CN111840296A - 一种5H-噻唑并[3,2-a]嘧啶-5-酮类化合物在制备单胺氧化酶抑制剂中的用途 - Google Patents
一种5H-噻唑并[3,2-a]嘧啶-5-酮类化合物在制备单胺氧化酶抑制剂中的用途 Download PDFInfo
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- 239000002899 monoamine oxidase inhibitor Substances 0.000 title claims abstract description 10
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 title claims abstract description 9
- -1 5H-thiazolo[3,2-a]pyrimidin-5-one compound Chemical class 0.000 title claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 102000010909 Monoamine Oxidase Human genes 0.000 abstract description 21
- 108010062431 Monoamine oxidase Proteins 0.000 abstract description 21
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 3
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000002858 neurotransmitter agent Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 206010041250 Social phobia Diseases 0.000 description 2
- UEZROEGYRDHMRV-UHFFFAOYSA-N [1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical class O=C1C=CN=C2SC=CN12 UEZROEGYRDHMRV-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 2
- 229960003946 selegiline Drugs 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 102100028661 Amine oxidase [flavin-containing] A Human genes 0.000 description 1
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000694718 Homo sapiens Amine oxidase [flavin-containing] A Proteins 0.000 description 1
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
本发明公开了结构如式(Ⅰ)所示的5H‑噻唑并[3,2‑a]嘧啶‑5‑酮类化合物在制备单胺氧化酶抑制剂中的用途，经过体外酶活性实验测试，该类化合物对单胺氧化酶A和B具有良好的抑制活性，为开发新型MAO抑制剂提供参考和启发新思路。
Description
技术领域
本发明属于医药技术领域，涉及一种5H-噻唑并[3,2-a]嘧啶-5-酮类化合物的制药新用途，尤其是在制备单胺氧化酶抑制剂中的新用途。
背景技术
单胺类神经递质包括去甲肾上腺素、肾上腺素、多巴胺和五羟色胺，是神经递质中最重要的一类。这些神经递质及其代谢产物的表达水平与诸多疾病密切相关，影响着人类的注意力、情感和行为。例如，人体内5-HT浓度的降低会引起抑郁症；神经系统中多巴胺浓度的降低会诱发帕金森综合症和阿尔茨海默症。这些单胺类神经递质的降解调节主要通过单胺氧化酶(monoamine oxidase,MAO)来完成，因此，抑制MAO的活性就能够提高单胺类神经递质的表达水平并减少有害的胺代谢产物的生成。由此可见，MAO是一类重要的药物发现靶标。
单胺氧化酶是一类重要的氧化还原酶。人体内存在两种MAO亚型，MAO-A和MAO-B。这两个亚型之间具有高度的相似性。但是它们对底物的选择性有较大的差别。MAO-A通常催化五羟色胺、去甲肾上腺素、肾上腺素。MAO-B亚型则对苯甲胺、苯乙胺等神经递质具有高度的亲和力。由于它们底物的选择性不同，因此目前临床上使用这两个亚型的抑制剂治疗不同的疾病。例如MAO-A抑制剂主要用于治疗抑郁症、社交恐惧症、疼痛、偏头痛；而MAO-B抑制剂主要用于治疗阿尔茨海默症和帕金森综合症。
5H-噻唑并[3,2-a]嘧啶-5-酮类衍生物作为嘌呤结构类似物而具有潜在的生物活性，近几年来该骨架化合物因其在抗肿瘤、抑菌、抗病毒等生物活性方面而备受关注，但尚没有将其用作单胺氧化酶抑制剂的相关报导。
发明内容
本发明的目的是提供一种5H-噻唑并[3,2-a]嘧啶-5-酮类化合物在制备单胺氧化酶抑制剂中的应用。
为了实现本发明的上述目的，本发明采用了如下技术方案：
所述5H-噻唑并[3,2-a]嘧啶-5-酮类化合物的结构式如下：
其中，
所述R1、R2选自氢或烷基；
所述R3选自氢、烷基、
所述R4选自氢、
优选地，所述烷基为甲基。
表1中列出的是33个具体化合物，但本发明的保护范围不限于以下具体化合物。
表1化合物种类及其取代基
本发明首次发现并通过活性测试，验证了式(Ⅰ)所示的5H-噻唑并[3,2-a]嘧啶-5-酮类化合物具有单胺氧化酶A、B抑制活性，提供了该类化合物作为单胺氧化酶抑制剂的新用途，有望被开发成抑郁症、社交恐惧症、疼痛、偏头痛、阿尔茨海默症、帕金森综合症等疾病的治疗药物。
具体实施方式
下面通过实施例对本发明进行详细地说明，但并不以此来限定本发明。实施例中所使用到的化合物均可购自荷兰specs公司(http://www.specs.com)，均为specs公司化合物库中的化合物。
实施例1：本发明化合物对单胺氧化酶抑制剂活性的测试
1.实验试剂
本发明化合物、MAOA(Active Motif,Cat.No.31502)、MAOB(Active Motif,Cat.No.31503)、氯吉兰Clorgyline(Sigma,Cat.No.M3778)、司里吉兰R(-)-deprenyl(Abcam,Cat.No.ab120604)、384孔板(from Perkin Elmer,Cat.No.6007299)
2.实验方法
1)用100％的DMSO将本发明化合物溶解至100mM，在多孔板中加入HEPES位缓冲液，将化合物转移至多孔板中，使DMSO的浓度降低至1％。
2)将酶和底物分别溶解到缓冲溶液中，移入10μL的底物溶液，启动反应，静置60分钟，加入20μL的荧光素，混匀，室温下静置20分钟，测量并记录荧光信号的相对亮度，分别在10个浓度条件下测定化合物对酶的百分抑制率。
3)实验中，分别以氯吉兰、司里吉兰为对照，实验重复2-3次，分别计算最大荧光值和最小荧光值及其标准差，以最大荧光值和最小荧光值之比计算每一组多孔版数据的可靠性。
3.数据处理
1)使用Excel按照那个公式一计算每个化合物的抑制率
Inh％＝(Max-Signal)/(Max-Min)*100 Equation(1)
2)采用GraphPad Prism5将各个化合物在10个浓度条件下所得的酶的百分抑制率按照公式二进行拟合，计算化合物的IC50值，式中Y和X分别是百分抑制率和化合物浓度。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope)) Equation(2)
4.实验结果
本发明化合物经单胺氧化酶抑制活性筛选，并测得相应半数有效抑制浓度(IC50)。选自式(Ⅰ)的33个5H-噻唑并[3,2-a]嘧啶-5-酮类化合物的化学结构及其对单胺氧化酶的抑制率和IC50活性如下表所示。
表2化合物对单胺氧化酶的抑制活性
从上表结果可以看出，本发明提供的化合物对MAO-A和MAO-B均表现出良好的抑制活性。
Claims (3)
1.结构如式(Ⅰ)所示的5H-噻唑并[3,2-a]嘧啶-5-酮类化合物在制备单胺氧化酶抑制剂中的用途，
其中，
所述R1、R2选自氢或烷基；
所述R3选自氢、烷基、
所述R4选自氢、
2.如权利要求1所述的应用，其特征在于：所述烷基为甲基。
3.一种单胺氧化酶抑制剂，其活性成分是权利要求1中所述的结构如式(Ⅰ)所示的5H-噻唑并[3,2-a]嘧啶-5-酮类化合物。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105612162A (zh) * | 2013-10-11 | 2016-05-25 | 豪夫迈·罗氏有限公司 | 作为nmda受体活性的调节剂的噻唑并嘧啶酮类 |
| WO2017040879A1 (en) * | 2015-09-04 | 2017-03-09 | Lysosomal Therapeutics Inc. | Thiazolo(3,2-a) pyrimidinone and other heterobicyclic pyrimidinone compounds for use in medical therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105612162A (zh) * | 2013-10-11 | 2016-05-25 | 豪夫迈·罗氏有限公司 | 作为nmda受体活性的调节剂的噻唑并嘧啶酮类 |
| WO2017040879A1 (en) * | 2015-09-04 | 2017-03-09 | Lysosomal Therapeutics Inc. | Thiazolo(3,2-a) pyrimidinone and other heterobicyclic pyrimidinone compounds for use in medical therapy |
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