Pyrazole acc inhibitors and uses thereof

a technology of pyrazole and acc inhibitors, which is applied in the direction of antibacterial agents, drug compositions, metabolic disorders, etc., can solve the problems of not providing the long-term health benefit needed for sustainable weight loss, t2dm, stroke and coronary heart disease, and dramatic reduction in quality of li

Inactive Publication Date: 2017-06-15
NIMBUS DISCOVERY INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of Acetyl-CoA carboxylase (ACC). Such compounds have the general formula I:

Problems solved by technology

Obesity also leads to social stigmatization and discrimination, which decreases quality of life dramatically.
Furthermore, about half of the obese population, and 25% of the general population, have metabolic syndrome, a condition associated with abdominal obesity, hypertension, increased plasma triglycerides, decreased HDL cholesterol, and insulin resistance, which increases the risk for type-2 diabetes (T2DM), stroke and coronary heart disease.
Diet and exercise, even when used in conjunction with the current pharmacotherapy, do not provide sustainable weight loss needed for long-term health benefit.
Unfortunately, poor efficacy and unappealing gastrointestinal side effects limit the use of orlistat.
Surgery can be effective but is limited to patients with extremely high body-bass indices (BMI) and the low throughput of surgery limits the impact of this modality to about 200 k patients per year.
However, the FDA has taken an unfavorable position against CNS-active agents, due to their modest efficacy and observed / potential side-effect profiles.
Another ongoing problem is the lack of antifungal drugs with activity against a broad range of fungal pathogens.

Method used

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  • Pyrazole acc inhibitors and uses thereof
  • Pyrazole acc inhibitors and uses thereof
  • Pyrazole acc inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

of (R)-2-(1-(2-(5-fluoro-2-methoxyphenyl)-2-isopropoxyethyl)-5-methyl-2,4-dioxo-6-(1H-pyrazol-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-N-isopropyl-2-methylpropanamide, I-1

[0421]

[0422]Synthesis of Compound 1.2.

[0423]Into a 3000-mL 3-necked round-bottomed flask under nitrogen, was placed 1.1 (100 g, 487.75 mmol, 1.00 equiv), THF (1.5 L). This was followed by the addition of n-BuLi (215.6 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 1 hour at −78° C. To this was added DMF (71.54 g, 978.79 mmol, 2.01 equiv) dropwise with stirring at −78° C. The reaction was stirred for 1 h at room temperature, and then quenched by the addition of 800 mL of NH4Cl (aq.). The resulting solution was extracted with 500 mL of ethyl acetate, organic layers combined and concentrated under vacuum. The crude was purified by column chromatography to furnish 65.7 g (87%) of 1.2 as a light yellow solid.

[0424]Synthesis of Compound 1.3.

[0425]Into a 2000-mL 3-necked round-bottom...

example 2

of (R)-1-(2-(5-fluoro-2-methoxyphenyl)-2-isopropoxyethyl)-5-methyl-3-(2-methyl-1-oxo-1-(piperidin-1-yl)propan-2-yl)-6-(1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, I-2

[0459]

[0460]Into a 50-mL round-bottomed flask, was placed 1.991 (200 g, 0.37 mmol, 1.00 equiv), DCC (151.5 g, 0.73 mmol, 2.00 equiv), 4-dimethylaminopyridine (90 g, 0.74 mmol, 2.01 equiv), piperidine (60 g, 0.70 mmol, 1.92 equiv), and CH2Cl2 (20 mL). The reaction was stirred for 5 h at 50° C. The resulting mixture was concentrated under vacuum. The crude was purified by column chromatography to furnish 49 mg (22%) of I-2 as a white solid. LC-MS-PH (ES, m / z) [M-C5NH10]+ 527, [M+Na]+ 634; 1H NMR (400 MHz, DMSO-d6): δ 0.99-1.03 (m, 6H), 1.30-1.80 (m, 12H), 2.35 (s, 3H), 3.10-3.35 (m, 4H), 3.48-3.53 (m, 1H), 3.79 (s, 3H), 3.90-4.30 (m, 2H), 5.20 (t, 1H), 6.60 (s, 1H), 6.98-7.05 (m, 1H), 7.12-7.28 (m, 2H), 7.82 (s, 1H), 8.19 (s, 1H).

example 3

of (R)-1-(2-(5-fluoro-2-methoxyphenyl)-2-isopropoxyethyl)-5-methyl-3-(2-methyl-1-morpholino-1-oxopropan-2-yl)-6-(1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, I-3

[0461]

[0462]Compound I-3 was prepared from compound 1.991 and morpholine in 46% yield using similar procedure as described in Example 2. LC-MS (ES, m / z): [M+Na]+ 636; 1H NMR (400 MHz, DMSO-d6): δ 0.98-1.03 (m, 6H), 1.60-1.80 (d, 6H), 2.36 (s, 3H), 3.15-3.40 (m, 4H), 3.48-3.60 (m, 5H), 3.78 (s, 3H), 3.90-4.30 (m, 2H), 5.20 (t, 1H), 6.60 (s, 1H), 7.03-7.05 (m, 1H), 7.12-7.25 (m, 2H), 7.82 (s, 1H), 8.20 (s, 1H).

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Abstract

The present invention provides pyrazole compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 259,973, filed on Nov. 25, 2015, the entirety of which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Obesity is a health crisis of epic proportions. The health burden of obesity, measured by quality-adjusted life-years lost per adult, has surpassed that of smoking to become the most serious, preventable cause of death. In the US, about 34% of adults have obesity, up from 31% in 1999 and about 15% in the years 1960 through 1980. Obesity increases the rate of mortality from all causes for both men and women at all ages and in all racial and ethnic groups. Obesity also leads to social stigmatization and discrimination, which decreases quality of life dramatically. The chronic diseases that result from obesity cost the US economy more than $150 billion in weight-related medical bills each year. Furthermore, about half of t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D495/04C12N9/00A01N43/90
CPCC07D495/04A01N43/90C12N9/93C12Y604/01002A61P3/04A61P31/04A61P31/10A61P33/00C07D487/04C07D491/048
Inventor GHOSH, SHOMIRGREENWOOD, JEREMY ROBERTHARRIMAN, GERALDINE C.LEIT DE MORADEI, SILVANA MARCEL
Owner NIMBUS DISCOVERY INC
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