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Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists

a technology of urotensin-ii receptor and pyrimidine, which is applied in the field of urotensin-ii receptor antagonists, can solve problems such as pathological consequences of cardiac hemodynamic dysfunction

Inactive Publication Date: 2008-01-03
ENCYSIVE PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"This patent describes compounds and pharmaceutical compositions containing them, as well as their use as antagonists of urotensin II and inhibitors of urotensin II. The compounds can be used to treat various conditions associated with urotensin II imbalance, such as congestive heart failure, stroke, ischemic heart disease, cardiac arrhythmia, hypertension, renal disease, and others. The compounds can be used alone or in combination with other therapeutic agents such as endothelin receptor antagonists, angiotensin converting enzyme inhibitors, A-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and 1-adrenoceptor antagonists."

Problems solved by technology

Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.

Method used

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  • Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
  • Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
  • Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-ylamino)-benzenesulfonamide

[0152]

Step 1. N-(2-Dimethylamino-ethyl)-3-nitro-benzenesulfonamide (3)

[0153] To a solution of 3-nitrobenzenesulfonyl chloride (1, 1.0 g, 4.51 mmol) in anhydrous CH2Cl2 (9.0 mL) was added N,N-dimethyl-ethylenediamine (2, 0.5 mL, 4.55 mmol) dropwise. The resulting solution was stirred at room temperature overnight before it was diluted with EtOAc (80 mL). The organic mixture was washed with saturated NaHCO3 (90 mL), brine (90 mL), and dried over MgSO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 3 as a foam (0.8 g) which was used in the next step without further purification.

Step 2.3-Amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (4)

[0154] A solution of 3 (0.8 g) in ethanol (10 mL) was subjected to catalytic hydrogenation (10% Pd / C, Degussa, 0.8 g, 3 drops of AcOH, 1 atm.) overnight. To work up, the solids were filtered the filtrate was dried under vacuum to afford 4...

example 2

N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-yl-amino)-benzamide

[0156] The title compound was synthesized in the same manner as for Example 1 except that 3-nitrobenzoyl chloride was used instead of 1 in Step 1. It was obtained as a pale yellow solid.

example 3

(3-(2-Dimethylamino-ethoxy)-4-methyl-phenyl)-(2-methyl-quinolin-4-yl)-amine

[0157]

Step 1. tert-Butyl (3-hydroxy-4-methyl-phenyl)-carbamate (7)

[0158] A solution of 5-amino-2-methylphenol (6, 1.0 g, 8.12 mmol) and di-tert-butyl dicarbonate (1.95 g, 8.93 mmol) in THF (25 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (75 mL) and the resulting mixture was washed with water (70 mL), 1N HCl (2×70 mL) and brine (70 mL). The organic layer was then dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The desired product 7 was obtained as an oil (2.16 g) and was carried on to the next step without further purification.

Step 2. tert-Butyl (3-(2-dimethylamino-ethoxy)-4-methyl-phenyl)-carbamate (8)

[0159] A mixture of 7 (2.16 g, 9.68 mmol), 2-(dimethylamino)-ethyl chloride hydrochloride (1.53 g, 10.6 mmol) and K2CO3 (5.35 g, 3.87 mmol) in DME (28 mL) / H2O (7 mL) was heated under reflux...

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Abstract

The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation-in-part of U.S. application Ser. No. 10 / 783,916, filed Feb. 20, 2004 which application claims the benefit of provisional application No. 60 / 451,089, filed Feb. 28, 2003.FIELD OF THE INVENTION [0002] The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use. BACKGROUND OF THE INVENTION [0003] The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences. [0004] The principal mammalian vasoactive factors that comprise this neurohumoral axis are angiotensin-II, endothelin-1, and norepinephrine, all of which function via a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4709A61P1/04A61P11/00A61P19/02A61P21/00A61P43/00A61P9/10C07D215/44A61KA61K31/4706A61K31/503A61K31/513A61K31/5377C07D215/14C07D401/12C07D413/14
CPCA61P1/00A61P1/04A61P3/06A61P3/10A61P7/00A61P9/00A61P9/04A61P9/06A61P9/08A61P9/10A61P9/12A61P11/00A61P11/06A61P11/16A61P13/00A61P13/12A61P15/10A61P19/00A61P19/02A61P21/00A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P27/02A61P29/00A61P43/00C07D215/44C07D401/12C07D401/14
Inventor ANDERSON, ERICDUPRE, BRIANGAO, DAXINKESSLER, RAYMONDLI, WENWU, CHENGDE
Owner ENCYSIVE PHARMA INC
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