CA2651579A1 - Integrase inhibitors - Google Patents
Integrase inhibitors Download PDFInfo
- Publication number
- CA2651579A1 CA2651579A1 CA002651579A CA2651579A CA2651579A1 CA 2651579 A1 CA2651579 A1 CA 2651579A1 CA 002651579 A CA002651579 A CA 002651579A CA 2651579 A CA2651579 A CA 2651579A CA 2651579 A1 CA2651579 A1 CA 2651579A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- compound
- optionally substituted
- nmr
- independently
- 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.)
- Abandoned
Links
- 239000002850 integrase inhibitor Substances 0.000 title description 6
- 229940124524 integrase inhibitor Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 352
- 238000000034 method Methods 0.000 claims abstract description 62
- 108010002459 HIV Integrase Proteins 0.000 claims abstract description 13
- 230000005764 inhibitory process Effects 0.000 claims abstract description 8
- -1 hydroxy, carboxy Chemical group 0.000 claims description 461
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 170
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 104
- 239000000203 mixture Substances 0.000 claims description 101
- 150000003839 salts Chemical class 0.000 claims description 95
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 69
- 239000000651 prodrug Substances 0.000 claims description 67
- 229940002612 prodrug Drugs 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- 229910052740 iodine Inorganic materials 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 31
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000004076 pyridyl group Chemical group 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 28
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 27
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 22
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 17
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 16
- 208000030507 AIDS Diseases 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 102100034343 Integrase Human genes 0.000 claims description 11
- 230000000840 anti-viral effect Effects 0.000 claims description 11
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
- 108010061833 Integrases Proteins 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- 125000005960 1,4-diazepanyl group Chemical group 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- KOAMXHRRVFDWRQ-UHFFFAOYSA-N 4,4-dimethyl-5h-1,3-oxazole Chemical compound CC1(C)COC=N1 KOAMXHRRVFDWRQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002955 immunomodulating agent Substances 0.000 claims description 6
- 229940121354 immunomodulator Drugs 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229960005475 antiinfective agent Drugs 0.000 claims description 5
- 239000004599 antimicrobial Substances 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 230000002584 immunomodulator Effects 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000006738 (C6-C20) heteroaryl group Chemical group 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZMSIFDIKIXVLDF-UHFFFAOYSA-N 2-methyl-1,3,4-oxadiazole Chemical compound CC1=NN=CO1 ZMSIFDIKIXVLDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229940122440 HIV protease inhibitor Drugs 0.000 claims description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 claims description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 claims description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 23
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims 2
- 241001465754 Metazoa Species 0.000 claims 2
- 229910019445 Mg(ClO4) Inorganic materials 0.000 claims 2
- IHCHOVVAJBADAH-UHFFFAOYSA-N n-[2-hydroxy-4-(1h-pyrazol-4-yl)phenyl]-6-methoxy-3,4-dihydro-2h-chromene-3-carboxamide Chemical compound C1C2=CC(OC)=CC=C2OCC1C(=O)NC(C(=C1)O)=CC=C1C=1C=NNC=1 IHCHOVVAJBADAH-UHFFFAOYSA-N 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 323
- 238000005481 NMR spectroscopy Methods 0.000 description 224
- 238000006243 chemical reaction Methods 0.000 description 174
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 163
- 101150041968 CDC13 gene Proteins 0.000 description 151
- 229910001868 water Inorganic materials 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 130
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 125
- 235000019439 ethyl acetate Nutrition 0.000 description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
- 239000000047 product Substances 0.000 description 107
- 239000000243 solution Substances 0.000 description 91
- 229940093499 ethyl acetate Drugs 0.000 description 82
- 239000012267 brine Substances 0.000 description 73
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 73
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 70
- 239000012044 organic layer Substances 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- 229910052938 sodium sulfate Inorganic materials 0.000 description 56
- 235000011152 sodium sulphate Nutrition 0.000 description 56
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 52
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 238000000746 purification Methods 0.000 description 47
- 239000007787 solid Substances 0.000 description 44
- 238000003756 stirring Methods 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- 239000007832 Na2SO4 Substances 0.000 description 43
- 230000015572 biosynthetic process Effects 0.000 description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 40
- 238000003786 synthesis reaction Methods 0.000 description 37
- 150000003951 lactams Chemical class 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 238000009472 formulation Methods 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- 229910000104 sodium hydride Inorganic materials 0.000 description 31
- 239000004480 active ingredient Substances 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 29
- 239000012043 crude product Substances 0.000 description 29
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 238000004293 19F NMR spectroscopy Methods 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- 238000010511 deprotection reaction Methods 0.000 description 23
- 150000002148 esters Chemical class 0.000 description 22
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 229910000024 caesium carbonate Inorganic materials 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000012512 characterization method Methods 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000012298 atmosphere Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- 238000007792 addition Methods 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 230000000875 corresponding effect Effects 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 239000002480 mineral oil Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 11
- 239000012448 Lithium borohydride Substances 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 150000003949 imides Chemical class 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 235000010446 mineral oil Nutrition 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 150000003009 phosphonic acids Chemical class 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 238000010626 work up procedure Methods 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000007821 HATU Substances 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
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- YFNGWGVTFYSJHE-UHFFFAOYSA-K trisodium;phosphonoformate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O YFNGWGVTFYSJHE-UHFFFAOYSA-K 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910009112 xH2O Inorganic materials 0.000 description 1
- 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 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80102006P | 2006-05-16 | 2006-05-16 | |
| US60/801,020 | 2006-05-16 | ||
| PCT/US2007/011851 WO2007136714A2 (en) | 2006-05-16 | 2007-05-16 | Integrase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2651579A1 true CA2651579A1 (en) | 2007-11-29 |
Family
ID=38573219
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002651579A Abandoned CA2651579A1 (en) | 2006-05-16 | 2007-05-16 | Integrase inhibitors |
Country Status (7)
| Country | Link |
|---|---|
| US (2) | US20090306054A1 (https=) |
| EP (1) | EP2066670A2 (https=) |
| JP (1) | JP2009537546A (https=) |
| AU (1) | AU2007254190A1 (https=) |
| CA (1) | CA2651579A1 (https=) |
| NZ (1) | NZ572367A (https=) |
| WO (1) | WO2007136714A2 (https=) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090291921A1 (en) * | 2007-11-20 | 2009-11-26 | Gilead Sciences, Inc. | Integrase inhibitors |
| US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
| US9018227B2 (en) | 2010-03-19 | 2015-04-28 | Indiana State University | Nicotinic acetylcholine receptor agonists |
| EP2691393B1 (en) | 2011-03-31 | 2016-09-14 | Pfizer Inc | Novel bicyclic pyridinones |
| EP4556010A3 (en) | 2011-11-30 | 2025-07-23 | Emory University | Jak inhibitors for use in the prevention or treatment of a viral disease caused by a coronaviridae |
| UA110688C2 (uk) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Біциклічні піридинони |
| MX368391B (es) | 2015-02-03 | 2019-09-30 | Pfizer | Ciclopropabenzofuranil-piridopirazindionas novedosas. |
| CN106632397B (zh) * | 2016-12-01 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | 一种6α-溴青霉烷-3α-羧酸二苯甲酯-1β-氧化物的制备方法 |
| ES2747768T3 (es) | 2017-03-20 | 2020-03-11 | Forma Therapeutics Inc | Composiciones de pirrolopirrol como activadores de quinasa de piruvato (PKR) |
| ES2989438T3 (es) | 2018-09-19 | 2024-11-26 | Novo Nordisk Healthcare Ag | Activación de la piruvato cinasa R |
| US12053458B2 (en) | 2018-09-19 | 2024-08-06 | Novo Nordisk Health Care Ag | Treating sickle cell disease with a pyruvate kinase R activating compound |
| CN112142714A (zh) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | 一种灭草烟的合成方法 |
| CN112142713A (zh) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | 一种咪草烟的合成方法 |
| CN112142712A (zh) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | 一种甲基咪草烟的合成方法 |
| US20220378756A1 (en) | 2019-09-19 | 2022-12-01 | Forma Therapeutics, Inc. | Activating pyruvate kinase r |
| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
| CN116675684B (zh) * | 2023-08-02 | 2023-11-07 | 上海翰森生物医药科技有限公司 | 含炔基稠环类衍生物拮抗剂、其制备方法和应用 |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816570A (en) * | 1982-11-30 | 1989-03-28 | The Board Of Regents Of The University Of Texas System | Biologically reversible phosphate and phosphonate protective groups |
| US4968788A (en) | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
| ATE131825T1 (de) | 1990-06-13 | 1996-01-15 | Arnold Glazier | Phosphorylierte prodrugs |
| EP0481214B1 (en) | 1990-09-14 | 1998-06-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| US5543523A (en) | 1994-11-15 | 1996-08-06 | Regents Of The University Of Minnesota | Method and intermediates for the synthesis of korupensamines |
| US5683999A (en) * | 1995-03-17 | 1997-11-04 | The Dupont Merck Pharmaceutical Company | Cyclic urea HIV protease inhibitors |
| US6312662B1 (en) * | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| WO1999062513A1 (en) | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
| WO1999062520A1 (en) | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
| AU3118200A (en) | 1998-12-14 | 2000-07-03 | Merck & Co., Inc. | Hiv integrase inhibitors |
| JP3929244B2 (ja) | 1998-12-25 | 2007-06-13 | 塩野義製薬株式会社 | Ｈｉｖインテグラーゼ阻害活性を有する芳香族ヘテロ環誘導体 |
| KR100423781B1 (ko) | 1999-06-02 | 2004-03-22 | 시오노기세이야쿠가부시키가이샤 | 신규 치환 프로페논 유도체의 제조방법 |
| JP2003503386A (ja) | 1999-06-25 | 2003-01-28 | メルク エンド カムパニー インコーポレーテッド | １−（芳香族またはヘテロ芳香族置換）−３−（ヘテロ芳香族置換）−１，３−プロパンジオン類およびそれの使用 |
| US6245806B1 (en) | 1999-08-03 | 2001-06-12 | Merck & Co., Inc. | HIV integrase inhibitors |
| WO2001027309A1 (en) * | 1999-10-13 | 2001-04-19 | Merck & Co., Inc. | Hiv integrase inhibitors |
| US6919351B2 (en) | 2000-10-12 | 2005-07-19 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors |
| JP2004513134A (ja) | 2000-10-12 | 2004-04-30 | メルク エンド カムパニー インコーポレーテッド | Ｈｉｖインテグラーゼ阻害薬として有用なアザ−およびポリアザ−ナフタレニルケトン類 |
| JP2004517860A (ja) | 2000-10-12 | 2004-06-17 | メルク エンド カムパニー インコーポレーテッド | Ｈｉｖインテグラーゼ阻害薬として有用なアザ−およびポリアザ−ナフタレニルカルボキサミド類 |
| CA2425440C (en) | 2000-10-12 | 2010-04-13 | Merck & Co., Inc. | Aza- and polyaza-naphthalenyl carboxamides useful as hiv integrase inhibitors |
| EP1541558B1 (en) * | 2002-08-13 | 2008-08-13 | Shionogi & Co., Ltd. | Heterocyclic compounds having hiv integrase inhibitory activity |
| US20040157804A1 (en) | 2002-10-16 | 2004-08-12 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
| KR20060006047A (ko) * | 2003-04-28 | 2006-01-18 | 티보텍 파마슈티칼즈 리미티드 | Ｈｉｖ 인테그레이즈 저해제 |
| TW200510425A (en) * | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
| WO2005075475A1 (ja) | 2004-02-04 | 2005-08-18 | Shionogi & Co., Ltd. | Ｈｉｖインテグラーゼ阻害活性を有するナフチリジン誘導体 |
| EP1742642B1 (en) | 2004-04-14 | 2008-10-15 | Gilead Sciences, Inc. | Phosphonate analogs of hiv integrase inhibitor compounds |
| TW200716632A (en) * | 2005-05-16 | 2007-05-01 | Gilead Sciences Inc | Integrase inhibitor compounds |
| WO2007076005A2 (en) | 2005-12-21 | 2007-07-05 | Gilead Sciences, Inc. | Processes and intermediates useful for preparing integrase inhibitor compounds |
-
2007
- 2007-05-16 NZ NZ572367A patent/NZ572367A/en not_active IP Right Cessation
- 2007-05-16 EP EP07794999A patent/EP2066670A2/en not_active Withdrawn
- 2007-05-16 AU AU2007254190A patent/AU2007254190A1/en not_active Abandoned
- 2007-05-16 JP JP2009511069A patent/JP2009537546A/ja active Pending
- 2007-05-16 US US12/299,885 patent/US20090306054A1/en not_active Abandoned
- 2007-05-16 US US11/804,041 patent/US8008287B2/en not_active Expired - Fee Related
- 2007-05-16 CA CA002651579A patent/CA2651579A1/en not_active Abandoned
- 2007-05-16 WO PCT/US2007/011851 patent/WO2007136714A2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP2066670A2 (en) | 2009-06-10 |
| AU2007254190A1 (en) | 2007-11-29 |
| WO2007136714A2 (en) | 2007-11-29 |
| WO2007136714A3 (en) | 2008-12-18 |
| JP2009537546A (ja) | 2009-10-29 |
| US20090306054A1 (en) | 2009-12-10 |
| NZ572367A (en) | 2011-09-30 |
| US20080058315A1 (en) | 2008-03-06 |
| US8008287B2 (en) | 2011-08-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |
Effective date: 20130612 |