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Compounds useful in treatment of autoimmune and inflammatory disorders

A compound and hydrate technology, applied in allergic diseases, anti-inflammatory agents, drug combinations, etc., can solve problems such as adverse side effects, discomfort, toxicity, etc.

Pending Publication Date: 2021-06-11
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although they are effective in delaying or suppressing transplant rejection, classical immunosuppressants such as cyclosporine A and FK506 are known to cause a variety of adverse side effects, including nephrotoxicity, neurotoxicity, beta-cell toxicity, and gastrointestinal distress

Method used

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  • Compounds useful in treatment of autoimmune and inflammatory disorders
  • Compounds useful in treatment of autoimmune and inflammatory disorders
  • Compounds useful in treatment of autoimmune and inflammatory disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0339] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in the art. Some synthetic methods for incorporating tritium activity levels into target molecules include the following:

[0340] A. Catalytic reduction with tritium gas: This method usually produces high specific activity products and requires halogenated or unsaturated precursors.

[0341] B. Using sodium borohydride [ 3H] Reduction: This method is rather cheap and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

[0342] C. With lithium aluminum hydride [ 3 H] Reduction: This method provides products with almost theoretical specific activities. It also requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, etc.

[0343] D. Tritium Gas Exposure Labeling: This method involves exposing precursors containing exchangea...

example 1

[0349] Example 1: Synthesis of compounds of the present invention

[0350] exist Figure 1A , 1B Illustrative syntheses of compounds of the invention are shown in and 1C.

[0351] The compounds of the present invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention without restricting the invention to the details of these examples. according to Professional (version 17.0.0.206) names the compounds described herein (above and below). In certain instances, generic names are used, and it is understood that those skilled in the art will recognize such generic names.

[0352] Chemistry: Proton NMR was recorded on a Bruker Avance-400 equipped with QNP (Quadruple Nucleus Probe) or BBI (Broad Band Inverse) and z-gradient ( 1 H NMR) spectrum. Proton NMR was also recorded on a Bruker Avance-500 equipped with BBI (Broadband Inverse) and z-gradient ( 1 H NMR) spectrum. Chemical shifts are ...

Embodiment 11

[0354] Example 1.1: (2S, 3S, 4S, 5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1 , 2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 1) preparation.

[0355] Step A: Preparation of 1-cyclopentyl-2-(trifluoromethyl)benzene.

[0356] To a 50 L three necked round bottom flask equipped with mechanical stirrer, thermocouple and nitrogen inlet was added anhydrous THF (35 L) and cooled to 0-5 °C. Iron (III) chloride (2.7 kg, 0.15 equiv) was added to the flask in portions over 30-60 minutes and stirred for 15-30 minutes, resulting in a clear green solution. Under a nitrogen atmosphere, THF (87.5 L) and magnesium turnings (4.05 kg, 1.5 equiv) were added to a dry 100 gallon glass-lined reactor and cooled to 0-5°C. FeCl 3 The solution in THF was added to the mixture of THF and magnesium at a rate that kept the internal temperature below 10°C. To the resulting yellow / green mixture was added TMEDA (15.5 kg...

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Abstract

The present invention relates to certain compounds of Formula (Ia) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor: Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 receptor-associated disorders, for example, a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease or disorder, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne, microbial infections or diseases and viral infections or diseases.

Description

technical field [0001] The present invention relates to certain compounds of formula (Ia) and pharmaceutically acceptable salts thereof which exhibit useful pharmacological properties, eg as agonists of the S1P1 receptor. The invention also provides pharmaceutical compositions comprising the compounds of the invention, and methods of using the compounds and compositions of the invention to treat S1P1 receptor-associated disorders, such as lymphocyte-mediated diseases or disorder, autoimmune disease or disorder, inflammatory disease or disorder, inflammatory skin disease or disorder, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple Sexual sclerosis, systemic lupus erythematosus, ulcerative colitis, type 1 diabetes and acne, microbial infection or disease, and viral infection or disease. Background technique [0002] The present invention relates to compounds which are S1P1 receptor agonists having at least immunosupp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/94A61P29/00A61P37/00A61K31/403
CPCC07D209/94A61P37/00A61P29/00A61K31/403C07D405/12C07H15/26
Inventor A·J·M·萨德克丹尼尔·J·布扎德
Owner ARENA PHARMA
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