CN1144793C - 极性取代的烃类 - Google Patents
极性取代的烃类 Download PDFInfo
- Publication number
- CN1144793C CN1144793C CNB941941140A CN94194114A CN1144793C CN 1144793 C CN1144793 C CN 1144793C CN B941941140 A CNB941941140 A CN B941941140A CN 94194114 A CN94194114 A CN 94194114A CN 1144793 C CN1144793 C CN 1144793C
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- acyl group
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- 229930195733 hydrocarbon Natural products 0.000 title description 4
- 150000002430 hydrocarbons Chemical class 0.000 title description 4
- -1 thinner Substances 0.000 claims description 312
- 150000001875 compounds Chemical class 0.000 claims description 128
- 125000002252 acyl group Chemical group 0.000 claims description 76
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 70
- 229910052760 oxygen Inorganic materials 0.000 claims description 50
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 33
- 239000001301 oxygen Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 108091005804 Peptidases Proteins 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 17
- 241001430294 unidentified retrovirus Species 0.000 claims description 16
- 102000035195 Peptidases Human genes 0.000 claims description 14
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 14
- 239000003981 vehicle Substances 0.000 claims description 6
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- 125000004122 cyclic group Chemical group 0.000 description 114
- 125000003118 aryl group Chemical group 0.000 description 103
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- 125000002769 thiazolinyl group Chemical group 0.000 description 78
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- 229910052794 bromium Inorganic materials 0.000 description 23
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- 238000010168 coupling process Methods 0.000 description 16
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- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
- 230000008878 coupling Effects 0.000 description 15
- 125000000623 heterocyclic group Chemical group 0.000 description 14
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- 241000725303 Human immunodeficiency virus Species 0.000 description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 12
- 125000000524 functional group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 11
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- 230000002194 synthesizing effect Effects 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000001118 alkylidene group Chemical group 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 230000002085 persistent effect Effects 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
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- 238000003756 stirring Methods 0.000 description 8
- 125000005190 thiohydroxy group Chemical group 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 239000004744 fabric Substances 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 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 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 208000007976 Ketosis Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000009795 derivation Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229920000591 gum Polymers 0.000 description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 6
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
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- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 5
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/10—Hydrazines
- C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
- C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
- C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
- C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明是有关通式(I)反转录病毒蛋白酶抑制剂W-(A)n-B-(A*)m-V (I)其中W,A,B,A*,V,n和m如本文中的定义,包括含有一个在活体内不安定的溶解基团的通式(I)的前药。
Description
技术领域
本发明涉及某些带有极性取代基的烃衍生物,及其于抑制反转录病毒蛋白酶上的用途,例如:治疗HIV病毒感染如:后天免疫缺乏症候群(AIDS)。本发明也涉及这类带有极性取代基的烃衍生物的制法,含其之医药组合物及其于治疗或预防反转录病毒的方法。本发明还涉及加强医药用或兽医用物质的水溶性的方法。
背景技术
人类免疫缺乏病毒(HIV)为一种导致AIDS及其相关病变的病原性反转录病毒。由于HIV的发现,对抗AIDS的抗病毒化学疗法的发展已成为积极研究重点。(有关AIDS的分子目标的最近研究参见Mitsua等人,Science,1990,pp.1533-154)。HIV蛋白酶(HIV PR)及天门冬胺酰基蛋白酶首先被克拉玛(Kramer)等人(Science 231,1580(1986)认为是AIDS疗法的可能目标。从此以后,即广泛地确认HIV PR抑制剂在治疗AIDS时作为有效制剂的潜在用途(有关HIV PR的医疗用途参见托马希里(Tomaselli)等人,Chimica,Oggi,1991年5月,pp.6-27,及J.P.胡弗(Huff),J.Med.Chem.34,2341-2327(1991))。在传统模拟天门冬胺酰基蛋白酶的过渡状态中,羟基乙烯,二羟基乙烯,羟基乙胺和次膦酸电子等排物(Bostere)似乎和HIV PR具有最大亲合力。许多HIV PR的抑制剂已在不同细胞系统中,于毫微摩尔范围的浓度展现抗病毒活性,且已说明在专利文献中。
发明目的
本发明的目的为提供适用于反转录病毒蛋白酶抑制剂的化合物。本发明另一项目的为提供包括适用于治疗或预防反转录病毒感染的化合物的医药组合物。本发明另一个目的为提供治疗或预防反转录病毒感染,特别是AIDS的方法。本发明其他目的为提供制备适用于反转录病毒蛋白酶抑制剂的化合物的方法,及加强医药用或兽医用物质,特别是反转录病毒蛋白酶抑制剂的水溶性的方法。
发明概要
本发明提供适用为反转录病毒蛋白酶(特别是天门冬胺酰基蛋白酶,且更特别是HIV蛋白酶)的抑制剂的化合物,该等化合物可有效治疗会出现此等不期望的酵素活性特性的病症,特别是后天免疫缺乏症候群。
下列本发明说明中,所述及的每一份参考文献均已并为本文的参考文献。
本发明第一项具体实施例是有关通式(I)化合物或其医药上可接受的盐或前药:
W-(A)n-B-(A*)m-V (I)
其中
W是选自下列:R1-X-,R1*-X*-,-Y*,-CN,
-N=CR5R5*,-C(R5)=NR3,-C(R5)=NOR3,
-C(NR3R4)=NR5**,-C(D)OR3,-C(D)SR3和
-C(D)NR3R4,式中
Y*如下文定义,
R1,R3和R4分别选自下列:R6及在活体不安定的溶解基团Px,其中R6是选自下列:氢,R20,其中R20是选自下列:
可任选取代的(C1-C18)烷基,
可任选取代的(C2-C18)烯基,
可任选取代的(C2-C18)炔基,
可任选取代的(C3-C18)环烷基,
可任选取代的(C3-C18)环烷基(C1-C18)烷基,
可任选取代的(C3-C18)环烷基(C2-C18)烯基,
可任选取代的(C3-C18)环烷基(C2-C18)炔基,
可任选取代的(C6-C24)芳基,
可任选取代的(C6-C24)芳基(C1-C18)烷基,
可任选取代的(C6-C24)芳基(C2-C18)烯基,
可任选取代的(C6-C24)芳基(C2-C18)炔基,
可任选取代的(C1-C18)酰基,
可任选取代的杂环基,
可任选取代的杂环基(C1-C18)烷基
可任选取代的杂环基(C2-C18)烯基,及
可任选取代的杂环基(C2-C18)炔基,C(D)OR21,C(D)SR21,C(D)NR21R22,C(NR21)R22,C(NR21)OR22,及C(NR21)NR22R23,其中R21,R22,和R23分别选自:氢或如上述定义的R20,或
R21和R22,或R22和R23共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
或R3和R4,若存在时,共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
D是选自O和S,
X是选自:Y,S(O)和S(O)2,其中Y如下文定义;
X*是选自下列:NR10,O和S,其中R10如上述R6的定义;
R1 *是选自下列:如上述定义的R1,P(O)(OR7)R8,S(O)zOR7和S(O)zNR7R8,其中z为1或2,且R7和R8共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R5和R5 *分别选自下列:H,CF3,C(D)OR103,C(D)SR103,C(D)NR103R104和如上述定义的R20,其中D如上述定义,且其中R103和R104如上述R6的定义,或R103和R104共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,且
R5 **是选自氢及如上文定义的R20;
n为0至6;
m为0至6,且n+m≥1;
每次出现的A分别选自下列:
及天然或合成氨基酸的羟基;
每次出现的A*分别选自下列:
-C≡C-,
及天然或合成氨基酸的残基;其中
R12 *、R13 *、R9和R9 *分别选自下列:F,Cl,Br,I及如上述定义的R5,
R11如上述R1的定义,
R12如上述R6的定义,
R13是选自下列:
F,Cl,Br,I,如上述定义的R6,及R200,其中R200是
选自下列:
CN,
NCO,
NCS,
OCN,
SCN,
N3,
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61,
NR60C(D1)NR61R62,
NR60OR61,
脒基,
胍基,
S(O)R60,
S(O)2D1R60,
S(O)NR60R61,
S(O)2NR60R61,
D1S(O)R60,
D1S(O)2OR60,
D1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 and
ONR60R61,
其中D1,D2,D3和D4分别如上述D的定义,且R60,R61和R62分别如上述R6的定义,或R60,R61和R62中任何二者或多者形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,
或R12和R13共同形成选自下列的基团:=O,=S,
=NOR60,=NR60,-OQO-,-SQS-,-SQO-,其中Q为如下文定义的任选取代的(C1-C12)亚烷基,且R60如上述定义,及
L是选自下列:
一个键,
-CH2-和-CH2-CH2-,其中R11和D如上述定义,R11 *和D*分别如R11和D的定义,且z为1或2;
R13 **为F,Cl,Br,OR60或NR60R60,其中R60和R61如上述定义,
B是选自下列:
其中R203和R203*分别如上述R6的定义,R14*和R14**分别选自下列:
氢,
如上述定义的R20,
CF3,
C(D*)OR40,
C(D*)SR40及
C(D*)NR40R41,其中R40和R41分别如上述R21和R22的定义,或R40和R41形成如下文定义的饱和或不饱和环系,双环系或稠合环系之一部分,
R14是选自下列:F,Cl,Br,I,如上述定义的R14*,且R200如上述定义,
R17和R17*分别如上述R6的定义,
D*如上述D的定义
Z为饱和或不饱和(C2-C4)亚烷基,可任选一个或多个选自下列的基团取代:F,Cl,Br,I和如上述定义的R14*,
Z*为饱和或不饱和(C1-C3)亚烷基,可任选一个或多个选自下列的基团取代:F,Cl,Br,I和如上述定义的R14*,
M1是选自下列:OR15,SR15,和NR15R17,其中R15是选自下列:
如上述定义的Px,
如上述定义的R6,糖基,其是衍生自合成或天然的醛糖,酮糖,去氧醛糖,去氧酮糖,氨基醛糖,氨基酮糖或其寡糖,且
R17如上述定义,或
R15和R17共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
M和M*分别选自下列:如上述定义的M1,OCN,SCN,YR2,Y*和N=CR30R31,其中Y,Y*和R2如上述定义,且R30和R31分别如上述R20的定义,
M2是选自下列:如上述定义的R14*,-CR30*=Y**和-CH3O*=NR17 *,其中Y**如下文定义,R30*如上述R20的定义,且R17*如上述定义,
R18和R19分别如上述R20的定义,或R18和R19共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,且
R18 *和R19 *共同形成如下文定义的饱和或不饱和环系和双环系或稠合环系的一部分;
V是选自下列:YR2,Y*和C(R30)=Y**,其中
Y不存在或选自下列:
-S-S-,
其中D**是选自下列:一个键,O,S和NR50,R50如上述R6的定义,R51如上述R15的定义且R52如上述R20的定义,或R50和R51若存在时,可共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,且
R2如上述R6的定义,
Y*是选自下列:
-N=O,
和
其中D*和D**分别如上述D的定义;R114*,R114**,R115和R117*分别如上述R14*,R14**,R15和R17*的定义;R50和R51如上述定义或R50和R51可共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分;R2*为选自下列:如上述定义的R2,如上述定义的Px,S(O)zOR120和S(O)zR120R121,其中z为1或2;R33和R34分别选自:氢及如上述定义的R20,或R33和R34共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,且R120和R121分别如上述R20的定义,或R120和R121共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R30如上述定义,且
Y**是选自:=N-NR115R117和=N-OR115,其中R115和R117分别如上述R15和R6的定义,或R115和R117共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
且其中任何选自:R1,R1*,R2,R2*,R9,R11,R12,R13,R14,R14*,R17,R50和R51中的基团可和任何选自:R1,R1*,R2,R2*,R9*,R10,R11,R12,R13,R14,R14*,R17,R50和R51中的其他基团共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
通式(I)化合物适用为反转录病毒蛋白酶(特别是HIV蛋白酶)的抑制剂。
本发明第一项具体实施例的一种型式是有关通式(I′)化合物或其医药上可接受的盐或前药:
W′-(A)n′-B′-(A′*)m′-V′ (I′)
其中
W′是选自下列:R1-X,R1*-X*-,-Y′*,-CN,
-N=CR5R5*,-C(R5)=NR3,-C(R5)=NOR3,-C(D)OR3,
-C(D)SR3及-C(D)NR3R4,其中
Y*如下文定义,
R1,R3和R4分别选自下列:R6和在活体内不安定的溶解基团Px,其中R6是选自下列:
氢,
R20其中R20是选自下列:
可任选取代的(C1-C18)烷基,
可任选取代的(C2-C18)烯基,
可任选取代的(C2-C18)炔基,
可任选取代的(C3-C18)环烷基,
可任选取代的(C3-C18)环烷基(C1-C18)烷基,
可任选取代的(C3-C18)环烷基(C2-C18)烯基,
可任选取代的(C3-C18)环烷基(C2-C18)炔基,
可任选取代的(C6-C24)芳基,
可任选取代的(C6-C24)芳基(C1-C18)烷基,
可任选取代的(C6-C24)芳基(C2-C18)烯基,
可任选取代的(C6-C24)芳基(C2-C18)炔基,
可任选取代的(C1-C18)酰基,
可任选取代的杂环基,
可任选取代的杂环基(C1-C18)烷基
可任选取代的杂环基(C2-C18)烯基,及
可任选取代的杂环基(C2-C18)炔基,
C(D)OR21,
C(D)SR21,及
C(D)NR21R22,其中R21和R22分别选自氢及如上述定义的R20,或R21和R22,共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
或R3和R4,若存在时,共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
D是选自O和S,
X是选自:Y′,S(O)和S(O)2,其中Y′如下文定义,
X*是选自下列:NR10,O和S,其中R10如上述R6的定义;
R1 *是选自:如上述定义的R1,S(O)zOR7和S(O)zNR7R8,其中z为1或2,且R7和R8分别如上述R20的定义,或R7和R8共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R5和R5 *分别选自下列:H,CF3,C(D)OR103,C(D)SR103,C(D)NR103R104和如上述定义的R20,其中D如上述定义,且其中R103和R104如上述R6的定义,或R103和R104共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
n′为0至8;
m′为0至8,且n′+m′≥1;
A′和A′*每次出现时,是分别选自下列:O,S,S(S),S(O)2,NR11,CR12R13和CR12*R13*,或两个连续基团A′-A′或A′*-A′*为选自下列的结构单位:
和-C≡C-,
其中
R12*,R13*,R9和R9*分别选自下列:F,Cl,Br,I及如上述定义的R5,
R11如上述R1的定义,
R12如上述R6的定义,
R13是选自下列:
F,Cl,Br,I,如上述定义的R6,及R200,其中R200是选自下列:
CN,
NCO,
NCS,
OCN,
SCN,
N3,
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61,
NR60C(D1)NR61R62,
NR60OR61,
脒基,
胍基,
S(O)R60,
S(O)2D1R60,
S(O)NR60R61,
S(O)2NR60R61,
D1S(O)R60,
D1S(O)2OR60,
D1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 和
ONR60R61,其中D1,D2,D3和D4分别如上述D的定义,且R60,R61和R62分别如上述R6的定义,或R60,R61和R62中任何二者或多者形成如下文定义的饱和或不饱和环系,双环系或稠合环系之-部分,
或R12和R13共同形成选自下列的基团:=O,=S,=NOR60,=NR60,-OQO-,-SQS-和-SQO-,其中Q为如下文定义的可任选取代的(C1-C12)亚烷基,且R60如上述定义;
B′是选自下列:
-O-,-S-,
和
其中R203和R203*分别如上述R6的定义,R14*和R14**分别选自下列:
氢,
如上述定义的R20,
CF3,
C(D*)OR40,
C(D*)SR40及
C(D*)NR40R41,其中R40和R41分别如上述R21和R22的定义,或R40和R41形成如下文定义的饱和或不饱和环系,双环系或稠合环系之一部分,
R14是选自下列:F,Cl,Br,I,如上述定义的R14*及如上述定义的R200,
R17和R17*分别如上述R6的定义,
D*如上述D的定义,
Z为饱和或不饱和(C2-C4)亚烷基,可任选一个或多个选自下列的基团取代:F,Cl,Br,I和如上述定义的R14*,
Z*为饱和或不饱和(C1-C3)亚烷基,可优选一个或多个选自下列的基团取代:F,Cl,Br,I和如上述定义的R14*,
M1是选自下列:OR15,SR15,和NR15R17,其中R15是选自下列:
如上述定义的Px,
如上述定义的R6,
及糖基,其是衍生自合成或天然的醛糖,酮糖,去氧醛糖,去氧酮糖,氨基醛糖,氨基酮糖或其寡糖,且
R17如上述定义,或
R15和R17共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
M和M*分别选自下列:如上述定义的M1,OCN,SCN,Y′R2,Y′*和N=CR30R31,其中Y,Y′*和R2如上述定义,且R30和R31分别如上述R20的定义,
M2是选自下列:如上述定义的R14*,-CR30*=Y**和-CR3 *=NR17 *,其中Y**如下文定义,R30*
如上述R20的定义,且R17*如上述定义,
R18和R19分别如上述R20的定义,或R18和R19共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,且
R18 *和R19 *共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系;
V′是选自下列:YR2,Y*和C(R30)=Y**,其中
Y′选自下列:
和
其中
R50如上述R6的定义,R51如上述R15的定义且R52如上述R20的定义,或R50和R51共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,且
R2如上述R6的定义,
Y*是选自下列:
-N=O,
和
其中D*和D**分别如上述D的定义;R114*,R114**,R115和R117*分别如上述R14*,R14**,R15和R17*的定义;R50和R51如上述定义或R50和R51可共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分;R2*为选自下列:如上述定义的R2,S(O)zOR120和S(O)zR120R121,其中z为1或2;R33和R34分别选自:氢及如上述定义的R20,或R33和R34共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,且R120和R121分别如上述R20的定义,或R120和R121共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R30如上述定义,且
Y**是选自:=N-NR115R117和=N-OR115,其中R115和R117分别如上述R15和R6的定义,或R115和R117共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,且其中任何选自:R1,R1*,R2,R2*,R9,R11,R12,R50和R51中的基团可和任何选自:R1,R1*,R2,R2*,R9*,R10,R11,R12,R50和R51中的其他基团共同形成一个或多个如下文定义的饱和或不饱和环系,双环系或稠合环系,
且其中任何三级氨基氮原子可被
基团置换,且若式W′-(A′)n′-B′-(A′*)m′-V′含有三个杂原子共同形成的基团时,这三个杂原子中一个原子为呈S(O)或S(O)2形式的氧化态硫,或呈P(O)形式的氧化态磷,或这三个杂原子包含两个形成杂环一部分的氮原子,但其限制条件为式W′-(A′)n′-B′-(A′*)m′-V′不包含两个连接的氧原子或三个连接的硫原子;
且其中(a)当W′为R1*X*时,其中X*为NR10且V′为Y*,其中Y*为
其中R81是选自下列:氢,-R100H,-R100C(O)OR101,-R100C(O)NR101R102,-R100NR102C(O)R100*,及-R100C(O)R100,
其中R101和R102分别选自下列:氢,
可任选取代的(C1-C18)烷基,
可任选取代的(C3-C18)环烷基,
可任选取代的(C3-C18)环烷基(C1-C18)烷基,
可任选取代的(C6-C24)芳基,
可任选取代的(C7-C25)芳烷基,
可任选取代的(C2-C18)烯基,
可任选取代的(C8-C26)芳烯基,
可任选取代的(C2-C18)炔基,
可任选取代的(C8-C26)芳炔基,及
可任选取代的杂环基,
且其中R100和R100*分别为衍生自下列的二价自由基:(C1-C18)烷基,(C3-C18)环烷基,(C3-C18)环烷基(C1-C18)烷基,(C6-C24)芳基,(C7-C25)芳烷基,(C2-C18)烯基,(C8-C26)芳烯基,(C2-C18)炔基,(C8-C26)芳炔基及杂环基,任何该基团可按如下定义任选取代,
且R80是选自下列:如上述定义的R81及在活体内不安定的溶解和/或保护基团Px,
则适用下列至少一项:
(i)R50为R53基团,其中R53是选自下列:C(D*)OR21*,C(D*)NR21*R22*,C(D*)SR21*,C(D*)R55,CF3,R55及在活体内不安定的溶解基团Px,其中
D*如上述D的定义,
R21*和R22*分别如上述R21和R22的定义,
且其中R55是选自下列:
可任选取代的(C1-C18)烷基(C6-C24)芳基,
可任选取代的(C2-C18)烯基(C6-C24)芳基,
可任选取代的(C2-C18)炔基(C6-C24)芳基,
可任选取代的(C3-C18)环烷基(C2-C18)烯基,
可任选取代的(C3-C18)环烷基(C2-C18)炔基,
可任选取代的(C3-C18)环烷基(C6-C24)芳基,
可任选取代的酰基(C6-C24)芳基,
可任选取代的杂环基(C1-C18)烷基,
可任选取代的杂环基(C2-C18)烯基,
可任选取代的杂环基(C2-C18)炔基,及
可任选取代的杂环基(C6-C24)芳基,
且n′,m′,R1*,R10,A′,A′*,R51和R2*如上述定义,
(ii)R2*和R51中之一为R54基团,其中R54是选自下列:R55*,C(D*)NR21*R22*,C(D*)OR55*,C(D*)R55,C(D*)SR21*,CF3,S(O)zOR120,S(O)zR120R121,及在活体内不安定的溶解基团Px,其中z为1或2,且R120和R121如上述定义的或R120和R121共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,且其中R21*和R22*分别如上述R21和R22的定义,且R55*如上述R55的定义,
且n′,m′,R1*,R10,A′,A′*,R50及和R2*和R51中另一者如上述定义,
(iii)至少一个A′或A′*是选自下列:CR112R13,CR12R113,CR112R13*和CR12*R113,其中R112和R113分别选自下列:如上述定义的R55,C(D)OR21*,C(D)SR21*,C(D)NR21*R22*,F,Cl,Br和I,其中R21*和R22*分别如上述R21和R22的定义,
且D,n′,m′,R1*,R2*,R10,R11,R12,R12*,R13,R13*,R50和R51如上述定义,
(iv)R1*是选自下列:
可任选取代的(C2-C18)烯基,
可任选取代的(C2-C18)炔基,
可任选取代的(C3-C18)环烷基(C2-C18)烯基,
可任选取代的(C3-C18)环烷基(C2-C18)炔基,
可任选取代的(C6-C24)芳基(C2-C18)烯基,
可任选取代的(C6-C24)芳基(C2-C18)炔基,
可任选取代的(C2-C18)酰基,其中该可任选使用的取代基不为氨基,
可任选取代的(C6-C24)芳基(C2-C18)酰基,
可任选取代的杂环基(C1-C18)烷基
可任选取代的杂环基(C2-C18)烯基,
可任选取代的杂环基(C2-C18)炔基,
C(O)OR90,C(O)NR91R92,CF3,S(O)zOR120,S(O)zR120R121及在活体内不安定的溶解基团Px,
其中z为1或2,且R120和R121如上述定义,
其中R90是选自下列:(C3-C18)环烷基,(C3-C18)环烷基(C1-C18)烷基,杂环基,(C1-C18)烷基杂环基,(C6-C24)芳基,(C6-C24)芳基(C1-C18)烷基及(C6-C24)芳基(C1-C18)烷基杂环基,
且其中R91和R92分别选自下列:
可任选取代的(C2-C18)烯基,
可任选取代的(C2-C18)炔基,
可任选取代的(C3-C18)环烷基
可任选取代的(C3-C18)环烷基(C1-C18)烷基,
可任选取代的(C3-C18)环烷基(C2-C18)烯基,
可任选取代的(C3-C18)环烷基(C2-C18)炔基,
可任选取代的(C6-C24)芳基(C2-C18)烯基,
可任选取代的(C6-C24)芳基(C2-C18)炔基,
可任选取代的(C2-C18)酰基,
可任选取代的(C6-C24)芳基(C2-C18)酰基,
可任选取代的杂环基,
可任选取代的杂环基(C1-C18)烷基
可任选取代的杂环基(C2-C18)烯基,及
可任选取代的杂环基(C2-C18)炔基,或R91和R92共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
且m′,n′,A′,A′*,R2*,R50,R51和R10如上述定义,
(v)一个选自:R1,R1*,R2,R2*,R9,R11,R12,R50和R51中的基团和另一个选自:R1,R1*,R2,R2*,R9*,R10,R11,R12,R50和R51中的基团共同形成选自:-C(O)-和可任选取代的亚甲基中的基团;
(b)当W′为R1*X*时,其中X*为NR10,且V′为Y*,其中Y*为
且B′是选自:-CH(OH)-和-C(O)-中,且当适用上述(a)中定义的条件(i)至(iv)中的一项时,则也适用下列至少一项:
(vi)n′>1,
(vii)n′=0,
(viii)m′>1,
(ix)m′=0,
(x)R50和R51共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系的一部分,
(xi)R50为R56基团,其中R56是选自下列:
C(D*)OR21*,C(D*)NR21*R22*,C(D*)SR21*,C(D*)R55及在活体内不安定的溶解和/或保护基团Px,其中R21*和R22*如上述定义,及
(xii)n′=m′=1,且A′*不为-CH2-,及
(c)当B′是选自下列:
其中R14,R14*和R17如上述定义时,
则至少一个选自:R2R2*,R11,R12,R50和R51中的基团和另一个选自:R1,或R1*,R10,R11和R12中的基团共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,该环是经至少一个选自=O,=S,OH,SH,NHR10*和C(O)OH中的极性基团取代,其中R10*如上述R10的定义,该极性基团在空间上可以位于式(I)化合物中和B基团的P,O,S,N或C原子相距5单位以内的位置上,
可任选取代的苯基,
可任选取代的萘基,
可任选取代的苯基(C1-C2)烷基,及
可任选取代的萘基(C1-C2)烷基,
且当
(a)B′为-CH(OH)-,且(A′)n为-CH(R73)-,其中R73为选自下列:(C1-C6)烷基,可任选1至5个氟原子取代,(C3-C6)烯基,(C1-C6)烷氧基-CH2-,(CH2)p苯基,(CH2)p萘基,(CH2)p-(C5-C6)环烷基及(CH2)p吲哚基,其中该(CH2)p苯基,(CH2)p萘基,(CH2)p-(C5-C6)环烷基及(CH2)p吲哚基可任选硝基,卤基,(C1-C4)烷基,(C1-C4)烷氧基或(C1-C4)烷硫基取代,且其中p为0,1或2时,则(A′*)m′不为
其中R74如上述R73的定义,且当(b)B′为
其中R74如上述R73的定义且(A′)n′为
其中R73如上述定义时,则(A′*)m′不为-C(O)-,且当(c)B′为-C(O)-且(A′)n′为
其中R73如上述定义时,则m′不为0。
本文所使用的“(C1-C18)烷基”一词的定义包括含有1至18个碳原子的直链和分支链烷基。此类基团实例为:甲基,乙基,丙基,异丙基,丁基,异丁基,二级丁基,三级丁基,戊基,异戊基,二级戊基,1,2-二甲基丙基,1,1-二甲基丙基,己基,4-甲基戊基,1-甲基戊基,2-甲基戊基,3-甲基戊基,1,1-二甲基丁基,2,2-二甲基丁基,3,3-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,1,2,2-三甲基丙基,1,1,2-三甲基丙基,庚基,5-甲基己基,1-甲基己基,2,2-二甲基戊基,3,3-二甲基戊基,4,4-二甲基戊基,1,2-二甲基戊基,1,3-二甲基戊基,1,4-二甲基戊基,1,2,3-三甲基丁基,1,1,2-三甲基丁基,1,1,3-三甲基丁基,辛基,6-甲基庚基,1-甲基庚基,1,1,3,3-四甲基丁基,壬基,1-,2-,3-,4-,5-,6-,或7-甲基辛基,1-,2-,3-,4-,或5-乙基庚基,1-,2-或3-丙基己基,癸基,1-,2-,3-,4-,5-,6-,7-或8-甲基壬基,1-,2-,3-,4-,5-,或6-乙基辛基,1-,2-,3-或4-丙基庚基,十一烷基,1-,2-,3-,4-,5-,6-,7-,8-或9-甲基癸基,1-,2-,3-,4-,5-,6-或7-乙基壬基,1-,2-,3-,4-或5-丙基辛基,1-,2-或3-丁基庚基,1-戊基己基,十二烷基,1-,2-,3-,4-,5-,6-,7-,8-,9-或10-甲基十一烷基,1-,2-,3-,4-,5-,6-,7-,或8-乙基癸基,1-,2-,3-,4-,5-或6-丙基壬基,1-,2-,3-,或4-丁基辛基,1-或2-戊基庚基,十三烷基,十四烷基,十六烷基,十八烷基,等等。
典型的烷基是(Ca-Cb)烷基,其中a选自下表A中“a”栏1-17的值,b选自“b”栏有关值。
表 A
Entry | a | b |
1 | 1 | 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 |
2 | 2 | 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 |
3 | 3 | 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 |
4 | 4 | 5,6,7,8,9,10,11,12,13,14,15,16,17,18 |
5 | 5 | 6,7,8,9,10,11,12,13,14,15,16,17,18 |
6 | 6 | 7,8,9,10,11,12,13,14,15,16,17,18 |
7 | 7 | 8,9,10,11,12,13,14,15,16,17,18 |
8 | 8 | 9,10,11,12,13,14,15,16,17,18 |
9 | 9 | 10,11,12,13,14,15,16,17,18 |
10 | 10 | 11,12,13,14,15,16,17,18 |
11 | 11 | 12,13,14,15,16,17,18 |
12 | 12 | 13,14,15,16,17,18 |
13 | 13 | 14,15,16,17,18 |
14 | 14 | 15,16,17,18 |
15 | 15 | 16,17,18 |
16 | 16 | 17,18 |
17 | 17 | 18 |
本文所采用“(C2-C18)烯基”一词的定义包括含有2至18个碳原子且可呈直链或分支的烯系单一,二-或多-不饱和烷基。此类烯基实例为:乙烯基,烯丙基,1-甲基乙烯基,1-丙烯基,1-丁烯基,2-丁烯基,3-丁基基,1,3-丁二烯基,2-甲基-1-丙烯基,2-甲基-2-丙烯基,1-戊烯基,2-戊烯基,3-戊烯基,4-戊烯基,1,3-戊二烯基,2,4-戊二烯基,1,4-戊二烯基,3-甲基-2-丁烯基,1-己烯基,2-己烯基,3-己烯基,1,3-己二烯基,1,4-己二烯基,2-甲基戊烯基,1-庚烯基,3-庚烯基,1-辛烯基,1,3-辛二烯基,1-壬烯基,2-壬烯基,3-壬烯基,1-癸烯基,3-癸烯基,1-十一烯基,油基,亚油基和亚麻基。
典型的烯基是(Ca-Cb)烯基,其中a选自上表A中“a”栏2-17的值,b选自“b”栏有关值。
本文中所采用“(C2-C18)炔基”一词的定义包括含有2至18个碳原子且可呈直链或分支的单一,二-及多-炔系不饱和烷基。此类炔基实例为:乙炔基,丙炔基,正丁炔基,3-甲基-1-丁炔基,正己炔基,甲基戊炔基及(C7-C12)炔基。
典型的炔基是(Ca-Cb)炔基,其中a选自上表A中“a”栏2-17的值,b选自“b”栏有关值。
本文中所采用“(C3-C18)环烷基”一词是指含有3至18个碳原子的可任选不饱和的单环,二环或多环烷基。此等基团实例包括:环丙基,环丁基,环戊基,环戊烯基,环戊二烯基,环己基,环己烯基,环己二烯基,环庚基,环庚烯基,环庚二烯基,环庚三烯基,环辛基,环辛烯基,环辛二烯基,环辛三烯基,环辛四烯基,环壬基,环癸基,环十一烷基,环十二烷基,(C9-C12)-环炔基,双环[2,2,1]庚基,双环[2,2,1]庚烯基,双环[2,2,1]庚二烯基,双环[2,2,2]辛基,双环[2,2,2]辛烯基,双环[3,3,1]壬基,双环[3,1,0]-己基,双环[4,1,0]庚基,双环[3,2,1]辛基,双环[3,3,0]辛基,双环[3,3,0]辛烯基,双环[3,3,1]-壬基,双环[4,4,0]癸基,金刚烷基,三环[5,2,1,02.6]-癸基,等等。
典型的环烷基是(Ca-Cb)环烷基,其中a选自上表A中“a”栏3-17的值,b选自“b”栏有关值。
本文所采用“(C3-C18)环烷基(C1-C18)烷基”一词是指经一个如上述定义的(C3-C18)环烷基取代的如上述定义(C1-C18)烷基。环烷基烷基实例包括:环烷基-低烷基,如:环烷基甲基,环烷基乙基,环烷基丙基,环烷基丁基,环烷基异丙基,环烷基异丁基,环烷基戊基和环烷基己基,其中环烷基的实例如前一段所述。
本文所采用“(C3-C18)环烷基(C2-C18)烯基”一词是指经一个如上述定义的(C3-C18)环烷基取代的如上述定义的(C2-C18)烯基。环烷基烯基实例包括环烷基低烯基,如:环烷基乙烯基,环烷基丙烯基,环烷基丁烯基,环烷基异丁烯基,环烷基戊烯基及环烷基己烯基,其中环烷基的实例如:“(C3-C18)环烷基”中所述。
本文所采用“(C3-C18)环烷基(C2-C18)炔基”一词是指经一个如上述定义的(C3-C18)环烷基取代的如上述定义的(C2-C18)炔基。环烷基炔基实例包括环烷基低炔基,如:环烷基乙炔基,环烷基丙炔基,环烷基丁炔基,环烷基戊炔基和环烷基己炔基,其中环烷基的实例如上述:“(C3-C18)环烷基”所述。
本文中所采用“(C6-C24)芳基”一词是指含有6至24个碳原子的单一,多核,共轭和稠合的芳香烃残基。此类基团实例为:苯基,联苯基,联三苯基,联四苯基,萘基,四氢萘基,苊基,蒽基,二氢蒽基,苯并蒽基,二苯并蒽基,菲基,芴基,芘基,茚基,茚满基,甘菊环基,等等。所有情况下,稠合或共轭双环系上任何可利用的位置均可用来附接式(I)分子的其余部分。
典型的芳基是(Ca-Cb)芳基,其中a选自下表B中“a”栏1-18的值,b选自“b”栏有关值。
表B
Entry | a | b |
1 | 6 | 10,12,13,14,15,16,17,18,19,20,21,22,23,24 |
2 | 10 | 12,13,14,15,16,17,18,19,20,21,22,23,24 |
3 | 12 | 13,14,15,16,17,18,19,20,21,22,23,24 |
8 | 13 | 14,15,16,17,18,19,20,21,22,23,24 |
9 | 14 | 15,16,17,18,19,20,21,22,23,24 |
10 | 15 | 16,17,18,19,20,21,22,23,24 |
11 | 16 | 17,18,19,20,21,22,23,24 |
12 | 17 | 18,19,20,21,22,23,24 |
13 | 18 | 19,20,21,22,23,24 |
14 | 19 | 20,21,22,23,24 |
15 | 20 | 21,22,23,24 |
16 | 21 | 22,23,24 |
17 | 22 | 23,24 |
18 | 23 | 24 |
本文中所采用“(C6-C24)芳基(C1-C18)烷基”一词是指经一个或多个如上述定义的(C6-C24)芳基取代的(C1-C18)烷基。此类基团实例为:芳基低烷基,如:芳甲基,芳乙基,芳异丙基,芳丙基,芳丁基,芳异丁基,芳戊基和芳己基,其中芳基的实例如前一段所述,如:苄基,二苯甲基,2-苯乙基,1-苯乙基,萘甲基,3-苯丙基,三苯甲基,1,3-二苯丙基,2-或3-萘丙基,2-苄丙基,等等。
本文中所采用“(C7-C25)芳烷基”一词是指经芳基取代的烷基,其中经芳基取代的烷基的碳原子总数为7至25。(C7-C25)的可任选使用的取代基是如上述(C6-C24)芳基(C1-C18)烷基中的相关定义。
本文中所采用“(C6-C24)芳基(C2-C18)烯基”一词是指经一个或多个如上述定义的(C6-C24)芳基取代的(C2-C18)烯基。此类基团实例为芳基-低烯基,如:芳乙烯基,芳丙烯基,芳丁烯基,芳异丁烯基,芳戊烯基或芳己烯基,其中芳基实例如:“(C6-C24)芳基”中所述者,如:苯乙烯基,肉桂基,2-萘乙烯基,1-苯基-2-甲基-1-丙烯基,2-苯基-2-丁烯基,等等。
本文中所采用“(C8-C26)芳烯基”一词是指经芳基取代的烯基,其中经芳基取代的烯基中碳原子总数为8至26。(C8-C26)芳烯基中可任选使用的取代基是如上述(C6-C24)芳基(C2-C18)烯基中的相关定义。
本文中所采用“(C6-C24)芳基(C2-C18)炔基”一词是指经一个或多个如上述定义的(C6-C24)芳基取代的(C2-C18)炔基。此类基团实例为芳基-低炔基,如:芳乙炔基,芳丙炔基,芳丁炔基,芳异丁炔基,芳戊炔基或芳己炔基,其中芳基实例如:“(C6-C24)芳基”,如:苯乙炔基,等等。
本文中所采用“(C8-C26)芳炔基”一词是指经芳基取代的炔基,其中经芳基取代的炔基中碳原子总数为8至26。(C8-C26)芳炔基中可任选使用的取代基是如上述(C6-C24)芳基(C2-C18)炔基中的相关定义。
本文中所采用“(C1-C18)酰基”是指R300C(O)-或R300C(S)-,其中R300为选自下列:氢,(C1-C18)烷基,(C2-C18)烯基,(C2-C18)炔基,(C3-C18)环烷基,(C3-C18)环烷基(C1-C18)烷基,(C3-C18)环烷基(C2-C18)烯基,(C3-C18)环烷基-(C2-C18)炔基,(C6-C24)芳基,(C6-C24)芳基(C1-C18)烷基,(C6-C24)芳基(C2-C18)烯基,(C6-C24)芳基-(C2-C18)炔基,杂环基,杂环基(C1-C18)烷基,杂环基(C2-C18)-烯基,及杂环基(C2-C18)炔基。
典型的酰基是(Ca-Cb)酰基,其中a选自上表A中“a”栏1-17的值,b选自“b”栏有关值。
酰基实例包括:低烷羰基如:甲酰基,乙酰基,丙酰基,丁酰基;低烯羰基如:特戊酰基,丙烯酰基,乙烯乙酰基,巴豆酰基,3-戊烯酰基,4-戊烯酰基;及低炔羰基,如:丙炔酰基,2-丁炔酰基和3-丁炔酰基,任何该基团均可经本文所例举的环烷基,芳基或杂环基取代;如,例如:环丙羰基,环丁羰基,环戊羰基,1-环戊烯羰基,环戊基乙酰基,环己羰基,1-环己烯羰基,1,4-环己二烯羰基,环己基乙酰基,环己烯乙酰基,1,4-环己二烯乙酰基,双环[2,2,1]庚-2-基羰基,双环[2,2,1]庚基乙酰基,双环[2,2,1]庚烯-2-基羰基,双环[2,2,2]辛-2-基羰基,双环[2,2,2]辛基乙酰基,双环[2,2,2]辛基-3-丙酰基,双环[2,2,2]辛烯-2-基羰基,双环[3,3,1]壬-9-基羰基,双环[3,3,1]壬-9-基乙酰基,双环壬基-3-丙酰基,双环[4,4,0]癸-2-基羰基,双环[4,4,0]癸-2-基乙酰基,1-金刚烷羰基,2-金刚烷羰基,1-金刚烷乙酰基,2-金刚烷乙酰基,三环[5,2,1,02.6]癸-8-基乙酰基,苯甲酰基,二苯基乙酰基,三苯基乙酰基,3-苯基丙酰基,二苄基乙酰基,α-萘酰基,β-萘酰基,α-萘基乙酰基,β-萘基乙酰基,茚羰基,茚满羰基,菲羰基,9-芴羰基,吡咯羰基,吡咯乙酰基,呋喃羰基,呋喃乙酰基,噻吩羰基,噻吩乙酰基,吡嗪羰基,吡嗪乙酰基,吡咯烷羰基,吡咯烷乙酰基,吡啶羰基,吡啶乙酰基,嘧啶羰基,嘧啶乙酰基,六氢吡啶羰基,六氢吡啶乙酰基,六氢吡嗪羰基,六氢吡嗪乙酰基,吗啉羰基,吗啉乙酰基,硫吗啉羰基,硫吗啉乙酰基,吲哚羰基,吲哚乙酰基,喹啉羰基,喹啉乙酰基,异喹啉羰基,异喹啉乙酰基,喹噁啉羰基,苯并呋喃羰基,苯并呋喃乙酰基,吲哚啉羰基,吲哚啉乙酰基,1,2,3,4-四氢喹啉羰基,1,2,3,4-四氢喹啉乙酰基,1,2,3,4-四氢异喹啉羰基,1,2,3,4-四氢异喹啉乙酰基,环己基丙酰基,肉桂酰基,苯乙烯乙酰基及苯基丙酰基。
本文中所采用“杂环基”一词是指任何含有1个或多个分别选自氧,氮和硫中杂原子的饱和或不饱和3到16员单环,双环或多环。“杂环基”一词包括其中杂环和一个或多个苯,萘或环烷环稠合的任何基团。含硫杂环的硫可经一个或两个氧原子取代。杂环实例为:吡啶基,噻吩基,呋喃基,吡咯基,吲哚基,哒嗪基,全氢哒嗪基,吡唑基,吡唑烷基,2,3,5,6-四氢吡嗪基,酞嗪基,1,2,3,4-四氢酞嗪基,全氢2,3-二氮杂萘基,噻唑基,嘧啶基,喹啉基,异喹啉基,苯并呋喃基,苯并噻吩基,嘌呤基,喹唑啉基,吩嗪基,吖啶基,苯并噁唑基,苯并噻唑基,六氢吡啶基,四氢呋喃基,咪唑基,噁唑基,噻唑烷并基,噁唑烷基,异噁唑基,异噻唑基,异噁唑烷基,咪唑烷基,吗啉基,吡咯烷基,吡唑啉基,苯并噻吩基,苯并异噁唑基,苯并异噻唑基,苯并噻二唑基,四唑基,三唑基,噻二唑基,苯并咪唑基,吡咯啉基,奎宁环基,1,4-噻噁烷基,1,3-噻噁烷基,氮杂-原冰片基,异奎宁环基,吡喃基,呋咱基,氮杂基,1H-吲唑基,2,3-二氢-1H-吲唑基,喹噁啉基,噌啉基,1,2,3,4-四氢噌啉基,蝶啶基,萘啶基,4H-喹嗪基,苯并[e]吲哚基,苯并噁嗪基,苯并噁二唑基,苯并噻嗪基,苯并三唑基,咔唑基,β-咔啉基,1,2,3,4,5,6-六氢-β-咔啉基,菲啶基,吩噁嗪基,吩噻嗪基,1-氮杂苊基,噻三唑基,噁二唑基,噻二唑基,色满基,噻色满基,异色满基,色烯基,环己稠[b]吡咯基,环庚稠[b]吡咯基,环己稠[d]吡咯基,环己稠[b]吡啶基,环己稠[b]吡嗪基,环己稠[b]嘧啶基,环己稠[b]-1,4-噁嗪基,环己稠[b]-1,4-噻嗪基,2-咪唑啉基,2,3-二氢吡啶基,六氢吡嗪基,硫吗啉基,S,S-,二氧-硫吗啉基,吲哚啉基,S,S-二氧-1,2,3-苯并噻二唑基,S,S-二氧-1,2-噻噁烷基,S,S-二氧-1,4-噻噁烷基,异吲哚啉基,4,5,6,7-四氢吲哚基,1,2,3,4-四氢喹啉基,1,2,3,4-四氢异喹啉基,六氢喹啉基,六氢异喹啉基,1,2,3,4-四氢-3,1-苯并二嗪基,3,4-二氢-3H-4,1-苯并噁嗪基,3,4-二氢-3H-4,1-苯并噻嗪基,2,3,4,5-四氢-1H-5,1-苯并氮杂基及5,6-二氢菲啶基,等等。
会造成不安定杂环的构型不包括在“杂环”或“饱和或不饱和环系,双环系或稠合环系”的定义范围内。
本文所采用“杂环基(C1-C18)烷基”一词是指经一个如上述定义的杂环基取代的如上述定义的(C1-C18)烷基。此等基团实例为杂环基-低烷基,如:杂环基甲基,杂环基乙基,杂环基异丙基,杂环基丙基,杂环基丁基,杂环基异丁基,杂环基戊基,及杂环基己基,其中杂环基的实例如上述。
本文所采用“杂环基(C1-C18)烯基”一词是指经一个如上述定义的杂环基取代的(C1-C18)烯基。此类基团实例为杂环基-低烯基,如:杂环基乙烯基,杂环基丙烯基,杂环基丁烯基,杂环基异丁烯基,杂环基戊烯基和杂环基己烯基,其中杂环基的实例如上述“杂环基”。
本文所采用“杂环基(C1-C18)炔基”一词是指经一个如上述定义的杂环基取代的如上述定义的(C1-C18)炔基。
本文所采用“亚烷基”一词是指衍生自烷基的二价自由基。此类自由基实例为-CH2-,-CH2CH2-,-CH=CH-,-CH2CH2CH2-,-C(=CH2)CH2-,-CH2CH=CH-,-(CH2)4-,-CH2CH2CH=CH-,-CH2CH=CHCH2-与-(CH2)r-,其中r为5至12。该名词亦指其中一个或多个键结形成环系一部分的自由基,及其中一个或多个碳原子被O,S或NH置换的自由基。此类自由基实例为如下结构式的基团
and
及类似基团,包括上述基团中然后N或O原子被S置换者。
本文所采用“饱和或不饱和环系,双环系或稠合环系”是指至多16个碳原子的安定环系,其中该等环系中:3员与4员环可包含1个杂原子;5员环可包含1或2个杂原子;6与7员环可包含1至3个杂原子;8与9员环可包含1至4个杂原子;10与11员环可包含1至5个杂原子;12与13员环可包含1至6个杂原子;14与15员环可包含1至7个杂原子;16员环可包含1至8个杂原子;该等杂原子可分别选自:氧,氮和硫,该环系可经一个或多个分别选自:R150与T基团中的取代基取代,其中R150如上述R20的定义,且其中T是选自下列:-F,-C1,-Br,-I,-CF3,-CN,-NCO,-NCS,-OCN,-SCN,-OR’,-NR’R”,-NR’C(O)R”,-NR’C(O)OR”,-NR’(O)NR”R,-NO2,-SR’,-S(O)R’,-S(O)2R’,-S(O)OR’,-S(O)2OR’,-S(O)NR’R”,-S(O)2NR’R”,=O,=S,=N2,=NOH,=NOR’,-NR”OR’,-CHO,-OC(O)R’,-OC(O)OR’,-OC(O)NR’R”,-C(O)R’,-C(O)OR’,-C(O)NR’R”,-OC(S)R’,-OC(S)OR’,-OC(S)NR’R”,-C(S)R’,-C(S)OR’,-C(S)NR’R”,-SC(O)R’,-SC(O)OR’,-SC(O)NR’R”,-C(O)SR’,-SC(S)R’,-SC(S)OR’,-SC(S)NR’R”,-C(S)SR’,-C(=NR’)OR”,-C(=NR’)SR”,-C(=NR’)NR”R,-OS(O)R’,-OS(O)2R’,-OS(O)OR’,-OS(O)2OR’,-OS(O)NR’R”,-OS(O)2NR’N”,NR’S(O)2NR”R,-NR’S(O)2R”,-NHC(=NH)NR’,-C(=NH)NR’,-P(O)(OR’)R”,-P(O)(SR’)R”,-P(O)(OR’)OR”,-P(O)(OR’)NR”R,-P(O)R’R”,-OP(O)(OR’)R”,-OP(O)(OR’)OR”,-OP(O)(SR’)OR”,-OP(O)(OR’)NR”R,-OP(O)R’R”且R’,R”和R分别选自下列:氢,(C1-C18烷基),典型者(C1-C12)烷基,(C3-C18)环烷基,典型者(C3-C12)环烷基;(C3-C18)环烷基(C1-C18)烷基,典型者(C3-C12)环烷基-(C1-C6)烷基;(C6-C24)芳基,典型者(C6-C16)芳基;(C6-C24)芳基(C1-C18)烷基,典型者(C6-C10)芳基(C1-C6)烷基;(C2-C18)烯基,典型者(C2-C12)烯基;(C6-C24)芳基(C2-C18)烯基,典型者(C6-C10)芳基-(C2-C6)烯基;(C2-C18)炔基,典型者(C2-C12)炔基;(C6-C24)芳基(C2-C18)芳炔基,典型者(C6-C10)芳基(C1-C6)炔基,杂环基,杂环基(C1-C18)烷基,典型者杂环基(C1-C12)烷基,杂环基(C2-C18)烯基,典型者杂环基(C2-C12)烯基及杂环基(C2-C18)炔基,典型者杂环基(C2-C12)炔基,且其中R’,R”和R可任选至多6个分别选自下列的基团取代:羟基,(C1-C6)烷氧基,(C1-C6)芳氧基,(C1-C6)硫烷氧基,(C1-C6)硫芳氧基,(C1-C6)烷氧基(C1-C6)烷氧基,氨基,(C1-C6)烷胺基,二(C1-C6)烷胺基,氟,氯,溴,碘,羧基及(C1-C6)烷氧羰基。饱和或不饱和环系,双环系或稠合环系实例为上文中例举的杂环基与环状亚烷基。
本文所采用“可任选取代的(C1-C18)烷基”一词是指如上述定义的(C1-C18)烷基,其中一个或多个氢原子被一个或多个如上述定义的T取代基取代。
经取代(C1-C18)烷基实例包括:羟基-低烷基如:羟甲基,羟乙基和3-羟丙基;低烷氧基-低烷基如:甲氧甲基,2-甲氧乙基,2,2-二甲氧乙基,和3-甲氧丙基;芳氧基-低烷基如:苯氧甲基,苯氧乙基,α-萘氧甲基和β-萘氧乙基;芳基低烷氧基-低烷基如:苄氧甲基,苄氧乙基和3-苄氧丙基;卤-低烷基如:氯甲基,三氟甲基,2-氟,2-氯-,2-溴-或2-碘-乙基,2,2,2-三氟乙基,2,2,2-三氯乙基,3-氯丙基和3-溴丙基;氨基低烷基如:氨基甲基,2-氨基乙基,3-氨基丙基,5-氨基戊基,二甲氨基甲基,2-二甲氨基乙基,及3-苯氨基丙基;羧基-低烷基如:羧甲基,羧乙基和3-羧丙基;酰基低烷基如:酰基甲基,酰基乙基,酰基丙基,酰基异丙基,酰基丁基,酰基异丁基,酰基戊基及酰基己基,其中酰基的实例如上述“(C1-C18)酰基”;酰氧基-低烷基,如:乙酰氧甲基,乙酰氧乙基,2-乙酰氧丙基,3-乙酰氧丙基,丙酰氧乙基及3-丙酰氧丙基;低烷羰氨基-低烷基,如:乙酰氨基甲基,乙酰氨基乙基,2-乙酰氨基丙基,丙酰氨基甲基和丙酰氨基乙基;低烷胺羰氨基-低烷基如:二甲胺羰氨基乙基;磺酰基-低烷基如:甲磺酰基-甲基,乙磺酰基-甲基,叔丁磺酰基-甲基,苯磺酰基甲基,苯磺酰基乙基,4-甲磺酰基乙基与4-甲苯磺酰基甲基;氰基-低烷基如:氰甲基,2-氰丙基,3-氰丙基,2-氰丁基,3-氰丁基与4-氰丁基;氧低烷基如:2-氧丙基,2-氧丁基,3-氧丁基,2-,3-或4-氧戊基与2,4-二氧戊基;及经两个或多个如上述相异取代基取代的低烷基。
本文所采用“可任选取代的(C1-C18)烯基”一词是指如上述定义的(C1-C18)烯基,其中一个或多个氢原子被一个或多个如上述定义的T取代基取代。
本文所采用“可任选取代的(C1-C18)炔基”一词是指如上述定义的(C1-C18)炔基,其中一个或多个氢原子被一个或多个如上述定义的T取代基取代。
本文所采用“可任选取代的(C3-C24)环烷基”一词是指如上述定义的(C3-C24)环烷基,其中一个或多个氢原子被一个或多个分别选自如上述定义的RIV与T中的取代基取代,其中RIV是选自:(C1-C18)烷基,(C2-C18)烯基,(C2-C18)炔基,(C3-C18)环烷基,(C3-C18)环烷基(C1-C18)烷基,(C3-C18)环烷基(C2-C18)烯基,(C3-C18)环烷基(C2-C18)炔基,(C2-C18)酰基,(C6-C24)芳基(C2-C18)酰基,杂环基,杂环基(C1-C18)烷基,杂环基(C2-C18)烯基,及杂环基-(C2-C18)炔基,且其中RIV可被至多6个分别选自下列的基团取代:羟基,氨基,(C1-C6)烷氧基,(C1-C6)烷氧基(C1-C6)烷氧基,氨基,(C1-C6)烷氨基,二(C1-C6)-烷氨基,氟,氯,溴,碘,羧基和(C1-C6)烷氧羰基。
本文所采用“可任选取代的(C3-C24)环烷基(C1-C18)烯基”一词是指如上述定义的(C3-C24)环烷基(C1-C18)烯基,其中环烷基被一个或多个分别选自如上述定义(C3-C24)环烷基的取代基中的取代基取代,且/或其烯基被一个或多个如上述定义的T取代基取代。
本文所采用“可任选取代的(C3-C24)环烷基-(C1-C18)炔基”一词是指如上述定义的(C3-C24)环烷基(C1-C18)炔基,其中环烷基被一个或多个分别选自如上述定义(C3-C24)环烷基的取代基取代,且/或炔基被一个或多个如上述定义的T取代基取代。
本文所采用“可任选取代的(C6-C24)芳基”一词是指如上述定义的(C6-C24)芳基,其中一个或多个氢原子被一个或多个分别选自RV及T*中的取代基置换,其中T*是选自下列:-F,Cl,-Br,-I,-CF3,-CN,-NCO,-NCS,-OCN,-SCN,-OR’,-NR’R”,-NR’C(O)R”,-NR’C(O)OR”,-NR’(O)NR”R,-NO2,-SR’,-S(O)R’,-S(O)2R’,-S(O)OR’,-S(O)2OR’,-S(O)NR’R”,-S(O)2NR’R”,-NR”OR’,-CHO,-OC(O)R’,-OC(O)OR’,-OC(O)NR’R”,-C(O)R’,-C(O)OR’,-C(O)NR’R”,-OC(S)R’,-OC(S)OR’,-OC(S)NR’R”,-C(S)R’,-C(S)OR’,-C(S)NR’R”,-SC(O)R’,-SC(O)OR’,-SC(O)NR’R”,-C(O)SR’,-SC(S)R’,-SC(S)OR’,-SC(S)NR’R”,-C(S)SR’,-C(=NR’)OR”,-C(=NR’)SR”,-C(=NR’)NR”R,-OS(O)R’,-OS(O)2R’,-OS(O)OR’,-OS(O)2OR’,-OS(O)NR’R”,-OS(O)2NR’N”,NR’S(O)2NR”R,NR’S(O)2R”,-NHC(=NH)NR’,-C(=NH)NR’,-OP(O)(OR’)R”,-OP(O)(OR’)OR”,,-OP(O)(SR’)OR”,-OP(O)(OR’)NR”R,-OP(O)R’R”,且R’,R”和R如上述T取代基中的相关定义;且其中RV是选自:(C1-C18)烷基,(C2-C18)烯基,(C2-C18)炔基,(C3-C18)-环烷基,(C3-C18)环烷基(C1-C18)烷基,(C3-C18)环烷基(C2-C18)烯基,(C3-C18)环烷基(C2-C18)炔基,(C2-C18)酰基,(C6-C24)芳基(C2-C18)酰基,杂环基,杂环基(C1-C18)烷基,杂环基(C2-C18)烯基,及杂环基-(C2-C18)炔基,且其中RV可经至多6个分别选自下列的基团取代:羟基,氨基,(C1-C6)烷氧基,(C1-C6)芳氧基,(C1-C6)硫烷氧基,(C1-C6)硫芳氧基,(C1-C6)烷氧基(C1-C6)烷氧基,氨基,(C1-C6)烷氨基,二(C1-C6)烷氨基,氟,氯,溴,碘,羧基及(C1-C6)烷氧羰基,(C1-C6)烷氨羰基和二(C1-C6)烷氨羰基。“可任选取代的(C6-C24)芳基”一词包括单取代,二取代与多取代的(C6-C24)芳基。
经取代的芳基实例为低烷基-芳基,低烯基-芳基,芳基-低烷基-芳基低烷基羰基-芳基,杂环基-芳基与杂环基低烷基-芳基,其中芳基实例如上述,卤-芳基如:4-氯苯基,2,4-二氯苯基,1-氯-2-萘基和4-氯-1-萘基;羟基-芳基如:2-羟基苯基,1-羟基-2-萘基,2-羟基-1-萘基,2-羟基-8-萘基,3,4,5-三羟基苯基与2,4,5-三羟基苯基;低烷氧芳基如:4-甲氧苯基,3,4-二甲氧苯基,2,4-二甲氧苯基和1-甲氧基-2-萘基;羧基芳基如:2-羧基苯基,2-羧基-1-萘基,1-羧基-2-萘基及9-羧基-2-蒽基;酰基芳基,其中酰基实例如上述“(C1-C18)-酰基”,如:4-甲酰苯基,4-乙酰苯基,2-苯甲酰苯基,2-甲氧羰基-苯基,2-乙氧羰基-1-萘基,1-甲氧羰基-2-萘基,9-甲氧羰基-2-蒽基,2-氨基甲酰基-苯基,2-氨基甲酰基-1-萘基,1-氨基甲酰基-2-萘基,4-二甲胺羰基-苯基,4-吗啉羰基苯基,4-(2-吡啶甲氧基)羰基-苯基及4-苄氧羰基-苯基;硝基-芳基如:4-硝基苯基和2,4-二硝基苯基;氨基-或(经取代的氨基)-芳基,如:4-氨基苯基,2,4-二氨基苯基,4-二甲氨基苯基,4-苯氨基苯基,2-(2,6-二氯苯氨基)苯基,2,4-二(苄氧羰氨基)苯基及4-(2-喹啉羰氨基)苯基;及氰基-芳基如:4-氰基苯基,及经两个或多个上文例举的取代基取代的芳基。
本文所采用“可任选取代的(C6-C24)芳基(C1-C18)烷基”一词是指如上述定义的(C6-C24)芳基(C1-C18)烷基,其芳基经一个或多个如上述定义(C6-C24)芳基的取代基取代且/或烷基经一个或多个如上述定义(C1-C18)烷基的取代基取代。此类基团实例为(经取代的芳基)-低烷基如:(经取代的芳基)甲基,(经取代的芳基)乙基,(经取代的芳基)丙基,(经取代的芳基)异丙基,(经取代的芳基)丁基,(经取代的芳基)戊基及(经取代的芳基)己基,芳基(经取代的低烷基)如:苯基(经取代的低烷基),萘基(经取代的低烷基),联苯基(经取代的低烷基),四氢萘基(经取代的低烷基),茚基(经取代的低烷基)及茚满基(经取代的低烷基),及(经取代的芳基)(经取代的低烷基),其中该各经取代的芳基的实例是如上述“可任选取代的(C6-C24)芳基”中的相关实例,且(经取代的低烷基)的实例是如上述“可任选取代的(C1-C18)烷基”中的相关实例。
本文所采用“可任选取代的(C6-C24)芳基(C1-C18)烯基”一词是指如上述定义的(C6-C24)芳基(C1-C18)烯基,其芳基经一个或多个如上述定义(C6-C24)芳基的取代基取代且/或烯基经一个或多个如上述定义(C1-C18)烷基的取代基取代。
本文所采用“可任选取代的(C6-C24)芳基(C1-C18)炔基”一词是指如上述定义的(C6-C24)芳基(C1-C18)炔基,其芳基经一个或多个如上述定义(C6-C24)芳基的取代基取代且/或炔基经一个或多个如上述定义(C1-C18)烷基的取代基取代。
本文所采用“可任选取代的(C1-C18)酰基”一词是指如上述定义的(C1-C18)酰基,其可经一个或多个选自如上述定义(C1-C18)烷基的取代基中的基团取代,且其定义中包括天然或合成氨基酸或氮离氨基酸的酰基残基,或含2至4个天然或合成氨基酸与/或氮离氨基酸的胜肽链的酰基残基。
经取代的酰基实例包括:本文所例举任何天然或合成氨基酸的酰基残基,羟基低烷酰基,低烷氧低烷酰基,乙酰低烷酰基,氰基低烷酰基,羧基低烷酰基,羟基羧低烷酰基,氟低烷酰基,氯低烷酰基,溴低烷酰基,硫低烷酰基,低烷硫低烷酰基,氨基低烷酰基,低烷氨基低烷酰基二(低烷氨基)低烷酰基,氨基甲酰基低烷酰基,低烷氧羰基,氨基甲酰基,低烷胺羰基,及二(低烷氨基)羰基,其中低烷酰基为1至6个碳原子的烷酰基,例如:甲酰基,乙酰基,丙酰基,丁酰基,异丁酰基,戊酰基,及己酰基,且其中低烷基代表(C1-C6)烷基如:甲基,乙基,正丙基,异丙基,正丁基,异丁基,二级丁基,叔丁基,正戊基,异戊基,新戊基及己基。
本文所采用“可任选经取代杂环基”一词是指如上述定义的杂环基,其中一个或多个氢原子可被选自如上述可任选经取代的(C6-C24)芳基中相关定义的取代基中的基团取代。经取代的杂环基实例包括:低烷基杂环基,芳基杂环基,芳氧基杂环基,低烷氧基杂环基,氧-杂环基,羟基杂环基,低烷氧羰基杂环基及低烷酰基杂环基。
本文所采用“可任选经取代杂环基(C1-C18)烷基”一词是指如上述定义的杂环基(C1-C18)烷基,其杂环基经一个或多个如上述定义杂环基的取代基取代且/或烷基经一个或多个如上述定义(C1-C18)烷基的取代基取代。此类基团实例为(经取代的杂环基)低烷基,如:(经取代的杂环基)甲基,(经取代的杂环基)乙基,(经取代的杂环基)丙基,(经取代的杂环基)异丙基,(经取代的杂环基)丁基,(经取代的杂环基)戊基,及(经取代的杂环基)己基;杂环基(经取代的低烷基)如:吡咯基(经取代的低烷基),吲哚基(经取代的低烷基),喹啉基(经取代的低烷基),四氢喹啉基(经取代的低烷基),吡啶基(经取代的低烷基),吗啉基(经取代的低烷基),六氢吡啶基(经取代的低烷基),硫吗啉基(经取代的低烷基),噻吩基(经取代的低烷基),呋喃基(经取代的低烷基),苯并呋喃基(经取代的低烷基),吡咯烷基(经取代的低烷基),及异喹啉基(经取代的低烷基);及(经取代的杂环基)(经取代的低烷基),其中各该经取代的杂环基实例是如上述“可任选经取代杂环基”中的相关实例,且(经取代的低烷基)实例是如上述“可任选经取代(C1-C18)烷基”中的相关实例。
本文所采用“可任选经取代杂环基(C1-C18)烯基”一词是指如上述定义的杂环基(C1-C18)烯基,其杂环基经一个或多个如上述定义杂环基的取代基取代且/或烯基经一个或多个如上述定义(C1-C18)烯基的取代基取代。
本文所采用“可任选经取代的杂环基(C1-C18)炔基”一词是指如上述定义的杂环基(C1-C18)炔基,其杂环基经一个或多个如上述定义杂环基的取代基取代且/或炔基经一个或多个如上述定义(C1-C18)炔基的取代基取代。
本文所采用“可任选经取代亚烷基”一词是指如上述定义的亚烷基,其中一个或多个氢原子被选自如上述“可任选经取代的(C1-C18)烷基”中相关定义的取代基中的基团取代。
本文所采用“天然或合成氨基酸”是指如式NH(R401)(CH(R400))pCOOH的化合物,其中R400和R401,分别如上述R20的定义,且p为1,2或3,且其中R400和R401,及其所附接的碳和氮共同形成饱和或不饱和环系,双环系或稠合环系。天然或合成氨基酸实例包括:丙氨酸,环己基丙氨酸,胺茴酸,精氨酸,天门冬酰胺,天门冬氨酸,半胱氨酸,β-苯基半胱氨酸,胱氨酸,麸氨酸,麸氨酸酰胺,甘氨酸,环己基甘氨酸,四氢呋喃基甘氨酸,组氨酸,高丝氨酸,羟基脯氨酸,异白氨酸,白氨酸,离氨酸,4-氮杂离氨酸,δ-羟基离氨酸,甲硫氨酸,原白氨酸,原氨酸,乌氨酸,苯基丙氨酸,4-氨基苯基丙氨酸,4-羧基苯基丙氨酸,4-氯基苯基丙氨酸,苯基甘氨酸,8-苯基丝氨酸,脯氨酸,丝氨酸,苏氨酸,反-3-羟基脯氨酸,反-4-羟基脯氨酸,色氨酸,酪氨酸,缬氨酸,吲哚啉-2-羧酸,1,2,3,4-四氢异喹啉-3-羧酸,氨基丙二酸,氨基丙二酸单酰胺,α-氨基丁酸,α,β-二氨基丁酸及α,β-二氨基丙酸。其他氨基酸及衍生此等氨基酸的胜肽揭示于J.S.戴维斯(Davies)编辑的“氨基酸和胜肽”,1988年,伦敦,查普曼和毫尔出版社(Amino Acids andPeptdes,Chapman and Hall,London,1985),该文献已并为本文的参考文献。
本文所采用“天然或合成氨基酸的残基”一词是指如式-N(R401)(CH(R400))pC(O)-基团,其中R400,R401和p如上述“天然或合成氨基酸”中的相关定义。
本文所采用“氮杂氨基酸”一词是指其中-CH(R400)-基团己被-N(R401)-基团置换的氨基酸,其中如R401上述R20的定义。
式(I)化合物的合适的医药上可接受的盐为,当式(I)化合物含有碱性氮原子时,为医药上可接受的无机酸的酸加成盐,如:盐酸,硫酸,磷酸,硝酸,碳酸,硼酸,氨基磺酸,氢溴酸或氢碘酸的盐类,或与医药上可接受的有机酸如:乙酸,丙酸,丁酸,酒石酸,马来酸,羟基马来酸,甲基马来酸,富马酸,苹果酸,柠檬酸,乳酸,粘酸,葡糖酸,葡庚糖酸,糖二酸,葡糖醛酸,乳糖醛酸,苯甲酸,萘甲酸,琥珀酸,草酸,苯基乙酸,甲磺酸,乙磺酸,2-羟基乙磺酸,乙烷-1,2-二磺酸,月桂基磺酸,甲苯磺酸,苯磺酸,萘-2-磺酸,水杨酸,4-氨基水杨酸,磺氨酸,天门冬氨酸,麸氨酸,乙二胺四乙酸,硬脂酸,棕榈酸,油酸,月桂酸,泛酸,单宁酸,抗坏血酸,戊酸,乙醇酸,肉桂酸,扁桃酸,2-苯氧基苯甲酸,2-乙酰氧苯甲酸,二羟基二萘甲烷二羧酸(embonicacid),菸碱酸,异菸芋碱酸,N-环己基氨基磺酸,或其他酸性有机化合物如:2-或3-磷酸甘油酸酯及葡萄糖-6-磷酸酯等形成的盐类。若式(I)化合物含有酸根时,式(I)化合物的合适的医药上可接受的盐为医药上可接受的碱的加成盐,如:锂,钠,钾,铵,镁,钙和锌盐,或与有机胺如:甲胺,二甲胺,三甲胺,乙胺,二乙胺,三乙胺,N-甲基-N-乙胺,单-,双-或叁-(2-羟乙基)胺,2-羟基-叔丁胺,叁(羟甲基)甲胺,N,N-二甲基-N-(2-羟乙基)胺,三-(2-羟乙基)胺,N-甲基-D-葡糖胺,或三丁胺形成的盐类。含有酸根和碱根的式I化合物也可形成内盐。其他合适盐类过于例如:S.M.柏奇(Berge)等人的“医药用盐类”(Pharmaceutical Salts),J.Pharm.Sci.,66,1-19(1977),该文献已并为本文的参考文献。
本文所采用“前药”一词是指式(I)化合物的医药上可接受的衍生物,为活的动物或人类投与这种前药后,可以转形成式(I)化合物,且比原来的式(I)化合物具有加强的安定性,传送特性和/或医疗价值。
本文中“保护基团”一词是指可暂时用来修饰官能基的基团,例如:防止官能基受到分子中另一个官能基所涉及的所需反应的影响,或不期望地影响该反应的结果及/或防止式(I)化合物在投与患者后,于化合物到达所需作用位置之前提早代谢。合适的保护基团述于例如:T.W.葛林(Greene)的“有机合成的保护基团”(1981年纽约强威利父子公司)(“Protective Groups in OrganicSynthesis”,(John Wiley & Sons,New York,1981))及J.F.W.麦欧米(McOmie),“有机化学的保护基团”(1973年伦敦普雷能出版社)(“Protective Groups in Organic Chemistry”(Plenum Press,London,1973))。
羟基或氢硫基取代基的合适保护基团实例包括:经取代的甲醚,例如:甲氧甲基,苄氧甲基,叔丁氧甲基,2-甲氧乙氧甲基,1-乙氧乙基,甲硫甲基,1-甲硫乙基,苄基,烯丙基,三苯甲基,等等,其他醚化基团如:2-四氢呋喃基,2-四氢吡喃基与乙烯基,或酰基与碳酸根如:甲酰基,2,2-二氯乙酰基,2,2,2-三氯乙酰基,叔丁氧羰基,苄氧羰基,4-硝基苄氧羰基,及4-甲氧苄氧羰基,或硅烷基如:三甲硅烷基,叔丁基二甲硅烷基,三苄硅烷基,三苯硅烷基,等等。
氨基取代基的合适保护基团包括酰基,如:甲酰基,乙酰基,3-苯基丙酰基,氯乙酰基,三氟乙酰基,三氯乙酰基,苯甲酰基,4-硝基苯甲酰基,4-甲氧苯甲酰基,叔丁氧羰基,苄氧羰基,4-硝基苄氧羰基,4-氯苄氧羰基,4-甲氧苄氧羰基,9-芴基甲氧羰基,(2-吡啶基)甲氧羰基,喹啉-2-羰基,2-三甲硅烷基乙氧羰基,或三甲硅烷基,或氨基酰基残基。
羧基取代基的合适保护基团包括酯,例如:甲酯,乙酯,叔丁酯,苄酯,4-硝基苄酯,4-甲氧基苄酯,甲氧甲酯,2-甲氧基乙氧甲酯,苄氧甲酯,甲硫甲酯,2,2,2-三氯乙酯,2-溴乙酯,2-碘乙酯,2-三甲硅烷基乙酯,2-三苯硅烷基乙酯,叔丁基二甲硅烷基酯或三甲硅烷基酯。
羰基取代的合适保护基团包括缩醛如:二甲基-,二乙基-,二丁基-与二苯基-缩醛;硫缩醛如:S,S-二甲基-与S,S-二乙基-硫缩醛;环状缩醛与硫缩醛如:1,3-二氧陆圜,1,3-二氧戊圜,1,3-噁硫醇烷,1,3-二噻烷,与1,3-二硫醇烷,及肟与腙类如:O-苄基肟,O-苯硫甲基肟及N,N-二甲基腙。
本文所采用“溶解基团”一词是指可用来暂时修饰官能基,以便加强式(I)化合物于水中或水性介质中溶解性的基团。式(I)化合物中可包含的溶解基团实例为如下式的基团,或其盐:
-NO2
其中R与R′分别为氢或C1-C4烷基。
下列通式的基团也包括在Px的含义之内,其中Px *和D如前述定义,R是H或C1-C4烷基:
若式(I)化合物包含两个可接受溶解基团衍化的官能基时,这两个官能基将会互相接近,应当了解,上文例举的某些溶解基团可以形成环状结构,例如:包括下列结构单位:
其中X1与X2分别选自O,S与NR6,其中R6如上述定义。环状结构中的溶解基团,如上述例举者,也在本文所采用“溶解基团”的定义范围内。
若溶解基团为酸性时,其盐主要为碱金属或铵,如:Na+,K+,NH4+的盐。若溶解基团为碱性时,其盐主要为强无机酸如:盐酸,硫酸,磷酸或硝酸的盐。典型的溶解基团为磷酸根或亚磷酸根的钠或钾盐。
式(I)化合物所包含的溶解或保护基团必须可在活体内水解或代谢分解。
本发明一种形式中,通式(I)化合物中的B主要选自下列:
其中Z,Z*,M,M1,M2,D*,R14,R14 *,R14 **,R15,R18,R18 *,R19和R19 *如上述定义,且V为YR2,Y*或C(R30)=Y**,其中R2,R30与Y*如上述定义,且其中Y是选自:
-N=N-,
且其中Y*是选自:
其中R33,R34,R50,R51,和R2 *如上述定义。
更典型者,此形式的本发明中,通式(I)化合物的结构以式(IA)代表:
其中R1 *,R10,R12,R12 *,R13,和R13 *如上述定义,B*是选自下列:
其中Z,Z*,M,M1,M2,D*,R14,R14 *,R14 **,R18与R19如上述定义,且是选自下列
其中R50,R51与R2 *如上述定义。
更典型者,此形式的本发明中,通式(I)化合物的结构式以式(IB)代表:
其中X与Y分别为0或1,
B是选自下列:
其中R14 *,R14 **,R15,R18与R19如上述定义且各R560分别为氢或(C1-C4)烷基,
R502与R506分别为R600基团,其中R600是选自下列:氢,C(O)OR621,C(O)SR621,C(O)NR621R622,(C1-C6)烷基,(C2-C6)烯基,(C5-C10)环烷基,(C5-C10)环烷基(C1-C6)烷基,(C5-C10)环烷基(C2-C6)烯基,(C6-C10)芳基,(C6-C10)芳基(C1-C6)烷基,(C6-C10)芳基(C2-C6)烯基,(C1-C6)酰基,杂环基,杂环基(C1-C6)烷基及杂环基(C2-C6)烯基,各该基团可经至多3个选自上述定义“可任选取代的(C1-C18)烷基”的取代基中的取代基取代,且R621与R622分别如上述R21与R22的定义,或R621与R622共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R501是选自下列:如上述定义的R600,S(O)OR632,S(O)2R632,S(O)NR632R633,S(O)2R632R633,NH2,NHR631与NR631R632,其中R631如上述R6的定义,且R632与R633分别如上述R20的定义,或R501与R506共同形成饱和或不饱和环系,双环系或稠合环系的一部分,或R631与R632,或R632与R633共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,
R512和R542分别如上述R600的定义,
R522和R532分别选自下列:如上述定义的R600,F,Cl,Br和I,
R513和R543分别选自下列:如上述定义R600和如上述定义的R200,
R523和R533分别选自下列:如上述定义的R600,F,Cl,Br和I和如上述定义的R200,
R550是如上述R6的定义,且R551是选自下列:R650,氢,S(O)OR632,S(O)2R632,S(O)NR632R633,S(O)NR632R633和S(O)2NR632R633,其中R650如上述R6的定义,且R632和R633如上述定义,或R632和R633共同形成如下文定义的饱和或不饱和环系,双环系或稠合环系,或R550和选自R551及R502中之一共同形成重氮杂环,其中R550,R551或R502及其所附接的两个氮原子共同形成安定的5至10员环的一部分,该环中可包含至多两个选自:O,S和N中的其他杂原子,且该环可与一个或多个环烷基,环烯基,芳基或杂环环基残基稠合,该重氮杂环可经一个或多个环烷基,环烯基,芳基或杂环环基残基稠合,该重氮杂环可经一个或多个上述定义“可任选取代的(C1-C18)烷基”的取代基取代,且其中两个取代基可共同形成环的一部分,
或一对选自:R512和R513,R522和R523(若存在时),R532和R533(若存在时),且R542和R543中的基团可共同形成=O;其中当B不为
或
时,下列(i)至(xi)
中至少一项条件适用:
(i)R512和R542中至少一者为R655基团,其中R655是选自下列:(C1-C6)烷基(C6-C10)芳基,(C2-C6)烯基(C6-C10)芳基,(C5-C10)环烷基(C2-C6)烯基,(C5-C10)环烷基(C6-C10)芳基,酰基(C6-C10)芳基,杂环基(C1-C6)烷基,杂环基(C2-C6)烯基,杂环基(C6-C10)芳基,C(D*)OR21 *,C(D*)SR21 *和C(D*)NR21 *R22 *,其中D*,R21*
和R22 *如上述定义,
(ii)R522和R523若存在时,其中至少一者是选自下列:如上述定义的R655,F,Cl,Br,和I,
(iii)R513和R543若存在时,其中至少一者是选自下列:如上述定义的R655,和如上述定义的R200,
(iv)R523和R533若存在时,其中至少一者是选自下列:如上述定义的R655,F,Cl,Br,I和如上述定义的R200,
(v)R550为R656基团,其中R656是选自下列:(C1-C6)烷基(C6-C10)芳基,(C2-C6)烯基(C6-C10)芳基,(C5-C10)环烷基(C2-C6)烯基,(C5-C10)环烷基(C6-C10)芳基,酰基(C6-C10)芳基,杂环基(C1-C6)烷基,杂环基(C2-C6)烯基,杂环基(C6-C10)芳基,
(vi)R551是选自下列:如上述定义的R656,S(O)OR632,S(O)2R632,S(O)NR632R633和S(O)2NR632R633,其中R632和R633如上述定义,
(vii)R502是选自下列:如上述定义的R656,C(D*)SR21 *和C(D*)NR21 *R22 *,其中D*,R21 *和R22 *如上述定义,
(viii)R502和R551均为氢或均为(C1-C6)酰基,
(ix)R14*
是选自下列:C(D*)OR40,C(D*)SR40和C(D*)NR40R41,其中R40和R41如上述定义,
(x)R501是选自下列:如上述定义的R656,S(O)OR632,S(O)2R632,S(O)NR632R633,S(O)2NR632R633,NH2,NHR631与NR631R632,其中R632与R633如上述定义,
(xii)X+Y>0
(xiii)X+Y=0,且R532和R533中至少一者不为氢,
(xiv)R50和R51共同形成如上述定义的重氮杂环,
(xv)R501,R502,R506和R551中至少一者为可任选取代的杂环基(C1-C18)烷基,及
(xvi)R512,R542,R522,R532,R513,R543,R523和R533中至少一者是选自下列:C(O)OR621,C(O)SR621,和C(O)NR621R622,其中R621和R622如上述定义。典型的未经取代的重氮杂环实例为:
本发明第一项具体实施方案的其他形式具有如下式(IC)至(IAW)代表的结构,其中各AA分别为如本文定义的天然或合成氨基酸的残基;R1 *,R1,X和X*如上述定义,Ra至Rj分别为-(CH2)0-6OPy或R6,更典型者为-(CH2)0-3OPy、氟、氯或R6*,其中Py为如本文定义的溶解基团Px,R6如上述定义,且R6*是选自下列:
氢,
R20*,其中R20*是选自下列:
可任选取代的(C1-C6)烷基,
可任选取代的(C2-C6)烯基,
可任选取代的(C2-C6)炔基,
可任选取代的(C3-C8)环烷基,
可任选取代的(C3-C8)环烷基(C1-C6)烷基,
可任选取代的(C3-C8)环烷基(C2-C6)烯基,
可任选取代的(C3-C8)环烷基(C2-C6)炔基,
可任选取代的(C6-C10)芳基,
可任选取代的(C6-C10)芳基(C1-C6)烷基,
可任选取代的(C6-C10)芳基(C2-C6)烯基,
可任选取代的(C1-C6)酰基,
可任选取代的杂环基,及
可任选取代的杂环基(C1-C6)烷基
C(O)OR21,
C(O)SR21,及
C(O)NR21R22,其中R21和R22分别选自氢和如上述定义的R20*,或R21和R22共同形成如上述定义的饱和或不饱和环系,双环系或稠合环系:
其中D′为O或S,且各G分别为氢或如上述定义的R200,其中R′d和R′f为Rd和Rf,或可共同形成最好经-C(O)OR任选取代的三亚甲基或四亚甲基;或-C(O)NRiRj;
其中G选自R1*和X*R1*;
其中Ra′为OPy或如上述定义的R6,M1为上述定义的R6,(CH2)1-2OPy或(CH2)1-2NHPy,G*为OR2或NR1R2;
其中G是氢,Ra,R1*X*或R1*X*C(Ra)(Rb)C(O),且其中Ra,R1*与其所附接的原子可任选形成饱和或不饱和环系,双环系或稠合环系;
其中Ra,R1*与其所附接的原子可任选形成饱和或不饱和环系,双环系或稠合环系;
其中W2为R1X或如上述定义的R6,且R′为Py或如上述定义的R6,或R′和Py与其所附接的氧原子共同形成一个选自下列的基团:
其中各L如上述定义,且各Pz分别为氢或Py,但其限制条件为其中至少一个Pz为Py;或当Pz是Py时,Py基团与其所附接的氧原子共同形成选自如下的基团;
其中Q为O或NRf且G为R1*或X*R1*;
其中W1是选自:R1X和R1*X*,且Q是选自:O和NRh;
其中W1是选自:R1X和R1*X*,且Pz分别为氢或Py,但其限制条件为至少一个Pz为Py,且Q是选自:O和NRh;
其中各Pz分别为氢或Py,但其限制条件为至少一个Pz为Py;
其中Ra′和Rj′分别选自如上述定义的R1和R1*:
其中G是选自
及饱和或不饱和环系,
双环系或稠合环系,Q为O或NH且G*为如上述定义的X或X*;
其中G是选自氢和R1*X*,Q是O、S或NH,Q*是O或NH,且G,是选自R1和R1*X*;
其中R200如上述定义;
其中
为含有一个氮原子且可任选另含有1至4个选自氮,氧和硫中杂原子的5至12员饱和或不饱和环系,双环系或稠合环系;
其中b为0、1或2,但至少一个b大于0,各Pz分别为氢或Py,但至少一个Pz为Py;及
其中各G*分别选自O,S和NR6,且G是选自OR6,NHR6和R20;
其中G为-C(O)-或-CH2-,G*为R1或R1*,G**为-O-或-NRh-,Q为-O-或-NRi且Pz是选自下列:
-NO2,
其中R和R′分别为氢或C1-C4烷基;D为O或S,Px*如前定义;
其中G为R1或R1*,G*为-O-或-NRf-且Pz是选自下列:
其中R和R′分别为氢或C1-C4烷基;D为O或S,Px*如前定义;
其中G为R1或R1 *,各Q独自为H,-OP2或-NRdPz,其中各Pz分别为氢或Py,但其限制条件为至少一个Pz为Py;
其中
为含氮的饱和或不饱和环系,双环系或稠合环系,且G为一个键或为-O-或-NRf;
其中G不存在或为X*R1*,且
为含有一个氮原子且可任选另包含一至三个选自氮,氧及硫中杂原子的3至10员饱和或不饱和杂环;
其中Q是选自-O-,-S-和-NRf;
其中G为O,S,S(O)或S(O)2,且Ra′和Rb′如Ra和Rb的定义,或Ra′和Rb′共同形成三亚甲基或四亚甲基;
其中各Ar分别为(C6-C14)芳基,Rc′和Rd′为Rc和Rd,或共同形成-C(O)或-CH(OH)-,且其中Pz和Pz′分别为氢或Py,但其限制条件为Pz和Pz′中至少-者为Py或Pz和Pz′及所附接的氧原子共同形成一个选自下列的基团:
其中G为一个键或如上述定义的X,Rg′和Rh′为Rg和Rh,或共同形成一个饱和或不饱和环系,双环系或稠合环系,且Pz和Pz′分别为氢或Py,但其限制条件为Pz和Pz′中至少一者为Py,或Pz和Pz′及所附接的氧原子共同形成一个选自下列的基团:
其中G为一个键,O,S或NRj,Rg′和Rh′为Rg和Rn,或一起为C(O)-,且Pz和Pz′分别为氢或Py,但其限制条件为Pz和Pz′中至少一者为Py,或Pz和Pz′及所附接的氧原子共同形成一个选自下列的基团:
其中G为OPy,NHRe,NPyRe或Re;
其中G和G*分别为一个键, O,S或NH,且Rd′和Rh′为Rd和Rh,或共同形成-CR′2-或-CR′2-CR′2-,其中各R′分别如上述R6的定义,Q和Q*独自为N或CR6,或当Q*为CR6则Rg和R6一起可形成一个双键;
其中G为-C(O)-或-C(R6)(CH2)0-4OG*其中G*为R6或Py;
其中G是选自氢和X*R1*,且其中
代表如本文定义的4至10员饱和或不饱和环系,双环系或稠合环系;
其中Q是选自:O,S和NR9
,G和G*分别选自:R1,R1*,-C(R5)=NR3和-C(R5)=NOR3,其中R3和R5如上述定义,Re′和Rf′为Re和Rf,且G**为前面定义的R20;
其中各R2分别选自R1和PyOG*,其中G*是任选取代的烯基,条件是至少一个R2是PyOG*,G为-NRd-或-CRdRe-;
其中
表示任选含有最高3个选自N、O和S的杂原子的,任选取代饱和或不饱和环体系,G为选自R1、XR1或X*R1*,Ra和Rb一起也可为-C(O)-;
其中B*为如前所述,由溶解基团Py衍生的B基;
其中Q和Q2分别选自O和S,R′f和R′g分别为Rf和Rg,或选自OR′、SR′和NRhR′,其中R′为H、Ri或Py;
其中各G分别选自O和NRi,R′为(CH2)1-2OPy或R6;
其中G和G*分别选自
和L,其中L如前所述,Q为H或Py,条件是G和G*至少之一不为L,而且至少一个Q是Py,或其中两个基团OQ一起为选自下列环基
其中Rx和Ry分别选自R6或(CH2)1-2OPy;
其中G和G*分别选自R1、R1*、-C(R5)=NR3和-C(R5)N=OR3,其中R3和R5如前述定义。
第一项具体实施方案其他化合物为彼等例举于国际专利申请案No.WO 93/18006中的化合物,即:
(i)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(ii)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-缬胺酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(iii)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(iv)3-(1-甲基-3-苯基丙烯-3-基)-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(v)3-(1-甲基-3-苯基丙烯-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(vi)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(vii)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]-重氮双环[4,4,0]癸烷,
(viii)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-缬胺酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(ix)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(N-(2-吡啶基)甲氧羰基)-L-缬胺酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(x)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-[N-(2-喹啉酰基-L-缬胺酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(xi)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-麸酰氨基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(xii)顺-1,6,3-叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-苏胺酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
(xiii)2-叔丁氧羰基-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]-2,3-重氮双环[2,2,1]庚-5-烯,
(xiv)2-叔丁氧羰基-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]-2,3-重氮双环[2,2,1]庚烷,
(xv)2-叔丁氧羰基-3-[(2R或S,3S)-2-羟基-3-(N-(2-吡啶基)甲氧基-L-缬胺酰基]氨基-4-苯丁基]-2,3-重氮双环[2,2,1]庚烷,
(xvi)2-[N-(1S)(2-甲基-1-甲氧羰丙基)氨基甲酰基]-3-[(2R或S,3S)-2-羟基-3-(N-(2-吡啶基)甲氧基-L-缬胺酰基]氨基-4-苯丁基]-2,3-重氮双环[2,2,1]庚烷,
(xvii)2-叔丁氧羰基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-2,3-重氮双环[2,2,1]庚烷,
(xviii)1-[2-(2-吡啶基)甲氧羰氨基]苯甲酰基-2-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-2-异丙基肼,
(xix)2-叔丁氧羰基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-1,2,3,4-四氢酞嗪,
(xx)1-三甲基乙酰基-2-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]-2-异丙基肼,
(xxi)1-三甲基乙酰基-2-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-2-异丙基肼,
(xxii)1-(叔丁氨基)羰基-2-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-2-异丙基肼,
(xxiii)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-皮考啉酰基-L-天门冬酰基)氨基-4-苯丁基]-肼基甲酸叔丁酯,
(xxiv)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-(2-吡啶基)甲氧羰氨基胺茴酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxv)3-苄基-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxvi)3-苄基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxvii)3-环己基-3-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxviii)3-环己基-3-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxix)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-(1-氨基甲酰基-甲基)丙烯酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxx)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-(2(RS)-3-叔丁硫基-2-氨基甲酰基-甲基丙酰基))氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxxi)3-异丙基-3-[(2R或S,3S)-2-羟基-3-(N-(1-苯甲酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯,
(xxxii)1-叔丁氧羰基-2-[(2R或S,3S)-2-羟基-3-(苯甲氧羰基)氨基-4-苯丁基]六氢哒嗪,
(xxxiii)1-叔丁氧羰基-2-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]六氢哒嗪,及
(xxxiv)顺-1,6,3叔丁氧羰基-4-[(2R或S,3S)-2-羟基-3-(N-喹啉酰基-3-氰基-L-丙胺酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷,
其中2-羟基已经本文所定义的溶解基团Px衍化。典型地,此第一具体实施方案中,上述化合物(i)至(xxxiv)是指经过一个选自
式(I)至(IAW)化合物可呈旋光异构型出现,且本发明范围内包括依所有比例的所有此等形式,包括所有非对映异构物及其混合物及所有对映异构物,对映异构物混合物和消旋混合物。若本发明化合物中出现一个双键时,双键可呈顺-(Z)或反-(E)构型。应当了解,仅有含有组合的取代基或官能基而产生安定的式(I)化合物涵括在本发明范围内。
通式(I)化合物可依相关技艺上一般已知方法制备。适合合成式(I)化合物和其中间物的方法述于例如:胡本-惠而(huoben-Weyl)的“有机化学方法”(Methoden der Organischen Chemie);J.马奇(March)的“高级有机化学”(Advanced Organic Chemistry),第3版(纽约强威利父子公司(John Wiley & Sons,New York),1985年);D.C.李鸥塔(Liotta)和M.佛莫(Volmer)编辑的“有机合成反应指南”(Organic Syntheses Reaction Guide)(纽约强威利父子公司,1991年);R.C.拉洛克(Larock)的“高级有机转形作用”(ComprehensiveOrganic Transformations)(纽约VCH公司,1989年);H.O.毫斯(Huose),“现代合成反应”(Modern Synthetic Reactions),第2版(蒙洛公园W.A.班杰明公司(W.A.Benjamin,Inc.,Menlo Park,)1972年);N.S.辛浦金(Simpkins)编辑,“100种新试剂”(100 ModernReagents)(伦敦皇家化学会(The Royal Society of Chemistry,London),1989年);A.H.哈尼斯(Haines),“有机化合物的氧化法”(Methodsfor the Oxidation of Organic Compounds)(伦敦学院出版社(Academic Press,London),1988年)及B.J.威克菲(Wakefield),“有机锂方法”(Organolithium Methods)(伦敦学院出版社,1988年)。
例如:式(I)化合物可由合成单位(synthons)W*,{(A)n-B-(A*)m}*及V*制备,其中以*代表的各合成单位为W-(A)n-B-(A*)m-V分子的相应部分的合成前体。因此式(I)化合物可例如:依下列任何方式制备:
(a)由W-(A)n-B-(A)m-G和H-V反应;
(b)由W-(A)n-B-(A)m-H和G-V反应;
(c)由W-H和G-(A)n-B-(A)m-V反应;及
(d)由W-G和H-(A)n-B-(A)m-V反应;
其中G为离去基,如:卤素,主要指氯,溴或碘;碘酸根如:甲磺酸根,三氟甲磺酸根,苯磺酸根或甲苯磺酸根;烷氧基,硫烷氧基,芳氧基或硫芳氧基,如:乙氧基,甲氧基,硫甲氧基或苯氧基;酰氧基如:乙酰基,三氟乙酰基或苯甲酰基;羟基;氨基或质子化氨基;硝酸根;磷酸根;硼酸根;等等。若适当时,这些反应可在强碱如:三乙胺,吡啶或其他叔胺,丁基锂,叔丁醇钠,或类似物质及/或偶合剂如:碳化二亚胺的存在下进行。
当V为YR2,其中Y为-N=N-时,或当V为Y*,其中Y*为如下一种基团时:
式(I)化合物可依图1或图1a所示制备。本文图中及实例中,Me、Et、Pr,Ph和Bz等名词分别代表甲基,乙基,丙基,苯基和苄基,并采用下列缩写:
THP 四氢吡喃基
t-Bu或But 叔丁基
n-Bu 正丁基
iPr或Pri 异丙基
Hal 卤素,即氟,氯,溴或碘
Ts 对甲苯磺酰基
DMF 二甲基甲酰胺
CDI N,N′羰基二咪唑
BOP 苯并三唑-1-基氧叁(二甲氨基)鏻六氟
磷酸盐
HBT 1-强碱苯并三唑
AcCN 乙腈
DMSO 二甲亚砜
Py,xSO3 吡啶/三氧化硫复合物
QC 喹啉-2-羰基
PC 2-吡啶甲氧羰基
MC N-吗啉羰基
TMC N-硫吗啉羰基
Val 缬胺酰基
Asn 天门冬酰基
Ile 异白胺酰基
Gly 甘胺酰基
Glu 麸酰氨基
Thr 苏胺酰基
Ala 丙胺酰基
(CN)Ala 氰基丙酰基
(p-F)Bz 4-氟苄基
(p-CN)Bz 4-氰苄基
Z 苄氧羰基
Boc 叔丁氧羰基
Ac 乙酰基
TFA 三氟乙酰基
C6H11 环己基
图1
其他式(I)化合物可依类似方法制备,由合成单位W-(A)n-B-(A*)m-Hal和HV反应,若适当时在强碱的存在下进行。
图1a
图1a中,R代表烷基,芳基或芳烷基,如:叔丁基,苯基或苄基,合适碱类包括:吡啶,三乙胺及其他叔胺类,碱金属碳酸盐,及碱金属氢氧化物。W-(A)n-B-(A*)m-部分体可以Ra代表,此时Rb代表如上述定义的R50,且Rc代表如上述定义的R2,或W-(A)n-B-(A*)m-可以Rc代表,此时Rb代表R51,且Ra代表R2。
当V为Y*,其中Y*为
时,式(I)化合物可由肼(式中R51和R2*均为氢,可依图1或图1a所示制得)与醛或酮反应制备,
图1b
当V为YR2,其中Y为如下一种基团时,
-S-S-,
式(I)化合物的合成可由合成单位W-(A)n-B-(A*)m-Za和合成单位Zb偶合,其中Za包括Y的一种杂原子,且Zb包括其他杂原子或原子,如图2a及2b所示:
图2a
图2b
可采用类似方法得到相应的硫代磷酸酯及硫代膦酸酯。
当V为C(R30)=Y**,式(I)化合物可由具有一个酮或醛官能基的合成单位和相应于Y**的经取代的肼或经取代的羟基胺缩合制成;
当V为Y*时,其中Y*为-N=O时,式(I)化合物可例如:使用卡洛氏酸(Caro′s acid)或含H2O2的乙酸,或含H2O2的钨酸钠,氧化相应的一级胺制成。应当了解,当带Y*的碳原子没有α-氢时,式(I)中,Y*为-N=O的化合物仅可作为亚硝基化合物的形式分离。
W-(A)n-B-(A*)m-S-R114* (IV)
硫醚(IV)可由卤化物W-(A)n-B-(A*)m-Hal,和硫醇R114*在碱性条件下偶合,或由二硫化物R114*SSR114*和衍生自相应卤化物的有机锂试剂W-(A)n-B-(A*)m-Li反应而合成。
图3
合成单位W-(A)n-B-(A*)m-Z中,Z为和图1至3中(A*)m结合的任何官能基,其制法可由合适的官能化片段W*和相应的官能化片段Z*-(A)n-B-(A*)m-Z偶合。或者,式(I)化合物的合成可先依上图1至3,由V和(A)n-B-(A*)m-先偶合,所得分子再与官能化片段W*偶合。W基团的前体与官能化片段Z*-(A)n-B-(A*)m-Z偶合的方法是本领域中公知的,且包括类似图1至3所代表的方法。例如:当W为R1X且X为Y时,可依上图1至3完成偶合作用。当W为R1X且X为NR10,O或S时,可分别由任何已知的胺类烷化作用,及醚和硫醚的合成法完成偶合,亦即,可由片段Z*-(A)n-B-(A*)m-Z,其中Z*为离去基(如:卤素,磺酸酯,乙酸盐或三烷铵盐),与R1R10NH,R1OH或R1SH反应,若必要时,于非亲核性强碱如:丁基锂,氨基钠或叔丁醇钾的存在下进行,完成偶合作用。式中X为S(O)或S(O)2的化合物可由式中X为S的相应化合物进行氧化制得。式中W为-CN,-C(R5)=NR3,-C(R5)=NOR3,-C(D)OR3,-C(D)SR3或-C(D)NR3R4的化合物可由片段Z*-(A)n-B-(A*)m-Z,其中Z为醛,酮或羧基,依图3a所示制备。
图3a
式中W为-N=CR5R5*的化合物可由片段Z*-(A)n-B-(A*)m-Z(其中Z*为NH2)与具有R5及R5*基团和羰基结合的醛或酮反应制得。
片段Z*-(A)n-B-(A*)m-Z可依B的性质选用方法制备。若B为经取代的碳原子时,该片段宜由片段E-C(O)-E*制备,其中E为片段Z*-(A)n,且E*为片段(A*)m-Z,如图4所示:
图4
作为式(I)化合物起始物质的片段
为已知化合物或可依制备已知化合物所使用的类似方法制备而已知化合物的类似物。已知片段
的合成法可见于参考文献,例如:拜斯坦有机化学手册(Beilsteins Handbuch der Organischen Chemie)或J.布金汉(Buckingham)编辑的“有机化合物字典”(Dictionary of OrganicCompounds)第5版(纽约查普曼与豪尔(Chapman & Hall),1982年)。或者,官能基E可与基团E*C(O)H偶合,或官能基E*可与基团EC(O)H偶合,随后进行氧化作用。例如:卤化物EBr可使用衍生自EBr的有机锂或有机镁试剂与E*C(O)H偶合,随后若需要时,所得的二级醇氧化成相应酮。或者,羧酸EC(O)OH可转化成活化衍生物如:酯或酰胺:例如,由羧酸与N,O-二甲基羟胺盐酸盐于碳化二亚胺与叔碱的存在下反应得到酰胺后,与衍生自E*Br,E*Cl或E*I的有机锂或有机镁试剂进行加成。
当B为
型环氧化物时,片段E-B-E*可由相应的烯烃与一种过酸类如:三氟过乙酸,过苯甲酸或间氯过苯甲酸反应制得。适合转化成片段E-B-E*的烯烃为可自商品取得者,或可依已知方法合成者,例如:利用威特反应(Wittig reaction)或利用醇,醇磺酸酯,酯,卤化物,等等的消去反应合成。
当B为杂原子或经取代的杂原子时,片段Z*-(A)n-B-(A*)m-Z为经取代的胺,膦或膦化氧,或为醚,硫醚,亚砜或砜。经取代的胺,醚,硫醚,亚砜和砜可依上述制备。二级或叔膦可依例如述于J.D.罗勃斯(Roberts)与M.C.卡希洛(Caserio)的“有机化学基本原理”(Basic Principles of Organic Chemistry)(纽约W.A.班杰明公司(Benjamin),1965年),由相应的一级或二级膦进行烷化作用制得。
上述任何反应中,可能必须使用保护基团保护式(I)化合物中其他不参与所需偶合或氧化反应的反应性基团,以便进行所需偶合或氧化反应,不会在化学上影响此等反应性基团。供此目的的合适保护基团述于上述葛林(Greene)和麦欧米(McOmie)的参考文献中。
式(IB)中x和y均为1的化合物,可依上述一般方法制备。式(IB)化合物,如下式
式中Ra和Rb如上述R501和R506的定义,且Rc和Rd如上述R551和R502的定义,可依图5所示方法,由亚乙基氰醇制得。
图5
式(IB)经取代化合物可依据图5的一般方法制备,若需要时,使取代基R512,R513,R522,R523,R532,R533,R542,R543及R550,依图5a所示方法,引入图5所示的式(Va),(Vb),(Vc)和(Vd)化合物中。
图5a
上述反应5a-1中,应当了解,引进第二个取代基R′的步骤仅当需要R522与R523均不为氢时才进行。5a-2与5a-3所示反应若需要时可以重复,以便在带有R″或R″C(O)的碳原子上引入第二个取代基。第二个取代基可与第一个相同或相异。若R522与R523中之一或二者为酰基时,可依反应5a-3中化合物(Vb′)的相关说明所示引入此基团。若R522与R523均为氢时,5a-2与5a-3所示反应可产生产物混合物,此时最好以得自相应图5b所示烯烃的适当取代的溴醇置换图5所示的伸乙基溴醇,引入所需基团R532,R543,R542与R543.应当了解,基团R532,R543,R542与R543的性质将决定HOBr与烯烃的加成反应基环氧化物的开环的立体化学性质。
图5b
式(IB)中B不为-CH(OH)-的化合物,可待二级醇氧化成相应酮后,依图4所示方法制备。
式(IB)中B为经取代的碳原子且y为0的化合物,可由式(II),(IIA)或(IIB)化合物
其中R14*,R501,R502,R506,R512,R513,R522,R523,R542与R543如上述定义,且Hal为选自-Cl,-Br或-I的基团
与式(III)化合物反应制得
式中R502,R550与R551如上述定义,若使用式(II)化合物时,该反应后可继续氧化所得到的二级醇,选出相应酮。该酮可依图4所示,用来完成B上的取代基。
式(II),(IIA)或(IIB)化合物可依图6所示,由β-氨基酸或β-酰氨酸制备。式III化合物可依图1a所示制备,
图6
图6所示β-氨基醛的另一条途径为使用二异丁基铝化氢还原相应β-氨基醛的甲酯。
β-氨基酸,或β-酰氨酸宜由胺或酰胺和可烯醇化的酮于甲醛或其他醛的存在下进行曼尼希(Mannich)反应制备。
式(IB)式中x和y均为0的化合物,可由式(IIC)或(IID)化合物
与式(III)化合物反应如上述制备。依类似制程,使用一级或二级胺替代式(III)所示的肼,产生羟基二胺。式(IIC)化合物可类似图6所示方法,由α-氨基酸制备,如述于下列文献中的方法:
B.E.伊凡斯(Evans)等人,J.Org.Chem.,50,4615-4625(1985);
J.R.路利(Luly)等人,J.Org.Chem.,52,1487-1492(1987);
B.K.汉塔(Handa)等人,欧洲专利申请案No.346,847-A2(1989)及
G.R.马歇尔(Marshall)等人,国际专利申请案No.WO91/08221。
合适的α-氨基酸可例如:依史奇克合成法(Streckersynthesis),以适当酮为起始物质制备。制备式(IIC)化合物的完整途径示于图7。其他合适方法述于柯宝拉(Coppola)等人,“不对称合成法,使用氨基酸构成手性分子”(Asymmetric Synthosis,Construction of Chiral Molecules using Amino Acids)(纽约威利科际公司(Wiley Interscience),1987年)。
图7
若W为含氮基团,且R1与R10中一者为受保护的氨基酸残基时,可依图8所示,完成受保护的氨基酸残基的偶合作用,其中氨基酸(以AA表示)保护基团为苄氧羰基,以Z表示。形成胜肽键及保护胜肽残基的方法述于例如:葛洛斯与曼赫福(Gross andMeienhofer)编辑的“肽学”(The Peptides)(纽约学院出版社(Academic Press),1983年)。其他合适偶合剂包括1-(3-二甲胺丙基)-3-乙基碳化二亚胺盐酸盐(EDC)及二苯基-磷酰基叠氮化物(DPPA)。
图8
有多种合成途径可制备经取代的肼,包括适用于合成式(I)化合物的式(III)肼。肼中间物(III)可使用已知方法制得,如彼等述于下列文献者:
A.S.杜塔(Dutta)等人,J.Chem.Soc.Perkin Trans.I,(1975)1712-1720,
N.I.加里(Ghali)等人,J.Org.Chem.,46,5413-5414(1981)
J.甘特(Gante),Synthesis(1989)405-413,及胡本惠尔(Houben-Weyl′s)的“有机化学方法”(Methoden derOrganische Chemie),等16a卷,第1部,pp.421-855,司徒加特乔治狄姆出版社(Georg thieme Verlag,Stuttgart),1990年。
其他制备经取代的肼的方法述于图9。
图9
式(I)中一个选自:R1,R1*,R2,R2*,R9,R11,R12,R50和R51中的基团,与另一个选自:R1,R1*,R2,R2*,R9*,R10,R11,R12,R50和R51中的基团共同形成环系,双环系或稠合环系的化合物,其制法可由本领域技术人员由上述说明即可了解的上述各项方法制备。
一种制备一类式(I)环状化合物的方法实例示于图10:
图10
不包含溶解基团Px的根据本发明化合物典型地具有低至极低的水溶性。迄今噌说明的HIV蛋白酶抑制剂,及许多种其他医药用或兽医用活性物质也典型地出现低至极低的水溶性。此性质容易导致这种物质的生物可利用率相当低。因此需要具有加强水溶性的HIV蛋白酶抑制剂。令人惊讶地,已发现在水溶性低至极低的物质中包含一个如本文定义的溶解基团Px时,可加强该物质的水溶性。
因此,根据本发明第二项具体实施例,是提供加强医药用或兽医用物质水溶性的方法,其包括以溶解具体Px衍生该物质的官能基,其中Px是选自下列:P*,
其中D为O或S,R为H或C1-C4烷基,其中P*选自
-NO2,
该官能基可被该溶解基团Px衍化。
通常根据第一项具体实施例的化合物包括至少一个如上述定义的溶解基团。更一般而言,第一项具体实施例的化合物中或第二项具体实施例的方法中的溶解基团是选自:
和
典型地,在其合成法中最后一个步骤,将溶解基团引入分子中。例如:溶解基团P(O)(OH)2可经由氨基,羟基或氢硫基与氯磷酸二甲酯反应而进人游离氨基,羟基或氢硫基中,然后温和水解,去除甲酯基团。上述其他溶解基团可依类似方法引入;意即使氨基,羟基,氢硫基或其他可经溶解基团衍化的基团,与试剂PxX′反应,若必要时,可适当地保护PxX′(例如:呈甲酯或苄酯),其中Px如上述定义且X′为脱离基如:Cl,Br,OH,OS(O)2R,等等,其中R为C1-C6烷基,例如:甲基,C6-C10芳基,例如:苯基或4-甲苯基,或C7-C11芳烷基,例如:苄基。或者,溶解基团P(O)(OH)2可经由与磷酸及汞盐,于叔胺的存在下反应,引入游离羟基中,如Obata与Mukaiyama述于J.Org.Chem.,32,1063(1967)。另一种方法,可使氨基,羟基或氢硫基与磷酸,最好在偶合剂(如:二环己基碳化二亚胺及吡啶)的存在下反应,产生具有溶解基团-OP(O)(OH)H的分子。此基团可任选氧化成相应磷酸酯衍生物,例如:使用双(三甲硅烷基)过氧化物(见下图14说明此方法)。另一种引进基团P(O)(OH)2的方法述于澳洲专利申请案No.54311/86,且涉及由氨基,羟基或氢硫基与某些磷酸的酰胺的二酯类反应,所得中间化合物随后氧化及水解。
引入溶解基团-NO2的合适试剂为硝酸低烷基酯如:硝酸甲酯或硝酸乙酯,及硝酸酰基酯如:硝酸乙酰酯或硝酸苯甲酰酯。
制备本文所述式(I)至(IAN)化合物的其他方法揭示于美国专利案Nos.5,116,835;5,126,326;5,132,400;5,145,957;5,198,426;5,212,157;5,215,968;5,212,667;5,294,720与5,296,604;国际专利申请案Nos.91/08221;91/10442;92/151319与92/21696;欧洲专利申请案Nos.0528242;0519433与0432595及澳洲专利申请案Nos.35700/89;53716/90;63221/90;71319/91;71320/91;71323/91;82313/91;83206/91;87594/91;90531/91;90851/94;90925/91;91251/91;91332/91;18355/92;26424/92;37160/93;38808/93及44930/93,各该文献已并本文的参考文献。
本发明第三项具体实施例是有关包含式(I)化合物及一种或多种医药上可接受的载体,稀释剂,辅剂和/或赋形剂的医药组合物。
本发明第四项具体实施例中,是提供一种为有需要这种抑制作用的哺乳动物抑制反转录病毒蛋白酶的方法,其包括为哺乳动物投与有效量的第一项具体实施例的化合物或第二项具体实施例的组合物。第三项具体实施例的一种形式是提供治疗或预防HIV病毒感染如:AIDS的方法。
抑制反转录病毒蛋白酶或治疗HIV病毒感染时,第二项具体实施例的组合物可经口,局部,非经肠式(例如:注射及动脉内灌流),直肠或吸人式喷洒投与。
经口投与时,医药组合物可呈锭剂,药片,丸剂,糖锭,胶囊,酏剂,散剂(包括冷冻干燥粉末),溶液,粒剂,悬浮液,乳液,糖浆及酊剂。也可制备缓释或延滞释出的形式,例如:呈包衣颗粒,多层药片或微粒子形式。
经口投与的固体形式可包含医药上可接受的结合剂,甜味剂,崩解剂,稀释剂,香料,包覆剂,防腐剂,润滑剂和/或时间延滞剂。合适结合剂包括金合欢胶,动物胶,玉米淀粉,黄芪胶,藻酸钠,羧甲基纤维素或聚乙二醇。合适甜味剂包括:蔗糖,乳糖,葡萄糖,阿斯巴甜(aspartame)或糖精。合适崩解剂包括:玉米淀粉,甲基纤维素,聚乙烯吡咯烷酮,黄原胶,皂土,藻酸或洋菜。合适稀释剂包括:乳糖,山梨糖醇,甘露糖醇,葡萄糖,高岭土,纤维素,碳酸钙,硅酸钙或磷酸二钙。合适香料包括:薄荷油,冬青,樱桃,柑橘或覆盆子等的油。合适的包覆剂包括丙烯酸和/或甲基丙烯酸和/或其酯的聚合物或共聚物,蜡,脂肪醇,玉米蛋白,虫胶或麸蛋白。合适防腐剂包括:苯甲酸钠,维生素E,α-生育酚,抗坏血酸,甲基帕拉本,丙基帕拉本或亚硫酸氢钠。合适的润滑剂包括:硬脂酸镁,硬脂酸,油酸钠,氯化钠或滑石。合适的时间延滞剂包括单硬脂酸甘油酯或二硬脂酸甘油酯。
供经口投与的液体形式除了上述制剂外,尚可包含液体载体。合适的液体载体包括水,油类如:橄榄油,花生油,芝麻油,葵花油,红花油,花生油(arachis oil),椰子油,液体石蜡,乙二醇,丙二醇,聚乙二醇,乙醇,丙醇,异丙醇,甘油,脂肪醇,甘油三酸酯或其混合物。
经口投与的悬浮液尚可包含分散剂和/或悬浮剂。合适的悬浮剂包括:羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,聚乙烯吡咯烷酮,藻酸钠或鲸蜡醇。合适的分散剂包括:卵磷脂,脂肪酸(如:硬脂酸)的聚氧乙烯酯,聚氧乙烯山梨糖醇单-或二-油酸酯,-硬脂酸酯或-月桂酸酯,聚氧乙烯山梨糖醇酐单-或二-油酸酯,-硬脂酸酯或-月桂酸酯,等等。
经口投与的乳液尚可包含-种或多种乳化剂。合适的乳化剂包括上文例举的分散剂或天然胶如:金合欢胶或黄芪胶。
供局部投与时,医药组合物可呈乳霜,软膏,凝胶,冻胶,酊剂,悬浮液或乳液形式。医药组合物可包含上文例举的医药上可接受的结合剂,稀释剂,崩解剂,防腐剂,润滑剂,分散剂,悬浮剂和/或乳化剂。
供非经肠式投与时,式I化合物或其盐可制成无菌水溶液或油质乳液或悬浮液。合适的无毒性非经肠式可接受的稀释剂或溶剂包括:水,林格氏溶液(Ringer′s solution),等张性盐溶液,5%葡萄糖水溶液,缓冲的乙酸钠或乙酸铵溶液,1,3-丁二醇,乙醇,丙二醇或聚乙二醇和水的混合物。水性溶液或悬浮液可另包含一种或多种缓冲剂。合适缓冲剂包括例如:乙酸钠,柠檬酸钠,硼酸钠或酒石酸钠。供非经肠式投与的水溶液也适合经口投与或吸人投与。
供经直肠投与时,式I化合物宜呈灌肠剂或栓剂形式投与。合适栓剂的制法可由活性物质与常温下呈固体但会在直肠内溶解的无刺激性赋形剂混合。这种合适物质为可可奶油,蜡,脂肪,甘油,动物胶及聚乙二醇。合适的灌肠剂可保护上述局部投药用形式所例举的制剂。
适当时,式I化合物的吸人式喷雾剂可呈上文例举的溶液,悬浮液或乳液形式。吸入式喷雾剂可另包含低毒性的可吸入的推进剂。合适的推进剂包括二氧化碳或一氧化二氮。
式I化合物的剂量形式可包含0.01至99重量%活性物质。通常,根据本发明的剂量形式可包含0.1至约10重量%活性物质。
式I化合物可与一种或多种已知或咸信具有抗病毒活性的其它活性物质共同投与或连续投与。这类其它活性物质实例包括:AZT,艾赛克菲(acyclovir),ddC,ddA,亚磷羧基甲酸三钠,卡斯坦史普明(castanospermine),里布丁(rifabutin),里巴菲南(ribaviran),布比明(bropirimine),寡去氧核苷酸硫代膦酸酯,葡聚糖硫酸酯,α干扰素,及安皮金(ampligen)。
附图的简要说明
图1出示实例5化合物(“前药”)于活体外,在兔子血液中转形成国际专利申请案No.PCT/AU93/00103的实例20化合物(“前药”)的作用图形。
图2与3出示“前药”分别经静脉内及肌内投与兔子后,于活体内转形成“药物”的作用图形。
本发明的最佳进行模式
制备式(IB)中x与y均为0,B为-CH(OH)-且R506,R513,R542和R543为氢的化合物 的方法述于下列图11和12中:
图11
图12
图13代表实例11和12的制法实例,它以图12的产物开始,其中R501为苄氧羰基,R512为甲氧羰基,R550与R551共同形成3,4-重氮双环[4,4,0]癸烷系,及R502为叔丁氧羰基:
图13
图14代表下表4所示化学式化合物的制法实例,其中溶解基团Px为P(O)(OH)H或P(O)(OH)2:
图14
第三项具体实施例的组合物可由本领域已知制备医药组合物的方法制备,包括:掺合,研磨,均质化,悬浮,溶解,乳化,分散及混合式(I)化合物和特定的赋形剂,载体,辅剂和/或稀释剂。
根据本发明第四项具体实施例治疗HIV病毒感染的方法中,第一项具体实施例的化合物通常经口或注射投与。合适的治疗法包括投与单一或多重剂量的式(I)化合物或第三项具体实施例的组合物。通常该治疗法包括每日投与一酯五次剂量历时一天至数天,最长可达患者的生命期。该治疗法通常包括投与式(I)化合物一天至一年。
式I化合物的投药剂量可随多个因子变化,如:患者的病症。剂量范围为每公斤0.01毫克至200毫克。通常,活性物质的剂量为每公斤体重0.01毫克至25毫克。
根据本发明剂量形式实例如下:
1.
药片
式I化合物 0.01至20毫克,通常0.1至10毫克
淀粉 10至20毫克
乳糖 100至250毫克
动物胶 0至5毫克
硬脂酸镁 0至5毫克2.
胶囊
式I化合物 0.01至20毫克,通常0.1至10毫克
甘油 100至200毫克
蒸馏水 100至200毫克
糖精 0至2毫克
甲基帕拉本 1至2毫克
聚乙烯吡咯烷酮 0至2毫克3.
注射溶液
式I化合物 0.01至20毫克,通常0.1至10毫克
氯化钠 8.5毫克
氯化钾 3毫克
氯化钙 4.8毫克
注射用水,适量至 10毫升4.
酊剂
式I化合物 0.01至20毫克,通常0.1至10毫克
蔗糖 100毫克
甘油 2毫升
羧甲基纤维素 20毫克
樱桃香料 2毫克
水 适量至10毫升
实例
下列实例说明制备根据本发明化合物的方法。下列实例所述合成法的起始物质说明于国际专利申请案No.PCT/AU93/00103中。此等实例中,熔点是于热分段设备上测定,且未校正。除非另外说明,否则质子与磷NMR光谱是分别于柏金艾玛(Perkin Elmer)R32或布鲁克(Bruker)EM 300光度计上,于CDCl3中,在100MHz或300MHz下记录。质子NMR的化学迁移为偏离四甲硅烷下游的ppm,P31NMR的化学迁移为偏离1,2-双(二苯膦基)乙烷内标准下游的ppm。薄层层析法(TLC)是于硅胶60-F254板(默克公司(Merck))上进行。利用紫外光和/或2%过锰酸钾水溶液检视化合物。TLC溶剂系统的组成(体积比)为(A)己烷/乙酸乙酯3∶2,及(B)浓NH4OH/异丙醇1∶3。
实例1
4S,5S-5,6-二苄基-1,2(顺-1,2-环己烷)二甲基-4-羟基-7-氧-全氢-1,2,6-三氮杂
步骤A:4S,5S-5-苄基-1,2(顺-1,2-环己烷)二甲基-4-叔丁
基二甲硅烷氧基-7-氧-全氢-1,2,6-三氮杂:
于室温下,使氯化氢通过含0.51克(1.26毫摩尔)顺-1,6-3-叔丁氧羰基-4-[(2S,3S)-2-羟基-3-氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷(当以含8%甲醇的二氯甲烷溶离时的Rf(A)=0.16的异构物)的10毫升含1%甲醇的二氯甲烷溶液30分钟。以氮气冲刷过量氯化氢后,减压排除溶剂,产生0.42克(100%收率)顺-1,6-4-[(2S,3S)-3-氨基-2-羟基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷的盐酸盐,为吸湿性白色固体。于氮气下,将此固体溶于1毫升无水DMF中,添加0.114克(1.68毫摩尔)咪唑及0.21克(1.38毫摩尔)叔丁基二甲硅烷基氯。所得混合物于室温下搅拌一夜,并真空蒸发至干。以乙酸乙酯稀释残质至20毫升,以饱和碳酸氢钠洗涤,经无水碳酸钾脱水,并过滤。滤液减压浓缩至干,残质溶于20毫升无水二氧六圜中。在其中添加0.204克(1.26毫摩尔)1,1′-羰基二咪唑,所得混合物在室温下搅拌24小时。减压蒸发溶剂后,以乙酸乙酯稀释残质至15毫升,以水(3×)及饱和氯化钠水溶液洗涤,然后经无水硫酸镁脱水。减压蒸发溶剂,残质经管柱层析法纯化(硅胶:己烷/乙酸乙酯3∶2),产生0.095克(收率17%)标题化合物,熔点145-146℃;Rf(A)=0.43;NMR0.07,0.09(s,s 6H,CH3);0.94(s,9H,叔丁基CH3);1.2-2.0(m,10H,环己烷CH2,CH);2.5-2.8(m,4H,CH2 -3,苄基CH2);3.2-3.7(m,4H,二甲基CH2);3.9-4.0(m,3H,CH-4,5,NH);7.1-7.32(m,5H,芳香系)。
步骤B:4S,5S-5,6-二苄基-1,2(顺-1,2-环己烷)二甲基-4-
叔丁基二甲硅烷氧基-7-氧-全氢-1,2,6-三氮杂:
添加4.5毫克(0.15毫摩尔)80%氢化钠的矿物油分散液至室温下,含0.0665克(0.15毫摩尔)步骤A产物的0.2毫升无水DMF中。于室温下搅拌30分钟后,添加0.0179毫升(0.15毫摩尔)苄基溴。所得混合物搅拌一夜后,以乙酸乙酯稀释至15毫升,以水,饱和氯化钠水溶液洗涤,经无水硫酸镁脱水。减压蒸发溶剂,残质经管柱层析,产生0.029克(收率36%)标题化合物的浓稠浆状物;Rf(A)=0.77;NMR-0.35,-0.18(s,s CH3);0.8(s,9H,叔丁基CH3);1.2-2.2(m,10H,环己烷CH2,CH);2.56-4.18(m,12H,苄基CH2,二甲基CH2,CH2 -3,CH-4,5);6.8-7.4(m,10H,芳香系)。
步骤C:4S,5S-5,6-二苄基-1,2(顺-1,2-环己烷)二甲基-4-
羟基-7-氧-全氢-1,2,6-三氮杂:
取含29毫克(0.0543毫摩尔)步骤B产物与0.0426克(0.163毫摩尔)四丁铵化氟水合物混合物的1毫升无水乙腈,于45±5℃下搅拌3小时,并蒸发至干。残质经管柱层析法纯化(硅胶:己烷/乙酸乙酯3∶2),产生0.019克(收率86%)标题化合物的无色泡沫物;Rf(A)=0.26;NMR 1.2-2.1(m,18H,环己烷CH2,CH,OH,3.5×H2O);2.6-4.0(m,11H,苄基CH2,二甲基CH2,CH2 -3,CH-5);4.83(m,1H,CH-4);7.0-7.4(m,10H,芳香系)。
实例2
4S,5S-1,5,6-三苄基-2-异丙基-4-羟基-7-氧-全氢-1,2,6-三氮杂:
步骤A:4S,5S-5-苄基-2-异丙基-4-叔丁基二甲硅烷氧基-7
-氧-全氢-1,2,6-三氮杂:
当以3-异丙基-3-[(2S,3S)-3-氨基-2-羟基-4-苯丁基]-嗪基甲酸叔丁酯替代实例1步骤A的顺-1,6,3-叔丁氧羰基-4-[(2S,3S)-2-羟基-3-氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷时,依相同制程,产生标题化合物,总收率20%;熔点=131-132℃
(己烷):Rf(A)=0.18;NMR 0.10,0.11(s,s,6H,硅烷基CH3);0.95(s,9H,叔丁基CH3);1.1-1.35(m,6H,异丙基CH3);2.8-3.2(m,5H,CH2-3,CH-5,苄基CH2);3.45(m,1H,异丙基CH);4.18(m,1H,CH-4);4.41(m,1H,NH-6);5.63(s,1H,NH-1);7.1-7.4(m,5H,芳香系)。
步骤B:4S,5S-1,5,6-三苄基-2-异丙基-4-叔丁基二甲硅烷
氧基-7-氧-全氢-1,2,6-三氮杂:
使含0.07克(0.185毫摩尔)步骤A产物和0.012克(0.371毫摩尔)氢化钠混合物的0.2毫升无水DMF溶液于室温下搅拌30分钟后,添加0.0441毫升(0.371毫摩尔)苄基溴。所得混合物搅拌一夜,并依实例1步骤B所述操作。粗产物经管柱层析法纯化(硅胶:己烷/乙酸乙酯3∶2),产生0.031克(收率30%)标题化合物的无色浆状物;Rf(A)=0.74;NMR-0.28,-0.22(s,s,6H,硅烷基CH3);0.8(s,9H,叔丁基CH3);1.0-1.35(m,6H,异丙基CH3);2.35-3.3(m,5H,CH2-3,CH-5,5-苄基CH2);3.45-3.82(m,2H,异丙基CH,CH-4);4.0-5.38(m,4H,1.6-苄基CH2);6.6-7.8(m,15H,芳香系)。
合并Rf(A)=0.63的溶离份,减压蒸发至干,也得到0.061克(收率70%)4S,5S-5,6-二苄基-2-异丙基-4-叔丁基-二甲硅烷氧基-7-氧-全氢-1,2,6-三氮杂的无色固体;NMR 0.11(d,6H,硅烷基CH3);0.93(s,9H,叔丁基CH3);1.24(m,6H,异丙基CH3);2.4-3.4(m,5H,CH2-3,CH-5,5-苄基CH2);3.75(m,1H,异丙基CH,);4.0-4.7(m,3H,CH-4,6-苄基CH2);5.05(m,1H,NH);7.0-7.7(m,15H,芳香系)。步骤C:4S,5S-1,5,6-三苄基-2-异丙基-4-羟基-7-氧-全
氢-1,2,6-三氮杂:
当以步骤B的标题化合物替代实例1步骤C的4S,5S-5,6-二苄基-1,2(顺-1,2-环己烷)二甲基-4-叔丁基二甲硅烷氧基-4-氧-全氢-1,2,6-三氮杂时,依相同制程得到标题化合物,收率98%,泡沫状物;Rf(A)=0.68;NMR(CDCl3)1.07,1.19(d,d,6H,异丙基CH3);1.58(s,1H,OH);2.6-3.15(m,5H,CH2-3,CH-5,5-苄基CH2);3.2-5.3(m,6H,异丙基CH,CH-4,1,6-苄基CH2);6.8-7.6(m,15H,芳香系)。
实例3
4S,5S-5,6-二苄基-2-异丙基-4-羟基-7-氧-全氢-1,2,6-三氮杂
当以4S,5S-5,6-二苄基-2-异丙基-4-叔丁基二甲硅烷氧基-7-氧-全氢-1,2,6-三氮杂替代实例2步骤C的4S,5S-1,5,6-三苄基-2-异丙基-4-叔丁基二甲硅烷氧基-7-氧-全氢-1,2,6-三氮杂时,依相同制程,得到标题化合物,收率88%,熔点=191-193℃;
Rf(A)=0.17;NMR(DMSO-d6,80℃)2.5-3.0(m,4H,CH2 -3,5-苄基CH2);3.28(m,1H,CH-5);3.6(m,1H,CH-4);3.8(m,1H,异丙基CH);4.2-4.7(m,3H,6-苄基CH2;OH);5.41(m,1H,NH);7.0-7.4(m,10H,芳香系)。
实例4
3-异丙基-3-[(2S,3S)-2-次膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯
于室温,氮气下,搅拌添加0.28克(1.4毫摩尔)二环己基碳化二亚胺至含0.4克(0.67毫摩尔)3-异丙基-3-[(2S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基嗪基甲酸叔丁酯与0.12克(1.47毫摩尔)无水亚磷酸混合物的1.5毫升无水吡啶中。于60℃搅拌2小时后,减压蒸发溶剂,以28毫升0.1ml碳酸氢钠水溶液处理,于室温下激烈搅拌1小时。滤出沉淀物,以水洗涤,以浓盐酸酸化滤液酯PH~1.5。以乙酸乙酯(3×50毫升)萃取吸收产物,有机物经无水硫酸镁脱水。溶剂蒸发,产生0.42克(收率95%)标题产物的无色固体Rf(B)=0.62;H1NMR(CDCl3);1.08(m,6H,异丙基CH3);1.41(s,9H,叔丁基CH3);2.7-4.8(m,14H,asn CH2,丁基CH2-1,4;CH-2,3;异丙基CH;P-OH×2H2O);5.12(m,1H,asn CH);5.89(s,0.5H,PH);6.2-8.5(m,15.5H,芳香系,酰胺NH,0.5PH);9.02(m,1H,asn NH);p31NMR(CDCl3)14.99(J=636Hz)。
实例5
3-异丙基-3-[(2S,3S)-2-膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯
使含0.4克(0.6毫摩尔)实例4产物的2毫升六甲基二硅胺烷悬浮液于120℃±5℃下搅拌45分钟。此时反应混合物转呈均质化。添加0.3毫升双(三甲硅烷基)过氧化物(P.G.库森(Cookson)等人,J.Organometal,Chem.,1975,
99,C31),接着在上述温度下搅拌1小时。反应混合物冷却至室温后,真空蒸发至干。残质溶于20毫升甲醇中,减压蒸发至干,再溶于12毫升0.1ml碳酸氢钠水溶液中,所得混合物以浓盐酸酸化至pH~1.5,经氯化钠饱和,以乙酸乙酯(3×50毫升)萃取。合并的乙腈相经无水硫酸镁脱水,蒸发至干,产生0.39克(收率96%)标题化合物的无色固体;Rf(B)=0.07;H1NMR(CDCl3):1.2(m,6H,异丙基CH3);1.4(s,9H,叔丁基CH3);2.8-4.2(m,8H,asn CH2,丁基CH2-1,4;CH=3;异丙基CH);4.2-6.4(m,5H,asn CH丁基CH-2,NH,POH);6.5-8.4(m,14H,芳香系,NH,8.78(m,2H,NH);p31NMR(CDCl3)9.6(s)。
实例6
顺-1,6,3-叔丁氧羰基-4-[(2S,3S)-2-次膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-3,4-重氮双环[4.4.0]癸烷
当以顺-1,6,3-叔丁氧羰基-4-[(2S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-3,4-重氮双环[4,4,0]癸烷替代实例4中的3-异丙基-3-[(2S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基肼基甲酸叔丁酯时,依相同制程得到标题化合物,收率89%,无色固体,Rf(B)=0.64;H1NMR(CDCl3):1.1-1.8(m,19H,叔丁基CH3,癸烷CH2-7,8,9,10,CH-1,6);2.12(m,1H,丁基CH-3);2.6-5.1(m,19H,asn CH2,CH,丁基CH2-1,4;CH-2,癸烷CH2-2,5,POH×2.5H2O);6.1-8.4(m,15H,酰胺NH,PH,芳香系);9.08(m,1H,asn NH);p31NMR(CDCl3)16.43(JpH=700Hz)。
实例7
顺-1,6,3-叔丁氧羰基-4-[(2S,3S)-2-膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-3,4-重氮双环[4.4.0]癸烷
当以实例6产物替代实例5的3-异丙基-3-[(2S,3S)-2-次膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸丁酯时,依相同制程得到标题化合物,收率83%,无色固体;Rf(B)=0.12;H1NMR(CDCl3):1.1-2.4(m,20H,叔丁基CH3,癸烷CH2-7,8,9,10,CH-1,6,丁基CH-3);2.7-3.9(m,9H,asn CH2,丁基CH2-1,4,CH-2,癸烷CH2-5);5.1(m,1H,asn CH);6.1-8.3(m,21H,酰胺NH,芳香系,POH×2.5 H2O);9.05(m,1H,asn NH);p31NMR(CDCl3)10.5(s)。
根据本发明其他代表性化合物述于表1至5中。根据本发明其他化合物为实例及下列文献所揭示的化合物中任何羟基,氨基或氢硫基已经过如本文定义的溶解基团Px衍化的物质:美国专利案Nos.5,116,835;5,126,326;5,132,400;5,145,951;5,198,426;5,212,157;5,215,968;5,212,667;5,250,563;5,268,361;5,294,720;和5,296,604;国际专利申请案Nos.91/09191;91/08221;91/10442;92/151319和92/21696;欧洲专利申请案Nos.0574135;0528242;0519433和0432595及澳洲专利申请案Nos.35700/89;42308/89;45665/89;46115/89;53716/90;63221/90;66334/90;71319/91;71320/91;71323/91;77326/91;81910/91;82054/91;88900/91;82313/91;83234/91;83206/91;85877/91;87309/91;87409/91;87594/91;88900/91;89941/91;90531/91;90851/91;90925/91;91223/91;91251/91;91332/91;91790/91;10812/92;18355/92;19373/92;21944/92;22889/92;24129/92;24690/92;26424/92;31628/93;35165/93;35621/93;37160/93;38808/93;41230/93;41659/93;44930/93;和49072/93,各该文献均已并为本文的参考文献。
实例8
活体内排除膦羧酸
溶液:实例5产物经2当量0.2M碳酸氢钠处理该游离酸,转化成相应的二钠盐,所得溶液冷冻干燥。供进行血液与动物实验的实例5产物的二钠盐的保存溶液是以无菌水制备。
分析:逆相分析法(HPLC)是于华特斯(Waters)三元梯度液相层析仪装置996二极排列检测器,该定在238nm上进行。以Alltima RP-18(250×4.6毫米内径,5微米粒子),流速1毫升/分钟完成分离过程。分析法所采用的等浓度流动相组合物包含40%0.1%三氟乙酸水溶液(TFA)及60%含0.1%TFA和10%水的乙腈。实例5产物(下文中称为“前药”)的滞留时间在3.6-3.9分钟的范围内,3-异丙基-3-[(2S,3S)-2-羟基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]肼基甲酸叔丁酯(下文称为“药物”)的滞留时间约6.2分钟。检测器反应在0.5至120μM“前药”及0.05至50μM“药物”时呈线性。
标准物和样本的处理:在已收集兔子血液且经肝素处理的试管中一系列稀释“前药”或“药物”,制成标准物。将血样移至含150单位肝素小瓶中,并保存在冰上,直到进行处理时为止。血样随后丁6000rpm下离心10分钟进行分离。血浆样本冷冻,并存放在-20℃下,直到分析时为止。
HPLC分析用的血浆样本:取等体积(100微升)解冻的血浆与于乙腈以漩涡式混合机搅拌,于室温下静置5分钟后,于14000rpm下离心10分钟。注入上澄液样本(50微升),进行层析。
“前药”经过血液转形成“药物”:此过程的确立是于“前药”在36℃的兔子全血(100μM)中培养19小时后,测定血浆中“前药”与“药物”浓度。
“前药”经过静脉内(IV)投与后转形成“药物”;此过程的确立是为兔子投与9.2毫克/公斤“前药”后,测在120分钟期间血浆中“前药”/“药物”浓度。兔子对经过调配的产品(含有30毫克/毫升“前药”)具有良好耐受性。“前药”与“药物”在血浆中消失的过程图形示于图2。
“前药”经过肌内(IM)投与后转形成“药物”;此过程的确立是为兔子投与“前药”(7.9毫克/公斤)后,在330分钟期间测定血浆中“药物”浓度。兔子对经过调配的产品(含有30毫克/毫升“前药”)具有良好耐受性。血浆中“药物”随时间的变化图示于图3。
表1
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表2
化合物通式 W-(A)n-B-(A*)m-V
表2(续)
表2(续)
表2(续)
表2(续)
表2(续)
表2(续)
表3
式(I)化合物的其它实例
表3(续)
表3(续)
表3(续)
表3(续)
表3(续)
表3(续)
表3(续)
表3(续)
表4
化合物通式
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表4(续)
表5
式(I)化合物的其它实例
Claims (12)
1.一种选自下组的化合物:
顺-1,6-3-叔丁氧羰基-4-[(2S,3S)-2-膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-3,4-重氮双环[4.4.0]癸烷;顺-1,6-3-叔丁氧羰基-4-[(2S,3S)-2-次膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基]-3,4-重氮双环[4.4.0]癸烷;
3-异丙基-3-[(2S,3S)-2-膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基肼基甲酸叔丁酯;及
3-异丙基-3-[(2S,3S)-2-次膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基肼基甲酸叔丁酯。
2.化合物3-异丙基-3-[(2S,3S)-2-膦羧氧基-3-(N-喹啉酰基-L-天门冬酰基)氨基-4-苯丁基肼基甲酸叔丁酯。
3.一种药物组合物,包含有效量的权利要求1的化合物和至少一种医药上可接受的载体,稀释剂,赋形剂和/或辅剂。
4.权利要求3的组合物,所述组合物是口服组合物。
5.权利要求1的化合物用于制备在需要抑制反转录病毒蛋白酶的哺乳动物体内抑制反转录病毒蛋白酶的药物的用途。
6.权利要求5的用途,其中反转录病毒蛋白酶是一种HIV蛋白酶。
7.权利要求5或6的用途,其中药物是口服药物。
8.权利要求2的化合物用于制备在需要抑制反转录病毒蛋白酶的哺乳动物体内抑制反转录病毒蛋白酶的药物的用途。
9.权利要求8的用途,其中反转录病毒蛋白酶是一种HIV蛋白酶。
10.权利要求1或2的化合物用于制备在需要治疗的哺乳动物体内治疗或预防获得性免疫缺陷综合征的药物的用途。
11.一种药物组合物,包含有效量的权利要求2的化合物和至少一种医药上可接受的载体,稀释剂,赋形剂和/或辅剂。
12.权利要求11的组合物,所述组合物是口服组合物。
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KR20180095622A (ko) | 2015-12-18 | 2018-08-27 | 헤래우스 크바르츠글라스 게엠베하 & 컴파니 케이지 | 내화성 금속으로 제조된 용융 도가니에서 실리카 유리 제품의 제조 |
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1994
- 1994-09-08 IL IL11089894A patent/IL110898A0/xx unknown
- 1994-09-09 AP APAP/P/1994/000667A patent/AP597A/en active
- 1994-09-09 TW TW083108353A patent/TW505636B/zh not_active IP Right Cessation
- 1994-09-12 AT AT94926731T patent/ATE267180T1/de not_active IP Right Cessation
- 1994-09-12 KR KR1019960701314A patent/KR100424544B1/ko not_active IP Right Cessation
- 1994-09-12 DE DE69433793T patent/DE69433793T2/de not_active Expired - Fee Related
- 1994-09-12 SK SK315-96A patent/SK31596A3/sk unknown
- 1994-09-12 PL PL94313407A patent/PL313407A1/xx unknown
- 1994-09-12 EP EP94926731A patent/EP0717736B1/en not_active Expired - Lifetime
- 1994-09-12 WO PCT/AU1994/000538 patent/WO1995007269A1/en active IP Right Grant
- 1994-09-12 CA CA002171471A patent/CA2171471A1/en not_active Abandoned
- 1994-09-12 CN CNB941941140A patent/CN1144793C/zh not_active Expired - Lifetime
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1998
- 1998-11-17 HK HK98112089A patent/HK1011024A1/xx not_active IP Right Cessation
Also Published As
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EP0717736A4 (en) | 1996-08-28 |
HK1011024A1 (en) | 1999-07-02 |
PL313407A1 (en) | 1996-06-24 |
AP597A (en) | 1997-07-15 |
DE69433793T2 (de) | 2005-05-04 |
EP0717736B1 (en) | 2004-05-19 |
KR960704863A (ko) | 1996-10-09 |
ATE267180T1 (de) | 2004-06-15 |
AP9400667A0 (en) | 1994-10-31 |
TW505636B (en) | 2002-10-11 |
IL110898A0 (en) | 1994-11-28 |
CA2171471A1 (en) | 1995-03-16 |
DE69433793D1 (de) | 2004-06-24 |
CN1135212A (zh) | 1996-11-06 |
SK31596A3 (en) | 1997-01-08 |
KR100424544B1 (ko) | 2004-07-22 |
EP0717736A1 (en) | 1996-06-26 |
WO1995007269A1 (en) | 1995-03-16 |
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