Compounds, compositions and methods

A compound and mixture technology, applied in the field of pharmaceutical compositions, compounds for the treatment of systolic heart failure, and compounds for selectively regulating myocardial ganglion, can solve the problem of not meeting the gold standard of heart failure treatment, prolonging patient survival time, poor cardiac tissue, etc. question

Active Publication Date: 2007-10-31
CYTOKINETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a class of drugs, all current dopamine injections fail to meet the gold standard required for heart failure treatment, namely, prolonging the patient's survival time
In addition, current drugs all have poor selectivity for cardiac tissue, partly resulting in known side effects, which limit their application

Method used

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  • Compounds, compositions and methods
  • Compounds, compositions and methods
  • Compounds, compositions and methods

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0168] Scheme 3 shows the preparation of the compound of formula 305, which can be used as an intermediate in the synthesis of the compound of formula I.

[0169] Schemes 4 and 5 show the preparation of stereospecific reagents that can be used in the asymmetric synthesis of individual enantiomers of the compound of formula I.

[0170] Those skilled in the art will recognize that one or more of the reactants, steps and / or conditions described in these reaction routes can be adjusted to suit R 1 And R 2 Various substituents at the place.

[0171] material

[0172] Many of the optionally substituted starting compounds 101, 103, 201, 301a and 301b and other reagents are commercially available, for example from Aldrich Chemical Company (Milwaukee, WI), or by those skilled in the art through routine use The synthetic method is easily prepared.

[0173] Reaction route 1

[0174]

[0175] Preparation of compounds of formula I

[0176] Referring to reaction route 1...

Embodiment 1

[0446] (R)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea

[0447] 1A. Preparation of SM 3

[0448]

[0449] (The amount shown below is the total amount used; therefore one-fourth of the total amount is added to each 50L flask)

[0450] Four 50L three-port RBF extractors equipped with a mechanical stirrer add 10.76kg (46.14mol) under nitrogen (IS)-(+)-Camphor-10-sulfonic acid (SM 2), 23.3 L (2.5 vol) ethanol (anhydrous), and 9.34 kg (92.27 mol) 3-hydroxypiperidine (SM 1). Add 142L of MTBE to make the solution cloudy. The solution was left overnight, then the solid was filtered out, and washed with 8L (1:1) MTBE: EtOH, 8L (2:1) MTBE: EtOH, and 8L MTBE to obtain 10.68 kg of white solid (35% yield, 75.8% ee, these values ​​are the average of two batches). These solids were added to a 22L three-neck RBF flask equipped with a mechanical stirrer, thermometer, and reflux condenser. 10.7 L (1 vol) of ethanol (anhydrous) was added to the flask, and then the solut...

Embodiment 2

[0476] 3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-sulfonic acid dimethylamide

[0477] 2A. (R)-tert-Butyl-3-(3-fluoro-5-nitrophenoxy)-pyrrolidine-1-carboxylate

[0478]

[0479] DMF (300 mL) and NaH (12.8 g, 320 mmol, 1.2 eq) were added to a round bottom flask, and then stirred in an ice bath. A solution of N-tert-butyl-(R)-3-hydroxypyrrolidine (50 g, 267 mmol, 1 eq) in DMF (100 mL) was slowly added to the flask, and then stirred for about 30 minutes. A solution of difluoronitrobenzene (51 g, 320 mmol, 1.2 eq) and DMF (50 mL) was added dropwise in about 30 minutes. The resulting solution was warmed to room temperature and stirred for about 4 hours. Water is added to the reaction mixture. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate, and brine solution. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chro...

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PUM

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Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

Description

[0001] Cross reference to related patent applications [0002] This application requires U.S. Provisional Patent Application No. 60 / 440,133 and 60 / 440,183 filed on January 14, 2003, and U.S. Provisional Patent Application No. 60 / 476,086 filed on June 4, 2003, in June 2003 The contents of the United States Provisional Patent Application No. 60 / 476,517 filed on the 5th and the United States Provisional Patent Application No. 60 / 501,376 filed on September 8, 2003 are incorporated herein by reference. Technical field [0003] The present invention relates to substituted urea derivatives, especially compounds that selectively modulate myocardial ganglia, especially compounds, pharmaceutical compositions and methods for the treatment of systolic heart failure (including congestive heart failure). Background technique [0004] Myocardial ganglion [0005] The term "sarcomere" is a cell structure of fine tissue that is present in the myocardium and skeletal muscle composed of interlaced f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C273/02C07D213/02A61K31/17A61K31/44
Inventor 布拉德利·保罗·摩根凯瑟琳·A.·伊莱亚斯埃丽卡·安妮·克雷纳克卢普平法迪·马利克亚历克斯·穆奇钱向平惠特尼·沃尔特·史密斯枥本托德亚当·刘易斯·托马西小戴维·J.·摩根斯
Owner CYTOKINETICS INC
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