CN1024006C - 具有类视黄酸活性的乙炔基芳香杂环酸的制备方法 - Google Patents

具有类视黄酸活性的乙炔基芳香杂环酸的制备方法 Download PDF

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CN1024006C
CN1024006C CN87107535A CN87107535A CN1024006C CN 1024006 C CN1024006 C CN 1024006C CN 87107535 A CN87107535 A CN 87107535A CN 87107535 A CN87107535 A CN 87107535A CN 1024006 C CN1024006 C CN 1024006C
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罗山发·A·S·陈德拉勒娜
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Abstract

具有类视黄酸活性的下式化合物的制备方法，式中A为吡啶基、呋喃基或噻吩基；n为0-5；及B为H、-COOH及其酯、酰胺和药物可接受的盐；-CHO及其缩醛衍生物；-COR1及其缩酮衍生物，其中R1为-(CH2)nCH3，其中n如上所定义；或-CH2OH及其醚和酰基酯衍生物。

Description

本发明涉及具有类视黄酸活性的新颖化合物，更具体地说，本发明涉及其中在视黄酸的含酸末端单位的三个烯烃单位都被含乙炔基芳香杂环基的官能基所取代的化合物。对视黄酸的结构作此种修正可保持有类视黄酸的活性。
日本专利56-123903所揭示的杀线虫化合物，具有结构式2-（2-（1，1-二甲基）-二甲基甲硅烷基）氧基）乙基-α-（4-（2，6-6-三甲基-1-环己烯-1-基）-3-丁烯-1-炔基）-1-环戊烯-1-甲醇，该化合物采用本文所揭示的化合物的1-（2′，6′，6′-三甲基-环己-1′-烯基）-丁-1-烯-3-炔部分。然而，这仅仅是日本专利和本文所揭示的唯一类似的部分，此种化合物并未包括本发明。
本发明包括式Ⅰ化合物
Figure 871075350_IMG4
其中A是吡啶基、呋喃基、噻吩基、哒嗪基、嘧啶基或吡嗪基;n为0-5，而B为H、-COOH及其酯、酰胺和药物上可接受的盐、-CHO及其缩醛衍生物、-COR1及其缩酮衍生物其中R1为-（CH2）nCH3，n为如上所定义、或-CH2OH及其醚和酰基酯衍生物;或药物可接受的盐。
本发明的第二个特点是涉及式Ⅰ化合物用于治疗皮肤病，例如痤疮、毛囊角化病、牛皮癣、鱼鳞癣、湿疹、异位性皮肤炎和小上皮癌。这些化合物也可用于治疗关节疾病及其他免疫疾患（例如，红斑性狼疮），用于促进创伤愈合及治疗干眼病候群。
本发明也涉及包含式Ⅰ化合物与药用可接受的赋形剂混合的药物配方。
本发明的另一特点是涉及式Ⅰ化合物的制法，该方法包括使式Ⅱ化合物与式Ⅲ化合物在pd（PQ3）4（Q为苯基）或类似的复合物存在下进行反应，
Figure 871075350_IMG5
其中X是卤素，最好是碘;A是吡啶基、呋喃基、噻吩基、哒嗪基、嘧啶基或吡嗪基;n为如上所定义;而B是氢或被保护的酸、醇、醛或酮、得到对应于式Ⅰ的化合物;或下式同系化的化合物
Figure 871075350_IMG6
其中n为0-4而A为如上定义的杂环;或将式Ⅰ的酸转化为酸或酸式盐;或将式Ⅰ的酸转化为酯;或将式Ⅰ的酸转化为酰胺;或将酸还原为醇或醛;或将醇转化为醚或酯;或将醇氧化为醛;或将醛转化为缩醛;或将酮转化为缩酮。
一般实施例
本文所用的“酯”一词代表且包括所有有机化学传统使用的名词定义范围内的任一种化合物，包括有机酯及无机酯。当B为-COOH时，本词包括使用醇或硫醇处理此官能团所衍生的产物。当从B为-CH2OH的化合物衍生得到酯时，本词包括从可形成酯的有机酸例如磷基及硫基酸衍生得到的化合物，或式-CH2OCOR化合物，式中R为任何经取代或未经取代的脂肪族，芳香族，杂芳香族或脂肪族一芳香族基。
较佳酯系从10或10以下的碳原子的饱和脂肪族醇或酸衍生而得，或从5至10碳原子的环状或饱和脂肪族环醇或酸衍生而得。特佳的脂肪族酯为从低级烷基酸或醇衍生而得。在此处和其它处，低级烷基是代表具有1-6碳原子的，也属较佳者为苯基或低级烷基苯基酯。
酰胺具有机化学界传统使用的该名词定义。此种情况下包括未取代酰胺及所有脂肪族及芳香族一-及二-取代酰胺。较佳酰胺为从10或10以下碳原子的饱和脂肪族基或5至10碳原子的环状或饱和脂肪族环状基衍生而得的一-及二-取代酰胺。特佳酰胺为从取代及未取代低级烷基胺类衍生而得。也属较佳者为从取代及未取代的苯基或低级烷基苯基胺类衍生而得的一-及二-取代酰胺，未取代的酰胺也属较佳。
缩醛和缩酮包括式-CK的基团其中K为（-OR2），在此，R为低级烷基。同时K可为-OR1O-其中R1为2-5碳原子的直链或支链低级链烯烃。
对本发明具有可形成盐类官能度，例如酸或胺官能度的任何化合物均可制成药物可接受的盐。药物可接受的盐为任何保持有母体化合物活性并且在用药给个体以及在其投药范围内，不产生任何有害或副作用的任何一种盐。
药物可接受盐可从有机或无机酸或碱衍生而得。盐可为一价或多价离子。特别感兴趣者为无机离子，钠、钾、钙及镁。有机盐可使用胺，尤其铵盐例如一-、二-及三烷基胺或乙醇胺制得。盐也可使用咖啡因， 托美沙明及类似分子而生成。
本发明较佳化合物是乙炔基和B基分别连接到吡啶环的2和5位上（烟酸命名中的6和3位等于吡啶命名中的2/5位）或分别连接到噻吩基的5和2位的那些化合物;n为0，1或2;B为-COOH、碱金属盐或有机胺盐、或低级烷基酯、或-CH2OH及其低级烷基酯。最佳化合物为：
6-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]烟酸乙酯;
6-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]烟酸;
5-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]噻吩-2-羧酸乙酯;及
5-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]噻吩-2-羧酸。
本发明化合物的全身性或局部性投药，是依据如有待处理的病情，所需要治疗的具体部位，投药的药量，及一些其他考虑因素而定。
在皮肤病的治疗中，通常采用局部用药较好，唯某些例中例如治疗严重性痤疮，也可使用口服投药。
任何常用的局部治疗配方例如溶液、悬浮液、胶浆、软膏或油膏等均可使用。此种局部用配方的制备，在药物配方领域中已有详细叙述，例如，叙述于雷明顿药物科学，17版，宾州，伊斯顿市，麦克出版公司。该化合物供局部用药也可以粉剂或喷洒剂，尤其以气溶胶形式投药。
若化合物是经全身性投药，则可调配成粉剂、丸剂、片剂等，或者配成糖浆或酏剂适用于口服投药。化合物供静脉或腹内投药则可制成可经注射投药的溶液剂或悬浮液剂。某些情况下，可将该化合物调配成栓剂剂型或以持续释放配方以供经皮肤或肌肉注射而沉积。
其他药物可加入该局部配方中达到其第二目的，例如治疗皮肤干燥，提供防晒保护等;也可加入其他治疗皮肤病药物，预防感染、减少刺激发炎等。
可经由投药与治疗有效剂量的一种或多种本发明化合物，治疗皮肤病或任何其他已知或已发现对类视黄酸化合物的治疗具有敏感性的任何其他相应的病。治疗浓度以可减少特定病情或延迟其扩展的该种浓度。在某些病例中，该药物可以预防方式用以防止特定病情的出现。
特定的治疗浓度随着各病情而异，某些情况下可能随有待治疗的病情严重度及病人对治疗的敏感度而异。因此，最好在发病期和发病区通过常规实验来确定特定的治疗浓度。
预期用于治疗，例如痤疮或其它此类皮肤病的治疗有效浓度，为含有0.01至1.0mg/ml的配方若经全身性投药，则预期0.01至5mg/kg/日体重的用量可获得疗效。
该化合物的类视黄酸活性可按传统测定视黄酸活性而加以验证，包括测定视黄酸对鸟氨酸脱羧酶的功效。对于视黄酸与细胞增生降低间的关系最初是由Verma及Boutwell进行研究，癌症研究，1977，37，2196-2201。该参考文献揭示，在聚胺生物合成之前有鸟氨酸脱羧酶（ODC）的活性增高。其他研究者已经确定聚胺合成的增加可能与细胞增生有关。因此，若可抑制ODC活性，则可调节细胞过度增生的问题。虽然ODC活性增高的因素仍未知，但已知12-O-十四烷基佛波醇-13-乙酸酯（TPA）可诱出ODC活性，而视黄酸可抑制由TPA诱出ODC活性。基本上遵照癌症研究：1662-1670，1975所述的程序进行检定可验证本发明化合物也可抑制TPA诱出ODC。
特殊实施例
预期本发明化合物可由多种不同的化学合成途径来制备，为说明本发明，可用反应式Ⅰ所示的一系列反应步骤制得某些有代表性的式Ⅰ化合物。合成化学家将可了解在此所列的条件是指特定具体实施例，这些实施例可应用于任何或所有由式Ⅰ所代表的化合物。
反应式Ⅰ列出了制备式Ⅰ化合物的一般程序。
反应式Ⅰ
Figure 871075350_IMG7
在反应式中，“卤取代杂环酯”上的卤可以是溴、氯或碘，而以溴和碘较好。A、B、n具有如式Ⅰ取代基定义中所述的相同含义。
一般地说，通过将式Ⅰ的酮与强碱及氯磷酸二烷基酯一起处理，接着再用碱处理，以引入炔属官能基。然后将炔属基转化为重金属盐，即ZnCl盐，使芳环增加炔属功能。由于该ZnCl盐的碱性，致使B基团的酸性减至最小。为获得最佳的反应得率，衍生的酸、醇、醛和酮都是必要的。在前述反应步骤后，需通过如Arndt-Eistert反应的同系化作用使烷基链（-CH2-）延长。
式Ⅰ的化合物由Aldrich化学公司以β-芷香酮之名出售。在减温及于惰性气氛下用二异丙酰胺锂（LDA）或类似碱的方法，将酮转化为三键，反应是在醚型溶剂例如三烷基醚或环醚，如四氢呋喃，吡喃等中进行。
更确切地说，二异丙酰胺锂是经由将二异丙胺在无水溶剂例如四氢呋喃中混合，然后在惰性气氛下冷却至-70至-50℃间的温度生成。然后在减温下加入等摩尔量的烷基锂化合物例如正丁基锂于合适溶剂中并混合，经适当时间生成二异丙酰胺锂（LDA）。式Ⅰ的酮（至少10%摩尔过量）溶解于该反应溶剂中，溶液冷却至LDA混合物的温度，且加入该溶液内，经短暂混合后，将溶液用氯磷酸二烷基酯，较好为氯磷酸二乙酯以约20%摩尔过量处理。然后将反应溶液逐渐升回室温，接着将此溶液加到第二部分二异丙酰胺锂溶液中，该二异丙酰胺锂溶液是使用无水溶剂及在惰性气氛下，较好是在氩之下于减温（-78℃）下同一反应器中制备。随后，将反应混合物再度温热至室温，搅拌一段时间，较好10至20小时，最好约15小时。接着将溶液酸化且用常规分离方法回收产物。
式3化合物在完全无水和无氧的条件下制备。可使用无水醚型溶剂例如二烷基醚或环醚如呋喃或吡喃，较好为四氢呋喃作溶剂。首先在惰性气氛如氩或氮下制得式2的溶液，然后加入强碱如正丁基锂（约10% 摩尔过量）。该反应始于-10°至+10℃的减温下，较好约为0℃。将反应混合物搅拌短时间，即30分钟至2小时，然后使用约10%摩尔过量的熔融氯化锌溶解于反应溶剂中来处理。该混合物于约开始温度下，再搅拌1-3小时，然后将温度升高至约室温10至40分钟。
囟取代杂环酯从其对应的酸、卤素（氯，溴，碘）制备。吡啶基、呋喃基、噻吩基、二嗪基的酸均可从化学制造商处得到或用已公开的方法制得。通过使酸在适合的醇溶液中，于亚硫酰氯的存在下回流或通过使酸和醇在二环己基碳二亚胺和二甲基氨基吡啶的存在下进行酯化反应。用常规方法回收和纯化所得到的酯，亦可用其他常规方法进行酯化反应。
欲生成式4化合物，可将卤呋喃糖烷酯或对应的噻吩，吡啶或几种二嗪异构体的烷基囟酯溶解在无水溶剂中。酯的用量约等于化合物3开始用量的摩尔量。将该溶液引进到四（三苯膦）钯（约为反应物摩尔量的5至10%）的反应溶剂的悬浮液内，此悬浮液的温度约为-10°至+10℃间。短暂搅拌该混合物约15分钟，然后向刚制得的该混合物中加入预先制备好的化合物3的溶液，并在约室温下加入氯化锌盐，该溶液在室温下搅拌长时间，约15至25小时。然后用酸猝熄反应，产物用常规方法分离和纯化得到式4化合物。
使皂化的式4的酯和所得到的酸按Arndt-Eistert方法连续进行同系化作用，得到n为1-5的式5化合物。然后用上述所列程序使囟取代杂环酸酯化，即可将这些酸转化为式Ⅰ的酯。
可用本领域已知的任何适合的酰胺化方法生成酰胺。在这种情况下，该化合物的一种制备方法是首先制成酰基氯，然后用氢氧化铵处理该化合物。例如用醇碱如乙醇氢氧化钾（约10%摩尔过量）于室温下处理该酯约半小时，去除溶剂，残渣溶解于有机溶剂如醚内，用二烷基甲酰胺处理，接着用10倍过量的草酰氯处理，全部反应都在约-10°至+10℃的减温下进行。然后，将后述溶液在减温下搅拌1-4小时，较好2小时。 去除溶剂，留下残渣溶解于惰性溶剂如苯中，冷却至约0℃并用浓氢氧化铵处理，所得混合物于减温下搅拌1-4小时，用常规方法回收产物。
醇的制法，可将对应的酸用亚硫酰氯或其它的方法转化成酰基氯（J.March，“先进有机化学”，第二版，麦克罗-希耳出版公司），然后用硼氢化钠还原酰基氯（March同文，1124页），可得对应的醇。此外，还可用氢化锂铝于减温下还原酯。用适合的烷基囟化物于威廉森氏（Wil-liamson）反应条件（March同文，357页）下烷基化此种醇得对应的醚。
可用温和氧化剂如重铬酸吡啶鎓的二氯甲烷（Corey，E.J.，Schmidt，G.Tetlett.，399，1979），或二甲基亚砜/草酰氯的二氯甲烷（Omura，K.，Swern，D.Tetrahedron，1978，34，1651），从对应的伯醇制备醛。
酮可通过用烷基格利雅试剂或类似的试剂处理醛，随后进行氧化，从适合的醛制备而得。
缩醛或缩酮可用March同文，810页所述的方法从对应的醛或酮制备而得。
其中B为-CH3的化合物可从对应的囟杂环部分来制备，其中囟素最好是碘。该杂环化合物如反应式Ⅰ中，更确切地说，是如实施例3中所述与乙炔基氯化锌部分反应。其中B为-CH3的卤取代杂环化合物可由市面购得或可用文献中的方法制备。
列举如下实施例以说明本发明，而非限制其范围。
实施例1
1-（2，6，6-三甲基环己-1-烯基）丁-1-烯-3-炔
将12.17克（120.27mmol）二异丙胺的200ml无水四氢呋喃溶液在氩气下冷却至-78℃，并用75ml1.6M（120mmol）正丁基锂的己烷溶液经由注射筒逐滴处理。该混合物于约-78℃下搅拌一小时，然后用21.99g（114.35mmol）β-芷香酮（1）的20ml的无水四氢呋喃的冷溶液（-78℃），经由导管处理。该混合物于约-78℃搅拌一小时，用21.73g （125.93mmol）的氯磷酸二乙酯逐滴处理，并使其在2小时内温热至室温。然后，于氩气及-78℃下将该溶液经导管移入26.57g（262.57mmol）二异丙胺的150ml无水四氢呋喃和164ml1.6M（262.4mmol）正丁基锂的己烷溶液经搅拌0.5小时而制备的二异丙酰胺锂的溶液中。使该混合物温热至室温，搅拌15小时，用250ml    3N盐酸酸化并用戊烷萃取，有机萃取液用1N盐酸、水、饱和的碳酸氢钠和饱和的氯化钠洗涤并用硫酸镁干燥。产物于硅藻土装置（50℃;0.1mm）上浓缩及蒸馏得无色油状的标题化合物。
PMR（CDCl3）：δ1.0（2CH3，s），1.45（2H，m），1.65（CH3，s），1.92（2H，m）2.85（1H，d，J～3Hz），5.35（1H，dd，J～16Hz，3Hz），6.6（1H，d，J～16Hz）.
实施例2
6-氯烟酸乙酯
将15.75g（0.1mol）6-氯烟酸、6.9g（0.15mol）乙醇、22.7g（0.11mol）二环己基碳化二亚胺和3.7g二甲基氨基吡啶（0.03mol）的混合物于200ml的二氯甲烷中加热回流2小时，使该混合物冷却，真空除溶剂，残渣进行闪蒸色谱法分析得16.7g低熔点白色固体的标题化合物。
PMR（CDCl3）：δ1.44（3H，t，J～6.2Hz），4.44（2H，q，J～4.4Hz），7.44（1H，d，J～8.1Hz），8.27（1H，dd，J～8.1Hz，3Hz），9.02（1H，d，J～3Hz）
实施例3
6-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]烟酸乙酯
将本程序中所用的反应容器于真空下经火焰干燥，并在无氧的氩或氮气氛下进行所有的操作。于0℃，向实施例1化合物，620.7mg （3.5614mmol）4ml无水四氢呋喃的溶液滴加2.25ml的1.6M（3.6mmol）正丁基锂的己烷。该混合物于0℃搅拌10分钟，于室温再搅拌10分钟，再冷却到0℃。于0℃，经导管向该溶液加入500mg（3.6689mmol）熔融氯化锌的4ml无水四氢呋喃，搅拌一小时，又于室温再搅拌10分钟。经导管将664mg（3.5774mmol）6-氯烟酸乙酯的4ml无水四氢呋喃的溶液移入430mg（0.3721mmol）四（三苯膦）钯的6ml无水四氢呋喃悬浮液中，搅拌10分钟。经导管将该混合物与炔基锌的溶液一起处理，所得混合物于室温下搅拌60小时。加水（100ml），产物用3×100ml醚萃取，用饱和氯化钠溶液洗涤合并的醚萃取液，干燥（MgSO4）及浓缩得褐色油，该油经闪蒸色谱法分析（硅胶;10%乙酸乙酯的己烷），接着经高压液相色谱法（Waters）6000;Partisil M-9 10/50;5%乙酸乙酯的己烷）进行纯化得淡黄色油状的标题化合物。
PMR（CDCl3）;δ1.06（2CH3，s），1.42（3H，t，J～7Hz），1.46（2H，m），1.61（2H，m），1.78（CH3，s）2.05（2H，m），4.42（2H，t，J～7Hz），5.75（1H，d，J～16.5Hz），6.89（1H，d，J～16.5Hz），7.48（1H，d，J～7.8Hz），8.25（1H，dd，J～7.8，～2Hz），9.15（1H，d，J～2Hz）.
用类似的方法，但用适合的卤取代杂环酯代替6-氯烟酸乙酯，可制得下列各化合物：
2-[2-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）-5-吡啶基]乙酸乙酯;
3-[2-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）-5-吡啶基]丙酸乙酯;
4-[2-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）-5-吡啶基]丁酸乙酯;及
5-[2-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）-5-吡啶基]戊酸乙酯。
实施例4
5-溴-2-糠酸乙酯
向搅拌着的8.43g（44.14mmol）的5-溴-2-糠酸的100ml无水乙醇的悬浮液中，加入4ml亚硫酰氯，于回流下，搅拌该混合物3小时，又于室温下搅拌18小时，真空除溶剂，残留油用100ml水处理并用3×75ml醚萃取，用饱和碳酸氢钠和饱和氯化钠溶液洗涤合并的醚萃取液并干燥（MgSO4）。真空除溶剂，残渣在硅藻土装置（60℃;0.4mm）上蒸馏得无色油状的标题化合物。
PMR（CDCl3）;δ1.35（3H，t，J～7Hz），4.37（2H，q，J～7Hz），6.45（1H，d，J～4Hz），7.1（1H，d，J～4Hz）.
实施例5
5-溴噻吩-2-羧酸乙酯
向1.092g（5.7157mmol）的5-溴噻吩-2-羧醛依次加入1.507g（30.75mmol）氰化钠、60ml乙醇、602.5mg（10.04mmol）的乙酸和10.62g（122.16mmol）的二氧化锰，于室温下搅拌该混合物24小时，然后经硅藻土过滤，残渣用醚洗涤几次。浓缩合并的滤液，然后将残渣溶解在水中并用3×75ml醚萃取，用饱和碳酸氢钠、饱和氯化钠洗涤合并的醚萃取液，干燥（MgSO4），真空浓缩并在硅藻土装置（70℃;0.1mm）蒸馏得淡黄色油的标题化合物。
PMR（CDCl3）：δ1.3（3H，t，J～7Hz），4.35（2H，t，J～7Hz），7.12（1H，d，J～4Hz），7.6（1H，d，J～4Hz）.
实施例6
5-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]-2-糠酸乙酯
5-[4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基]噻吩-2-羧酸乙酯
用实施例3所述的方法和条件，但用实施例4所制备的5-溴-2-糠酸乙酯或实施例5所制备的5-溴-噻吩-2-羧酸乙酯代替，分别制得标题化合物。糠酸酯具有下列PMR光谱特性：
PMR（CDCl3）：
δ1.1（6H，s），1.43（3H，t，J～7.6Hz），1.52（2H，m），1.65（2H，m），1.81（3H，S），2.1（2H，m），4.42（2H，q，J～7.6Hz），5.73（1H，d，J～16.8Hz），6.66（1H，d，J～3.5Hz），6.83（1H，d，J～16.8Hz），7.21（1H，d，J～3.5Hz）.
噻吩-2-羧酸酯化合物具有下列PMR光谱特性：
PMR（CDCL3）：δ
1.08（6H，s），1.39（3H，t，J～7.2Hz），1.50（2H，m），1.62（2H，m），1.79（3H，s），2.08（2H，m），4.37（2H，q，J～7.5Hz），5.72（1H，d，J～16.5Hz），6.76（1H，d，J～16.5Hz），7.14（1H，d，J～3.9Hz），7.67（1H，d，J～3.9Hz）.
用类似的方法，但用适合的杂环酯代替噻吩-2-羧酸乙酯和5-溴-2-糠酸乙酯，可制得下列化合物：
2-〔5-（4-（2，6，6-三甲基环己烯基）-丁-3-烯-1-炔基〕呋喃-2-基〕乙酸乙酯;
3-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕呋喃-2-基〕丙酸乙酯;
4-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕呋喃-2-基〕丁酸乙酯;
5-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕呋喃-2-基〕戊酸乙酯;
2-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-基〕丙酸乙酯;
3-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-基〕丙酸乙酯;
4-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-基〕丁酸乙酯;及
5-〔5-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-基〕戊酸乙酯。
实施例7
6-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕烟酸
使用前立即将氮气发泡通入本实验所用的溶液中。于氮气氛下，向53mg（0.1641mmol）6-〔4-（2，6，6，-三甲基环己-1-烯基）-丁-3-烯-1 -炔基）烟酸乙酯的200ml乙醇的搅拌溶液中，加入132ml1.86M（0.2459mmol）氢氧化钾的乙醇和水的溶液。室温搅拌3小时后，真空除溶剂，残渣用1ml水处理，用醚萃取2次，每次1ml，用50%乙酸水溶液酸化水层，并用3×2ml醚萃取。硫酸镁干燥合并的醚萃取液并真空浓缩得淡黄色粉末状的标题产物。PMR（CDCl3）：δ
1.06（6H，s），1.48（2H，m），1.62（2H，m），1.78（3H，s），2.05（2H，m），5.75（1H，d，J～16.4Hz），6.93（1H，d，J～16.4Hz），7.55（1H，d，J～8.1Hz），8.35（1H，dd，J～8.1，2.3Hz），9.29（1H，d，J～2.3Hz）.
用类似的方法，将按实施例6而制备的酯转化为对应的酸，例如：
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）呋喃糖酸;及
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-羧酸。
实施例8
2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基）-5-羟基甲基吡啶。
将一个250ml三颈烧瓶装上一个搅拌器、一个滴液漏斗，一个氮气入口及一个温度计。烧瓶内盛放379.5mg（10mmol）氢化锂铝的30ml无水乙醚的溶液。在氮气下，将溶液冷却至-65℃，在温度不超过-60℃下，滴加3，2343g（10mmol）6-（4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-烟酸乙酯的15ml无水乙醚。于-30℃搅拌混合物一小时，然后通过加入300mg（3.4mmol）乙酸乙酯以破坏过量的氢化物。再加入3ml饱和的氯化铵溶液使反应混合物进行水解并使温度升至室温，过滤混合物，残渣用醚洗涤，用饱和氯化钠溶液洗涤醚层、干燥（MgSO4），真空浓缩。残渣经色谱分析，接着经重结晶纯化得标题化合物。
实施例9
2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-5-乙氧甲基吡啶
2.81g（10mmol）2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-5-羟甲基吡啶、600mg（10mmol）冰醋酸、2.06g（10mmol）二环己基二碳化亚胺及460mg（3.765mmol）4-二甲基氨基吡啶的150ml二氯甲烷的溶液于室温下搅拌48小时。过滤反应混合物，残渣用50ml二氯甲烷洗涤。滤液真空浓缩，残渣经色谱分折，接着经重结晶得标题化合物。
用相同的方法，可将上述实施例3和6所制备的任何酸或酯转化为其对应的伯醇类似物。
实施例10
2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-吡啶-5-羧醛
将1.396g（11mmol）闪蒸蒸馏的草酰氯的25ml的二氯甲烷的溶液装入一个装有一搅拌器、一温度计和2个带有干燥管的均压添加漏斗的四颈烧瓶内。将溶液冷却到-60℃，在5分钟内，用1.875g（24mmol）的二甲亚砜（从氯化钙蒸馏而得）的5ml二氯甲烷滴加处理，反应混合物于60℃下再搅拌10分钟。然后将2.81g（10mmol）2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-5-羟甲基吡啶的10ml二氯甲烷的溶液于5分钟内加到反应混合物中。再搅拌混合物15分钟，用5，06g（50mmol）的三乙胺处理，撤除冷浴，使混合物温热至室温，将30ml水加入混合物中，再继续搅拌10分钟。分离有机层，水层用20ml二氯甲烷萃取，合并有机层，依次用稀盐酸、水及稀碳酸钠溶液洗涤，干燥（MgSO4）。过滤溶液并真空浓缩，残渣经色谱法接着经重结晶纯化得标题化合物。
用该方法可将实施例8所制备的所有醇氧化为其对应的醛。
实施例11
2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-5-（1-羟丙基）吡啶
将4ml3M（12mmol）溴化乙基镁的醚溶液装入一个三颈烧瓶内。此烧瓶是装有一个机械搅拌器，一个附有干燥管的回流冷凝器，一个附有干燥管的均压滴加漏斗。将烧瓶在冰浴上冷却并在据烈搅拌下将2.8g（10mmol）的2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕吡啶-5-羧醛的10ml无水醚的溶液慢慢加入。撤除冷却浴，混合物于回流下加热3小时。混合物再于冰盐浴上冷却并加入5ml饱和氯化铵溶液。混合物再搅拌一小时并过滤，残渣用醚洗涤两次，每次10ml。分离醚溶液，干燥（MgSO4），真空除醚，残渣经色谱分折接着经重结晶纯化得标题化合物。
用相同方法，以实施例10所制备的任何其他的芳香杂环醛代替上述吡啶化合物，可将其醛转化为仲醇。
用实施例10所述的相同试剂，约相同的试剂与反应物的用量及基本相同的反应条件，可将这些仲醇转化其对应的酮。
实施例12
2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-5-二甲氧甲基吡啶
在装有干燥管的回流冷凝器下方装上附有迪安一斯达克装置的一个圆底烧瓶。将3.35g（12mmol）2-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕吡啶-5-羧醛、4.80mg（15mmol）无水甲醇、2mg对甲苯磺酸一水合物和10ml无水苯的混合物装入烧瓶，混合物于氮气下回流加热，用迪安一斯达克榻分水器收集水分，直至收集到接近水的理论量。反应混合物冷却至室温，用5ml10%氢氧化钠溶液依次萃取，并用水洗涤两次，每次5ml，干燥（MgSO4），过滤溶液，真空除溶剂。残渣经色 谱法分析，接着经重结晶纯化得标题化合物。
用类似方法，可将按实施例10和11所制得的任何含芳香杂环的化合物的醛或酮转化为缩醛或缩酮。

Claims (10)

1、一种制备式Ⅰ化合物的方法：
Figure 871075350_IMG2
式中A是吡啶基、呋喃基或噻吩基；n为0-5，而B为H、-COOH及其酯，药物上可接受的盐和酰胺；-CHO及其缩醛衍生物；-CH2OH及其醚和酰基酯衍生物、或-COR1及其缩酮衍生物其中R1为-(CH2)nCH3(其中n如上所定义)；该方法包括使式Ⅱ的化合物与式Ⅲ的化合物于四(三苯膦)钯[pd(PQ3)4](其中Q为苯基)或类似配合物存在下进行反应，
其中X是囟素，最好是碘；A是吡啶基、呋喃基或噻吩基；n为如上所定义；而B是氢、或被保护的酸、醇、醛或酮，如果需要，按常规方法将所得产物脱保护基或将其转化，得到相应的式Ⅰ化合物。
2、根据权利要求1的方法，其中A为吡啶基。
3、根据权利要求2的方法，其中B为-COOH及其低级烷基酯，药物可接受的盐，或-CH2OH，及其低级烷基酯。
4、根据权利要求3的方法，其中n为0，其化合物为：
6-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕烟酸乙酯，或
6-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕烟酸或其药物可接受的盐。
5、根据权利要求1的方法，其中A为呋喃基。
6、根据权利要求5的方法，其中B为-COOH及低级烷基酯，药物可接受的盐，或-CH2OH，及其低级烷基酯。
7、根据权利要求6的方法，其中n为0，制得化合物为：
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕呋喃糖乙酯，或
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕呋喃糖酸。
8、根据权利要求1的方法，其中A为噻吩基。
9、根据权利要求8的方法，其中B为-COOH及其低级烷基酯，药物可接受的盐，或-CH2OH，及其低级烷基酯。
10、根据权利要求9的方法，其中n为0，制得化合物为：
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕噻吩-2-羧酸乙酯，或
5-〔4-（2，6，6-三甲基环己-1-烯基）-丁-3-烯-1-炔基〕-噻吩-2-羧酸。
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EP0272921A1 (en) 1988-06-29
FI875681A0 (fi) 1987-12-22
KR880007411A (ko) 1988-08-27
DK682087D0 (da) 1987-12-22
ATE62899T1 (de) 1991-05-15
AU8292587A (en) 1988-06-30
NO875422D0 (no) 1987-12-23
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FI875681A (fi) 1988-06-25
ES2036591T3 (es) 1993-06-01
EG19587A (en) 1995-06-29
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MY103040A (en) 1993-04-30
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FI90766C (fi) 1994-03-25
IL84878A0 (en) 1988-06-30
PT86442A (en) 1988-01-01
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IL84878A (en) 1992-06-21
JPS63190878A (ja) 1988-08-08
ZA879595B (en) 1989-09-27
DE3769618D1 (de) 1991-05-29
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HUT46307A (en) 1988-10-28
EP0272921B1 (en) 1991-04-24
NO175205C (no) 1994-09-14
AU599444B2 (en) 1990-07-19
PH23861A (en) 1989-11-23
NO875422L (no) 1988-06-27
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HU198295B (en) 1989-09-28

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