CN1393444A - 一种治疗阳痿的新化合物 - Google Patents
一种治疗阳痿的新化合物 Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明涉及一种式(I)的新的选择性的磷酸二酯酶抑制剂化合物及其可药用盐或其构型异构体，本发明还提供了一种制备式(I)化合物的方法，以及式(I)化合物合成路线中涉及到新的中间体化合物；本发明的式(I)化合物不仅对阳痿疾病的治疗，如对男性勃起障碍的治疗具有良好的效果，而且还具有药效持续时间长和毒性低的特点。
Description
本发明涉及一种治疗阳痿的新化合物，具体而言，本发明涉及一种治疗阳痿的新化合物及其制备方法和用途。
西地那非(Sildenafil)是一种选择性的磷酸二酯酶抑制剂，其化学名称为：1-[4-乙氧基-3-(6，7-二氢-1-甲基-7-氧化-3-丙基-1H-吡唑并[4，3-d]嘧啶-5-基)苯基磺酰基]-4-甲基哌嗪的化合物，专利公开说明书CN1057464A中公开了该化合物及其制备方法和该化合物用于治疗心血管疾病的用途；CN1124926A中公开了将该化合物用于制备治疗雄性动物勃起机能障碍药物的用途；CN1168376A中公开了一种制备西地那非的新方法；CN1246478A中公开了另一种制备西地那非的新方法。尽管西地那非对男性勃起障碍的治疗具有良好的效果，但是该化合物具有较大的毒副作用。
本发明的目的是提供了一种新的选择性的磷酸二酯酶抑制剂，即下面的通式(I)化合物及其可药用盐或其构型异构体，该类化合物具有下面通式(I)的结构式：
其中R1和R2可以相同或不同，分别可以是C1-6烷基，优选甲基，最优选的是R1和R2均处于哌嗪环的顺式位，并且都是甲基；
本发明的另一目的是提供了一种制备式(I)化合物的方法；
本发明化合物的合成路线中涉及到新的中间体化合物，因此，本发明的另一目的是提供了制备式I化合物的中间体化合物；
本发明的另一目的是提供了一种含有式(I)化合物作为活性成分的药物组合物；
本发明的另一目的是提供了一种式(I)化合物用于制备治疗阳痿疾病的药物的用途。
本发明式(I)化合物的哌嗪环上有两个取代基R1和R2，有两个不对称碳原子，并且R1和R2可以处于哌嗪环的顺式或反式，因此，式(I)化合物存在各种构型异构体，这些异构体及其可药用盐都属于本发明化合物的范围。
本发明优选的化合物是R1和R2处于顺式的式(I)化合物，本发明最优选的化合物是R1和R2均为甲基并且处于顺式的化合物，其化学名称是：5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮，即下面的式(I’)化合物：
本发明的式(I)化合物不仅对阳痿疾病的治疗，如对男性勃起障碍的治疗具有良好的效果，而且还具有药效持续时间长和毒性低的特点。
下面以式(I’)化合物为例说明式(I)化合物的制备方法。
本发明的式(I’)化合物的合成路线如下：
式(I’)化合物的制备是以2-乙氧基苯甲酸为原料，在二氯亚砜存在下与氯磺酸反应得到5-氯磺酰基-2-乙氧基苯甲酸(化合物II)；将化合物(II)与顺式-2，6-二甲基哌嗪(其制备方法参见：《中国医药工业杂志》，1997年，28(11)，第524-525页)反应得到2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酸(化合物III)；将化合物(III)的酸酰氯化得到2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰氯(化合物IV)，该化合物是新化合物；将化合物(IV)与化合物(V)(该化合物的制备参见CN1246478A中的式(IX)化合物的合成)在4-二甲氨基吡啶和三乙胺存在下反应制备得到4-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰胺基]-1-甲基-3-正丙基吡唑-5-甲酰胺(化合物VI)，该化合物是新化合物；化合物(VI)在叔丁醇钾作用下合环得到5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮(化合物I’)。
下面通过实施例进一步说明本发明式(I’)化合物及其可药用盐的制备。应该理解的是，本发明实施例的制备方法仅仅是用于说明本发明，而不是对本发明的限制，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。实施例1：5-氯磺酰基-2-乙氧基苯甲酸(II)的制备
在250ml的三颈瓶中，搅拌下，将2-乙氧基苯甲酸50g(0.30mol)滴入冰浴冷却的22ml(0.30mol)二氯亚砜和82.6ml(1.24mol)氯磺酸的混合物中，同时保持反应混合物的温度低于25℃，将得到的混合物室温搅拌18小时后，倒入搅拌下的冰水中，出现白色沉淀。继续搅拌1小时后，过滤，水洗，真空干燥得白色固体化合物(II)粗品64.4g(收率81％)，熔点：108-110℃。粗产物不需纯化，直接投入下步反应。实施例2：2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酸(III)的制备
在250ml三颈瓶中，搅拌下，将52.6g(0.23mol)顺式-2，6-二甲基哌嗪在约10℃下，加到53.0g(0.2mol)化合物(II)的水(170ml)悬浮液中，同时保持反应混合物温度低于20℃。加毕，于10℃继续搅拌2小时，析出沉淀，过滤，冰水洗涤，干燥，丙酮回流1小时，纯化，得到白色结晶化合物(III)48.0g(收率70％)，熔点：260.5-273.0℃(分解)。HNMR(DMSO)δ：7.72-7.75(2H，苯环上4-H，6-H)，7.26-7.28(1H，苯环上3-H)，4.12-4.17(2H，-OCH2-)，3.5-3.53(2H，哌嗪环上-CH2-)，2.89-2.92(2H，哌嗪环上的两个-CH-)，1.80-1.86(2H，哌嗪环上-CH2-)，1.31-1.34(3H，乙氧基上的-CH3)，1.0-1.04(6H，哌嗪环上的两个甲基取代基-CH3)。实施例3：2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰氯(IV)的制备
将34.2g(0.1mol)化合物(III)与二氯亚砜73.0ml(0.5mol)的混合物置于250ml三颈瓶内，加热回流3小时，减压蒸除氯化亚砜至尽，剩余物加入乙酸乙酯搅拌，析出沉淀过滤，乙酸乙酯洗涤，真空干燥，得黄色固体化合物(IV)29.4g，收率74％。熔点：206.0-209.5℃。HNMR(D2O)δ：8.0(1H，苯环6-H)，7.74-7.76(1H，苯环4-H)，7.14-7.16(1H，苯环上3-H)，4.08-4.11(2H，-OCH2-)，3.74-3.77(2H，哌嗪环上-CH2-)，3.32(2H，哌嗪环上的两个-CH-)，2.19-2.25(2H，哌嗪环上的另一个-CH2-)，1.24-1.27(3H，乙氧基上-CH3)，1.09-1.10(6H，哌嗪环上的两个甲基取代基-CH3)。实施例4：4-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰胺基]-1-甲基-3-正丙基吡唑-5-甲酰胺(VI)的制备
在500ml三颈瓶中，依次加入二氯甲烷125ml，1-甲基-4-氨基-3-丙基吡唑-5-甲酰胺化合物(V)9.1g(0.05mol)，4-二甲氨基吡啶0.06g(0.0005mol)和三乙胺(10.1g，0.1mol)，用冰浴冷却到10℃以下，向该溶液中滴加25.80g(0.065mol)化合物(IV)的二氯甲烷溶液(125ml)，加毕，保温搅拌2小时，蒸干溶剂，残余物加水搅拌析出固体，过滤，乙酸乙酯洗涤，干燥得灰白色固体化合物(VI)19.2g，收率76％。熔点：197-198.5℃。HNMR(CDCl3)δ：8.62(1H，苯环上的6-H)，7.90-7.92(1H，苯环4-H)，7.90(1H，-CO-NH-)，7.17-7.27(1H，苯环3-H)，5.73(1H，哌嗪环上的-NH-)，4.37-4.41(2H，-OCH2-)，4.06(3H，吡唑环上N-CH3)，3.63-3.66(2H，哌嗪环上-CH2-)，3.0(2H，哌嗪环上的两个-CH-)，2.52-2.56(2H，吡唑环上的取代丙基1’位的-CH2-)，1.84-1.90(2H，哌嗪环上的另一个-CH2-)，1.65-1.69(2H，吡唑环上的取代丙基2’位的-CH2-)，1.58-1.63(3H，苯环取代乙氧基上-CH3)，1.03-1.05(6H，哌嗪环上的两个甲基取代基-CH3)，0.94-0.97(3H，吡唑环上取代丙基上的-CH3)。实施例5：5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮(I’)的制备
在250ml三颈瓶中，加入金属钾1.8g(0.046mol)，干燥的叔丁醇96ml，再向该溶液中加入19g(0.038mol)化合物(VI)，混合物被搅拌，加热回流8小时。冷却至室温后，加水96ml稀释，用0.5mol/L盐酸调节pH＝7，析出沉淀，10℃以下放置1小时。过滤，冰水洗涤，干燥，得到白色结晶化合物(I’)17.0g(93％)。熔点：202.2-203.2℃。HNMR(MeOD)δ：8.15(1H，苯环上的6-H)，7.90-7.93(1H，苯环上4-H)，7.36-7.38(1H，苯环3-H)，4.32(2H，-OCH2-)，4.23(3H，吡唑环上N-CH3)，3.75-3.78(2H，哌嗪环上-CH2-)，3.10(2H，哌嗪环上的两个-CH-)，2.86-2.89(2H，吡唑环上的取代丙基1’位的-CH2-)，2.04-2.10(2H，哌嗪环上的另一个-CH2-)，1.80-1.84(2H，吡唑环上的取代丙基2’位的-CH2-)，1.45-1.48(3H，乙氧基上-CH3)，1.14-1.17(6H，哌嗪环上的两个取代甲基-CH3)，0.97-1.01(3H，吡唑环上取代丙基上的-CH3)。如果必要，可以用常规的方法将式(I’)化合物转化成其可药用盐。
本发明人研究发现，本发明的化合物对男性勃起障碍的治疗具有良好的效果，并且毒副作用很小，具体药效学和毒性试验结果归纳如下：一.药效学试验：试验1.式(I’)化合物对摘除睾丸大鼠的壮阳试验：
试验结果表明，式(I’)化合物在给药量为24mg/kg和12mg/kg时，可以明显地缩短电刺激(10伏特)大鼠阴茎勃起的潜伏期(P＜0.05和P＜0.01)，对照化合物西地那非化合物具有相同的作用(P＜0.01)。试验2.式(I’)化合物对摘除睾丸小鼠性功能的影响：
结果a：试验结果表明，式(I’)化合物在给药量为24mg/kg和12mg/kg时，可以明显地缩短雄鼠扑捉雌鼠的潜伏期(P＜0.05和P＜0.01)。
结果b：试验结果表明，式(I’)化合物在给药量为24mg/kg和12mg/kg时，可以明显增加雄性小鼠对雌性小鼠的爬背次数(性交次数)(P＜0.05和P＜0.01)。二.毒性试验：
应用Bliss法，测得式(I’)化合物小白鼠灌胃给药的半数致死量LD50是901.5mg/kg，95％可信限是772.5-1052.1mg/kg。
据《中国临床药理学与治疗学杂志》，1999，4(3)，237-240中报道，雄性小鼠一次口服西地那非的半数致死量LD50是625mg/kg，95％可信限是50-672mg/kg。
Claims (8)
1.一种具有通式(I)结构的化合物及其可药用盐或其构型异构体：
其中R1和R2可以相同或不同，分别可以是C1-6烷基。
2.根据权利要求1的化合物，该化合物是5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮，具有下面式(I’)结构：
3.一种式(1’)化合物的制备方法，该方法包括下列步骤：
a.以2-乙氧基苯甲酸为原料，在二氯亚砜存在下与氯磺酸反应得到5-氯磺酰基-2-乙氧基苯甲酸(II)；
b.将化合物(II)与顺式-2，6-二甲基哌嗪反应得到2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酸(III)；
c.将化合物(III)酰氯化得到2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰氯(IV)；
d.将化合物(IV)与化合物(V)在4-二甲氨基吡啶和三乙胺存在下反应制备得到4-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯甲酰胺基]-1-甲基-3-正丙基吡唑-5-甲酰胺(VI)； 
e.化合物(VI)在叔丁醇钾作用下合环得到5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮(I’) ：
4.一种式(VI)化合物，该化合物是4-[2-乙氧基-5-(顺式-2.6-二甲基哌嗪-1-磺酰基)苯甲酰胺基]-1-甲基-3-正丙基吡唑-5-甲酰胺，具有下面的式(VI)结构式：
5.一种治疗阳痿的药物组合物，其含有有效量的作为活性成分的式(I)化合物或其可药用盐或其构型异构体和可药用载体。
6.根据权利要求5的药物组合物，其中式(I)化合物是5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮。
7.式(I)化合物用于制备治疗阳痿疾病的药物的用途。
8.根据权利要求7的用途，其中式(I)化合物是5-[2-乙氧基-5-(顺式-2，6-二甲基哌嗪-1-磺酰基)苯基]-1-甲基-3-正丙基-7，6-二氢-1H-吡唑并[4，3-d]嘧啶-7-酮。
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| PT2754139T PT1400522E (pt) | 2001-06-29 | 2002-06-21 | Compostos para tratar a impotência |
| KR1020037016805A KR100878739B1 (ko) | 2001-06-29 | 2002-06-21 | 발기부전 치료를 위한 신규한 화합물 |
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| BRPI0211025A BRPI0211025B8 (pt) | 2001-06-29 | 2002-06-21 | um novo composto para o tratamento da impotência |
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| EP02754139.0A EP1400522B1 (en) | 2001-06-29 | 2002-06-21 | Compounds for treating impotence |
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| US10/736,732 US6960592B2 (en) | 2001-06-29 | 2003-12-16 | 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one compound for the treatment of impotence |
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| CN100360531C (zh) * | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 用于预防或治疗阳萎和性冷淡的新吡唑并嘧啶类化合物 |
| CN101914100A (zh) * | 2010-04-13 | 2010-12-15 | 漆又毛 | 苯磺酰基二甲基哌嗪衍生物及制备方法 |
| CN109970744A (zh) * | 2019-04-10 | 2019-07-05 | 重庆康刻尔制药有限公司 | 一种枸橼酸西地那非中间体的合成方法 |
| CN112745323A (zh) * | 2020-12-30 | 2021-05-04 | 北京悦康科创医药科技股份有限公司 | 枸橼酸爱地那非晶型h及其制备方法和用途 |
| CN113350301A (zh) * | 2021-06-03 | 2021-09-07 | 刘宝顺 | 一种治疗阳痿的新化合物中药蜜丸 |
| CN116262118A (zh) * | 2021-12-14 | 2023-06-16 | 真奥金银花药业有限公司 | 爱地那非或其盐在制备预防或治疗缺血性脑损伤的药物中的应用 |
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| EP2024369A4 (en) * | 2006-06-05 | 2010-10-27 | Matrix Lab Ltd | NEW PROCESS FOR THE PREPARATION OF SILDENAFIL CITRATE |
| CN101891747B (zh) * | 2010-07-02 | 2012-04-25 | 张南 | 抑制5型磷酸二酯酶的化合物及制备方法 |
| KR102580664B1 (ko) | 2023-01-25 | 2023-09-21 | (주)나인팩토리커뮤니케이션 | 남성 성기에 부종감 및 온열감을 주고 혈행을 개선하는 피부 외용제 조성물 |
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| CN100360531C (zh) * | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 用于预防或治疗阳萎和性冷淡的新吡唑并嘧啶类化合物 |
| CN101914100A (zh) * | 2010-04-13 | 2010-12-15 | 漆又毛 | 苯磺酰基二甲基哌嗪衍生物及制备方法 |
| CN101914100B (zh) * | 2010-04-13 | 2013-01-30 | 漆又毛 | 苯磺酰基二甲基哌嗪衍生物及制备方法 |
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| CN113350301A (zh) * | 2021-06-03 | 2021-09-07 | 刘宝顺 | 一种治疗阳痿的新化合物中药蜜丸 |
| CN116262118A (zh) * | 2021-12-14 | 2023-06-16 | 真奥金银花药业有限公司 | 爱地那非或其盐在制备预防或治疗缺血性脑损伤的药物中的应用 |
| CN116262118B (zh) * | 2021-12-14 | 2024-03-29 | 真奥金银花药业有限公司 | 爱地那非或其盐在制备预防或治疗缺血性脑损伤的药物中的应用 |
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| Publication number | Publication date |
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| AU2002323774B2 (en) | 2007-10-25 |
| CN1127506C (zh) | 2003-11-12 |
| WO2003016313A1 (fr) | 2003-02-27 |
| MXPA03011929A (es) | 2005-03-07 |
| JP2005500381A (ja) | 2005-01-06 |
| RU2004102513A (ru) | 2005-03-27 |
| IL159386A0 (en) | 2004-06-01 |
| US20040152709A1 (en) | 2004-08-05 |
| CA2451990C (en) | 2008-06-17 |
| DK1400522T3 (da) | 2014-11-10 |
| KR100878739B1 (ko) | 2009-01-14 |
| EP1400522A1 (en) | 2004-03-24 |
| EP1400522A4 (en) | 2006-04-05 |
| US6960592B2 (en) | 2005-11-01 |
| KR20040010779A (ko) | 2004-01-31 |
| RU2279433C2 (ru) | 2006-07-10 |
| CA2451990A1 (en) | 2003-02-27 |
| NZ530548A (en) | 2005-04-29 |
| EP1400522B1 (en) | 2014-08-06 |
| PT1400522E (pt) | 2014-10-30 |
| BRPI0211025B1 (pt) | 2016-03-01 |
| MA26117A1 (fr) | 2004-04-01 |
| CY1115687T1 (el) | 2017-01-25 |
| ES2519441T3 (es) | 2014-11-07 |
| BRPI0211025B8 (pt) | 2021-05-25 |
| BR0211025A (pt) | 2004-10-19 |
| JP4469174B2 (ja) | 2010-05-26 |
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