CN101691373A - 一种治疗勃起功能障碍和早泄的药物及其制备 - Google Patents
一种治疗勃起功能障碍和早泄的药物及其制备 Download PDFInfo
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- CN101691373A CN101691373A CN200910206711A CN200910206711A CN101691373A CN 101691373 A CN101691373 A CN 101691373A CN 200910206711 A CN200910206711 A CN 200910206711A CN 200910206711 A CN200910206711 A CN 200910206711A CN 101691373 A CN101691373 A CN 101691373A
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Abstract
本发明涉及一种治疗勃起功能障碍和早泄的药物化合物及其制备和应用，本发明的化合物，其结构为，5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮分子中的氯基团被具有局部麻醉作用的分子取代。
Description
技术领域：
本发明涉及一种治疗勃起功能障碍和早泄的药物化合物及其制备和应用。
背景技术：
西地那非为一种治疗男性勃起功能障碍的药物，其化学名称为5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H吡唑并[4，3-d]-嘧啶-7-酮。
临床研究表明该产品对某些病人有头晕、心绞痛，和心慌等副作用，而且除了治疗勃起功能障碍外，在男性性生活过程中还有过早射精即早泄问题，因此设计一种具有治疗治疗勃起功能障碍同时治疗早泄的药物是需要的。
西地那非和伐地那非与其靶酶PDE-5的复合物已用晶体X光衍射的方法得到了其请晰的图象(Nature 2003.425 98)从而对结构和功能的关系有进一步的了解，也为新药的设计提供了新的基础。
男性性生活时射精潜伏期短过早射精常称为早泄，与勃起功能障碍一样是常见的男性功能疾病。根据报道成年男子的早泄发病率高达35-50％，早泄的病因有心理因素，也可能有器质性因素，实验表明有些早泄患者的感觉特别是阴茎头部的感觉非常灵敏，对性刺激的感受性过高而诱发早泄。据此，临床上用局部麻醉剂和利多卡因的喷雾制剂，喷涂阴茎头部以降低其敏感度从而延长射精潜伏期，但这些制剂不够规范，因药量过高，局部麻醉作用过强，可导致性快感障碍和勃起功能障碍。
迄今还没有治疗早泄的口服药批准上市，实验发现多巴胺能增高大脑皮层射精中枢的兴奋，但被与5-羟色胺所抑制，因而己批准上市的选择性5-羟色胺抑制剂(SSRI)舍曲林，帕罗西丁等，就被直接在临床上试用于早泄的治疗。但结果表明，服用舍曲林，帕罗西丁等药数周甚至数月后有效率趋于50％而副作用也达到50％，因此目前均未被批准为治疗早泄的口服药。
发明内容：
本发明以西地那非与PDE-5酶复合物的单晶X光衍射图为依据，进行了结构设计。西地那非与PDE-5酶有效结合部分为吡唑并嘧啶酮结构部分，而西地那非的4-甲基哌嗪为可取代部分。由此本发明利用西地那非的吡唑并嘧啶酮部分作为脱敏结构的载体，可使整个分子被引向阴茎海绵体内，由局部麻醉药类分子取代西地那非的4-甲基哌嗪作为脱敏官能基团，从而设计合成由吡唑并嘧啶酮作载体，由麻醉脱敏官能基团作功能主体的可能有治疗勃起功能障碍或可能治疗早泄的化合物。
单晶X光衍射图表明西地那非的苯基吡唑并嘧啶酮结构包含在PDE-5酶的Q口袋中，而磺酰哌嗪结构则在袋盖之外，本发明设想西地那非中吡唑并嘧啶酮是与PDE-5结合较紧密部份而与磺酰基相连的4-甲基哌嗪则在Q口袋之外为可取代部份，如取代基团有脱敏作用，则整个分子以其吡唑并嘧啶酮与PDE-5酶结合，同时也是脱敏基团的载体引向阴茎海绵体，从而使化合物具有促使阴茎勃起的功能，脱敏作用可延长射精潜伏期，可治疗早泄。
为此，经过筛选，本发明提供一种化合物，其结构为，5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮分子中的氯基团被具有局部麻醉作用的分子取代。
所述具有局部麻醉作用的分子包括如下分子：
丁卡因，羟普鲁卡因，氨部卡因，美布卡因，丙美卡因，布他卡因，匹多卡因本发明优选的化合物，结构如下
其中，
R1＝C1-C3烷基
R2＝H，C1-C3烷基，羟乙基
X＝0，NH
n＝1-3
R3＝R4＝C1-C3烷基
优选的其中
R1，R3，R4＝C2H5、
R2＝H、
X＝0，NH，
n＝2
本发明还提供本发明化合物的制备方法，该方法包括5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并(4，3-d)嘧啶-7-酮化合物与具有局部麻醉作用的化合物进行反应。
优选的如将5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(II)与4-氨基苯甲酸酯或酰胺(III)与碱在适当溶剂中反应生成(I)
R2，R3，R4，X和n的定义如前述。
其中4-氨基苯甲酸酯或4-氨基苯甲酰胺优选为4-氨基苯甲酸2-(二乙氨基)乙酯或4-氨基苯甲酰N-(2-(二乙氨基)乙胺。
所用的碱为无水碳酸钾，三乙胺，N，N-二甲基苯胺和吡啶，优选的碱是吡啶。
所用的溶剂为二氯甲烷，三氯甲烷，丙酮，丁酮，四氢呋喃和二氧六圜。优选的溶剂为二氯甲烷，丙酮和四氢呋喃。反应温度为10-30℃。
本发明还提供一种以本发明的化合物为活性成分的药物组合物，该组合物必要时可以含有药物可接受的载体，其中本发明化合物的量可以是1-99％，药物可接受的载体的量可以是1-99％，所述药物可接受的载体可以是，但不限于是以下产品：水、醇、蜂蜜、淀粉、蔗糖、乳糖、焦糖、甘露糖醇、硅衍生物、纤维素类及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β--环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁和大豆异黄酮等。
本发明药物组合物可以通过口服，口含或其他方式服用，如注射方式，外帖方式，阴道给药方式，鼻内给药方式等。
本发明的组合物可以制成任何一种适合服用的剂型，这些剂型可以是：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。本发明的组合物，优选的是口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂。
本发明的组合物还可以含有其他治疗作用的成分，也可以和其他治疗疾病的药物一同服用。
本发明的化合物经过实验证明，具有治疗男性性功能障碍作用和早泄作用。本发明还提供本发明的化合物及其药物组合物在治疗男性勃起障碍或早泄药物中的应用。
以下通过实验数据说明本发明的有益效果。
本发明优选的化合物I-1，(官能团为：R1、R3、R4＝C2H5，R2＝H，X＝O，n＝2)化学名称：5-{2-乙氧基-5-[(4-(2-二乙氨基乙氧羰基)-苯氨基)]-磺酰基-苯基}-1-甲基-3-正丙基-正丙基-1.6-二氢-7H-吡唑并[4.3-D]嘧啶-7-酮(I-1)与I-2(官能团为：R1、R3、R4＝C2H5，R2＝H，X＝NH，n＝2)化学名称：5-[2-乙氧基-5-[4-(2-二氨基-乙氨羰基)苯氨基]磺酰基]-苯基-1-甲基-3-正西基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(I-2)
的活性与毒性体外检测结果如下：两者对PDE-5酶抑制作用的IC50，分别为3.3nM和2.7nM，对小白鼠急性毒性LD50均大于5克/公斤，说明I-1和I-2对PDE-5酶的抑制作用很强，而急性毒性则很小(重庆医科大学生化教研室药理教研室)。I-1和I-2经少数志愿者服用50-150mg能不同程度延长射精潜伏期，而且有剂量依赖性。
具体实施方式：
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1：
5-{2-乙氧基-5-[(4-(2-二乙氨基乙氧羰基)-苯氨基)]-磺酰基-苯基}-1-甲基-3-正丙基-正丙基-1.6-二氢-7H-吡唑并[4.3-D]嘧啶-7-酮(I)4-氨基苯甲酸-2-(＝乙氨基)乙酯(普罗卡因)5.4g(22.5mmol)溶于丙酮110ml和吡啶4.5ml；搅拌下分次加入5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(II)9克(22.5mmol)，加毕，室温搅拌八小时，得黄色混悬液，滤出固体，丙酮洗，得黄色固体，加热溶于乙醇，加活性炭，脱色，过滤，滤液放置于冰箱(7℃)过夜，过滤，烘干9克，熔点168-170℃(重结晶溶剂种类或量的不同可得不同熔点)。
1H NMR(300MHz DMSO)
δ0.936(3H，t)，1.230(2×3H，t)，1.293(3H，t)，1.907-1.765(2H，m)，2.770(2H，t)，3.154-3.295(2×2H，q)，3.460(2H，t)，4.144(3H，s)，4.154(2H，t)，4.548(2H，t)7.279-7.316(3H，m)，7.906-7.935(3H，m)，8.036(1H，t)11.012(1H，s)，12.127(1H，s).
实施例2
5-[2-乙氧基-5-[4-(2-二氨基-乙氨羰基)苯氨基]磺酰基]-苯基-1-甲基-3-正西基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(I-2)
N-(2-乙氨基乙基)-4-氨基苯甲酰胺4g(17mmol)普罗酰胺)溶于丙酮90ml和吡啶3.5ml中，5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮(II)6.15克(15mmol)搅拌下分次加入成桔红色混悬物，室温搅拌5小时，过滤，用丙酮洗，淡黄色固体8克，用乙醇加热溶解，活性炭脱色，过滤，滤液冰箱7℃过夜，过滤烘干6.2克，熔点215-216℃。
1HNMR(500MHz，DMSO)
δ0.952(3H，t)，1.212(2×3H，t)，1.302(3H，t)，1.730-1.775(2H，m)，2.763(2H，t)，3.132-3.193(3×2H，m)3.584-3.619(2H，q)，4.144(2H，t)，4.155(3H，s)7.223(2×1H，d)，7.298(1H，d)，7.832(2×1H，d)，7.909-7.931(1H，dd)8.036(1H，d)，10.327(1H，s)10.765(1H，s)，12.109(1H，s)
实施例3
I-1和I-2片剂的制备
处方：
1-1 50.0克
微晶纤维素 80.0克
乳糖 100.0克
碳酸氢钙 18.0克
淀粉 8.0克
硬脂酸镁 30.0克
预胶化淀粉 20.0克
丙基纤维素 80.0克
羟甲基纤维素钠 1.0克
经制粒压片成I-1片1000片含I-150mg/片以I-2取代处方中I-1可得I-2片1000片含I-250mg/片
实施例4
I-1和I-2胶囊的制备
I-150克 维晶纤维素200克 混匀装胶囊1000粒，含I-150mg/粒。
以I-2取代I-1可得I-2胶囊1000粒，含I-2 50mg/粒
实施例5
丁卡因，羟普鲁卡因，氨部卡因，美布卡因，丙美卡因，布他卡因，匹多卡因和5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮反应制备得到响应的化合物，制备方法同实施例1。
Claims (10)
1.一种化合物，其结构为，5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮分子中的氯基团被具有局部麻醉作用的分子取代。
2.根据权利要求1的化合物，结构如下：
其中，R1＝C1-C3烷基，R2＝H，C1-C3烷基或羟乙基，
X＝O或NH n＝1-3 R3＝R4＝C1-C3烷基。
3.根据权利要求2的化合物，其特征在于，其中R1＝R3＝R4＝C2H5，R2＝H，X＝O或NH，n＝2。
4.权利要求1的化合物的制备方法，其特征在于，5-[2-烷氧基-5-(氯磺酰基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并(4，3-d)嘧啶-7-酮与具有局部麻醉作用的分子反应。
5.权利要求4的制备方法，其特征在于，具有局部麻醉作用的分子为4-氨基苯甲酸酯或4-氨基苯甲酰胺。
6.权利要求4的制备方法，其特征在于，反应在碱存在下进行。
7.权利要求4的制备方法，其特征在于，4-氨基苯甲酸酯或4-氨基苯甲酰胺为4-氨基苯甲酸2-(二乙氨基)乙酯或4-氨基苯甲酰N-(2-(二乙氨基)乙胺。
8.含权利要求1的化合物的药物组合物。
9.权利要求1的化合物在制备治疗男性勃起障碍或早泄药物中的应用。
10.保护本发明所述化合物的设计以及类似设计：利用由西地那非的吡唑并嘧啶酮作载体结构并以局部麻醉药类分子替代西地那非的4-甲基哌嗪可取代部分作为治疗勃起功能障碍或早泄药物的类似设计。
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