CN109053803A - A new class of compound and application thereof - Google Patents
A new class of compound and application thereof Download PDFInfo
- Publication number
- CN109053803A CN109053803A CN201810726307.8A CN201810726307A CN109053803A CN 109053803 A CN109053803 A CN 109053803A CN 201810726307 A CN201810726307 A CN 201810726307A CN 109053803 A CN109053803 A CN 109053803A
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- Prior art keywords
- general formula
- compound
- pharmaceutically acceptable
- acceptable salt
- stereoisomer
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 241000700605 Viruses Species 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000002672 hepatitis B Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 241000700739 Hepadnaviridae Species 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 108091036055 CccDNA Proteins 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 208000036141 Viral hepatitis carrier Diseases 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- -1 phenol amine Chemical class 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
Classifications
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new class of compound and application thereof or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, solvate, crystal form, general structure are as follows: general formula A1:Or general formula A2:Or general formula A3:
Description
Technical field
The present invention relates to a new class of compound and application thereof, such compound is further related in sides such as preparation antiviral drugs
The application in face.
Background technique
HBV (hepatitis type B virus) abbreviation hepatitis B.It is a kind of DNA virus, belongs to Hepadnaviridae
(hepadnaviridae).According to currently known, HBV just only has neurological susceptibility to people and orangutan, causes virus B hepatitis disease
Disease.Complete hepatitis B can also be referred to as red Na particle (Dane) at graininess.Nineteen sixty-five is found by red Na.Diameter is 42
Nanometer.Particle is divided into shell and core two parts.
The hepatitis B virus infection rate about 60%-70% in China；Hepatitis B surface antigen carrying rate accounts for about the 7.18% of total population,
It is calculated with this, the whole nation is there are about 93,000,000 people's Hepatitis B carriers, wherein chronic hepatitis B patient about 20,000,000.
The research and development of HBV drug are all one of emphasis and the hot spot of medicament research and development all the time.
Summary of the invention
The present inventor is during developing new HBV antiviral drugs, it has unexpectedly been found that a kind of noval chemical compound,
Such compound unexpectedly has excellent resisting HBV virus activity.
In order to complete the purpose of the present invention, the present invention provides a new class of compound and application thereof, sends out by pharmacological evaluation
Existing, such noval chemical compound is in antiviral pharmacological evaluation, significant effect.The report to such compound is had no in the prior art.
Such noval chemical compound or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, solvate, crystalline substance
Type, general structure are as follows:
General formula A1:
Or general formula A2:
Or general formula A3:
Wherein Ra is
OrR5、R7、R10、R12It is respectively alkylidene or substituted alkylene；R6、R8、
R9、R11、R13It is respectively alkyl or substitution alkyl；W, X, Y are respectively O or S.
Or the halides or its stereoisomer of A1, A2, A3, it is pharmaceutically acceptable salt and/or hydrate, molten
Object or crystal form are closed in agent, general structure such as A4-A6:
General formula A4:
Or general formula A5:
Or general formula A6:
Wherein R1、R2、R3、R4In 1 or 2 or 3 or 4 be halogen or OH, remaining is H；Ra is R5YR6、-
NR7R8COOR9 -OR10OCOOR11 Or-OR12OCOR13 R5、R7、R10、R12It is respectively alkylidene or substituted alkylene；R6、R8、R9、R11、R13Respectively
Respectively alkyl or substitution alkyl；W, X, Y are respectively O or S.
A1, A2, A3 are advanced optimized are as follows:
General formula A7:
Or general formula A8:
Or general formula A9:
Or general formula A10:
Wherein m, n are respectively the integer of 1-40.
A4, A5, A6 are advanced optimized are as follows:
General formula A11:
Or general formula A12:
Or general formula A13:
Or general formula A14:
Wherein R1、R2、R3、R4In 1 or 2 or 3 or 4 be halogen or OH, remaining is H；M, n is respectively
The integer of 1-40.
By advanced optimizing, A7, A8, A9, A10 are advanced optimized as noval chemical compound each in table 1 or its alloisomerism
Body, pharmaceutically acceptable salt and/or hydrate, solvate or crystal form, structural formula are any one of following:
Table 1:
By advanced optimizing, A11, A12, A13, A14 advanced optimize for noval chemical compound each in table 2 or its solid it is different
Structure body, pharmaceutically acceptable salt and/or hydrate, solvate or crystal form, structural formula are any one of following:
Table 2:
The detailed description of each general structure of the above present invention and structural formula, is not considered as limitation of the present invention.
The present invention also provides application of the above-mentioned new compound in preparation antiviral drugs.Particularly, which uses
Application in the drug for preparing anti-hepatitis virus.
The present invention determines the Anti-viral activity in vitro of the compounds of this invention using cell culture method, the results showed that, this hair
Bright each compound is relatively strong to the inhibiting effect of HBV virus.
Specific embodiment
The present invention is described in further detail by way of examples below, provides implementation detail of the invention, but
It is to be not considered as limitation of the present invention.
Embodiment 1: the Anti-HBV effect evaluation of compound is synthesized:
The chromosomal integration of HepG2 2.2.15 cell (SELLS, PNAS, 1987andSELLS, JV, 1988) has completely
HBV gene group, and stablize expression viral RNA, cccDNA and virus protein.In addition, the cell secreted also into culture medium at
Ripe hepatitis B particle.The duplication of virus can be measured by the method that qPCR quantifies virion DNA.Untested compound is used
DMSO is dissolved as the storing liquid of 30mM and is stored in -20 DEG C.10,000, every hole HepG2 is added in 96 porocyte culture plates
2.2.15 cell, every 200 μ L cell culture medium of hole, at 37 DEG C, 5%CO2It cultivates in cell incubator 3 days and covers with to cell.It abandons
Fall old culture medium and the fresh detection culture medium (5%FBS) of 200 μ L is added.The diluted 1 μ L of compound of 100%DMSO is added:
Different specified test concentrations are diluted to, in CO2It is incubated for 10 days in incubator, every other day (the 2nd, 4,6,8,10 day) changes one
Not good liquor (5%FBS), and the compound of Fresh concentration is added.150 μ L supernatants are taken to extract viral DNA in the 11st day every hole.Carefully
Cellular toxicity detection plate is also processed similarly: maximum concentration is 150 μM.The extracts kit of virus genom DNA is
QIAamp96DNA Blood Kit.By conventional centrifugation and QPCR process.With the plasmid (viral copies comprising HBV gene group
Number: 2*10E6,2*10E5,2*10E4,2*10E3) do standard curve, and viral copy number is calculated with standard curve.Inhibiting rate
Calculation formula it is as follows: antiviral inhibiting rate=100- (detected value-HPE average value)/(ZPE average value-HPE average value) *
100 (ZPE: minimum concentration compound well average value, HPE: maximum concentration compound well average value).Inhibiting rate data pass through
5 software of Graphpad Prism handles and draws curve, EC50And EC90It is calculated by four parameter nonlinear regression models.Cell
Toxicity %=100- (detected value/DMSO control wells average value * 100).Cytotoxicity % data pass through Graphpad Prism 5
Software handles and draws curve, CC50It is calculated by four parameter nonlinear regression models.
The Anti-HBV effect of compound is evaluated:
Table 3:
Experimental result shows that all noval chemical compounds have very strong Anti-HBV effect.It ends with tenofovir and draws phenol amine
(TAF) compare, each noval chemical compound all shows more excellent activity, and M3, M4, M19, M23 performance are more excellent.
Claims (8)
1. a new class of compound or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, solvate, crystalline substance
Type, general structure are as follows:
General formula A1:
Or general formula A2:
Or general formula A3:
Wherein Ra is R5、R7、R10、R12It is respectively alkylidene or substituted alkylene；R6、R8、
R9、R11、R13It is respectively alkyl or substituted alkyl；W, X, Y are respectively O or S.
2. a new class of compound or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, solvate, crystalline substance
Type, general structure are general formula A4- general formula A6:
General formula A4:
Or general formula A5:
Or general formula A6:
Wherein R1、R2、R3、R4In 1 or 2 or 3 or 4 be halogen or OH, remaining is H；Ra is
R5、R7、R10、R12It is respectively alkylidene or substituted alkylene；R6、R8、R9、R11、R13
It is respectively alkyl or substitution alkyl；W, X, Y are respectively O or S.
3. noval chemical compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, molten
Object or crystal form are closed in agent, which is characterized in that its general structure is general formula A7- general formula A10:
General formula A7:
Or general formula A8:
Or general formula A9:
Or general formula A10:
Wherein m, n are respectively 1-40 integer.
4. noval chemical compound according to claim 2 or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, molten
Object, crystal form are closed in agent, which is characterized in that its general structure is general formula A11- general formula A14:
General formula A11:
Or general formula A12:
Or general formula A13:
Or general formula A14:
Wherein R1、R2、R3、R4In 1 or 2 or 3 or 4 respectively be halogen or OH, remaining is H；M, n is respectively
For the integer of 1-40.
5. according to claim 1,3 noval chemical compound or its stereoisomer, pharmaceutically acceptable salt and/or hydrate,
Solvate or crystal form, which is characterized in that its structural formula is any one of following:
6. according to the noval chemical compound or its stereoisomer of claim 2,4, pharmaceutically acceptable salt and/or hydrate,
Solvate, crystal form, which is characterized in that its structural formula is any one of following:
7. compound described in any one of claims 1-6 or its stereoisomer, pharmaceutically acceptable salt and/or water
Close the application of object, solvate, crystal form, which is characterized in that the compound is used to prepare antiviral drug.
8. drug according to claim 7 or its stereoisomer, pharmaceutically acceptable salt and/or hydrate, molten
Object, crystal form are closed in agent, which is characterized in that the drug is used to prepare the drug of anti-hepatitis virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810726307.8A CN109053803A (en) | 2018-07-04 | 2018-07-04 | A new class of compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810726307.8A CN109053803A (en) | 2018-07-04 | 2018-07-04 | A new class of compound and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109053803A true CN109053803A (en) | 2018-12-21 |
Family
ID=64819099
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810726307.8A Pending CN109053803A (en) | 2018-07-04 | 2018-07-04 | A new class of compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109053803A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020151296A1 (en) * | 2019-01-25 | 2020-07-30 | 博瑞生物医药（苏州）股份有限公司 | Dinucleotide precursor for drug and preparation method therefor |
| WO2020151295A1 (en) * | 2019-01-25 | 2020-07-30 | 博瑞生物医药（苏州）股份有限公司 | Compound having dinucleotide structure |
| JP2022541667A (en) * | 2019-07-27 | 2022-09-26 | ブリー バイオサイエンシーズ， インコーポレイテッド | Adenosine derivative and pharmaceutical composition containing the same |
| US12257264B2 (en) | 2021-01-25 | 2025-03-25 | Brii Biosciences, Inc. | Combination therapy for HIV with adenosine derivative and capsid inhibitors |
| US12390484B2 (en) | 2021-01-25 | 2025-08-19 | Brii Biosciences, Inc. | Adenosine derivative and pharmaceutical composition comprising the same |
-
2018
- 2018-07-04 CN CN201810726307.8A patent/CN109053803A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020151296A1 (en) * | 2019-01-25 | 2020-07-30 | 博瑞生物医药（苏州）股份有限公司 | Dinucleotide precursor for drug and preparation method therefor |
| WO2020151295A1 (en) * | 2019-01-25 | 2020-07-30 | 博瑞生物医药（苏州）股份有限公司 | Compound having dinucleotide structure |
| CN111484541A (en) * | 2019-01-25 | 2020-08-04 | 博瑞生物医药（苏州）股份有限公司 | Dinucleotide precursor medicine and its preparing method |
| CN111484540A (en) * | 2019-01-25 | 2020-08-04 | 博瑞生物医药（苏州）股份有限公司 | Compound containing dinucleotide structure |
| CN111484541B (en) * | 2019-01-25 | 2023-06-02 | 博瑞生物医药（苏州）股份有限公司 | Dinucleotide prodrugs and methods of making same |
| CN111484540B (en) * | 2019-01-25 | 2023-09-08 | 博瑞生物医药（苏州）股份有限公司 | Compounds containing dinucleotide structures |
| JP2022541667A (en) * | 2019-07-27 | 2022-09-26 | ブリー バイオサイエンシーズ， インコーポレイテッド | Adenosine derivative and pharmaceutical composition containing the same |
| JP7700096B2 (en) | 2019-07-27 | 2025-06-30 | ブリー バイオサイエンシーズ， インコーポレイテッド | Adenosine derivatives and pharmaceutical compositions containing same |
| US12370208B2 (en) | 2019-07-27 | 2025-07-29 | Brii Biosciences, Inc. | Adenosine derivative and pharmaceutical composition comprising the same |
| US12257264B2 (en) | 2021-01-25 | 2025-03-25 | Brii Biosciences, Inc. | Combination therapy for HIV with adenosine derivative and capsid inhibitors |
| US12390484B2 (en) | 2021-01-25 | 2025-08-19 | Brii Biosciences, Inc. | Adenosine derivative and pharmaceutical composition comprising the same |
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Application publication date: 20181221 |