Fused tricyclic compounds as adenosine receptor antagonist

A technology of compounds and solvates, applied in the field of fused tricyclic compounds

Inactive Publication Date: 2013-08-21
ADVINUS THERAPEUTICS PVT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Thus, in contrast to the neuroprotection induced by endogenous A1 activation, it appears that A 2A Tonic activation of AR may generate danger signals during injury

Method used

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  • Fused tricyclic compounds as adenosine receptor antagonist
  • Fused tricyclic compounds as adenosine receptor antagonist
  • Fused tricyclic compounds as adenosine receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0430] Example A1: 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl ]-1-Methyl-[1,2,4]triazolo[5,1-f]purin-2-one

[0431]

[0432] Step-1: 2-[(2,5-Diamino-6-chloro-pyrimidin-4-yl)amino]ethanol

[0433] A mixture of 4,6-dichloropyrimidine-2,5-diamine (28g, 156mmol), ethanolamine (18ml, 312mmol) and ethanol (250ml) was heated at 100-110°C for 16 hours. The mixture was cooled and the solvent was removed. Methanol (100 ml) was added to the residue and stirred for 20 minutes. The solid was filtered off to obtain 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (22.0 g, 70%).

[0434] 1 HNMR(400MHz,DMSO d6):δ3.36-3.40(m,2H);3.50-3.54(m,2H);3.88(bs,2H);4.74(t,J=5.6Hz,1H);5.63(bs ,2H);6.51(t,J=5.6Hz,1H)

[0435] Step-2: 2-Amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one

[0436] A mixture of 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (10.0 g, 49.26 mmol) obtained in step 1 in acetonitrile (400 ml) was cooled to 0°C. To the reaction...

Embodiment B1

[0474] Example B1: 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-hydroxyethoxy)phenyl]piperazin-1-yl]ethyl]- 1-Methyl-[1,2,4]triazolo[5,1-f]purin-2-one

[0475]

[0476] To the compound 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl] at 0°C Ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (Example A1) (0.075g, 0.140mmol) in DCM (10ml) The solution was added dropwise to BBr 3 (0.15ml, 0.154mmol), and stirred at 25°C for 20 hours. use sat.NaHCO 3 (25ml) to quench the reaction mixture and extract with DCM (3 x 20ml). The crude product was purified by column chromatography to obtain 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-hydroxyethoxy)phenyl]piperazine as an off-white solid -1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (70 mg, 90%).

[0477] HNMR(400MHz,DMSO d6):δ2.60(bs,4H);2.67(t,J=6Hz,2H);2.95(bs,4H);3.55(s,3H);3.65(q,J=5.2Hz ,2H);3.87(t,J=5.2Hz,2H);3.95(t,J=6.4Hz,2H);4.8(t,J=5.2Hz,1H);6.71-6.72(m,1H);6.78 -6.85(m,4H);7.19(d,J=2.8Hz,1H);7.79(bs,2H);7...

Embodiment C1

[0480] Example C1: 5-amino-1-(cyclopropylmethyl)-3-[2-[4-(4-ethoxyphenyl)piperazin-1-yl]ethyl]-8-(2 -furyl)-[1,2,4]triazolo[5,1-f]purin-2-one

[0481]

[0482] Step-1: 2-Amino-6-chloro-7-(cyclopropylmethyl)-9-(2-hydroxyethyl)purin-8-one (the procedure is the same as Step-3 in Example A1)

[0483] 1 HNMR(400MHz,DMSO d6):δ0.35-0.39(m,2H);0.41-0.49(m,2H);1.16-1.23(m,1H),3.63-3.67(m,2H);3.77-3.81( m,4H);4.87(t,J=5.2Hz,1H);6.71(bs,2H)

[0484] Step-2: 2-Amino-7-(cyclopropylmethyl)-6-hydrazino-9-(2-hydroxyethyl)purin-8-one (the procedure is the same as Step-4 in Example A1)

[0485] 1 HNMR(400MHz,DMSO d6):δ0.28-0.30(m,2H);0.35-0.37(m,2H);1.00-1.04(m,1H),3.57-3.66(m,2H);3.72-3.79( m,4H);4.33(bs,2H);4.88(t,J=5.6Hz,1H);6.00(bs,2H);7.52(bs,1H).

[0486] Step-3: N'-[2-amino-7-(cyclopropylmethyl)-9-(2-hydroxyethyl)-8-oxo-purin-6-yl]furan-2-carbohydrazide (step is identical with step-5 in embodiment A1)

[0487] The crude product was used in the next step.

[0488] Step-4: 5-Am...

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Abstract

The present disclosure relates to fused tricyclic compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate or a pharmaceutically acceptable salts, or pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by thereof as A2A adenosine receptor antagonists. [Formula should be inserted here] The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by the mediation of adenosine A2A receptor.; Such conditions include, but are not limited to, Parkinsons disease, restless leg syndrome, Alzheimers disease, neurodegenerative disorder, inflammation, wound healing, dermal fibrosis, nocturnal myoclonus, cerebral ischaemia, myocardial ischemia, Huntington's disease, multiple system atrophy, corticobasal degeneration, Wilson's disease or other disorders of basal ganglia which results in dyskinesias, post traumatic stress disorder, hepatic cirrhosis, sepsis, spinal cord injury, retinopathy, hypertension, social memory impairment, depression, neuroprotection, narcolepsy or other sleep related disorders, attention deficit hyperactivity disorder, drug addiction, post traumatic stress disorder and vascular injury and the like. The present disclosure also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

Description

technical field [0001] The present invention relates to a series of substituted fused tricyclic compounds, their tautomers, polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts, pharmaceutical compositions containing them and Methods of treatment of conditions and diseases mediated by adenosine receptor (AR) activity. These compounds are useful in the treatment, prevention or inhibition of diseases and disorders which are readily ameliorated by antagonism of adenosine receptors. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions containing them. Background technique [0002] The actions of adenosine are mediated through at least four specific cell membrane receptors that are currently identified and classified as belonging to the G protein-coupled receptor family A 1 、A 2A 、A 2B and A 3 . A 1 and A 3 The receptor downregulates cellular cAMP levels by coupling to G proteins that inh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61K31/519A61K31/52A61K31/522A61P25/16A61P25/28
CPCA61K31/519A61K31/5377A61P1/16A61P3/06A61P3/10A61P5/50A61P9/10A61P9/12A61P9/14A61P17/02A61P21/02A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P25/20A61P25/24A61P25/28A61P25/36A61P27/00A61P29/00A61P31/04A61P43/00C07D487/14C07D519/00A61K45/06
Inventor D·巴拉卡尔S·巴苏V·拉姆达斯M·纳亚考迪M·帕特尔Y·谢约勒S·淘拉特A·潘曼蒂
Owner ADVINUS THERAPEUTICS PVT LTD
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