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Aryl sulfonamides as blt1 antagonists

a technology of aryl sulfonamide and blt1, which is applied in the field of aryl sulfonamides as blt1 antagonists, can solve the problems of increased and premature morbidity and mortality, inadequate insulin-mediated repression of lipolysis in adipose tissue and glucose output from the liver, and insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscl

Inactive Publication Date: 2019-12-19
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about new compounds that can treat a variety of diseases, including Type 2 diabetes, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Non-alcoholic fatty liver disease / nonalcoholic steatohepatitis, metabolic syndrome, atherosclerosis, and cancer, by blocking a receptor called leukotriene B4 (BLT1). The invention also includes pharmaceutical compositions and methods of manufacturing the compounds.

Problems solved by technology

This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle; inadequate insulin-mediated repression of lipolysis in adipose tissue and glucose output from the liver.
Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality.
Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
However, the currently marketed glitazones do not greatly improve lipid metabolism and may negatively effect on the lipid profile.

Method used

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  • Aryl sulfonamides as blt1 antagonists
  • Aryl sulfonamides as blt1 antagonists
  • Aryl sulfonamides as blt1 antagonists

Examples

Experimental program
Comparison scheme
Effect test

examples 1 and 2

N-(2-((3,4-Rac-cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide (1) and

N-(2-((3,4-Rac-trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide (2)

[0322]

Step 1

[0323]1,1,1-Trifluoro-N-(2-(4-oxochroman-7-yl)phenyl)methanesulfonamide (350 mg, 0.943 mmol), pyrrolidine (80 mg, 1.131 mmol), benzaldehyde (120 mg, 1.131 mmol) and methanol (3 mL) were combined, placed under an argon atmosphere, and stirred for 3 hours. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica (0-20% EtOAc / hexanes) to afford (E)-N-(2-(3-benzylidene-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide. MS ESI calculated. for C23H17F3NO4S [M+H]+ 460, found 460.

Step 2

[0324](E)-N-(2-(3-Benzylidene-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide (product of Step 1, 390 mg, 0.849 mmol), 10% palladium on carbon (90 mg, 0.085 mmol) and degassed ethyl acetate (3 mL) we...

example 3

N-(2-((3,4-Rac-cis)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

[0326]

[0327]This compound was synthesized according to the procedure described for Example 1 (first eluting), starting with the appropriate starting materials. MS ESI calcd. for C29H23F3NO4S [M−H]− 538, found 538. 1H NMR (400 MHz, CD3OD) δ 7.64-7.54 (m, 4H), 7.45-7.27 (m, 10H), 6.93 (dd, J=7.8, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 4.61 (d, J=3.3 Hz, 1H), 4.16-4.00 (m, 2H), 2.97 (dd, J=13.4, 7.4 Hz, 1H), 2.68 (dd, J=13.7, 7.9 Hz, 1H), 2.40-2.28 (m, 1H).

example 4

N-(2-((3,4-Rac-trans)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

[0328]

[0329]This compound was synthesized according to the procedure described for Example 2 (second eluting) using the appropriate starting materials. MS ESI calcd. for C29H23F3NO4S [M−H]− 538, found 538. 1H NMR (400 MHz, CD3OD) δ 7.64-7.52 (dd, J=7.5 Hz, 4H), 7.46-7.34 (m, 7H), 7.34-7.25 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 6.89 (s, 1H), 4.50 (d, J=4.2 Hz, 1H), 4.27 (dd, J=11.3, 2.6 Hz, 1H), 4.02 (dd, J=11.0, 4.1 Hz, 1H), 2.81 (dd, J=14.0, 6.6 Hz, 1H), 2.59 (dd, J=13.1, 9.1 Hz, 1H), 2.31-2.20 (m, 1H).

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Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are antagonists of leukotriene B4 receptor 1 (BLT1) and may be useful in the treatment, prevention and suppression of diseases mediated by the leukotriene B4 receptor 1 (BLT1). The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Non-alcoholic fatty liver disease / nonalcoholic steatohepatitis, metabolic syndrome, atherosclerosis, and cancer.

Description

BACKGROUND OF THE INVENTION[0001]Diabetes mellitus is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose homeostasis. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body, however patients have a resistance to the effects of insulin in stimulating glucose and lipid metabolism in the insulin-sensitive tissues such as muscle, liver and adipose. Early stage of type 2 diabetes patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as the islet beta cells try to compensate for the reduced effectiveness of insulin by secretin...

Claims

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Application Information

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IPC IPC(8): C07D311/22C07D409/06C07D405/06C07D417/06C07D413/06C07D405/14
CPCC07D417/06C07D311/22C07D405/06C07D409/06C07D405/14C07D413/06C07D311/26
Inventor HAN, YONGXINLIM, JONGWONTUMMANAPALLI, SATYANARAYANASILIPHAIVANH, PHIENGSPENCER, KERRIE
Owner MERCK SHARP & DOHME CORP