ES2254367T3 - Derivados azaindoles antivirales. - Google Patents
Derivados azaindoles antivirales.Info
- Publication number
- ES2254367T3 ES2254367T3 ES01904970T ES01904970T ES2254367T3 ES 2254367 T3 ES2254367 T3 ES 2254367T3 ES 01904970 T ES01904970 T ES 01904970T ES 01904970 T ES01904970 T ES 01904970T ES 2254367 T3 ES2254367 T3 ES 2254367T3
- Authority
- ES
- Spain
- Prior art keywords
- compound
- group
- carbon
- alkynyl
- alkyl
- 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
Links
- 230000000840 anti-viral effect Effects 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 83
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 44
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 42
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 39
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
- 125000004429 atom Chemical group 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- 208000030507 AIDS Diseases 0.000 claims description 77
- -1 atoms halogen Chemical class 0.000 claims description 60
- 239000000460 chlorine Substances 0.000 claims description 38
- 208000031886 HIV Infections Diseases 0.000 claims description 32
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 208000037357 HIV infectious disease Diseases 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 28
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 28
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 6
- 229960005475 antiinfective agent Drugs 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000002955 immunomodulating agent Substances 0.000 claims description 6
- 229940121354 immunomodulator Drugs 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 230000002584 immunomodulator Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 106
- 230000014759 maintenance of location Effects 0.000 description 104
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- 238000005481 NMR spectroscopy Methods 0.000 description 66
- 238000002360 preparation method Methods 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 52
- 238000000034 method Methods 0.000 description 51
- 238000012512 characterization method Methods 0.000 description 44
- 239000000243 solution Substances 0.000 description 44
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 41
- 241000725303 Human immunodeficiency virus Species 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000000203 mixture Substances 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 30
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 30
- 239000003112 inhibitor Substances 0.000 description 30
- 208000015181 infectious disease Diseases 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- 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 description 26
- 230000005764 inhibitory process Effects 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 24
- 229960002555 zidovudine Drugs 0.000 description 24
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 229940079593 drug Drugs 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical class C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000002777 nucleoside Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- 108091005804 Peptidases Proteins 0.000 description 8
- 239000004365 Protease Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 8
- 150000004820 halides Chemical class 0.000 description 8
- 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 8
- 229960001936 indinavir Drugs 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 229910052727 yttrium Inorganic materials 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- NRSGWEVTVGZDFC-UHFFFAOYSA-N 6-chloro-4-n-[3,5-difluoro-4-[(3-methyl-1h-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]pyrimidine-2,4-diamine Chemical compound C=12C(C)=CNC2=NC=CC=1OC(C(=C1)F)=C(F)C=C1NC1=CC(Cl)=NC(N)=N1 NRSGWEVTVGZDFC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 208000007766 Kaposi sarcoma Diseases 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 150000002148 esters Chemical class 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
- 239000000543 intermediate Substances 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 5
- 229940127007 Compound 39 Drugs 0.000 description 5
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 5
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 5
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 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 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229960003804 efavirenz Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 229940079322 interferon Drugs 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 description 5
- 150000004885 piperazines Chemical class 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- 239000011592 zinc chloride Substances 0.000 description 5
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 4
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 4
- UPDSOLUKSUHRDC-UHFFFAOYSA-N 4-methoxy-1h-pyrrolo[2,3-c]pyridine Chemical compound COC1=CN=CC2=C1C=CN2 UPDSOLUKSUHRDC-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- LCTSNWJDFWULAX-UHFFFAOYSA-N 7-chloro-4-fluoro-1h-pyrrolo[2,3-c]pyridine Chemical compound FC1=CN=C(Cl)C2=C1C=CN2 LCTSNWJDFWULAX-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
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- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 1
- 229960004517 thymopentin Drugs 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 229960000838 tipranavir Drugs 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
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
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- 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
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
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- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US18400400P | 2000-02-22 | 2000-02-22 | |
| US184004P | 2000-02-22 |
Publications (1)
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|---|---|
| ES2254367T3 true ES2254367T3 (es) | 2006-06-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| ES01904970T Expired - Lifetime ES2254367T3 (es) | 2000-02-22 | 2001-01-19 | Derivados azaindoles antivirales. |
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| NZ (1) | NZ520317A (enExample) |
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| US20040110785A1 (en) * | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| US20030207910A1 (en) * | 2001-02-02 | 2003-11-06 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| PL364279A1 (en) * | 2001-02-02 | 2004-12-13 | Bristol-Myers Squibb Company | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| US6825201B2 (en) * | 2001-04-25 | 2004-11-30 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic amidopiperazine derivatives |
| US20030236277A1 (en) | 2002-02-14 | 2003-12-25 | Kadow John F. | Indole, azaindole and related heterocyclic pyrrolidine derivatives |
| US20040162298A1 (en) * | 2002-02-23 | 2004-08-19 | Hsu-Tso Ho | Method of treating HIV infection by preventing interaction of CD4 and gp120 |
| US20040063744A1 (en) * | 2002-05-28 | 2004-04-01 | Tao Wang | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
| US20050075364A1 (en) * | 2003-07-01 | 2005-04-07 | Kap-Sun Yeung | Indole, azaindole and related heterocyclic N-substituted piperazine derivatives |
| JP5138938B2 (ja) | 2003-12-19 | 2013-02-06 | プレキシコン インコーポレーテッド | Ｒｅｔ調節剤の開発のための化合物および方法 |
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| CN1953985B (zh) * | 2004-03-15 | 2010-06-09 | 布里斯托尔-迈尔斯斯奎布公司 | 哌嗪和取代的哌啶抗病毒药物的前药 |
| US20050252408A1 (en) * | 2004-05-17 | 2005-11-17 | Richardson H W | Particulate wood preservative and method for producing same |
| DK1753764T3 (da) | 2004-06-09 | 2009-02-16 | Glaxo Group Ltd | Pyrrolopyridin-derivater |
| US7498342B2 (en) | 2004-06-17 | 2009-03-03 | Plexxikon, Inc. | Compounds modulating c-kit activity |
| US20060100209A1 (en) * | 2004-11-09 | 2006-05-11 | Chong-Hui Gu | Formulations of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethane-1,2-dione |
| US20060100432A1 (en) * | 2004-11-09 | 2006-05-11 | Matiskella John D | Crystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethane-1,2-dione |
| US7183284B2 (en) * | 2004-12-29 | 2007-02-27 | Bristol-Myers Squibb Company | Aminium salts of 1,2,3-triazoles as prodrugs of drugs including antiviral agents |
| US7601715B2 (en) | 2005-06-22 | 2009-10-13 | Bristol-Myers Squibb Company | Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein |
| EP1910573B1 (en) | 2005-07-22 | 2013-09-04 | CytoDyn, Inc. | Methods for reducing viral load in hiv-1-infected patients |
| US7598380B2 (en) * | 2005-08-03 | 2009-10-06 | Bristol-Myers Squibb Company | Method of preparation of azaindole derivatives |
| US7396830B2 (en) * | 2005-10-04 | 2008-07-08 | Bristol-Myers Squibb Company | Piperazine amidines as antiviral agents |
| US7622466B2 (en) * | 2005-11-18 | 2009-11-24 | Hoffman-La Roche Inc. | Azaindole-2-carboxamide derivatives |
| US7851476B2 (en) * | 2005-12-14 | 2010-12-14 | Bristol-Myers Squibb Company | Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-YL)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-YL]-1,2-dioxoethyl]-piperazine |
| US7807671B2 (en) * | 2006-04-25 | 2010-10-05 | Bristol-Myers Squibb Company | Diketo-piperazine and piperidine derivatives as antiviral agents |
| WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
| MX2009013431A (es) * | 2007-06-18 | 2010-01-15 | Sanofi Aventis | Derivados de pirrol como antagonistas de p2y12. |
| JP2010533729A (ja) | 2007-07-17 | 2010-10-28 | プレキシコン，インコーポレーテッド | キナーゼ調節のための化合物と方法、及びそのための適応 |
| WO2009011912A1 (en) * | 2007-07-18 | 2009-01-22 | Bristol-Myers Squibb Company | A composition for treating hiv comprising virus-like particles |
| CA2712701A1 (en) | 2008-01-31 | 2009-08-06 | Henning Steinhagen | Cyclic azaindole-3-carboxamides, their preparation and their use as pharmaceuticals |
| CN102143739B (zh) * | 2008-09-04 | 2014-12-17 | 百时美施贵宝公司 | 用于最优化传递hiv附着抑制剂的稳定的药用组合物 |
| CA2738573C (en) | 2009-04-03 | 2013-02-19 | F. Hoffmann-La Roche Ag | Compositions of propane-1 sulfonic acid {3-[5-(4-chloro-phenyl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and uses thereof |
| JP2013510166A (ja) | 2009-11-06 | 2013-03-21 | プレキシコン インコーポレーテッド | キナーゼ調節のための化合物、方法およびその適用 |
| US8912195B2 (en) | 2010-12-02 | 2014-12-16 | Bristol-Myers Squibb Company | Alkyl amides as HIV attachment inhibitors |
| PE20141360A1 (es) | 2011-02-07 | 2014-10-13 | Plexxikon Inc | Compuestos y metodos para la modulacion de quinasas e indicaciones para los mismos. |
| TWI558702B (zh) | 2011-02-21 | 2016-11-21 | 普雷辛肯公司 | 醫藥活性物質的固態形式 |
| WO2012142080A1 (en) | 2011-04-12 | 2012-10-18 | Bristol-Myers Squibb Company | Thioamide, amidoxime and amidrazone derivatives as hiv attachment inhibitors |
| EP2751119B1 (en) | 2011-08-29 | 2016-11-23 | VIIV Healthcare UK (No.5) Limited | Fused bicyclic diamine derivatives as hiv attachment inhibitors |
| WO2013033059A1 (en) | 2011-08-29 | 2013-03-07 | Bristol-Myers Squibb Company | Spiro bicyclic diamine derivatives as hiv attachment inhibitors |
| US9193725B2 (en) | 2012-03-14 | 2015-11-24 | Bristol-Meyers Squibb Company | Cyclic hydrazine derivatives as HIV attachment inhibitors |
| US9150570B2 (en) | 2012-05-31 | 2015-10-06 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| CN102746295B (zh) * | 2012-06-20 | 2014-10-15 | 上海阿达玛斯试剂有限公司 | 4位取代-7-氮杂吲哚的制备方法 |
| WO2014025854A1 (en) | 2012-08-09 | 2014-02-13 | Bristol-Myers Squibb Company | Piperidine amide derivatives as hiv attachment inhibitors |
| ES2616432T3 (es) | 2012-08-09 | 2017-06-13 | VIIV Healthcare UK (No.5) Limited | Derivados de alquenos tricíclicos como inhibidores de la unión del VIH |
| CN109528749B (zh) * | 2017-09-22 | 2023-04-28 | 上海交通大学医学院附属瑞金医院 | 长链非编码rna-h19在制备治疗垂体瘤药物中的用途 |
| CA3196620A1 (en) | 2020-10-05 | 2022-04-14 | Enliven Therapeutics, Inc. | 5- and 6-azaindole compounds for inhibition of bcr-abl tyrosine kinases |
| CN118515629A (zh) * | 2020-11-24 | 2024-08-20 | 中国人民解放军海军军医大学 | 一类取代苯甲酰哌嗪类化合物及其应用 |
| CN115855899B (zh) * | 2022-11-24 | 2025-06-10 | 常熟理工学院 | 一种荧光探针检测二氧化硫衍生物的应用 |
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| MX9203454A (es) * | 1989-12-28 | 1992-08-01 | Upjohn Co | Compuestos anti sida diaromaticos substituidos. |
| US5424329A (en) * | 1993-08-18 | 1995-06-13 | Warner-Lambert Company | Indole-2-carboxamides as inhibitors of cell adhesion |
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- 2001-01-19 NZ NZ520317A patent/NZ520317A/en not_active IP Right Cessation
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- 2001-01-19 AU AU2001232895A patent/AU2001232895B2/en not_active Ceased
- 2001-01-19 PT PT01904970T patent/PT1257276E/pt unknown
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- 2001-01-19 PL PL01357434A patent/PL357434A1/xx not_active Application Discontinuation
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- 2001-02-06 MY MYPI20010516A patent/MY128458A/en unknown
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- 2001-02-19 AR ARP010100742A patent/AR029469A1/es active IP Right Grant
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- 2001-02-20 CO CO01013156A patent/CO5271657A1/es not_active Application Discontinuation
- 2001-02-21 UY UY26593A patent/UY26593A1/es not_active IP Right Cessation
- 2001-02-22 PE PE2001000190A patent/PE20020786A1/es not_active Application Discontinuation
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2002
- 2002-07-30 ZA ZA200206073A patent/ZA200206073B/en unknown
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2006
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