CN1086809A - 5-氧代-二苯并[a,d]环庚-1,4-二烯 - Google Patents
5-氧代-二苯并[a,d]环庚-1,4-二烯 Download PDFInfo
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- CN1086809A CN1086809A CN93117991A CN93117991A CN1086809A CN 1086809 A CN1086809 A CN 1086809A CN 93117991 A CN93117991 A CN 93117991A CN 93117991 A CN93117991 A CN 93117991A CN 1086809 A CN1086809 A CN 1086809A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
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Abstract
本发明涉及通式(I)的取代的5-氧代-二苯并
[a,d]-环庚-1,4-二烯、其制备方法和作为抗逆转录
病毒药物的用途。
式中各取代基的定义同说明书。
Description
本发明涉及5-氧代-二苯并[a,d]环庚-1,4-二烯、其制备方法和作为抗逆转录病毒药物的用途。
顺/反-10,11-二氢-5-氧代-二苯并[a,d]环庚-1,4-二烯及相应的二乙酸酯已知发表于Bull.Soc.Chim.Fr.(1960),400。
本发明现在涉及通式(Ⅰ)的取代的5-氧代-二苯并[a,d]环庚-1,4-二烯和其半缩醛形式(R5或R6为氢时)及其盐:
式中
R1和R3是相同或不相同的,并代表氨基保护基或式R7-CO的基团,
其中
R7代表氢、三氟甲基、或具有多至8个碳原子的直链或支链烷氧基、或多至18个碳原子的直链或支链烷基,所述的烷基可任选地被相同或不同的、含6到10个碳原子的芳基或吡啶基取代两次;或者R7代表含6-10个碳原子的芳基,所述芳基可任选地被卤素、三氟甲氧基或含多至8个碳原子的直链或支链烷基取代;或者R7代表有3-7个碳原子的环烷基,或代表喹啉基、喹啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基;或代表如下列各式的基团:
其中
R8代表苯基或萘基,
R9、R10和R11各自独立地代表多至14个碳原子的直链或支链烷基,该烷基上可任意地被苯基或萘基取代;或代表有6-10个碳原子的芳基,该芳基可被多至4个碳原子的烷基取代;或者
R10代表下式的基团:
m为0,1或2,
T代表吗啉代或环己基,
P为1,2或3,
Y和Y′各自独立地代表CO-或SO2-,
t为0或1,
R12和R13各自独立地代表羟基,或多至8个碳原子的烷氧基,
S为1或2;
R2和R4可相同或不同,并代表氢、或有多至8个碳原子的直链或支链的烷基;
R5和R6可相同或不同,代表氢或有多至8个碳原子的直链或支链酰基或烷氧羰基,或代表羟基保护基。
取代的5-氧代-二苯并[a,d]环庚-1,4-二烯的生理可接收的盐可以是本发明的化合物与矿酸、羧酸或磺酸形成的盐。特别优选的盐是:例如与盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、酒石酸、柠檬酸、富马酸、马来酸或苯甲酸形成的盐。
与常规碱形成的盐可提及的是:例如碱金属盐(如钠或钾盐);碱土金属盐(如钙或镁盐);或由氨或有机胺衍生的铵盐,例如与二乙胺、三乙胺、乙基二异丙胺、普鲁卡因、二苄胺、N-甲基吗啉、去氢枞胺、N-甲基-1,2-二苯基-2-羟基乙胺或甲基哌啶等形成的盐。
本发明化合物可以立体异构形式存在,这些立体异构体或者相互呈镜像体(对映异构体)或不呈镜像体(非对映异构体)。本发明既涉及纯的对映体,也涉及消旋体和非对映体混合物。消旋体及非对映异构体可用已知的方法分离成单一的立体异构体成分[见E.L.Eliel,碳化合物化学,McGraw Hill,1962]。
在本发明范围内,氨基保护基是肽化学中所用的常规的氨基保护基。
优选的氨基保护基包括:苄氧羰基、3,4-二甲氧基苄氧羰基、3,5-二甲氧基苄氧羰基、2,4-二甲氧基苄氧羰基、4-甲氧基苄氧羰基、4-硝基苄氧羰基、2-硝基苄氧羰基、2-硝基-4,5-二甲氧基苄氧羰基、甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、叔丁氧羰基、烯丙氧羰基、乙烯氧羰基、3,4,5-三甲氧基苄氧羰基、环己基氧羰基、1,1-二甲基乙氧羰基、金刚基羰基、邻苯二甲酰基、2,2,2-三氯乙氧羰基、2,2,2-三氯叔丁氧羰基、
基氧羰基、苯氧羰基、4-硝基苯氧羰基、芴基-9-甲氧羰基、甲酰基、乙酰基、丙酰基、新戊酰基、2-氯乙酰基、2-溴乙酰基、2,2,2-三氟乙酰基、2,2,2-三氯乙酰基、苯甲酰基、4-氯苯甲酰基、4-溴苯甲酰基、4-硝基苯甲酰基、苯二甲酰亚氨基、异戊酰基或苄氧亚甲基、4-硝基苄基、2,4-二硝基苄基或4-硝基苯基。
在式(Ⅱ)的残基中,
-OR5和-OR6彼此可处于顺式或反式位置,或者是以顺/反式混合物形式存在。
半缩醛形式的定义可用式(Ⅱa)的例子说明:
羟基保护基通常是:三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基、三甲基甲硅烷基乙氧羰基、苄基、苄氧羰基、2-硝基苄基、4-硝基苄基、2-硝基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基、三氯乙基、2,2,2-三氯乙氧羰基、2,4-二甲氧基苯氧羰基、2,4-二甲氧基苄氧羰基、甲氧基甲基、甲硫基甲基、甲氧基乙氧基甲基、[2-(三甲基甲硅烷基)乙氧]甲基、2-(甲硫基甲氧)乙氧羰基、四氢吡喃基或苯甲酰基。
其中优选的是:三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基、苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基和三氯乙酰基。
优选的通式(Ⅰ)的化合物为:下述化合物及其半缩醛(当R5和R6之一为氢时)和其盐的形式:其中
R1和R2可相同或不相同,并代表苄氧羰基、4-甲氧基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、2-硝基苄氧羰基、芴基-9-甲氧羰基或2,2,2-三氟乙酰基,或代表式R7-CO-基团,其中
R7代表氢、三氟甲基、或有多至4个碳原子的直链或支链烷氧基、有多至16个碳原子的直链或支链烷基,所述基团可任选地被相同或不相同的苯基、萘基或吡啶基取代两次;或者R7代表苯基或萘基,所述基团可任选地被氟、氯、三氟甲基、三氟甲氧基或有多至6个碳原子的直链或支链烷基取代;或者R7代表环丙基、环戊基、环己基、喹啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基;或者R7代表下列各式的基团:
其中
Y为CO或SO2基,
R8为苯基或萘基,
R9、R10和R11各自独立为有多至8个碳原子的直链或支链烷基、甲苯基、苯基或萘基,或者R10为下式基团:
m为1或2;
R2和R4可相同或不相同,并代表氢或有多至6个碳原子的直链或支链烷基;
R5和R6可相同或不相同,并代表氢或有多至6个碳原子的直链或支链酰基或烷氧羰基;或代表三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基、苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基或三氯乙酰基。
特别优选的式(Ⅰ)化合物是下述化合物及其半缩醛形式(当R5和R6之一为氢时)和其盐的形式:其中
R1和R3可相同或不相同,并代表苄氧羰基、4-甲氧基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、2-硝基苄氧羰基、芴基-9-甲氧羰基或2,2,2-三氯乙酰基;或代表式R7-CO-基团,其中
R7为氢、三氟甲基、或有多至4个碳的直链或支链烷氧基和有多至14个碳原子的直链或支链烷基,所述基团可任选地被苯基、萘基或吡啶基取代两次;R7或者为苯基或萘基,所述基团可任选地被氟、氯、三氟甲基、三氟甲氧基、或有多至4个碳原子的直链或支链烷基取代;R7或者为环丙基、环戊基、环己基、喹啉基、啉啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基,或者R7为下式的基团
其中
Y代表CO或SO2基,
R8代表苯基或萘基,
R9和R10相互独立代表有多至4个碳原子的直链或支链烷基、甲苯基、苯基或萘基,或者
R10代表下式的基团:
R2和R4可相同或不相同,并代表氢、有多至4个碳原子的直链或支链烷基;
R5和R6可相同或不相同,并代表氢或有多至4个碳原子的直链或支链的酰基或烷氧羰基;或者代表三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基-二甲基甲硅烷基、三苯基甲硅烷基、苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基或三氯乙酰基。
此外,还发现了本发明式(Ⅰ)化合物的制备方法,其特征在于:在相应的盐存在下,将通式(Ⅲ)化合物与通式(Ⅳ)的羧酸反应,首先转变成通式(Ⅰa)和(Ⅰb)的化合物,
式中R14和R15可相同或不相同,并代表氨基保护基,优选为苯基甲氧羰基;R16代表上述的取代基R5和R6的各自定义的基团(氢除外),优选乙酰基;
然后,将生成的(Ⅰa)和(Ⅰb)经水解游离出羟基(R5/R6=H);和当其余的取代基为上述的R1和R3时,首先将R14和R15用常规方法除去,最好用氢解法,使氨基游离出;最后一步,在惰性溶剂中、在一种碱和/或辅助化合物的存在下,再与通式(Ⅴ)的羧酸或其活化形式反应,
式中R17代表上述R1和R3的定义。
本发明的方法可以举例的方式用下列反应式加以解释:
与通式(Ⅳ)的羧酸的反应,其温度为-20℃至80℃,优选0℃至+40℃,并常压下进行。
适宜的羧酸/盐系统一般是乙酸/乙酸银、丙酸/丙酸银或丁酸/丁酸银,优选乙酸/乙酸银。
常用的无机碱是适于水解用的碱,优选为碱金属氢氧化物或碱土金属氢氧化物(例如氢氧化钠、氢氧化钾或氢氧化钡),或碱金属碳酸盐(如碳酸钠、碳酸钾或碳酸氢钠)。特别优选氢氧化钠和氢氧化钾。
适于水解用的溶剂是水或常规用于水解的有机溶剂,它们最好包括:醇类如甲醇、乙醇、丙醇、异丙醇或丁醇,或醚类如四氢呋喃或二噁烷、或二甲基甲酰胺或二甲基亚砜。特别优选醇类,如甲醇、乙醇、丙醇或异丙醇。还可用上述溶剂的混合溶剂。
水解反应温度一般为0℃至100℃,优选20℃至80℃。
通常水解反应在常压下进行,但也可在减压或加压下进行(例如0.5~5.0巴)。
水解用的碱量为每摩尔酯一般用1~3摩尔,优选1~1.5摩尔,特别优选的是用与反应物等摩尔的碱量。
氨基保护基(R14/R15)的除去是用已知的方法,在酸性或碱性条件下进行,或用还原性催化氢解反应除去,如用pd/C在有机溶剂中进行,例如醚类(如四氢呋喃或二噁烷)或醇类(如甲醇、乙醇或异丙醇)。
氢化温度一般为0℃至80℃,优选0℃至40℃。
氢化一般在加压下进行,压力为2~8巴,优选为3~5巴。
适合于与通式(Ⅴ)化合物进行反应的溶剂是在反应条件下不会发生变化的惯用的惰性溶剂。它们最好包括:醚类如乙醚、乙二醇单甲醚或双甲醚、二恶烷或四氢呋喃;或烃类,如苯、甲苯、二甲苯、环己烷或石油醚;或卤代烃类,如二氯甲烷、氯仿、四氯化碳;或二甲基亚砜、二甲基甲酰胺、六甲基磷酰三胺、乙酸乙酯、吡啶、三乙胺或甲基吡啶。也可用上述溶剂的混合物。特别优选的是二氯甲烷、氯仿、二甲基甲酰胺或四氢呋喃。
作为辅助化合物,最好采用缩合剂,也可用碱类,特别是当羧酸基以活化的形式如酸酐形式存在时。优选的常用缩合剂是:例如碳化二亚胺类,如N,N-二乙基-、N,N′-二异丙基-或N,N′-二环己基-碳化二亚胺,N-(3-二甲氨基异丙基)-N′-乙基碳化二亚胺盐酸盐,或N-环己基-N′-(2-吗啉代乙基)-碳化二亚胺对甲基磺酸盐;或羰基化合物,如羰基二咪唑;或1,2-噁唑鎓化合物,如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸盐或2-叔丁基-5-甲基-异噁唑鎓过氯酸盐;或酰胺类化合物,如2-乙氧基-1-乙氧羰基-1,2-二氢喹啉;或丙烷膦酸酐;或氯甲酸异丁酯;或苯并三唑氧基三(二甲氨基)鏻鎓六氟磷酸盐;或1-羟基苯并三唑。
此外,也可采用碱金属碳酸盐(例如碳酸钠或钾、碳酸氢钠或钾)或有机碱(如三烷基胺,如三乙胺、乙基二异丙胺、N-乙基吗啉、N-甲基哌啶、或N-甲基吗啉)。优选N-甲基吗啉。
辅助化合物和碱的用量,以1摩尔通式(Ⅴ)计,为1.0~3.0摩尔,优选为1.0~1.2摩尔。
反应在-30℃至100℃、优选0℃至30℃下和常压下进行。
反应既可在常压下,也可在加压或减压(例如0.5~5巴)下进行,优选在常压下进行。
通式(Ⅳ)和(Ⅴ)化合物是已知物或可按常规方法制备。
通式(Ⅰa)和(Ⅰb)是新化合物,可按上述方法制备。
通式(Ⅲ)化合物也是新化合物,可按下法制备:
将式(Ⅵ)的2,8-双(叠氮甲基)-5-氧代-二苯并[a,d]环庚基-1,4,6-三烯
溶解于醚中(优选为THF),先与三苯膦/水反应,生成二胺;
然后与通式(Ⅶa)或(Ⅶb)的化合物反应,
(式中R18和R19同上述R14/R15的定义),此反应是在惰性溶剂、碱和辅助化合物的存在下进行的,若是羧酸(Ⅶa)时,预先将羧基活化;和
最后一步是在惰性溶剂中用溴来溴化。
与三苯膦/水的反应在0℃~50℃、优选在室温下和常压下进行。
与通式(Ⅶ)化合物的反应与上述同通式(Ⅳ)化合物的反应相类似。
溴化反应在卤代烷/冰醋酸混合物中,优选在二氯甲烷/冰醋酸中,并在室温下进行。
式(Ⅵ)的化合物也是新的,并可按下法制备:例如,可首先将式(Ⅷ)的2,8-二甲基-5-氧代-二苯并[a,d]-环庚-1,4,6-三烯于上述溶剂中的一种溶剂(优选为四氯化碳)中,并在光照射下,与N-溴代琥珀酰亚胺反应,使其转变成式(Ⅸ)化合物,
接着在二甲基亚砜中与叠氮化锂反应。
溴化温度为50至120℃,优选为70至100℃。
与叠氮化锂的反应一般在0°~70℃,优选室温下进行。
式(Ⅸ)化合物是新化合物,可按前述方法制备。
式(Ⅷ)化合物是新化合物,可按下法制备:例如,首先将式(Ⅹ)的4-甲基-2-[2-(3-甲基苯基)乙基]苯甲酸于环丁砜中与多磷酸反应,转变成式(Ⅺ)化合物
下一步,如已多次所述,在四氯化碳中,在光照射下用N-溴代琥珀酰亚胺溴化,然后在碱的作用下消除溴化氢。
生成式(Ⅹ)化合物的反应,在温度为+20℃至+120℃、优选为60至100℃进行溴化反应,消除反应在+20℃至+60℃进行。
消除反应在惰性溶剂中进行,优选二甲基甲酰胺。优选的碱是DBN、DBU和DABCO。
式(Ⅺ)化合物是新化合物,并可按上述方法制备。
式(Ⅹ)化合物也是新化合物,是在LDA/THF/正己烷溶液中将2,4-二甲基苯甲酸与3-甲基苄基溴反应而制得。
该反应在-40℃至+40℃、优选为-30℃至+20℃下进行。
这里所述的抑制剂是HIV蛋白酶抑制剂,它可用于适于该酶抑制剂的所有目的。例如可用于诊断,以改善测定酶活性的精确度和选择性。它们可在亲合色谱法中作为亲合标记物,并可在研究中用来解释反应机制和酶反应的特异性。
此外,还意外地发现,通式(Ⅰ)化合物对于逆转录酶有异常强的作用,这可用HIV-特异性蛋白酶测定加以证实。
下面所列出的实施例的结果是按如下文献所述的HIV测定系统进行测定的(见Hansen,J.,Billich,S.,Schulze,T.Sukrow,S.和Moelling,K.(1988),EMBO Joarnal,Vol.7,No.6,PP.1785-1791):纯化过的HIV蛋白酶与合成肽温育,合成肽模拟Gag前体蛋白的断裂部位,并代表HIV蛋白酶的体内断裂部位。生成的合成肽断裂产物用反相高压液相色谱(RP-HPLC)分析。得到的IC50值为试验条件下对蛋白酶活性产生50%抑制作用的物质的浓度。
表1
实施例号 | IC50 (μm) |
46 | 0.0052 |
此外,本发明化合物对痘病毒感染的细胞培养物有作用。这可用HIV病毒为例来证明。
细胞培养中的HIV感染
HIV试验按照Panwels等的方法[见Journal of Viro-logical Methods,20(1988),309-321)]进行,只作微小的改变。
正常人血淋巴细胞(PBLs)的富集是通过Ficoll-Hypague方法,并在RPMI1640,含植物血球凝集素的20%胎牛血清和白细胞介素2(40单位/ml)中进行制激。为了用HIV进行感染,使PBLs呈小团状,然后将细胞团悬浮于1ml HIV病毒吸附液中,并37℃温孵1小时。
病毒吸附液离心后,被感染的细胞团用生长培养基处理,使每毫升悬浮液中含1×105个细胞。将用这种方法感染的细胞分加到有96井的微量滴定板上,使每个井中有1×104个细胞。
微量滴定板的第1纵行只有培养基和未感染的细胞。但仍已接上述操作进行处理(细胞对照组);第2纵行是培养基中只含HIV感染过的细胞(病毒对照组);其余井中含有不同浓度的本发明化合物,从第3纵行开始,受试物质以倍增法进行210倍稀释。
受试混合液于37℃温育,直到形成合体细胞,合体细胞的形成在未经处理的病毒对照组出现的HIV是有代表性的(感染后3~6日),然后显微镜计数。在这些试验条件下,未处理的病毒对照组产生大约20个细胞合体,而未处理的细胞对照组不含细胞合体。
本发明化合物IC50值是用该化合物处理后使病毒诱发产生的细胞合体发生50%抑制时的本发明化合物的浓度。
现已发现,本发明化合物可保护受HIV感染的细胞免于病毒引起的细胞破坏。
表2
实施例号 | IC50 (μm) |
45 | 1010 |
本发明化合物对于人体类和动物医学中逆转录病毒引起的疾病防治是有价值的活性化合物。
对人类医学中可提及的运应症范围举例如下:
1)治疗和预防人逆转录病毒感染。
2)治疗或预防HIV Ⅰ(人免疫缺陷病毒;以前称作HILV Ⅲ/LAV)和HIV Ⅱ引起的疾病(爱滋病),以及与此疾病有关的各阶段,例如ARC(爱滋病相关综合症)和LAS(淋巴结病症候群),以及该病毒引起的免疫缺陷和脑疾患。
3)治疗和预防HTLV-Ⅰ或HILV-Ⅱ感染。
4)治疗或预防爱滋病毒携带者。
可提及的对兽医的适应症举例如下:
下列病毒的感染
a)meadi-visna病毒(绵羊与山羊),
b)进行性肺炎病毒(PPV)(绵羊与山羊),
c)正亮氨酸关节炎-脑炎病毒(绵羊与山羊),
d)Zwoegerziekte病毒(绵羊),
e)马鼻疽传染性贫血病毒,
f)猫白血病病毒引起的各种感染,
g)猫免疫缺陷病毒(FIV)引起的各种感染,
h)猴免疫缺陷病毒(SIV)引起的各种感染。
在人的适应症中,优选前述第2、3、4项。
除含有无毒的惰性的适于药用的赋形剂外,还含有一种或多种式(Ⅰ)/(Ⅰa)/(Ⅰb)化合物,或是只由一种或多种式(Ⅰ)/(Ⅰa)/(Ⅰb)化合物所组成的药物制剂,以及制备这些制剂的方法均包括在本发明范围内。
在上述药物制剂中,(Ⅰ)/(Ⅰa)/(Ⅰb)的活性化合物存在的浓度为大约0.1~99.5%,优选为0.5~95%(以混合物总重量计)。
上述药物制剂中除含有式(Ⅰ)/(Ⅰa)/(Ⅰb)化合物外,也可含有其它药用活性化合物。
上述药物制剂按照已知方法用常规方式制备,例如,将活性化合物与赋形剂混合。
为达到所希望的治疗效果,本发明活性化合物作为人和兽药,其用量是每24小时按每Kg体重的总用药量,为0.5至大约500mg,优选为1至100mg,可任选地分几个单剂量给药。一个单剂量最好为约1至80mg/Kg,特别是1至30mg/Kg体重,但也可偏离上述的剂量,主要取决于受治疗者的种属、体重、疾病的性质和严重性、药物的剂型和给药方式以及给药的时间和间隔。
起始化合物
实施例Ⅰ
4-甲基-2-[2-(3-甲基苯基)乙基]苯甲酸
将2,4-二甲基苯甲酸(54g,0.36mol)溶解于THF(500ml)中,于10至20℃下滴加到LDA(0.76mol)的THF/正己烷(1∶1,300ml)溶液中。室温下搅拌此混合物30分钟,再冷却到-20℃。于此温度下滴加3-甲基苄基溴(80g,0.43mol)的THF(300ml)溶液,并于此温度下再搅拌混合物15分钟。进行后处理,将混合物于2N盐酸及乙酸乙酯间分配,水相用乙酸乙酯萃取,合并有机相,用饱和NaCl洗涤,MgSO4干燥,真空浓缩,剩余物经硅胶色谱纯化,用甲苯/乙酸乙酯(10∶1)洗脱,得到的产品用乙醚/石油醚结晶。产量45.3g(理论量的42%)。
1H-NMR(CDCl3):δ=2.32(s,3H);2,38(s,3H);2.90(m,2H);3.30(m,2H);7.00-7.25(m,6H);8.00(d,J=9Hz,1H).
实施例Ⅱ
2,8-二甲基-5-氧代-2-苯并[a,d]环庚-1,4-二烯
将实施例Ⅰ的产物22.65g(89mmol)于环丁砜(110g)中与多磷酸(460g)于110℃加热4小时。冷却后,溶液倾入水(21)中,用乙酸乙酯萃取3次,合并有机相,水洗,用MgSO4干燥。真空浓缩,硅胶色谱纯化,用纯甲苯作洗脱液,得到的产物用乙醚/石油醚结晶。产量:21.05g(理论量的100%)
1H-NMR(CDCl3):δ=2.35(s,6H),3.12(s,4H);7.00(s,2H);7.12(d,J=8Hz,2H);7.98(d,J=8Hz,2H).
实施例Ⅲ
2,8-二甲基-5-氧代-二苯并[a,d]环庚-1,4,6-三烯
将21g(88.9mmol)实施例Ⅱ的产物溶解于450ml四氯化碳中,于55℃下和在250W照相灯光照射下,与19g(107mmol)N-溴代琥珀酰亚胺反应7小时。冷却后过滤,滤液真空浓缩,剩余物溶解于70ml DMF中,溶液加热到80℃,于此温度下加入13.25g(107mmol)DBN,15分钟后,冷却此混合物,加入水及乙醚使其分配,水相用乙醚萃取1次,合并有机相,用1N盐酸洗涤3次。水洗涤2次,MgSO4干燥,真空浓缩。剩余物用乙醚/石油醚结晶。得产物11.4g,母液经硅胶色谱并用纯甲苯洗脱,又得2.2g产物。产量13.6g(理论量的65%)。
1H-NMR(CDCl3)δ=2.46(s,6H);6.95(s,2H);7.32(s,2H);7.36(d,J=8Hz,2H);8.19(d,J=8Hz,2H).
实施例Ⅳ
2,8-二(溴甲基)-5-氧代-二苯并[a,d]环庚-1,4,6-三烯
将39.8g(170mmol)实施例Ⅲ的产物和N-溴代琥珀酰亚胺于1.51四氯化碳中加热回流大约4小时,同时用250W照相灯光照射。用TLC检测,当看到在原料、一溴和二溴化合物以及副产物的混合物中,二溴化合物是主要成分时,停止反应,趁热吸滤出不溶物,用四氯化碳洗涤。该固定物用二氯甲烷重结晶,得20g产物,其中混有琥珀酰亚胺,开始的滤液与重结晶母液合并后,真空浓缩,剩余物经硅胶色谱,用纯甲苯洗脱。得到12g产物和17g-溴化合物。该一溴化合物按上述方法精确地同N-溴代琥珀酰亚胺(11.6g,65mmol)反应,又得到所需的二溴化合物8.6g。产量40.6g(65.5%)。
1H-NMR(CDCl3):δ=4.56(s,4H);7.03(s,2H);7.53(s,2H);7.57(d,J=8Hz,2H);8.20(d,J=8Hz,2H).
实施例Ⅴ
2,8-二(叠氮甲基)-5-氧代-二苯并[a,d]环庚-1,4,6-三烯
将36.5g(93mmol)实施例Ⅳ的产物悬浮于250ml DMSO中,然后于室温下与叠氮化锂(13.7g,280mmlo)混合,10分钟后固体完全溶解。30分钟后进行处理。为此,加入乙酸乙酯和饱和NaCl,水相用乙酸乙酯萃取,合并有机相,用饱和NaCl洗涤3次,MgSO4干燥,浓缩不要完全干(室温真空下),浓缩液与石油醚混合,吸滤出得到的固体,母液浓缩,剩余物经硅胶色谱纯化,洗脱液为甲苯/乙酸乙酯(10∶1),又得到本标题化合物3.6g。产量18.75g(收率63.5%)。
1H-NMR(CDCl3)∶δ=4.50(s,6H);7.08(s,2H);7.48(m,4H);8.24(d,J=8Hz,2H).
实施例Ⅵ
2,8-二(苯甲氧羰基氨甲基)-5-氧代-二苯并[a,d]环庚-1,4,6-三烯
将45ml水和29.5g(112.3mmol)三苯膦加到实施例Ⅴ的产物(18.75g;51.1mmlo)于THF(700ml)的溶液中,室温搅拌过夜。真空浓缩混合物,加入二氯甲烷,分出水层,有机相经MgSO4干燥,真空浓缩,高真空彻底干燥。将得到的二胺粗品溶解于1升二氯甲烷中,于-5℃下相继加入33.3g(330mmol)三乙胺和37.5g(220mmol)苄氧基甲酰氯,混合物于室温下搅拌3.5小时。用1升二氯甲烷稀释混合物,用水萃取1次,然后吸滤以除去固体并弃去。水相用二氯甲烷萃取,合并有机相,用饱和NaHCO3溶液洗涤,MgSO4干燥。真空浓缩至大约300ml,吸滤出剩下的胶冻状固体,完全浓缩母液,并经硅胶色谱纯化,洗脱液为甲苯/乙酸乙酯(2∶1)。将含有产物的组分浓缩后与前面得到的胶冻状物合并,溶解于热的二氯甲烷/甲醇(1∶1)中,加入200ml乙酸乙酯和200ml甲苯,混合物浓缩至大约100ml。此时析出容易过滤的沉淀,过滤得到11.5g产物(理论量的42%)。
1H-NMR(DMSO-d6):δ=4,39(d,J=7Hz,4H),5.00(s,4H);7.10(s,2H);7.30(m,10H);7.45(d,J=8Hz,2H);7.51(s,2H);7.91(t,J=7Hz,2H);8.03(d,J=8Hz,2H).
实施例Ⅶ
2,8-二(苯甲氧基羰基氨甲基)-10,11-二溴-5-氧代-二苯并[a,d]环庚-1,4-二烯
将10g(18.8mmol)实施例Ⅵ的产物与6g(38mmol)溴素在600ml二氯甲烷和200ml冰乙酸中避光搅拌过夜。混合物真空浓缩,剩余物用硅胶色谱纯化,洗脱液为甲苯/乙酸乙酯/甲酸(5∶1∶0.02)。产量11.0g(理论量的84.5%)。
1H-NMR(DMSO-d5)∶δ=4.30(d,J=7Hz,4H);5.08(s,4H);6.12(s,2H);7.35(m,12H);7.95(m,4H).
制备实施例
实施例1,2和3
(反式)-2,8-二(苯甲氧基羰基氨甲基)-10,11-二(乙酰氧基)-5-氧代-二苯并[a,d]环庚-1,4-二烯
(顺式)-10-乙酰氧基-2,8-二(苯甲氧基羰基氨甲基)-11-羟基-5-氧代-二苯并[a,d]环庚-1,4-二烯
(顺式)-11-乙酰氧基-5-羟基-2,8-二(苯甲氧基羰基氨甲基)-二苯并[b,e]双环-[2.1.3]1-氧杂辛烷
将2.44g(3.53mmol)实施例Ⅶ的产物与1.77g(10.6mmol)乙酸银在无水乙酸(100ml;由150ml乙酸和10ml乙酸酐加热回流3小时制得)中维持回流3小时。然后冷却混合物并滤除固体,滤液真空浓缩,剩余物用硅胶色谱纯化,先用甲苯/乙酸乙酯(2∶1)洗脱,洗脱的产物是反式化合物(实施例1);然后用乙酸乙酯/丙酮(1∶1)洗脱,产物是顺式化合物(实施例2)。
实施例1
得量:1.57g(理论量的68.5%)
1H-NMR(DMSO-d6)∶δ=1.82(s,6H);4.28(d,J=7Hz,4H);5.05(s,4H);6.21(s,2H);7.35(m,14H),7.82(d,J=8Hz,2H);7.95(t,J=7Hz,2H).
实施例2
得量:0.43g(理论量的20%)
1H-NMR(DMSO-d6)∶δ=2.02(s,3H);4.29(d,J=7Hz,4H);5.06(m,5H);6.12(s,1H);6.19(d,J=5Hz,1H);7.31(m,13H);7.50(s,1H);7.73(d,J=8Hz,1H);7.79(d,J=8Hz,1H);7.96(t,J=7Hz,2H).
实施例3化合物(11%)与实施例2化合物(89%)呈平衡状态,这也可由1H-NMR看到,其特征信号为:
1H-NMR(DMSO-d6)∶δ=4.10(d,J=2Hz,2H);4.19(d,J=7Hz,2H);5.42(s,1H);7.00-7.25(m,6H).
实施例4
(反式)-2,8-二(苯甲氧基羰基氨甲基)-10,11-二羟基-5-氧代-二苯并[a,d]环庚-1,4-二烯
将0.1N NaOH(126ml)加到1.8g(2.76mmol)实施例1化合物180ml乙醇溶液中,混合物于室温搅拌1小时。然后于真空下蒸发乙醇,水相用乙酸乙酯萃取3次,合并有机相,用饱和NaCl液洗涤,MgSO4干燥,真空浓缩,剩余物与二氯甲烷一起搅拌,吸滤析出的固体1.38g)。母液浓缩后,经硅胶色谱纯化,洗脱液是甲苯/乙酸乙酯,先用1∶1,然后1∶2,又得到0.18g产物。
MS(FAB)∶567(M++H,100%)
1H-NMR(DMSO-d6)∶δ=4.26(d,J=7Hz,4H);4.86(m,2H);5.08(s,4H);5.82(m,2H);7.23(d,J=8Hz,2H);7.25(s,2H);7.32(s,10H);7.65(d,J=8Hz,2H);7.93(t,J=7Hz,2H).
除94%的实施例4化合物外,类似于实施例3从1H-NMR也可看到有6%的异构的半缩醛。其特征峰是:
1H-NMR(DMSO-d6)∶δ=4.10(d,J=7Hz,2H);4.17(dm,J=7Hz,2H);5.02(m,1H);5.22(d,J=6Hz,1H);5.76(d,J=5Hz,1H);7.80(s,1H,OH).
实施例5
(顺式)-2,8-二(苯甲氧基羰基氨甲基)-10,11-二羟基-5-氧代-二苯并[a,d]环庚-1,4-二烯
按照类似于实施例4所述的方法,由实施例2的化合物制备了本化合物。收率:81%。
1H-NMR(DMSO-d6)∶δ=4.28(d,J=7Hz,4H);4.89(d,J=6Hz,2H);5.07(s,4H);5.70(d,J=6Hz,2H);7.23(d,J=8Hz,2H);7.32(s,10H);7.50(s,2H);7.73(d,J=8Hz,2H);7.94(t,J=7Hz,2H).
除91%的实施例4化合物外,从1H-NMR中可以看到9%的类似于实施例3的异构的半缩醛,其特征信号为:
1H-NMR(DMSO-d6):δ=4.10(d,J=7Hz,2H);4.17(d,J=7Hz,2H);5.02(m,1H);5.28(s,1H);7.86(s,1H,OH).
实施例6
(反式)-10,11-二羟基-2,8-二-[5,5-二甲基-4,4-二氧代-2-(1-萘甲基)-4-硫杂己酰氨基甲基]-5-氧代-二苯并[a,d]环庚-1,4-二烯
将200mg(0.35mmol)实施例4的化合物于100ml甲醇中和在10%Pd/C(400mg)存在下于1巴氢压下氢化3.5小时。然后滤除催化剂,滤液真空浓缩。将95mg(0.70mmol)HOBT和160mg(0.78mmol)DCC加到冷却下的235mg(0.70mmol)5,5-二甲基-4,4-二氧代-2-(1-萘甲基)-4-硫代己酸的THF(4ml)溶液中。在室温下搅拌此混合物1小时,然后将其加到前面氢化的二胺粗品的二氯甲烷(2ml)溶液中。混合物于室温下搅拌5小时,用150ml乙酸乙酯稀释,溶液用4%乙酸(25ml)、饱和NaHCO3和饱和NaCl洗涤,然后用MgSO4干燥,真空浓缩。剩余物经硅胶色谱纯化,洗脱液为乙酸乙酯/丙酮,先用5∶1,然后用5∶2,胶冻状产物于二氯甲烷中研磨,得到结晶,母液浓缩后,溶解于丙酮/甲醇中,加入乙醚,放于冰箱中结晶,又得到部分产物。得量46mg(理论量的14%)。
1H-NMR(DMSO-d6)∶δ=1,24(s,9H);3.10(dd,J=14Hz and 3Hz,2H);3.35(m,6H);3.59(dd,J=14 Hz and 6Hz,2H);4.16(dd,J=16 and 5 Hz,2H);4.30(dd,J=16Hz and 5Hz,2H),4.82(m,2H);5.71(m,2H);6.88(d,J=8Hz,2H);7.21(s,2H);7.30-7.60(m,10H),7.83(d,J=8Hz,2H);7.95(d,J=8Hz,2H);8.24(d,J=7Hz,2H);8.64(t,J=5Hz,2H).
按类似于实施例6所述的方法制备了表1中列出的化合物:
实施例11
(反式)-10,11-二(叔丁基-二甲基甲硅烷氧基)-2,8-二(苯甲氧基羰基氨甲基)-5-氧代-二苯并[a,d]环庚-1,4-二烯
将1.9g咪唑(28.4mmol)和叔丁基二甲基甲硅烷基氯(2.35g,15.6mmol)于室温下加到4g(7.1mmol)实施例4化合物中,然后于50℃搅拌此混合物2.5小时。用乙酸乙酯稀释该混合物,用水洗涤,然后用1N盐酸洗涤2次,并用饱和NaCl洗涤,MgSO4干燥,真空干燥,剩余物用硅胶色谱纯化,洗脱液为甲苯-乙酸乙酯(10∶1)。收量5.1g(理论量的90.5%)。
1H-NMR(CDCl3)∶δ=0.19(s,6H),0.07(s,6H);0.61(s,18H),4.42(d,J=6Hz,4H);4.93(s,2H);5.04(t,br,J=6Hz,2H);5.15(s,4H);7.15(s,2H);7.24(m,2H);7.35(m,10H);7.89(d,J=8Hz,2H).
实施例12
(反式)-10,11-二羟基-2,8-二[甲基(苯甲氧基羰基)氨基甲基]-5-氧代-二苯并[a,d]环庚-1,4,6-三烯
将35%氢化钾混悬液(11.3mg,0.283mmol)和48mg(0.34mmol)碘甲烷加到冰冷却下的90mg(0.113mmol)实施例11化合物和9ml DMF构成的溶液中。同温下搅拌15分钟后,将混合物于乙酸乙酯和1N盐酸中分配,水相用乙酸乙酯萃取,合并有机相,用饱和NaCl洗涤,MgSO4干燥,真空浓缩,剩余物经硅胶色谱纯化,洗脱液为甲苯/乙酸乙酯(10∶1),得到48mg中间体,后者用常规除去甲硅烷基的方法除掉甲硅烷基保护基(n-Bu4NF,THF,室温)。产量:22mg(理论量的33%)。
1H-NMR(CDCl3):δ=3.86 and 3.92(2s,6H),4.52(s,4H);4.90(br,2H);5.17(s,4H);7.20-7.40(m,14H);7.46 7.58(2br,2H);7.84(d,J=8Hz,2H).
Claims (5)
1、通式(Ⅰ)的5-氧代-二苯并[a,d]环庚-1,4-二烯和其半缩醛形式(当R5或R6为氢时)及其盐
式中
R1和R3是相同或不相同的,并代表氨基保护基或式R7-CO的基团,其中
R7代表氢、三氟甲基、或具有多至8个碳原子的直链或支链烷氧基、或多至18个碳原子的直链或支链烷基,所述的烷基可任选地被相同或不同的、含6到10个碳原子的芳基或吡啶基取代两次;或者R7代表含6-10个碳原子的芳基,所述芳基可任选地被卤素、三氟基或含多至8个碳原子的直链或支链烷基取代;或者R7代表有3-7个碳原子的环烷基,或代表喹啉基、喹啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基,或代表如下列各式的基团:
其中
R8代表苯基或萘基,
R9、R10和R11各自独立地代表多至14个碳原子的直链或支链烷基,该烷基上可任意地被苯基或萘基取代;或代表有6-10个碳原子的芳基,该芳基可被多至4个碳原子的烷基取代,或者R10代表下式的基团:
m为0,1或2,
T代表吗啉代或环己基,
P为1,2或3,Y和Y′各自独立地代表CO-或SO2-,t为0或1,
R12和R13各自独立地代表羟基,或多至8个碳原子的烷氧基,
S为1或2;
R2和R4可相同或不同,并代表氢、或有多至8个碳原子的直链或支链的烷基;
R5和R6可相同或不同,代表氢或有多至8个碳原子的直链或支链酰基或烷氧羰基,或代表羟基保护基。
2、按照权利要求1的式(Ⅰ)化合物,其中,
R1和R2可相同或不相同,并代表苄氧羰基、4-甲氧基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、2-硝基苄氧羰基、基-9-甲氧羰基或2,2,2-三氟乙酰基,或代表式R7-CO-基团,其中
R7代表氢、三氟甲基、或有多至4个碳原子的直链或支链烷氧基、有多至16个碳原子的直链或支链烷基,所述基团可任选地被相同或不相同的苯基、萘基或吡啶基取代两次;或者R7代表苯基或萘基,所述基团可任选地被氟、氯、三氟甲基、三氟甲氧基或有多至6个碳原子的直链或支链烷基取代;或者R7代表环丙基、环戊基、环己基、喹啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基;或者R7代表下列各式的基团:
其中
Y为CO或SO2基,
R8为苯基或萘基,
R9、R10和R11各自独立为有多至8个碳原子的直链或支链烷基、甲苯基、苯基或萘基,或者R10为下式基团:
m为1或2;
R2和R4可相同或不相同,并代表氢或有多至6个碳原子的直链或支链烷基;
R5和R6可相同或不相同,并代表氢或有多至6个碳原子的直链或支链酰基或烷氧羰基;或代表三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基、苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基或三氯乙酰基;
以及上述化合物的半缩醛形式(当R5或R6为氢时)和它们的盐。
3、按照权利要求1的通式(Ⅰ)化合物,其中
R1和R3可相同或不相同,并代表苄氧羰基、4-甲氧基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、2-硝基苄氧羰基、芴基-9-甲氧羰基或2,2,2-三氯乙酰基;或代表式R7-CO-基团,其中R7为氢、三氟甲基、或有多至4个碳的直链或支链烷氧基和有多至14个碳原子的直链或支链烷基,所述基团可任选地被苯基、萘基或吡啶基取代两次;R7或者为苯基或萘基,所述基团可任选地被氟、氯、三氟甲基、三氟甲氧基、或有多至4个碳原子的直链或支链烷基取代;R7或者为环丙基、环戊基、环己基、喹啉基、啉啉基N-氧化物、吲哚基、吡啶基、吗啉代或哌嗪基,或者R7为下式的基团
其中
Y代表CO或SO2基,
R8代表苯基或萘基,
R9和R10相互独立代表有多至4个碳原子的直链或支链烷基、甲苯基、苯基或萘基,或者
R10代表下式的基团:
R2和R4可相同或不相同,并代表氢、有多至4个碳原子的直链或支链烷基;
R5和R5可相同或不相同,并代表氢或有多至4个碳原子的直链或支链的酰基或烷氧羰基;或者代表三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基-二甲基甲硅烷基、三苯基甲硅烷基、苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧基苄氧羰基、甲酰基、乙酰基或三氯乙酰基;以及上述化合物的半缩醛形式(当R5或R6为氢时)和它们的盐。
5、含有一种或多种权利要求1到3的化合物的药物。
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DE4232173A DE4232173A1 (de) | 1992-09-25 | 1992-09-25 | 5-Oxo-dibenzo(a,d)cyclohepta-1,4-diene |
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CN (1) | CN1086809A (zh) |
AT (1) | ATE150450T1 (zh) |
AU (1) | AU659337B2 (zh) |
CA (1) | CA2106892A1 (zh) |
DE (2) | DE4232173A1 (zh) |
DK (1) | DK0589322T3 (zh) |
ES (1) | ES2099879T3 (zh) |
GR (1) | GR3023196T3 (zh) |
HU (2) | HUT65291A (zh) |
IL (1) | IL107068A (zh) |
MX (1) | MX9305773A (zh) |
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WO2015188309A1 (zh) * | 2014-06-10 | 2015-12-17 | 华东理工大学 | 6,7,8,9-四氢-5h-苯并[7]轮烯-2-烷基胺类化合物及其用途 |
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USRE37781E1 (en) | 1991-10-11 | 2002-07-02 | Dupont Pharmaceuticals Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
BR9306058A (pt) | 1992-03-11 | 1997-11-18 | Narhex Ltd | Derivados de amina de hidrocarbonetos oxo- e hidroxi- substituidos |
US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
MXPA93002392A (es) | 1992-03-11 | 2005-02-04 | Narhex Ltd | Derivados amino de hidrocarburos-oxo e hidroxi-substituidos. |
US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
US5705524A (en) * | 1994-11-04 | 1998-01-06 | Gilead Sciences, Inc. | Thiepane compounds |
US6034118A (en) * | 1994-11-04 | 2000-03-07 | Gilead Sciences, Inc. | Thiepane compounds |
US6169911B1 (en) | 1997-09-26 | 2001-01-02 | Sun Microsystems, Inc. | Graphical user interface for a portable telephone |
US6313110B1 (en) | 1999-06-02 | 2001-11-06 | Dupont Pharmaceuticals Company | Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor |
DE10238818A1 (de) | 2002-08-23 | 2004-03-04 | Wacker-Chemie Gmbh | Cyclodextrinreste aufweisende Organosiliciumverbindungen |
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US3401192A (en) * | 1962-07-17 | 1968-09-10 | Merck & Co Inc | Esters of 5h-dibenzo [a, d] cycloheptene |
US3264342A (en) * | 1963-05-24 | 1966-08-02 | Geigy Chem Corp | Derivatives of 5h-dibenzo[a, d] cycloheptene |
US3390179A (en) * | 1963-07-22 | 1968-06-25 | Merck & Co Inc | Novel 10, 11-dihydro-10, 11-dihydroxy-(3-substituted aminopropylidene)-5h-dibenzo [a, d] cycloheptenes |
US3403157A (en) * | 1965-09-01 | 1968-09-24 | American Home Prod | Benzo[6, 7]cyclohepta[1, 2, 3-d, e]isoquinoline derivatives |
US3436402A (en) * | 1966-03-11 | 1969-04-01 | Lilly Co Eli | 1,1 diaryl-2-propynyl carbamates |
US3513201A (en) * | 1966-10-25 | 1970-05-19 | Merck & Co Inc | Process for preparing 5-(3-alkylaminopropyl)-5h-dibenzo(a,d)cycloheptenes |
US3911017A (en) * | 1969-04-04 | 1975-10-07 | Sandoz Ag | 5-Aminomethyl-5H-dibenzo{8 a,d{9 cycloheptenes |
US3992445A (en) * | 1972-08-25 | 1976-11-16 | Merck & Co., Inc. | 5-Formamidomethyl-5H-dibenzo[a,d]cycloheptene derivatives |
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US3994961A (en) * | 1973-07-30 | 1976-11-30 | Sandoz, Inc. | 10-(2-Substituted-amino-ethyl)-10,11-dihydro-5-methylene-5H-debenzo[a,d]cycloheptenes |
US4317910A (en) * | 1978-03-20 | 1982-03-02 | E. R. Squibb & Sons, Inc. | Benzo-cyclitolamines |
US4596892A (en) * | 1982-08-19 | 1986-06-24 | Fmc Corporation | Methanamine intermediates to insecticidal 2,2'-bridged [1,1'-biphenyl]-3-ylmethyl carboxamides |
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- 1992-09-25 DE DE4232173A patent/DE4232173A1/de not_active Withdrawn
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WO2015188309A1 (zh) * | 2014-06-10 | 2015-12-17 | 华东理工大学 | 6,7,8,9-四氢-5h-苯并[7]轮烯-2-烷基胺类化合物及其用途 |
CN106414392A (zh) * | 2014-06-10 | 2017-02-15 | 华东理工大学 | 6,7,8,9‑四氢‑5h‑苯并[7]轮烯‑2‑烷基胺类化合物及其用途 |
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DK0589322T3 (da) | 1997-09-22 |
US5457108A (en) | 1995-10-10 |
HU9302706D0 (en) | 1993-12-28 |
MX9305773A (es) | 1994-05-31 |
DE59305855D1 (de) | 1997-04-24 |
NZ248737A (en) | 1995-07-26 |
EP0589322A1 (de) | 1994-03-30 |
ZA937077B (en) | 1994-04-18 |
JPH06239827A (ja) | 1994-08-30 |
ATE150450T1 (de) | 1997-04-15 |
CA2106892A1 (en) | 1994-03-26 |
KR940006996A (ko) | 1994-04-26 |
HUT65291A (en) | 1994-05-02 |
GR3023196T3 (en) | 1997-07-30 |
AU4493093A (en) | 1994-03-31 |
ES2099879T3 (es) | 1997-06-01 |
AU659337B2 (en) | 1995-05-11 |
IL107068A (en) | 1997-07-13 |
HU211175A9 (en) | 1995-11-28 |
EP0589322B1 (de) | 1997-03-19 |
TW278071B (zh) | 1996-06-11 |
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