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Alpha2C adrenoreceptor agonists

a technology of adrenergic agonists and alpha2c, which is applied in the field of alpha2c adrenergic agonists, can solve the problems that compounds having adrenergic activity, such as 2a agonists, may be associated with undesirable side effects

Inactive Publication Date: 2007-04-26
SCHERING CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034] A further embodiment of the present invention is a method for the treatment of congestion in a mammal in need thereof which comprises administering to a mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a selective agonist of the α2c adrenergic receptor, wherein the functional selective agonist of the α2c receptor has an efficacy that is greated than or equal to 30% Emax when assayed in the GTPγS assay.

Problems solved by technology

It is also known that compounds having adrenergic activity, such as α2A agonists, may be associated with undesirable side effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparative Example 1

[0205]

[0206] A solution of 3,4-dihydro-2H-1,4-benzoxazine 1A (0.1 g, 0.75 mmol) in DCE (10 mL) was treated with imidazole-4-carboxaldehye 1B (0.11 g, 1.1 mmol), NaBH(OAc)3 (0.47 g, 2.2 mmol), and ACOH (one drop) and stirred at 60° C. overnight. The reaction was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography (0-4% 7 N NH3-MeOH / CH2Cl2) provided 1 as a beige solid (0.08 g, 50%). LMCS m / z 216 (MH+).

[0207] Alternatively, the title compound 1 can be synthesized by the reaction of 1A and resin bound imidazole-4-carboxaldehye 1D as described below:

[0208] Novabiochem Resin 1C (100-200 mesh, 1% DVB, 1.4 mmol / g, 5 g) was suspended in anhydrous DMF (25 mL) and DCE (25 mL) and treated sequentially with 1B (2 g, 21 mmol) and TEA (2.96 mL, 21 mmol). The resin was shaken overnight and washed with DMF (3×), MeOH (3×), and DCM (4×) then dried in vacuo overnight. The resulting resin 1D (100 mg, 1.4 mmol / g, 0.1...

example 2

Preparative Example 2

[0209]

[0210] A solution of 3,4-dihydro-2H-1,4-benzoxazine (0.52 g, 3.8 mmol) and thiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1 CH2Cl2:DMF (20 mL) was treated with DIPEA (2.6 ml, 15 mmol), HOBt (1.29 g, 9.5 mmol), and EDCI (1.83 g, 9.5 mmol) and stirred at 70° C. overnight. The reaction was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography (0-10% 1 N NH3-MeOH / EtOAc) provided 2A as a red solid (0.54 g, 55%)

Step 2

[0211] A solution of 2A (0.094 g, 0.36 mmol) in THF (10 mL) was treated with BH3—SMe2 (2M / THF, 0.27 mL, 0.54 mmol) and stirred at reflux for 2 h. The reaction was concentrated and subjected to chromatography (EtOAc) to provide 2 as a white solid (0.040 g, 45%). LMCS m / z 246 (MH+).

example 3

Preparative Example 3

[0212]

[0213] A mixture of 2-amino-4-nitrophenol (3A, 25.03 g, 0.16 mol) in 4-methyl-2-pentanone and water (420 mL, 1:1) was treated with sodium bicarbonate (32.74 g, 0.39 mol), cooled to 0° C., and treated then with chloroacetyl chloride (15.52 mL, 0.19 mol). The reaction mixture was heated to reflux overnight. After cooling to RT, the mixture was concentrated under vacuum. The residue was diluted with water (200 mL) and EtOAc (100 mL), and filtered to give the pale gray solid 3B (26.05 g). The filtrate was separated and the aqueous was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, and dried (MgSO4), filtered, and concentrated under vacuum to give additional light gray solid 3B (7.7 g). The resulting solid (quantitative yield) was used for next reaction without further purification.

[0214] To compound 3B (6.76 g, 34.84 mmol) in anhydrous THF (200 mL) was added BH3—SMe2 (2.0M / THF, 35 mL, 69.68 mmol). The mixture was heated ...

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Abstract

In its many embodiments, the present invention relates to a novel class of phenylmorpholine and phenylthiomorpholine compounds useful as α2C adrenergic receptor agonists, pharmaceutical compositions containing the compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the α2C adrenergic receptor agonists using such compounds or pharmaceutical compositions.

Description

RELATED APPLICATIONS [0001] This application claims priority to provisional application U.S. Ser. No. 60 / 711,453, filed on Aug. 25, 2005, herein incorporated by reference.FIELD OF THE INVENTION [0002] The present invention relates to phenylmorpholine and phenylthiomorpholine compounds useful as α2C adrenergic receptor agonists, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states such as congestion (including nasal congestion), migraine, congestive heart failure, cardiac ischemia, pain, glaucoma, and psychotic disorders without substantial adverse side effects associated with α2A receptor agonist treatments. BACKGROUND OF THE INVENTION [0003] The initial classification of adrenergic receptors into α- and β-families was first described by Ahlquist in 1948 (Ahlquist RP, “A Study of the Adrenergic Receptors,” Am. J. Physiol. 153:586-600 (1948)). Functionally, the α-adrenergic receptors...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5415A61K31/538A61K31/498C07D413/02C07D417/02
CPCC07D403/06C07D413/04C07D413/06C07D413/14C07D417/06C07D471/04C07D487/04C07D498/04A61P1/12A61P11/00A61P11/02A61P13/00A61P13/02A61P25/00A61P25/04A61P25/06A61P25/18A61P25/22A61P25/24A61P27/06A61P29/00A61P37/08A61P43/00A61P9/00A61P9/04A61P9/10A61K31/41
Inventor MCCORMICK, KEVINBOYCE, CHRISTOPHERSHIH, NENG-YANGASLANIAN, ROBERTMANGIARACINA, PIETRODE LERA RUIZ, MANUELYU, YOUNONGBIJU, PURAKKATTLEHUANG, CHIA-YULIANG, BOLIU, RUIYANLIU, RONG-QIANGGUISE-ZAWACKI, LISA
Owner SCHERING CORP
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