CN1040982C - 吡喃并喹啉类及其盐的制备方法 - Google Patents
吡喃并喹啉类及其盐的制备方法 Download PDFInfo
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- CN1040982C CN1040982C CN93115028A CN93115028A CN1040982C CN 1040982 C CN1040982 C CN 1040982C CN 93115028 A CN93115028 A CN 93115028A CN 93115028 A CN93115028 A CN 93115028A CN 1040982 C CN1040982 C CN 1040982C
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Abstract
本发明公开了式(Ⅰ)化合物的制备方法和药学用途,式(Ⅰ)化合物结构如下,其中各取代基定义见说明书。
Description
本发明涉及药用化合物及其制备和用途。
先有技术公开了某些吡喃并喹啉,例如下述文献所述的4H-吡喃并[3,2-h]喹啉:
Z.H.Khalilet a1.Bull.Chem.Soc.Jpn.,64,668-670(1991),A.G.A.Elagamey et al.Collection Czechoslovak Chem.Commun.,53(7),1534-8(1988),F.M.A.El-Taweel et al.Pharmazie,45(9),671-3(1990),and K.D.Paull et al.CancerRes.,52(14),3892-3900(1992).我们发现,下述通式的化合物及其盐可用作药物:
R1是苯基或选自噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基的杂芳基,所述苯基或杂芳基可带有取代基;或者R1是可被C1-4烷基取代的呋喃基;
R2是氰基、羧基、-COOR4(其中R4是酯基)、-CONR5R6(其中R5和R6各自是氢或C1-4烷基)或R7SO2-(其中R7是C1-4烷基或可被取代的苯基),
R3是-NR8R9,-NHCOR8,-N(COR8)2,-N=CHOR8(其中R8和R9各自是氢或C1-4烷基)或-NHSO2R10(其中R10是C1-4烷基或可被取代的苯基);或式中X是C2-4亚烷基;基团代表与苯并吡喃核稠合的吡啶环。
我们发现,本发明化合物在治疗过度细胞增生或酶释放起主要作用的免疫性疾病的试验中具有活性,显示出其治疗效能。
R2是氰基,且R3是-NH2,(ii)R1是苯基或在对位上被一个氯、羟基或甲氧基基团取代的苯基
,R2是COOC2H5,且R3是-NH2,或者(iii)R1是苯基,R2是氰基,且R3是-NHCOCH,或-N=CHOC2H5。
排除在新化合物之外的具体化合物的一个例子是2-氨基-4-苯基-4H-吡喃并[3,2-h]喹啉-3-甲腈。
优选的化合物是用结构式(II)、(III)和(IV)表示的化合物,特别优选式(II)和(IV)表示的化合物。结构式(II)表示的新化合物中有某些化合物不属于新化合物,详见上文。
在上述式(I)中,C1-4烷基包括例如:甲基、乙基、丙基和丁基,优选甲基或乙基。
取代的苯基基团是被一个或多个、最好是一个或两个取代基取代的苯基,所述取代基选自例如:卤素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、三氟甲氧基、羧基、COOR11(R11是酯基)、-CONR12R13或-NR12R13(其中R12和R13各自是羟基或C1-4烷基)。当取代基为-COOR11时,R11可以是例如芳基-CH2-,如苄基,最好是C1-4烷基,尤其是甲基或乙基。取代的萘基和杂芳基可类似地被取代。此外,取代的苯基包括相邻原子被-O(CH2)mO-(其中m是1,2或3)取代的苯基。
当R1是杂芳基时,它最好是α-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-苯并噻吩基、3-苯并噻吩基、2-喹啉基、3-喹啉基、2-苯并呋喃基、3-苯并呋喃基、2-苯并咪唑基、2-呋喃基或3-呋喃基。在1位或2位上连有萘基基团。所述基团可在任何空位上被取代,但最好是不被取代。
优选的R1是苯基或取代的苯基,最好是被单个取代基取代的苯基,尤其是被硝基、三氟甲基、C1-4烷氧基、特别是甲氧基取代的苯基。或者是被-COOR11取代的苯基,其中R11是C1-4烷基,特别是甲基。一组优选的化合物是其中R1是在间位上被一个取代基取代的苯基的化合物,所述取代基是任何上述的就苯基取代基所列的取代基。
基团R2最好是氰基。当R2是-COOR4时,R4可以是任何酯基,例如:芳基-CH2-如苄基,最好是C1-4烷基,尤其是甲基或乙基。
基团R3最好是-NR8R9,尤其是-NH2。
优选的化合物是那些R1是可被取代的苯基、R2是氰基并且R3是-NH2的化合物。
一组优选的上述式II化合物是其中R1是在间位上被一个取代基取代的苯基,R2是氰基并且R3是-NH2。
还有一组优选的式II化合物,其中R1是被硝基、三氟甲基、甲氧基或-CO2Me取代的苯基,R2是氰基并且R3是-NH2。
应当理解,例如当R2是-COOH时,有可能形成盐。它们可自任何公知的碱衍生而来。碱盐的例子是那些从氢氧化铵和碱金属氢氧化物和碱土金属氢氧化物、碳酸盐和碳酸氢盐衍生而来的盐,以及从脂肪胺和芳香胺、脂肪二胺和羟烷基二胺衍生而来的盐。在制备上述盐时特别有用的碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化锂、氢氧化钙、甲胺、二乙胺、乙二胺、环己胺和乙醇胺。特别优选钾盐、钠盐和锂盐的形式。
应当明白,吡啶核还提供了制备酸加成盐的机会。酸加成盐可由适当的酸制得,例如:无机酸如盐酸、氢溴酸、硝酸、硫酸或磷酸,或有机酸如有机羧酸象乙醇马来酸、富马酸、马来酸、酒石酸、柠檬酸、水杨酸或邻乙酰氧基苯甲酸,或有机磺酸象甲磺酸、2-羟基乙磺酸、对甲苯磺酸或萘二磺酸。
除药学上可接受的盐之外,本发明还包括其它盐。它们可用作化合物纯化中的中间产物,或可用来制备其它如药学上可接受的酸加成盐,或者可用于鉴定、表征或纯化。
应当明白,本发明化合物含有能产生对映体的不对称碳原子。制备的化合物通常是外消旋体,可方便地直接使用,但如果需要,亦可用常规技术分离出单独的对映体。上述外消旋体和单独的对映体构成了本发明的一部分。
本发明还包括上述式(I)化合物的制备方法,它包括:
(1)将式(VI)化合物与式(VII)化合物反应,得到R3是-NH2的式(I)化合物;或者(2)将式(VIII)化合物转化为R3是-NR8R9,NHCOR8,-N(COR8)2,-N=CHOR8,-NHSO2R10或的式(I)化合物。
作为方法之一的(1),该反应最好于0-100℃并且在有机溶剂(例如乙醇)存在下进行。式(VI)化合物是已知的或可按已知方法容易地合成。
式(VII)反应物可通过使适当的腈R2CH2CN与醛R1CHO反应而制得。反应最好于20-100℃并且在有机碱(例如哌啶)催化剂和有机溶剂(例如乙醇)存在下进行。反应物腈和醛是已知的化合物或是可按本领域公知的方法制备的化合物。
至于方法(2),游离烯胺可通过反应(I)制得,随后转化为R取其它值的化合物。例如:游离氨基可用式R8X或R9X(X=卤素)的反应物烷基化,得到一或二烷基化的产物。类似地,氨基也可用式R8COX或(R8CO)2O酰化剂酰化,得到R3是-NHCOR8或-N(COR8)2的化合物。R3是-N=CHOR8的化合物通过与适当的原甲酸三烷酯反应制得,R3是-NHSO2R10的化合物通过与磺酰氨R10SO2X反应制得。
如上所述,该化合物具有药学活性。它们对于细胞类具有抗增生效应,从而表明可用来治疗过度细胞增生或酶释放是主要病源的疾病。
例如,本发明化合物抑制313纤维细胞的自然增生,其IC50浓度低于10μM。
此外,该化合物在P.Lacombe等人所述的试验(FEBS,3048,191,227-230)中通过抑制伴刀豆球蛋白A引起的T细胞增生而显示出对免疫应答的改善。
该化合物还抑制NS-1鼠B-淋巴瘤系的细胞增生和佛波醇酯激发的血浆酶原活化剂在牛视网膜毛细内皮细胞中的合成。
在K.Deshmukh-Phadke,M.Lawrence和S.Nanda所述的试验(Biochem.Biophys.Res.Commun.,1978,85,pp.490-496)中还观察到对巨噬细胞调节的中介物质引起的中性蛋白酶释放的抑制作用。
这些性质表明,本发明化合物能有效地治疗很宽范围的疾病,例如:类风湿性关节炎、动脉粥样硬化、肝硬交和癌症;并可用来治疗自动免疫疾病,例如:治疗全身性狼疮;和用来预防移植物排斥。它们也适用于骨关节炎和糖尿病并发症。
此外,本发明化合物显示出对血管平滑肌细胞增生的抑制作用,这点已通过使用取自兔子主动脉的、经培养的平滑细胞而证实,增生的测定是测定DNA的合成。细胞是按照Ross所述的移出方法(J.ofCell Bio.50:172(1971))获得的。将细胞置于96穴微量滴定板上5天时间。培养物融合并停止生长。然后将细胞转移到Dulbecco′s改性Eagle′s培养基(DMEM)中,该培养基含0.5-2%贫血小板血浆、2mML-谷氨酰胺、100U/ml素霉素、100μg/ml链霉素、1μC/ml 3H-胸苷、20ng/ml血小板衍生的生长因子和不同浓度的化合物。化合物的常备溶液在二甲亚砜中制备,然后在上述评定介质中稀释至适当浓度(0.01-10μg/ml)。然后于37℃在5%CO2/95%空气的条件下将细胞培养24小时。24小时后,在甲醇中将细胞固定。混入DNA的3H-胸苷随后用闪烁计数器测定,测定方法参见Bonin等人,Exp.CellRes.181:475-482(1989)。
本发明化合物对平滑肌细胞的抑制还可通过测定其对指数生长细胞的效应而证实。将取自兔子主动脉的平滑肌细胞置于12穴组织培养板上在DMEM中接种。该DMEM中含有10%胎牛血清、2mM L-谷氨酰胺、100μ/ml青霉素和100μg/ml链霉素。24小时后,将细胞附好,将培养基换成含2%贫血小板血浆、2mM L-谷氨酰胺、100μ/ml青霉素、100μg/ml链霉素、40ng/ml血小板衍生的生长因子和指定浓度化合物的DMEM。让细胞生长4天,用胰蛋白酶处理细胞各培养物的细胞数用ZM-Coulter计数器进行计数测定。
上述试验中的活性表明,本发明化合物能有效地治疗再狭窄,其特征为由外伤引起的平滑肌的胞迁移和增生。
因此,本发明还包括一种药用组合物,该组合物中含有药学上可接受的稀释剂或载体以及式(I)化合物或其药学上可接受的盐。
该化合物可以多种途径给药,例如:口服或直肠给药,局部或肠道外给药例如注射,通常以药用组合物的形式使用。所述组合物构成了本发明的一部分,可按制药行业公知的方式制得,通常包含至少一种活性化合物以及药学上可接受的稀释剂或载体。在制备本发明组合物时,活性成分通常与载体混合,或用载体稀释,和/或用例如胶囊、小药囊、纸或其它包容物形式的载体包裹。当载体起稀释剂作用时,它可以是固体、半固体或液体材料,它起活性成分的载体、赋形剂或介质的作用。因此,组合物可以是片剂、锭剂、小药囊、扁囊剂、酏剂、混悬液、固体或液体介质形式,含有例如不超过10%(重量)活性化合物的软膏、软和硬明胶囊、栓剂、注射溶液和混悬液和灭菌粉剂。
适当载体的一些例子是乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、藻朊酸盐、黄蓍胶、明胶、糖浆、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石粉、硬脂酸镁和矿物油。注射用组合物可按本领域公知的方法制成向病人给药后能快速、延缓或延迟释放活性成分的制剂。
当本发明化合物制成单位剂型时,它最好含5mg-500mg,例如10-200mg。“单位剂型”是指适于人和动物宿主单位剂量的物理上不连续的单元。每一单元包含所需的药用载体和予先计算好能产生期望的治疗效果量的活性物质。
活性化合物在很宽的剂量范围内都是有效的,例如日剂量通常为0.5-300mg/kg,更常用5-100mg/kg。但是,应当明白,用药量应由医师根据相应情况包括待治病性、给药选用的化合物及给药途径来确定,因此,上述剂量范围决无制定本发明范围之意。
下列实施例是对本发明的说明。
实施例1
将丙二腈(7.52g)和3,4-二甲氧基苯甲醛(18.95g)在乙醇(100ml)中的悬浮液搅拌下温热至回流温度。将桔色溶液移离热源,从冷凝管上部加哌啶(0.5ml)。剧烈的反应一旦变缓,则再将反应混合物加热至回流温度,这样持续35分钟。这时出现大量亮黄色固体。将混合物在冰浴中冷却10分钟,滤出黄色固体,用乙醇和乙醚洗涤,于70℃真空干燥,得3,4-二甲氧基亚苄基丙二腈,m.p.137℃。
按类似方法制得下列化合物:3-硝基亚苄基丙二腈,m.p.108℃3-甲氧基亚苄基丙二腈,m.p.102℃3-甲酯基亚苄基丙二腈,m.p.125℃3-三氟甲基亚苄基丙二腈,m.p.81℃3-二氯亚苄基丙二腈,m.p.154℃
实施例2
搅拌下,将哌啶(1.70g)滴加到5-羟基异喹啉(2.90g)和3,4-二甲氧基亚苄基丙二腈(4.28g)的乙醇(11ml)混悬液中。然后将混悬液加热回流一小时,得红色溶液。然后让它冷却至室温,有棕色固体析出。将其滤出,用乙醇和乙醚洗涤,于60℃真空干燥,得2-氨基-4-(3,4-二甲氧基苯基)-4H-吡喃并[2,3-f]异喹啉-3-甲腈黄棕色固体,m.p.225-228℃。
按类似方法制得下列化合物2-氨基-4-(3,4-二氯苯基)-4H-吡喃并[2,3-f]异喹啉
-3-甲腈,m.p.215-218℃。2-氨基-4-(3-甲氧基苯基)-4H-吡喃并[2,3-f]异喹啉-
3-甲腈,m.p.223-224℃。2-氨基-4-(3-硝基苯基)-4H-吡喃并[2,3-f]异喹啉-3
-甲腈,m.p.239-243℃。2-氨基-4-(3-三氟甲基苯基)-4H-吡喃并[2,3-f]异喹啉
-3-甲腈,m.p.117-118℃。3-(2-氨基-3-氰基-4H-吡喃并[2,3-f]异喹啉-4-基)
苯甲酸甲酯,m.p.229-230℃。
实施例3
搅拌下,用哌啶(1.70g)处理8-羟基喹啉(2.90g)和3,4-二甲氧基亚苄基丙二腈(4.28g)的乙醇(15ml)悬浮液中,室温下搅拌1小时。然后将混合物加热回流90分钟。然后让此红色溶液冷却至室温过夜。滤出沉淀的桔色固体,用乙醇和乙醚洗涤,于60℃真空干燥,得2-氨基-4-(3,4-二甲氧基苯基)-4H-吡喃并[3,2-h]喹啉-3-甲腈黄褐色固体,m.p.118-120℃。
按类似方法制得了下列化合物:2-氨基-4-(3,4-二氯苯基)-4H-吡喃并[3,2-h]喹啉-3
-甲腈,m.p.218-222℃。2-氨基-4-(3-甲氧基苯基)-4H-吡喃并[3,2-h]喹啉-3-
甲腈,m.p.190-192℃2-氨基-4-(3-硝基苯基)-4H-吡喃并[3,2-h]喹啉-3-
甲腈,m.p.198-200℃。2-氨基-4-(3-三氟甲基苯基)-4H-吡喃并[3,2-h]喹啉-
3-甲腈,m.p.228-231℃。3-(2-氨基-3-氰基-4H-吡喃并[3,2-h]喹啉-4-基)苯
甲酸甲酯,m.p.208-210℃。
实施例4
搅拌下,用哌啶(410mg)处理5-羟基喹啉(703mg)和3-三氟甲基亚苄基丙二腈(1.07g)在乙醇(5ml)中的悬浮液。将此红色溶液于室温搅拌过夜,然后真空浓缩。残留物经合成硅酸镁层析,以二氯甲烷为洗脱剂,得188mg 2-氨基-4-(3-三氟甲基)-4H-吡喃并[2,3-f]喹啉-3-甲腈乳白色固体,m.p.167-168℃。
按类似方法制得了下列化合物:2-氨基-4-(3,4-二氟苯基)-4H-比喃并[2,3-f]喹啉-3
-甲腈,m.p.223-228℃。2-氨基-4-(3-甲氧基苯基)-4H-吡喃并[2,3-f]喹啉-3
-甲腈,m.p.218-222℃。2-氨基-4-(3-硝基苯基)-4H-吡喃并[2,3-f]喹啉-3-
甲腈,m.p.200-202℃。2-氨基-4-(3,4-二甲氧基苯基)-4H-吡喃并[2,3-f]喹
啉-3-甲腈,m.p.160-163℃。3-(2-氨基-3-氰基-4H-吡喃并[2,3-f]喹啉-4-基)苯甲
酸甲酯,m.p.203-206℃
实施例5软明胶胶囊
每一粒软明胶胶囊包含:
活性成分 150mg
花生油 150mg
混合在一起后,用适当的设备将混合物装入软明胶胶囊。
实施例6硬明胶胶囊
每一粒胶囊包含:
活性成分 50mg
PEG4000 250mg
将PEG4000烷化后与活性成分混合,在熔化状态下装入胶囊壳中,自然冷却。
实施例7片剂
每片含10mg活性成分的片剂制备如下:
活性成分 10mg
淀粉 160mg
微晶纤维素 100mg
聚乙烯吡咯烷酮 13mg
(在水中的10%溶液)
羧甲基淀粉钠 14mg
硬脂酸镁 3mg
共计 300mg
将活性成分、淀粉和纤维素充分混合。向所得粉末中混入聚乙烯吡咯烷酮溶液,过筛。将制得的颗粒干燥后再过筛。然后向颗粒中加入羧甲基淀粉钠和硬脂酸镁,混合物用压片机压成重300mg的片剂。
实施例8
用大鼠脾细胞的伴刀豆球蛋白A反应作为本发明化合物活性的体外评估测定。文献中已描述了许多伴刀豆球蛋白A反应的测定方法。所用方法类似于P.Lacombe等人(FEBS 3048191,227-230)所述的方法。我们在每个培养池中加2×105个细胞,伴刀豆球蛋白A的浓度为1μg/ml。必须加入2-巯基乙醇(2×10M-5),加入氚化胸苷0.25μCi,6小时后收集细胞。实施例1-4公开的全部化合物均能抑制细胞增生,在本试验中IC50低于5μM。
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---|
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IL107627A (en) | 1997-04-15 |
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AU668602B2 (en) | 1996-05-09 |
CN1092072A (zh) | 1994-09-14 |
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KR940011465A (ko) | 1994-06-21 |
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