Sphaelactone dimethylamine fumarate

Accenda Tech Co Ltd; Nankai University

Acute leukemia

Protein farnesyltransferase inhibitor; Ras GTPase inhibitor

Accendatech, 天津尚德药缘科技有限公司,Nankai University, 南开大学

 crystalline lactone dimethylamine fumaric and method of the present invention belongs to the field of pharmaceutical technology, in particular, relates to a lactone dimethylamine smile crystalline fumarate ship their preparation.  Patent CN 101978959 A discloses a lactone and derivatives thereof, pharmaceutical compositions for use in the treatment of cancer, including the formula (π) compounds, lactone dimethylamine. Activity test results show that the compounds of formula (Π) of the test cell comprising: HepG-2, Ec9706, SGC790K SW1116, A498, ASPC-1, H -29, HeLa, GL15, B16F1, T24, SKOV3, SW579, PC -3, are showing strong inhibitory activity; rather stab at 50 μ Μ normal cells, the filaments exhibit significant killing effect.

WO 2011/131103 A1 discloses a formula including the inner (I) compound smile lactone derivative or a salt thereof a pharmaceutical composition, preparation and use for the preparation of anticancer drugs. But no problem about the compound of formula polymorph (I), have not been reported for formula (I) compounds of the crystalline areas. The present invention provides compounds of formula (I) dimethylamine smile lactone crystalline fumarate and its preparation method.

An object of the present invention to provide a compound of formula (I) a lactone compound smile dimethylamine i.e. crystalline fumarate polymorph A. Another object of the present invention to provide a method for preparing crystalline compound of formula (I). A lactone compound of dimethylamine fumaric polymorph A boat characteristics of formula (I):

http://www.google.com/patents/EP2562172A1?cl=en

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http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011131103&recNum=103&maxRec=618&office=&prevFilter=&sortOption=&queryString=%28AAD%2Ftianjin%29+&tab=PCTDescription

Example 1:

11PH, 13 – two smiling Yue amino lactone (Compound II) (the structural formula of the formula (II)) Preparation of

Smile lactone (106 mg, 0.40 mmol), triethylamine (2.0mL), Yue alcohol (30 mL) was added lOO mL round bottom flask and heated at reflux for 3 hours, concentrated under reduced pressure, cross stone column chromatography (petroleum ether : ethyl acetate: triethylamine = 50: 50: 0.5) to give a white solid 107.4 mg, yield: 86%.

Formula: C ₁₇ H ₂₇ N0 ₃

Weight: 293

Appearance: white amorphous 4 minutes late

Spectral data:

¾ NMR (CDCl ₃ , 400 MHz) delta 3.76 (t, J = 5.0 Hz, 1H), 2.96 (s, 1H), 2.49-2.67 (m, 3H), 2.28-2.34 (m, IH), 2.30-2.34 (m, 2H), 2.18 (s, 6H), 2.09 (br s, 2H), 1.96 (d, J = 11.2, IH), 1.67-1.73 (m, 2H), 1.60 (s, 3H) 1.22 (br s, 3H), 1.18 (br s, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) delta 177.0, 131.8, 131.3, 84.0, 80.2, 58.3, 58.1, 50.9, 46.0, 44.6, 38.4, 35.3, 30.0, 27.2, 23.7, 22.8.

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WO-2014056410

A new crystalline form of sphaelactone dimethylamine fumarate and its preparation are claimed. The parent compound is ACT-001 (DMAMCL) which Accenda Tech and Nankai University are investigating for potential oral treatment of acute leukemia. Preclinical studies were completed in October 2012, and an application for clinical trials was planned for 2013. Picks up from WO2013163936, which claims preparation of similar compounds.