CN114805364B - Fused ring compound of pyrrolidine and piperazine dione, preparation and pharmaceutical use thereof - Google Patents
Fused ring compound of pyrrolidine and piperazine dione, preparation and pharmaceutical use thereof Download PDFInfo
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- CN114805364B CN114805364B CN202210397995.4A CN202210397995A CN114805364B CN 114805364 B CN114805364 B CN 114805364B CN 202210397995 A CN202210397995 A CN 202210397995A CN 114805364 B CN114805364 B CN 114805364B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention is applicable to the field of pharmaceutical chemistry, and provides a fused ring compound of pyrrolidine and piperazinedione, a preparation method thereof and application thereof in pharmacy, wherein the compound is shown in the formula
A compound of formula (I) or other pharmaceutically acceptable salt; the compound of the present invention has the function of inhibiting infection and replication of dengue virus, and thus, the compound of the present invention can be used as a medicament for preventing and treating diseases caused by dengue virus.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a fused ring compound of pyrrolidine and piperazinedione, and preparation and pharmaceutical application thereof.
Background
Dengue Fever (DF) is an acute infectious disease caused by dengue virus (DENV), which is transmitted by the bites of female mosquitoes and is classified into Dengue Fever (DF), dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS) according to clinical symptoms from mild to severe. Approximately 3.9 million people are infected with DENV each year, covering 128 countries.
Under the influence of a plurality of factors such as global environment deterioration and warming, the dengue epidemic situation has a tendency to expand in recent years, but currently, only 1 limited region dengue vaccine is available, and no effective anti-dengue virus medicine can be used for clinical treatment of dengue diseases, and clinical treatment is mainly progressive supportive therapy, wherein maintaining fluid balance is a main means. Therefore, the research on the drugs for the diseases caused by the infection of the dengue virus and other arboviruses is very important and urgent.
The dengue virus is a single-strand positive-strand RNA virus which contains about 11000 bases and has 4 serotypes, namely DENV-1, DENVV-2, DV-3 and DV-4, wherein DV-2 has the strongest toxicity. The dengue virus genomic RNA can be divided into two parts: the 5' 1/4 sequence encodes 3 structural proteins of the virus (C-capsid, prM-precusor membrane and E-envelope), and the 3/4 sequence encodes 7 nonstructural proteins of the virus (NS 1, NS2, NS3, NS4A, NS4B and NS 5). Although these proteins are important for the survival of dengue viruses, they may be used as drug targets against dengue viruses, dengue virus NS3 is the most studied and probably the most important drug target for dengue viruses since maturation of these proteins is dependent on NS3 protease activity, and effective inhibition of NS3 protease activity may serve the purpose of reducing or blocking replication and reproduction of dengue viruses (Aruna Sampath, r. Padmanahan Antiviral res.2009, 81, 6-15). Research has shown that NS2B plays a crucial role as a cofactor for NS3 protease in order to exert enzymatic activity on NS3, so that NS3-NS2B complex (Aruna Sampath, r. Padmanahan Antiviral res.2009, 81, 6-15) has been used for the study of the ability of inhibitors to inhibit the enzymatic activity of NS 3.
Disclosure of Invention
The invention aims to provide a five-membered ring and six-membered ring fused compound with corresponding activity based on the prior art. Therefore, as one aspect of the present invention, the present invention provides a fused ring compound of pyrrolidine and piperazinedione, and a preparation method and a pharmaceutical use thereof.
In order to solve the technical problems, the invention provides the following technical scheme: a fused ring compound of pyrrolidine and piperazinedione, a compound of formula (I) or other pharmaceutically acceptable salt:
in the formula (I), the compound is shown in the specification,
x is methylene, R is one of substituted or unsubstituted benzene rings;
or X is null and R is C 1 -C 6 One of an alkyl group, a substituted or unsubstituted benzene ring;
said substitutedThe substituents are selected from: nitro, methoxy, methyl, ester, CF 3 CN, carboxyl and acetyl.
Preferably, the compound of the present invention is represented by formula (II),
wherein R is C 1 -C 6 The alkyl group of (1).
Preferably, the compound of the present invention is represented by formula (III)
In the formula, R' is H, nitryl, methoxyl, methyl, ester group, CF 3 CN, carboxyl and acetyl, and the substituted position of R' is ortho-position, meta-position or para-position.
Preferably, the compound of the present invention is represented by formula (IV)
In the formula, R 'is one of H, nitryl, methoxyl, methyl, ester group, CF3, CN, carboxyl and acetyl, and the substituted position of R' is ortho-position, meta-position or para-position.
Preferably, the compound is selected from the following compounds:
the second object of the present invention is to provide a process for preparing a heterocyclic compound of pyrrolidine and piperazinedione, comprising the steps of:
the third purpose of the invention is to provide the application of the compound in the aspect of pharmacy, and the application of the compound in preparing medicines for treating or preventing diseases caused by dengue viruses, and more particularly, preparing medicines for preventing or treating diseases related to dengue virus protease NS3 inhibitors.
The fourth purpose of the invention is to provide a pharmaceutical composition, which takes the compound as a main active ingredient and is supplemented with a pharmaceutically acceptable carrier.
The compound shown in the formula (I) has the function of inhibiting infection and replication of the dengue virus, and can be used as a medicament for preventing and treating diseases caused by the dengue virus.
Drawings
FIGS. 1 to 11 show the H spectra of some compounds in the examples of the present invention.
FIGS. 12-18 are mass spectra of some compounds in examples of the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Specific implementations of the present invention are described in detail below with reference to specific embodiments.
Example 1
The invention provides a preparation method of the compound, which comprises the following steps:
the following specific compounds were prepared as described above:
example 2
The protease activity assay procedure is described in published articles. (Zhou G C, weng Z, shao X, et al discovery and SAR students of methyl-proline acids as dendritic viruses NS2B-NS3 protease inhibitors [ J ]. Bioorganic & medicinal chemistry letters,2013,23 (24): 6549-6554.) the data on the activity of some compounds on NS2B-NS3 are given below.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (9)
1. A fused ring compound of tetrahydropyrrole and piperazinedione, characterized in that a compound represented by formula (I):
in the formula (I), the compound is shown in the specification,
x is methylene, R is one of substituted or unsubstituted benzene rings;
or X is null and R is C 1 -C 6 One of an alkyl group, a substituted or unsubstituted benzene ring;
the substituted substituents are selected from: nitro, methoxy, methyl, ester, CF 3 CN, carboxyl and acetyl.
2. The fused ring compound of pyrrolidine and piperazinedione according to claim 1, wherein the compound is represented by formula (II),
in the formula, R is C 1 -C 6 Alkyl group of (1).
3. The fused compound of pyrrolidine and piperazinedione according to claim 1, wherein the compound is represented by formula (III),
in the formula, R' is H, nitryl, methoxyl, methyl, ester group, CF 3 CN, carboxyl and acetyl, and the substituted position of R' is ortho-position, meta-position or para-position.
4. The fused cyclic compound of pyrrolidine and piperazinedione according to claim 1, wherein the compound is represented by formula (IV),
in the formula, R' is H, nitryl, methoxyl, methyl, ester group, CF 3 CN, carboxyl and acetyl, and the substituted position of R' is ortho-position, meta-position or para-position.
5. The tetrahydropyrrole and piperazinedione fused compound according to claim 1, wherein said compound is selected from the following compounds:
6. the fused cyclic compound of pyrrolidine and piperazinedione according to any one of claims 1 to 5, wherein the fused compound of pyrrolidine and piperazinedione is prepared by:
7. use of a fused cyclic compound of pyrrolidine and piperazinedione according to any one of claims 1-5 in the manufacture of a medicament for the prevention or treatment of a disease associated with dengue virus propagation, replication or infection.
8. A pharmaceutical composition for preventing or treating a disease associated with dengue virus NS3-NS2B protease inhibitor, which comprises the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as a main active ingredient, together with a pharmaceutically acceptable carrier.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210397995.4A CN114805364B (en) | 2022-04-12 | 2022-04-12 | Fused ring compound of pyrrolidine and piperazine dione, preparation and pharmaceutical use thereof |
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| CN202210397995.4A CN114805364B (en) | 2022-04-12 | 2022-04-12 | Fused ring compound of pyrrolidine and piperazine dione, preparation and pharmaceutical use thereof |
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| CN114805364B true CN114805364B (en) | 2023-04-07 |
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000327575A (en) * | 1999-05-26 | 2000-11-28 | Teika Seiyaku Kk | Remedy for inflammatiory disease containing diketopiperazine derivative and new diketopiperazine derivative |
| CN103118540A (en) * | 2010-07-15 | 2013-05-22 | 农村振兴厅 | Agricultural chemical containing 2,5-diketopiperazine derivative as active ingredient |
| CN103585616A (en) * | 2013-08-14 | 2014-02-19 | 南京工业大学 | Use of dipeptide analogue |
| CN103800330A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of cyclic dipeptide C5 in phellinus igniarius in resisting avian influenza H5N1 virus |
| CN103800331A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of cyclic dipeptide C7 in Phellinus igniarius in resisting avian influenza H5N1 virus |
| CN103816156A (en) * | 2013-09-06 | 2014-05-28 | 青岛农业大学 | Application of cyclic dipeptide C2 in phellinus igniarius to resisting H5N1 avian influenza virus |
| KR20150057636A (en) * | 2013-11-20 | 2015-05-28 | 서울대학교산학협력단 | Composition comprising cyclic dipeptides and DL-3-phenyllactic acid for antibacterial, antifungal and antiviral agents |
| KR20160001017A (en) * | 2014-06-26 | 2016-01-06 | 주식회사 나프로바이오텍 | Cyclic Dipeptide purified from fermented liquor of Bacillus vallismortis BS07M and Method for producing the same |
| WO2017034011A1 (en) * | 2015-08-27 | 2017-03-02 | アサヒグループホールディングス株式会社 | Beneficial intestinal bacteria proliferation agent |
| JPWO2017014120A1 (en) * | 2015-07-17 | 2018-04-26 | サントリーホールディングス株式会社 | TRPV1 stimulating composition |
-
2022
- 2022-04-12 CN CN202210397995.4A patent/CN114805364B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000327575A (en) * | 1999-05-26 | 2000-11-28 | Teika Seiyaku Kk | Remedy for inflammatiory disease containing diketopiperazine derivative and new diketopiperazine derivative |
| CN103118540A (en) * | 2010-07-15 | 2013-05-22 | 农村振兴厅 | Agricultural chemical containing 2,5-diketopiperazine derivative as active ingredient |
| CN103585616A (en) * | 2013-08-14 | 2014-02-19 | 南京工业大学 | Use of dipeptide analogue |
| CN103800330A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of cyclic dipeptide C5 in phellinus igniarius in resisting avian influenza H5N1 virus |
| CN103800331A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of cyclic dipeptide C7 in Phellinus igniarius in resisting avian influenza H5N1 virus |
| CN103816156A (en) * | 2013-09-06 | 2014-05-28 | 青岛农业大学 | Application of cyclic dipeptide C2 in phellinus igniarius to resisting H5N1 avian influenza virus |
| KR20150057636A (en) * | 2013-11-20 | 2015-05-28 | 서울대학교산학협력단 | Composition comprising cyclic dipeptides and DL-3-phenyllactic acid for antibacterial, antifungal and antiviral agents |
| KR20160001017A (en) * | 2014-06-26 | 2016-01-06 | 주식회사 나프로바이오텍 | Cyclic Dipeptide purified from fermented liquor of Bacillus vallismortis BS07M and Method for producing the same |
| JPWO2017014120A1 (en) * | 2015-07-17 | 2018-04-26 | サントリーホールディングス株式会社 | TRPV1 stimulating composition |
| WO2017034011A1 (en) * | 2015-08-27 | 2017-03-02 | アサヒグループホールディングス株式会社 | Beneficial intestinal bacteria proliferation agent |
| JPWO2017034011A1 (en) * | 2015-08-27 | 2018-07-26 | アサヒグループホールディングス株式会社 | Intestinal useful bacteria growth agent |
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