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Novel compounds, pharmaceutical compositions containing same, methods of use for same, and methods for preparing same

A compound, selected technology, applied in the direction of drug combination, chemical instrument and method, botany equipment and method, etc., can solve the problem of reducing β-oxidation

Inactive Publication Date: 2012-03-28
FASGEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Overexpression in vivo also resulted in decreased β-oxidation

Method used

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  • Novel compounds, pharmaceutical compositions containing same, methods of use for same, and methods for preparing same
  • Novel compounds, pharmaceutical compositions containing same, methods of use for same, and methods for preparing same
  • Novel compounds, pharmaceutical compositions containing same, methods of use for same, and methods for preparing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] The chemical synthesis of embodiment 1 compound 5a-5d

[0098] use this article figure 1 Scheme 1 is shown for the synthesis of compounds 5a-5d.

[0099] Reaction conditions: (a) NBS, hv, CH 3 CN; (b)NaN 3 , EtOH, reflux; (d) C 9 h 19 SO 2 Cl or C 5 h 11 SO 2 Cl, pyridine, CH 2 Cl 2 , 0°C to room temperature; (e) K + o - t-Bu, ether, water, 0°C to room temperature.

[0100] A first series of compounds were obtained from various substituted methyl toluates. The meta and / or para amines were prepared according to literature protocols. (Okada, Y. et al., Bromination by means of Sodium monobromoisocyanurate (SMBI) (bromination with sodium monobromoisocyanurate (SMBI)). Org. Biomolec. Chem. 2003, 1, 2506-2511). Using NBS in CH 3 After bromination of the methyl radical in CN, by reacting with NaN 3 / EtOH was refluxed to displace the bromine. Under Staudinger conditions, the azide was reduced to the free amine 3, which was then coupled with 1-pentanesulfo...

Embodiment 2

[0112] The synthesis of embodiment 2 compound 5e and 5f

[0113] use this article figure 2 Scheme 2 is shown for the synthesis of compounds 5e-5f.

[0114] Reaction conditions: (a) NH 3 , MeOH, reflux; (b) NaH, RSO 2 Cl, DMF, 0°C to room temperature; (c) NaOH, THF / water, 0°C to room temperature.

[0115] Ortho-substituted carboxylates require a different approach than meta- and para-compounds. Formation of indolinone 6 in the reaction between o-bromide and ammonia / MeOH (Kovtunenko, V.A. et al.; Condensation of o-(bromomethyl)benzoic acid with amines (o-(bromomethyl)benzoic acid and amine condensation), Ukrainskii Khimicheskii Zhurnal 1983, 49, 1099-1103), the indolinone 6 was coupled with alkanesulfonyl chloride and NaH in DMF to obtain The γ-lactam bond was readily cleaved by NaOH in THF / water to prepare carboxylic acids 5e and 5f.

[0116] General procedure for 7a-b. 1.5 mmol 6 was added to DMF (8 mL), and the solution was cooled to 0°C. NaH (1.65 mmol) was added f...

Embodiment 3

[0122] The synthesis of embodiment 3 compound 13a-13f

[0123] use this article image 3 Shown scheme 3 carries out the synthesis of compound 13a-13f

[0124] Reaction conditions: (a) NBS, hv, CH 3 CN; (b)P(OEt) 3 , reflux; (c) H 2 SO 4 , EtOH, reflux; (d) C 9 h 19 SO 2 Cl or C 5 h 11 SO 2 Cl, pyridine, CH 3 CN, 0°C to room temperature; (e) TMSBr, CH 2 Cl 2 , room temperature.

[0125] The synthesis of alkyl phosphonates 13a-f begins with protection of the starting toluidine as di-acylated aniline 8 (Brown, J.J.; Brown, R.K. Preparation of o-and p-acetamidobenzaldehydes (Preparation of o-acetaminobenzaldehyde and p-acetaminobenzaldehyde), Can. J. Chem. 1955, 33, 1819-1823). Use NBS / CH 3 Radical bromination of CN afforded benzyl bromide 9, which was converted to phosphonate 10 by Arbuzov reaction with triethylphosphite. Deprotection to aniline by exposure to refluxing acidic EtOH solution. After coupling of amine with alkanesulfonyl chloride to generate sul...

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Abstract

The present invention relates to a novel class of compounds comprising formula I, wherein n is 0 or 1. A is NR1, O, or S, wherein R1 is H, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, alkenyl, aryl, alkylaryl or arylalkyl. X is a carboxylate, a phosphonate, or a phosphate residue, or a C1-C10 alkyl residue optionally substituted with a carboxylate, phosphonate or phosphate residue. Y is a C1-C20 alkyl, alkenyl, halide, hydroxyl, C1-C20 alkoxy, aryl, alkylaryl, arylalkyl, cycloalkyl, cycloalkenyl, or a heterocyclic ring and is optionally substituted with one or more halides. Z is a H, a hydroxyl group, a halide, an aryl group, an alkylaryl group, an arylalkyl group, a cycloalkyl group, a cycloalkenyl group or a heterocyclic ring and is optionally substituted with one or more C1-C10 alkyl groups, C1-C10alkoxy groups, hydroxyl groups, cyano groups, carboxylate groups, halides, aryl groups, alkylaryl groups, arylalkyl groups, cycloalkyl groups, cycloalkenyl groups or heterocyclic rings.

Description

[0001] priority document [0002] This application claims priority to US Patent Provisional Application No. 61 / 129,578, filed July 7, 2008, which is incorporated herein by reference. field of invention [0003] The present invention relates to novel compounds, pharmaceutical compositions containing said compounds, methods of use for a variety of therapeutically valuable uses including, but not limited to, the treatment of obesity by inhibiting the activity of glycerol 3-phosphate acyltransferase (GPAT) . Background of the invention [0004] The incidence of obesity and other diseases associated with high levels of triglycerides is increasingly recognized as a major public health problem. The World Health Organization estimates that obesity currently affects at least 400 million adults worldwide. In the United States alone, it is estimated that about two-thirds of adults are overweight or obese. A variety of diseases are associated with obesity, including type 2 diabetes, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N41/06A61K31/18
CPCC07D213/55A61K31/18C07C311/06C07C311/21C07F9/3834C07C311/13C07C311/08C07F9/3882C07D333/24A61P3/00A61P3/04A61P3/06A61P43/00
Inventor C·A·汤森F·库哈达S·梅哈尔基
Owner FASGEN