CN1031058C - 制备抗病毒用四氢咪唑并苯并二氮杂䓬酮类化合物的方法 - Google Patents
制备抗病毒用四氢咪唑并苯并二氮杂䓬酮类化合物的方法 Download PDFInfo
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- CN1031058C CN1031058C CN89101474A CN89101474A CN1031058C CN 1031058 C CN1031058 C CN 1031058C CN 89101474 A CN89101474 A CN 89101474A CN 89101474 A CN89101474 A CN 89101474A CN 1031058 C CN1031058 C CN 1031058C
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- methyl
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- 230000000840 anti-viral effect Effects 0.000 title abstract description 12
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- 150000001875 compounds Chemical class 0.000 claims abstract description 77
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- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000002253 acid Substances 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 27
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- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
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- HGELNBUIEDMFTL-UHFFFAOYSA-N ctk5c5249 Chemical compound C1=NC=CN2C=NC3=CC=CC1=C32 HGELNBUIEDMFTL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
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- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 5
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- 125000003368 amide group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
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- CYBAWVCMEUZAGR-UHFFFAOYSA-N N1N=CC=CC2=C1C=CC=C2.[N+](=O)(O)[O-] Chemical compound N1N=CC=CC2=C1C=CC=C2.[N+](=O)(O)[O-] CYBAWVCMEUZAGR-UHFFFAOYSA-N 0.000 claims 1
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- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
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Abstract
本发明提供了新的具有抗病毒活性的四氢咪唑并[1,4]苯并二氮杂䓬-2-酮类化合物及其制备方法。含有这些化合物作为活性成分的组合物以及通过服用所述化合物来治疗遭受病毒感染的主体的方法。
Description
在文献Eur.J.Med.Chem.1978,13,53—59中描述了三种四氢咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_类化合物,它们没有任何有用的药理学活性。本发明的化合物与之区别在于本发明化合物中的咪唑部分为氧所取代,并且所述化合物显示有重要的抗病毒活性。
本发明涉及式(I)所示的四氢咪唑〔1,4〕苯并二氮杂_—2—酮类化合物及其可药用的酸加成盐和其立体异构形式。式中,R1为氢、C1~8烷基、C3~6烯基、C3~6炔基、C1~6烷羰
基,C3-6环烷基或被芳基、羟基、氰基或C3~6环烷基取
代的C1~6烷基;
R2为氢C1~6烷基或C3~6烯基;
R3为氢、C1~6烷基;
R4为氢,被羟基、氰基、羟基羰基或C1-6烷氧羰基任意取
代的C1-6烷基,C1-6烷羰基,C3-6烯基,C3-6环烷基,
C5-6环烯基;
R5为氢、C1-6烷基或卤素,
芳基为最多被3个取代基任意取代的苯基,其中所述的取代基独立地选自C1~6烷基、卤素、羟基、C1-6烷氧基、氨基、硝基和三氟甲基。
R4为氢的式(I)化合物可以两种互变异构形式存在,虽然上式中没有明确地表示出所述的互变异构形式,但打算把它们也包括在本发明的范围内。
在上述定义中,术语卤素是氟、氯、溴和碘的通称;C1~6烷基是指含有1~6个碳原子的直链和支链的饱和烃基诸如甲基、乙基、丙基、1—甲基乙基、丁基、1—甲基丙基、2—甲基丙基、1,1—二甲基乙基戊基、己基等;C1~8烷基指C1~6烷基和其含有7个和8个碳原子的高级同系物;C3~6烯基指含有一个双键和3~6个碳原子的直链和支链烃基诸如2—丙烯基、2—丁烯基、3—丁烯基、2—甲基—2—丙烯基、戊烯基、己烯基等;C3~6炔基指含有一个叁键和3~6个碳原子的直链和支链烃基诸如2—丙炔基、2—丁炔基、3—丁炔基、戊炔基、己炔基等;C3~6环烷基指环丙基、环丁基、环戊基和环己基;C5~6环烯基指环戊烯基和环己烯基。
根据各种取代基的性质,式(I)化合物可以有几个不对称碳原子。除非另有说明,化合物的化学名称表示所有可能的立体异构体的混合物,所述的混合物包括基本分子结构表示的所有非对映异构体和对映体。每个手性中心的绝对构型可用立体化学符号R和S表示,这种R和S表示法对应于Pure Appl.Chem.1976,45,11—30中所述的规则。很明显,式(I)化合物的立体异构形式包括本发明的范围内。
式(I)化合物的纯立体异构体可用技术上已知的方法获得。非对映体可通过物理分离方法诸如选择结晶法和层析技术(如逆流分配法、液相层析法等)分离;而对映体可通过与旋光活性的酸形成的非对映体盐的选择结晶而彼此分离。如果反应立体专一地进行,那么纯的立体异构体也可由其相应的合适的起始原料的立体异构体衍生得到。
式(I)化合物具有碱性,所以可用合适的酸处理把它们转化成具有治疗活性的无毒酸加成盐,所述酸的例子有无机盐如盐酸、氢溴酸、硫酸、硝酸、磷酸等,或有机酸如乙酸、丙酸、羟乙酸、2—羟丙酸、2—氧丙酸、乙二酸、丙二酸、丁二酸、(Z)—2—丁烯二酸、(E)—2—丁烯二酸、2—羟基丁二酸、2,3—二羟基丁二酸、2—羟基—1,2,3—丙三酸、甲磺酸、乙磺酸、苯磺酸、4—甲基苯磺酸、环己烷氨基磺酸、2—羟基苯甲酸、4—氨基—2—羟基苯甲酸等。相反,用碱处理可把盐转化成游离碱。术语可药用酸加成盐也包括式(I)化合物可能形成的溶剂化物,并且该溶剂化物包括在本发明范围内。这种溶剂化物的例子有水合物、醇合物等。
较好的式(I)化合物为,其中
R1为氢、C1~8烷基、C3~6烯基、C3~6炔基、C1~6烷羰基或由芳基、羟基、氰基或C3~6环烷基取代的C1~6烷基;
R2为氢或C1~6烷基;
R4为氢,由羟基任意取代的C1~6烷基,或C1~6烷羰基。
更好的化合物有,其中
R1为C1~8烷基,C3~6烯基,C3~6炔基或由芳基、羟基、氰基或C3~6环烷基取代的C1~6烷基;
R4为氢;
R5为氢。
本发明的最好的化合物选自4,5,6,7—四氢—5—甲基—6—(2—丙烯基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;4,5,6,7—四氢—5—甲基—6—(2—甲基—2—丙烯基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;(+)—(S)-4,5,6,7—四氢—5—甲基—6—(2—丙烯基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;6—(3—丁烯基)—4,5,6,7—四氢—5—甲基咪唑〔4,5,1—jk〕〔1,4〕—苯并二氮杂_—2(1H)—酮;4,5,6,7—四氢—5—甲基—6—丙基咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;(+)—(S)—4,5,6,7—四氢—5—甲基—6—(2—甲基—2—丙烯基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;6—(环丙基甲基)—4,5,6,7—四氢—5—甲基咪唑〔4,5,1—jk〕〔1,4〕—苯并二氮杂_—2(1H)—酮—水合物;及4,5,6,7—四氢—5—甲基—6—(3—甲基—2—丁烯基)咪唑〔4,5,1—jk〕〔1,4〕—苯并二氮杂_—2(1H)—酮。
式(I)化合物一般可通过式(II)的9—氨基—2,3,4,5—四氢—1H—1,4—苯并二氮杂_与式(III)的羰基试剂(其中,L为合适的离去基团)的缩合来制备。式(II)中R1,R2,R3,R4和R5如在式(I)中所定义的。合适的式(III)羰基试剂有例如脲、碳酸二(C1~6烷基)酯、光气、氯甲酰三氯甲酯、1,1′—羰基双〔1H—咪唑〕等。所述的缩合反应可方便地在反应惰性的最好沸点较高的溶剂中通过搅拌和加热(也可以不加热)进行,所述溶剂有例如芳烃类如苯、甲苯、二甲苯等;卤代烃类如氯仿、四氯化碳、氯苯等;醚类如四氢呋喃、1,4—二氧六环、丁醚、二(2—甲氧基乙基)醚、1,2—双(2—甲氧乙氧基)乙烷等;极性非质子溶剂如N,N—二甲基甲酰胺、N,N—二甲基乙酰胺、二甲基亚砜、1—甲基—2—吡咯烷酮、吡啶、甲基吡啶、二甲吡啶、四氢噻吩的1,1—二氧化物等;或这些溶剂的混合物。然而,在一些情况下,最好在没有溶剂时加热反应物,更合适地是于反应混合物中加入碱如叔胺如三乙胺,N—(1—甲乙基)—2—丙胺、4—甲基吗啉等。
式(I—a)所示的R1为氢的式(I)化合物也可以用技术上已知的氢解法由式(I—b)的苄基化了的化合物得到,式(I—a)和(I—b)中,R2,R3,R4和R5具有上述给定的意义。所述的脱苄基反应可通过在氢气气氛中,在合适的金属催化剂存在下在适当的反应惰性溶剂中搅拌式(I—b)化合物完成。合适的溶剂有醇类如甲醇、乙醇等;羧酸酯类如乙酸乙酯;羧酸类如乙酸、丙酸等。可被提及的合适的催化剂有pd/c、pt/c等催化剂。为了防止起始原料和/或反应产物的过度氢化,合适的做法是于反应混合物中加入催化剂毒剂如噻吩。
R1不是氢的式(I)化合物(在此R1用R1-a表示,所述化合物用I—C表示)也可以用式(IV)试剂对式(I—a)的化合物N—烷基化得到。在式(IV)中,W表示合适的反应离去基团诸如卤素如氯、溴或碘;或磺酰氧基如苯磺酰氧基、4—甲基苯磺酰氧基、甲磺酰氧基等。所述的N—烷基化反应可方便地在反应惰性的溶剂中进行,所述的溶剂有,例如芳烃类如苯、甲苯、二甲苯等;低级醇类如甲醇、乙醇、1—丁醇等;酮类如丙酮、4—甲基—2—戊酮等;醚类如1,4—二氧六环、乙醚、四氢呋喃等;N,N—二甲基甲酰胺;N,N—二甲基乙酰胺;硝基苯;二甲基亚砜;1—甲基—2—吡咯烷酮等。可加入适当的碱来中和反应过程中释放出来的酸,所述碱有,例如,碱金属碳酸盐或碳酸氢盐如碳酸钠、碳酸氢钠;氢化钠;或有机碱如三乙胺或N—(1—甲乙基)—2—丙胺等。在一些情况下,加入碘化物,最好是碱金属碘化物如碘化钾是适宜的。略微提高反应温度并搅拌可以加快反应速度。
R1-a不是C3~6烯基或C3~6炔基并且与连有R1-a的氮原子相邻的R1-a中的碳原子上至少含有一个氢原子的式(I—c)化合物(在此所述基团用R1-a-1表示,所述化合物用式(I—d)表示),也可以用式R1-b=O(V)的酮或醛对式(I—a)化合物进行还原性N—烷基化反应制备。式(V)中,R1-b表示由两个偕氢原子被=0替换的R1-a1-H衍生而来的偕二价基团。所述的还原性N—烷基化反应可方便地按技术上已知的催化氢化方法在合适的反应惰性有机溶剂中通过对反应物催化氢化来进行,为了加快反应速度,可以搅拌和/或加热反应混合物。合适的溶剂有,例如水;C1~6醇如甲醇、乙醇、2—丙醇等;醚类如1,4—二氧六环等;卤代烃类如氯仿等;N,N—二甲基甲酰胺;二甲基亚砜;或这些溶剂的混合物。术语“技术上已知的催化氢化方法”是指反应在氢气气氛中和在合适催化剂如pd/c,pt/c等存在下近行。为了防止反应物和反应产物中某些功能基产生不需要的过度氢化,于反应混合物中加入适当的催化剂毒剂如噻吩等是有利的。或者,所述的还原性N—烷基化反应也可以按照技术上已知的还原方法,用还原剂诸如硼氢化钠、氰基硼氢化钠、甲酸或其盐(特别是其铵盐)处理搅拌着的和需要时加热着的反应混合物来进行。
R1为R1-a和R4不是氢的式(I)化合物(在此所述的R4用R4-a表示,所述的化合物用式(I—e)表示),可以通过用式(VI)试剂(其中W为上述定义的合适的反应离去基团)与R4为氢的式(I—f)化合物进行N—烷基化或N—酰基化反应而得到。所述的N—烷基化或N—酰基化反应可以按技术上已知的将胺烷基化或将胺酰基化方法进行。
在本文的所有制备中,反应产物可以从反应混合物中分离到,并且如果需要,可按技术上已知的方法进行进一步纯化。
上述制备中的一些中间体和起始原料为已知化合物,可按照技术上已知的制备它们或其相似化合物的方法制备,而一些中间体为新化合物。下文中将详细地描述一些制备方法。
式(II)中间体通常可以按技术上已知的还原硝基和酰氨基成氨基的方法从下式所示的2,3,4,5—四氢—9—硝基—1H—1,4—苯并二氮杂_—5—酮制备,式中R1,R2,R3和R5如上所定义,例如使式(VIII)中间体在反应惰性的溶剂如乙醚、四氢呋喃、1,4—二氧六环、1,2—二甲氧基乙烷等中,也可在其溶剂如芳烃类(如苯、甲苯等)存在下和提高的温度下与复合金属氢化物如氢化铝锂或氢化物如乙硼烷或氢化铝等反应。
式(VIII)中间体可以通过在合适的反应惰性溶剂中使适当取代的硝基苯(IX)与式(X)的二氨基试剂进行缩合得到,所述溶剂有,例如醇类如甲醇、乙醇、2—丙醇、1—丁醇等;芳烃类如苯、甲苯、二甲苯等;卤代烃类如氯仿、四等化碳等;醚类如四氢呋喃、1,4—二氧六环、丁醚、2—甲氧乙基醚等;酮类如丙酮、4—甲基—2—戊酮等;偶极非质子性溶剂如N,N—二甲基甲酰胺、N,N—二甲基乙酰胺、二甲亚砜等;或这些溶剂的混合物。合适的做法是将碱如碱金属或碱土金属的碳酸盐如碳酸钠、碳酸氢钠等加到反应混合物中
中间体(XI)可通过式(XII)中间体(其中R表示如C1~6烷基或芳基)的环化反应制备
a)通过在惰性气氛中和在没有溶剂的情况下加热,也可在减压条件下加热(XII);
b)通过在反应惰性溶剂例如芳烃类如甲苯、二甲苯等中,也可在提高的温度下,用双功能基催化剂如2—羟基吡啶,吡唑,1,2,4—三唑等处理(XII);或
c)通过水解酯(XII),然后用合适的酸例如氢卤酸如盐酸、硫酸、磷酸等酸或用卤化剂如亚硫酰氯等处理其相应的羧酸(R=H)。
所述的催化还原反应可方便地通过在反应惰性溶剂例如醇类(如甲醇、乙醇、丙醇等)、酯类(乙酸乙酯、乙酸丁酯等)中,在氢和合适的金属催化剂例如pd/c、阮内镍等存在下,也可在提高的温度和/或压力下搅拌起始原料进行,中间体(XIII)也可按照技术上已知的N—酰基化方法从适当保护的氨基酸(XIV)和Q为氨基或硝基的苯甲酸(XV)制备。
胺(XIX)和/或亚胺(XX)可以通过在氢和合适的金属催化剂例如pd/c、pto2等存在下还原硝基衍生物(XXI)制备。式(XXI)的酮同样也可以按照技术上已知的N—酰基化方法从2—氨基—3—硝基苯甲酸(XXII)和α—氨基酮(XXIII)制备。
式(I)化合物显示出抗病毒,并且特别是抗反转病毒性质。直到最近,反转病毒才被认为只是引起许多非人类温血动物疾病的致病物,不象病毒那样,人们早已被知道它们对温血动物和人类同样能引起许多疾病。然而,自从确立反转病毒即人体免疫缺乏病毒(HIV,也称为LAV,HTLV—III或ARV)为人类获得性免疫缺乏综合症(AIDS)的病原体以来,反转病毒感染和遭受此感染的主体的治疗已受到极大关注。HIV病毒择先感染人体T—4细胞并破坏它们或改变它们的正常功能,特别是免疫系统的协调。所以,受感染的病人的T—4细胞数目不断减少,且此出现行为异常。因此,免疫防御系统不能抵抗感染和肿瘤并且受HIV感染的主体的死亡通常是由于偶然感染如肺炎或由于癌,而非HIV感染的直接结果。与HIV感染有关的其它疾病包括血小板减少(症)、卡波济氏肉瘤和以进行性脱髓鞘为特征的、导致痴呆和诸如进行性构音障碍、共济失调和定向力障碍症状的中枢神经系统感染。此外,HIV感染还与外周神经病、进行性全身淋巴节病(PGL)和与AIDS有关的综合症(ARC)有关。式(I)化合物的抗病毒,特别是抗反转病毒和抗HIV性质,使其可能成为防治遭受病毒感染的温血动物有用的抗病毒化疗试剂。
式(I)化合物的抗反转病毒活性和细胞毒性可以用Journalof Virological Methods,1987,171—185上所述的体外抗HIV测定系统测定。50%抗病毒有效量(ED50;μg/ml)用基于台盼蓝染料排除法测定的细胞活力的细胞病理效应(CPE)得到。50%细胞毒剂量(CD50;μg/ml)用模拟感染的MT—4细胞测定。对于化合物17,22,23,25,27和33(见24~25页表),发现其CD50约为165~250μg/ml,而ED50约为8~22μg/ml,没有观察到安定和镇静活性。
由于其具有抗病毒特别是抗反转病毒的性质,所以式(I)化合物及其可药用的盐和其立体异构形式可用于治疗各种病毒特别是反转病毒感染的温血动物,或对所述的温血动物进行预防。人类反转病毒感染的例子包括HIV和HTLV—I(I型人类T—淋巴性病毒),它们引起白血病和淋巴瘤。作为非人类动物反转病毒感染可被提及的例子为FeLV(猫白血病病毒),它引起白血病和免疫缺乏症。本发明的化合物可防治的疾病,特别是与HIV和其它病原性反转病毒有关的疾病,包括爱滋病(AIDS)、与AIDS有关的综合症(ARC)、进行性全身淋巴结病(PGL)以及由反转病毒引起的慢性CNS疾病如HIV介入的痴呆(脑脊髓)多发性硬化。
鉴于其抗病毒特别是抗反转病毒活性,可以把目的化合物配制成各种可供服用的药物形式。为了制备本发明的药物组合物,将有效量的处于碱或酸加成盐形式的特定化合物作为活性成分与可药用载体制成紧密混合物,所述载体可为各种形式,这取决于给药所需的制剂形式。这些药物组合物可按需要制成合适的单位剂量形式,最好可供口服给药、直肠给药、皮下给药或肠道外注射用的形式。例如,在制备口服剂量形式组合物时,可以使用任何常规的药物载体。例如,对于口服液制剂如悬浮液、糖浆、酏剂和溶液等,可使用水、二醇类、油类、醇类等;对于粉剂、丸剂、胶囊和片剂,可使用固体载体和淀粉、糖、高岭土、润滑剂、粘结剂、分散剂等。由于易于服用,片剂和胶囊为最有利的口服剂量单位形式,在此情况下,显然使用的是固体药物载体。对于肠道外给药的组合物,载体通常含有无菌水(至少大部分),虽然也含有其它成分如助溶性成分。例如,可以配制成注射液,其中载体有盐水、葡萄糖溶液或盐水和葡萄糖溶液混合物。也可以配制成可注射悬浮液,这种情况下可以使用合适的液体载体、悬浮剂等。对于适于皮下给药的组合物,其中载体可任意地含有渗透增强剂和/或合适的湿润剂,它们可以不受限制地与任何性质的少量合适的添加剂结合,其中添加剂不对皮肤引起严重的有害影响。所述添加剂可促进皮肤给药和/或有助于制备所需的组合物。这些组合物可以各种方式给药,例如作为皮用膏药、点剂(Spot—on)、软膏给药。式(I)化合物的酸加成盐由于其比相应碱的水溶解度大,显然更适于制备组合物水溶液。由于易于服用和剂量均一,把药物组合物配制成剂量单位形式。本说明书和权利要求书中所用的“剂量单位形式”是指适于作为一个剂量的物理上不连续的单位,每一单位含有与所需的药物载体结合的预定量的活性成分,该量是根据产生所需治疗效果计算的。这种剂量单位形式的例子有片剂(包括片核或包衣片)、胶囊、丸剂、散剂、糯米纸囊剂、注射液或注射悬浮液、茶匙、食匙等及其整倍数。
本发明也涉及治疗遭受所述病毒性疾病的温血动物的病毒性疾病的方法,即使之服用抗病毒有效量的式(I)化合物或其可药用的酸加成盐或其立体异构形式。治疗病毒性疾病的技术人员能够容易地根据本发明中的结果确定抗病毒的有效量。一般地,期望有效量为每公斤体重为0.1~200mg,最好为每公斤体重1~50mg。合适的做法是把所需的剂量在金天内按适当的间隔以2,3,4或多个分剂量给药。可把所述的分剂量配制成剂量单位形式,例如每单位剂量形式含1~1000mg,特别是5~200mg活性成分。
下述实施例是用于说明本发明的各个方面,而不是限制本发明的范围。除非另有说明,所有份数都以重量计。A)中间体的制备实施例1
a)将2.6份2—溴—3—硝基苯甲酸甲酯,1.75份N—〔(2—氨基—1—甲基)乙基〕苯甲基胺和1.06份碳酸钠在8份1—丁醇中的溶液搅拌回流30分钟。蒸发溶剂。于残留物中加入20份水并用30份氯仿提取产物两次。将合并的提取物干燥、过滤并蒸发。接通常的方式由油状游离碱制备其盐酸盐。过滤,用2—丙醇洗涤并干燥,得到3.4份(89.5%)的3—硝基—2—〔〔2—甲基—2—〔(苯甲基)氨基〕乙基〕氨基〕苯甲酸甲酯盐酸盐;mp.204℃(中间体1)。
b)将3.8份中间体1,15份2N氢氧化钠溶液和4份2—丙醇的混合物搅拌回流1小时。然后于煮沸的反应混合物中加入3份浓盐酸和5份水的溶液。冷却后,产物沉淀,过滤用水洗涤,经80份冰乙酸重结晶,得到3份(82%)的3—硝基—2—〔〔〔2—〔(苯甲基)氨基〕—2—甲基〕乙基〕氨基〕苯甲酸;M.P.227℃(中间体2)。
c)将189.3份中间体2,400份亚硫酰氯和400份甲苯的混合物搅拌回流2小时,蒸发溶剂后将残留物溶于600份甲苯中。用碳酸氢钠溶液处理。将分离出的有机层用无水碳酸钠干燥,过滤并浓缩至约500份体积。室温放置后,部分产物沉淀。过滤(滤液单放),连续地用2—丙醇和乙醚洗涤、干燥,得到123.5份2,3,4,5—四氢—3—甲基—9—硝基—4—(苯甲基)—1H—1,4—苯并二氮杂_—5—酮粗品(第一部分)。蒸除母液中的溶剂。将残留物溶于160份煮沸的2—丙醇并在室温下结晶。过滤沉淀的产物,连续地用2—丙醇和乙醚洗涤,干燥,得到第二部分纯度较低的28份2,3,4,5—四氢—3—甲基—9—硝基—4—(苯甲基)—1H—1,4—苯并二氮杂_—5—酮。两部分粗产物都用乙醇重结晶,得到137份(85%)2,3,4,5—四氢—3—甲基—9—硝基—4—(苯甲基)—1H—1,4—苯并二氮杂_—5—酮;m.p.125℃(中间体3)
d)征搅拌回流下,于14份氢化铝锂在40份苯和50份四氢呋喃中的悬浮液中加入20.2份中间体3在200份四氢呋喃中的溶液,继续搅拌回流2.5小时。将反应混合物用碎冰冷却,并连续地加入水、15%氢氧化钠溶液及水分解。过滤无机物并蒸发滤液,于残留物中加入40份甲苯,并将该溶液蒸发至干,得到19.8份(87.6%)红色油状的9—氨基—2,3,4,5—四氢—3—甲基—4—(苯甲基)—1H—1,4—苯并二氮杂_—5—酮(中间体4),无需进一步纯化即可用于下一步制备中。实施例2
a)在氢气气氛下,于9.10份2—氨基—3—硝基苯甲酸,6.95份(L)—2—氨基丙酸甲酯盐酸盐,13.50份1—羟基—1H—苯并三唑水合物和180份四氢呋喃的搅拌着的冷却(-12℃)混合物中加入5.05份4—甲基吗啉。搅拌5分钟后,于该混合物中加入10.30份N,N—二环己基碳化二亚胺。5.5小时后,使混合物升至室温并搅拌16小时。在℃时冷却混合物30分钟,然后过滤。减压浓缩滤液,将残留物于225份乙酸乙酯和250份饱和碳酸氢钠溶液之间进行分配。将分出的有机层用100份饱和碳酸氢钠溶液洗涤,干燥,过滤,并在真空下浓缩,得到13.08份(97.9%)(—)—(S)—2—〔(2—氨基—3—硝基苯甲酰基)氨基〕丙酸甲酯,m.p.132.9℃(中间体5)。
b)在帕尔器中,在3×105巴和室温下,将12.58份中间体5和160份乙醇的混合物用3.50份10%的Pa/c催化剂氢化4小时。通过硅藻土滤掉催化剂,减压浓缩滤液。在3.3×103巴压力下将油状残留物置于150℃的油浴中,搅拌下将温度维持在200℃达40分钟。冷却后,过滤沉淀产物并用12份乙醇研制。过滤产物,用少量冷乙醇和乙醚洗涤,干燥,得到5.58份(57.5%)(+)—(S)—9—氨基—2,3—二氢—3—甲基—1H—1,4—苯并二氮杂_—2,5—(4H)—二酮(中间体6)。实施例3
a)于11.32份N,N—二环己基碳化二亚胺在45份四氢呋喃中的搅拌液中先加入10份2—氨基—3—硝基苯甲酸和7.42份1—羟基—1H—苯并三唑水合物在180份四氢呋喃中的溶液,然后加入5.55份4—甲基吗啉在45份四氢呋喃中的溶液。在氮气气氛下于得到的混合物中加入6份1—氨基—2—丙酮盐酸盐在47份N,N—二甲基甲酰胺中的溶液并搅拌22小时。加入另外的1.5份1—氨基—2—丙酮盐酸盐和1.4份4—甲基吗啉。搅拌24小时后,再加入1.5份1—氨基—2—丙酮盐酸盐和4—甲基吗啉。反应3天(总反应时间)后,过滤,浓缩滤液。残留物溶于二氯甲烷中,有机层连续地用水饱和碳酸氢钠溶液和氯化钠溶液洗涤两遍,干燥、过滤并蒸发。残留物用乙醇结晶,得到8.34份(63.9%)2—氨基—3—硝基—N—(2—氧丙基)苯甲酰胺(中间体7)。
b)在帕尔器中于3.5×105巴压力下,将7.2份中间体7和120份乙醇的混合物用1.7份10%pd/c催化剂氢化。计算量的氢被吸收后,通过硅藻土滤除催化剂,用二氯甲烷洗涤,浓缩滤液,得到5.5份(96.9%)的9—氨基—3,4—二氢—2—甲基—5H—1,4—苯并二氮杂_—5—酮(中间体8)。
B)最终产物的制备实施例4
将19.8份中间体4和7.2份脲的混合物加热至210~220℃,直至发泡并且不再有氨气放出(约10分钟)。将反应物冷却至约100℃并与120份1N的盐酸溶液一起煮沸。倾析,使溶液与油状残留物分离,活性炭处理后过滤。冷却滤液,用氨水碱化,并用75份氯仿和150份氯仿各提取一次。将合并的提取液干燥并蒸发。残留物用24份2—丙醇研制,过滤,再先后用乙醇和4—甲基—2—戊酮重结晶,得到2.5份(11.5%)4,5,6,7—四氢—5—甲基—6—(苯甲基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮,m.p.205℃(化合物14)。实施例5
在约38℃下,将8份化合物14和1份10%pd/c催化剂在80份冰乙酸中的混合物进行氢化,计算量的氢被吸收后,滤除催化剂。蒸发掉乙酸。将残留物溶于75份水中,用30份浓氨水碱化该溶液。在室温下结晶产物,过滤,用水洗涤;经20份2—丙醇重结晶,得到3.7份(66.8%)4,5,6,7—四氢—5—甲基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;m.p.190.5℃(化合物11)。实施例6
在25℃和氩气保护下,将5.0份中间体6加到5.55份氢化铝锂在154.5份1,4—二氧六环中的悬浮液中。将反应混合物回流5小时。冷却至10℃,依次加入5.55份水、9.16份15%氢氧化钠溶液和16.65份水。使整个混合物搅拌2小时后过滤。沉淀物依次用178份热四氢呋喃和133份二氯甲烷洗涤。将合并的滤液干燥、过滤并蒸发,将残留物倒入7.36份4—甲基吗啉在133份二氯甲烷中的溶液中。在0℃和氩气保护下,将整个混合物在15分钟时间内加到4.82份氯甲酸三氯甲基酯在160份二氯甲烷中的溶液中。在0℃搅拌10分钟后,将反应混合物温至室温,并蒸发浓缩。将70份15%的1,4—二氧六环的水溶液加到残留物中,在氮气保护下将混合物在蒸气浴上加热45分钟,冷却并用二氯甲烷(2×66.5份)提取。过滤水层并用浓氨水碱化。滤出沉淀,用少量冷水洗涤,干燥后用6.24份2—丙醇研制两次,得到1.59份(32.1%)(+)—(5)—4,5,6,7—四氢—5—甲基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;m.p.206.5℃(化合物12)。实施例7
将6.5份化合物11,4.65份3—溴—1—丙烯,3.85份三乙胺和少量碘化钾结晶在80份1—丁醇中的溶液搅拌回流15小时。蒸发溶剂。于残留物中加入100份水,并用氯仿提取产物两次。将合并的提取液干燥并蒸发,残留物用160份热异丙醚研制,与活性炭煮沸,过滤并浓缩滤液,用通常的方法经草酸盐纯化产物,转化成游离碱。后者先后用20份丙醚和12份2—丙醇结晶,得到2.5份(32.1%)4,5,6,7—四氢—5—甲基—6—(2—丙烯基)咪唑〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;m.p.138℃(化合物22)实施例8
于1.0份化合物11,0.816份碘化钾和0.782份碳酸钠在56.4份N,N—二甲基甲酰胺中的搅拌液中滴加0.88份4—溴—2—甲基—1—丁烯在14份N,N—二甲基甲酰胺中的溶液。于室温下搅拌22.5小时后,在~70℃真空浓缩反应混合物。残留物在130份二氯甲烷和100份水与饱和碳酸氢钠水溶液的混合物(50∶50体积)之间分配两次。用78份二氯甲烷提取合并的水层。合并二氯甲烷层并用100份饱和氯化钠溶液提取。将提取液干燥、过滤并在~40℃下真空浓缩。残留物用16份乙腈结晶两次。在0~5℃时冷却45分钟后,过滤结晶产物,用4份冷(0~5℃)乙腈洗涤,并于78℃下真空干燥过夜,得到0.805份(60.3%)(±)—4,5,6,7—四氢—5—甲基—6—(3—甲基—2—丁烯基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;m.p.158℃(化合物28)。实施例9
在氩气保护下,于1.00份化合物11,1.33份1—羟基—1H—苯并三唑和23.5份N,N—二甲基甲酰胺冷(0℃)搅拌液中加入9份冰乙酸。在0℃搅拌5分钟后,加入1.02份N,N—二环己基碳化二亚胺。继续在0℃搅拌1.5小时,在室温下搅拌2天。反应混合物在0℃冷却1小时,然后过滤。滤液蒸发浓缩,残留物溶于饱和碳酸氢钠溶液中,用二氯甲烷提取产物,提取物依次用2N柠檬酸水溶液和饱和碳酸氢钠溶液洗涤,干燥、过滤并蒸发。残留物用柱层析纯化(硅胶,二氯甲烷/甲醇97.5∶2.5).蒸发纯组分洗脱液,残留物用甲醇重结晶,在82℃时将产物真空干燥过夜,得到0.48份(39.9%)6—乙酰基—4,5,6,7—四氢—5—甲基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;m.p.294.3℃(化合物35)。实施例10
将4.2份化合物2,10份乙酸酐和10份冰乙酸的混合物搅拌回流4小时,蒸发溶剂。在冰水冷却下于残留物中加入氨水,产物用75份三氯甲烷提取三次。将合并的提取液干燥、过滤并蒸发。将固体残留物与40份甲醇振摇,再过滤,用20份2—甲氧基乙醇重结晶三次,得到2.5份1—乙酰基—6—苯甲基—4,5,6,7—四氢咪唑并〔4,5,1—jk〕〔1,4〕—苯并二氮杂_—2(1H)—酮;m.p.168—173℃(化合物3)。实施例11
搅拌5.6份化合物2和1.05份50%氢化钠分散液在64份甲苯中的混合物直至不再有氢气放出。然后搅拌回流30分钟,蒸发甲苯层。于残留液中加入3.4份碘甲烷在40份N,N—二甲基甲酰胺中的溶液。不加热时搅拌1小时后,再在50℃时搅拌15分钟。蒸发N,N—二甲基甲酰胺,于残留物中加入50份水,用75份氯仿提取产物两次。将合并的提取液干燥、过滤并蒸发。残留物溶于30份盐酸和30份水中,用50份石油英洗涤该溶液,并用活性炭处理。用氨水碱化,再用40份甲苯提取产物两次。将合并的提取液干燥、过滤并蒸发。按通常的方法从油状游离碱制备草酸盐,过滤盐粗品,用甲醇重结晶并干燥,得到2.7份6—苄基—4,5,6,7—四氢—1—甲基咪唑并〔4,5,1—jk〕〔1,4〕—苯并二氢杂_—2(1H)—酮草酸盐;m.p.200—202.5℃(化合物4)。实施例12
将4份化合物9,10份40%甲醛水溶液和40份2—丙醇的混合物搅拌回流16小时。蒸发溶剂。于残留物中加入20份4—甲基—2—戊酮,再次蒸发。然后将残留物溶于40份丙酮中,于其中加入过量的预先用HCl饱和的2—丙醇。将沉淀物滤出、干燥,并用25份水重结晶,得到3.7份4,5,6,7—四氢—1—羟甲基—6—(2—苯乙基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮盐酸盐;m.p.217.5℃(化合物10)。
按照实施例序号栏中所给实施例中的步骤制备下表中所列的所有其它化合物:
化合物序号 | 实施例编号 | R1 | R2 | R3 | R4 | 物理数据 |
12345678910111213141516171819202122232425 | 541011712712712566478888877888 | HCH2C6H5CH2C6H5CH2C6H5CH2-CH=CH2CH2-CH=CH2C7H15-nC7H15-n(CH2)2C6H5(CH2)2C6H5HHHCH2C6H5CH2)2C6H5C2H5C3H7-nC3H7-iC4H9-nC4H9-iC7H15-nCH2-CH=CH2CH2-CH=CH2CH2-CH=CH2CH2-C(CH3)=CH2 | HHHHHHHHHHCH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3 | HHHHHHHHHHHHHHHHHHHHHHHHH | HHCOCH3CH3HCH2OHHCH2OHHCH2OHHHHHHHHHHHHHHHH | mp.208-220℃HCl/mp.258.5-262℃(dec.)mp.168-173℃(COOH)2/mp.200-202.5℃HCl/mp.244.5℃HCl/mp.174℃(COOH)2/mp.220℃(COOH)2/mp.217℃mp.165.5℃HCl/mp.217.5℃mp.190.5℃(+)-(S)/mp.206.5℃(-)-(R)/mp.207.8℃mp.205℃mp.150℃mp.143.2℃mp.149.7℃mp.165.6℃mp.138.0℃0.5H2O/mp.119.7℃(COOH)2/mp.163.5℃mp.138℃(+)-(S)/mp.113.8℃(-)-(R)/mp.113.2℃mp.150.1℃ |
化合物序号 | 实施例编号 | R1 | R2 | R3 | R4 | 物理数据 |
26272829303132333435363738394041424344 | 8888888889868686868 | CH2-C(CH3)=CH2(CH2)2-CH=CH2CH2-CH=C(CH3)2CH2-CH=CH-CH3CH2-CH=CH-CH3CH2-C(CH3)=CHCH3CH2-C≡CHCH2-C3H5-cCH2-C≡NCOCH3CH2-CH2-OHHCH2-C(CH3)=CH2HCH2-C(CH3)=CH2HCH2-C(CH3)=CH2HCH2-C(CH3)=CH2 | CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3C2H5C2H5C3H7-nC3H7-nC3H7-iC3H7-iHH | HHHHHHHHHHHHHHHHHCH3CH3 | HHHHHHHHHHHHHHHHHHH | (+)-(S)/mp.152.4℃mp.107.2℃(±)/mp.158.0℃(E)/mp.127.6℃(Z)/mp.106.0℃(E)/mp.151.6℃mp.146.0℃H2O/mp.97.6℃mp.193.1℃mp.249.3℃mp.156.2℃mp.148.5℃(±)/mp.120.5℃mp.156℃mp.116℃mp.162.3℃(±)/mp.146.7℃mp.220.2℃mp.142.1℃ |
c)组合物实施例
下述制剂是举例说明呈剂量单位形式的典型的药物组合物,根据本发明,它们适于温血动物系统服用。
所有实施例中所用的“活性成分”(A.I.)是指式(I)化合物,其可药用的酸加成盐或其立体异构形式。实施例13:口腔滴剂
在60~80℃下将500g活性成分溶于0.5l 2-羟基丙酸和1.5l聚乙二醇中,当冷却至30~40℃时,加入35l聚乙二醇,并充分搅拌混合物,然后再加入1750g糖精钠在2.5l纯水中的溶液,并且在搅拌下加入2.5l可可调味香料和适量聚乙二醇至体积50l,得到含10mg/ml A.I.的口腔滴液,将得到的溶液装入合适的容器中。实施例14:口服液
将9g4—羟基苯甲酸甲酯和1份4—羟基苯甲酸丙酯溶于4l煮沸的纯水中。先后将10g 2,3—二羟基丁二酸和20g活性成份溶于3l此溶液中。将得到的后一种溶液与剩余的前一种溶液合并,再于其中加入12l 1,2,3—丙三醇和3l 70%的山梨醇溶液。将40g糖精钠溶于0.5l水中,加入2ml红莓和2ml醋粟露(gooseberry essence)。将后一种溶液与前一种合并,加入适量水至体积为20l,得到每茶匙(5ml)含5mg A.I.的口服液,将得到的溶液装入合适的容器中。实施例15:胶囊剂
将20g A.I.、6g硫酸月桂酯钠、56g淀粉、56g乳糖、0.8g胶态二氧化硅和1.2g硬脂酸镁一起剧烈搅拌。随后将得到的混合物装入1000个合适的硬明胶胶囊中,每个胶囊含20mg A.I.。实施例16:薄膜片片核制备
将100g A.I.、570g乳糖和200g蔗糖很好地混合,然后用5g十二烷基硫酸钠和10g聚乙烯吡咯烷酮(Kollidon—K90_),在约200m(水中的溶液湿化。将湿的粉状混合物过筛、干燥、再过筛,然后加入100g微晶纤维素(Avicel_)和15g氢化植物油(Sterotex_)。很好混合后压成片,得到10,000片,每个含有10mg A.I。包覆
于10g甲基纤维素(Methocel 60HG_)在75ml变性酒精中的溶液中加入5g乙基纤维素(Ethocel 22cps_)在150ml二氯甲烷中的溶液。然后加入75ml二氯甲烷和2.5ml 1,2,3—丙三醇。使10g聚乙二醇熔化并溶于75ml二氯甲烷中。将后一种溶液加到前一种中,然后加入2.5g硬脂酸镁、5g聚乙烯吡咯烷酮和30ml浓的色悬液(Opaspray K—1—2109_),并使整个混合物匀化。用包覆器给片核包覆此所得混合物。实施例17:注射液
将1.8g 4—羟基苯甲酸甲酯和0.2g 4—羟基苯甲酸丙酯溶于约0.5l煮沸的注射用水中,冷却至约50℃后,搅拌下加入4g乳酸、0.05g丙二醇和4g A.I.。将溶液冷却至室温;补加适量注射用水至体积为1l,得到每毫升含4mg A.I.的溶液。将该溶液过滤灭菌(U.S.P.XVII p.811)并装入无菌容器中。实施例18:栓剂
将3g A.I.溶于3g 2,3—二羟基丁二酸在25ml聚乙二醇400中的溶液中。将12g表面活性剂(SPAN_)和甘油三酸酯(Witepsol 555_)适量(约300g)熔化在一起。将后一种混合物与前一种溶液很好地混合。在37—38℃温度下将由此得到的混合物倒入模子中以形成每剂含有30mg A.I.的栓剂。
Claims (7)
1、制备式(I)化合物、其可药用的酸加成盐或其立体化学异构形式的方法,式中R1为氢、C1~8烷基、C3~6烯基、C3~6炔基、C1~6烷羰基
或被芳基、羟基、氰基或C3~6环烷基取代的C1~6烷基;
R2为氢或C1~6烷基;
R3为氢或C1~6烷基;
R4为氢;C1~6烷基或被羟基取代的C1~6烷基;或C1~6烷羰
基;
R5为氢、C1~6烷基或卤素,
芳基为苯基或最多被三个取代基取代的苯基,其中所述取代基独立
地选自C1~6烷基、卤素、羟基、C1~6烷氧基、氨基、硝基和
三氨甲基,
其特征在于:
a)在碱存在下,可在反应惰性的溶剂中,使式(II)所示的9-氨基—2,3,4,5—四氢—1H—1,4—苯并二氮杂_与其中L为离去基团的式L-C(=0)-L(III)所示的羰基形成试剂发生缩合反应,式中R1,R2,R3,R4和R5如在式(I)中所定义;
b)在反应惰性的溶剂中,在金属催化剂存在下和氢气气氛下对式(I—b)所示的苄基化了的化合物进行氢解,式中R2,R3,R4和R5如在式(I)中所定义,由此得到了式(I—a)化合物,式中R1为氢,R2,R3,R4和R5如在式(I)中所定义;为了制备R1不为氢的式(I)化合物,可在反应惰性溶剂中,在碱存在下,同时也可在碘化物存在下用其中W表示活性离去基团而R1-a为式(I)中定义的R1但不是氢的式R1-a-W(IV)所示的试剂对所述的式(I—a)化合物进行N—烷基化,由此得到式(I—C)化合物,式中R2,R3,R4和R5如在式(I)中所定义,R1-a如上所定义,或者,在反应惰性的有机溶剂中,使用还原剂或在催化剂存在时在氢气气氛下用式R1-b=O(V)所示的试剂对所述的式(I—a)化合物进行还原性N—烷基化,由此得到式(I—d)化合物,其中式(V)中,R1-b表示由R1-a-1—H衍生而来的偕二价基,后者有两个偕氢原子为=O所替代,而R1-a-1与R1相同,但不是氢、C3~6烯基或C3~6炔基,式中R2,R3,R4和R5如在式(I)中所定义,R1-a-1如上定义;
c)用其中W为活性离去基团、R4-a如式(I)中定义的R4,但不是氢的式R4-a-W(VI)所示的试剂对式(I—f)化合物进行N—烷基化或N—酰基化,式中R2,R3和R5如式(I)中所定义,R1-a如上所定义,R4为氢,由此得到了式(I—e)化合物,式中R2,R3和R5如式(I)中所定义,R1-a和R4-a如上所定义;并且需要时,可按技术上已知的功能基转变方法使式(I)化合物进行相互转变;
进一步需要时,可用酸处理式(I)化合物,将之转变成有治疗活性的无毒的酸加成盐;或者反过来,用碱处理酸加成盐,将之变成游离碱形式;和/或制备它们的立体异构形式。
2.根据权利要求1的方法,其中,在起始原料和制备的化合物中,R1为C1~8烷基、C3~6烯基、C3~6炔基或被芳基、羟基、氰基或C3~6环烷基取代的C1~6烷基;R4为氢;R5为氢。
3.根据权利要求1的方法,其中在起始原料中R1为丙基、2—丙烯基、3—丁烯基、环丙基甲基、2—甲基—2—丙烯基或3—甲基—2—丁烯基;R2为甲基;R3为氢;R4为氢;及R5为氢;所制得的化合物选自:
4,5,6,7—四氢—5—甲基—6—(2—丙烯基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2—(1H)—酮;
4,5,6,7—四氢—5—甲基—6—(2—甲基—2—丙烯基)咪唑并〔4,5,1—jk〕〔1,4 〕苯并二氮杂_—2(1H)—酮;
(+)—(S)—4,5,6,7—四氢—5—甲基—6—(2—丙烯基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;
6—(3—丁烯基)—4,5,6,7—四氢—5—甲基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;
4,5,6,7—四氢—5—甲基—6—丙基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;
(+)—(S)—4,5,6,7—四氢—5—甲基—6—(2—甲基—2—丙烯基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮;
6—(环丙基甲基)—4,5,6,7—四氢—5—甲基咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮—水合物;及
4,5,6,7—四氢—5—甲基—6—(3—甲基—2—丁烯基)咪唑并〔4,5,1—jk〕〔1,4〕苯并二氮杂_—2(1H)—酮。
4.根据权利要求1a)的方法,其中包括其中R1、R3和R4为氢的式(II)化合物,其酸加成盐或其立体化学异构形式的制备方法,所述化合物用式(II-a)表示:其中R2为氢、C1-6烷基或C3-6烯基;及R5为氢、C1-6烷基或卤素;所述方法的特征在于,按照技术上已知的还原酰氨基成氨基的方法,还原式(XI)苯并二氮杂_酮,式中R2和R5如在式(II-a)中所定义;或者按照技术上已知的还原硝基和酰氨基成氨基的方法,还原式(XVI)的硝基衍生物,式中R2和R5如在式(II-a)中所定义;然后,如果需要的话,用酸处理将式(II-a)化合物转化成酸加成盐;或者反过来,用碱处理将酸加成盐转化成游离碱;和/或制备其立体化学异构形式。
5.根据权利要求4的方法,其中包括下式化合物、其酸加成盐或其立体化学异构形式的制备方法,式中R2为氢、C1-6烷基或C3-6烯基;及R5为氢、C1-6烷基或囟素;所述方法的特征在于,通过下述方法使下式中间体环化,式中R2和R5如在式(XI)中所定义,R表示基团如C1-6烷基或芳基,
a)在无溶剂条件下,在惰性气氛中,以及需要时在减压下,加热(XII);
b)在反应惰性溶剂中,需要时在升高的温度下,用双官能团催化剂处理(XII);或者
c)水解式(XII)酯,然后用适当的酸或囟化试剂处理相应的酸(R=H);然后,需要的话,用酸处理,将式(XI)化合物转化成酸加成盐形式;或者反过来,用碱处理,将酸加成盐形式转化成游离碱;和/或制备其立体化学异构形式。
6.根据权利要求4的方法,其中包括下式化合物、其酸加成盐或其立体化学异构形式的制备方法,式中R2为氢、C1-6烷基或C3-6烯基;以及R5为氢、C1-6烷基或卤素;所述方法的特征在于,在浓硫酸存在下,用浓硝酸对苯并二氮杂_酮(XVII)进行硝化,式中R2和R5如在式(XVI)中所定义,然后,需要的话,用酸处理,将式(XVI)化合物转化成酸加成盐形式;或者反过来,用碱处理,将酸加成盐转化成游离碱形式;和/或制备其立体化学异构形式。
7.根据权利要求6的方法,其中包括下式化合物、其酸加成盐或其立体化学异构形式的制备方法,式中R2为氢、C1-6烷基或C3-6烯基;以及R5为氢、C1-6烷基或囟素;所述方法的特征在于,在合适的反应惰性溶剂中,在回流温度下,使适当保护的氨基酸(XIV)与中间体(XVIII)反应,式中R2和R5如在式(XVII)中所定义,R为适当的保护基,然后,需要的话,用酸处理,将式(XVII)化合物转化成酸加成盐形式;或者反过来,用碱处理,将酸加成盐转化成游离碱;和/或制备其立体化学异构形式。
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GB88.6.449 | 1988-03-18 | ||
GB88.06.449 | 1988-03-18 | ||
GB888806449A GB8806449D0 (en) | 1988-03-18 | 1988-03-18 | Antiviral hexahydroimiazo(1 4)benzodiazepin-2-ones |
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CN1036957A CN1036957A (zh) | 1989-11-08 |
CN1031058C true CN1031058C (zh) | 1996-02-21 |
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EP (1) | EP0336466B1 (zh) |
JP (1) | JP2693559B2 (zh) |
KR (1) | KR0133073B1 (zh) |
CN (1) | CN1031058C (zh) |
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FI (1) | FI89800C (zh) |
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GR (1) | GR3006728T3 (zh) |
HU (2) | HU203757B (zh) |
IE (1) | IE63108B1 (zh) |
IL (1) | IL89633A (zh) |
JO (1) | JO1589B1 (zh) |
MY (1) | MY104942A (zh) |
NO (1) | NO167737C (zh) |
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US5270464A (en) * | 1989-03-14 | 1993-12-14 | Janssen Pharmaceutica N.V. | Anti-HIV-1 tetrahydroimidazo[1,4]benzodiazepin-2-(thi) ones |
IL93136A (en) * | 1989-02-23 | 1995-01-24 | Janssen Pharmaceutica Nv | History of tetrahydroimidazo [1,4] benzodiazepine-2-thione, their preparation and pharmaceutical preparations containing them |
NZ235137A (en) * | 1989-09-13 | 1992-02-25 | Janssen Pharmaceutica Nv | Tetrahydroimidazo(1,4)benzodiazepine derivatives, preparation and pharmaceutical compositions thereof |
US5164376A (en) * | 1989-10-30 | 1992-11-17 | Hoffmann-Laroche Inc. | Method for treating retroviral infections with aryl-(2-pyrryl) keytone compound |
EP0436245A1 (en) * | 1989-12-27 | 1991-07-10 | Duphar International Research B.V | Substituted 3,4-annelated benzimidazol-2(1H)-ones |
US5141735A (en) * | 1990-06-18 | 1992-08-25 | Hoffman-La Roche, Inc. | Substituted amino-benzodiazepines having anitviral activity |
NZ238664A (en) * | 1990-07-06 | 1992-12-23 | Janssen Pharmaceutica Nv | Substituted tetrahydroimidazo(1,4)benzodiazepin-2-(thi)ones and pharmaceutical anti-viral compositions |
GB9018601D0 (en) * | 1990-08-24 | 1990-10-10 | Fujisawa Pharmaceutical Co | Tricyclic compounds |
DE4036552C1 (zh) * | 1990-11-16 | 1992-02-06 | Boehringer Mannheim Gmbh, 6800 Mannheim, De | |
GB9109557D0 (en) | 1991-05-02 | 1991-06-26 | Wellcome Found | Chemical compounds |
ES2138624T3 (es) * | 1992-05-13 | 2000-01-16 | Wellcome Found | Combinaciones terapeuticas. |
US6177435B1 (en) | 1992-05-13 | 2001-01-23 | Glaxo Wellcome Inc. | Therapeutic combinations |
WO2009024325A2 (en) | 2007-08-20 | 2009-02-26 | Evotec Neurosciences Gmbh | Treatment of sleep disorders |
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IL93136A (en) * | 1989-02-23 | 1995-01-24 | Janssen Pharmaceutica Nv | History of tetrahydroimidazo [1,4] benzodiazepine-2-thione, their preparation and pharmaceutical preparations containing them |
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