CN109666053A - A kind of A3 adenosine receptor agonist and application thereof - Google Patents
A kind of A3 adenosine receptor agonist and application thereof Download PDFInfo
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- CN109666053A CN109666053A CN201710956316.1A CN201710956316A CN109666053A CN 109666053 A CN109666053 A CN 109666053A CN 201710956316 A CN201710956316 A CN 201710956316A CN 109666053 A CN109666053 A CN 109666053A
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- 101150046889 ADORA3 gene Proteins 0.000 title claims abstract description 17
- 239000003379 purinergic P1 receptor agonist Substances 0.000 title claims abstract description 6
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- 150000001875 compounds Chemical class 0.000 claims abstract description 13
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- 150000003839 salts Chemical class 0.000 claims abstract description 7
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- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
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- 125000002252 acyl group Chemical group 0.000 claims description 2
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- HUJXGQILHAUCCV-MOROJQBDSA-N 3-iodobenzyl-5'-N-methylcarboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=C(I)C=CC=3)=C2N=C1 HUJXGQILHAUCCV-MOROJQBDSA-N 0.000 description 2
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides formula (I) compound, a kind of A3 adenosine receptor agonist, its stereoisomer, tautomer or pharmaceutically acceptable salt, it is as A3 adenosine receptor agonist and its application in drug or pharmaceutical composition of the preparation treatment by A3 adenosine receptor associated diseases, compound disclosed by the invention is with a wide range of applications in therapeutic field of tumor.
Description
Technical field
The present invention relates to therapy fields, and the method for more particularly, to inducing hepatocyte differentiation and liver regeneration.
Background technique
In recent years, hepatectomy has become safety, this is because preoperative diagnosis, surgical technic and postoperative care change
It is kind.Postoperative death rate is directly related with the liver volume of preoperative liver function and excision.It is remaining in the patient with normal liver parenchyma
The fast quick-recovery of the function of liver, because liver cell can be proliferated to restore the loss of volume.However, in the item that there is substantive hepatopathy
Under part, such as with cirrhosis, serious fatty degeneration of liver or colorectum hepatic metastases, before hepatectomy due to new auxiliary
Learn therapy and lead in debilitant patient, hepatocyte growth can be damaged, this make patient be exposed to hepatosis and it is related simultaneously
Disease is sent out, is termination with Hepatectomy hepatic failure, with high mortality (60-90%).
In addition to brain, liver is only vitals, does not have pharmacology, machinery or vitro formats to it to support decline
Organ, as found for lung, kidney and heart.Liver or unique, because it is only mammalian organs, is cutting
Its biological function essence quality (parenchymal tissue quality) that can regenerate it after removing or damaging, rather than by means of nothing on biology
The cicatricial tissue of function is healed.
In terms of Liver Regeneration, number of ways, including cytokine pathway have been identified, has largely been responsible for liver cell
It is a kind of to be referred to as the process caused into cell cycle (being transitioned into G1 from G0)；And growth factor approach, it is responsible for the cell cycle
It is in progress (G1 phase to S phase).
In addition, the ischemia-reperfusion injury of liver is the performance of known, surgical operation the clinical meaning of another kind,
Such as liver transfer operation and partially hepatectomized.After ischemia reperfusion injury, there are two different times of hepatic injury.Initial stage
(< 2h after Reperfu- sion) is characterized in that oxidative stress, and wherein the production and release of reactive oxygen species (ROS) seem directly to lead
Cause hepatocellular injury.Later period, (6-48h after Reperfu- sion) was mediated by the neutrocyte (neutrophil cell) collected
Inflammatory disorder.It is mutual between the Kupffer cell (Kupffer Cell, Kupffer cell) and the product of neutrocyte of activation
Relationship is locally lacked such as tumor necrosis factor (TNF-α), interleukins (IL) -1, nitric oxide (NO) and leukotriene with liver
The pathogenesis of blood reperfusion injury is related.The biological effect of TNF-α extends to promotion cytothesis from inducing cell death.
Really, nearest studies have shown that in the murine animal models of part liver IR damage, in subsequent ischaemic
In the 2h of Reperfu- sion, ischemic preconditioning can enter the cell cycle with liver cell.
Adenosine is named as A1, A2A, A2B and A3 by the combination of the relevant membrane receptor of itself and selective G-protein,
After ischaemic can extracellular accumulation, and known can provide cytoprotection.In particular, it has been found that A3AR is related to mediate cardiac
Nerve and chemotherapeutic protection.
Have proposed A3 adenosine receptor, the relevant cell surface receptor of a kind of Gi albumen, as the mark to anticancer and inflammation
Target.This receptor is highly expressed in various tumor cell types, and low expression is then presented in adjacent normal tissue.In vivo
Studies have shown that A3AR agonist can inhibit the development of colon, prostate and cancer of pancreas and melanoma and hepatocellular carcinoma.
A3AR agonist also shows to can be used as anti-inflammatory agent, wherein by changing in different experiments autoimmune model
Kind inflammatory process, such as rheumatoid arthritis, multiple sclerosis and Crohn's disease.
In addition, A3AR agonist, which has shown that, has different effects to tumour and normal cell growth.Although A 3AR
Activation can inhibit the growths of various tumor cell lines, but it can stimulate the proliferation of normal cell such as bone marrow cell.
Currently, no pharmaceutical intervention is proved to weaken liver cell after the acute or chronic damage of this vitals
Damage or the regeneration for increasing liver.Can-Fite biopharmaceutical company announces the II for the treatment of hepatocellular carcinoma (HCC) new drug CF102
Clinical trial phase formally starts the treatment of the first patient.This is random, and the II phase clinical research of double blind, placebo will be in beauty
State, Europe and Israel recruit 78 HCC patients altogether.After the research will assess the failure of Sorafenib first-line treatment, Child-
B grades of advanced stage HCC patients of Pugh receive the validity and safety of CF102 treatment, and primary endpoint is overall survival phase.This
Item II clinical trial phase is the advantageous data of the previous item I/II clinical trial phase based on Can-Fite company.The I/II phase is clinical
In test, 18 advanced primary HCC patients take orally CF102, and Overall survival is (to receive Suo Lafei before 67% in 7.8 months
Buddhist nun's treatment), B grades of patients' (28%) of Child-Pugh are 8.1 months.4 patient diseases were stablized more than 4 months, and 1 HCC causes
Metastatic skin tag 3 months treatment during subside completely.
CF102 is one orally active, highly selective and high-affinity A3 adenosine receptor (A3AR) agonist.But
The clinical research drug is there is also many disadvantages, and the shortcomings that in order to overcome CF102, the present invention devises a kind of such as general formula chemical combination
The A3AR agonist of object I.
Summary of the invention
The present invention provides a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1 is selected from hydrogen, halogen, cyano, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, Asia
Sulfonyl, alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group；
R2, R3It independently is halogen.
Formula (I) compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt,
In include logical formula (II) compound
Wherein, R1For C1~C6 alkyl, naphthenic base.
Compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt, as A3 adenosine
Receptor stimulating agent, in preparation treatment by the application in the disease mediated drug of A3 adenosine receptor or pharmaceutical composition.
Drug of the present invention or pharmaceutical composition are used for the treatment of various cancers.
Of the present invention, the various cancers for the treatment of include: liver cancer, lung cancer, the cancer of the esophagus, gastric cancer, clear-cell carcinoma, sarcoma, gallbladder
Pipe cancer, colon cancer, prostate cancer, oophoroma, breast cancer.
Specific embodiment:
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
Embodiment 1:
The present invention provides similar testing program according to document WO2013111132, is prepared into compound 1, ESI-MS:m/z:
571.3[M+H]+。
Biological test result: the biological test method provided according to document WO2013111132, the compounds of this invention 1 and text
Expression activitiy in offering is as follows: (IC50, nM)
| Compound name | A3 | A1 | A2A | A2B |
| Compound 1 | 0.11 | It is inactive | It is inactive | It is inactive |
| IB-MECA | 0.68 | >1000 | 685 | 47600 |
| CI-IB-MECA | 0.717 | 5390 | 2090 | It is inactive |
As can be seen that the compounds of this invention 1 is high to the activity of A3 receptor, the 6 of respectively IB-MECA and CI-IB-MECA
Times and 7 times or so, and to the other three hypotype without activity.
Claims (5)
1. a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1 is selected from hydrogen, halogen, cyano, amino, amide groups, hydroxyl, ester group, acyl group, acyloxy, sulfonyl, sulfenyl
Base, alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group；
R2, R3It independently is halogen.
2. formula (I) compound as described in claim 1, stereoisomer, tautomer or pharmaceutically acceptable salt,
Including logical formula (II) compound
Wherein, R1For C1~C6 alkyl, naphthenic base.
3. the compound as described in any one of claims 1 to 2, stereoisomer, tautomer or pharmaceutically acceptable
Salt, as A3 adenosine receptor agonist, in preparation treatment by the disease mediated drug of A3 adenosine receptor or pharmaceutical composition
Application.
4. drug as claimed in claim 3 or pharmaceutical composition are used for the treatment of various cancers.
5. as claimed in claim 4, the various cancers for the treatment of include: liver cancer, lung cancer, the cancer of the esophagus, gastric cancer, clear-cell carcinoma, sarcoma,
Cholangiocarcinoma, colon cancer, prostate cancer, oophoroma, breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956316.1A CN109666053A (en) | 2017-10-16 | 2017-10-16 | A kind of A3 adenosine receptor agonist and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956316.1A CN109666053A (en) | 2017-10-16 | 2017-10-16 | A kind of A3 adenosine receptor agonist and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109666053A true CN109666053A (en) | 2019-04-23 |
Family
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109310695A (en) * | 2016-04-21 | 2019-02-05 | 阿斯特罗赛特制药公司 | Compounds and methods for treating neurological and cardiovascular conditions |
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| US20090258836A1 (en) * | 2006-10-06 | 2009-10-15 | The Trustees Of The University Of Pennsylvania | Effective delivery of cross-species a3 adenosine-receptor antagonists to reduce intraocular pressure |
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|---|---|---|---|---|
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| CN109310695B (en) * | 2016-04-21 | 2022-04-01 | 阿斯特罗赛特制药公司 | Compounds and methods for treating neurological and cardiovascular conditions |
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| US12239654B2 (en) | 2016-04-21 | 2025-03-04 | Astrocyte Pharmaceuticals, Inc. | Compounds and methods for treating neurological and cardiovascular conditions |
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