CN111840296B - Application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound in preparation of monoamine oxidase inhibitor - Google Patents
Application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound in preparation of monoamine oxidase inhibitor Download PDFInfo
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- CN111840296B CN111840296B CN202010713053.3A CN202010713053A CN111840296B CN 111840296 B CN111840296 B CN 111840296B CN 202010713053 A CN202010713053 A CN 202010713053A CN 111840296 B CN111840296 B CN 111840296B
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- monoamine oxidase
- thiazolo
- pyrimidine
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- oxidase inhibitor
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- 239000002899 monoamine oxidase inhibitor Substances 0.000 title claims abstract description 11
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 5
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- -1 5H-thiazolo [3,2-a ] pyrimidin-5-one compound Chemical class 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 21
- 102000010909 Monoamine Oxidase Human genes 0.000 abstract description 19
- 108010062431 Monoamine oxidase Proteins 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 108090000790 Enzymes Proteins 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
- 230000005764 inhibitory process Effects 0.000 description 7
- 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
- 239000000758 substrate Substances 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 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
- 208000019695 Migraine disease Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 206010041250 Social phobia Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-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
- 229940076279 serotonin Drugs 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
- 208000020401 Depressive disease Diseases 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 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
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 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
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical group C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a 5H-thiazolo [3,2-a ] with a structure shown as a formula (I)]The application of the pyrimidine-5-ketone compounds in preparing monoamine oxidase inhibitors is shown in an in vitro enzyme activity experiment test, and the compounds have good inhibitory activity on monoamine oxidase A and monoamine oxidase B, so that reference and a new idea are provided for developing novel MAO inhibitors.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a new pharmaceutical application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compounds, in particular to a new application in preparation of monoamine oxidase inhibitors.
Background
The monoamine neurotransmitters, including norepinephrine, epinephrine, dopamine and serotonin, are the most important group of neurotransmitters. The expression levels of these neurotransmitters and their metabolites are closely related to many diseases, affecting human attention, emotion and behavior. For example, a decrease in 5-HT concentrations in humans can cause depression; a decrease in dopamine concentration in the nervous system induces parkinson's disease and alzheimer's disease. The degradation regulation of these monoamine neurotransmitters is mainly performed by monoamine oxidase (MAO), and thus, inhibition of MAO activity can increase the expression level of monoamine neurotransmitters and reduce the production of harmful amine metabolites. Therefore, MAO is an important target for drug discovery.
Monoamine oxidases are an important class of oxidoreductases. Two MAO subtypes, MAO-A and MAO-B, exist in humans. There is a high degree of similarity between these two subtypes. But they differ greatly in their selectivity for the substrate. MAO-A typically catalyzes serotonin, norepinephrine, and epinephrine. MAO-B subtype has high affinity for neurotransmitters such as phenylmethylamine, phenylethylamine, etc. Because of their different substrate selectivities, inhibitors of these two subtypes are currently used clinically to treat different diseases. MAO-A inhibitors, for example, are used primarily for the treatment of depression, social phobiA, pain, migraine; MAO-B inhibitors are mainly used for the treatment of Alzheimer's disease and Parkinson's disease.
The 5H-thiazolo [3,2-a ] pyrimidine-5-ketone derivative has potential biological activity as a purine structural analogue, and the skeleton compound attracts attention in the aspects of biological activity such as tumor resistance, bacteriostasis, virus resistance and the like in recent years, but no related report that the skeleton compound is used as a monoamine oxidase inhibitor exists.
Disclosure of Invention
The invention aims to provide application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compounds in preparation of monoamine oxidase inhibitors.
In order to achieve the above purpose of the present invention, the present invention adopts the following technical scheme:
the structural formula of the 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound is as follows:
wherein the content of the first and second substances,
the R is1、R2Selected from hydrogen or alkyl;
the R is3Selected from hydrogen, alkyl,
The R is4Selected from hydrogen,
Preferably, the alkyl group is methyl.
Listed in table 1 are 33 specific compounds, but the scope of the present invention is not limited to the following specific compounds.
Table 1 classes of Compounds and substituents thereof
The invention discovers and verifies that the 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound shown in the formula (I) has monoamine oxidase A, B inhibition activity through activity test for the first time, provides a new application of the compound as a monoamine oxidase inhibitor, and is expected to be developed into a therapeutic drug for diseases such as depression, social phobia, pain, migraine, Alzheimer's disease, Parkinson's syndrome and the like.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited thereto. The compounds used in the examples are all available from specs in the Netherlands (http:// www.specs.com), and are compounds from the specs library.
Example 1: testing of Compounds of the invention for monoamine oxidase inhibitor Activity
1. Experimental reagent
The compound of the invention, MAOA (Active Motif, Cat.No.31502), MAOB (Active Motif, Cat.No.31503), Clorgyline (Sigma, Cat.No. M3778), Sergilan R (-) -deprenyl (Abcam, Cat.No. ab120604), 384-well plate (from Perkin Elmer, Cat.No.6007299)
2. Experimental methods
1) The compounds of the invention were dissolved to 100mM in 100% DMSO, HEPES buffer was added to the multiwell plate, and the compounds were transferred to the multiwell plate to reduce the DMSO concentration to 1%.
2) Respectively dissolving enzyme and a substrate into a buffer solution, transferring 10 mu L of substrate solution, starting a reaction, standing for 60 minutes, adding 20 mu L of fluorescein, uniformly mixing, standing for 20 minutes at room temperature, measuring and recording the relative brightness of a fluorescence signal, and respectively determining the percent inhibition rate of the compound on the enzyme under the condition of 10 concentrations.
3) In the experiment, the experiment is repeated for 2-3 times by respectively taking clorgyline and serigiline as controls, the maximum fluorescence value, the minimum fluorescence value and the standard deviation thereof are respectively calculated, and the reliability of each group of porous plate data is calculated by the ratio of the maximum fluorescence value to the minimum fluorescence value.
3. Data processing
1) The inhibition rate of each compound was calculated using Excel according to that formula one
Inh％＝(Max-Signal)/(Max-Min)*100 Equation(1)
2) The percent inhibition of enzyme obtained at 10 concentrations for each compound was fitted using GraphPad Prism5 according to equation two and the IC of the compound was calculated50Values, where Y and X are percent inhibition and compound concentration, respectively.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope)) Equation(2)
4. Results of the experiment
The compounds of the invention are screened for monoamine oxidase inhibitory activity and the corresponding half effective Inhibitory Concentration (IC) is determined50). 33H-thiazolo [3,2-a ] selected from the group consisting of]Chemical structure of pyrimidine-5-ketone compound and inhibition rate and IC of pyrimidine-5-ketone compound on monoamine oxidase50The activity is shown in the following table.
TABLE 2 inhibitory Activity of Compounds on monoamine oxidase
As can be seen from the above table results, the compounds provided by the present invention showed good inhibitory activity against both MAO-A and MAO-B.
Claims (3)
1. The application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound with the structure shown in formula (I) in the preparation of monoamine oxidase inhibitor,
wherein the content of the first and second substances,
the R is1、R2Selected from hydrogen or alkyl;
the R is3Selected from hydrogen, alkyl,
The R is4Selected from hydrogen,
2. The use of claim 1, wherein: the alkyl group is a methyl group.
3. A monoamine oxidase inhibitor, the active ingredient of which is a 5H-thiazolo [3,2-a ] pyrimidin-5-one compound represented by the structural formula (I) as defined in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010713053.3A CN111840296B (en) | 2020-07-22 | 2020-07-22 | Application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound in preparation of monoamine oxidase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010713053.3A CN111840296B (en) | 2020-07-22 | 2020-07-22 | Application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound in preparation of monoamine oxidase inhibitor |
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| Publication Number | Publication Date |
|---|---|
| CN111840296A CN111840296A (en) | 2020-10-30 |
| CN111840296B true CN111840296B (en) | 2021-05-04 |
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| CN202010713053.3A Expired - Fee Related CN111840296B (en) | 2020-07-22 | 2020-07-22 | Application of 5H-thiazolo [3,2-a ] pyrimidine-5-ketone compound in preparation of monoamine oxidase inhibitor |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105612162A (en) * | 2013-10-11 | 2016-05-25 | 豪夫迈·罗氏有限公司 | Thiazolopyrimidinones as modulators of NMDA receptor activity |
| 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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- 2020-07-22 CN CN202010713053.3A patent/CN111840296B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105612162A (en) * | 2013-10-11 | 2016-05-25 | 豪夫迈·罗氏有限公司 | Thiazolopyrimidinones as modulators of NMDA receptor activity |
| 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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| CN111840296A (en) | 2020-10-30 |
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