ES2337794T3 - Inhibidores no nucleosidos de la transcriptasa inversa. - Google Patents
Inhibidores no nucleosidos de la transcriptasa inversa. Download PDFInfo
- Publication number
- ES2337794T3 ES2337794T3 ES04809207T ES04809207T ES2337794T3 ES 2337794 T3 ES2337794 T3 ES 2337794T3 ES 04809207 T ES04809207 T ES 04809207T ES 04809207 T ES04809207 T ES 04809207T ES 2337794 T3 ES2337794 T3 ES 2337794T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- mmol
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- cis
- difluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000003112 inhibitor Substances 0.000 title description 3
- 239000002777 nucleoside Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- -1 C1-C6 haloalkanoyl Chemical group 0.000 claims abstract description 71
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 125000005843 halogen group Chemical group 0.000 claims abstract description 21
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000468 ketone group Chemical group 0.000 claims abstract description 5
- 229930194542 Keto Natural products 0.000 claims abstract description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 4
- 125000002720 diazolyl group Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 97
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 49
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 30
- 239000004202 carbamide Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 230000035772 mutation Effects 0.000 claims description 11
- 230000009471 action Effects 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 229940121357 antivirals Drugs 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 229960000311 ritonavir Drugs 0.000 claims description 4
- 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 claims description 4
- 208000031886 HIV Infections Diseases 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 claims description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 claims description 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 abstract 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 209
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 112
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 238000005481 NMR spectroscopy Methods 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 98
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 97
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 239000011541 reaction mixture Substances 0.000 description 90
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- 239000002253 acid Substances 0.000 description 64
- 239000000243 solution Substances 0.000 description 63
- 238000004440 column chromatography Methods 0.000 description 62
- 239000000047 product Substances 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- 235000019439 ethyl acetate Nutrition 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- 239000012043 crude product Substances 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 125000004494 ethyl ester group Chemical group 0.000 description 28
- 239000000377 silicon dioxide Substances 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 150000002148 esters Chemical class 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 22
- 235000019198 oils Nutrition 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 11
- ZCQSJUGIZGMDDA-UHFFFAOYSA-N 4-(methylsulfinyl)phenol Chemical compound CS(=O)C1=CC=C(O)C=C1 ZCQSJUGIZGMDDA-UHFFFAOYSA-N 0.000 description 11
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- KECCFSZFXLAGJS-UHFFFAOYSA-N 4-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=C(O)C=C1 KECCFSZFXLAGJS-UHFFFAOYSA-N 0.000 description 8
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- ATXXLNCPVSUCNK-UHFFFAOYSA-N 5-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)C=N1 ATXXLNCPVSUCNK-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000010948 rhodium Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- BZENWVMGGHIOMD-UHFFFAOYSA-N 1-(1,1a,2,7b-tetrahydrocyclopropa[c]quinolin-3-yl)ethanone Chemical compound C12=CC=CC=C2N(C(=O)C)CC2C1C2 BZENWVMGGHIOMD-UHFFFAOYSA-N 0.000 description 6
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 6
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 6
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 6
- QEVFHSARMKZJDY-UHFFFAOYSA-N 5,8-difluoro-2h-chromene Chemical compound C1=CCOC2=C1C(F)=CC=C2F QEVFHSARMKZJDY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- IDJURXRPTLNZPD-BTZDVCGTSA-N (1s,1ar,7bs)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylic acid Chemical compound C1=CC(F)=C2[C@@H]3[C@H](C(=O)O)[C@@H]3COC2=C1F IDJURXRPTLNZPD-BTZDVCGTSA-N 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- VPUZXEGGNFLNNF-UHFFFAOYSA-N 4,7-difluoro-3-methyl-2,3-dihydroinden-1-one Chemical compound FC1=CC=C(F)C2=C1C(C)CC2=O VPUZXEGGNFLNNF-UHFFFAOYSA-N 0.000 description 5
- OMSOZMDPJCEEDR-UHFFFAOYSA-N 5,8-difluoro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=C1C(F)=CC=C2F OMSOZMDPJCEEDR-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 5
- ICSNLGPSRYBMBD-UHFFFAOYSA-N alpha-aminopyridine Natural products NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000011592 zinc chloride Substances 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- DNWYKNASZCPJOV-UHFFFAOYSA-N 1-(5-fluoro-2h-chromen-8-yl)propan-1-one Chemical compound C1=CCOC2=C1C(F)=CC=C2C(=O)CC DNWYKNASZCPJOV-UHFFFAOYSA-N 0.000 description 4
- QCELVCNDJKBEOC-UHFFFAOYSA-N 1-(5-hydroxy-2h-chromen-6-yl)ethanone Chemical compound O1CC=CC2=C(O)C(C(=O)C)=CC=C21 QCELVCNDJKBEOC-UHFFFAOYSA-N 0.000 description 4
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
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- YNWSXIWHOSSPCO-UHFFFAOYSA-N rhodium(2+) Chemical class [Rh+2] YNWSXIWHOSSPCO-UHFFFAOYSA-N 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical group OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 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 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
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- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- YRQMBQUMJFVZLF-UHFFFAOYSA-N tert-butyl n-(4-hydroxyphenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(O)C=C1 YRQMBQUMJFVZLF-UHFFFAOYSA-N 0.000 description 1
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
- CDVLKBNEFHFWOW-UHFFFAOYSA-N tert-butyl n-[4-(5-bromopyridin-2-yl)oxyphenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1OC1=CC=C(Br)C=N1 CDVLKBNEFHFWOW-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 150000003672 ureas Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0400021A SE0400021D0 (sv) | 2004-01-08 | 2004-01-08 | Non-nucleoside reverse transcriptase inhibitors |
| SE2004100021 | 2004-01-08 | ||
| SE0400585A SE0400585D0 (sv) | 2004-03-09 | 2004-03-09 | NNRTI Antivirals |
| SE2004100585 | 2004-03-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2337794T3 true ES2337794T3 (es) | 2010-04-29 |
Family
ID=34752289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04809207T Expired - Lifetime ES2337794T3 (es) | 2004-01-08 | 2004-12-30 | Inhibidores no nucleosidos de la transcriptasa inversa. |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US7915295B2 (enExample) |
| EP (1) | EP1701942B1 (enExample) |
| JP (1) | JP4762917B2 (enExample) |
| AT (1) | ATE451357T1 (enExample) |
| AU (1) | AU2004312284B2 (enExample) |
| BR (1) | BRPI0418306B8 (enExample) |
| CA (1) | CA2550187C (enExample) |
| DE (1) | DE602004024584D1 (enExample) |
| DK (1) | DK1701942T3 (enExample) |
| EA (1) | EA009700B1 (enExample) |
| ES (1) | ES2337794T3 (enExample) |
| IL (1) | IL176740A (enExample) |
| NZ (1) | NZ548367A (enExample) |
| SG (1) | SG149070A1 (enExample) |
| WO (1) | WO2005066131A1 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20050033663A (ko) * | 2002-09-05 | 2005-04-12 | 메디비르 아베 | 비-뉴클레오시드 역전사효소 억제제 |
| US7388008B2 (en) | 2004-08-02 | 2008-06-17 | Ambrilia Biopharma Inc. | Lysine based compounds |
| US20060287316A1 (en) * | 2005-04-27 | 2006-12-21 | Ambrilia Biopharma Inc. | Method for improving pharmacokinetics of protease inhibitors and protease inhibitor precursors |
| WO2007062526A1 (en) | 2005-11-30 | 2007-06-07 | Ambrilia Biopharma Inc. | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
| GB0608876D0 (en) * | 2006-05-05 | 2006-06-14 | Medivir Ab | Combination therapy |
| AU2007254325B2 (en) * | 2006-05-15 | 2012-05-10 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| ES2628730T3 (es) | 2006-09-21 | 2017-08-03 | Taimed Biologics, Inc. | Inhibidores de proteasa |
| EP3250552B1 (en) * | 2015-01-30 | 2019-03-27 | Genentech, Inc. | Therapeutic compounds and uses thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9906933A (pt) * | 1998-01-16 | 2001-11-27 | Medivir Ab | Antiviróticos |
| WO1999051613A1 (en) * | 1998-04-03 | 1999-10-14 | Medivir Ab | Prodrugs of phosphorous-containing pharmaceuticals |
| SE0100733D0 (sv) | 2001-03-05 | 2001-03-05 | Medivir Ab | Non-nucleoside reverse transcriptase inhibitors |
| SE0102867D0 (sv) * | 2001-08-28 | 2001-08-28 | Medivir Ab | Non-nucleoside reverse transcriptase inhibitors |
| KR20050033663A (ko) * | 2002-09-05 | 2005-04-12 | 메디비르 아베 | 비-뉴클레오시드 역전사효소 억제제 |
-
2004
- 2004-12-30 DE DE602004024584T patent/DE602004024584D1/de not_active Expired - Lifetime
- 2004-12-30 US US10/584,933 patent/US7915295B2/en not_active Expired - Fee Related
- 2004-12-30 JP JP2006549182A patent/JP4762917B2/ja not_active Expired - Fee Related
- 2004-12-30 SG SG200809639-8A patent/SG149070A1/en unknown
- 2004-12-30 AU AU2004312284A patent/AU2004312284B2/en not_active Ceased
- 2004-12-30 BR BRPI0418306A patent/BRPI0418306B8/pt not_active IP Right Cessation
- 2004-12-30 NZ NZ548367A patent/NZ548367A/en not_active IP Right Cessation
- 2004-12-30 WO PCT/SE2004/002034 patent/WO2005066131A1/en not_active Ceased
- 2004-12-30 CA CA2550187A patent/CA2550187C/en not_active Expired - Fee Related
- 2004-12-30 EP EP04809207A patent/EP1701942B1/en not_active Expired - Lifetime
- 2004-12-30 DK DK04809207.6T patent/DK1701942T3/da active
- 2004-12-30 ES ES04809207T patent/ES2337794T3/es not_active Expired - Lifetime
- 2004-12-30 AT AT04809207T patent/ATE451357T1/de not_active IP Right Cessation
- 2004-12-30 EA EA200601289A patent/EA009700B1/ru not_active IP Right Cessation
-
2006
- 2006-07-06 IL IL176740A patent/IL176740A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004312284A1 (en) | 2005-07-21 |
| US7915295B2 (en) | 2011-03-29 |
| BRPI0418306B1 (pt) | 2018-09-18 |
| JP2007519640A (ja) | 2007-07-19 |
| SG149070A1 (en) | 2009-01-29 |
| DK1701942T3 (da) | 2010-04-06 |
| BRPI0418306A (pt) | 2007-05-02 |
| IL176740A0 (en) | 2006-10-31 |
| CA2550187A1 (en) | 2005-07-21 |
| CA2550187C (en) | 2012-08-07 |
| WO2005066131A1 (en) | 2005-07-21 |
| EA200601289A1 (ru) | 2006-12-29 |
| IL176740A (en) | 2011-09-27 |
| EP1701942A1 (en) | 2006-09-20 |
| ATE451357T1 (de) | 2009-12-15 |
| US20080070951A1 (en) | 2008-03-20 |
| AU2004312284B2 (en) | 2010-08-05 |
| BRPI0418306B8 (pt) | 2021-05-25 |
| AU2004312284A2 (en) | 2005-07-21 |
| HK1101400A1 (en) | 2007-10-18 |
| EP1701942B1 (en) | 2009-12-09 |
| DE602004024584D1 (de) | 2010-01-21 |
| NZ548367A (en) | 2010-06-25 |
| EA009700B1 (ru) | 2008-02-28 |
| JP4762917B2 (ja) | 2011-08-31 |
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