CN1214013C - 抑制hiv复制的嘧啶类 - Google Patents
抑制hiv复制的嘧啶类 Download PDFInfo
- Publication number
- CN1214013C CN1214013C CNB998119180A CN99811918A CN1214013C CN 1214013 C CN1214013 C CN 1214013C CN B998119180 A CNB998119180 A CN B998119180A CN 99811918 A CN99811918 A CN 99811918A CN 1214013 C CN1214013 C CN 1214013C
- Authority
- CN
- China
- Prior art keywords
- amino
- alkyl
- compound
- group
- cyano group
- 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
- 150000003230 pyrimidines Chemical class 0.000 title description 4
- 230000002401 inhibitory effect Effects 0.000 title 1
- 230000010076 replication Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 150
- -1 cyano, nitro, amino Chemical group 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract description 19
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 13
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 11
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 127
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 93
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 74
- 229910052736 halogen Inorganic materials 0.000 claims description 68
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 45
- 239000002585 base Substances 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 26
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000000654 additive Chemical class 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000012298 atmosphere Substances 0.000 claims description 9
- 230000000798 anti-retroviral effect Effects 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 2
- 229940079593 drug Drugs 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
- 238000000746 purification Methods 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 4
- 239000003937 drug carrier Substances 0.000 claims 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 3
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 239000000890 drug combination Substances 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 abstract 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 abstract 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 abstract 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 abstract 1
- 150000001204 N-oxides Chemical class 0.000 abstract 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 81
- 239000000203 mixture Substances 0.000 description 60
- 239000000543 intermediate Substances 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- 238000000935 solvent evaporation Methods 0.000 description 38
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000007789 gas Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000004587 chromatography analysis Methods 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 229920000858 Cyclodextrin Polymers 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000007701 flash-distillation Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000007789 sealing Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000002131 composite material Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000036436 anti-hiv Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 3
- 229920013820 alkyl cellulose Polymers 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- 125000000524 functional group Chemical group 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
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- 238000001556 precipitation Methods 0.000 description 3
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- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
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- 208000011580 syndromic disease Diseases 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- VORGEKLKDILWPU-UHFFFAOYSA-N 1,1'-biphenyl;1h-tetrazol-1-ium;bromide Chemical compound [Br-].[NH2+]1C=NN=N1.C1=CC=CC=C1C1=CC=CC=C1 VORGEKLKDILWPU-UHFFFAOYSA-N 0.000 description 2
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- UNBMPKNTYKDYCG-UHFFFAOYSA-N 4-methylpentan-2-amine Chemical compound CC(C)CC(C)N UNBMPKNTYKDYCG-UHFFFAOYSA-N 0.000 description 2
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- XTVRVBVKLVPELA-UHFFFAOYSA-N C(C)(=O)ClC(C)=O Chemical compound C(C)(=O)ClC(C)=O XTVRVBVKLVPELA-UHFFFAOYSA-N 0.000 description 2
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- 239000001116 FEMA 4028 Substances 0.000 description 2
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- 230000005526 G1 to G0 transition Effects 0.000 description 2
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- 238000004566 IR spectroscopy Methods 0.000 description 2
- 208000008771 Lymphadenopathy Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 2
- 101100366940 Mus musculus Stom gene Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- AXDLCFOOGCNDST-UHFFFAOYSA-N N-methyl-DL-tyrosine Natural products CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- WTTIBCHOELPGFK-LBPRGKRZSA-N r82150 Chemical compound C1N(CC=C(C)C)[C@@H](C)CN2C(=S)NC3=CC=CC1=C32 WTTIBCHOELPGFK-LBPRGKRZSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229940104230 thymidine Drugs 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
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- SYUVAXDZVWPKSI-UHFFFAOYSA-N tributyl(phenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1 SYUVAXDZVWPKSI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
Abstract
本发明是关于下式化合物,其N-氧化物,制药上可接受的加成盐类,季胺类及立体化学异构型式于制备用来治疗患HIV(人类免疫缺乏病毒)感染的疾病的医药品的用途,其中,-a1=a2-a3=a4-与相连的乙烯基一起形成一苯基,吡啶基,嘧啶基,哒嗪基或吡嗪基;n为0至4;且可能为5;R1为氢,芳基,甲酰基,C1-6烷基羰基,C1-6烷基,C1-6烷氧基羰基,取代的C1-6烷基,或经取代的C1-6烷氧基C1-6烷基羰基;每一个R2各自独立为羟基,卤素,选择性取代的C1-6烷基,C2-6烯基或C2-6炔基,C3-7环烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或一个五元杂环;P为1或2;L为选择性取代的C1-10烷基,C2-10烯基,C2-10炔基或C3-7环烷基;或L为-X-R3,其中R3为选择性取代的苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基;X为-NR1-,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)-或-S(=O)2-;Q为氢;C1-6烷基,卤素,多卤素-C1-6烷基或经选择取代的氨基,Y代表羟基,卤素,C3-7环烷基,经选择取代的C1-6烷基,C2-6烯基或C2-6炔基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或芳基,芳基为经选择取代的苯基,Het为经选择取代的杂环基。
Description
本发明是关于具有人类免疫缺乏病毒(HIV)复制抑制特征的嘧啶衍生物的用途。其亦关于嘧啶衍生物的新颖种类,其作为医药品的用途,其制备方法及含其的制药组合物。
EP-0,834,507中揭示具有HIV复制抑制特征的经取代的二氨基1,3,5-三嗪衍生物。本发明化合物与已知的1,3,5-三嗪类不同处在于结构及在于其改良的抑制HIV复制的特征。
本发明是关于下式(I)化合物,其N-氧化物,制药上可接受的加成盐类,季胺类及立体化学异构型式于制备用来治疗患HIV(人类免疫缺乏病毒)感染的疾病的医药品的用途,
其中
-a1=a2-a3=a4-代表下式的二价基
-CH=CH-CH=CH- (a-1);
-N=CH-CH=CH- (a-2);
-N=CH-N=CH- (a-3);
-N=CH-CH=N- (a-4);
-N=N-CH=CH- (a-5);
n为0,1,2,3或4;且当-a1=a2-a3=a4-为(a-1)时,则n亦可为5;
R1为氢;芳基,甲酰基;C1-6烷基羰基,C1-6烷基,C1-6烷氧基羰基,被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰基氧基取代的C1-6烷基;被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
每一个R2独立地为羟基,卤素,选择地被氰基或-C(=O)R6取代的C1-6烷基,C3-7环烷基,选择性地被一个或多个卤素原子或氰基取代的C2-6链烯基,选择地被一或多个卤素原子或氰基取代的C2-6炔基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或下式的基
其中每一个A独立地为N,CH或CR6;
B为NH,O,S或NR6;
p为1或2;且
R6为甲基,氨基,单-或二甲基氨基或多卤素甲基;
L为C1-10烷基,C2-10烯基,C2-10炔基,C3-7环烷基,其中每一个该脂族基可被一或二个独立选自下列的取代基所取代:
*C3-7环烷基,
*吲哚基或异吲哚基,每一个可选择地被一、二、三或四个各自独立选自卤素,C1-6烷基,羟基,C1-6烷氧基,氰基,氨基羰基,硝基,氨基,多卤素甲基,多卤素甲氧基及C1-6烷基羰基的取代基所取代,
*苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,其中每一个该芳族环可选择地被一、二、三、四或五个各自独立选自定义于R2中的取代基所取代;或
L为-X-R3,其中
R3为苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,其中每一个该芳族环可选择地被一、二、三、四或五个各自独立选自定义于R2中的取代基所取代;且
X为-NR1-,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)-或-S(=O)2-;
Q代表氢,C1-6烷基,卤素,多卤素C1-6烷基或-NR4R5;且
R4及R5为各自独立地选自氢,羟基,C1-12烷基,C1-12烷氧基,C1- 12烷基羰基,C1-12烷氧基羰基,芳基,氨基,单-或二(C1-12烷基)氨基,单-或二(C1-12烷基)氨基羰基,其中每一个前述C1-12烷基可选择地且各独立地被一或二个各自独立选自羟基,C1-6烷氧基,羟基C1-6烷氧基,羧基,C1-6烷氧基羰基,氰基,氨基,亚氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6,芳基及Het的取代基所取代;或
R4及R5可一起形成吡咯烷基,哌啶基,吗福啉基,叠氮基或单-或二(C1-12烷基)氨基C1-4亚烷基;
Y代表羟基,卤素,C3-7环烷基,选择地被一或多个卤素原子取代的C2-6烯基,选择地被一或多个卤素原子取代的C2-6炔基,被氰基或-C(=O)R6取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或芳基;
芳基为苯基或被一、二、三、四或五个各自独立选自卤素,C1-6烷基,C3-7环烷基,C1-6烷氧基,氰基,硝基,多卤素C1-6烷基及多卤素C1-6烷氧基的取代基所取代的苯基;
Het为脂族或芳族杂环基;该脂族杂环基是选自吡咯烷基,哌啶基,高哌啶基,哌嗪基,吗福啉基,四氢呋喃基及四氢噻吩基,其中每一个该等脂族杂环基可选择地被一个氧代基所取代;且该芳族杂环基是选自吡咯基,呋喃基,噻吩基,吡啶基,嘧啶基,吡嗪基,及哒嗪基,其中每一个该等芳族杂环基可选择地被羟基所取代。
本发明亦有关于治疗患HIV(人类免疫缺乏病毒)感染的温血动物的方法。该方法包括将治疗有效剂量的式(I)化合物或其N-氧化物型式,制药上可接受的加成盐或立体化学异构型式与制药载体掺和而给药。
本发明亦有关于具有下式的新颖化合物,其N-氧化物,加成盐类,季胺及立体化学异构型式,
其中
-b1=b2-C(R2a)=b3-b4=代表下式的二价基:
-CH=CH-C(R2a)=CH-CH= (b-1);
-N=CH-C(R2a)=CH-CH= (b-2);
-CH=N-C(R2a)=CH-CH= (b-3);
-N=CH-C(R2a)=N-CH= (b-4);
-N=CH-C(R2a)=CH-N= (b-5);
-CH=N-C(R2a)=N-CH= (b-6);
-N=N-C(R2a)=CH-CH= (b-7);
q为0,1,2;或q可能为3或4;
R1为氢;芳基,甲酰基;C1-6烷基羰基,C1-6烷基,C1-6烷氧基羰基,被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰基氧基取代的C1-6烷基;被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
R2a为氰基,氨基羰基,单-或二(甲基)氨基羰基,被氰基,氨基羰基或单-或二(甲基)氨基羰基取代的C1-6烷基;被氰基取代的C2-6烯基,或被氰基取代的C2-6炔基;
每一个R2独立地为羟基,卤素,选择地被氰基或-C(=O)R6取代的C1-6烷基,C1-7环烷基,选择地被一或多个卤素原子或氰基取代的C2-6烯基,选择地被一或多个卤素原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或下式的基
其中每一个A独立地为N,CH或CR6;
B为NH,O,S或NR6;
p为1或2;且
R6为甲基,氨基,单-或二甲基氨基或多卤素甲基;L为C1-10烷基,C2-10烯基,C2-10炔基,C3-7环烷基,其中每一个该脂族基可被一或二个独立选自下列的取代基所取代;
*C3-7环烷基,
*吲哚基或异吲哚基,每一个可选择地被一、二、三或四个各自独立选自卤素,C1-6烷基,羟基,C1-6烷氧基,氰基,氨基羰基,硝基,氨基,多卤素甲基,多卤素甲氧基及C1-6烷基羰基的取代基所取代,
*苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,其中每一个该芳族环可选择地被一、二、三、四或五个各自独立选自定义于R2中的取代基所取代;或
L为-X-R3,其中
R3为苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,其中每一个该芳族环可选择地被一,二,三,四或五个各自独立选自定义于R2中的取代基所取代;且
X为-NR1-,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)-或-S(=O)2-;
Q为氢;C1-6烷基,卤素,多卤素-C1-6烷基或-NR4R5;
且
R4及R5为各自独立地选自氢,羟基,C1-12烷基,C1-12烷氧基,C1- 12烷基羰基,C1-12烷氧基羰基,芳基,氨基,单-或二(C1-12烷基)氨基,单-或二(C1-12烷基)氨基羰基,其中每一个前述C1-12烷基可选择地且各独立地被一或二各自独立选自羟基,C1-6烷氧基,羟基C1-6烷氧基,羧基,C1-6烷氧基羰基,氰基,氨基,亚氨基,单-或二(C1-6烷基)氨基,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6,芳基及Het的取代基所取代;或
R4及R5可一起形成吡咯烷基,哌啶基,吗福啉基,叠氮基或单-或二(C1-12烷基)氨基C1-4亚烷基;
Y代表羟基,卤素,C3-7环烷基,选择地被一或多个卤素原子取代的C2-6烯基,选择地被一或多个卤素原子取代的C2-6炔基,被氰基或-C(=O)R6取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,,多卤素甲基,多卤素甲氧基,多卤素甲硫基,-S(=O)pR6,-NH-S(=O)pR6,-C(=O)R6,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R6,-C(=NH)R6或芳基;
芳基为苯基或被一、二、三、四或五个各自独立选自卤素,C1-6烷基,C3-7环烷基,C1-6烷氧基,氰基,硝基,多卤素C1-6烷基及多卤素C1-6烷氧基的取代基所取代的苯基;
Het为脂族或芳族杂环基;该脂族杂环基是选自吡咯烷基,哌啶基,高哌啶基,哌嗪基,吗福啉基,四氢呋喃基及四氢噻吩基,其中每一个该等脂族杂环基可选择地被一个氧代基所取代;且该芳族杂环基是选自吡咯基,呋喃基,噻吩基,吡啶基,嘧啶基,吡嗪基,及哒嗪基,其中每一个该等芳族杂环基可选择地被羟基所取代。
本文中,作为一基团或一基团的一部分的C1-6烷基是定义为直链或分支的、具有由1至6个碳原子的饱和烃基,例如,甲基,乙基,丙基,1-甲基乙基,丁基,戊基,己基,2-甲基丙基,2-甲基丁基等;作为一基团或一基团的一部分的C1-10烷基是定义为直链或分支的、具有由1至10个碳原子的饱和烃基,例如定义于C1-6烷基中的基及庚基,辛基,壬基,癸基等;作为一基团或一基团的一部分的C1-12烷基是定义为直链或分支的、具有由1至12个碳原子的饱和烃基,例如定义于C1-10烷基中的基及十一烷基,十二烷基等;C1-4亚烷基是定义为直链或分支的、具有由1至4个碳原子的饱和二价烃基,例如,亚甲基,1,2-乙二基或1,2-亚乙基,1,3-丙二基或1,3-亚丙基,1,4-丁二基或1,4-亚丁基等;C3-7环烷基通常是指环丙基,环丁基,环戊基,环己基及环庚基;C2-6烯基是指直链或分支的、具有由2至6个碳原子并含有1个双链的烃基,例如,乙烯基,丙烯基,丁烯基,戊烯基,己烯基等;C2-10烯基定义为直链或分支的、具有由2至10个碳原子并含有1个双链的烃基,例如定义于C2-6烯基中的基及庚烯基,辛烯基,壬烯基,癸烯基等;C2-6炔基是定义为直链或分支的、具有由2至6个碳原子并含有1个参链的烃基,例如,乙炔基,丙炔基,丁炔基,戊炔基,己炔基等;C2-10炔基是定义为直链或分支的、具有由2至10个碳原子并含有1个参链的烃基,例如定义于C2-6炔基中的基及庚炔基,辛炔基,壬炔基,癸炔基等;
如同前文中者,(=O)一词当连接至一碳原子时形成一羰基,当连接一次至一硫原子时形成一亚砜基,且当连接二次至一硫原子时形成一磺酰基。
卤素一词通常是指氟,氯,溴及碘。如前文及本文中,作为一基团或一基团的一部分的多卤素甲基是定义为单-或多卤素取代的甲基,特别是具有一或多个氟原子的甲基,例如,二氟甲基或三氟甲基;作为一基团或一基团的一部分的多卤素C1-6烷基是定义为单-或多卤素取代的C1-6烷基,例如,定义于卤素甲基中的基,1,1-二氟乙基等。当多于1个卤素原子连接到多卤素甲基或多卤素C1-6烷基定义中的烷基时,其可为相同或不同。
Het是指包括所有于Het定义中提及的杂环的可能异构型式,例如,吡咯基亦包括2H-吡咯基。
Het基可通过任何适当的环碳或杂原子而连接到式(I)或(I-a)分子残基上。因此,例如,当杂环为吡啶基时,其可为2-吡啶基,3-吡啶基或4-吡啶基。
当任何变数(例如,芳基,R2,R6等)于任何结构中出现大于一次时,每一个定义是独立的。
当线由取代基拉到环中时,是指该键可连接到任何适当的环原子上。
有些式(I)或(Ia)化合物及其N-氧化物,加成盐类,季胺及立体化学异构型式中可含有一或多个手性中心且以立体化学异构形式存在。
前文中所使用的“立体化学异构型式”一词定义为式(I)或(I-a)化合物,及其N-氧化物,加成盐类,季胺或生理性官能衍生物可具有的所有可能的立体异构型式。除非另有提及或指示,化合物的化学名称是为所有可能的立体化学异构型式的混合物,该混合物含有式(I)或(I-a)化合物及其N-氧化物,盐类,溶剂合物或季胺的基本分子结构式的所有非对映立体异构物及对映结构体的混合物,以及各别异构型式实质上不含其他异构物,亦即含量少于10%,以少于5%为较佳,以少于2%为最佳且以少于1%为特别佳。特别的,立体结构体中心可具有R-或S-构型;二价环状(部分)饱和基上的取代基可具有顺式-或反式-构型。含有双键的化合物在该双键上可具有E或Z-立体化学性质。式(I)或(I-a)化合物的立体化学异构型式显然意欲包括在本发明范围内。
为了治疗的用途,该式(I)或(I-a)化合物的盐类为那些其中平衡离子为制药上可接受的。然而,不为制药上可接受的酸及碱的盐类亦发现例如可用于制药上可接受的化合物的制备或纯化。所有的盐类无论属于或不属于制药上可接受者,均包含在本发明的范围内。
上述制药上可接受的酸及碱加成盐类是包括式(I)或(I-a)化合物可以形成的治疗活性无毒的酸及碱加成盐型式。制药上可接受的酸加成盐类可容易地通过用适当的酸处理碱型式而得到。适当的酸包括,例如,无机酸,如氢卤酸,如氢氯酸或氢溴酸,硫酸,硝酸,磷酸等;或有机酸,例如,醋酸,丙酸,羟基醋酸,乳酸,丙酮酸,草酸(亦即,乙二酸),丙二酸,琥珀酸(亦即,丁二酸),顺式丁烯二酸,反式丁烯二酸,苹果酸,酒石酸,柠檬酸,甲烷磺酸,乙烷磺酸,苯磺酸,对甲苯磺酸,环己氨磺酸,水杨酸,对氨基水杨酸,棕榈酸等。
相反的,该盐型式可通过用适当的碱处理而转化为游离碱型式。
含有一酸性质子的式(I)或(I-a)化合物亦可通过用适当有机及无机碱处理而转化为其无毒的金属或胺加成盐型式。适当的碱盐型式包括,例如,铵盐,碱金属及碱土金属盐类,如,锂,钠,钾,镁,钙等的盐类,与有机碱的盐类,如优卡因,N-甲基-D-还原葡糖胺,羟基胺盐类,以及与氨基酸的盐类,例如,精胺酸,赖胺酸等。
前文中所使用的加成盐一词亦包括式(I)或(I-a)化合物以及其盐类可以形成的溶剂合物。此等溶剂合物例如水合物、醇化物等。
一些式(I)或(I-a)化合物亦可以其互变异构型式存在。虽然没有很明确的在上述化学式中指明,此等型式意欲涵盖于本发明的范围内。
于下文中,“式(I)化合物”或“(I-a)化合物”一词亦包括N-氧化物,加成盐类,季胺及所有立体异构型式。
特别的化合物包括那些式(I)化合物,其中R1为氢,芳基,甲酰基,C1-6烷基羰基,C1-6烷基,C1-6烷氧基羰基,被甲酰基,C1-6烷基羰基,C1-6烷氧羰基取代的C1-6烷基;
其他特别的化合物包括那些式(I)化合物,其中是采用一或多项下列限定:
i)-a1=a2-a3=a4-为式(a-1)的基;
ii)R1为氢;
iii)n为1;
iv)R2为氰基,优选位于相对于-NR1-基的对位位置;
v)Y为氰基,-C(=O)NH2或一卤素,优选为卤素;
vi)Q为氢或-NR4R5,其中R4及R5优选为氢;
vii)L为-X-R3,其中X优选为NR1,O或S,X最好为NH,且R3为以C1-6烷基,卤素及氰基属较佳取代基的经取代的苯基。
另外其他特别的一组化合物包括那些式(I-a)化合物,其中R1为氢,芳基,甲酰基,C1-6烷基羰基,C1-6烷基,C1-6烷氧基羰基,被甲酰基,C1-6烷基羰基,C1-6烷氧羰基取代的C1-6烷基。
其他特别的一组化合物亦包括那些式(I-a)化合物,其中是采用一项或多项下列限定:
i)-b1=b2-C(R2a)=b3-b4=为式(b-1)的基;
ii)q为0;
iii)R2a为氰基或-C(=O)NH2,R2a优选为氰基;
iv)Y为氰基,-C(=O)NH2或卤素,优选为卤素;
v)Q为氢或-NR4R5,其中R4及R5优选为氢;
vi)L为-X-R3,其中X优选为NR1,O或S,X最好为NH,且R3为以C1-6烷基,卤素及氰基属较佳取代基的经取代的苯基。
令人感兴趣的化合物为那些式(I)或(I-a)化合物,其中,L为-X-R3,其中R3为2,4,6-三取代的苯基,每一个取代基独立地选自氯、溴、氟、氰基或C1-4烷基。
亦令人感兴趣者为那些式(I)或(I-a)化合物,其中,Y为氯或溴且Q为氢或氨基。
特别的化合物为那些式(I)或(I-a)化合物,其中位于嘧啶环上2-位置的部分为4-氰基-苯氨基。
较佳的化合物为那些式(I)或(I-a)化合物,其中,位于嘧啶环上2-位置的部分为4-氰基-苯氨基,L为-X-R3,其中R3为2,4,6-三取代的苯基,Y为卤素且Q为氢或NH2。
最佳的化合物为:
4[[4-氨基-5-氯-6-[(2,4,6,-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;
4[[5-氯-4-[(2,4,6,-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;
4[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;
4[[4-氨基-5-氯-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;
4[[5-溴-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;
4[[4-氨基-5-氨-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;及
4[[4-氨基-5-溴-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;其N-氧化物,可药用加成盐类,季胺及立体化学异构型式。
通常,式(I-a)化合物可通过将式(II)中间体,其中W1为一适当的离去基,例如,卤素,羟基,三氟甲烷磺酸盐,甲苯磺酸盐,硫代甲基,甲基磺酰基,三氟甲基磺酰基等,与式(III)氨基衍生物选择地在不含溶剂条件下或于一反应惰性溶剂中,例如,乙醇,1-甲基-2-吡咯烷酮,N,N-二甲基甲酰胺,1,4-二噁烷,四氢呋喃,二甲亚砜,1,2,3,4-四氢化萘,环丁砜,乙腈等中,在一反应惰性氛围中,例如不含氧气的氩气或氮气中,且选择地在一酸,例如,于二乙醚中的1N氢氯酸等存在下进行反应而制得。此反应可在50℃及250℃的温度范围间进行。
于此反应及下列的制备法中,反应产物可由反应介质中单离出来且,如果需要,进一步根据技艺已知的一般方法纯化,例如,萃取法,结晶法,蒸馏法,碾制法及色层分离法。
式(I-a)化合物,其中L为式-NR1-R3的基,此化合物以式(I-a-1)代表,可通过将式(IV)中间体,其中,W2为一适当的离去基,例如,卤素或三氟甲烷磺酸盐,与式(V)中间体,在不含溶剂的条件下或于一适当溶剂中,例如,乙醇,1-甲基-2-吡咯烷酮,N,N-二甲基甲酰胺,1,4-二噁烷,四氢呋喃,二甲亚砜,1,2,3,4-四氢化萘,环丁砜,乙腈等中,在一反应惰性氛围中,例如不含氧气的氩气或氮气中,且选择地在一酸,例如,于二乙醚中的1N氢氯酸等存在下进行反应而制得。此反应可在50℃及250℃的温度范围间进行。
式(I-a)化合物,其中L为式-O-R3,此化合物以式(I-a-2)代表,可通过将式(IV)中间体,其中,W2为一适当的离去基,例如,卤素或三氟甲烷磺酸盐,与式(VI)中间体,在一适当溶剂中,例如,1,4-二噁烷,二甲亚砜,1,2,3,4-四氢化萘,环丁砜等中,在一反应惰性氛围中,例如,不含氧气的氩气或氮气中,且在一碱,例如,氢化钠,氢化钾,氢氧化钠等存在下进行反应而制得。此反应可在50℃及250℃的温度范围间进行。
式(I-a)化合物可进一步根据技艺已知的转化反应通过将式(I-a)化合物互相转化而制得。
式(I-a)化合物可根据技艺已知的用来将三价氮转化为N-氧化物型式的步骤而转化为它的N-氧化物型式。该N-氧化反应通常可通过将式(I-a)起始物质与适当有机或无机过氧化物进行反应而进行。适当的无机过氧化物包括,例如过氧化氢,碱金属或碱土金属过氧化物,例如,过氧化钠,过氧化钾;适当的有机过氧化物可包括过氧酸,例如,苯羰过氧酸或卤素取代的苯羰过氧酸,如,3-氨苯羰过氧酸,过烷酸,如过醋酸,烷基氢过氧化物,如,叔丁基氢过氧化物。适当的溶剂为,例如,水,低级醇类,如乙醇等,烃类,如甲苯,酮类,如2-丁酮,卤化烃类,如,二氯甲烷,及此等溶剂的混合物。
例如,式(I-a)化合物,其中,Q为卤素,可用NH2R4作为试剂,在一反应惰性溶剂中,例如,1,4-二噁烷等,选择地在一适当碱,例如三乙胺或N,N-二异丙基乙基胺等存在下,转化为相关的化合物,其中Q为-NR4H。当R4含有羟基部分时,亦可采用保护型式的NH2R4容易地进行反应,其中的羟基部分携有一适当的保护基P,其例如可为一三烷基硅烷基,且随后根据技艺已知的方法移除该保护基。
本发明中的一些式(I-a)化合物及一些中间体可含有不对称碳原子。该化合物及该中间体的纯的立体化学异构型式可通过使用技艺已知的步骤得到。例如,非对映立体异构物可通过物理方法分离,例如,选择性结晶法或色层分离技艺,例如,逆流分布法,液体色层分离法等。对映结构体可由外消旋混合物中通过先将该外消旋混合物用适当的解析试剂,例如,对映酸,转化为非对映立体异构盐或化合物;然后将该非对映立体异构盐或化合物的混合物通过例如,选择性结晶法或色层分离技术,例如,液体色层分离法等进行物理性分离;且最后将该分离出的非对映立体异构盐或化合物转化为相关的对映结构体而获得。纯的立体化学异构型式亦可由纯的立体化学异构型式的适当中间体及起始物质制得,条件是该插入反应是立体有选择性发生。
分离式(I-a)化合物及中间体的对映结构体型式的替代方式包括液体色层分离法,特别是使用手性固定相的液体色层分离法。
一些中间体及起始物质为已知的化合物且为市售可得者或可依据技艺已知的步骤制得。
式(II)中间体,其中L为-X-R3,该中间体以式(II-1)代表,可通过将式(VII)的嘧啶衍生物,其中每一个W1定义如前,与HXR3(VIII)在一反应惰性溶剂中,例如,1,4-二噁烷,2-丙醇等,且在一碱,例如,三乙胺或N,N-二异丙基乙基胺等存在下进行反应而制得。可形成不同的专一区域异构体且可用适当的分离技术,例如,色层分离法,使彼此分离开来。
式(IV)中间体可通过将式(VII-a)中间体,其中,W2为一适当离去基,例如,卤素,与式(IX)中间体在一适当溶剂中,例如,1-甲基-2-吡咯烷酮,1,4-二噁烷等,在一酸,例如于二乙醚中的1N氢氯酸存在下进行反应而制得。此反应可在50℃及250℃的温度范围间进行。
替代的,式(IV)中间体可通过将式(X)中间体与磷酰氯,三氟甲烷磺酸酐或其官能性衍生物在一反应惰性氛围中,例如不含氧气的氩气或氮气中进行反应而制得。此反应可在20℃及150℃的温度范围间进行。
式(X)中间体可通过将式(XI)中间体或其官能性衍生物与式(IX)中间体进行反应而制得。此反应可在无溶剂条件下或在一适当溶剂中,例如,二甘咪(diglyme),1,2,3,4-四氢化萘等,于一反应-惰性氛围中,例如不含氧气的氩气或氮气中,且选择地在一碱,例如氢化钠,氢化钾等存在下进行。此反应可在100℃及250℃的温度范围间进行。
式(X)中间体亦可通过将式(XII)中间体,其中W2为一适当离去基且Y及Q定义如式(I-a)中所述,与式(XIII)中间体在一适当溶剂中,例如乙醇等,及在一碱,例如乙醇钠等存在下,在一反应-惰性氛围中,例如不含氧气的氩气或氮气中进行反应而制得。此反应可在20℃及125℃的温度范围间进行。
一种制备式(IV)中间体,其中Y为溴或氯原子,该中间体以式(IV-1)代表,的简易方法包括将溴或氯原子导引入式(XIV)中间体,其中W2定义如前,其是用N-溴琥珀酰亚胺或N-氯琥珀酰亚胺于一反应-惰性溶剂中,例如氯仿,四氯化碳等中进行。此反应可在20℃及125℃的温度范围间进行。
类似于式(I-a)化合物,其中Q为卤素,转化为式(I-a)化合物,其中Q为-NHR4的反应,式(II),(IV)及(VII)中间体亦可转化。
依前文所述制法制得的式(I-a)化合物可以立体异构型式的混合物合成,特别是以可根据技术上已知的解析步骤彼此分离的对映异构体的外消旋混合物型式。式(I-a)化合物的外消旋化合物可通过与适当的对映酸进行反应而转化为相关的非对映立体异构物盐型式。该非对映立体异构物盐型式则随后通过,例如,选择性或分级结晶法而分离,且对映结构体则用碱而由其间释出。式(I-a)化合物对映异构体的分离的代替方式包括用手性固定相的液体色层分离法。该纯的立体化学异构型式亦可由相关的适当起始物质的纯立体化学异构型式衍生出来,条件是反应是以立体有择性发生。如果想要特定的立体异构物,该化合物优选通过立体有择的制备方法合成。这些方法以使用对映结构的纯起始物质为有利的。
本领域技术人员知道,在上述制法中,中间体化合物的官能基需要被保护基保护。
需要被保护的官能基包括羟基,氨基及羧酸。羟基的适当的保护基包括三烷基硅烷基(例如,叔丁基二甲基硅烷基,叔丁基二苯基硅烷基或三甲基硅烷基),苄基及四氢吡喃基。氨基的适当的保护基包括叔丁氧羰基或苄氧羰基。羰酸的适当的保护基包括C1-6烷基或苄基酯。
官能基的保护及去保护可在反应步骤以前或以后进行。
保护基的使用完整的叙述于“有机化学的保护基”,JW,F McOmie编辑,Plenum Press(1973),及“于有机合成中的保护基”第二版,TW Greene及P GM Wutz,Wiley Interscience(1991)。
式(I)及(I-a)化合物显示出抗逆转录病毒特性,特别是抗人类免疫缺乏病毒(HIV),其为人类后天免疫缺乏征候群(AIDS)的病原。该HIV病毒首先感染人类T-4细胞且破坏它们或改变其正常功能,特别是免疫是统的协调作用。结果,被感染的病人具有非常少的T-4细胞数目,其亦表现不正常。因此,免疫性防卫系统不能对抗感染及肿瘤,且被HIV感染的个体通常会因趁机的感染,例如,肺炎,或因癌症而死亡。其余伴随着HIV感染的情况包括血小板减少症,克氏(Kaposi’s)肉瘤及以进行性脱髓鞘作为特征的中枢神经系统感染,造成了痴呆及例如,进行性发音不良,共济失调及定向力障碍等征候。HIV感染亦伴随着末稍神经病变,进行性全身性淋巴腺病(PGL)及AIDS-相关征候群(ARC)。
本发明化合物亦显示出对抗HIV-1株的活性,该株对于技艺已知的非核苷逆转录酶抑制具有后天的抗性。其对于人类α-1酸糖蛋白亦具很小或不具有结合亲合性。
由于其抗逆转录病毒特性,特别是其抗-HIV特性,尤其是其抗-HIV-1-活性,式(I)或(I-a)化合物,其N-氧化物,制药上可接受的加成盐类,季胺及立体化学异构型式可用来治疗HIV的个别感染及用来预防这些感染。通常,本发明化合物可用来治疗被病毒(其存在是通过酶逆转录酶传介或依赖于它而存在)感染的温血动物。可用本发明化合物来避免或治疗的症状,尤其是涉及到HIV及其他病原性逆转录病毒的症状,包括AIDS,AIDS-相关征候群(ARC),进行性全身性淋巴腺病(PGL),以及由逆转录病毒造成的慢性CNS疾病,例如,HIV传介的痴呆及多发性硬化。
本发明化合物或其任何副族因此可用作为对抗上述症状的医药品。该医药品的用途或治疗的方法包括将有效的剂量系统性的给药到HIV-感染的个体以对抗与HIV及其他病原性逆转录病素,尤其是与HIV-1有关联的症状。
本发明化合物或其任何副族可调配成为各种给药目的的制药型式。可以引用通常使用于全身性给药的药剂的所有组合物作为适当的组合物。于制备本发明的制药组合物时,将有效量的作为活性成分的特定化合物,选择性的以加成盐型式,与制药上可接受的载体一起结合到紧密掺合物中,该载体可根据所欲给药的制剂的型式而为多种型式。此等制药组合物宜为适用于经口,经直肠,经皮,或非经肠胃注射给药的单一剂量型式。例如,于制备口服剂量型式的组合物时,可使用任何一般的制药介质,于口服液态制剂如悬浮液,糖浆,酏剂,乳浊液及溶液剂型时可使用,如水、乙二醇,油类、醇类等;或于粉剂、药丸,胶囊、及片剂的情形时,可使用固态载体,如,淀粉、糖类、高岭土、稀释剂、润滑剂、粘合剂、崩散剂等。由于其易于给药,片剂及胶囊代表最有利的口服剂量单位型式,于此情形时,显然是使用固态制药载体。于非经肠胃用的组合物时,载体一般包含无菌水,至少为大部分,虽然亦可含有其他组分以例如帮助溶解。例如,可制备注射用溶液,其中载体包含食盐水溶液,葡萄糖溶液或食盐水及葡萄糖溶液的混合物。亦可制备注射用悬浮液,于此情形时是使用适当的液态载体,悬浮剂等。亦可包含的为固态型式制剂,其将于使用前转化为液态型式制剂。于适用于经皮给药的组合物中,载体选择地包含一渗透促进剂及/或适当的润湿剂,选择地包含少量的任何性质的适当添加剂,该添加剂不会在皮肤上造成显著的有害效应。该添加剂可帮助给药至皮肤及/或有助于制备所要的组合物。此等组合物可以借多种途径给药,例如,皮肤贴布,涂点,软膏。
为了帮助式(I-a)化合物的溶解,组合物中可包含适当的组分,例如,环糊精。适当的环糊精为α-,β-,γ-环糊精或醚类及其混合的醚类,其中环糊精的无水葡萄糖单位的一或多个羟基被下列所取代:C1-6烷基,特别是甲基,乙基或异丙基,如随意甲基化的β-CD;羟基C1-6烷基,特别是羟基乙基,羟基丙基或羟基丁基;羧基C1-6烷基,特别是羧基甲基或羧基乙基,C1-6烷基羰基,特别是乙酰基。尤其值得注意作为络合物及/或增溶剂的为β-CD,随意甲基化的β-CD,2,6-二甲基-β-CD,2-羟基乙基-β-CD,2-羟基乙基-γ-CD,2-羟基丙基-γ-CD及(2-羧基甲氧基)丙基-β-CD,且特别为2-羟基丙基-β-CD(2-HP-β-CD)。
混合的醚一词为环糊精衍生物,其中至少两个环糊精羟基被不同的基,例如羟基丙基及羟基乙基所醚化。
平均摩尔取代(M.S)是用作为每摩尔无水葡萄糖的烷氧基单位的平均摩尔数的量度单位。平均取代程度(D.S)是指每无水葡萄糖单位的经取代羟基的平均数。M.S.及D.S.值可借多种分析技术例如,核磁共振(NMR),质谱法(MS)及红外光谱学(IR)来测定。根据所使用的技术,每一给定的环糊精衍生物可得到稍许不同的值。借质谱法测量时,以M.S.范围0.125至10且D.S.范围0.125至3为宜。
其他经口或经直肠给药的适当组合物包括颗粒物,其是通过将包含式(I-a)化合物及一适当水可溶性聚合物的混合物溶融挤压且随即将该熔融挤压的混合物碾磨。然后该颗粒可用常用技术调配成制药剂量型式,例如片剂及胶囊。
该颗粒包含一个固态分散体,其含有式(I-a)化合物及一或多种制药上可接受的水可溶性聚合物。制备固态分散体的较佳技术为包含下列步骤的熔融-挤压法:
a)将式(I-a)化合物及一适当水可溶性聚合物混合,
b)选择地将添加物与如此得到的混合物掺合,
c)将如此得到的掺合物加热直到得到一均匀的熔融物,
d)将如此得到的熔融物强压通过一个或多个喷嘴;及
e)将熔融物冷却直到其固化。
将固态分散产物碾磨或磨碎成具有小于1500μm粒子尺寸的颗粒,优选为小于400μm,尤其是小于250μm且最好是小于125μm。
颗粒中的水可溶性聚合物当其于20℃以2%(w/v)溶解于水性溶液时具有1至5000mPa.s.,尤其是1至700mPa.s.,且特别是1至100mPa.s.的表观粘度。例如,适当的水可溶性聚合物包括烷基纤维素,羟基烷基纤维素,羟基烷基烷基纤维素,羧基烷基纤维素,羧基烷基纤维素的碱金属盐类,羧基烷基烷基纤维素,羧基烷基纤维素酯,淀粉,果胶,甲壳质衍生物,多糖类,聚丙烯酸及其盐类,聚甲基丙烯酸及其盐类及酯类,甲基丙烯酸酯共聚物,聚乙烯基醇,聚亚烷基氧化物及乙烯化氧及丙烯化氧的共聚物。较佳的水可溶性聚合物为Eudragit E(Rhm GmbH,Germany)及羟基丙基甲基纤维素。
还有一种或多种如揭示于WO 97/18839中的环糊精可于制备上述颗粒中用作为水可溶性聚合物。该环糊精包括技术上已知的制药上可接受的未经取代及经取代的环糊精,特别是α,β或γ环糊精或其制药上可接受的衍生物。
可使用的经取代的环糊精包括揭示于美国专利3,459,731的聚醚类。另外经取代的环糊精为醚类,其中,一个或多个环糊精羟基的氢被C1-6烷基,羟基C1-6烷基,羧基-C1-6烷基或C1-6烷氧基羰基C1-6烷基所取代或其混合的醚类。特别是此等经取代的环糊精为醚类,其中一个或多个环糊精羟基的氢被C1-3烷基,羟基C2-4烷基或羧基C1-2烷基所取代,特别是被甲基,乙基,羟基乙基,羟基丙基,羟基丁基,羧基甲基或羧基乙基所取代。
特别有用者为β-环糊精醚类,例如,由M.Nogradi(1984)于Drugsof the Future,Vol.9,No.8,第577-578页中所说明的二甲基-β-环糊精及聚醚类,例如,羟基丙基β-环糊精及羟基乙基β-环糊精。此等烷基醚可为一取代程度为约0.125至3,例如,约0.3至2的甲基醚。此等羟基丙基环糊精可例如由β-环糊精及氧化丙烯间的反应形成且具有约0.125至10,例如约0.3至3的MS值。
另一新颖型式的经取代的环糊精为磺酸基丁基环糊精。
式(I-a)化合物与环糊精的比值可有很大变化。例如,比值可为1/100至100/1。较令人感兴趣的式(I-a)化合物与环糊精的比值范围为约1/10至10/1。更令人感兴趣的比值范围为约1/5至5/1。
亦可方便地将式(I-a)化合物配制成小颗粒型式,其具有足量的表面改良剂吸附在其表面上,以足以维持其小于1000nm的有效平均颗粒。一般相信有用的表面改良剂是包括那些物理性吸附在式(I-a)化合物表面而非化学性键结至该化合物的物质。
适当的表面改良剂优选选自已知的有机及无机制药赋形剂。此等赋形剂包括各种聚合物,低分子量的齐聚物,天然产物及表面活性剂。较佳的表面改良剂包括非离子性及阴离子性表面活性剂。
仍有其他涉及制药组合物的调配式(I-a)化合物的有趣方式,其中式(I-a)化合物是加到亲水性聚合物中并将此混合物当作涂膜而涂敷在许多小球上,因此获得一可容易制得且适用来制备供经口给药的制药剂量型式的组合物。
该小球包括一中央,园形或球形的核心,一亲水性聚合物及式(I-a)化合物的涂膜及一密封的聚合物涂层。
适用作为小球中的核心的物质为多支管,条件是该物质为制药上可接受的且具有适当的直径及坚固性。此等物质的例为聚合物,无机物质,有机物质,及糖类及其衍生物。
尤其有利的是将前述制药组合物调配成单一剂量型式以便于给药或剂量的均质化。此处所用的单一剂量型式是指适用作为单一剂量的物理性的个别单位,每一单位中含有经计算可产生所要治疗效果的预定质量的活性组分以及所需的制药载体。此等单位剂量型式的实例为片剂(包括划线或包衣片剂),胶囊,药丸,粉末包,干胶片,栓剂,可注射的溶液或悬浮液等,以及其分离的复数包。
那些熟悉HIV-感染治疗者可以由此处所提供的试验结果来决定每日的有效量。通常,预计的每日有效剂量是由0.01毫克/千克体重至50毫克/千克体重,更佳者为由0.1毫克/千克体重至10毫克/千克体重。将所需剂量于适当期间于一天中分二、三、四或多个次剂量给药较适合。该次剂量可以单位剂量型式配制,例如,每单位剂量型式中含有1至1000毫克,且特别是5至200毫克活性组分。
给药的确实剂量及频率是根据所用式(I)或(I-a)的特定化合物所要治疗的特定症状,所要治疗的症状的严重程度,特定患者的年龄,体重及一般体能状况以及个体所服用的其他医药而定,如同本领域人员所熟知。再者,很显然的该每日有效剂量可根据所治疗的对象的反应及/或根据医生处方本发明化合物的评估而降低或增加。因此,前文所提及的每日有效剂量范围仅是导引且并非用来限制本发明的范围或用途至任何程度。
而且,一抗逆转录病毒化合物及式(I)或(I-a)化合物的组合可用作为医药品。因此,本发明亦关于含有(a)式(I)或(I-a)化合物,(b)另一个抗逆转录病毒化合物的合并的制剂产物以同时,分开或连续的用于抗-HIV治疗。不同的药物可与制药上可接受的载体一起合并于一单一制剂中。该其他抗逆转录病毒化合物可为已知的抗逆转录病毒化合物,例如,核苷逆转录酶抑制剂,如叠氮胸腺嘧啶核苷(3’-叠氮基-3’-去氧胸腺嘧啶核苷,AZT),二旦辛(didanosine)(二去氧次黄嘌呤核苷;ddI),若塞提宾(zalcitabine)(二去氧胞苷,ddC)或拉密威定(lamivadine)(3’-噻-2’-3’-二去氧胞苷,3TC)等,非-核苷逆转录酶抑制剂,例如,苏拉明(suramine),戊聚脒(pentamidine),胸腺五肽,卡坦诺普明(castanospermine),伊发威诺(efavirenz),葡聚糖(硫酸葡聚糖),福斯卡尼-钠(膦酸甲酸三钠),尼威拉派(nevirapine)(11-环丙基-5,11-二氢-4-甲基-6H-二吡啶并[3,2-b:2’,3’-e][1,4]二氨杂-6-酮),9-氨基四氢吖啶(四氢氨基吖啶)等;TIBO(四氢咪唑并[4,5,1-jk][1,4]-苯并二氮杂-2(1H)-酮及硫酮)-型式的化合物,例如,(S)-8-氯-4,5,6,7-四氢-5-甲基-6-(3-甲基-2-丁烯基)咪唑并[4,5,1-jk][1,4]苯并二氮杂-2(1H)-硫酮;α-APA(α-苯氨基苯基乙酰胺)型式的化合物,例如,α-[(2-硝基-苯基)氨基]-2,6-二氯苯-乙酰胺等,TAT-抑制剂,例如,RO-5-3335等;朊酶抑制剂,例如,因顶那微(indinavir),瑞坦微(ritanovir),史癸那微(saquinovir),ABT-378等;或免疫调节剂,例如,左旋咪唑等。式(I)或(I-a)化合物亦可与其他式(I)或(I-a)化合物合并。
下列实例是用来阐明本发明。
实验部分
A.中间体化合物的制备
实例A1
在氩气氛围中进行反应。将一含2,4,6-三甲基苯胺(0.00461摩尔)于1,4-二噁烷(5毫升)的溶液加到一含5-溴2,4-二氯嘧啶(0.00439摩尔)于1,4-二噁烷(5毫升)的溶液中。将N,N-双(1-甲基乙基乙胺(0.00548mol)加入。将反应混合物搅拌并回流20小时。将溶剂蒸发。将残质溶解于醋酸乙酯中,用饱和水性碳酸氢钠溶液,水及食盐水清洗,用硫酸钠干燥,过滤,并将溶剂蒸发。将残质用管柱色层分离法于硅胶上予以纯化(洗提液:1∶5,1∶2及1∶1CH2Cl2∶己烷)。收集两个纯馏份组并将其溶剂蒸发,得到0.35克(24%)5-溴-4-氯-N-(2,4,6-三甲基苯基)-2-嘧啶胺(中间体1)及0.93克(65%)5-溴-2-氯-N-(2,4,6-三甲基苯基)-4-嘧啶胺(中间体2)。
实例A2
a)4-羟基-5-氯-2-甲基硫代嘧啶(0.0156摩尔)及4-氨基苄腈(0.078摩尔)以熔融物合并且于180-200℃搅拌6小时。将反应混合物冷却,且随即用沸腾的CH2Cl2及CH3CN碾制以得到95%纯化合物,将其干燥,得到1.27克(33%)4-[(5-氯-4-羟基-2-嘧啶基)氨基]苄腈(中间体3;熔点>300℃)。
b)将POCl3(10毫升)加到中间体(3)(0.0028摩尔)中。将烧瓶装置以一冷凝器并加热至80℃达35分钟。将物质于冰中骤冷并收集产生的沈淀物且用水(50毫升)清洗。将样品干燥。将其馏份用柱层析进一步纯化。将纯级分收集起来并将溶剂蒸发,得到4-[(4,5-二氯-2-嘧啶基)氨基]苄腈(中间体4)。
c)将含中间体(4)(0.0132摩尔)的四氢呋喃(75毫升)及CH2Cl2(10毫升)的混合物搅拌15分钟。将含于二乙醚(0.0145摩尔)的HCl缓缓加入,且将混合物搅拌5分钟。将溶剂于减压下移除,得到3.98克4-[(4,5-二氯-2-嘧啶基)氨基]苄腈一氢氯化物(中间体5)。
实例A3
a)将2,4,5,6-四氢嘧啶(0.0134摩尔),1,4-二噁烷(30毫升),2,4,6-三甲基苯胺(0.0134摩尔),及N,N二双(1-甲基乙基)乙胺(0.0136摩尔)于氩气中加到一烧瓶内且于55℃搅拌16小时。蒸发出溶剂,并将残质溶解于CH2Cl2中,然后用管柱色层分离法于硅胶上(洗提液:CH2Cl2/己烷1/4,及1/2)予以纯化。收集所要的馏份并将其溶剂蒸发,得到0.15克,4,5,6-三氯-N-(2,4,6-三甲基苯基)-2-嘧啶胺(中间体6)及3.15克2,5,6-三氯-N-(2,4,6-三甲基苯基)-4-嘧啶胺(中间体7)。
b)将含中间体7(0.00474摩尔)于NH3(2.0M于2-丙醇;20毫升)的混合物于一压力皿中在75-80℃时加热40小时。将温度提高至110-115℃。将溶剂蒸发以产生1.85克残质。于125℃将样品与NH3(0.5M于1,4-二噁烷;20毫升)一起加热18小时。将溶剂蒸发,得到1.7克两个异构物的混合物,亦即,2,5-二氯-N4-(2,4,6-三甲基苯基)-4,6-嘧啶二胺(中间体8)及5,6-二氯-N4-(2,4,6-三甲基苯基)-2,4-嘧啶二胺(中间体9)。
实例A4
a)将一含4[(1,4-二氢-4-氧代-2-嘧啶基)氨基]苄腈(0.12摩尔)于POCl3(90毫升)的混合物于氩气中搅拌并回流20分钟,将反应混合物缓缓的倒到750毫升冰/水中,并将固体通过过滤法分离。将固体悬浮于500毫升水中,并将悬浮液的pH通过添加20%NaOH溶液而调整至中性。再次将固体用过滤法分离,悬浮于200毫升2-丙酮中,并加入1000毫升CH2Cl2。将混合物加热直到所有固体溶解。冷却至室温后,分离出水性层,并将有机层干燥。在通过过滤法移除干燥试剂期间,于滤液中形成一白色固体。再将滤液于冷冻器中冷却,接着过滤,得到21.38克(77.2%)4-[(4-氯-2-嘧啶基)氨基]苄腈(中间体10)。
b)将中间体(10)(0.005摩尔),1-溴-2,5-吡咯烷二酮(0.006摩尔)及三氯甲烷(10毫升)合并于一密封管中并于100℃加热过夜。将反应混合物冷却至室温。加入硅胶(2克),并将溶剂蒸发。将残质用闪蒸管柱色层分离法于硅胶上(洗提液:CH2Cl2/己烷9/1)予以纯化。收集纯馏份并将溶剂蒸发,得到1.31克(84.5%)4-[(5-溴-4-氯-2-嘧啶基)氨基]苄腈(中间体11)。
实例5
于氩气下将4-氨基-2,5,6-三氯嘧啶(0.08564摩尔),4-氨基-苄腈(0.1071摩尔),1-甲基-2-吡咯烷酮(17毫升)及HCl于二乙醚(1M;85.6毫升)加到一烧瓶中。将混合物于氮气流中置于130℃的油浴中直到醚蒸发完。另外加入10毫升1-甲基-2-吡咯烷酮。将混合物于145℃氩气中加热16小时。加入1,4-二噁烷。将混合物回流,冷却,然后过滤。将滤液蒸发。残留物溶解于CH2Cl2,用1N NaOH洗涤,然后过滤。将固体溶解于2-丙酮中,于硅胶上蒸发,并用1-3%2-丙酮于己烷中作洗脱液层析。收集纯级分且将溶剂蒸发,得到1.63克(6.8%)4-[(4-氨基-5,6-二氨-2-嘧啶基)氨基]苄腈(中间体12)。
B最终化合物的制备
实例B1
a)于氩气中将醚加到装有中间体(1)(0.00107摩尔)的烧瓶中。将HCl/二乙醚(1M;0.00109摩尔)加到此均匀溶液中。将溶剂蒸发并加入1,4-二噁烷(35毫升)及4-氨基苄腈(0.00322摩尔)。将反应混合物搅拌并回流4天。将溶剂蒸发。将残质溶解于CH2Cl2中,用饱和碳酸氢钠溶液清洗,干燥,过滤并将溶剂蒸发得到0.79克琥珀色油。将油用反相HPLC纯化。收集所要的馏份并将溶剂蒸发,得到残质1及2。
残质1用管柱色层分离法于硅胶上(洗涤液:0及2%CH3OH∶CH2Cl2)予以纯化。收集纯馏份并将溶剂蒸发,得到0.0079克(2.0%)4-[[5-氯-2-[(2,4,6-三甲基苯基)氨基]-4-嘧啶基]氨基]苄腈(化合物1)。
将残质2用管柱色层分离法于硅胶上(洗提液:0及2%CH30H∶CH2Cl2)予以纯化。收集纯馏份并将溶剂蒸发,得到0.0044克(1%)4-[[5-溴-2-[(2,4,6-三甲基苯基)氨基]-4-嘧啶基]氨基]苄腈(化合物2)。
b)将醚加到装有中间体2(0.00285摩尔)的烧瓶中。将HCl/二乙醚(1M;0.00855摩尔)加到此均匀溶液中。将溶剂蒸发并加入1,4-二噁烷(20毫升)。最后,加入4-氨基苄腈(0.00291摩尔)及1,4-二噁烷(15毫升)并将反应混合物搅拌并回流数天。将溶剂蒸发,将残质溶解于CH2Cl2中,用1M的NaOH清洗,并将溶剂蒸发。将残质溶解于CH2Cl2(10毫升)并将沉淀物过滤出来并干燥,得到0.15克(13%)4-[[5-溴-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(化合物3)。
实例B2
a)将中间体(8)及中间体(9)[实例A3b中制得]3∶1的混合物及4-氨基苄腈(0.01422摩尔)于180℃压力槽中加热5小时。将样品于CH2Cl2及稀NaHCO3之间分配,于K2CO3上干燥,过滤,并蒸发。将CH3CN搅拌加入,将产生的沉淀用过滤法移除。再将滤液用反相HPLC予以纯化。收集纯馏份并将溶剂蒸发,得到0.17克4-[[4-氨基-5-氯-6-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈三氟醋酸盐(1∶1)(化合物4)。
实例B3
将含于二乙醚的HCl(1M;0.0045摩尔)加到一含中间体(4)(0.003摩尔)于1,4-二噁烷(5毫升)的悬浮液中,于氩气中在可密封管中搅拌。将混合物加热以蒸发二乙醚,并加入2,4,6-三甲基苯胺(0.009摩尔)。将管子密封,且将反应混合物加热到150℃达12小时。将反应混合物予以冷却至室温。连续的加入硅胶(2.2克)及CH3OH(50毫升)。将溶剂蒸发后,将残质用闪蒸色层分离法(洗提级度:CH2Cl2∶CH3OH∶NH4OH99.5∶0.45∶0.05上至99∶0.9∶0.1)予以纯化。收集纯馏份并将溶剂蒸发。将残质干燥,得到0.80克(73.4%)4-[[5-氯-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(化合物5)。
实例B4
于氩气下将一含中间体(5)(0.0025摩尔)及2,6-二溴-4-甲基苯胺(0.0075摩尔)于1,3-二噁烷(5.0毫升)的混合物于一密封管中160℃加热并搅拌16小时。将反应混合物用旋转蒸发法于硅胶(2.0克)上浓缩。将物质藉闪蒸色层分离法(洗提液1∶1己烷∶CH2Cl2;纯CH2Cl2;0.5%,1%(10%NH4OH于CH3OH)于CH2Cl2)予以纯化达90%纯度。再结晶可得到0.15克(12.2%4-[[5-氯-4-[(2,6-二溴-4-甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(化合物10;95%纯度)。
实例B5
氩气下将NaH(0.0075摩尔;60%于油中的悬浮液)加到一可密封式管中的含2,4,6-三甲基苯酚(0.0075摩尔)于1,4-二噁烷(5毫升)的悬浮液中。将混合物搅拌15分钟,且加入中间体(4)(0.0025摩尔)。将管子密封,并将混合物在150℃加热15小时。将反应冷却至室温。加入硅胶(2.0克)后,将溶剂蒸发。将残质用闪蒸管柱色层分离法于硅胶上(洗提梯度:CH2Cl2∶己烷:9∶1至100∶0;然后CH2Cl2∶CH3OH∶NH4OH:100∶0∶0至97∶2.7∶0.3)予以纯化。收集纯馏份并将溶剂蒸发。将残质干燥,得到0.73克(80.2%)4-[[5-氯-4-(2,4,6-三甲基苯氧基)-2-嘧啶基]氨基]苄腈(化合物6)。
实例B6
a)于氩气下在一可密封式管子中将NaH,60%于油(0.003摩尔)中的悬浮液及1-甲基-2-吡咯烷酮(3毫升)加到一含4-羟基-3,5-二甲基苄腈(0.003摩尔)于1,4-二噁烷(3毫升)的悬浮液中。于H2放出后,加入中间体(11)(0.001摩尔)。将管子密封并将反应混合物加热至160℃16小时。将混合物冷却至室温,移到一烧杯中并用甲醇(20毫升)稀释。逐滴加入水(200毫升)。将水性混合物用CH2Cl2/CH3OH90/10(3×300毫升)萃取。将有机层分离,干燥,过滤并吸附在硅胶上(1克)。将溶剂蒸发并将残质用闪蒸管柱色层分离法于硅胶上(洗提液:CH2Cl2/CH3OH/NH4OH由100/0/0至98/1.8/0.2)予以纯化。收集所要的馏份并将溶剂蒸发。将残质用热CH3CN碾制,过滤出来,然后干燥,得到0.20克(47.6%)4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈(化合物17)。
b)将正丁基锂(0.010摩尔)加到一含N-(1-甲基乙基)-2-丙胺(0.010摩尔)于四氢呋喃(250毫升)的溶液中,于0℃搅拌。搅拌冷却30分钟后,加入化合物(17)(0.005摩尔)。将产生的混合物搅拌冷却15分钟,于该点加入2-溴乙醇乙酯(0.015摩尔)且将温度上升至室温并将反应混合物搅拌16小时,其使得反应完成50%。用0.5毫升水骤冷,将样品用旋转蒸发法于硅胶上浓缩,且用闪蒸色层分离法(Biotage Flash 40M,用0,0.5,1%(10%于CH3OH的NH4OH)的CH2Cl2洗提)予以纯化,得到白色固体,其为1∶1的起始物质A∶产物。用制备性HPLC化法洗提至含1毫摩尔NaHCO3的管子进行最后的纯化。将冻干的物质于水/CH2Cl2(1∶1(全部50毫升))提取并分离。将水相用25毫升CH2Cl2再萃取两次。合并有机层并于硫酸钠上干燥,过滤,于65℃真空中旋转蒸发18小时成为一白色固体。产量:0.33克的(13%,白色固体);熔点:185-190℃(化合物59)。
c)于Ar气流中反应。将NaH60%(0.00600摩尔)于四氢呋喃(20毫升)中搅拌。加入化合物(17)(0.00476摩尔)并将混合物搅拌15分钟。加入氯甲基-2,2-二甲基丙酸酯(0.00600摩尔)且将反应混合物于室温搅拌16小时,然后搅拌并回流4.5小时,然后冷却。加入四氢呋喃(20毫升)。加入NaH 60%(0.00600摩尔)及氯甲基-2,2-二甲基丙酸酯(0.00600摩尔)且将产生的反应混合物搅拌24小时。将溶剂蒸发。将残质溶解于CH2Cl2中,用水清洗,且将溶剂蒸发。将残质用柱色层分离法于硅胶上(洗提液:CH2Cl2/CH3OH 100/0及99.5/0.5)予以纯化。收集所要的馏份并将溶剂蒸发。将残质于Gilson上纯化。将此馏份由2-丙醇中结晶出来,过滤出来并干燥。产量:0.60克的(23.6%,白色固体)(化合物60)。
d)将一含化合物(17)(0.0020摩尔)于四氢呋喃(40毫升)的悬浮液用0.24克NaH一次性处理。将起泡的混合物搅拌2小时以得到嫩黄色悬浮液。制备一含2,2’-氧基双乙酰氯(0.020摩尔)于四氢呋喃(10毫升)的溶液并于冰浴中冷却。通过套管,将产生的A/B悬浮液于10分钟期间逐滴转移到2,2’-氧基双乙酰氯的冷溶液中。将混合物加温至室温并搅拌3天。再加入0.24克的NaH且于两天后将反应于冰浴中冷却且用甲醇(0.150摩尔)及N,N-二乙基乙胺(0.150摩尔)的混合物于30分钟期间逐滴处理。将反应混合物加温至室温且于16小时后倒至醚中且用饱和NaHCO3萃取。将水性馏份用醚萃取两次且将合并的醚萃出物用水回洗三次且于MgSO4上干燥。浓缩得到2.91克油状残质,将其经过反相制备性HPLC。将适当馏份冻干,得到0.16克灰棕色粉末样品(14.5%纯化产品收率)(化合物61)。
实例B7
于氩气下将中间体12(0.00286摩尔),4-氰基-2,6-二甲基苯胺(0.00571摩尔),1MHCl于二乙醚(0.00140摩尔)及1,4-二噁烷(8毫升)加到一压力槽中。将反应混合物于油浴中在氮气流下加热直到所有的溶剂蒸发出来。加入1-甲基-2-吡咯烷酮(3毫升),且将反应混合物于220-240℃加热3小时。继续于210-220℃加热6小时。将残质溶解于1,4-二噁烷,蒸发,于CH2Cl2及1N及NaOH间分配,过滤,用碳酸钾干燥有机层并蒸发。将所要的化合物用制备性反相色层分离法予以分离并纯化。收集纯馏份并将溶剂蒸发,得到0.0165克(1.1%于冻干后)4-[[4-氨基-5-氯-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]-氨基]苄腈三氟醋酸盐(1∶1)(化合物19)。
实例B8
将一含有中间体(11)(0.0011摩尔)2,6-二甲基-4-(2-丙基)苯胺(0.0011摩尔),N,N,N’,N’-四甲基-1,8-萘二胺(0.0022摩尔)及1M HCl于醚(2.3毫升)(0.0023摩尔)于1,4-二噁烷(25毫升)的混合物搅拌并加热到95℃16小时。用旋转蒸发法移除溶剂并将残质用反相制备性HPLC予以纯化。将含有所要物质的合并馏份冻干,得到0.23克的(48%);溶点:198-201℃(化合物)。
实例B9
将N,N-二(甲基乙基)乙胺(0.0024摩尔)加到4-氨基-2,5-二甲基-3,4-苄腈(0.00219摩尔)及4-[[(5-溴-4,6-二氯)-2-嘧啶基]氨基]-苄腈(0.00218摩尔)中。将反应瓶密封并搅拌加热至155-160℃1.5天。将样品冷却至室温。将样品用闪蒸管柱色层分离法于硅胶上(洗提液:CH2Cl2)处理。通过制备性HPCL完成纯化,得到0.05克4-[[5-溴-4-氯-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(5.0%);熔点:259-260℃(化合物42)。
实例B10
连续将2,4,6-三甲基苯胺(0.0022摩尔)及N,N-二(甲基乙基)-乙胺(0.0024摩尔)加到一含4-[[(5-溴-4,6-二氯)-2-嘧啶基]氨基]苄腈(0.00218摩尔)于1,4-二噁烷(10毫升)的溶液中。将管子密封并将悬浮液在油浴中搅拌加热至120-130℃90小时。将混合物冷却至室温。再加入N,N-二(甲基乙基)-乙胺(15毫升),并将样品再加热至120-130℃64小时。将反应于150℃加热6天。将样品冷却至室温。将样品用醋酸乙酯稀释并用冷的1M NaOH萃取。将水相用乙酸乙酯回洗。将合并的有机相干燥并浓缩。于硅胶上(洗提液:CH2Cl2)进行闪蒸管柱色层分离。钭样品再次用制备性HPLC予以纯化,得到0.53克-4-[[5-溴-4-氯-6-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(54.9%);熔点220-221℃(化合物41)。
实例11
将一含4-氨基苄腈(0.0043摩尔)及
(0.0021摩尔)于1.4-二噁烷(30毫升)的混合物于100℃搅拌16小时。将溶剂用旋转蒸发法移除。将固体残质碾制并将残质于40℃真空中干燥16小时,得到0.452克的(55%);熔点:>300℃(化合物43)。
实例B12
将
(0.00567摩尔),4-氨基苄腈(0.01163摩尔)及1-甲基-2-吡咯烷酮(20毫升)加到一压力槽中。将反应混合物于140℃加热达16小时。将反应混合物冷却至室温并加入乙腈及水。将产生的沉淀过滤出来,并将固体用乙腈再结晶,得到1.27克4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-甲基-2-嘧啶基]氨基]苄腈(52);熔点:260-262℃(化合物44)。
实例B13
将中间体(11)(0.001摩尔)及2,6-二甲基-4-氨基苄腈(0.00473摩尔)合并且于搅拌时加热至150℃16小时。将样品溶解于CH3OH并蒸发至硅胶(1克)且用1∶1己烷∶CH2Cl2,4∶1CH2Cl2∶己烷,及纯CH2Cl2(2L)洗提。将所要的馏份蒸发并将残质于45℃真空中干燥16小时。将如此所得者移转到4毫升小管中的CH2Cl2,且将溶剂蒸发,得到0.120克4-[[5-溴-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(28.6%);
熔点:277-280℃(化合物45)。
实例B14
将4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-氯-2-嘧啶基]氨基]苄腈(0.00250摩尔)及NH3/1,4-二噁烷0.5M(0.015摩尔)于一压力槽中于150℃加热4天。将样品于周围条件下静置2天。缓缓将水加到混合物中直到形成沉淀。将混合物搅拌2小时并过滤。将固体由NH3CN中再结晶出来得到0.58克(馏份1)。将滤液蒸发(馏份2)。合并两个馏份并用管柱色层分离法用CH2Cl2洗提而予以纯化。将产生的所要馏份残质由NH3CN中再结晶出来得到0.44克4-[[4-氨基-5-溴-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈(40.5%)。将样品于80℃0.2mmHg干燥16小时(化合物46)。
实例B15
将4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-氯-2-嘧啶基]氨基]苄腈(0.000660摩尔),四氢呋喃(1毫升),及1-吡咯烷乙胺(0.00198摩尔)加到一压力槽中。将混合物于75℃加热16小时。加入CH2Cl2,并将混合物用水清洗,干燥,过滤并将滤液蒸发。用闪蒸管柱色层分离法用1∶9的甲醇∶二氯甲烷洗提而予以纯化,得到一固体,其再溶解于CH3CN中。加入HCl/二乙醚1.0M(0.48毫升),并将混合物于冰中冷却。过滤得到0.19克4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-[(1-吡咯烷基)乙氨基]-2-嘧啶基]氨基]苄腈氢氯酸盐(1∶1)(50.6%);熔点:208-210℃(化合物47)。
实例B16
将4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-氯-2-嘧啶基]氨基]苄腈(0.00064摩尔),四氢呋喃(3毫升),O-甲基羟基胺(0.06克),四氢呋喃及NaOH 1N(0.00067摩尔)加到一压力槽中。将反应混合物于室温下搅拌3天,然后于75℃搅拌1天,于90℃搅拌1天且于110℃搅拌2天。将四氢呋喃(4毫升)及NaOH 50%(0.00719摩尔)加到O-甲基羟基胺(0.60克)中。将液体倾析至反应瓶中并将反应混合物于110℃加热3天。将溶剂蒸发。将残质溶解于CH2Cl2,用饱和NaHCO3溶液及水清洗,干燥(Na2SO4),过滤并将溶剂蒸发。将残质用管柱色层分离法于硅胶上(洗提液:CH2Cl2/CH3OH 98/2)予以纯化。收集纯馏份并将溶剂蒸发。将残质由CH3CN中结晶出来,过滤出来并干燥,得到0.15克4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-6-(甲氧基氨基)-2-嘧啶基]氨基]苄腈(51%);熔点:185-186℃。将样品干燥(0.2mmHg,80℃,16小时)(化合物48)。
实例B17
a)于0℃时将正-丁基锂(2.0毫升,0.005摩尔)加到一含1-(甲基乙基)-2-丙胺(0.70毫升,0.005摩尔)及四氢呋喃(300毫升)的经搅拌的溶液中。搅拌冷却达30分钟后,加入化合物(17)(0.005摩尔)。将产生的混合物搅拌冷却达30分钟,于该点加入1,1-二甲基乙基溴醋酸酯(1.5毫升,10毫摩尔)并将温度提升至室温并将反应搅拌3小时。于另一烧瓶中将正-丁基锂(2.0毫升,5摩尔)加到一含1-(甲基乙基)-2-丙胺(0.70毫升,5毫摩尔)于四氢呋喃(50毫升)的经搅拌的0℃溶液中,且使其反应30分钟,于此时其转化为室温反应。重覆此过程。用0.5毫升H2O骤冷,将样品通过旋转蒸发法浓缩至硅胶上,且通过闪蒸色层分离法(用0,10,20%的于己烷的醋酸乙酯洗提)予以纯化,得到一白色固体的熔点:195-197℃(化合物56)。
b)将一含化合物(17)于40毫升,N,N-二甲基甲酰胺的悬浮液用0.24克NaH处理。将起泡的混合物搅拌90。制备一含1,4-二氯-1,4-丁二酮于10毫升N,N-二甲基甲酰胺的溶液且于冰浴中冷却。将由化合物(17)制得的混合物转移到1-(甲基乙基)-1-丙胺的冷溶液中并搅拌42小时而温热至室温。再加入0.24克NaH,将反应搅拌3天,且用醚稀释并倒至冰中。用过滤法移除沉淀。将2相滤液分离并将酸的水性馏份再用醚萃取两次。将合并醚馏份用少量的蒸馏水清洗并干燥。将溶剂蒸发并将残质予以硅胶管柱色层分离。逆相制备性HPLC及立即冷却以冻干适当馏份,得到0.07克的(7.8%);熔点:232-233℃(化合物57)
c)于氩气下将NaH60%及四氢呋喃加到一烧瓶中。将反应于室温中搅拌10分钟并加入化合物(17)。搅拌1小时后加入氯化碳酸乙酯。将反应混合物于室温再搅拌16小时并将溶剂蒸发。将残质部分地溶解于二甲亚砜中并过滤。将滤液用反相色层分离法予以纯化并冻干,得到0.47克(18%)的(化合物58)。
d)将含有4-[[5-氨基-4-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]-氨基]苄腈(0.00147摩尔)于醋酸酐(10毫升)及2-丙酮(10毫升)的混合物于室温搅拌16小时。然后将混合物加热至55℃,且再加入醋酸酐(3毫升)。将混合物于18小时后由热源移开并于室温搅拌6天。将样品旋转蒸发法浓缩成一固体。管柱色层分离法(用0,0.5,1,1.5,2%(10%NH4OH于CH3OH)溶于二氯甲烷洗提)予以纯化,得到熔点:290-295℃。将该固体于60℃真空中干燥16小时(化合物49)。
实例B18
将一含有4-[[4-(4-氰基-2,6-二甲基苯氧基)-5-硝基-2-嘧啶基]氨基]-苄腈(0.0005摩尔)于四氢呋喃(20毫升)的混合物用Pd/C10%(0.100克)作为催化剂而氢化过夜。吸收H2后(3倍量;0.0015摩尔),过滤出催化剂并将滤液用旋转蒸发法浓缩并于40℃真空中干燥16小时,得到0.15克4-[[5-氨基-4-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]-苄腈(84%);熔点:>300℃(化合物50)。
实例B19
将4-[[4-[(2,4,6-三甲基苯基)氨基]-5-硝基-2-嘧啶基]氨基]苄腈(0.001摩尔),Pd/C 10%(0.025克),乙醇(20毫升),及肼(0.030摩尔)合并以形成一浆料并于室温搅拌16小时。将溶剂用旋转蒸发法移除。将残质于四氢呋喃(20毫升)及甲醇(1毫升)中提取。加入第2份肼(0.5克),并将反应于室温搅拌16小时。加入第3份肼(0.5毫升)并将反应于室温再搅拌16小时。将样品用旋转蒸发法浓缩至硅胶上(1克),且用闪蒸色层分离法(洗提液:0.5,1.2%,10%(NH4OH于CH3OH)于CH2Cl2)予以纯化。将所要的馏份用制备性HPLC予以纯化,得到0.24克4-[[5-氨基-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(70%);熔点:224-225℃(化合物51)。
实例B20
将化合物(3)(0.001摩尔),三甲基硅烷腈(0.0012摩尔)Pd(PPh3)2Cl2(0.020克),CuI(0.010克)及CF3COOH/H2O(3毫升)合并于一密封管中并加热至110℃10小时。加入第二份的催化剂Pd(PPh3)2Cl2(0.020克)及CuI(0.010克)及CF3COOH/H2O(3毫升)并将反应混合物于100℃搅拌10小时。将物质用旋转蒸发法浓缩。将残质用制备性逆相HPLC予以纯化。将所要的馏份浓缩并用逆相HPLC予以纯化并用N2气流干燥,然后于40℃真空中达16小时。产量:0.011克的4-[[5-乙炔基-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;熔点:165-175℃(化合物52)。
实例B21
于N2下将化合物(3)(0.000906摩尔),三丁基苯基锡烷(stannane)(0.000906摩尔),Pd(PPh3)4(0.002718摩尔),及1,4-二噁烷(3毫升)合并于一密封管子中并加热至110℃达16小时。将反应混合物冷却并用旋转蒸发法而浓缩。将样品用制备性逆相HPLC予以纯化,然后于Ar气流中干燥,于真空中干燥,得到0.0845克的4-[[5-苯基-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;熔点:209-214℃(化合物53)。
实例B22
于Ar下将化合物(3)(0.001摩尔),四乙烯基锡烷(0.22毫升),1,4二噁烷(2毫升)及Pd(PPh3)4(0.112克合并于一密封管中)。将混合物搅拌并加热至100℃达16小时。再加入四丁烯基锡烷及Pd(PPh3)4。将反应置于Ar中,搅拌并加热。将反应用旋转蒸发法浓缩且于制备性HPLC上纯化。将物质用N2气流干燥,并于60℃真空中干燥4小时,得到0.422克4-[[5-乙烯基-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;熔点:237-242℃(化合物54)。
实例B23
于氩气中将化合物(3)(0.001225摩尔),CuCN(0.01470摩尔)及N,N-二甲基甲酰胺(2毫升)合并于一密封管中,然后搅拌并加热至160℃达16小时。将残质用管柱色层分离法(洗提液:CH2Cl2/己烷1/1,然后为纯CH2Cl2)予以纯化。收集所要的馏份并将溶剂蒸发。将残质于室温用CH2Cl2碾制。将固体干燥(真空,40℃,24小时),得到0.0864克的(24%);熔点:254-259℃(化合物55)。
表1、2、3及4中所列出的式(I-a)化合物是依类似于上述实例之一制备的。
表1
化合物号码 | 实例号码 | Y | 物理数据 |
1222 | B1aB1aB1l | ClBrNO2 | -mp.227-228℃mp.224-226℃ |
表2
化合物号码 | 实例号码 | Ra | Rb | Rc | X | Y | Q | mp./盐 |
3456789 | B1bB2B3B5B5B5B3 | CH3CH3CH3CH3CH3CH3CH3 | CH3CH3CH3CH3CH3BrBr | CH3CH3CH3CH3CH3CH3CH3 | NHNHNHOSONH | BrClClClClClCl | HNH2HHHHH | mp.227-228℃mp.241-242℃;三氟醋酸盐(1∶1)mp.224-226℃mp.218-219℃mp.264-266℃mp.237-238℃mp.217-219℃ |
化合物编号 | 实例号码 | Ra | Rb | Rc | X | Y | Q | mp./盐 |
101112131415161718192021232425262728293031323334353637404142434445 | B4B4B4B4B4B5B5B6B5B7B3B3B23B23B14B14B14B14B14B14B14B11B5B5B5B6B5B8B10B9B11B12B13 | BrBrCH3CH3ClClCH3CH3CH3CH3ClCH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3 | CH3BrC(CH3)3CNClBrClCNCNCNClBrCNBrCNCNCH3CH3CNCNCH3CH3CH3CH3CNCNCH3CH(CH3)2CH3CNCNCNCN | BrFCH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3 | NHNHNHNHNHOOOONHNHNHNHNHOOOOOOONHOOOOONHNHNHOONH | ClClClClClClClBrClClBrBrCNCNBrBrBrBrBrClClNO2BrClClClClBrBrBrNO2BrBr | HHHHHHHHHNH2HHHHNH-CH3NH2NH2NH-CH3NH-C2H5NH2NH2HHClClBrBrHClClHCH3H | mp.262-263℃mp.200-202℃mp.214-215℃mp.281-283℃mp.243-245℃mp.244-247℃mp.232-235℃mp.288-289℃mp.283-284℃mp.266-268℃;三氟醋酸盐(1∶1)mp.253-254℃mp.243-245℃mp.275-290℃;三氟醋酸盐(1∶1)mp.291-299℃mp.248-250℃mp.255-256℃-mp.213-214℃mp.263-264℃mp.272-274℃mp.199-202℃mp.>300℃mp.207-215℃mp.225-226℃mp.273-276℃mp.281-282℃mp.214-215℃mp.198℃;三氟醋酸盐(1∶2)mp.220℃mp.259℃mp.>300℃mp.260℃mp.277℃ |
表3
化合物编号 | 实例号码 | Z | |
38565758596061 | B17CB17aB17bB17cB6bB6cB6d | -C(=O)-CH3-CH2-COOC(CH3)3-CH=O-COOC2H5-CH2-COOC2H5-CH2-COOC(CH3)2-CO-CH2-OCH2-CO-OCH3 | mp.194-196℃mp.195-197℃mp.232-233℃mp.209-210℃mp.185-190℃mp.168-169℃mp.184-185℃ |
表4
化合物编号 | 实例号码 | Ra | Rb | X | Y | Q | |
39 | B5 | Cl | Cl | S | Br | H | mp.198-200℃ |
C.药理实例
实例C.1
使用一快速、光敏且自动化的分析过程来进行抗-HIV试剂的生物体外评估。用HIV-1变性的T4-细胞作为目标细胞系,其如前所示(Koyanagi等,Int.J.Cancer,
36,445-451,1985)为对HIV感染高度易受影响且可接受。对于HIV-诱发的细胞病变效应的抑制作用是作为终点。HIV-感染及模拟感染细胞两者的生存能力用现场3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物(MTT)的还原作用来进行分光光度分析。以50%细胞毒性浓度(CC50,μM)定义为可减少模拟感染控制组样品吸附50%的化合物浓度。化合物在HIV-感染细胞上所达到的保护百分比用下列公式计算:
其中,(ODT)HIV是用HIV-感染细胞的测试化合物的给定浓度所测定的光密度;(ODC)HIV是控制组未经处理的HIV-感染细胞所测得的光密度;(ODC)MOCK控制组未经处理的模拟-感染细胞所测得的光密度;所有光密度值是于540nm测定。根据上述公式,可达到50%保护作用的剂量定义为50%抑制浓度(IC50,μM)。CC50与IC50,的比值是定义为选择性指数(SI)。式(I-A)化合物显示出抑制HIV-1的功效。特定的IC50,CC50及SI值列于下表5中。
表5
化合物编号 | IC50(μM) | CC50(μM) | SI |
2314567894661 | 0.0300.0060.0040.0020.0020.0090.0840.0120.0030.0020.002 | 82.64.410.910.00.4>100>100>1001.2>200>100 | 273073827875555178>11049>1182>8298376>71428>52631 |
化合物编号 | IC50(μM) | CC50(μM) | SI |
10111213141516171860 | 0.0050.0020.0200.00050.0020.0100.0100.0020.0010.002 | 0.40.448.50.40.4>100>100>10>1074.52 | 921832393860191>9661>10416>6451>714239223 |
Claims (22)
1.一种具下式的化合物,其N-氧化物,加成盐或立体化学异构形式,
其中
-b1=b2-C(R2a)=b3-b4=代表下式的二价基:
-CH=CH-C(R2a)=CH-CH= (b-1);
-N=CH-C(R2a)=CH-CH= (b-2);
-CH=N-C(R2a)=CH-CH= (b-3);
-N=CH-C(R2a)=N-CH= (b-4);
-N=CH-C(R2a)=CH-N= (b-5);
-CH=N-C(R2a)=N-CH= (b-6);
-N=N-C(R2a)=CH-CH= (b-7);
q为0、1、2、3或4;
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基、C1-6烷基羰基、C1-6烷氧基羰基、C1-6烷基羰基氧基取代的C1-6烷基;被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
R2a为氰基;氨基羰基;单-或二(甲基)氨基羰基;被氰基、氨基羰基或单-或二(甲基)氨基羰基取代的C1-6烷基;被氰基取代的C2-6烯基,或被氰基取代的C2-6炔基;
每一个R6独立地为羟基;卤素;任选地被氰基或-C(=O)R6取代的C1-6烷基;C3-7环烷基;任选地被一或多个卤素原子或氰基取代的C2-6烯基;任选地被一或多个卤素原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷氧基羰基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代甲基;多卤代甲氧基;多卤代甲硫基;-S(=O)pR6;-NH-S(=O)pR6;-C(=O)R6;-NHC(=O)H;-C(=O)NHNH2;-NHC(=O)R6;-C(=NH)R6或下式的基团
其中每一个A独立地为N、CH或CR6;
B为NH、O、S或NR6;
p为1或2;且
R6为甲基、氨基、单-或二甲基氨基或多卤代甲基;
L为C1-10烷基、C2-10烯基、C2-10炔基、C3-7环烷基,其中每一个所述脂族基团可被一或二个独立选自下列的取代基所取代:
*C3-7环烷基,
*吲哚基或异吲哚基,每一个可任选地被一、二、三或四个各自独立选自卤素、C1-6烷基、羟基、C1-6烷氧基、氰基、氨基羰基、硝基、氨基、多卤代甲基、多卤代甲氧基及C1-6烷基羰基的取代基所取代,
*苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基,其中每一个所述芳族环可任选地被一、二、三、四或五个各自独立选自在R2中定义的取代基取代;或
L为-X-R3,其中
R3为苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基,其中每一个所述芳族环可任选地被一、二、三、四或五个各自独立选自在R2中定义的取代基所取代;且
X为-NR1-、-NH-NH-、-N=N-、-O-、-C(=O)-、-CHOH-、-S-、-S(=O)-或-S(=O)2-;
Q代表氢、C1-6烷基、卤素、多卤代C1-6烷基或-NR4R5;且
R4及R5各自独立地选自氢、羟基、C1-12烷基、C1-12烷氧基、C1-12烷基羰基、C1-12烷氧基羰基、芳基、氨基、单-或二(C1-12烷基)氨基、单-或二(C1-12烷基)氨基羰基,其中每一个前述C1-12烷基可任选地且各独立地被一或二个各自独立选自羟基、C1-6烷氧基、羟基C1-6烷氧基、羧基、C1-6烷氧基羰基、氰基、氨基、亚氨基、单-或二(C1-6烷基)氨基、多卤代甲基、多卤代甲氧基、多卤代甲硫基、-S(=O)pR6、-NH-S(=O)pR6、-C(=O)R6、-NHC(=O)H,-C(=O)NHNH2、-NHC(=O)R6,-C(=NH)R6、芳基及Het的取代基所取代;或
R4及R5可一起形成吡咯烷基、哌啶基、吗啉基、叠氮基或单-或二(C1- 12烷基)氨基C1-4亚烷基;
Y代表羟基、卤素、C3-7环烷基、任选地被一或多个卤素原子取代的C2- 6烯基、任选地被一或多个卤素原子取代的C2-6炔基、被氰基或-C(=O)R6取代的C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、羧基、氰基、硝基、氨基、单-或二(C1-6烷基)氨基、多卤代甲基、多卤代甲氧基、多卤代甲硫基、-S(=O)pR6、-NH-S(=O)pR6、-C(=O)R6、-NHC(=O)H、-C(=O)NHNH2、-NHC(=O)R6、-C(=NH)R6或芳基;
芳基为苯基或被一、二、三、四或五个各自独立选自卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基及多卤代C1-6烷氧基的取代基所取代的苯基;
Het为脂族或芳族杂环基;该脂族杂环基选自吡咯烷基、哌啶基、高哌啶基、哌嗪基、吗啉基、四氢呋喃基及四氢噻吩基,其中每一个所述脂族杂环基可任选地被氧代基所取代;且所述芳族杂环基选自吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、及哒嗪基,其中每一个所述芳族杂环基可任选地被羟基所取代。
2.权利要求1的化合物,其中R1是氢、芳基、甲酰基、C1-6烷基羰基、C1-6烷基、C1-6烷氧基羰基、被甲酰基、C1-6烷基羰基、C1-6烷氧基羰基取代的C1-6烷基;
3.权利要求1或2的化合物,其中L为-X-R3,其中,R3为2,4,6-三取代的苯基。
4.权利要求1或2中任一项的化合物,其中,Y为氰基、-C(=O)NH2或卤素。
5.权利要求3的化合物,其中,Y为氰基、-C(=O)NH2或卤素。
6.权利要求1或2中任一项的化合物,其中,Q为氢或NR4R5。
7.权利要求3的化合物,其中,Q为氢或NR4R5。
8.权利要求4的化合物,其中,Q为氢或NR4R5。
9.权利要求5的化合物,其中,Q为氢或NR4R5。
10.权利要求1的化合物,其中,化合物为4-[[4-氨基-5-氯-6-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;4-[[5-氯-4-[2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;4-[[5-溴-4-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;4-[[4-氨基-5-氯-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;4-[[5-溴-6-[(4-氰基-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基]苄腈;4-[[4-氨基-5-氯-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;或4-[[4-氨基-5-溴-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈;其N-氧化物,加成盐及立体化学异构形式。
11.权利要求10的化合物,其中该化合物是4-[[4-氨基-5-溴-6-(4-氰基-2,6-二甲基苯氧基)-2-嘧啶基]氨基]苄腈,其N-氧化物,加成盐及立体化学异构形式。
13.权利要求1至11中任一项要求保护的化合物在制备用于治疗患有人类免疫缺乏病毒感染的个体的药物中的用途。
14.权利要求1至11中任一项要求保护的化合物在制备用于治疗耐多种药物的HIV感染的药物中的用途。
15.权利要求14中要求的用途,其中耐多种药物的HIV感染是耐非核苷逆转录酶抑制剂而不耐权利要求1~11中定义的化合的HIV感染。
16.权利要求15中要求的用途,其中所述HIV感染是HIV1感染。
17.权利要求1至11中任一项要求的化合物在制备用于治疗患有HIV感染的个体的药物中的用途,其中R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基、C1-6烷基羰基、C1-6烷氧基羰基取代的C1-6烷基;
18.一种药物组合物,它包含可药用载体与治疗活性剂量的如权利要求第1至11项中任一项要求的化合物。
19.权利要求18中要求的药物组合物的制备方法,其特征在于将治疗有效量的如权利要求第1至11项中任一项要求的化合物与可药用载体充分混合。
20.权利要求1要求的化合物的制备方法,其特征在于
a)将式(II)中间体与式(III)氨基衍生物在无溶剂条件下或在反应惰性溶剂中,在反应惰性氛围中进行反应
其中,W1为适当的离去基且L、Y、Q、R1、R2、R2a、q及-b1=b2-C(R2a)=b3-b4=如权利要求1所定义;
b)将式(IV)中间体与式(V)中间体在不含溶剂条件下或在适当溶剂中于反应惰性氛围中进行反应
其中W2为适当的离去基团,且Y、Q、R1、R2、R2a、R3、q及-b1=b2-C(R2a)=b3-b4=如权利要求1所定义;
c)将式(IV)中间体与式(VI)中间体在适当溶剂中在反应惰性氛围中于适当碱存在下进行反应
其中,W2为适当离去基,且Y、Q、R1、R2、R2a、R3、q及-b1=b2-C(R2a)=b3-b4=如权利要求1所定义;
或,如果需要,可根据本领域已知的转化反应将式(I-a)化合物互相转化;而且,如果需要,可将式(I-a)化合物通过用酸处理而转化为酸加成盐,或相反地,可通过用碱处理而将酸加成盐形式转化为游离碱;且,如果需要,可制备其立体化学异构形式。
21.权利要求1或12的化合物与其他抗逆转录病毒化合物的组合药。
22.一种药物组合物,其含有可药用载体和作为活性组分的(a)如权利要求1或12定义的化合物,及(b)其他抗逆转录病毒化合物。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110066273A (zh) * | 2019-06-05 | 2019-07-30 | 山东大学 | 一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 |
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