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Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-C]pyridine derivatives for the treatment of obesity

a technology of pyridine and tetrahydropyrrolo[3,2-c]pyridine, which is applied in the field of obesity treatment, can solve the problems of increasing body weight, increasing the number of chronic conditions, and increasing the number of deaths, so as to suppress appetite and induce weight loss

Inactive Publication Date: 2006-06-08
BAYER PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The present invention provides substituted 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine and substituted 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]-pyridine-4-one derivatives which have been found to suppress appetite and induce weight loss in laboratory animals. The invention also provides methods for synthesis of the compounds, pharmaceutical compositions comprising the compounds, and methods of using such compositions for suppressing appetite, inducing weight loss, and treating obesity and obesity-related disorders.

Problems solved by technology

Furthermore, it complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease, and dyslipidemias.
The enormity of this problem is best reflected in the fact that death rates escalate with increasing body weight.
Accompanying the devastating medical consequences of this problem is the severe financial burden placed on the health care system in the United States.
These methods have limited efficacy and are associated with recidivism rates exceeding 95% (NIH Technology Assessment Conference Panel, Ann. Intern. Med. 119:764-770, 1993).
However, anorectic agents such as dextroamphetamine, the combination of the non-amphetamine drugs phentermine and fenfluramine (Phen-Fen), and dexfenfluramine (Redux) alone, are associated with serious side effects.
Therefore, this approach is not an alternative for the majority of overweight patients unless and until they become profoundly obese and are suffering the attendant complications.

Method used

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  • Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-C]pyridine derivatives for the treatment of obesity
  • Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-C]pyridine derivatives for the treatment of obesity
  • Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-C]pyridine derivatives for the treatment of obesity

Examples

Experimental program
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Effect test

experimental examples

[0083] The following specific preparative examples are included as illustrations of preparation of specific compounds of the invention, and are not to be construed as limiting the scope of the invention in any way.

NMR Methods:

[0084] Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (δ 0.00) or residual protonated solvent (CHCl3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as reference standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl3 δ 77.0; d3-MeOD; δ 49.0; d6-DMSO δ 39.5) as reference standard.

LC-MS Instrumentation:

[0085] (a) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2×23 mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 se...

example 1

Preparation of 5-benzyl-2-(4-chlorophenyl)-3-methyl-1-(2-methylphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo-[3,2]-pyridine

[0094]

[0095] The preparation of this and other pyrrolopyridines was carried out in three steps using the methods described by (a) Borne, et al., J. Med. Chem. 27:1274, 1984; (b) Archibald, U.S. Pat. No. 3,992,544; (c) Nagai, et al., Chem. Pharm. Bull. 25:1911-1922, 1977; (d) Nagarajan, et al., Ind. J. Chem. 24B:98-111, 1985. The following example is illustrative of the third, or ring-forming step.

[0096] To a solution of 4-anilino-2-[2-(4-chlorophenyl)-1-methyl-2-oxoethyl]-cyclohexanone (1.58 g, 4.46 mmol) in AcOH (15 mL) at rt was added o-toluidine (478 mg, 4.46 mmol). The resulting solution was heated at reflux for 2 h. The cooled solution was treated with 1N NaOH and NaOH pellets until a pH of 10 was achieved. EtOAc was added and the phases were separated. The combined organic extracts were dried over MgSO4, and evaporated. The residue was purified by flash chromato...

example 2

Preparation of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo [3,2]-pyridine

[0097]

[0098] A solution of N-carbobenzyloxy (CBZ) protected amine (5.4 g, 11.4 mmol; prepared by methods as described in Example 1) in THF (25 mL) was added to Pd / C catalyst (1.08 g, Degussa type) in 10 mL THF. The mixture was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column, eluting with ethyl acetate, followed by 20% methanol in ethyl acetate. The product was obtained as a pale yellow solid (3.06 g, 79%). LC-MS m / z (MH+) 339.2, retention time 1.85 min (method 1). An alternative procedure, using potassium tert-butoxide to remove the CBZ group, was carried out according to the method described in J. Amer. Chem. Soc., 109:1587, 1987.

[0099] In a similar manner, 1-(2-chlorophenyl)-2-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine was prepared; LC-MS m / z (H+) 343, retention ti...

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Abstract

This invention relates to 1,5,6,7-tetrahydropynolo[3,2-c]pyridine derivatives which have been found to suppress appetite and induce weight loss. The invention also provides methods for synthesis of the compounds, pharmaceutical compositions comprising the compounds, and methods of using such compositions for inducing weight loss and treating obesity and obesity-related disorders.

Description

[0001] This application claims benefit of U.S. Provisional Application Ser. No. 60 / 324,443, filed Sep. 24, 2001, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] This invention relates to the field of pharmaceuticals, in particular to the field of obesity treatment. More specifically, it relates to certain 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine compounds which are useful in the treatment of obesity and obesity-related disorders, and as weight-loss and weight-control agents. BACKGROUND OF THE INVENTION [0003] Obesity, which is defined as an excess of body fat relative to lean body mass, is a well-established risk factor for a number of potentially life-threatening diseases such as atherosclerosis, hypertension, diabetes, stroke, pulmonary embolism, sleep apnea, and cancer. Furthermore, it complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease, and dyslipidemia...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/02A61K31/4745A61K31/437A61K31/444A61K31/4545A61K45/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P11/00A61P15/00A61P19/02A61P25/00A61P25/28A61P25/30A61P35/00C07D471/04
CPCC07D471/04A61P11/00A61P15/00A61P19/02A61P25/00A61P25/28A61P25/30A61P3/04A61P35/00A61P3/06A61P9/00A61P9/10A61P9/12A61P3/10
Inventor SMITH, ROGER A.O'CONNOR, STEPHEN J.WONG, WAI C.CHOI, SOONGYUKLUENDER, HAROLD C. E.FAN, JIANMEIZHANG, ZHONGHUALAVOIE, RICO C.PODLOGAR, BRENT L.
Owner BAYER PHARMA CORP
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