to the meglumine salt of compound of Formula (1).
In l, the invention relates to all compounds that upon administration to
patients in need of treatment of disorders and diseases d to the modulation of a
prolyl hydroxylase enzyme.
Some embodiments of the invention include hydrates, solvates or polymorphs
of such nds, and mixtures thereof, even if such forms are not explicitly stated
in the present ication. Preferably, some embodiments of compounds of
Formula (1) or pharmaceutically acceptable salts thereof include solvates. More
preferably, some embodiments of compounds of Formula (1) or pharmaceutically
acceptable salts thereof include hydrates.
Yet another embodiment of the invention es crystalline forms of
compounds of Formula (1) or pharmaceutically acceptable salts of compounds of
Formula (1) may be obtained as co-crystals.
In certain embodiments of the invention, compounds of Formula (1) were
obtained in a crystalline form. In other embodiments, crystalline forms of nds
of Formula (1) were cubic in nature. In other embodiments, pharmaceutically
acceptable salts of compounds of Formula (1) were obtained in a crystalline form. In
still other embodiments, nds of Formula (1) were ed in one of several
polymorphic forms, as a mixture of lline forms, as a polymorphic form, or as an
PRD3240WOPCT
amorphous form. In other embodiments, compounds of Formula (1) convert in
solution between one or more crystalline forms and/or polymorphic forms.
Drug compounds of the present invention also include a mixture of
stereoisomers, or each pure or ntially pure isomer. For example, the present
compound may optionally have one or more asymmetric centers at a carbon atom
containing any one substituent. Therefore, the compound may exist in the form of
enantiomer or reomer, or a mixture thereof. When the present compound
contains a double bond, the present compound may exist in the form of geometric
isomerism (cis-compound, trans-compound), and when the t compound
contains an unsaturated bond such as carbonyl, then the present compound may
exist in the form of a tautomer, and the present compound also includes these
isomers or a mixture thereof. The starting compound in the form of a racemic
mixture, enantiomer or diastereomer may be used in the ses for preparing the
present compound. When the present compound is obtained in the form of a
diastereomer or omer, they can be ted by a conventional method such
as chromatography or onal crystallization. In addition, the present compound
includes an intramolecular salt, hydrate, solvate or polymorphism thereof. Suitable
drug compounds are those that exert a local physiological , or a systemic
effect, either after penetrating the mucosa, dermis or – in the case of oral
administration – after transport to the intestinal tract with saliva.
Also described herein are pharmaceutically acceptable salts of compounds of
Formula (1) and methods of using such salts. A pharmaceutically acceptable salt
refers to a salt of a free acid or base of the compound that is xic, biologically
tolerable, or otherwise biologically suitable for administration to the subject. See,
generally, S.M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19,
and ok of Pharmaceutical Salts, Properties, Selection, and Use, 2002, Stahl
and Wermuth, Eds., VCH and VHCA, Zürich. Preferred pharmaceutically
able salts are those that are pharmacologically effective and suitable for
contact with the tissues of patients without undue toxicity, irritation, or allergic
response. A nd may possess a sufficiently acidic group, a sufficiently basic
PRD3240WOPCT
group, or both types of functional groups, and accordingly react with a number of
inorganic or c bases, and inorganic and c acids, to form a
pharmaceutically able salt. Examples of pharmaceutically acceptable salts
include sulfates, pyrosulfates, bisulfates, es, bisulfites, phosphates,
monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,
osphates, chlorides, bromides, iodides, acetates, nates, decanoates,
ates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,
oxalates, malonates, succinates, suberates, sebacates, fumarates, es,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,
phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, alenesulfonates, naphthalene
sulfonates, and mandelates.
In the presence of a basic en, the desired pharmaceutically acceptable
salt may be prepared by any suitable method available in the art, for example,
treatment of the free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, hydriodic acid, perchloric acid, sulfuric acid, sulfamic acid, nitric
acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic
acid, trifluoroacetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid,
ascorbic acid, maleic acid, hydroxymaleic acid, malic acid, pamoic acid, isethionic
acid, succinic acid, valeric acid, fumaric acid, saccharinic acid, malonic acid, pyruvic
acid, oxalic acid, glycolic acid, lic acid, oleic acid, palmitic acid, lauric acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy
acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as
aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-
acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as
laurylsulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, ptoluenesulfonic
acid, methanesulfonic acid, ethanesulfonic acid,
yethanesulfonic, a cyclohexanesulfamic acid, any compatible mixture of acids
such as those given as examples herein, and any other acid and mixture thereof that
PRD3240WOPCT
are regarded as equivalents or acceptable substitutes in light of the ordinary level of
skill in this technology.
In the presence of an acid group, such as a carboxylic acid or ic acid,
the desired pharmaceutically able salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic or organic base,
such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline
earth metal hydroxide, any compatible mixture of bases such as those given as
examples herein, and any other base and mixture thereof that are regarded as
equivalents or acceptable substitutes in light of the ordinary level of skill in this
technology. rative examples of suitable salts include c salts d from
amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates,
primary, secondary, and tertiary , and cyclic amines, such as amines,
idines, piperidine, morpholine, and piperazine, and inorganic salts derived from
sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,
and lithium. Representative organic or inorganic bases further e benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine.
Also described herein are pharmaceutically acceptable prodrugs of the
compounds, and treatment methods employing such pharmaceutically acceptable
prodrugs. The term "prodrug" means a sor of a designated compound that,
following administration to a subject yields the nd in vivo via a chemical or
physiological process such as solvolysis or enzymatic cleavage, or under
physiological conditions. A "pharmaceutically acceptable prodrug” is a prodrug that is
non-toxic, biologically tolerable, and otherwise biologically suitable for administration
to the subject. Illustrative procedures for the selection and preparation of suitable
prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H.
Bundgaard, 1985, Elsevier.
Additional types of prodrugs may be produced, for instance, by tizing
free carboxyl groups of ures of the compound as amides or alkyl esters.
Examples of amides include those d from ammonia, primary alkyl amines and
PRD3240WOPCT
secondary di-alkyl amines. ary amines include 5- or 6-membered
heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that
are derived from ammonia, alkyl y amines, and di-alkyl amines. Examples of
esters e alkyl, cycloalkyl, phenyl, and phenyl-alkyl esters. Preferred esters
include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy
groups using groups including hemisuccinates, phosphate esters,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following
procedures such as those outlined in Fleisher et al., Adv. Drug ry Rev., 1996,
19:115-130. Carbamate derivatives of hydroxy and amino groups may also yield
prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy
groups may also provide gs. Derivatization of hydroxy groups as acyloxymethyl
and acyloxy-ethyl ethers, wherein the acyl group may be an alkyl ester,
ally tuted with one or more ether, amine, or carboxylic acid
functionalities, or where the acyl group is an amino acid ester as described above, is
also useful to yield prodrugs. Prodrugs of this type may be prepared as described in
Greenwald, et al., J. Med. Chem., 1996, 39 (10):1938–40. Free amines can also be
derivatized as amides, sulfonamides or onamides. All of these prodrug
es may incorporate groups including ether, amine, and carboxylic acid
functionalities.
Also described herein are pharmaceutically active metabolites of the
compounds of Formula (1), which may also be used in the methods described
herein. A “pharmaceutically active metabolite” means a pharmacologically active
product of metabolism in the body of the compound or salt f. Prodrugs and
active metabolites of a compound may be determined using routine techniques
known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem., 1997,
40:2011-2016; Shan, et al., J. Pharm. Sci., 1997, 86 (7):765-767; Bagshawe, Drug
Dev. Res., 1995, 34:220-230; Bodor, Adv. Drug Res., 1984, 13:224-331; Bundgaard,
Design of Prodrugs, 1985, Elsevier Press; and Larsen, Design and ation of
Prodrugs, Drug Design and Development, 1991, Krogsgaard-Larsen, et al., eds.,
Harwood Academic Publishers.
PRD3240WOPCT
C) Pharmaceutical Compositions
In particular embodiments of the invention, the salts of compounds of Formula
(1), more particularly the meglumine salt, are used alone, or in combination with one
or more additional ingredients, to ate pharmaceutical compositions. A
pharma-ceutical composition comprises an effective amount of at least one
compound in accordance with the invention.
The disclosure also provides itions (including pharmaceutical
compositions) sing a compound or derivatives bed , and one or
more of pharmaceutically able carrier, excipient, and diluent. In certain
embodiments of the invention, a composition may also contain minor amounts of
wetting or emulsifying agents, or pH buffering agents. In a specific embodiment, the
pharmaceutical ition is pharmaceutically acceptable for administration to a
human. In certain embodiments, the pharmaceutical composition comprises a
therapeutically or prophylactically effective amount of a nd or derivative
described . The amount of a compound or derivative of the invention that will
be therapeutically or prophylactically effective can be determined by standard clinical
techniques. Exemplary effective amounts are described in more detail in below
sections. In certain embodiments of the invention, a composition may also contain a
stabilizer. A stabilizer is a compound that s the rate of chemical degradation
of the composition of compound (1). Suitable stabilizers e, but are not limited
to, antioxidants, such as ascorbic acid, pH buffers, or salt buffers.
The pharmaceutical compositions can be in any form suitable for
administration to a subject, preferably a human subject. In certain embodiments, the
itions are in the form of solutions, suspensions, on, tablets, pills,
capsules, powders, and sustained-release formulations. The compositions may also
be in particular unit dosage forms. Examples of unit dosage forms e, but are
not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules;
cachets; troches; lozenges; dispersions; suppositories; ointments; asms
(poultices); pastes; powders; dressings; creams; plasters; solutions; patches;
aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or
PRD3240WOPCT
mucosal administration to a patient, including suspensions (e.g., aqueous or non
aqueous liquid suspensions, oil in water ons, or a water in oil liquid
emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral
administration to a subject; and sterile solids (e.g., crystalline or amorphous solids)
that can be reconstituted to provide liquid dosage forms suitable for eral
administration to a subject.
In a specific embodiment, the subject is a mammal such as a cow, horse,
sheep, pig, fowl, cat, dog, mouse, rat, rabbit, or guinea pig. In a preferred
embodiment, the subject is a human. Preferably, the pharmaceutical ition is
suitable for veterinary and/or human administration. In accordance with this
embodiment, the term “pharmaceutically acceptable” means approved by a
regulatory agency of the Federal or a state government or listed in the U.S.
copeia or other generally recognized pharmacopeia for use in animals, and
more particularly for use in humans.
Suitable pharmaceutical carriers for use in the compositions are sterile s,
such as water and oils, including those of petroleum, animal, vegetable or synthetic
. In a specific embodiment, the oil is peanut oil, soybean oil, mineral oil, or
sesame oil. Water is a preferred carrier when the pharmaceutical composition is
administered intravenously. Saline solutions and aqueous dextrose and glycerol
solutions can also be employed as liquid carriers, particularly for injectable solutions.
Further examples of suitable pharmaceutical carriers are known in the art, e.g., as
described in Remington's Pharmaceutical Sciences (1990) 18th ed. (Mack
Publishing, Easton Pa.).
Suitable excipients for use in the itions include starch, glucose,
lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, ol
monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, ,
water, and l. Whether a ular excipient is suitable for incorporation into a
pharmaceutical composition depends on a variety of factors well known in the art
PRD3240WOPCT
including, but not limited to, the route of administration and the ic active
ingredients in the composition.
ceutical compositions comprising the compounds or derivatives
described herein, or their pharmaceutically acceptable salts and solvates, are
formulated to be compatible with the intended route of administration. The
formulations are preferably for topical stration, but can be for administration by
other means such as by inhalation or insufflation (either through the mouth or the
nose), intradermal, oral, aneous, buccal, parenteral, vaginal, or rectal.
Preferably, the compositions are also formulated to provide increased al
ity of the compound during storage and transportation. The formulations may
be lyophilized or liquid formulations.
D) Administration
A compound or derivative described herein, or a pharmaceutically acceptable
salt thereof, is preferably administered as a ent of a composition that
optionally comprises a ceutically acceptable vehicle. The compound or
derivative is preferably stered . Another preferred method of
administration is via topical application of the compound or derivative.
In certain embodiments, the compound or derivative is administered by any
other convenient route, for example, by absorption through skin, epithelial or
mucocutaneous linings (e.g., (epi-)dermis, oral mucosa, rectal, and inal
mucosa). Methods of administration include but are not d to parenteral,
intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,
epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally,
by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In most
instances, administration will result in the release of the compound or derivative into
the bloodstream. In preferred embodiments, the compound or derivative is delivered
orally.
PRD3240WOPCT
Also described herein are methods of using the compounds described herein
to treat subjects diagnosed with or suffering from a disease, er, or condition
mediated by prolyl hydroxylase, such as: anemia, vascular ers, metabolic
disorders, and wound healing.
In a preferred ment, compounds of the present invention are useful in
the treatment or prevention of anemia comprising ent of anemic conditions
ated with chronic kidney e, polycystic kidney disease, aplastic anemia,
autoimmune hemolytic anemia, bone marrow transplantation anemia, Churg-Strauss
me, Diamond Blackfan anemia, Fanconi's , Felty syndrome, graft
versus host disease, hematopoietic stem cell transplantation, hemolytic uremic
syndrome, ysplastic syndrome, nocturnal paroxysmal hemoglobinuria,
osteomyelofibrosis, pancytopenia, pure red-cell aplasia, purpura Schoenlein-
Henoch, refractory anemia with excess of blasts, rheumatoid arthritis, Shwachman
syndrome, sickle cell disease, thalassemia major, thalassemia minor,
thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery,
anemia associated with or secondary to trauma, sideroblastic anemia, anemic
secondary to other treatment ing: reverse transcriptase inhibitors to treat HIV,
osteroid es, cyclic cisplatin or non-cisplatin-containing
chemotherapeutics, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors,
anthracyclines, alkylating agents, particularly anemia secondary to inflammatory,
aging and/or c diseases. PHD inhibition may also be used to treat symptoms
of anemia including chronic fatigue, pallor and dizziness.
In another preferred embodiment, molecules of the present invention are
useful for the treatment or prevention of diseases of metabolic disorders, including
but not limited to diabetes and obesity. In another preferred embodiment, molecules
of the present invention are useful for the treatment or prevention of vascular
disorders. These include but are not limited to hypoxic or wound g related
diseases requiring pro-angiogenic mediators for vasculogenesis, angiogenesis, and
arteriogenesis
PRD3240WOPCT
In treatment methods described herein, an ive amount of a
pharmaceutical agent according to the invention is administered to a subject
suffering from or diagnosed as having such a disease, er, or condition. An
"effective amount" means an amount or dose sufficient to generally bring about the
desired therapeutic or prophylactic t in patients in need of such treatment for
the designated e, disorder, or condition. Effective amounts or doses of the
compounds of the present invention may be ascertained by routine methods such as
modeling, dose escalation studies or clinical trials, and by taking into consideration
e factors, e.g., the mode or route of administration or drug delivery, the
pharmacokinetics of the compound, the severity and course of the disease, disorder,
or condition, the subject's previous or ongoing therapy, the subject's health status
and response to drugs, and the nt of the treating physician. An example of a
dose is in the range of from about 0.001 to about 200 mg of compound per kg of
t's body weight per day, preferably about 0.05 to 100 day, or about 1 to
mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg
human, an illustrative range for a suitable dosage amount is from about 0.05 to
about 7 g/day, or about 0.2 to about 2.5 g/day.
Oral tablets may include a compound according to the invention mixed with
pharmaceutically acceptable excipients such as inert diluents, disintegrating agents,
binding agents, lubricating agents, sweetening agents, flavoring agents, ng
agents and preservative . Suitable inert fillers e sodium and calcium
carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl
cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral
excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone
(PVP), sodium starch glycolate, microcrystalline cellulose, and c acid are
suitable disintegrating agents. Binding agents may include starch and gelatin. The
lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If
desired, the tablets may be coated with a material such as yl monostearate or
glyceryl distearate to delay tion in the gastrointestinal tract, or may be coated
with an enteric coating.
0WOPCT
Capsules for oral administration include hard and soft gelatin capsules. To
prepare hard gelatin capsules, compounds of the invention may be mixed with a
solid, olid, or liquid t. Soft gelatin capsules may be prepared by mixing
the compound of the invention with water, an oil such as peanut oil or olive oil, liquid
paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene
glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions,
ons or syrups or may be presented as a dry product for reconstitution with
water or other suitable vehicle before use. Such liquid compositions may optionally
contain: ceutically-acceptable excipients such as ding agents (for
example, sorbitol, methyl cellulose, sodium te, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles,
e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl
alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or
sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring
The active agents of this invention may also be administered by non-oral
routes. For example, the compositions may be formulated for rectal administration
as a suppository. For eral use, including enous, intramuscular,
intraperitoneal, or subcutaneous routes, the nds of the invention may be
provided in sterile aqueous ons or suspensions, buffered to an appropriate pH
and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-
dose form such as ampules or disposable injection devices, in multi-dose forms such
as vials from which the appropriate dose may be withdrawn, or in a solid form or preconcentrate
that can be used to prepare an injectable formulation. Illustrative
infusion doses may range from about 1 to 1000 µg/kg/minute of compound, admixed
with a pharmaceutical carrier over a period ranging from several minutes to several
days.
PRD3240WOPCT
For topical administration, the compounds may be mixed with a
ceutical carrier at a concentration of about 0.1% to about 10% of drug to
vehicle. Examples include lotions, creams, ointments and the like and can be
formulated by known methods. Another mode of administering the nds of
the invention may utilize a patch formulation to affect transdermal delivery.
A election evaluation was carried to identify a salt of compound (1) with
properties most suitable for development. The criteria considered essential for the
selection process were crystallinity, form reproducibility from a recrystallization
s, chemical and physical stability under accelerated ions and adequate
solubility to support both drug substance and drug product development.
In embodiments, the compound is formulated into dosage forms suitable for
administration to patients in need thereof. The processes and equipment for
preparing drug and carrier particles are disclosed in ceutical Sciences,
Remington, 1985, 17th Ed., 1585-1594; Chemical Engineers Handbook, Perry, 1984,
6th Ed., pp. 21-13 to 21-19 (1984); Parrot et al., 1974, J. Pharm.Sci., 61(6): 813-829;
and Hixon et al., 1990, Chem. Engineering, pp. 94-103.
The amount of compound incorporated in the dosage forms of the present
invention may generally vary from about 10% to about 90% by weight of the
ition depending upon the eutic indication and the desired
administration , e.g., every 12 hours, every 24 hours, and the like. Depending
on the dose of compound desired to be administered, one or more of the dosage
forms can be administered. Depending upon the formulation, the compound will
preferably be in the form of an acetate salt or free base form.
Further, this invention also relates to a pharmaceutical ition or a
pharmaceutical dosage form as described hereinbefore for use in a method of
therapy or diagnosis of the human or non-human animal body.
PRD3240WOPCT
This invention also relates to a pharmaceutical composition for use in the
manufacture of a pharmaceutical dosage form for oral administration to a mammal in
need of treatment, characterized in that said dosage form can be administered at
any time of the day independently of the food taken in by said mammal.
Also described herein is a method of therapy or sis of the human or
non-human animal body that comprises administering to said body a therapeutically
or diagnostically effective dose of a ceutical composition bed herein.
This invention also relates to a ceutical package suitable for
commercial sale comprising a container, a dosage form as described herein, and
associated with said package written matter non-limited as to whether the dosage
form can be administered with or without food.
The following formulation examples are illustrative only and are not intended
to limit the scope of the inventions in any way.
EXAMPLES
Five versions of compound (1), namely the free acid, sodium, potassium,
tromethamine and meglumine salts were ed and their physical properties and
manufacturability potential guided the selection of an preferred form of the
compound.
E) Example Synthesis
To obtain the nds described in the examples below and their
corresponding analytical data, the following experimental and analytical protocols
were adhered to unless otherwise indicated. Unless otherwise stated, reaction
mixtures were magnetically stirred at room ature (rt), solutions were generally
“dried” over a drying agent such as Na2SO4 or MgSO4, and mixtures, ons, and
extracts were typically “concentrated” on a rotary evaporator under reduced
pressure.
PRD3240WOPCT
Data Analysis Setup
Thin-layer chromatography (TLC) was performed using Merck silica gel 60
F254 2.5 cm x 7.5 cm 250 µm or 5.0 cm x 10.0 cm 250 µm pre-coated silica gel
plates. Preparative ayer chromatography was performed using EM Science
silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm
concentrating zone.
Normal-phase flash column chromatography (FCC) was performed on silica
gel (SiO2) eluting with hexanes/ethyl acetate, unless otherwise noted, whereas
reversed-phase HPLC was performed on a Hewlett Packard HPLC Series 1100, with
a Phenomenex Luna C18 (5 µm, 4.6x150 mm) column, and detection was done at λ
= 230, 254 and 280 nm with a gradient of 10 to 99% acetonitrile/water (0.05%
oroacetic acid) over 5.0 min with a flow rate of 1 . Alternately,
preparative HPLC purification was med on a Gilson automated HPLC system
running Gilson Unipoint LC software with UV peak detection done at λ = 220 nm and
fitted with a reverse phase YMC-Pack ODS-A (5 µm, 30 x 250 mm) column; mobile
nt of 10-99% of acetonitrile/water (0.05% trifluoroacetic acid) over 15-20 min
and flow rates of 10-20 mL/min.
Mass spectra (MS) were obtained on an Agilent series 1100 MSD equipped
with a ESI/APCI positive and negative multimode source unless otherwise indicated,
and nuclear magnetic resonance (NMR) spectra were obtained on Bruker model
DRX spectrometers with the 1H NMR data showing chemical shifts in ppm downfield
of the tetramethylsilane nce ent multiplicity, coupling constant J in Hz,
integration).
Example 1: Free acid of 1-(5,6-Dichloro-1H-benzoimidazolyl)-1H-pyrazole
carboxylic acid (compound (1))
Cl N N
Cl N OH
PRD3240WOPCT
Method A:
The free acid of nd (1) was prepared by using 2,5,6-trichloro-1H-
benzoimidazole and 1H-pyrazolecarboxylic acid. MS (ESI/CI): mass calculated
for l2N4O2, 297.1; m/z found, 296.0 [M-H]-. 1H NMR (500 MHz, DMSO-d
14.18-12.52 (br s, 2H), 8.89 (d, J = 0.5 Hz, 1H), 8.31 (d, J = 0.5 Hz, 1H), 7.80 (s,
2H).
Method B:
Step A: 5,6-Dichloro-1,3-dihydro-benzoimidazolone: To the on of
4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL), was added
CDI (23 g, 0.14 mol) as the solid. The reaction solution was stirred at room
ature for 1 hour, then water (500 mL) was added. The precipitated solid was
ted by filtration, washed with water, dried thoroughly to afford the titled
compound (26.0 g, 90%). The crude product was used in the following reaction
without further purification.
Step B: 2,5,6-Trichloro-1H-benzoimidazole: Thoroughly dried 5,6-dichloro-
1,3-dihydro-benzoimidazolone (28.4 g, 0.14 mol) was suspended in POCl3 (75
mL). The reaction solution was heated to reflux temperature for 3 hours and cooled
to room temperature. The solution was poured into crushed ice/water (1.5 L) slowly
with sufficient stirring. The solution was neutralized to pH = 7.0 with NaOH. The
precipitated solid was collected by filtration, washed with water, and dried to afford
the title compound (27.9 g, 90%). The crude product was used in the following
reaction without further purification.
Step C: 1-(5,6-Dichlorodimethylsulfamoyl-1H-benzoimidazolyl)-1H-
pyrazolecarboxylic acid ethyl ester. 2,5,6-Trichloro-1H-benzoimidazole 2 (27.6 g,
0.125 mol) was dissolved in dry DMF (200 mL) and then K2CO3 (20.7 g, 0.15 mol)
and dimethylsulfamoyl chloride (17.9 g, 0.125 mol) were added. The reaction
mixture was stirred at room temperature for 16 hours. HPLC analysis showed the
complete formation of 2,5,6-trichloro-benzoimidazolesulfonic acid dimethylamide.
In the same pot, t isolation of 2,5,6-trichloro-benzoimidazolesulfonic acid
ylamide, was added 1H-pyrazolecarboxylic acid ethyl ester (17.5 g, 0.125
mol) and K2CO3 (20.7 g, 0.15 mol). The reaction mixture was stirred at 70 °C for 4
PRD3240WOPCT
hours and water (500 mL) was added while the reaction solution was still hot. The
reaction solution was cooled to room ature. The precipitated solid was
collected via filtration, washed with water and dried. The crude t was used in
the following on without further purification.
Step D: 1-(5,6-Dichloro-1H-benzoimidazolyl)-1H-pyrazolecarboxylic
acid. Crude -Dichlorodimethylsulfamoyl-1H-benzoimidazolyl)-1H-
pyrazolecarboxylic acid ethyl ester was dissolved in THF (125 mL) and LiOHH2O
(21 g, 0.5 mol) in water (250 mL) was added. The reaction mixture was stirred at
reflux ature for 2 hours and cooled to room temperatue. Concentrated HCl
was added to adjust pH to 2.0. The solid precipitated was collected by filtration,
washed with water and dried. The solid was triturated in hot EtOAc (1L). After
cooling to room temperature and filtration, the compound of Formula (I) was obtained
as a tan solid (18.5 g, 50%). MS [M+H]+ found 297.0. 1H NMR (500 MHz, DMSO-
d6): 13.71 (s, 1H), 12.99 (s, 1H), 8.90 (s, 1H), 8.3 2 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H).
The thermal properties, lline nature, apparent purity and moisture
uptake of a 6.0 g batch of the free acid of compound (1) are summarized in Table 1.
Saturation data for compound (1) is shown in Figure 1.
Table 1
Apparent Crystallinity Melting Point Adsorption Desorption
Purity (HPLC) (PXRD) (DSC) (40-90% RH) (90-0% RH)
99.8% Weakly 343 °Ca +0.59 % -0.96%
crystalline
a decomposition
Example 2: Potassium salt of compound (1)
The potassium salt of 1-(5,6-dichloro-1H-benzoimidazolyl)-1H-pyrazole
carboxylic acid was prepared by suspending the free acid (55 g, 1.7 mol) in EtOH
(1.5 L) at reflux temperature with K2CO3 (12.79 g, 0.85 mol) in 20 mL water added
dropwise over 5 min. Strong mechanic stirring was required to ensure proper
agitation. The suspension was stirred at reflux temperature for eight hours and then
cooled to room temperature over five hours. The precipitated solid was collected by
tion and quickly washed with 100 mL of water followed by EtOH. The potassium
PRD3240WOPCT
salt was obtained as a white solid (38 g, 65%). Subsequently, the mother liquor was
concentrated and the above process was repeated once to give the second crop of
the potassium salt (13 g, 22%). MS [M+H]+ = 297.0. 1H NMR (500 MHz, DMSO-d6):
8.65 (s, 1H), 7.96 (s, 1H), 7.57 (s, 2H).
The potassium salt as prepared by the above re-slurry methodology is nonhygroscopic
and consistent with a poorly lline hydrate as seen by PXRD and
thermal analysis. Two broad endothermic peaks of the potassium salt of compound
(1) were seen by DSC that can be associated with a dehydration event and
melt/decomposition, respectively (Table 2).
Table 2
Melting
nt Crystallinity Point Adsorption Desorption
Purity (HPLC) (PXRD) (DSC) (40-90% RH) (90-0% RH)
lline
100.0 % 277 °Cd +0.53% -0.89%
drate
ddecomposition
Example 3: Sodium salt of compound (1)
The sodium salt of compound (1) is a poorly crystalline, hydrated solid as
shown by PXRD and thermal analysis. The DSC reveals two broad endothermic
peaks; the first event is associated with a loss of water (~9% by TGA), while the
second endotherm is caused by melting/decomposition of the salt. The sodium salt
was prepared in a method r to that used to prepare the potassium salt (slurry
method).
e 4: Crystallization procedure of the tromethamine salt of compound (1)
Two forms of the tromethamine salt have been produced to date. The first
form was ed from the slurry of compound (1) and tromethamine in aqueous
ethanol (14% water). Although not a salt, this physical mixture was not pursued. The
second form was produced from an aqueous workup containing excess amounts of
counterion. This form was a hydrated salt that was observed to have a lower
PRD3240WOPCT
nt s solubility than the potassium salt. This compound also exhibited
poor bulk properties.
Example 5: Crystallization procedure of the ine salt of compound (1)
A clear solution (30 mg/mL) of the free acid of compound (1) and 1.2 molar
equivalent of meglumine was produced in aqueous methanol (12% water) ing
slight heating. Room temperature stirring with seeding or refrigeration with or
without seeding consistently led to crystallization of the meglumine salt, which was
collected via filtration. This methodology was used to produce a 2 g batch of the
salt. The solvent composition in the above procedure was modified to aqueous
ethanol and used by the PDMS API SM Development team to produce 8.7-kg of
GMP-grade material in support of FIH-enabling and FIH studies.
The l properties, crystalline nature, and apparent purity of the
meglumine salt of compound (1) are summarized in Table 3. s 2 and 3 show
salt bulk properties of the meglumine salt of compound (1), including PXRD data and
DSC, TGA and x-ray data, respectively. The single crystal data confirmed the
meglumine salt of compound (1) to be a dihydrate with the simulated powder pattern
in excellent agreement with the experimental powder pattern as shown in s 4A
and 4B. The meglumine salt of compound (1) was observed to have improved bulk
properties, solubility, and ed processability compared to the free acid or the
potassium salt of compound (1).
Table 3
Apparent Purity Melting
Sample ID (HPLC) Crystallinity (PXRD) Point (DSC)
Meglumine salt of
> 99.9 % crystalline dihydrate 80 ºC
compound (1)
Example 6: l formulations of meglumine salt of compound (1)
Materials and excipients that used in the development of topical formulations
of a ine salt of compound (1) are listed in Table 4.
PRD3240WOPCT
Table 4
Materials
Meglumine salt of
compound (1)
Hydroxypropyl Methylcellulose
(HPMC K15M)
Poloxamer 407*
Methylcellulose
(MC)
PEG4000
Meglumine
(NMDG)
Vitamin E-TPGS
Carbomer 941
Carbomer 934P
Carboxymethylcellulose
(Na-CMC)
HP-β-CD
Sterile Water for Irrigation
*solubilization at 5 °C due to the thermo-reversible property of the excipient.
Table 5 lists the al and chemical stability results performed on ed
formulations of the ine salt of compound (1) after 4 weeks of storage.
Table 5
Meglumine salt of compound (1)
remaining (%)
Experiment Formulation
2 °C 20 °C 40 °C
Composition
1 0.5% HPMC
K15M 99.89 101.14 101.44
(pH 8.33)
2 1.0% HPMC
K15M 99.59 99.21 99.08
(pH 8.33)
3 2.0%
Methylcellulose 98.49 99.71 97.20
(pH 8.32)
PRD3240WOPCT
4 15% Poloxamer
407 99.19 100.03 87.29*
(pH 8.10)
20% Poloxamer
407 97.60 99.57 96.43*
(pH 8.03)
6 VitETPGS
/PEG4000
/water 100.27 100.32 98.87
(20:20:60; pH
8.06)
*Precipitation ed in the vial
HPLC analysis showed that the six formulation compositions were chemically
stable for four weeks under the studied storage conditions. The nt loss of
mass balance for the poloxamer-based ation (Experiment 4) was attributed to
the precipitation of the free acid of nd (1) at 40° Celsius and not degradation.
At 40° Celsius, the polymers degraded that resulted in the formation of acetic acid,
aldehydes, and a concurrent loss of viscosity and drop in pH. The resulting acidic
nment caused precipitation of the ble free acid of nd (1) and
discoloration of the formulation. The instability of poloxamer (or lutrol) is known and
has been disclosed in Erlandsson, B., 2002, Polym. Degrad. and Stab., 78:571-575.
Such a degradation was not observed in samples stored at room temperature or
refrigerated.
The results of the solubility screen of formulations of the meglumine salt of
compound (1) are shown in Table 6. Four of the ten vehicles investigated, namely
1% Na-CMC (Experiment 1), 1% Carbomer 941 (Experiment 2), 1% Carbomer 934P
(Experiment 3) and 20% HP-β-CD (Experiment 4), did not meet the targeted
solubility criterion of 10 mg/mL (free acid equivalent) or were toxic to Hela cells. The
1% MC vehicle did not have notable advantages over the product containing 2% MC.
The ine salt of compound (1) was sufficiently soluble within an acceptable
pH range (6-8.5) in Experiments 5 and 7-11.
Table 6
Experiment
Formulation Composition Compound (1) Solubility
0WOPCT
1 1% Na-CMC < 10 mg/mL
2 1% Carbomer 941 < 10 mg/mL
3 1% Carbomer 934P < 10 mg/mL
4 0.5% HPMC K15M ≥ 10 mg/mL
1.0% HPMC K15M ≥ 10 mg/mL
1% Methylcellulose ≥ 10 mg/mL
2% Methylcellulose ≥ 10 mg/mL
% Poloxamer 407 ≥ 10 mg/mL
% Poloxamer 407 ≥ 10 mg/mL
VitE-TPGS/PEG4000/water
≥ 10 mg/mL
(20:20:60)
% HP-β –CD* ≥ 10 mg/mL
*Formulation was toxic to the Hela cells
F) Biological Examples
Cellular Assay for HIF1-α
Hela cells (ATCC, Manassas, VA) were plated in 96-well plates at 20,000
cells per well in 100 µl of DMEM ning 10% fetal bovine serum, 1% non-
ial amino acids, 50 IU/mL of penicillin and 50 µg/mL of streptomycin (all cell
culture reagents from Invitrogen, Carlsbad, CA). 24 hours after g, changed
media to 100 µl of DMEM without 10% fetal bovine serum, 1.1 µl of the stock
solution for each nd was added and incubated for six hours. All compounds
were tested with a final compound concentration of 100 µM. The supernatant was
removed and the cells were lysed in 55µl of MSD lysis buffer containing protease
inhibitors. 50 µl of the cell lysate was then transferred to a blocked MSD human HIF-
1α detection plate (Meso-Scale Discovery, Gaithersburg, MD, as per manufacturers
protocol), and incubated at room temperature on an orbital shaker for two hour.
After three washes in PBS, 25 µl of 20nM anti-HIF1α detection antibody was added
and incubated for 1 hour at room temperature on an orbital shaker. After three
washes in PBS, 150 µl of 1X read buffer was added and the plate was then read on
0WOPCT
a MSD SECTOR instrument. Data was ed by determining the percent of HIF
stimulation in the presence of 100 µM compound ve to an assay control
compound, 7-[(4-Chloro-phenyl)-(5-methyl-isoxazolylamino)-methyl]-quinolinol.
This biological data for the meglumine salt of compound (1) is presented in Figure 5.
onal biological data for formulations of the meglumine salt of compound
(1) is presented in Figures 6 through 8.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be understood
that the practice of the invention encompasses all of the usual variations,
adaptations and/or modifications as come within the scope of the following claims
and their equivalents.
PRD3240WOPCT
Claims (10)
1. A formulation comprising the meglumine salt of 1-(5,6-dichloro-1H- d]imidazolyl)-1H-pyrazolecarboxylic acid. 10
2. A compound of the formula in the form of a meglumine salt. 15
3. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable excipient.
4. The formulation of claim 1, wherein said meglumine salt is in the form of a dihydrate.
5. A topical ointment comprising the formulation of claim 1.
6. A compound of the formula in the form of the dihydrate meglumine salt.
7. A pharmaceutical ition sing the dihydrate meglumine salt of the compound of formula given in claim 6 and a pharmaceutically acceptable 30 ent.
8. A topical ointment comprising the pharmaceutical composition of claim 7. PRD3240WOPCT 5
9. A formulation according to claim 1 substantially as herein described with reference to any example f.
10. A pharmaceutical composition according to claim 3 or 7 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161551395P | 2011-10-25 | 2011-10-25 | |
US61/551,395 | 2011-10-25 | ||
PCT/US2012/061847 WO2013063221A1 (en) | 2011-10-25 | 2012-10-25 | Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ624022A NZ624022A (en) | 2015-05-29 |
NZ624022B2 true NZ624022B2 (en) | 2015-09-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10807969B2 (en) | Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid | |
US10975062B2 (en) | 4-aminoquinazolinyl compounds as prolyl hydroxylase inhibitors | |
US20150284335A1 (en) | Benzoimidazoles as prolyl hydroxylase inhibitors | |
AU2010213814A1 (en) | Quinazolinones as prolyl hydroxylase inhibitors | |
NZ624022B2 (en) | Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid |