Novel dual action receptors antagonists (DARA) at the AT1 and ETA receptors

A technology of medicinal salts and enantiomers, which can be used in medical preparations containing active ingredients, antitumor drugs, allergic diseases, etc., and can solve the problem that the affinity of ETA cannot be zero.

Inactive Publication Date: 2009-05-20
TORRENT PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the affinity for ETA cannot be zero

Method used

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  • Novel dual action receptors antagonists (DARA) at the AT1 and ETA receptors
  • Novel dual action receptors antagonists (DARA) at the AT1 and ETA receptors
  • Novel dual action receptors antagonists (DARA) at the AT1 and ETA receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212]

[0213] 3-[4-(2-Butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-2-ethoxymethyl-benzene base]-5-methyl-thiophene-2-sulfonic acid (4,5-dimethyl-isoxazol-3-yl)-amide

[0214] Step 01: Synthesis of ethyl 4-bromo-3-methylbenzoate

[0215]

[0216] To a cooled (0° C.) solution of 4-bromo-3-methylbenzoic acid (25 g, 0.116 mol) in (100 ml) ethanol was added (8 ml) concentrated sulfuric acid with stirring. After complete addition, the reaction mixture was refluxed for 6 hours. The reaction mixture was cooled, then concentrated in vacuo. Cold water (50 ml) was added to the residue (residue), followed by extraction with diethyl ether (100 ml×2). The organic layer was washed with saturated sodium bicarbonate solution followed by water and brine solution washes. Finally, the ether layer was dried over sodium sulfate and evaporated in vacuo to yield 26 g of ethyl 4-bromo-3-methylbenzoate.

[0217] Step 02: Synthesis of ethyl 4-bromo-3-(bromomethyl)benzoate

[02...

Embodiment 2

[0267]

[0268] 3-[4-(6-Ethyl-4-methyl-3-phenyl-pyrazolo[4,3-c]pyridin-1-ylmethyl)-phenyl]-thiophene-2-sulfonic acid (4,5-Dimethyl-isoxazol-3-yl)amide

[0269] Step 01: Synthesis of 1-phenyl-butane-1,3-dione

[0270]

[0271] Sodium ethoxide (13.5 g, 0.198 mol) was added to a stirred solution of dry ethyl acetate (80 ml, 0.72 mol) at -5°C. To this reaction mixture was added acetophenone (20 g, 0.185 mol) at -5°C, and then the temperature of the reaction mixture was maintained at 0°C for 12 hours. Then the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100ml×2). The combined organic layers were washed with water and brine. The organic layer was dried over sodium sulfate and evaporated to yield 21 g of 1-phenyl-butane-1,3-dione as a yellow solid.

[0272] Step 02: Synthesis of 3-amino-1-phenyl-but-2-en-1-one

[0273]

[0274] A mixture of 1-phenyl-butane-1,3-dione (20 g, 0.123 mol) and ammonium acetate (38 g, 0.49 mol...

Embodiment 3

[0325]

[0326] 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfanyl)-2H-[1,6]naphthyridin (naphthyridin)-1 methyl Base)-phenyl]-thiophene-2-sulfonic acid (4,5-dimethyl-isoxazol-3-yl)-amide

[0327] Step 01: Synthesis of methyl 3-aminopentenoate

[0328]

[0329] A mixture of methyl propionoacetate (50 g, 0.3842 mol) and ammonium acetate (148 g, 1.921 mol) in dry methanol (500 mL) was stirred and refluxed for two days. The reaction mixture was cooled and concentrated in vacuo. The residue thus obtained was basified to pH 8 and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, the organic layer was dried over sodium sulfate and concentrated to yield 50 g of methyl 3-aminopentenoate as a pale yellow liquid.

[0330] Step 02: Synthesis of methyl 2,6-diethyl-4-oxo-1,4-dihydro-pyridine-3-carboxylate

[0331]

[0332] To a mixture of methyl 3-aminopentenoate (50 g, 0.387 mol) and methyl propionoacetate (50 g, 0.384 mol) in o-xylene (200 ml) was...

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Abstract

The present invention relates to new compounds of the formula [Chemical formula should be inserted here. Please see paper copy] wherein R1, R2, R3, and R31 are as specified herein. The invention also relates to a method for preparation thereof, as well as combinations of the new compounds with previously known agents. The invention also relates to the use of the above-mentioned compounds and combinations for the preparation of a medicament for treating hypertension of different kinds, alleviating organ damage of different kinds, treating or preventing diabetic nephropathy, treating endothelin and angiotensin mediated disorders, and treating prostate cancer.

Description

technical field [0001] The present invention relates to novel compounds and processes for their preparation. These compounds are dual-acting receptor antagonists (DARAs) of AT1 and ETA receptors. The invention also relates to combinations of novel compounds with previously known agents. The present invention also relates to the above-mentioned compounds and combinations used in the preparation of medicines for treating different kinds of hypertension, alleviating different kinds of organ damage, treating or preventing diabetic nephropathy, and treating endothelin and angiotensin-mediated disorders (mediated disorder) application in medicine. Background technique [0002] Hypertension is clearly a pervasive condition with important health and economic implications for individuals and society. Although there are many types of antihypertensive drugs on the market, more than 40% of treated hypertensive patients do not keep their blood pressure well controlled. Given the mult...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/422A61K31/437A61K31/4375A61K31/4439A61K31/4709A61P35/00A61P9/12C07D413/14
CPCC07D413/14C07D471/04C07D417/14A61P35/00A61P37/06A61P43/00A61P7/00A61P9/10A61P9/12A61P3/10A61K31/422A61K31/437
Inventor 拉梅什·钱德拉·古普塔维克兰特·维贾伊库马尔·贾格塔普阿帕吉·巴布拉奥·曼德哈雷蒂姆·珀金斯克里斯特·韦斯特隆德
Owner TORRENT PHARMA LTD
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