MXPA01009885A - Viral treatment - Google Patents
Viral treatmentInfo
- Publication number
- MXPA01009885A MXPA01009885A MXPA/A/2001/009885A MXPA01009885A MXPA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- hydrogen
- carbamic acid
- composition according
- hiv
- Prior art date
Links
- 230000003612 virological Effects 0.000 title description 7
- 241000700605 Viruses Species 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 34
- 239000011780 sodium chloride Substances 0.000 claims abstract description 28
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 206010047461 Viral infection Diseases 0.000 claims abstract description 16
- 208000001756 Virus Disease Diseases 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 16
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 15
- 230000017613 viral reproduction Effects 0.000 claims abstract description 15
- 238000007792 addition Methods 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000000651 prodrug Substances 0.000 claims abstract description 10
- 229940002612 prodrugs Drugs 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000001301 oxygen Substances 0.000 claims abstract description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052717 sulfur Chemical group 0.000 claims abstract description 5
- 239000011593 sulfur Chemical group 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 31
- 239000000969 carrier Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 9
- 208000006454 Hepatitis Diseases 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 7
- 239000008297 liquid dosage form Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 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 claims description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N Zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 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 claims description 6
- 108010010803 Gelatin Proteins 0.000 claims description 5
- 229960002555 Zidovudine Drugs 0.000 claims description 5
- 239000003623 enhancer Substances 0.000 claims description 5
- 230000002708 enhancing Effects 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 4
- 229920001817 Agar Polymers 0.000 claims description 3
- 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 claims description 3
- 241000709661 Enterovirus Species 0.000 claims description 3
- 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 claims description 3
- 239000008272 agar Substances 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 208000006572 Human Influenza Diseases 0.000 claims description 2
- 206010022000 Influenza Diseases 0.000 claims description 2
- 230000002378 acidificating Effects 0.000 claims description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- 150000001649 bromium compounds Chemical class 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- 150000002823 nitrates Chemical class 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003873 salicylate salts Chemical class 0.000 claims description 2
- 150000003871 sulfonates Chemical class 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- 150000003892 tartrate salts Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims 1
- 150000000994 L-ascorbates Chemical class 0.000 claims 1
- 241001533173 Yua Species 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 150000003841 chloride salts Chemical class 0.000 claims 1
- -1 bromo, hydroxy Chemical group 0.000 abstract description 55
- 150000001875 compounds Chemical class 0.000 abstract description 41
- GAWCRULEMQFHTI-UHFFFAOYSA-N (4-chlorophenyl)carbamic acid Chemical compound OC(=O)NC1=CC=C(Cl)C=C1 GAWCRULEMQFHTI-UHFFFAOYSA-N 0.000 abstract description 11
- 241001465754 Metazoa Species 0.000 abstract description 6
- 241000124008 Mammalia Species 0.000 abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 abstract 1
- 125000005430 oxychloro group Chemical group 0.000 abstract 1
- 230000001340 slower Effects 0.000 abstract 1
- 210000004027 cells Anatomy 0.000 description 48
- 229940079593 drugs Drugs 0.000 description 27
- 102000033147 ERVK-25 Human genes 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 12
- 239000002775 capsule Substances 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 108010092799 EC 2.7.7.49 Proteins 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 201000009910 diseases by infectious agent Diseases 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 8
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 7
- 102000014150 Interferons Human genes 0.000 description 7
- 108010050904 Interferons Proteins 0.000 description 7
- 108091005771 Peptidases Proteins 0.000 description 7
- 239000004365 Protease Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 229940079322 interferon Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XYWJNTOURDMTPI-UHFFFAOYSA-N 3-(1H-benzimidazol-1-ium-2-yl)propanoate Chemical group C1=CC=C2NC(CCC(=O)O)=NC2=C1 XYWJNTOURDMTPI-UHFFFAOYSA-N 0.000 description 6
- 208000005176 Hepatitis C Diseases 0.000 description 6
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamate Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000002354 daily Effects 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000003442 weekly Effects 0.000 description 6
- 208000005721 HIV Infections Diseases 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 230000000840 anti-viral Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000003000 nontoxic Effects 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 208000002672 Hepatitis B Diseases 0.000 description 4
- 208000009889 Herpes Simplex Diseases 0.000 description 4
- CBVCZFGXHXORBI-PXQQMZJSSA-N Indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 108010061833 Integrases Proteins 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M Lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N Rescriptor Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 229960001852 Saquinavir Drugs 0.000 description 4
- QWAXKHKRTORLEM-UGJKXSETSA-N Saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 4
- 230000036436 anti-hiv Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- WREGKURFCTUGRC-POYBYMJQSA-N ddC Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N ddIno Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 4
- 229960005319 delavirdine Drugs 0.000 description 4
- 229960002656 didanosine Drugs 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 229960001936 indinavir Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 229950000989 procodazole Drugs 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 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 4
- JTEGQNOMFQHVDC-NKWVEPMBSA-N 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- 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 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 229960000689 Nevirapine Drugs 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N Nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- NCDNCNXCDXHOMX-XGKFQTDJSA-N Ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 3
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 229960000311 ritonavir Drugs 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N Amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 2
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 2
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 2
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 2
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229960000724 Cidofovir Drugs 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovirum Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L Copper(II) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 229940088900 Crixivan Drugs 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
- 229940088598 Enzyme Drugs 0.000 description 2
- 208000001860 Eye Infections Diseases 0.000 description 2
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 2
- 229940093915 Gynecological Organic acids Drugs 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 208000001688 Herpes Genitalis Diseases 0.000 description 2
- 229960000905 Indomethacin Drugs 0.000 description 2
- 229960001627 Lamivudine Drugs 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N N'-amino-N-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229940063627 Rescriptor Drugs 0.000 description 2
- 229960000329 Ribavirin Drugs 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 2
- CBEQULMOCCWAQT-WOJGMQOQSA-N Triprolidine Chemical group C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 2
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclover Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N Vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- 210000002845 Virion Anatomy 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000000172 allergic Effects 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000004569 blindness Diseases 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940112021 centrally acting muscle relaxants Carbamic acid esters Drugs 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- HSLBPQGVXMOSRA-UHFFFAOYSA-N hydroxy hypochlorite Chemical compound OOCl HSLBPQGVXMOSRA-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229940079866 intestinal antibiotics Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 230000001603 reducing Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 239000003104 tissue culture media Substances 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- 229960001128 triprolidine Drugs 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 229960005486 vaccines Drugs 0.000 description 2
- 229960001234 valaciclovir Drugs 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- OAQKFULUNYIBBR-UHFFFAOYSA-N (2-chlorophenyl)carbamic acid Chemical compound OC(=O)NC1=CC=CC=C1Cl OAQKFULUNYIBBR-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GAOZTHIDHYLHMS-GDMSFIFLSA-N (2R,3S,4R)-4-[(2R,5R,7S,8R,9S)-2-[(2R,5S)-5-ethyl-5-[(2S,3R,5S)-5-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]oxolan-2-yl]-7-hydroxy-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-3-methoxy-2-methylpentanoic acid Chemical compound C([C@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@@H]2[C@@H](C[C@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@H](C)[C@H](OC)[C@@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-GDMSFIFLSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- ZWXPDGCFMMFNRW-UHFFFAOYSA-N 1-methylazepan-2-one Chemical compound CN1CCCCCC1=O ZWXPDGCFMMFNRW-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N 2-mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
- CFBVWCHTNQHZLT-UHFFFAOYSA-N 4-methoxy-5-[3-(2-methoxy-4-nitro-5-sulfophenyl)-5-(phenylcarbamoyl)tetrazol-3-ium-2-yl]-2-nitrobenzenesulfonate Chemical compound COC1=CC([N+]([O-])=O)=C(S([O-])(=O)=O)C=C1N1[N+](C=2C(=CC(=C(C=2)S(O)(=O)=O)[N+]([O-])=O)OC)=NC(C(=O)NC=2C=CC=CC=2)=N1 CFBVWCHTNQHZLT-UHFFFAOYSA-N 0.000 description 1
- TZYVRXZQAWPIAB-FCLHUMLKSA-N 5-amino-3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound O=C1SC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TZYVRXZQAWPIAB-FCLHUMLKSA-N 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N 9-(4-hydroxy-3-(hydroxymethyl)butyl)guanine Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 102100009254 ACOT1 Human genes 0.000 description 1
- 101700030167 ACOT1 Proteins 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 1
- 229960003272 ASPARAGINASE Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N Abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 1
- 229940023040 Acyclovir Drugs 0.000 description 1
- 229940009456 Adriamycin Drugs 0.000 description 1
- 229960003805 Amantadine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N Amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241001135975 BK virus variant RF Species 0.000 description 1
- 229960003071 Bacitracin Drugs 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 102000006734 Beta-Globulins Human genes 0.000 description 1
- 108010087504 Beta-Globulins Proteins 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N Betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N Bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- 229950004398 Broxuridine Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 229960005091 Chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N Chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 229960004926 Chlorobutanol Drugs 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000006154 Chronic Hepatitis C Diseases 0.000 description 1
- 206010008909 Chronic hepatitis Diseases 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N Cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960001380 Cimetidine Drugs 0.000 description 1
- 229940047120 Colony stimulating factors Drugs 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 210000004087 Cornea Anatomy 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 241000557626 Corvus corax Species 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
- 208000000993 Dendritic Keratitis Diseases 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N Dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 Dipyridamole Drugs 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- SDIXRDNYIMOKSG-UHFFFAOYSA-L Disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 description 1
- 229960004679 Doxorubicin Drugs 0.000 description 1
- 229940022766 EGTA Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N Efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014599 Encephalitis Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 229940072253 Epivir Drugs 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229940012017 Ethylenediamine Drugs 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 229960003973 Fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N Fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- ZJAOAACCNHFJAH-UHFFFAOYSA-N Foscarnet Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 1
- 229960002963 Ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N Ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 229960004905 Gramicidin Drugs 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- IUAYMJGZBVDSGL-XNNAEKOYSA-N Gramicidin S Chemical compound C([C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)=O)CC(C)C)C(C)C)C1=CC=CC=C1 IUAYMJGZBVDSGL-XNNAEKOYSA-N 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 229940093912 Gynecological Sulfonamides Drugs 0.000 description 1
- 206010020159 HIV carrier Diseases 0.000 description 1
- 206010019233 Headache Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- 206010019641 Hepatic cirrhosis Diseases 0.000 description 1
- 208000005252 Hepatitis A Diseases 0.000 description 1
- 208000005331 Hepatitis D Diseases 0.000 description 1
- 206010019773 Hepatitis G Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 102000000420 Human immunodeficiency virus 1 p16 protease Human genes 0.000 description 1
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 1
- 102000001311 Human immunodeficiency virus 1 p31 integrase protein Human genes 0.000 description 1
- 108010069733 Human immunodeficiency virus 1 p31 integrase protein Proteins 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 210000000987 Immune System Anatomy 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 229940088976 Invirase Drugs 0.000 description 1
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L MANGANESE CHLORIDE Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 239000007993 MOPS buffer Substances 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
- 230000035633 Metabolized Effects 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910021380 MnCl2 Inorganic materials 0.000 description 1
- 229960005358 Monensin Drugs 0.000 description 1
- CHZUOCHJHAJYNO-UHFFFAOYSA-N N-[4-(4-fluorophenyl)sulfonylphenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)C1=CC=C(F)C=C1 CHZUOCHJHAJYNO-UHFFFAOYSA-N 0.000 description 1
- 101710024861 NRT2.2 Proteins 0.000 description 1
- 229960000210 Nalidixic Acid Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N Nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229940072250 Norvir Drugs 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 102000030951 Phosphotransferases Human genes 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N RIFAMPICIN Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 102000002490 Rad51 Recombinase Human genes 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 108060006943 RdRp Proteins 0.000 description 1
- 229940064914 Retrovir Drugs 0.000 description 1
- 229940081190 Rifampin Drugs 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N Rimantadine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 231100000735 Select agent Toxicity 0.000 description 1
- 206010040490 Sexually transmitted disease Diseases 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229960001203 Stavudine Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229960000894 Sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229940040944 Tetracyclines Drugs 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N Triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 229940032699 Vistide Drugs 0.000 description 1
- 229940045997 Vitamin A Drugs 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 230000035969 Vmax Effects 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N acyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive Effects 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 201000004384 alopecia Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000003569 amebicidal Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000000118 anti-eoplastic Effects 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000000692 anti-sense Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000002958 antiviral enhancer Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001055 chewing Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- 230000002498 deadly Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 201000010284 hepatitis E Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-O hydron;2H-tetrazole Chemical compound C1=NN=[NH+]N1 KJUGUADJHNHALS-UHFFFAOYSA-O 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000001146 hypoxic Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002480 immunoprotection Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960001691 leucovorin Drugs 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
- 201000007270 liver cancer Diseases 0.000 description 1
- 201000004044 liver cirrhosis Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000018984 mastication Effects 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000002438 mitochondrial 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
- 239000003068 molecular probe Substances 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 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
- 239000007935 oral tablet Substances 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-M oxolane-2-carboxylate Chemical compound [O-]C(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-M 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- QGVLYPPODPLXMB-UBTYZVCOSA-N phorbol derivatives Chemical class [H][C@@]12C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@@]3([H])[C@@]1(O)[C@H](C)[C@@H](O)[C@]1(O)[C@@]2([H])C1(C)C QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive Effects 0.000 description 1
- 230000002250 progressing Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 230000000306 recurrent Effects 0.000 description 1
- 230000003362 replicative Effects 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 108040002590 retroviral 3' processing activity proteins Proteins 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 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
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 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
Abstract
A pharmaceutical composition that inhibits or slows the growth of viruses in animals, particularly in mammals, is disclosed. This same composition can be used to treat viral infections, particularly HIV. The composition comprises from about 10 mg to about 10000 mg of a carbamic acid ester derivative of formula (I) wherein X is independently oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, R1 is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, wherein R2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chloro, fluoro, bromo, hydroxy, oxychloro and sulfhydryl or pharmaceutical addition salt or prodrug thereof. The most preferred compound is (4-chlorophenyl)-carbamic acid, 3-(hexahydro-3-ethyl-1-methyl-2-oxo-1H-azepin-3-yl) 2 phenyl ester.
Description
VIRAL TREATMENT
TECHNICAL FIELD This invention relates to certain esters of carbamic acid which are effective against viruses and can be used to treat viral infections in -amals. The preferred compound is (-chlorophenyl) carbamic acid, 3- (hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester. The composition may contain one or more of the carbamic acid esters, its pharmaceutical drug addition salt thereof.
BACKGROUND OF THE INVENTION HIV and other viral infections such as, for example, hepatitis are among the few causes that lead to death. It is known that HIV. It is the virus that causes the acquired immunodeficiency syndrome (AIDS) in humans. HIV is a disease in which a virus replicates in the body or in host cells. The virus attacks the body's immune system Several drugs have been approved for the treatment of this devastating disease, including azidovudine (AZT), didanosine (dideoxyinosine, ddl), d4T, zalcitabine (dideoxycytosine, ddC), nevirapine, lamivudine. (epivir, 3TC), saquinavir (Invirase), ritonavir (Norvir), indinavir (Crixivan), and delavirdine (Rescriptor). See M. I. Johnston & D. F. Hoth, Science, 260 (5112), 1286-1293 (1993) and D. D. Richman, Science, 272 (5270), 1886-1888 (1996). A vaccine for AIDS (Salk vaccine) has been tried and it has been discovered that various proteins that are chemokines from CD8 act as suppressors of HIV. In addition to the above nucleoside analogs, proteins and antibodies, it has been found that various plants and substances derived therefrom have anti-HIV activity in vitro. However, HIV is not easily destroyed nor is there a good mechanism to prevent host cells from replicating the virus. In this way, medical professionals continue to search for drugs that can prevent HIV infections, treat HIV carriers to prevent their disease from progressing to fully developed deadly AIDS, and to treat the patient with AIDS. Herpes simplex virus (HSV) types 1 and 2 are persistent viruses that commonly infect humans; they cause a variety of diseases that afflict the human being. HSV type 1 causes "febrile vesicles", oral (recurrent cold sores), and HSV type 2 causes genital herpes, which has been seen to be the main venereal disease in many parts of the world. Currently there is no completely satisfactory treatment for genital herpes. In addition, although it is rare, HSV can also cause encephalitis, a life-threatening infection of the brain. (The Merck Manual, Holvey, Ed., 1972, hitley, Herpes Simplex Virus, In: Virology, 2nd Ed., Raven Press (1990)). A more serious disorder caused by HSV is dendritic keratitis, an ocular infection that produces a branched injury to the cornea, which in turn can lead to permanent scarring and loss of vision. Eye infections with HSV are a leading cause of blindness. The HSV is also difficult, if not impossible to cure. Hepatitis is a disease of the human liver. It is manifested by inflammation of the liver and is usually caused by viral infections and sometimes from toxic agents. Hepatitis can progress to liver cirrhosis, liver cancer, and eventually death. It is known that various viruses such as, for example, hepatitis A, B, C, D, E and G cause various types of viral hepatitis. Among them, HBV and HCV are the most serious. HBV is a DNA virus with a virion size of 42 nm. HCV is an RNA virus with a virion size of 30-60 nm. See D. S. Chen, J. Forays Med. Assoc., 95 (1), 6-12 (1996). Hepatitis C infects 4 to 5 times the number of people infected with it. HIV Hepatitis C is difficult to treat and it is estimated that there are 500 million people infected with it worldwide (approximately 15 times of those infected with HIV). Currently no effective immunization is available, and hepatitis C can only be controlled by other preventive measures such as, for example, improving hygiene and sanitary conditions and interrupting the route of transmission. Currently, the only acceptable treatment for chronic hepatitis C is interferon that requires at least six (6) months of treatment and / or ribavaren that can inhibit viral replication in infected cells and also improve liver function in some people . Treatment with interferon, however, has a limited long-term efficacy with a response rate of approximately 25%. Infection with the hepatitis B virus can lead to a broad spectrum of liver damage. In addition, chronic hepatitis 3 infection has been linked to the subsequent development of hepa tocellular carcinoma, a leading cause of death. The current prevention of HBV infection is a vaccination against hepatitis B that is safe and effective. However, vaccination is not effective in treating those who are already infected
(ie, carriers and patients). Many drugs have been used to treat chronic hepatitis B and none has proven effective, except interferon. The treatment of HCV and HBV with interferon has limited success and has often been associated with adverse side effects such as, for example, fatigue, fever, chills, headache, prialgia, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid malfunction. Because interferon therapy has limited efficacy and frequent adverse effects, a more effective regimen is necessary.
In the present invention it has been discovered that the compounds described above are useful for the treatment of hepatitis C virus, hepatitis B virus, herpes simplex and the treatment of HIV infection and other viral infections.
BRIEF DESCRIPTION OF THE INVENTION A pharmaceutical composition for the treatment of animals and in particular, warm-blooded animals, including humans, is disclosed, comprising a pharmaceutical carrier and an effective amount of an arylcarbamic acid ester which has the following formula:
wherein X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms , wherein R2 is independently selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, and sulfhydryl or a halo; of pharmaceutical addition or a pro-drug thereof. The preferred compound is (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-ethyl-1-methyl-2-oxo-l-azepin-3-yl) 2-phenyl ester; wherein X is oxygen, Y is chlorine, R is hydrogen, R2 is ethyl and Ri is methyl.
The compositions can be used in a method for treating HIV, in particular chronic HIV, and other viral infections. The drug can be administered daily in one or more doses and 1 to 4 times a week. The compositions may be used in conjunction with other treatments for viral infections.
DETAILED DESCRIPTION OF THE INVENTION A. Definitions: In the sense in which it is used in the present "alkyl" includes straight chain, branched and cyclic alkanes. In the sense in which it is used in the present "aryl" it includes phenyl or phenyl derivatives, for example, chlorophenyl, fluorophenyl or methylphyl. In the sense in which it is used herein, the term "safe and effective amount" refers to the amount of a component that is sufficient to provide a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) in proportion to a reasonable benefit / risk ratio when used in the manner of this invention. In the sense in which it is used herein, the term "therapeutically effective amount" means an amount of a compound of the present invention effective to provide the desired therapeutic response. For example, to inhibit HIV infection or treat the symptoms of infection in a host or an effective amount to treat hepatitis. The specific and therapeutically effective safe and effective amount will vary, obviously, according to factors such as the particular condition that will be treated, the physical condition of the patient, the mammal or animal tlpc to be treated, the duration of the treatment, the nature of the concurrent therapy (in its case) and the specific formulations used and the structure of the compounds or their derivatives. As used herein, a "pharmaceutical addition salt" is a salt of the arylcarbamic acid ester derivative that is modified by producing an acid or basic salt of the compounds. Examples of pharmaceutical addition salts include, but are not limited to: mineral or organic acid salts of basic waste such as, for example,, amines, alkaline or organic salts of acidic residues such as, for example, carboxylic acids. Preferably, the salts are produced using an organic or inorganic acid. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the anti-viral agent to the animal or human. "The carrier can be liquid or solid and is selected with the intended administration form in mind, as used herein, the term "anti-viral compound" means an arylcarbamic acid ester or the pharmaceutically acceptable salt thereof or a prodrug thereof. Carbamic acid ester In the sense in which it is used herein, the term "ester derivative of carbamic acid" or "ester of aryl carbamic acid" are compounds having the formula:
in donate X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms , wherein R2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, oxychlor and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof. "Pro drugs" are considered any covalently attached carriers that release the active precursor drug according to the formula of derivatives described above when this pro-drug is administered to a mammalian subject or patient. The aryl carbamic acid ester drugs are prepared by modifying the functional groups present in the compounds in such a way that the modifications adhere, either in routine or in vivo manipulation, to the precursor compounds. The pro-drugs include compounds wherein the hydroxyl, sulfhydryl, or amine groups are attached to any group which, when administered to a mammalian subject, adheres to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of drug prodrugs include, but are not limited to: acetate, formate, or alcohol benzoate derivatives and amine functional groups in the carbamic acid ester derivatives; phosphate esters, dimet il glycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboalkyl alcohol esters and phenol functional groups in the ester derivatives of carbamic acid; and the like. In the sense in which it is used herein, "viruses" include viruses that infect animals or mammals, including humans, viruses include retroviruses, HIV, influenza, poliovirus, herpes simplex, hepatitis B, hepatitis C, and others. viral strains of hepatitis, Kaposi's sarcoma, rhinovirus, and the like In the sense in which it is used herein "combination therapy" means that the patient in need of the drug is treated or given another drug for the disease This combination therapy can be a sequential therapy where the patient is treated first with one drug and then the other, or the two drugs are administered simultaneously, in the sense in which it is used in combination with the carbamic acid ester derivatives. herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation and rejection). allergic response) in proportion to a reasonable benefit / risk ratio. In the sense in which it is used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the anti-viral agent to the animal or human. The ported can be liquid or solid and is selected with the planned form of administration in mind. In the sense in which it is used herein, "anti-viral compounds" are the carbamic acid ester derivatives described above.
B. THE ANT-VIRAL COMPOUNDS The aryl carbamic acid ester has the following formula:
wherein X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, "Ri is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms. carbon, wherein R2 is independently selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, oxychlor and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof The preferred compound is (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-ethyl-1-methyl-2-oxo-lH-azepin-3) -il) 2-phenyl ester, where X is oxygen, Y is chlorine, R is hydrogen, R2 is ethyl and Ri is methyl, its formula is:
The pharmaceutically acceptable salts of the carbamic acid ester derivatives include the conventional non-toxic salts or the quaternary ammonium salts of the carbamic acid ester derivatives formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as, for example, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroximic, phenolic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from carbamic acid ester derivatives containing a basic or acid entity by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or the basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
in general, non-aqueous media similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th. ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure thereof is incorporated herein by reference. The disclosures of all references cited herein are incorporated herein by reference in their entirety.
C. SYNTHESIS Ester derivatives of carbamic acid can be prepared in several of the ways well known to one skilled in the art of organic synthesis. Carbamic acid ester derivatives can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. The relevant portions of each of the references cited below are incorporated herein by reference. The preferred compound, carbamic acid (4-chlorophenyl), 3- (hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester, can be prepared as follows:
A in acetonitrile, lithium bromide, copper bromide at 25 ° C for 16 hours gives B B + [CH 3) 2CH] 2NLi + CH 3 CH 2 I in tetrahydrofuran at 10 ° C for 15 min and then at 65 ° C for six hours provides C.
First, 3-me t-oxycyclohexenone (see Shepherd, et al., J. Chem Soc. Perkin Trans I, 2153 (1987), for a synthetic method to produce 3-me toxiciclohexenone of 1,3-cyclohexanedione and orthoformiate trimethyl) is reacted with N-methyl caprolactam in the presence of an organolithium compound, preferably lithium diisopropylamide, (see for example, US 4,197,241). The resulting product is treated with lithium bromide and copper bromide in acetonitrile to convert the unsaturated ketone to the corresponding aromatic compound which is then treated with ethyl iodide in the presence of a lithium catalyst (lithium diisopropylamide) to prepare the ethyl intermediate. . Reaction with para-chlorophenylisocyanate in pyridine using dibutyltin dilaurate as a catalyst results in 3-hexahydro-3-yl-1-yl-yl-2-oxo-lH-a-zepin-3-yl) phenyl ester of (4-chlorophenyl) -carbamic acid. Similar routes can be used to produce the other derivatives of arylcarbamic acid esters of the type described herein.
D. DOSAGE AND FORMS OF DOSING SUPPLY
The compounds in general are safe. The compounds can be administered orally and are not very soluble, preferably they are provided in tablet form or as an oral or intravenous suspension. Any suitable dosage can be provided in the method of the invention. The type of compound and the carrier and the amount will vary depending on the species of animal or human of warm blood, body weight, and the virus that will be treated. Of course, the dosage administered will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and / or weight of the recipient; to the nature and degree of the symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. The ester of carbamic acid is preferably micronized or pulverized in such a way that it is dispersed and solubilized more easily by the body. Processes for grinding or spraying the drugs are well known in the art. For example, grinding by hammer or similar grinding device. The preferred particle size is less than about lOOμ and preferably less than 50μ .. As a general guide, a dosage as small as approximately 1 milligram (mg) per kilogram (kg) of body weight and preferably as small as 10 mg / kg and up to approximately 10,000 mg per kg of body weight is adequate. Preferably, 10 mg / kg and 5000 mg / kg body weight are used. More preferably, the doses are between about 250 mg / kg and 5000 mg / kg. Intravenously, the most preferred dose may vary from about 1 to 10 mg / kg / minute during an infusion at a constant rate. The ester compounds of carbamic acid can be administered in divided doses of two, three, or four times daily. Carbamic acid ester derivatives can be administered in one or more doses on a daily basis or one to three times a week. Dosing is preferred two times a week for a period of at least several weeks and antiviral compounds will often be administered for prolonged periods of time and may be administered during the patient's lifetime. Carbamic acid ester derivatives can also be administered in intranasal form by topical use of intranasal vehicles, or by transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, of course, administration will be continuous rather than intermittent throughout the dosage regimen. In general, the dosage in man will be lower than for small warm-blooded mammals such as mice. A dosage unit may comprise a single compound or mixtures thereof with other compounds or other compounds for viral inhibition. The dosage unit may also comprise diluents, extenders, carriers and the like. The unit may be in the form of a solid or gel such as, for example, pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection in or around to the virus. The carbamic acid ester derivatives are usually mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type in general is selected based on the type of administration that will be used. The active agent can be coadministered in the form of a tablet or capsule, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. The capsule or tlabletas can be prepared easily and can be easily produced for swallowing or chewing; other solid forms include aggregates and powders. The tablets may contain suitable binders, "lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents Examples of suitable liquid dosage forms include pharmaceutically acceptable solutions or suspensions in water, fats and oils. , alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.Oral dosage forms optionally contain flavors and coloring agents. intravenous They could also include minerals and other materials to produce them that are compatible with the type of injection or delivery system selected.
EXAMPLES OF FORMULATION The ester derivatives to the carbamic acid of this invention can be administered as a treatment for viral infections by any means that produces contact of the active agent with the site of action of the agent in the body. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. • They can be administered alone, although in general they are administered with a pharmaceutical carrier selected on the basis of the selected administration route and standard pharmaceutical practice. The carbamic acid ester can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or time delay formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Carbamic acid ester derivatives can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using well-known dosage forms for those with normal experience in pharmaceutical techniques. In the methods of the present invention, the compounds of the present invention described in detail can form the active ingredient and are typically administered in a mixture with suitable diluents, excipients or carrier carriers (collectively referred to as a carrier or pharmaceutically acceptable carrier materials) appropriately selected with respect to the intended form of administration, ie, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the unit dosage form of a tablet or capsule, the active drug component can be combined with an inert carrier, pharmaceutically acceptable, non-toxic, oral, such as lactose, starch, sucrose, glucose, ti lcelulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
For oral administration in liquid dosage form, the oral drug components can be combined with any inert, pharmaceutically acceptable, non-toxic, oral carrier, such as ethanol, glyceroi, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate *, carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium venzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. The ester derivatives of carbamic acid can also be administered in the form of systems for delivery of liposomes, such as, for example, small unilamellar vesicles, large vesicles, etc.
unilamellar and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as for example, cholesterol, teari lamina, or phosphat idylcholine. Carbamic acid esters can also be packed with soluble polymers as carriers of the white drug. These polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug., for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoes, polyacetals, polyhydrodynamines, poly cyanoacrylates, and block copolymers of crosslinked or amphipathic hydrogels. The dosage forms (compositions suitable for administration) contain between about 1 milligram and 1000 milligrams of the active ingredient per dosage unit. From 2.9
Preferably, the dosage forms will contain between about 10 mg and 500 mg. In these pharmaceutical compositions the active ingredient will normally be present in an amount of between about 0.5 and 95% by weight based on the total weight of the unit dose. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally in liquid dosage forms including liposomes. The gelatin capsules may contain the active ingredient and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to produce compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide a continuous release of the drug over a period of hours. The compressed tablets may be coated with sugar or a coated film to mask the unpleasant taste and protect the tablet from the atmosphere, or with enteric coating for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavors to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient or a liposome, suitable stabilizing agents, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and disodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-parabeni and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The pharmaceutical dosage forms useful for the administration of the compounds of this invention are illustrated as follows:
Capsules Many unit capsules are prepared by filling standard two-piece hard gelatin capsules, each containing 100 milligrams of the powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.
Soft gelatin capsules A mixture of the active ingredient is prepared in a digestible oil such as, for example, soybean oil, cottonseed oil or olive oil and is injected by means of a gelatin positive displacement pump to form the capsules of soft gelatin containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets Many tablets are prepared by conventional procedures in such a way that the dosage unit is 100 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Suitable coatings can be applied to increase palatability or delay absorption.
Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension An aqueous suspension is prepared for oral administration in such a way that every 5 ml contains 100 mg of the finely divided active ingredient., 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin. The present invention also includes pharmaceutical kits useful, for example, for the treatment of HIV infection, comprising one or more containers containing a pharmaceutical composition comprising a compound of the formula (I). These kits may also include, if desired, one or more of the various components of the conventional pharmaceutical equipment, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. The technique. Printed instructions, either as inserts or as labels, indicating the quantities of components to be administered, directions for administration, and / or directions for mixing the components can also be included in the kit. In the present disclosure it should be understood that specific materials and conditions are important for practicing the invention although non-specific materials and conditions are not excluded as long as they do not prevent the benefits of the invention from being carried out.
F. TREATMENT METHOD The method of treatment can be any suitable method that is effective in the treatment of the particular virus. The above formulations can be used for treatment. The treatment can be by oral, rectal, topical, parenteral or intravenous administration and the like. The method for administering an effective amount also varies depending on the virus that will be treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the aryl carbamate ester compounds, is prepared with a suitable carrier, an additional compound or compounds for viral inhibition or a diluent to facilitate the application will be the preferred method for administering the compounds to mammals or warm-blooded animals. The actual duration of treatment and dosage will depend on the virus that will be treated and the desired blood levels. Carbamic acid ester derivatives can also be used as an antifungal treatment and are administered as the antiviral treatment or they can also be applied topically in a cream, gel or liquid form. They can also be prepared as a suppository.
G. COMBINATION THERAPY One or more of the carbamic acid ester derivatives may be combined with other antiviral agents or enhancers. Potentiators are materials that affect the body's response to the antiviral agent. In the case of HIV, combination therapy with AZT, TC-3 or protease inhibitors is effective. In the case of hepatitis, cyclovir, famcíclovir or valaciclovir, Ribavirin, interferon or combinations of Ribavirin and Inferior or beta globulins are administered as a combination therapy. For herpes, a recombinant alpha interferon can be used as a combination therapy. In some embodiments, the aryl carbamate ester compound is used in combination with one or more enhancers and / or antiviral agents for the treatment of viral infections. An exemplary enhancer is triprolidine or its cis-isomer which are used in combination with chemotherapeutic agents and the aryl carbamate ester compound. Triprolidine is described in US 5,114,951 (1992). Another enhancer is procodazole, lH-benzimidazole-2-propanoic acid; L- (2-benzimidazole) propionic acid; 2- (2-carboxyethyl) benzimidazole; propazole]. Procodazole is a non-specific immunoprotective agent against viral and bacterial infections which is used with the compositions claimed herein. This is effective with the aryl carbamate ester compound to treat viral infections. The procodazole can also combine the carbamate ester compound. Procodazole can also be combined with the carbamate ester compound and other anti viral agents. Other enhancers that can be used as aryl carbamate ester compounds include monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an immunotixin receptor for anti-trans fer brain, me toclopramide, 7-thia -8-oxoguanosine, N-solanesyl-N, N'-bis (3,4-dime toxibenci 1) ethylenediamine, leucovorin, heparin, N- [4- [(4-fluorophenyl) sulfonyl] phenyl] acetamide, heparin sulfate , cimetidine, a radiosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2'-deoxy cof ormicin, a bis-diketopiperazine derivative and dimethyl sulfoxide. In some embodiments of the invention, an aryl carbamate ester compound is used in combination with one or more other therapeutic agents, such as, for example, anti-inflammatory, anti-viral, anti-vaginal, amoebicidal, ricominoidal, analgesic, antineoplastic, ant i-hypertensive, ant i-microbial and / or steroidal, to treat viral infections. In some preferred embodiments, patients with viral infections are treated with a combination of one or more aryl carbamate ester compounds with one or more of the "antibiotics be ta-lact ama"., tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, nor rofurazone, nalidixic acid, cortisone, hydrocort isone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac, acyclovir, amantadine, rimantadine, soluble CD4 (rsCD4) recombinant, anti-i-receptor antibodies (for rhinoviruses), nevirapine, cidofovir (Vistide ™), trisodium phosphonoformate (Foscarnet ™), famciclovir, penciclovir, valaciclovir, nucleic acid / replication inhibitors, interferon, zidovudine (AZT, Retrovir didanosine (dideoxy inosine, ddl
VidexMR), stavudine (d4T, ZeritMR), zalcitabine
(dideoxycytosine, ddC, VihidMR), nevirapine
(ViramuneMR), lamivudine (EpivirMR, 3TC), protease inhibitors, saquinavir (InviraseMR, Fortovase R), ritonavir (NorvirMR), nelfinavir (ViraceptMR), efavirenz (SustivaMR), abacavir (ZiageriMR), amprenavir
(Agenerase ™) indinavir (Crixivan ™), ganciclovir,
AzDU, delavirdine (Rescriptor ™), rifampin, t iromycin, er 11 ropoyet ina, colony stimulating factors (G-CSF and GM-CSF), nucleoside reverse transcriptase inhibitors, nucleoside inhibitors, adriamycin, f luorouracil, methotrexate, asparaginase and combinations thereof. The combination therapy can be sequential, that is, the treatment with a first agent and then the second agent, or it can be the treatment with the agents at the same time. Sequential therapy may be within a reasonable time after completing the first therapy before starting the second therapy. Treatment with both agents at the same time can be in the same dose daily or in separate doses. For example, treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease that will be treated, the severity of the infection and the response to treatment.
MECHANISM The mechanism of action of esters of carbamic acid is not known. The aryl carbamic acid ester shows no activity as a protease inhibitor when selected using a fluorometric method or as an integrase inhibitor. These results are summarized below:
Protease inhibition analysis Protease inhibition is evaluated using a fluorometric method. The enzyme (Bachem) is diluted to μgm / ml in 50mM NaOAC, 5mM DTT, 2mM EDTA, 10% glycerol (pH 5.0) and stored as 10μl samples at -20 ° C, the protease substratum I HIV (molecular probes) is diluted to a working concentration of 0.32 nmoles / μl. The enzyme (20 μl) and the drug (20 μl) are added to each well of a microtiter plate as appropriate. The positive and negative control are evaluated in parallel. Fluorescence is quantified in Labsystems Fluroskan II using 355 nm / 460 nm at 37 ° C at time zero and at 30 minute intervals for 2 hours. In cases where autofluorescence avoids the use of flucometric HIV-1 protease analysis or confirmation of a result is required, an HPLC-based protease assay can also be used.
Analysis of Integrase Inhibition An analysis of biochemical integrase is described by Craigie et al (HIV, vol.2: A practical Approach) Biochemistry, Molecular Biology and Drug Discovery, Ed. J. Karn 1995) to select agents for their ability to inhibit the integrase of HIV-1. In this system, an oligonucleotide subjected to kinase treatment serves as the target of 3 'processing and the subsequent filament transfer reaction. The 3 'processing reaction includes the removal of 2 nucleotides from the 3' ends of the substrate and this is followed by the filament transfer reaction in which the ends 31 'are bound to the exposed 5' ends. The 20 μl reaction mixture contains 25 mM MOPS (pH 7.2), 100 g / ml BSA, 10 mM β-mercaptoethanol, 10% glycerol, 25 nM 7.5 mM MnCl2, (7 ng) substrate (Oligo's Etc., ilsonville, OR) and integrase 200 nM (128 ng) (NIAID AIDS Research and Reference Reagent Program, Bethesda, MD). The reaction proceeds at 37 ° C for 1-2 hours and is terminated by the addition of 20 μl of disruption solution by sequencing (USB Amersham, Ariington Heights, IL). The reaction products are visualized by autoradiography after electrophoresis in Urea 6M gel of 15% polyacrylamide. The substrate migrates as a 30 mer, the 3 'processing product migrates as an N-2 band and the filament transfer products migrate more slowly to various sizes larger than the substrate.
INHIBITION OF PROTEASE 3-HEXAHIDRQ-3-ETHYL-1-METHYL-2-QXQ-1H-AZEPIN-3-IL) PHENYL ESTER CARBAMIC 4-CHLOROPHENYL ACID
The EC50 value is > 100 μg / ml for (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-yl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester and 0.699 μM / ml for 654021.
INHIBITION OF INTEGRASA HIV-1 ACID (4-CHLOROPHENYL) -CARBÁMICO, 3 - (HEXAHIDRQ- 3 -ETIL- 1 -METIL-
The IC50 (μg / ml) is greater than 100 for this compound Inhibition of HIV-1 integrase by 654021F a control drug
The IC50 (nM) is 699.01
The compounds in general are safe. The LD50 is clearly higher and there are no special handling requirements. The compounds can be administered orally and as they are not very soluble, they are preferably administered in tablet form or as a suspension or liposome.
Preparation of the virus: An aliquot of the virus (-80 ° C) is removed from the frozen and left to thaw slowly at room temperature in a biological safety cabinet. The virus is resuspended and diluted in tissue culture medium such that the amount of virus added to each cavity in a volume of 50μl will be the amount determined to provide total cell killing at 6 days after infection . In general, virus collections produced with HIV IIIB isolate required the addition of 5μl of virus per cavity. The RF virus collections were 5 to 10 times more potent requiring 0.5-] μl of the virus per cavity. The calculation of TCID50 by final titration in CEM-SS cells indicated that the infection rate of these analyzes varied from 0.005 to 2.5.
Plate format: The format of the test plate has been standardized. Each plate contains cavities for cell control (cells only), cavities for virus control (cells plus viruses), cavities for toxicity control (cells plus drug only), cavities for calorimetric control of the drug (only drug) as well as cavities experimental (drug plus cells plus virus).
XTT staining of the selection plates: After 6 days (or the experimental period) of incubation at 37 ° C in a 5% carbon dioxide incubator, the test plates were analyzed by staining with the tetrazolium pigment, XTT .
The XTT-tetrazolium is metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of cell death "induced by HIV through an anti-HIV test substance. After infection, the plates were removed from the incubator and observed.The use of round bottom microtiter plates allows a rapid macroscopic analysis of the active of a test compound determined by the evaluation of the granule size. macroscopic observations were confirmed and intensified by additional microscopic analysis.The XTT solutions are prepared daily as a 1 mg / ml concentrate in PBS.The phenazine methosulphate solution (PMS) is prepared at 15 mg / ml in PBS and stored in the dark at 20 ° C. The XTT / PMS concentrate is prepared immediately before ut Isolate by diluting the PMS in 1: 100 in PBS and add 40 μl per ml of XTT solution. Fifty microtitre XTT / PMS were added to each well of the plate and the plate was re-incubated for 4 hours at 37 ° C. Adhesive sealants for plates were used in place of the lids and the sealed plate was inverted several times to mix the soluble formazan product. Plating on plates was read spectroscopically at 450 nm with a Molecular Devices Vmax plate reader. The reduction in cell percentage, the viability of the cell percentage, IC25 / 50 and 95 can then be calculated.
Analysis of reverse transcriptase activity: A reverse transcriptase (RT) reaction is used based on microtitre (Buckheit et al (1991) AIDS Research and Human _Re troviruses 7: 295-302). The titrated thymidine triphosphate (NEN) (TTP) is resuspended in distilled water at 5 ° Ci / ml. Poly rA and oligo dT are prepared as a concentrated solution maintained at -20 ° C. The reaction buffer RT is prepared fresh on a daily basis and consists of 125 μl of EGTA 1M, 125 μl of water, 125 μl of Triton X-100, 50 μl of Tris (pH 7.4), 50 μl of I MDDT, and 40 μl of 1M MgCl 2. These three solutions are mixed together in a ratio of 1 part TTP, 2.5 parts poly. rA: oligo dT, 2.5 parts of reaction buffer and 4 parts of distilled water. Ten microliters of this reaction are placed in a round bottom microtiter and 15 μl of the supernatant containing the virus are added and mixed. The plate is incubated at 37 ° C and incubated for 60 minutes. After the reaction, the reaction volume is stained on filter mats, washed 6 times for 5 minutes each time in a 5% sodium phosphate burner, 2 times for 1 minute each in distilled water, 2 times during 1 minute. minute each in 70% ethanol, and then dried. The filter mat is placed in a plastic sample bag, the Betaplate scintillation fluid is added and the bag is heat sealed. The incorporated radioactivity is quantified using a Wallac Microbeta scintillation counter. Acute infection of most human cell lines established with HIV-1 results in the eventual establishment of a chronically infected cell line that produces constitutive viruses. The cells are passed through for prolonged periods of time in culture without loss of virus production. These cells can be used to evaluate the effects of anti-HIV compounds on zinc formation or to evaluate the effects of anti-HIV compounds on the levels of virus production from these cells.
Chronically infected cell lines exhibit little or no CD4 cell surface and can not be super-infected with other HIV-1 isolates. Each of the cells contains an integrated HIV genome or provirus. The chronically infected CEM, H9 and U937 cell lines were prepared and cultured by the Southern Research Institute, Frederick MD and are available therefrom. CEM-SS cells chronically infected with the HIV isolate, for example SKI (CEM-SKI) are cultured in RPMI1640 tissue culture medium supplemented with 10% fetal bovine serum and antibiotics. The selection is made by culturing the cells in the presence of the compound that will be tested in T25 flasks. CEM-SKI or other infected cells without adding drugs are used as control cells. The cells are allowed to develop at a density of about 1 x 10 6 cells / ml and then passed at a 1:10 dilution. After a period of time, usually at one-week intervals of treatment with the drug, the cells were evaluated to determine whether the inhibitory activity of the compound was affected by treatment of the cells with any of the compounds. The concentration of the drug in the flask was then increased twice and the cells were maintained as above. Cell populations contain integrated copies of the HIV genome and produce constitutively HIV at relatively high levels or are latently infected and produce only virus after stimulation with phorbol esters, tumor necrosis factor or IL6 (IU and ACH2). Reductions in virus products were observed when the reverse transcriptase activity of the supernatant was quantified. The toxicity values by XTT and the activity of the compound in the tests were measured by an Inverse Transcriptase analysis.
EXAMPLE 1 HIV-1 A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-a zepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against HIV-1 cell line, CEMSKI, was conducted at three different levels. The results with CEMSKI cells are reported at weekly intervals. The reverse transcriptase data is summarized below.
CEMSKI CELLULAR LINE
This test was run for 222 days and the data remained consistent. The CEMSKI cell line is a viral strain of the CEMSS cell line.
EXAMPLE 3 CEMRF A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against an HIV cell line -1, CEMRF, was conducted to three different levels. The results with CEMRF cells are reported at weekly intervals. The reverse transcriptase data is summarized below. CEMRF is a chronic HIV cell line.
This test was run for 222 days and the data remained consistent.
EXAMPLE 4 CEMIIIB A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against an HIV cell line -1, CEMIIIB, was conducted at three different levels. The results with CEMIIIB cells are reported at weekly intervals. The reverse transcriptase data is summarized below.
CEMIIIB is a viral strain of the CEMSS cell line and is a chronic HIV cell line.
This test was run for 22 days and the data remained consistent.
EXAMPLE 5 CEMROD A long-term in vi tro study of 3-hexahyd o-3-ethyl-1-met il-2-oxo-lH-a zepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against a line Cellular HIV-2, CEMROD, was conducted at three different levels. The results with CEMROD cells are reported at weekly intervals. The reverse transcriptase data showed similar decreases as the previous ones.
EXAMPLE 6 U937IIIB A long-term in vitro study of 3-hexahydro-3-ethyl-1-methyl-yl-2-oxo-l-azepin-3-yl) phenyl ester with 4-chlorophenyl carbamic acid against an HIV cell line -1, U937IIIB, was conducted to three different levels. The results with cells
U937IIIB are reported at weekly intervals. The data of reverse transcriptase was similar to the data reported previously.
EXAMPLE 7 U937RF A long-term in vitro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against a U937RF cell line, a Protease-resistant strain, was conducted at three different levels. The results with U937RF cells are reported at weekly intervals. The reverse transcriptase data were similar to those reported previously. Similar results were obtained with U937KN1272, a strain resistant to the protease.
Claims (10)
- CLAIMS 1. The use of a pharmaceutical composition for producing a medicament for treating a viral infection wherein the composition comprises a safe and effective amount of a carbamic acid ester having the formula: wherein X independently is oxygen or sulfur; R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms; Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, wherein R 2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof.
- 2. The use according to claim 1, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and from 1 mg to 6000 mg of a carbamic acid ester or pharmaceutically acceptable acidic, organic or inorganic addition salt thereof.
- 3. The use of a pharmaceutical composition according to claim 1 or 2, wherein X is oxygen, Y is chlorine, R is hydrogen, Ri is methyl and R2 is ethyl.
- 4. The use of a composition according to claim 1, 2 or 3, comprising from 10 mg to 6000 mg of the carbamic acid ester having the formula: or the pharmaceutically acceptable salt thereof
- 5. The use of a composition according to claim 1, 2, 3 or 4, wherein the pharmaceutical addition salt is selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates and ascorbates.
- 6. The use of a composition according to claim 1, 2, 3, 4 or 5, wherein the pharmaceutical composition is a solid form comprising a carrier selected from the group consisting of lactose, sucrose, gelatin and agar.
- 7. The use of a composition according to claim 1, 2, 3, 4 or 5, wherein the pharmaceutical composition is in a liquid dosage form comprising a carrier selected from the group consisting of an aqueous solution, an emulsion, a solution of suspension yua reconstituted suspension from non-effervescent or effervescent preparations.
- 8. The use of a composition according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the viral infection is caused by a virus selected from the group consisting of HIV, influenza, hepatitis and rhinovirus.
- 9. The use of a composition according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the pharmaceutical composition further comprises an antiviral agent or an enhancer.
- 10. The use of a composition according to claim 9, wherein the viral infection is caused by HIV virus and the antiviral agent is selected from the group consisting of AZT, TC-3 and protease inhibitors.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/281,893 | 1999-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01009885A true MXPA01009885A (en) | 2002-05-09 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1165070B1 (en) | Thiadiazolyl urea or thiourea derivatives for antiviral treatment | |
US6245789B1 (en) | HIV and viral treatment | |
US6194430B1 (en) | Viral treatment | |
JP5543930B2 (en) | Use of 4'-thio-2'-deoxynucleosides as anti-orthopoxvirus agents | |
EP0809504B1 (en) | Anti-viral triazacyclododecane | |
AU764265B2 (en) | Viral treatment | |
AU763275B2 (en) | Viral treatment | |
MXPA01009885A (en) | Viral treatment | |
MXPA01009889A (en) | Thiadiazolyl urea or thiourea derivatives for antiviral treatment | |
MXPA00011360A (en) | Compositions for the treatment of hiv and other viral infections | |
MXPA01009887A (en) | Viral treatment | |
CZ20004242A3 (en) | Pharmaceutical preparation exhibiting activity for treating viral infections and method of reducing velocity of RNA or protein synthesis in a cell having viral infection |