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Patent Issued for Preparation Method of Fluoro-Substituted Deuterated Diphenylurea

July 7, 2014



By a News Reporter-Staff News Editor at Clinical Trials Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Feng, Weidong (Jiangsu, CN); Gao, Xiaoyong (Jiangsu, CN); Dai, Xiaojun (Jiangsu, CN), filed on March 17, 2011, was published online on June 24, 2014 (see also Suzhou Zelgen Biopharmaccceutical Co., Ltd.).

The assignee for this patent, patent number 8759531, is Suzhou Zelgen Biopharmaccceutical Co., Ltd. (Jiangsu, P.R., CN).

Reporters obtained the following quote from the background information supplied by the inventors: "The .omega.-diphenylurea derivatives are known compounds with c-RAF kinase inhibition activity. For example, WO2000/042012 disclosed a class of .omega.-carboxyl-aryl-substituted diphenylurea and the use thereof for treating cancer and related diseases.

"Initially, .omega.-diphenylurea compounds, such as Sorafenib, were firstly found as the inhibitor of c-RAF kinase. The other studies had shown that they could also inhibit the MEK and ERK signal transduction pathways and activities of tyrosine kinases including vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), and platelet-derived growth factor receptor-.beta. (PDGFR-.beta.) (Curr Pharm Des 2002, 8, 2255-2257). Therefore, they were called multi-kinase inhibitors that resulted in dual anti-tumor effects.

"Sorafenib (trade name Nexavar), a novel oral multi-kinase inhibitor, was developed by Bayer and Onyx. In December 2005, based on its outstanding performance in phase III clinical trials for treating advanced renal cell carcinoma, Sorafenib was approved by FDA for treating advanced renal cell carcinoma. It was marketed in China in November 2006. However, Sorafenib has various side-effects, such as hypertension, weight loss, rash and so on.

"BAY 73-4506 is a 3-fluoro derivative of Sorafenib, and is also a multi-kinase inhibitor targeting tumors and the vessel thereof. In particular, BAY 73-4506 is an effective inhibitor of Raf kinases, p38 kinase, platelet-derived growth factor receptor (PDGFR) kinase and vascular endothelial growth factor receptor (VEGFR) kinase 2 and 3. Inhibition of these special kinases is closely related to the prevention or treatment of osteoporosis, inflammatory diseases, hyperplastic diseases, angiogenic diseases and cancer (Dumas et al., PCT publication WO 2005009961 A2; Hedbom S et al., Journal of Clinical Oncology, 25, (Suppl. 18): Abs, 3593). At present, this compound is in the phase of clinical evaluation for treating renal cell carcinoma (ClinicalTrials. gov Web Site 2008, May 5), solid tumor (J Clin Oncol, 2008, 26(15, Suppl.): Abst 2558), liver cancer (ClinicalTrials. gov Web Site 2010, May 17) and metastatic colon cancer (ClinicalTrials. gov Web Site 2010, May 17). BAY 73-4506 is in the phase of preclinical evaluation for treating multiple myeloma (Blood, 2008, 112(11): Abst 2766).

"However, development of compounds with inhibition efficacy to Raf kinases or better pharmacodynamic properties, and the preparation processes thereof are still in need."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The object of the invention is to provide compounds which inhibit raf kinases and has better pharmacodynamic properties and the uses thereof.

"Another object of the invention is to provide a series of synthetic methods for deuterated .omega.-diphenylurea and the intermediates thereof, thereby meeting the production guidances in the pharmaceutical industry and improving the operability and safety.

"In the first aspect, the invention provides an intermediate of formula V,

"##STR00001##

"wherein, X is Cl, Br, I, or OSO.sub.2CF.sub.3.

"In one embodiment, Y is Cl, and the formula is

"##STR00002##

"In the second aspect, the invention provides a method for preparing the compound with the following formula,

"##STR00003##

"including:

"(a) in an inert solvent and in the presence of a base, reacting compound B2 with compound V to form said compound,

"##STR00004##

"wherein, X is Cl, Br, I, or OSO.sub.2CF.sub.3;

"or, including:

"(b) in an inert solvent, reacting compound B' with CD.sub.3NH.sub.2 or CD.sub.3NH.sub.2.HCl to form said compound;

"##STR00005##

"wherein, R is H, straight-chain or branched chain C1-C8 alkyl, or aryl;

"or, including:

" in an inert solvent, reacting 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (VIII) with compound 5 to form said compound;

"##STR00006##

"or, including:

"(d) in an inert solvent and in the presence of CDI and CH.sub.2Cl.sub.2, reacting compound 5 with compound 6 to form said compound;

"##STR00007##

"or, including:

"(e) in an inert solvent, reacting 3-fluoro-4-aminophenol with compound V to form compound B1; in an inert solvent, reacting compound B1 with compound W to form compound M; and in an inert solvent, reacting compound M with 4-chloro-3-trifluoromethylaniline to form said compound;

"##STR00008##

"wherein, R is hydrogen, methyl, nitro and chlorine; said inert solvent is selected from chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, pyridine, DMF, DMSO, or the combination thereof; said base is selected from pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diethyl isopropyl amine, N,N-dimethylamine pyridine, N-methylmorphine, or the combination thereof;

"or, including:

"(f) in an inert solvent, reacting 4-chloro-3-trifluoromethylaniline with compound W to form compound B; and in an inert solvent, reacting compound B1 with compound B to form said compound;

"##STR00009##

"wherein, R is hydrogen, methyl, nitro and chlorine; said inert solvent is selected from chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, pyridine, DMF, DMSO, or the mixed solvent thereof; said base is selected from pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diethyl isopropyl amine, N,N-dimethylamine pyridine, N-methylmorphine, or the combination thereof.

"In one embodiment, compound B2 is prepared through the following method:

"(i) in an inert solvent, condensing 3-fluoro-4-aminophenol with 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene to form compound B2;

"##STR00010##

"In one embodiment, said inert solvent includes (but is not limited to): dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or the combination thereof.

"In one embodiment, said base is selected from potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide or the combination thereof.

"In one embodiment, method (a) further includes conducting the reaction in the presence of a catalyst, wherein said catalyst is selected from cuprous iodide and proline; or cuprous iodide and pyridyl formic acid.

"In one embodiment, each reaction is conducted at 0-200.degree. C.

"In one embodiment, the reaction time is 0.2-72 h, preferably is 0.5-64 h, and more preferably is 1-48 h.

"In the third aspect, the invention provides a method for preparing 4-chloro-N-(methyl-d.sub.3)picolinamide, comprising:

"(a1) in a basic condition and in an inert solvent, reacting methyl 4-chloropicolinate with (methyl-d.sub.3)amine or salts thereof to form 4-chloro-N-(methyl-d.sub.3)picolinamide; or

"(a2) in an inert solvent, reacting 4-chloropicolinoyl chloride with (methyl-d.sub.3)amine to form 4-chloro-N-(methyl-d.sub.3)picolinamide.

"In one embodiment, said inert solvent includes tetrahydrofuran, ethanol, methanol, water, or the mixed solvent thereof.

"In one embodiment, in steps (a1) and (a2), the reaction temperature is -10.degree. C. to reflux temperature, preferably is -4.degree. C. to 60.degree. C., and more preferably is 5-50.degree. C.

"In one embodiment, in steps (a1) and (a2), the reaction time is 0.5-72 h, preferably is 1-64 h, and more preferably is 2-48 h.

"In one embodiment, in step (a1), said basic condition means that potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or the combination thereof is present in the reaction.

"In the fourth aspect, the invention provides an intermediate of formula B2,

"##STR00011##

"In the fifth aspect, the invention provides a method for preparing compound B2, comprising: in an inert solvent, condensing 3-fluoro-4-aminophenol with 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene to form compound B2:

"##STR00012##

"In the sixth aspect, the invention provides the use of the intermediate according to the first aspect or the fourth aspect of the invention for preparing deuterated diphenylurea or as the raw material for preparing deuterated diphenylurea.

"In one embodiment, said deuterated diphenylurea includes 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureido)-3-fluoro-phenoxy)-N-(- methyl-d.sub.3)picolinamide CM4309; 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureido)-3-fluorophenoxy)-2-((- methyl-d.sub.3)carbamoyl)pyridine-1-oxide; 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureido)-3-fluorophenoxy)-N-(m- ethyl-d.sub.3)picolinamide p-toluenesulfonate (CM4309.TsOH); 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureido)-3-fluorophenoxy)-N-(m- ethyl-d.sub.3)picolinamide hydrochloride; or 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureido)-3-fluorophenoxy)-N-(m- ethyl-d.sub.3)picolinamide methanesulfonate ethanol complex.

"In the seventh aspect, the invention provides the use of the following compound (CM4309) for preparing a pharmaceutical composition with inhibition of phosphokinases (such as raf kinases).

"##STR00013##

"In one embodiment, said pharmaceutical composition can be used to prevent or treat the following diseases: cancer, cardiovascular diseases, inflammation, immunological diseases, nephrosis, angiogenesis, or prostatosis.

"In one embodiment, said cancer includes (but is not limited to): non-small-cell lung cancer, uterine cancer, rectal cancer, cerebral cancer, head and neck cancer, bladder cancer, prostate cancer, breast cancer, solid tumor, kidney cancer, leukaemia, liver cancer, gastric cancer, or pancreatic cancer.

"In the eighth aspect, the invention provides a treating method, comprising the step: administrating compound CM4309 of the invention to a subject in need of, or the crystal form, pharmaceutically acceptable salts, hydrates or solvates thereof, or administrating a pharmaceutical composition containing said compound, thereby inhibiting phosphokinases (such as raf kinases). Preferably, said disease includes cancer, cardiovascular disease, inflammation, immunological diseases, nephrosis, angiogenesis, or prostatosis.

"It should be understood that in the present invention, any of the technical features specifically described above and below (such as in the Examples) can be combined with each other, thereby constituting new or preferred technical solutions that are not described one by one in the specification."

For more information, see this patent: Feng, Weidong; Gao, Xiaoyong; Dai, Xiaojun. Preparation Method of Fluoro-Substituted Deuterated Diphenylurea. U.S. Patent Number 8759531, filed March 17, 2011, and published online on June 24, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8759531.PN.&OS=PN/8759531RS=PN/8759531

Keywords for this news article include: Anions, Cancer, Kidney, Alkalies, Oncology, Carcinoma, Chemistry, Cardiology, Nephrology, raf Kinases, Angiogenesis, Bicarbonates, Electrolytes, Inflammation, Legal Issues, Carbonic Acid, Cardiovascular, Sodium Carbonate, Sodium Hydroxide, Membrane Proteins, Neoplasm Proteins, Peptide Receptors, Inorganic Chemicals.

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Source: Clinical Trials Week


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