CN116178148A - 一类抑制激肽释放酶活性的分子设计合成 - Google Patents
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Abstract
本发明涉及新型生理、药物活性分子制备，属于药物合成化学领域，涉及一类抑制人激肽释放酶活性的分子的设计和制备。首先以氟代丙烯酸和醇类化合物为原料，得到一类氟代烯丙醇类化合物；然后氟代烯丙醇与羧酸类化合物缩合，得到具有通式(I)可以抑制人激肽释放酶活性的氟代烯丙醇羧酸酯类结构化合物。该类化合物被认为可用于治疗糖尿病性并发症、眼部疾病及水肿相关疾病。此外在一些癌症的诊断和治疗有着潜在的应用。
Description
技术领域
本发明涉及新型生理、药物活性分子制备，属于药物合成化学领域，具体涉及一类抑制人激肽释放酶活性的分子的设计和制备。
背景技术
激肽释放酶(kallikrein，KLK)属丝氨酸蛋白酶的一种，存在于各种组织和生物液体中，是可催化大分子前体物(激肽原，kininogen)释放生物活性肽的酶。其有多种生理功能，参与调控大脑发育、机体的生理适应性以及其它生理代谢。激肽释放酶参与许多疾病反应，包括炎症、低血压、肾炎、糖尿病性肾病、皮肤病等。激肽释放酶在中枢神经系统中与癫痫症、阿尔茨海默氏病的发病有着重要的相关性。近来研究证实人工合成的激肽释放酶抑制剂可以有效抑制乳腺癌、前列腺癌和卵巢癌细胞的侵入，在癌症的治疗和预防中有着重要的潜在价值。
针对激肽释放酶的活性影响多种疾病的发生，并且在癌症的诊断、预防和治疗中的潜在应用价值。本发明专利设计和合成了一类新的有机化合物，在抑制激肽释放酶活性方面有着重要的潜力。因此，本发明合成的新化合物被认为可用于糖尿病性并发症、眼部疾病及水肿相关疾病，及乳腺癌、前列腺癌和卵巢癌的诊断和治疗有着巨大潜在的应用价值。
发明内容
本发明采用如下技术方案：一类抑制激肽释放酶活性的分子设计合成，其特征在于：首先以氟代丙烯酸和醇类化合物为原料，以三(2-苯基吡啶)合铱为催化剂、三乙烯二胺为碱、过氧化苯甲酸叔丁酯为引发剂、乙腈为溶剂，按下述反应式进行反应，得到一类氟代烯丙醇类化合物；然后氟代烯丙醇与羧酸类化合物缩合，得到具有通式(I)的可以抑制激肽释放酶活性的氟代烯丙醇羧酸酯类结构化合物：
该发明设计了一类氟代烯丙醇羧酸酯类结化合物，被认为可用于治疗糖尿病性并发症、眼部疾病及水肿相关疾病。除此之外，其在一些癌症的诊断和治疗有着潜在的价值。
具体实施方式
下面通过具体实施方式对本发明的技术方案进行做进一步说明：
实施例1，该实施例的反应式如下所示：
步骤1：在空气下，三(2-苯基吡啶)合铱(1mol％)、三乙烯二胺(1equiv)、2-氟代-3-对氟苯基丙烯酸(1mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入2.5mL乙腈和2.5mL乙醇，在室温下465纳米光照下反应36小时。
步骤2：旋干步骤(1)中所得的有机相中的溶剂，得到粗产物，然后纯化粗产物，加入二氯甲烷10mL和1.1当量环戊基甲酸，室温搅拌下加入1.1当量N，N′-二环己基碳二亚胺，反应4小时。分离产物，综合收率70％，产物纯度100％。
实施例2
该实施例的反应式如下所示：
步骤1：在空气下，三(2-苯基吡啶)合铱(1mol％)、三乙烯二胺(1equiv)、2-氟代-3-对溴苯基丙烯酸(1mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入2.5mL乙腈和2.5mL乙醇，在室温下465纳米光照下反应36小时。
步骤2：旋干步骤(1)中所得的有机相中的溶剂，得到粗产物，然后纯化粗产物，加入二氯甲烷10mL和1.1当量环戊基甲酸，室温搅拌下加入1.1当量N，N′-二环己基碳二亚胺，反应4小时。分离产物，综合收率68％，产物纯度100％。
实施例3
该实施例的反应式如下所示：
步骤1：在空气下，三(2-苯基吡啶)合铱(1mol％)、三乙烯二胺(1equiv)、2-氟代-3-对氟苯基丙烯酸(1mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入2.5mL乙腈和2.5mL乙醇，在室温下465纳米光照下反应36小时。
步骤2：旋干步骤(1)中所得的有机相中的溶剂，得到粗产物，然后纯化粗产物，加入二氯甲烷10mL和1.1当量对氯苯乙酸，室温搅拌下加入1.1当量N，N′-二环己基碳二亚胺，反应4小时。分离产物，综合收率72％，产物纯度100％。
实施例4
该实施例的反应式如下所示：
步骤1：在空气下，三(2-苯基吡啶)合铱(1mol％)、三乙烯二胺(1equiv)、2-氟代-3-对氟苯基丙烯酸(1mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入2.5mL乙腈和2.5mL3-羟基丙腈，在室温下465纳米光照下反应36小时。
步骤2：旋干步骤(1)中所得的有机相中的溶剂，得到粗产物，然后纯化粗产物，加入二氯甲烷10mL和1.1当量环戊基甲酸，室温搅拌下加入1.1当量N，N′-二环己基碳二亚胺，反应4小时。分离产物，综合收率50％，产物纯度100％。
实施例5
该实施例的反应式如下所示：
步骤1：在空气下，三(2-苯基吡啶)合铱(1mol％)、三乙烯二胺(1equiv)、2-氟代-3-苯基丙烯酸(1mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入2.5mL乙腈和2.5mL3-羟基丙酸甲酯，在室温下465纳米光照下反应36小时。
步骤2：旋干步骤(1)中所得的有机相中的溶剂，得到粗产物，然后纯化粗产物，加入二氯甲烷10mL和1.1当量对氯苯乙酸，室温搅拌下加入1.1当量N，N′-二环己基碳二亚胺，反应4小时。分离产物，综合收率48％，产物纯度100％。
所用的各物质的量及反应条件同实施例进行实验拓展，以说明本发明的技术方案具有良好的官能团兼容性。
以上已将本发明做一详细说明，以上所述，仅为本发明实施例，当不能限定本申请实施范围，即凡依本申请范围所作均等变化与修饰，皆应仍属本发明涵盖范围。
附图说明
图1为本发明制备的产物3的核磁共振氢谱；
图2为本发明制备的产物3的核磁共振氟谱；
图3为本发明制备的产物3的核磁共振碳谱。
Claims (4)
1.一类抑制激肽释放酶活性的分子设计合成，其特征在于：首先以氟代丙烯酸和醇类化合物为原料，以三(2-苯基吡啶)合铱为催化剂、三乙烯二胺为碱、过氧化苯甲酸叔丁酯为引发剂、乙腈为溶剂，光照条件下按下述反应式进行反应，得到一类氟代烯丙醇类化合物；然后氟代烯丙醇与羧酸类化合物在N，N′-二环己基碳二亚胺为缩合剂条件下缩合，得到具有通式(I)可抑制激肽释放酶活性的氟代烯丙醇羧酸酯类结构化合物：
R1为氢、氟、溴等，R2为氢、甲基等，R3为甲基、乙基、酯基、氰基等，R3和R4为甲基、环戊基、苯乙基等。
2.一类抑制激肽释放酶活性的分子设计合成，其特征在于：第一步中所述催化剂的物质的量为氟代丙烯酸的物质的量的1％，三乙烯二胺为碱的物质的量为氟代丙烯酸的物质的量的1倍。
3.一类抑制激肽释放酶活性的分子设计合成，其特征在于：第二步中所述缩合剂的物质的量为氟代烯丙醇的物质的量的1.1倍，羧酸的物质的量为氟代烯丙醇的物质的量的1.1倍。
4.根据权利要求1所述的一类抑制激肽释放酶活性的分子设计合成，其特征在于：第一步反应光照波长为465纳米。
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