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Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof

a technology of azapolycycline and azapolycycline, which is applied in the field of pyridone-substituted azapolycycline, can solve the problems of economic and social costs, excessive body fat, and excessive weight, and achieves increased body mass index, increased waist circumference, and high affinity

Inactive Publication Date: 2012-03-08
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to compounds of formula I, wherein R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of H, halogen, —CN, —OR10, —NR10R11, and phenyl, which can be optionally substituted with from 1 to 3 substituents independently selected at each occurrence. The compounds have various uses, including as medicines, herbicides, and pesticides. The technical effects of the invention include improved efficacy, selectivity, and safety.

Problems solved by technology

The affluence of the 90's along with the exponential increase in food production particularly in Western and Asian economies has resulted in feeding patterns that lead to obesity.
Excessive weight is generally characterized by excessive body fat, because unused energy is stored in the adipose tissues as fat.
Obesity has associated with it, economic and social costs.
Moreover, obese persons are more likely to have medical problems associated with or exacerbated by the excess body weight.
Patient compliance, however, is usually poor.
The problem is compounded by the fact that there are currently only two medications approved for the treatment of obesity (sibutramine (MERIDIA™) and orlistat (XENICAL™)).

Method used

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  • Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof
  • Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof
  • Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Analytical Methods and Materials

[0143]Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using either a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) or a mass Varian 1200L single quadrapole mass spectrometer (ESI). High performance liquid chromatograph (HPLC) analyses were obtained using a Luna C18(2) column (250×4.6 mm, Phenomenex) or a Gemini C18 column (250×4.6 mm, Phenomenex) with UV detection at 254 nm or 223 nm using a standard solvent gradient program (Method A or Method B).

Method A:

[0144]

TimeFlow(min)(mL / min)% A% B0.01.090.010.0201.010.090.0301.010.090.0A = Water with 0.05% Trifluoroacetic AcidB = Acetonitrile with 0.05% Trifluoroacetic Acid

Metho...

example 2

Preparation of 4-(Benzyloxy)-1-(11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indol-9-yl)pyridin-2(1H)-one hydrochloride

a) 9-Bromo-11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole

[0146]

[0147]To a solution of 2-(6-bromo-1-methyl-1H-indol-3-yl)ethanamine (6.50 g, 25.7 mmol) in CH2Cl2 (50 mL) were added 4-bromobutyryl chloride (4.50 mL, 38.6 mmol) and NEt3 (7.20 mL, 51.4 mmol). After 2 h, the reaction mixture was diluted with CH2Cl2 and filtered through a layer of Celite. The filtrate was concentrated to give a brown oil. The oil was diluted with benzene (120 mL) and treated with POCl3 (12 mL, 0.13 mol). The reaction mixture was heated at reflux for 1 h. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the crude product (6.1 g) as a brown oil. The oil was diluted with EtOH and cooled to 0° C. NaBH4 (0.60 g, 16 mmol) was added, and the reaction was stirred from 0° C. to room temper...

example 3

Preparation of (−)4-(Benzyloxy)-1-(11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indol-9-yl)pyridin-2(1H)-one hydrochloride

[0150]

[0151]The (−) enantiomer was obtained by chiral separation of the racemate with a XHIPAΛΠAK AD column (heptane / EtOH, 40 / 60 (0.1% DEA)). The resulting solid (40 mg, 0.094 mmol) was dissolved in CH3OH (1 mL) and treated with 2 N HCl in Et2O (1 mL). The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the resulting solid was dried under vacuum to give the title compound (40 mg, 92%) as a yellow powder: mp 224-228° C.; 1H NMR (500 MHz, CD3OD) δ 7.68 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.51-7.37 (m, 6H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.39 (dd, J=7.5, 2.5 Hz, 1H), 6.19 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 5.13 (t, J=8.5 Hz, 1H), 3.83-3.79 (m, 1H), 3.75 (s, 3H), 3.72-3.69 (m, 1H), 3.65-3.58 (m, 2H), 3.20-3.16 (m, 2H), 2.86-2.83 (m, 1H), 2.39-2.34 (m, 2H), 2.22-2.17 (m, 1H); ESI MS m / z 426 [M+...

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Abstract

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described in the present invention.

Description

[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61 / 222,442, filed Jul. 1, 2009, and U.S. Provisional Patent Application Ser. No. 61 / 329,266, filed Apr. 29, 2010, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to pyridone-substituted azapolycycles, which are melanin-concentrating hormone (MCH-1) receptor antagonists, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. The compounds are useful in the treatment of obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders.BACKGROUND OF THE INVENTION[0003]Obesity and the multitude of co-morbidities associated with obesity such as diabetes, dyslipidemia, coronary heart disease, and certain cancers are major concerns for public health. The affluence of the 90's along with the exponential increase in food production particularly in Western and Asian ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C07D487/22A61K31/55A61K31/4375A61K38/34A61K38/22A61K31/5685A61P1/08A61P3/04A61P25/22A61P25/24A61P25/28A61P25/30A61P25/08A61P25/18C07D471/14
CPCC07D471/22C07D471/14A61P1/08A61P25/08A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P3/04
Inventor GUZZO, PETER R.SURMAN, MATTHEW DAVIDHENDERSON, ALAN JOHNJIANG, MAY XIAOWU
Owner ALBANY MOLECULAR RESEARCH INC
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