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Inhibitors of trka kinase

A solvate, alkyl technology, applied in the field of novel compounds

Inactive Publication Date: 2018-01-02
GVK BIOSCI PTE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is a large unmet need for pain relief without adverse effects caused by current pain therapies

Method used

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  • Inhibitors of trka kinase
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Examples

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example

[0104] Examples of compounds of the present invention are shown in Table 1.

[0105] Table 1: Exemplary Compounds of Formula I (Examples 1 to 202)

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] The compounds mentioned above are for exemplary purposes only and do not limit the scope of the present invention.

[0115] Several methods for preparing compounds of the invention are illustrated in the following reaction schemes and examples. Starting materials and necessary intermediates are in some cases commercially available or may be prepared according to literature procedures or as illustrated herein.

[0116] In addition to other standard manipulations known in the literature or exemplified in the experimental procedures, compounds of the invention can also be prepared by utilizing reactions as shown in the following schemes. Substituent numbering as shown in these schemes does not necessarily correlate to that used in...

example 1-202

[0297] Preparation of Example 1-202

example 1

[0298] Example 1: 1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(quinolin-3-yl)urea

[0299] The compounds were synthesized using method 3 as mentioned in the general scheme.

[0300] To a solution of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid (0.15 g, 0.6 mmol) in toluene (10 mL) was added diphenyl Phosphoryl azide (0.24 g, 0.96 mmol), diisopropylethylamine (0.32 mL, 1.80 mmol) and the resulting mixture was heated to reflux temperature for 1 h. The reaction mixture was then cooled to room temperature, after which 3-aminoquinoline (Intermediate A1 ) (0.1 g, 0.72 mmol) was added and it was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue thus obtained was diluted with 10% MeOH / dichloromethane, washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash c...

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Abstract

The present invention is directed to the compounds of Formula I which are inhibitors of tropomyosin-related kinase A (TrkA): Formula (I) or steroisomers, tautomers or a pharmaceutically acceptable salts, metabolites, isotopes, solvates or prodrugs thereof, wherein, Ra, Rb, Rc, Rd, R1, R2, L and Het-Ar are as defined herein. These compounds can be used for the preventive and / or therapeutic treatment of diseases or disorders associated with abnormal activities of nerve growth factor (NGF) receptor TrkA such as Pain, inflammation or an inflammatory diseases, Cancer, atherosclerosis, restenosis, thrombosis, Neurodegenerative diseases, Erectile Dysfunction (ED), Skin disorders, Autoimmune disease like Multiple sclerosis, Sj gren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis, Infectious diseases, diseases related to an imbalance of the regulation of bone remodeling, endometriosis, pelvic pain syndrome and diseases resulting from abnormal tissue remodelling and fibrotic disorders; or a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination.

Description

technical field [0001] The present invention relates to novel compounds useful as inhibitors of members of the Trk family of protein kinases. In particular, the present invention discloses compounds having inhibitory activity against TrkA. Background technique [0002] Currently available therapies for the treatment of pain utilize several classes of compounds, such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Most NSAIDs have one or more side effects such as irritation of the gastrointestinal (GI) tract leading to nausea / vomiting, gastric ulceration / bleeding, dyspepsia, inflammatory bowel disease, altered renal function, adverse effects on the cardiovascular system and more Many side effects. Opioids cause emetic, constipated and negative respiratory effects as well as addictive potential. Therefore, there is a large unmet need for pain relief without the adverse effects caused by current pain therapies. [0003] The effects of Trks and neurotrophic fa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C13/567C07D207/34
CPCC07D403/12C07D401/14C07D405/14C07D405/12C07D409/12C07D417/14C07D471/04C07D491/056C07D207/14C07D401/12A61P13/08A61P15/00A61P15/10A61P17/00A61P19/00A61P25/00A61P29/00A61P31/00A61P35/00A61P37/02A61P7/02A61P9/00A61P9/10A61P3/10
Inventor K·纳加什瓦米V·G·蒂鲁纳加吕
Owner GVK BIOSCI PTE LTD
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