CN1040326C - 咪唑并吡啶paf/h1拮抗剂的制备方法 - Google Patents
咪唑并吡啶paf/h1拮抗剂的制备方法 Download PDFInfo
- Publication number
- CN1040326C CN1040326C CN92100974A CN92100974A CN1040326C CN 1040326 C CN1040326 C CN 1040326C CN 92100974 A CN92100974 A CN 92100974A CN 92100974 A CN92100974 A CN 92100974A CN 1040326 C CN1040326 C CN 1040326C
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- China
- Prior art keywords
- pyridine
- compound
- formula
- subunit
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000005557 antagonist Substances 0.000 title abstract description 8
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- -1 pyridine-1-yl Chemical group 0.000 claims description 48
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 44
- 229940015043 glyoxal Drugs 0.000 claims description 43
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- 238000000034 method Methods 0.000 claims description 28
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 19
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- 238000006243 chemical reaction Methods 0.000 claims description 12
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- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
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- JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 5
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Abstract
本发明公开下式化合物,
式中X是CH或N;Z是CH=CH或S;A是CH2CH2,CH=CH,CH(OH)CH24,或COCH2;B是连接键或-CH2-,-CH(CH3)-或-C(CH3)2-,或者,当Z是CH=CH时,B可形成稠合到相连的苯环上环戊烷环,Y完成碉合的苯环或可任选地被卤素或C1-C4烷基取代的噻吩环,n是0,1或2,m是0或1,它们是PAF和组胺H1的拮抗剂,用于治疗过敏性炎症如过敏性鼻炎。
Description
本发明涉及咪唑并吡啶类化合物,尤其是某些4-取代的1-(2-甲基咪唑并[4,5-c]吡啶-1-基)-苯和烷基苯衍生物。该类化合物具有组胺(H1)和血小板激活因子(PAF)的拮抗活性,可用于呼吸道过敏性炎症(例如:过敏性鼻炎、鼻窦炎和气喘)和皮肤过敏性炎症(例如:特应性皮炎和荨麻疹)的临床治疗。
H1拮抗剂通常能很好地控制过敏性鼻炎的急性症状,例如:喷嚏、鼻眼分泌物过多和瘙痒。但是,该药物并不能或只能少许减轻由增加的血管通透性引起的水肿和血管扩张所导致的充血。此外,H1-拮抗剂并不影响炎症细胞的聚集,而这种聚集便是慢性病中对过敏原应答迟缓和应答过快的成因。PAF的潜在的致水肿作用及其已知的释放形式和许多种炎症细胞的作用表明:PAF拮抗剂对与组胺无关的充血和过敏性鼻炎的炎症是有效的。本发明化合物是PAF和H1-拮抗剂,因而具有使所有慢性过敏性鼻炎的主要症状转佳的能力。
此外,尽管组胺对气喘过敏原引起的支气管收缩有贡献,但对由下呼吸道的炎症细胞聚集引起的延迟的支气管缩肌反应或非特定支气管过敏几乎没效。在该炎症反应中包括PAF及其支气管缩肌活性,在气喘的治疗中都表明PAF/H1二元拮抗剂的潜在作用。类似地,对于过敏性皮肤病(如:特应性皮炎和荨麻疹)的治疗,PAF/H1二元拮抗剂比起单独抗组胺剂更好,因而,抗组胺剂可减轻瘙痒和发红,而对于由炎症细胞流入引起的疹块反应几乎没效。本发明化合物也可期望对由组胺和组胺无关的炎症参与的病理生理改变的其它疾病具有治疗价值。
在我们的欧洲申请No.0310386中,我们公开了一系列二氢吡啶PAF拮抗剂,其中2位取代基特别包括(2-甲基咪唑并[4,5-c]吡啶-1-基)苯基、美国专利No.3326924公开了某些作为抗组胺剂的氮杂-二苯并环庚烯类化合物,包括3-氮杂-5-(4-亚哌啶基)-10,11-二氢-5H-二苯并[a,d]环庚烯及其4-氮杂类似物(5,6-二氢-11-(4-亚哌啶基)-11H-苯并[5,6]环庚[1,2-b]吡啶)及其7-氯和8-氯和7,8和9-甲基衍生物。
X是CH或N;
Z是CH=CH或S;
A是CH2CH2,CH=CH,CH(OH)CH2,或COCH2;
B是连接键或-CH2-,-CH(CH3)-或-C(CH3)2-,
或者,当Z是CH=CH时,B可形成稠合到相连的苯环上的环戊烷环,
n是0,1或2;
m是0或1。
在上述定义中,卤素一词指氟、氯、溴或碘;含3个或更多碳原子的烷基和烷氧基可以是直链或支链的,当连接基团A是对称的时,它可以两个方向任意连接。当化合物包含不对称中心时,该化合物可以对映异构体和非对映异构体的形式存在。所述异构体可通过物理方法分离,例如:将母体化合物或适当的盐或其衍生物分馏或层析。本发明包括所有分离或未分离的对映异构体。
式(I)化合物药学上可接受的酸加成盐是指式(I)化合物与酸形成的无毒性的酸加成盐,例如:盐酸盐、氢溴酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、乳酸盐、马来酸盐、琥珀酸盐和酒石酸盐。
在本发明的优选实施例中,X是N,Z是CH=CH且Y形成下式苯并稠环:尤其是当R是H或氯时。B最好是一个连接键或CH2,且n和m都是0。特别优选的是式中R是Cl、B是连接键、A是CH2CH2、n是0和m是0的那些化合物。
化合物4-(8-氯-5,6-二氢-11H-苯并[5,6]-环庚烷[1,2-b]-吡啶-11-亚基)-1-[4-(2-甲基咪唑[4,5-c]吡啶-1-基)苯甲酰基]哌啶是特别优选的。
式(II)和式(III)化合物的反应可采用常规的酰胺偶合技术完成。因而,在一个方法中,将反应物溶于有机溶剂(例如:二氯甲烷),采用二酰亚胺缩合剂(例如:3-(二甲氨基丙基)-1-乙基碳化二亚胺或N,N′-二环己基碳化二亚胺),最好在1-羟基苯并***和有机碱(如:N-甲基吗啉的存在下完成反应。通常反应在室温下经2~24小时完成,产物用常规方法分离,例如:用水洗,或过滤,除去脲副产物并蒸发溶剂的方法。必要时,产物还可用结晶或层析的方法进一步纯化。
还可以进行许多后续的转化反应。例如用硼氢化钠还原A是COCH2的产物得到相应A是CH(OH)CH2的化合物。用例如3-氯过苯甲酸氧化相应咪唑并吡啶(m=0)可制得N-氧化物(式中m是1)。
式(II)的原料可按下列文献所述的方法制备:Engehardt等人J.Med.Chem.,1965,8,829;Waldvogel等人Helvetica Chimica Acta,1976,59,866和美国专利No.3326924。式(III)的原料可按照欧洲专利0310386和下文给出的制备方法制备。
本发明化合物作为H1拮抗剂的活性通过其体外抑制组胺引起豚鼠气管收缩的能力而显示出来。试验按下述方法进行:
将螺旋形切割的豚鼠气管条在张力(2g)下悬浮于含有15ml不断充气(95%O2,5%CO2)的Krebs缓冲液(118mM Nacl,4.62mM KCl,1.16mM MgSO4,1.18mM KH2PO4,25mM NaHCO3,11mM葡萄糖,2.5mM CaCl2),(含2μm消炎痛)的组织浴中。经45分钟平衡后,将组胺二盐酸盐加入组织浴中至最终浓度为10-5M,等距离记录所得收缩。收缩30分钟后,用缓冲液洗涤组织直至松弛到基线。接着再进行组胺收缩(30分钟),并洗涤。用组胺第三次收缩组织,但不要洗涤。经30分钟延迟收缩之后,将受试化合物的第一剂量加到组织浴中,记录效果20分钟。增加化合物的累积剂量,每20分钟加入组织浴中并将效果记录。将松弛第三延迟组胺收缩50%所需的化合物浓度作为IC50值,计算IC50。
本发明化合物作为PAF拮抗剂的活性通过其体外抑制血小板凝聚活性的能力显示出来。试验按下述方法进行:
从兔子身上提取血样,置入0.1vol(77mM)四乙酸乙二胺二钠中,试样在150×g离心15分钟,得到血小板富集血浆。将血浆再在2000×g离心10分钟,得到血小板小丸,将其用缓冲液(4mMKH2PO4,6mM Na2HPO4,100mM NaCl,55mM葡萄糖和0.1%牛血清白蛋白,pH7.25)洗涤最后以2×108血小板/ml的浓度再悬浮于缓冲溶液中。洗过的血小板在搅拌下、在ADP清除体系(1mM磷酸肌酸酐,27U/ml肌酸酐磷酸肌酶和10mM MgCl2)、1mM CaCl2和单独载体(二甲基亚砜)或含有特定受试化合物的载体存在下,在37℃的凝集计中搅拌预孵化两分钟。加入足够浓度的C18-PAF,以便在无受试化合物(10-8至10-9M)时得到最大的凝集反应,血小板的凝集通过跟踪溶液的光透过率的增加来测定。该实验在受试化合物的浓度范围内重复,将使反应降至极大值的50%所需的受试化合物的浓度记为IC50值。
式(I)化合物作为PAF和H1二元拮抗剂的活性通过下述体内试验证明:它们具有抑制向小鼠皮内注射PAF或组胺而引起的皮肤血管渗透性增加的能力。给动物以口服或静脉注射受试化合物,给药45分钟(口服)或10分钟(静脉注射)后,每个动物都在背部、正头后单一皮内注射组胺(13.5mmol)或PAF(30pmol)。注射后,立即静脉注射Evans兰染料(250μl,6.25mg/ml)。30分钟后,注射戊巴比妥将动物处死,剥离背部皮肤,切出皮内染兰的部分。通过用甲酰胺从切出皮肤中提取染料(70℃下,24小时),并用分光光度计在620nm处记录吸收来测定染兰的程度。将与对照组相比降低50%吸收(染兰)的化合物的剂量作为ID50。
在治疗中,式(I)化合物通常与药学载体混合给药。载体可根据给药途径和标准药学实践选择。例如,它们可以以含有象淀粉或乳糖那样的赋形剂的片剂形式口服,或者单独或与赋形剂混合以胶囊或卵状小体的形式口服,或者以含调味剂或着色剂的酏剂或混悬剂的形式口服。它们可非肠道注射给药,例如:静脉注射、肌内注射或皮下注射。对于非肠道给药,它们最好为无菌水溶液的形式,溶液中可含其它物质,例如,含足够的盐或葡萄糖使溶液与血液等渗。
就防治人的过敏反应和炎症给药而定,本发明化合物的口服剂量通常对平均成年患者(70kg)为每日2-1000mg。从而,对于一般的成年患者,每一片剂或胶囊含1-500mg活性化合物和适当的药学上可接受赋形剂或载体。静脉给药的剂量一般需要每单一剂量1-10mg。对于过敏性气喘和鼻炎的治疗,鼻内给药或通过喷雾或气雾剂吸入的方法可能是优选的给药途径。这一途径的剂量水平根据需要,每单一剂量可在0.1-50mg范围内。实践中,医师会根据具体患者确定最合适的实际剂量,它随患者的年龄、体重和反应而变化。上述剂量是一般情况的举例说明,当然,也可能存在值得使用更高或更低剂量的个别情况,这种情形包含在本发明范围之内。
从而,在另一方面,本发明提供含有式(I)化合物或药学上可接受稀释剂或载体的药用组合物。
本发明还包括将式(I)化合物或其药学上可接受的盐用作药物,尤其用于人类的过敏反应及炎症的治疗。
现在,我们用下列实验实施例更详细地叙述式(I)化合物的制备方法。化合物的纯度用Merck Kieselgel 60 F254薄板层析进行常规监控。1H-NMR谱用Micolet QE-300或Brucker AC-300波谱仪记录,全都与预定的结构相符。化学位移以四甲基甲硅烷为内标,单位为百万分之一,用常规缩写标示主要峰:S,单峰;d,双重峰;t,三重峰;m,多重峰;br,宽蜂。
实施例1
4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶半水合物。
将4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(224mg,0.75mmol)和4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸(190mg,0.75mmol)溶于二氯甲烷(12ml)中,依次用1-羟基苯并***水合物(102mg,0.75mmol),1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(290mg,1.5mmol)和4-甲基吗啉(165μl;1.5mmol)处理。混合物在室温下搅拌16小时,用水洗涤,硫酸镁干燥、蒸发。残留物用硅胶层析提纯,以二氯甲烷加3-4%甲醇洗脱。将适当的级分合并,蒸发得标题化合物(113mg,27%)无色泡沫,经鉴定为半水合物。
实测值:C,71.1; H,5.2;N,12.3.C33H28ClN5O.0.5H2O
理论值:C,71.4;H,5.3;N,12.6%.
实施例2-6
实施例7
4-(5H-二苯并[a,d]环庚烯-5-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶半水合物
采用实施例1的方法,用4-(5H-二苯并[a,d]环庚烯-5-亚基)哌啶盐酸盐(参见J.Med.Chem.,1965,8,829)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶。可制得标题化合物无色泡沫,经鉴定知为半水合物。
实测值:C,78.9;H,5.6;N,11.0.C34H28N4O.0.5H2O
理论值:C,78.9;H,5.8;N,10.8%.
实施例8
1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基]苯甲酰基]-4-(10-氧-9,10-二氢-4H-苯并[4,5]环庚烷[1,2-b]噻吩-4-亚基)哌啶
采用实施例1的方法,用4-(10-氧-9,10-二氢-4H-苯并[4,5]环庚烷[1,2-b]噻吩-4-亚基)哌啶(参见:Helv.Chim.Acta,1976,59,866)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,可制得标题化合物无色泡沫,经鉴定知为一水合物。
实测值:C,70.1;H,5.1;N,10.1.C32H26N4O2S.H2O
理论值:C,70.0;H,5.1;N,10.2%.
实施例9
4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基-5-氧化物)苯甲酰基]哌啶
用10分钟时间,向搅拌的4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶半水合物(200mg,0.37mmol)(实施例1)冰冷却溶液中滴加3-氯过苯甲酸(50%;126mg,0.37mmol)的二氯甲烷(3ml)溶液。混合物在0℃下搅拌19小时,再用3-氯过苯甲酸(25mg)进一步处理,冰冷却下继续搅拌25小时,用饱和碳酸氢钠水溶液和水洗涤,用硫酸镁干燥并蒸发。残留物用二氧化硅层析提纯,用二氯甲烷加5%甲醇和0.1-0.5%饱和氨水溶液的混合液洗脱。合并适当级分,蒸发得标题化合物(44mg,21%)无色玻璃体,m.p.176-180℃,用1H-NMR谱表征:
1H-NMR(CDCl3)δ=9.03(1H,s),8.39(1H,d,J=8Hz),8.04(1H,s),7.64(2H,d,J=8Hz),7.37(2H,d,J=8Hz),6.95-7.25(6H,m),3.25-4.15(4H,m),1.7-3.0(8H,m).
实施例10
4-(10-羟基-9,10-二氢-4H-苯并[4,5]环庚烷[1,2-b]噻吩-4-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
将1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]-4-(10-氧-9,10-二氢-4H-苯并[4,5]环庚烷[1,2-b]噻吩-4-亚基)哌啶(200mg,0.38mmol)(实施例8)和硼氢化钠(200mg)的甲醇(20ml)溶液在室温下搅拌4小时并蒸发之。残留物分配在二氯甲烷和水中,用水洗涤有机层,硫酸镁干燥并蒸发。残留物用己烷研磨得标题化合物(70mg,35%)无色泡沫,经鉴定为二水合物。
实测值:C,67.9;H,5.4;N,9.6.C32H28N4O2S.2H2O
理论值:C,67.5;H,5.6;N,9.9%.
实施例11
4-(8-氯-5,6-二氢-6-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(8-氯-5,6-二氢-6-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(参见J.Org.Chem,1990,55,3341)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物无色胶状物,鉴定知含1.5当量水。
实测值:C,67.2;H,5.2;N,11.4.C33H26ClN5O2.1.5H2O
理论值:C,67.0;H,4.9;N,11.9%.
实施例12
4-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-亚基)哌啶(参见EP-A-0347123,1989)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物无色泡沫(248mg,48%),鉴定为半水合物。
实测值:C,78.4;H,5.9;N,10.7.C34H30N4O.0.5H2O
理论值:C,78.5;H,6.0;N,10.8%.
实施例13
4-(8-氯-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(8-氯-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(参见WO88/03138,1988)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物无色胶状物。Rf0.25(二氧化硅,溶剂体系:CH2Cl2,CH3OH,NH4OH;98∶7∶1),以质谱表征M/e,M+=543(C33H26ClN5O)
实施例14
4-(5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(参见J.Med.Chem.,1972,15,750)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物米黄色固体,mp.243-245℃,经鉴定含0.67当量水。
实测值:C,75.7;H,5.9;N,13.4.C33H29N5O.0.67H2O
理论值:C,75.7;H,5.8;N,13.4%.
实施例15
4-(8-氯-5,6-二氢-6-羟基-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例10的方法,用硼氢化钠还原4-(8-氯-5,6-二氢-6-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶(参见实施例11),制得标题化合物无色胶状物,Rf 0.30(二氧化硅,溶剂体系:CH2Cl2,CH3OH,NH4OH;93∶7∶1),以质谱表征M/e,M+=561(C33H28ClN5O2)
实施例16
4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[5-(2-甲基咪唑并[4,5-c]吡啶-1-基)噻吩-2-酰基]哌啶
按实施例1的方法,用5-(2-甲基咪唑并[4,5-c]吡啶-1-基)噻吩-2-羧酸(参见制备8;185mg)替代4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸,制得标题化合物黄棕色泡沫(121mg,38.5%),经鉴定为倍半水合物。
实测值:C,64.3;H,4.8;N,12.0.C31H26ClN5OS.1.5H2O
理论值:C,64.3;H,5.0;N,12.1%.
实施例17
4-(8-甲基-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(8-甲基-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(参见J.Med.Chem.,1991,34,457-461;300mg)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物玻璃体(270mg,49.6%),经鉴定含0.25mol二氯甲烷。
实测值:C,74.8;H,6.0;N,12.7.C34H31N5O.0.25CH2Cl2
理论值:C,75.2;H,5.8;N,12.8%.
实施例18
4-(8-氯-5,6-二氢-5-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例1的方法,用4-(8-氯-5,6-二氢-5-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶(参见J.Org.Chem.,1990,55,3341;80mg)替代4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)哌啶,制得标题化合物棕色泡沫(60mg,43.5%)Rf0.08(二氧化硅,溶剂体系:CH3CO2C2H5,CH3OH,NH4OH;80∶20∶1),M/,M+=559(C33H26ClN5O2)
实施例19
4-(8-氯-5,6-二氢-5-羟基-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶
按实施例10的方法,用硼氢化钠还原4-(8-氯-5,6-二氢-5-氧-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酰基]哌啶(来自实施例18;40mg),制得标题化合物黄色泡沫(35mg,87%),经鉴定为含0.33当量乙酸乙酯的水合物。
实测值:C,67.7;H,5.2;N,11.4.C33H28ClN5O2.H2O.0.33C4H8O2
理论值:C,67.7;H,5.1;N,11.5%.
制备1
4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸
将4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯腈(参见EP-0310386)(12.0g,51.3mmol)和氢氧化钠(22.0g,0.55mmol)与乙醇(55ml)和水(55ml)的混合物在氮气氛中加热回流1.5小时,冷却,减压浓缩,将棕色残留物溶于冰水中,加入冰乙酸(33ml)。收集所得沉淀物,水洗,70℃下真空干燥得标题化合物(9.1g,70%)米色固体,用其1H-NMR谱表征。
1H NMR(DMSO-d6),2.50(3H,s),7.25(1H,d,J=5Hz),7.72(2H,d,J=8Hz),
8.16(2H,d,J=8Hz),8.30(1H,d,J=5Hz),8.92(1H,s).
制备2
4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯基乙酸乙酯a)将4-氨基苯基乙酸乙酯(17.7g,0.1mol)和碳酸氢钠(8.4g,0.1mol)在乙醇(200ml)中搅拌。加入4-氯-3-硝基吡啶(15.9g,0.1mol)的乙醇(50ml)溶液,混合物在室温下搅拌3小时。蒸发混合物使体积减小,将其注入乙酸乙酯(500ml)中,水(200ml)洗该溶液。然后用0.5M盐酸提取有机相,合并水相提取液,用2M氢氧化钠碱化,用二氯甲烷提取。合并有机相提取液,硫酸钠干燥,过滤并蒸发至干。残留物用乙醇水溶液重结晶,得4-(3-硝基吡啶-4-基氨基)苯基乙酸乙酯(7.32g)m.p.124-126℃。从母液中还可再回收8.56g。b)在5%钯—炭存在下,将上述产物(15.7g)在60p.s.i.(4.1巴)、室温下氢化3小时,过滤、蒸发溶剂得4-(3-氨基吡啶-4-基氨基)苯基乙酸乙酯(14.1g)c)将4-(3-氨基吡啶-4-基氨基)苯基乙酸乙酯(14.1g,52mmol)、乙酸(100ml)和乙酸酐(100ml)混合,氮气氛中加热回流1.5小时。溶液冷却后蒸发至干,用10%碳酸氢钠水溶液碱化,然后用二氯甲烷提取。将合并的有机相蒸发至干,用二氧化硅层析提纯,以二氯甲烷/乙醇洗脱,得4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯基乙酸乙酯(13.6g)。
制备3
4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯基乙酸
将4-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯基乙酸乙酯(750mg,2.54mmol)和硼氢化钠(160mg,4.0mmol)溶解于乙醇(5ml)和水(5ml)混合溶剂中,室温下搅拌16小时并蒸发之。将残留物溶于水中,以2M盐酸酸化至pH4-5,用1-丁醇提取。合并1-丁醇提取液,蒸发,残留物用***研制。收集所得固体,用己烷洗涤,干燥得标题化合物(267mg,39%)黄棕色固体。m.p.226-230℃,用其1H-NMR谱表征。
1H-NMR(d6-DMSO)δ=8.86(1H,s),8.23(1H,d,J=8Hz),7.48(4H,s),
7.15(1H,d,J=8Hz),3.70(2H,s),2.42(3H,s).
制备4
4-[(2-甲基咪唑并[4,5-c]吡啶-1-基)甲基]苯甲酸
按上述制备3所述方法,将4-[(2-甲基咪唑并[4,5-c]吡啶-1-甲基]苯甲酸乙酯(EP-A-0330327)水解得标题化合物无色固体,直接用于实施例3。
制备5
5-(2-甲基咪唑并[4,5-c]吡啶-1-基]茚-2-羧酸(a)搅拌下,向乙酸酐(80ml)中滴加发烟硝酸(40ml,1.5g/ml),保持混合物温度为0℃。加完后,保持反应温度在-5℃至0℃之间,用30分钟时间搅拌下滴加2-氰基茚(11.33g,79.5mmol),(J.Chem.Soc.(B),(1969),1197),混合物继续搅拌15分钟后倒在冰上。用二氯甲烷(4×150ml)提取混合物,提取液用碳酸氢钠饱和水溶液(3×150ml)洗涤,硫酸镁干燥,减压蒸发溶剂。残留物用乙醇重结晶,得2-氰基-5-硝基茚(12.09g,81%)黄色固体,m.p.80-82℃。(b)将2-氰基-5-硝基茚(11.90g,63.3mmol)的甲醇/二氯甲烷-1∶1(200ml)溶液在10%钯—炭(1.2g)存在下,在30p.s.i.、20℃氢化5小时。滤去催化剂,滤液减压浓缩得5-氨基-2-氰基茚(10.4g),直接用于下步反应。一部分用乙醇重结晶得粉红色针状体,m.p.73-76℃。(c)室温下,将4-氯-3-硝基吡啶(11.46g,72.3mmol)加入5-氨基-2-氰基茚(10.4g,65.7mmol)的乙醇(150ml)悬浮液中,将混合物于室温下搅拌过夜,然后注入过量冰冷的氨水中,滤去黄色固体,用热甲醇(150ml)部分蒸煮、冷却、再过滤得2-氰基-5-(3-硝基吡啶-4-基氨基)茚(13.61g,74%)。(d)将2-氰基-5-(3-硝基吡啶-4-基氨基)茚(12.46g,44.5mmol)悬浮在甲醇/二氯甲烷(1∶1,750ml)中,在10%钯-炭(1.25g)存在下,在20℃、30p.s.i.下氢化2小时。滤去催化剂,减压浓缩滤液得5-(3-氨基吡啶-4-基氨基)-2-氰基茚(12.28g,大约定量获得)黄色固体,m.p.98-100℃。(e)将5-(3-氨基吡啶-4-基氨基)-2-氰基茚(12.28g,约4.45mmol,来自上面步骤d)、乙酸(70ml)和乙酸酐(70ml)的混合物在氮气氛中加热回流1.75小时。冷却、减压浓缩。残留的棕色胶状物溶解于2M盐酸(40ml)中,用乙酸乙酯(50ml)洗涤。向水层中加2M氢氧化钠水溶液使其碱化,产物用二氯甲烷提取,合并提取液,用水(50ml)洗涤,硫酸镁干燥,蒸发溶剂。残留物用硅胶柱色谱提纯,以乙酸乙酯/甲醇(7∶1)洗脱,得棕色胶状物,用乙酸乙酯/甲醇重结晶,得2-氰基-5-(2-甲基咪唑并[4,5-c]吡啶-1-基)茚灰白色粉末(9.67g,79%),m.p.174-176℃。
实测值:C,74.4;H,5.2;N,20.7.C17H14N4
理论值:C,74.4;H,5.1;N,20.4%.(f)在氮气氛中,将2-氰基-5-(2-甲基咪唑并[4,5-c]吡啶-1-基)茚(739mg,2.70mmol)、50%氢氧化钠水溶液(1ml)和甲醇(6ml)混合物加热回流9小时、冷却、倒在冰上,加入2M盐酸将pH值调节至pH5。过滤收集所得沉淀物,真空干燥得标题化合物(426mg,54%)无色固体,m.p.264-267℃。
实测值:C,68.9;H,5.1;N,14.1;C17H15N3O2.0.2H2O
理论值:C,68.8;H,5.2;N,14.1%.
制备6
3-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸a)将3-氨基苯甲酸乙酯(3.3g,20mmol)和4-氯-3-硝基吡啶(3.17g,20mmol)的乙醇(150ml)溶液在室温下搅拌16小时,然后在冰浴中冷却。收集所得固体,用冰冷的乙醇洗涤,干燥得3-(3-硝基-4-吡啶氨基)苯甲酸乙酯盐酸盐(4.17g)黄色结晶固体,m.p.201-204℃。
实测值:C,5.2;H,4.4;N,12.9.C14H13N3O4.HCl
理论值:C,51.9;H,4.3;N,13.0%.
蒸发母液,残留物用乙醇重结晶再得到1.2g产物。(b)将上述产物分配在乙酸乙酯和10%碳酸钠水溶液中,用水洗涤有机层,硫酸镁干燥、蒸发。残留物溶解在乙醇(300ml)中,在5%钯—炭存在下,室温下将该溶液在氢气氛(40p.s.i.,2.76巴)中搅拌16小时。过滤混合物,蒸发滤液得3-(3-氨基-4-吡啶氨基)苯甲酸乙酯(4.8g)无色固体;m.p.89-91℃。(c)将上述产物(4.8g)的乙酸(25ml)和乙酸酐(25ml)溶液加热回流2小时并蒸发之。残留油状物注入水中,用固体碳酸钠碱化,用乙酸乙酯提取。合并有机提取液,用饱和氯化钠溶液洗涤,硫酸镁干燥、蒸发。残留物用乙酸乙酯重结晶得3-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸乙酯(2.9g)无色固体,m.p.120-121℃。
实测值:C,69.1;H,5.4;N,14.8.C15H15N3O2
理论值:C,68.3;H,5.3;N,14.9%.d)将上述产物(1.0g)和2M氢氧化钠水溶液(2.2ml)与乙醇(10ml)的混合物在室温下搅拌18小时。真空除去乙醇,剩下的水溶液用2M盐酸中和至pH6。收集所得残留物,用冰冷的水和***洗涤,干燥得3-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸(830mg)无色粉末,m.p.205-206℃,经鉴定含0.75当量水。
实测值:C,62.8;H,4.5; N,15.5.C13H11N3O2.0.75H2O
理论值:C,63.0;H,4.7;N,15.7%.
制备7
2-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸(a)将2-氨基苯甲酸乙酯(3.17g,20mmol)和4-氯-3-硝基吡啶(2.8ml)的乙醇(150ml)溶液在室温下搅拌60小时。收集所得沉淀物,用乙醇洗涤,干燥得2-(3-硝基-4-吡啶氨基)苯甲酸乙酯盐酸盐(3.9g)黄色结晶固体,m.p.192-205℃。
蒸发母液,残留物用乙醇重结晶再得1.5g产物。(b)将上述产物(5.3g)分配于乙酸乙酯和10%碳酸钠水溶液中,有机层用水洗涤、硫酸镁干燥、蒸发。残留物溶解于乙醇(800ml)中,在5%钯—炭存在下,将该溶液于氢气氛(40p.s.i.,2.76巴)中室温下搅拌16小时。过滤混合物,蒸发滤液得2-(3-氨基-4-吡啶氨基)苯甲酸乙酯(5.1g)无色油状物。(c)将上述产物(5.0g)的乙酸(25ml)和乙酸酐(25ml)溶液加热回流4小时并蒸发之。将残留油状物注入水中,用碳酸钠固体碱化,用乙酸乙酯提取。合并有机提取液,用饱和氯化钠溶液洗涤,硫酸镁干燥、蒸发。残留物用乙酸乙酯重结晶得2-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸乙酯(3.20g)无色晶体,m.p.125-127℃。d)将上述产物(1.0g)和2M氢氧化钠水溶液(2.2ml)与乙醇(10ml)的混合物在室温下搅拌18小时。真空除去乙醇,剩下的水溶液用2M盐酸中和至pH6。收集所得残留物,用冰冷的水和***洗涤,干燥得2-(2-甲基咪唑并[4,5-c]吡啶-1-基)苯甲酸(760mg)无色粉末,m.p.181-183℃,经鉴定含0.75当量水。
实测值:C,63.4;H,4.8;N,15.8.C13H11N3O2.0.75H2O
理论值:C,63.0;H,4.7;N,15.7%.
制备8
5-(2-甲基咪唑并[4,5-c]吡啶-1-基)噻吩-2-羧酸a)在30%钯—炭存在下,将2-氰基-5-硝基噻吩(Berichte,1943,76B 419;7.3g,47mmol)的乙醇(150ml)溶液在室温、20p.s.i.(1.4巴)下氢化4.5小时。过滤得2-氨基-5-氰基噻吩的甲醇溶液,立即使用。(b)将上述产物(5.8g,47mmol)的乙醇溶液在氮气氛与4-氯-3-硝基吡啶(8.89g,56mmol)一起在黑暗中搅拌18小时。加入二氯甲烷(100ml)和三乙胺(13ml,94mmol),接着加入二氧化硅(50g),真空除去溶剂。残留物加入色谱柱,先用二氯甲烷、再用二氯甲烷加10%乙酸乙酯洗脱。蒸发含产物的各级分,将暗红色固体悬浮于乙醇(100ml)中,混合物加热回流30分钟。冷却后,滤出固体,真空干燥得4-(5-氰基噻吩-2-基)氨基-3-硝基吡啶(6.1g,52%)。
实测值:C,48.77;H,2.42;N,23.37.C10H6N4O2S
理论值:C,48.77;H,2.46;N,22.75%.c)在30%钯—炭存在下,将上述产物在室温和20p.s.i.(1.4巴)下氢化4小时,过滤并蒸发溶剂得3-氨基-4-(5-氰基噻吩-2-基)氨基吡啶(5.35g,100%),立即用于环化步骤,按制备2C所述方法,制得2-氰基-5-(2-甲基咪唑并[4,5-c]吡啶-1-基)噻吩(2.25g,46%)。
1H NMR(CDCl3),δ=9.10(1H,s),8.53(1H,d,J=6Hz),7.75(1H,d,
J=4Hz),7.26(1H,d,J=6Hz),7.20(1H,d,J=4Hz),2.62(3H,s).d)将2-氰基-5-(2-甲基咪唑并[4,5-c]吡啶-1-基)噻吩(2.7g,11mmol)和氢氧化钠(1.76g,44mmol)溶于乙醇(23ml)和水(5ml)的混合物加热回流2小时。用2N盐酸调节pH值至6,用水稀释反应至500ml。将溶液分为两等分,每一部分均通过XAD-2离子交换树脂(350g)柱,先用水、接着用乙醇和水(1∶1)洗脱。将含产物的各馏分合并,真空除去溶剂。残留物用沸腾异丙醇溶解,过滤,真空蒸发溶剂;与甲苯形成共沸物,得标题化合物(1.8g,63%)。
1H NMR(DMSOd6),δ=8.91(1H,s),8.36(1H,d,J=5.5Hz),7.79(1H,d,
J=4.0Hz),7.47(1H,d,J=6Hz),7.40(1H,d,J=6Hz),2.55(3H,s).
Claims (8)
3.如权利要求2的方法,其中B是连接键或CH2。
4.如权利要求3的方法,其中n和m均为0。
5.如权利要求4的方法,其中R是Cl,B是连接键且A是CH2CH2。
6.如权利要求1的方法,其中式(I)化合物是4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚烷[1,2-b]吡啶-11-亚基)-1-[4-(2-甲基咪唑并[4,5-C]吡啶-1-基)苯甲酰基]哌啶。
7.如权利要求1的方法,其中反应在二酰亚胺偶合剂存在下、在有机溶剂中以及在室温进行。
8.如权利要求2的方法,其中所用的偶合剂是3-(二甲氨基丙基)-1-乙基碳化二亚胺或N,N’-二环己基碳化二亚胺。
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US7687515B2 (en) * | 2006-01-17 | 2010-03-30 | N.V. Organon | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
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WO1989010363A1 (en) * | 1988-04-28 | 1989-11-02 | Schering Corporation | Fused polycyclic compounds, compositions, methods of manufacture and their use as paf antagonists, antihistamines and/or antiinflammatory agents |
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