Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof

a technology of azabicycloalkane and pyrrolopyridine, which is applied in the field of azabi, can solve the problems of limited efficacy, current available pharmaceutical therapies for the treatment of obesity, and limit their use, and achieves the effects of increasing body mass index, increasing 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

[0019]It has now been found that compounds of formula I are MCH-1 receptor antagonists. This invention provides compounds that bind to the MCH-1 receptor with high affinity. The compounds provided by formula I are useful for the treatment of obesity, anxiety, depression, psychiatric disorders, and other disorders described herein. In particular, it is contemplated that the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-abdominal fat), Dual Energy X-Ray Absorptiometry (DEXA), and truncal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.

Problems solved by technology

The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use.
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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  • Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof
  • Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof
  • Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Analytical Methods and Materials

[0141]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 (6) 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, B, C, or D).

Method A:

[0142]

TimeFlow(min)(mL / min)% A% B0.01.090.010.0201.010.090.0251.010.090.0A = Water with 0.025% Trifluoroacetic AcidB = Acetonitrile with 0.025% Trifluoroacetic Acid

Met...

example 2

Preparation of 4-(Benzyloxy)-1-(5-methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 3-bromo-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-11-carboxylate

[0146]

[0147]3-Bromophenylhydrazine hydrochloride (919 mg, 4.12 mmol) and nortropanone hydrochloride (1000 mg, 6.18 mmol) were dissolved in ethanol (5 mL), and conc. HCl (2 mL) was added. The reaction mixture was heated at reflux for 18 h and then concentrated. The residue was suspended in a mixture of isopropanol (25 mL) and water (15 ml) and K2CO3 (1.70 g, 12.3 mmol) and Boc2O (1.79 g, 8.24 mmol) were added. After 18 h, the mixture was diluted with CH2Cl2 and the organic phase removed, dried over Na2SO4 and concentrated. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes / EtOAc, 100:0 to 50:50) to give the more polar title compound (240 mg, 15%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.92-7.64 (br s, 1H), 7.42 (s,...

example 3

Preparation of 1-(5-Methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indol-3-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

a) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine

[0154](CAS Registry Number 1173155-65-1) (WO 2009 / 089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

[0155]3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol), K2CO3 (310 mg, 2.25 mmol) and PdCl2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl solution, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes / EtOAc), 100:0 to 50:50) afforded the ti...

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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 benefit of U.S. Provisional Patent Application Ser. No. 61 / 222,440, filed Jul. 1, 2009, and U.S. Provisional Patent Application Ser. No. 61 / 329,428, filed Apr. 29, 2010, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to azabicycloalkane-indoles, 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 a major concern for public health. The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/22C07D471/08C07D471/18A61K31/4439A61K31/501A61K31/444A61K31/506A61K31/437A61K31/497A61K31/5685A61K38/18A61P3/04A61P25/22A61P25/24A61P1/16A61P1/08A61P25/28A61P25/16A61P25/30A61P25/00A61P25/08C07D487/04
CPCC07D471/22A61P1/08A61P1/16A61P3/04A61P25/00A61P25/08A61P25/16A61P25/22A61P25/24A61P25/28A61P25/30
Inventor GUZZO, PETER R.SURMAN, MATTHEW DAVIDHENDERSON, ALAN JOHNHADDEN, MARKFREEMAN, EMILY ELIZABETH
Owner ALBANY MOLECULAR RESEARCH INC
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