DE69028552T2 - Diaromatische substituierte verbindungen gegen den aids-virus - Google Patents
Diaromatische substituierte verbindungen gegen den aids-virusInfo
- Publication number
- DE69028552T2 DE69028552T2 DE69028552T DE69028552T DE69028552T2 DE 69028552 T2 DE69028552 T2 DE 69028552T2 DE 69028552 T DE69028552 T DE 69028552T DE 69028552 T DE69028552 T DE 69028552T DE 69028552 T2 DE69028552 T2 DE 69028552T2
- Authority
- DE
- Germany
- Prior art keywords
- piperazine
- carbonyl
- pyridinyl
- alkyl
- methylethylamino
- 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
- 208000030507 AIDS Diseases 0.000 title claims abstract description 48
- 241000700605 Viruses Species 0.000 title description 4
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 28
- 150000001412 amines Chemical class 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 369
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 317
- 238000004519 manufacturing process Methods 0.000 claims description 136
- -1 1-piperazinyl Chemical group 0.000 claims description 120
- 229910052757 nitrogen Inorganic materials 0.000 claims description 56
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 238000012360 testing method Methods 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- HWRZDBIPSJPLTJ-UHFFFAOYSA-N (4-methoxy-3,5-dimethylphenyl)-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl]methanone Chemical compound C1=C(C)C(OC)=C(C)C=C1C(=O)N1CCN(C=2C(=CC=CN=2)NC(C)C)CC1 HWRZDBIPSJPLTJ-UHFFFAOYSA-N 0.000 claims description 2
- QWFZFHMHIGEGDP-UHFFFAOYSA-N (5-nitro-1h-indol-2-yl)-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl]methanone Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(C=C3C=2)[N+]([O-])=O)CC1 QWFZFHMHIGEGDP-UHFFFAOYSA-N 0.000 claims description 2
- WRLCWJMJVYMYQG-UHFFFAOYSA-N 2-[4-[(4-methoxy-3,5-dimethylphenyl)methyl]piperazin-1-yl]-n-propylpyridin-3-amine Chemical compound CCCNC1=CC=CN=C1N1CCN(CC=2C=C(C)C(OC)=C(C)C=2)CC1 WRLCWJMJVYMYQG-UHFFFAOYSA-N 0.000 claims description 2
- VAMZJJLNVAPDHG-UHFFFAOYSA-N 4-[[4-[3-(ethylamino)pyridin-2-yl]piperazin-1-yl]methyl]-2,6-dimethylphenol Chemical compound CCNC1=CC=CN=C1N1CCN(CC=2C=C(C)C(O)=C(C)C=2)CC1 VAMZJJLNVAPDHG-UHFFFAOYSA-N 0.000 claims description 2
- DFUQBAUJUIJXHL-UHFFFAOYSA-N [4-(2-ethoxyphenyl)piperazin-1-yl]-(1h-indol-2-yl)methanone Chemical compound CCOC1=CC=CC=C1N1CCN(C(=O)C=2NC3=CC=CC=C3C=2)CC1 DFUQBAUJUIJXHL-UHFFFAOYSA-N 0.000 claims description 2
- CFZHWLLIVBYXAQ-UHFFFAOYSA-N [4-(2-ethoxyphenyl)piperazin-1-yl]-(5-methoxy-1h-indol-2-yl)methanone Chemical compound CCOC1=CC=CC=C1N1CCN(C(=O)C=2NC3=CC=C(OC)C=C3C=2)CC1 CFZHWLLIVBYXAQ-UHFFFAOYSA-N 0.000 claims description 2
- LRPXCPVJVMDJBM-UHFFFAOYSA-N [4-[2-(ethylamino)phenyl]piperazin-1-yl]-(1h-indol-2-yl)methanone Chemical compound CCNC1=CC=CC=C1N1CCN(C(=O)C=2NC3=CC=CC=C3C=2)CC1 LRPXCPVJVMDJBM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000427 antigen Substances 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- LVWUXBAJWLJDCW-UHFFFAOYSA-N n-ethyl-2-[4-(1h-indol-2-ylmethyl)piperazin-1-yl]pyridin-3-amine Chemical compound CCNC1=CC=CN=C1N1CCN(CC=2NC3=CC=CC=C3C=2)CC1 LVWUXBAJWLJDCW-UHFFFAOYSA-N 0.000 claims description 2
- ZVJUASLGRLJEDC-UHFFFAOYSA-N n-ethyl-2-[4-[(4-methoxy-3,5-dimethylphenyl)methyl]piperazin-1-yl]pyridin-3-amine Chemical compound CCNC1=CC=CN=C1N1CCN(CC=2C=C(C)C(OC)=C(C)C=2)CC1 ZVJUASLGRLJEDC-UHFFFAOYSA-N 0.000 claims description 2
- BNDLDBQZWUWSHU-UHFFFAOYSA-N n-ethyl-2-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]pyridin-3-amine Chemical compound CCNC1=CC=CN=C1N1CCN(CC=2C=CC(OC)=CC=2)CC1 BNDLDBQZWUWSHU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 39
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 24
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 23
- 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 22
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims 7
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims 6
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 150000004820 halides Chemical class 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 239000000651 prodrug Substances 0.000 claims 2
- 229940002612 prodrug Drugs 0.000 claims 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims 1
- BQDKZFFSOSZPRX-UHFFFAOYSA-N 2-[methyl-(3-nitropyridin-2-yl)amino]ethyl 1h-indole-2-carboxylate Chemical compound C=1C2=CC=CC=C2NC=1C(=O)OCCN(C)C1=NC=CC=C1[N+]([O-])=O BQDKZFFSOSZPRX-UHFFFAOYSA-N 0.000 claims 1
- LKDRXBCSQODPBY-VRPWFDPXSA-N D-fructopyranose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-VRPWFDPXSA-N 0.000 claims 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims 1
- ZQKMMJNODQBEMI-UHFFFAOYSA-N [4-[3-(ethylamino)pyridin-2-yl]piperazin-1-yl]-(4-methoxy-3,5-dimethylphenyl)methanone Chemical compound CCNC1=CC=CN=C1N1CCN(C(=O)C=2C=C(C)C(OC)=C(C)C=2)CC1 ZQKMMJNODQBEMI-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 158
- 150000002475 indoles Chemical class 0.000 abstract description 18
- 125000004193 piperazinyl group Chemical group 0.000 abstract description 7
- 150000001420 substituted heterocyclic compounds Chemical class 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 225
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 174
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 239000000243 solution Substances 0.000 description 150
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 135
- 239000011541 reaction mixture Substances 0.000 description 133
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 130
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- 230000002829 reductive effect Effects 0.000 description 76
- 239000000203 mixture Substances 0.000 description 74
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 73
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 64
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 239000012267 brine Substances 0.000 description 51
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 45
- 229910002027 silica gel Inorganic materials 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 39
- 238000002844 melting Methods 0.000 description 37
- 230000008018 melting Effects 0.000 description 37
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 34
- 238000003818 flash chromatography Methods 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 33
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-MZCSYVLQSA-N CD3OD Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 29
- 239000003921 oil Substances 0.000 description 29
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 235000011152 sodium sulphate Nutrition 0.000 description 29
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 28
- 235000017557 sodium bicarbonate Nutrition 0.000 description 28
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 24
- 239000012141 concentrate Substances 0.000 description 23
- 150000004885 piperazines Chemical class 0.000 description 23
- COALJHRGWIXLFP-UHFFFAOYSA-N 2-piperazin-1-yl-n-propan-2-ylpyridin-3-amine Chemical compound CC(C)NC1=CC=CN=C1N1CCNCC1 COALJHRGWIXLFP-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 17
- 239000000284 extract Substances 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 12
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- WTXBRZCVLDTWLP-UHFFFAOYSA-N 5-fluoro-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C2NC(C(=O)O)=CC2=C1 WTXBRZCVLDTWLP-UHFFFAOYSA-N 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 102100034343 Integrase Human genes 0.000 description 10
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 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 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 229960002555 zidovudine Drugs 0.000 description 9
- WXVQURJGDUNJCS-UHFFFAOYSA-N 4-methoxy-3,5-dimethylbenzoic acid Chemical compound COC1=C(C)C=C(C(O)=O)C=C1C WXVQURJGDUNJCS-UHFFFAOYSA-N 0.000 description 8
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- ACCRDWKRCKTUDR-UHFFFAOYSA-N n-ethyl-2-piperazin-1-ylpyridin-3-amine Chemical compound CCNC1=CC=CN=C1N1CCNCC1 ACCRDWKRCKTUDR-UHFFFAOYSA-N 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 230000029812 viral genome replication Effects 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 7
- 208000031886 HIV Infections Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
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- YGSYDJCBFJYLSN-UHFFFAOYSA-N n-(2-fluoroethyl)-2-piperazin-1-ylpyridin-3-amine Chemical compound FCCNC1=CC=CN=C1N1CCNCC1 YGSYDJCBFJYLSN-UHFFFAOYSA-N 0.000 description 1
- CKGUBZXFRULSDL-UHFFFAOYSA-N n-methyl-2-piperazin-1-ylpyridin-3-amine Chemical compound CNC1=CC=CN=C1N1CCNCC1 CKGUBZXFRULSDL-UHFFFAOYSA-N 0.000 description 1
- QVZOSZHSJGRRDC-UHFFFAOYSA-N n-tert-butyl-2-piperazin-1-yl-1h-pyridazin-4-amine Chemical compound N1C=CC(NC(C)(C)C)=CN1N1CCNCC1 QVZOSZHSJGRRDC-UHFFFAOYSA-N 0.000 description 1
- AWRKYBDOCSLWSW-UHFFFAOYSA-N n-tert-butyl-2-piperazin-1-ylpyridin-4-amine Chemical compound CC(C)(C)NC1=CC=NC(N2CCNCC2)=C1 AWRKYBDOCSLWSW-UHFFFAOYSA-N 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- XITQUSLLOSKDTB-UHFFFAOYSA-N nitrofen Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(Cl)C=C1Cl XITQUSLLOSKDTB-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- AQNAFTNCILTEEN-UHFFFAOYSA-N tert-butyl 4-(3-prop-2-enylpyridin-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=NC=CC=C1CC=C AQNAFTNCILTEEN-UHFFFAOYSA-N 0.000 description 1
- NUYLYDNIBBUHBD-UHFFFAOYSA-N tert-butyl 4-[3-(prop-2-enylamino)pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=NC=CC=C1NCC=C NUYLYDNIBBUHBD-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- FBZONXHGGPHHIY-UHFFFAOYSA-N xanthurenic acid Chemical compound C1=CC=C(O)C2=NC(C(=O)O)=CC(O)=C21 FBZONXHGGPHHIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Indole Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45748389A | 1989-12-28 | 1989-12-28 | |
| US60383890A | 1990-10-25 | 1990-10-25 | |
| PCT/US1990/007390 WO1991009849A1 (en) | 1989-12-28 | 1990-12-24 | Diaromatic substituted anti-aids compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69028552D1 DE69028552D1 (de) | 1996-10-17 |
| DE69028552T2 true DE69028552T2 (de) | 1997-03-06 |
Family
ID=27038621
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69028552T Expired - Lifetime DE69028552T2 (de) | 1989-12-28 | 1990-12-24 | Diaromatische substituierte verbindungen gegen den aids-virus |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0507861B1 (https=) |
| JP (1) | JPH07110852B2 (https=) |
| KR (1) | KR0179637B1 (https=) |
| AT (1) | ATE142621T1 (https=) |
| AU (1) | AU654808B2 (https=) |
| CA (1) | CA2071529C (https=) |
| DE (1) | DE69028552T2 (https=) |
| DK (1) | DK0507861T3 (https=) |
| ES (1) | ES2093090T3 (https=) |
| GR (1) | GR3021655T3 (https=) |
| HK (1) | HK1002235A1 (https=) |
| HU (2) | HUT61296A (https=) |
| MX (1) | MX9203454A (https=) |
| RU (1) | RU2099335C1 (https=) |
| WO (1) | WO1991009849A1 (https=) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5563142A (en) * | 1989-12-28 | 1996-10-08 | The Upjohn Company | Diaromatic substituted compounds as anti-HIV-1 agents |
| US5599930A (en) * | 1991-07-03 | 1997-02-04 | The Upjohn Company | Substituted indoles as anti-AIDS pharmaceuticals |
| DE69217224T2 (de) * | 1991-07-03 | 1997-06-05 | Pharmacia & Upjohn Co., Kalamazoo, Mich. | Substituierte indole als anti-aids pharmaceutische zubereitungen |
| WO1993005020A1 (en) * | 1991-09-06 | 1993-03-18 | Merck & Co., Inc. | Indoles as inhibitors of hiv reverse transcriptase |
| US5527819A (en) * | 1991-09-06 | 1996-06-18 | Merck & Co., Inc. | Inhibitors of HIV reverse transcriptase |
| JPH05255089A (ja) * | 1991-12-18 | 1993-10-05 | Sanwa Kagaku Kenkyusho Co Ltd | 抗ウイルス剤 |
| PH30258A (en) * | 1991-12-30 | 1997-02-05 | Janssen Pharmaceutica Nv | Heterocycle-substituted benzenemethanamine derivatives |
| US6177435B1 (en) | 1992-05-13 | 2001-01-23 | Glaxo Wellcome Inc. | Therapeutic combinations |
| ATE184787T1 (de) * | 1992-05-13 | 1999-10-15 | Wellcome Found | Therapeutische kombinationen |
| US5665720A (en) * | 1992-08-07 | 1997-09-09 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
| HUT74614A (en) * | 1993-02-24 | 1997-01-28 | Merck & Co Inc | Nindol derivates suitable for treatment of infection by hiv and pharmaceutical compositions containing them |
| US6169107B1 (en) | 1993-04-28 | 2001-01-02 | Sumitomo Pharmaceutical Co., Ltd. | Indoloylguanidine derivatives |
| SK282424B6 (sk) * | 1994-04-15 | 2002-01-07 | Pharmacia + Upjohn Company | "S" a "T" kryštalické formy 1-[5-metánsulfónamidoindolyl-2- karbonyl]-4-[3-(1-metyl-etylamino)-2-pyridinyl] piperazínu |
| TW406075B (en) * | 1994-12-13 | 2000-09-21 | Upjohn Co | Alkyl substituted piperidinyl and piperazinyl anti-AIDS compounds |
| UA56992C2 (uk) * | 1995-05-08 | 2003-06-16 | Фармація Енд Апджон Компані | <font face="Symbol">a</font>-ПІРИМІДИНТІОАЛКІЛЗАМІЩЕНІ ТА <font face="Symbol">a</font>-ПІРИМІДИНОКСОАЛКІЛЗАМІЩЕНІ СПОЛУКИ |
| AT403803B (de) | 1996-04-19 | 1998-05-25 | Sanochemia Ltd | Neue benzazepinderivate, diese enthaltende arzneimittel und verwendung derselben zum herstellen von arzneimitteln |
| CN1254334A (zh) * | 1997-05-27 | 2000-05-24 | 同和药品工业株式会社 | 新颖的对苯二甲酰胺衍生物 |
| JP4219554B2 (ja) * | 1997-10-01 | 2009-02-04 | 協和発酵キリン株式会社 | ベンゾフラン誘導体 |
| ATE491689T1 (de) * | 1997-10-27 | 2011-01-15 | Neurosearch As | Heteroaryl diazacycloalkane als cholinergische ligande für nikotin-acetylcholin-rezeptoren |
| PL343249A1 (en) * | 1998-03-26 | 2001-07-30 | Shionogi & Co | Indole derivatives with antiviral activity |
| US6228880B1 (en) | 1998-04-13 | 2001-05-08 | American Home Products Corp | 4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists |
| JP4865129B2 (ja) | 1999-01-13 | 2012-02-01 | ザ・リサーチ・ファウンデーション・オブ・ステイト・ユニバーシティ・オブ・ニューヨーク | タンパク質キナーゼ阻害剤を設計するための新規の方法 |
| US7635690B2 (en) * | 1999-01-22 | 2009-12-22 | Emory University | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine |
| US7115584B2 (en) * | 1999-01-22 | 2006-10-03 | Emory University | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine |
| DE19934432A1 (de) * | 1999-07-22 | 2001-02-01 | Merck Patent Gmbh | Indolderivate |
| US20020061892A1 (en) * | 2000-02-22 | 2002-05-23 | Tao Wang | Antiviral azaindole derivatives |
| US20030207910A1 (en) * | 2001-02-02 | 2003-11-06 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| WO2002072548A2 (en) * | 2001-03-09 | 2002-09-19 | Ortho-Mcneil Pharmaceutical, Inc. | Heterocyclic compounds and their use as histamine h4 ligands. |
| US7005445B2 (en) | 2001-10-22 | 2006-02-28 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
| US7129225B2 (en) | 2001-10-22 | 2006-10-31 | The Research Foundation Of State University Of New York | Protection against and treatment of hearing loss |
| TW200402417A (en) * | 2002-06-21 | 2004-02-16 | Akzo Nobel Nv | 1-[(Indol-3-yl)carbonyl]piperazine derivatives |
| WO2004022060A2 (en) * | 2002-09-06 | 2004-03-18 | Janssen Pharmaceutica, N.V. | (1h-benzoimidazol-2-yl)-(piperazinyl)-methanone derivatives and related compounds as histamine h4-receptor antagonists for the treatment of inflammatory and allergic disorders |
| WO2004108671A1 (en) * | 2003-06-06 | 2004-12-16 | Suven Life Sciences Limited | Substituted indoles with serotonin receptor affinity, process for their preparation and pharmaceutical compositions containing them |
| US20050075364A1 (en) * | 2003-07-01 | 2005-04-07 | Kap-Sun Yeung | Indole, azaindole and related heterocyclic N-substituted piperazine derivatives |
| US7829712B2 (en) | 2004-09-20 | 2010-11-09 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase |
| CA2580762A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as therapeutic agents |
| CA2580857A1 (en) | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| AR051091A1 (es) | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa |
| EP1807085B1 (en) | 2004-09-20 | 2013-08-21 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| AU2005286648A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| EP2289510A1 (en) | 2004-09-20 | 2011-03-02 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes |
| EP1870401A4 (en) | 2005-04-06 | 2011-06-15 | Msd Kk | 1,4-SUBSTITUTED PIPERAZINE DERIVATIVE |
| AU2006343359A1 (en) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| CN100463907C (zh) * | 2006-02-10 | 2009-02-25 | 上海医药工业研究院 | 一种1-(5-硝基-1h-吲哚-2-羰基)-4-{3-[(1-甲基乙基)氨基]-2-吡啶}哌嗪的制备方法 |
| CA2655933C (en) | 2006-06-23 | 2014-09-09 | Alethia Biotherapeutics Inc. | Polynucleotides and polypeptide sequences involved in cancer |
| US7838542B2 (en) | 2006-06-29 | 2010-11-23 | Kinex Pharmaceuticals, Llc | Bicyclic compositions and methods for modulating a kinase cascade |
| BRPI0915720A2 (pt) | 2008-06-12 | 2015-08-04 | Janssen Pharmaceutica Nv | Moduladores de diaminopiridina, pirimidina, e piridazina do receptor de histamina h4 |
| WO2010025375A1 (en) * | 2008-08-29 | 2010-03-04 | Treventis Corporation | Compositions and methods of treating amyloid disease |
| KR20110084280A (ko) | 2008-11-03 | 2011-07-21 | 알레시아 바이오쎄라퓨틱스 인코포레이티드 | 종양 항원의 생물 활성을 특이적으로 차단하는 항체 |
| WO2010141805A1 (en) | 2009-06-05 | 2010-12-09 | Janssen Pharmaceutica Nv | Heterocyclic amides as modulators of trpa1 |
| CN114010776A (zh) | 2010-06-09 | 2022-02-08 | 疫苗技术股份有限公司 | 用于增强抗逆转录病毒治疗的hiv感染者的治疗性免疫 |
| RS59080B1 (sr) | 2011-03-31 | 2019-09-30 | Adc Therapeutics Sa | Antitela protiv antigena 1 povezanog sa bubrezima i njihovi fragmenti koji se vezuju za antigen |
| CN102952062B (zh) * | 2011-08-12 | 2016-06-08 | 中国医学科学院医药生物技术研究所 | 取代苯并杂环类化合物及其制备方法和应用 |
| DE102011113749A1 (de) * | 2011-09-14 | 2013-03-14 | Aicuris Gmbh & Co. Kg | Sulfonsäuresalze Heterocyclylamid-substituiertr Imidazole |
| HRP20190946T1 (hr) | 2012-01-09 | 2019-07-26 | Adc Therapeutics Sa | Sredstva za liječenje trostruko negativnog raka dojke |
| CA2889903C (en) | 2012-10-29 | 2021-03-09 | Manjinder Singh Phull | Antiviral phosphonate analogues and process for preparation thereof |
| CN103351328A (zh) * | 2013-07-27 | 2013-10-16 | 上海泰坦科技股份有限公司 | 一种氟代吲哚酯的制备方法 |
| CN109776403B (zh) * | 2019-02-22 | 2022-06-14 | 吉林大学 | 一种制备1-叔丁氧羰基-4-[3-(烷基胺基)-2-吡啶基]哌嗪的方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4302589A (en) * | 1980-05-08 | 1981-11-24 | American Cyanamid Company | Cis-mono and disubstituted-2-methyl-3-[(piperazinyl) and (piperidino)ethyl]indolines, intermediates for their preparation and methods of preparation |
| US4613598A (en) * | 1984-03-13 | 1986-09-23 | Mitsubishi Chemical Industries Limited | Piperazine derivatives and their acid addition salts |
| CA1338012C (en) * | 1987-04-27 | 1996-01-30 | John Michael Mccall | Pharmaceutically active amines |
| US4954502A (en) * | 1988-06-10 | 1990-09-04 | Bristol-Myers Squibb Company | 1-indolyalkyl-4-(substituted-pyridinyl)piperazines |
-
1990
- 1990-12-24 HK HK98101254A patent/HK1002235A1/en not_active IP Right Cessation
- 1990-12-24 AU AU71732/91A patent/AU654808B2/en not_active Expired
- 1990-12-24 JP JP3502810A patent/JPH07110852B2/ja not_active Expired - Lifetime
- 1990-12-24 DK DK91902628.6T patent/DK0507861T3/da active
- 1990-12-24 CA CA002071529A patent/CA2071529C/en not_active Expired - Fee Related
- 1990-12-24 HU HU922131A patent/HUT61296A/hu unknown
- 1990-12-24 ES ES91902628T patent/ES2093090T3/es not_active Expired - Lifetime
- 1990-12-24 RU SU925011431A patent/RU2099335C1/ru active
- 1990-12-24 WO PCT/US1990/007390 patent/WO1991009849A1/en not_active Ceased
- 1990-12-24 AT AT91902628T patent/ATE142621T1/de not_active IP Right Cessation
- 1990-12-24 EP EP91902628A patent/EP0507861B1/en not_active Expired - Lifetime
- 1990-12-24 MX MX9203454A patent/MX9203454A/es unknown
- 1990-12-24 DE DE69028552T patent/DE69028552T2/de not_active Expired - Lifetime
-
1992
- 1992-06-27 KR KR1019920701536A patent/KR0179637B1/ko not_active Expired - Lifetime
-
1995
- 1995-06-23 HU HU95P/P00412P patent/HU211241A9/hu unknown
-
1996
- 1996-11-14 GR GR960403026T patent/GR3021655T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2099335C1 (ru) | 1997-12-20 |
| WO1991009849A1 (en) | 1991-07-11 |
| HU211241A9 (en) | 1995-11-28 |
| GR3021655T3 (en) | 1997-02-28 |
| EP0507861B1 (en) | 1996-09-11 |
| HUT61296A (en) | 1992-12-28 |
| KR0179637B1 (en) | 1999-03-20 |
| DK0507861T3 (https=) | 1997-03-03 |
| CA2071529C (en) | 2001-03-20 |
| DE69028552D1 (de) | 1996-10-17 |
| AU7173291A (en) | 1991-07-24 |
| HU9202131D0 (en) | 1992-10-28 |
| KR927003556A (ko) | 1992-12-18 |
| JPH07110852B2 (ja) | 1995-11-29 |
| ES2093090T3 (es) | 1996-12-16 |
| CA2071529A1 (en) | 1991-06-29 |
| EP0507861A1 (en) | 1992-10-14 |
| MX9203454A (es) | 1992-08-01 |
| AU654808B2 (en) | 1994-11-24 |
| HK1002235A1 (en) | 1998-08-07 |
| ATE142621T1 (de) | 1996-09-15 |
| JPH05503929A (ja) | 1993-06-24 |
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