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Heterocyclic organic compounds

A compound and composition technology applied in the field of heterocyclic organic compounds

Inactive Publication Date: 2009-08-26
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There is a clearly unmet need for small molecule inhibitors of SCD enzymatic activity, as compelling evidence currently exists that SCD activity is directly implicated in common human disease processes: see, e.g., Attie, A.D. et al., "In Human The relationship between stearoyl CoA desaturase activity and plasma triglycerides in blood and plasma triglycerides in mice" (Relationship between stearoyl CoAdesaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia), J. Lipid Res. (2002) , Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., "Role for stearoyl CoA desaturase-1 in leptin-mediated weight loss" (Role for stearoyl CoA desaturase -1 in leptin mediated weightloss), Science (2002), Vol. 297, No. 5579, p. 240-3, Ntambi, J.M. et al., "The loss of stearoyl CoA desaturase-1 function protects mice against "(Loss of stearoyl CoA desaturase-1 function protects mice against adiposity), Proc. Natl. Acad. Sci. U.S.A. (2002), Vol. 99, No. 7, pp. 11482-6

Method used

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Experimental program
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Embodiment approach

[0084] One embodiment of the present invention is a compound of formula (I) or its stereoisomer, enantiomer or tautomer, its pharmaceutically acceptable salt, its pharmaceutical composition or its prodrug:

[0085]

[0086] X is CH or N;

[0087] Y is NH, N-CH 3 O or S;

[0088] W is selected from -N(R 5 )C(O)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -S-, -N(R 5 )-, -S(O) t -, -N(R 5 )S(O)t -, -S(O) t N(R 5 )-, -OS(O) t N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -N(R 5 )C(=N(R 5a ))NR 5 -, -N(R 5 )((R 5a )N=)C-,-C(=N(R 5a ))N(R 5 )- or straight key;

[0089] V is selected from -N(R 5 )C(O)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -S-, -N(R 5 )-, -S(O) t -, -N(R 5 )S(O) t -, -S(O) t N(R 5 )-, -OS(O) t N(R 5 )-, -C(O)-, -OC(O)-, -C(O)O-, -N(R 5 )C(=N(R 5a ))NR 5 -, -N(R 5 )((R 5a )N=)C-,-C(=N(R 5a ))N(R 5 )-,=C(R 5 )- or straight key;

[0090] n is 0, 1, 2 or 3;

[0091...

Embodiment 1

[0318] Synthesis of N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide

[0319]

[0320] To N-benzyl-2-(4-bromobutyrylamino)-4-methylthiazole-5-carboxamide (1.80 g, 4.54 mmol) in acetone (50 mL) and water (5 mL) at ambient temperature Potassium carbonate (1.50 g, 10.8 mmol) was added to the solution. The resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was washed with water and tert-butyl methyl ether to afford the title compound in 78% yield (1.12 g): mp 222-224°C;

[0321] 1 H NMR (300MHz, DMSO-d 6 )δ8.60(t, J=6.0Hz, 1H), 7.33-7.16(m, 5H), 4.35(d, J=6.0Hz, 2H), 3.97(t, J=7.2Hz, 2H), 2.59( t, J=7.8Hz, 2H), 2.46(s, 3H), 2.14-1.94(m, 2H); MS(ES+) m / z 316.4(M+1).

Embodiment 11

[0323] Synthesis of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide

[0324]

[0325] The procedure was followed as described in Example 1, with modifications as appropriate to use 2-(4-bromobutyrylamino)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N -Benzyl-2-(4-bromobutyrylamino)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 85% yield:

[0326] 1 H NMR (300MHz, CD 3 OD) δ7.39-7.33(m, 2H), 7.09-7.02(m, 2H), 4.48(s, 2H), 4.15-4.09(m, 2H), 2.68(t, J=8.1Hz, 2H), 2.55(s, 3H), 2.25(m, 2H); MS(ES+) m / z 334.2(M+1).

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Abstract

The present application provides compounds of formula (I) that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

Description

[0001] The present invention relates generally to the field of stearoyl-CoA desaturase inhibitors, such as heterocyclic derivatives and the use of such compounds in the treatment and / or prevention of various human diseases involving Desaturase (SCD), preferably SCD1 mediated diseases, especially diseases involving elevated lipid levels, cardiovascular diseases, diabetes, obesity, metabolic syndrome, skin diseases and the like. Background of the invention [0002] Acyl desaturases catalyze double bond formation in fatty acids derived from dietary sources or synthesized de novo in the liver. In mammals, there are at least three fatty acid desaturases, each with a different specificity: δ-9, δ-6, and δ-5, at positions 9-10, 6-7, and 5-6, respectively Introduce a double bond. [0003] Stearoyl-CoA desaturase (SCD) with cofactors (other substances) such as NADPH, cytochrome b5, cytochrome b5 reductase, Fe, and molecular O 2 Act together to introduce a double bond at the C9-C10 po...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/427A61P3/10A61P3/04
CPCC07D417/14C07D417/04A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P25/02A61P3/00A61P3/04A61P3/06A61P43/00A61P7/00A61P7/02A61P9/10A61P9/12A61P3/10A61K31/427
Inventor N·达莱斯Z·张R·坎博J·付S·孙N·波克罗夫斯伽叶S·斯维里多夫
Owner NOVARTIS AG
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