New Drug Approvals

Home » Posts tagged 'E 7080'

Tag Archives: E 7080

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 3,047,053 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,542 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,542 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Eisai’s lenvatinib 兰伐替尼 レンバチニブ gets FDA approval


 

Lenvatinib Mesilate

Eisai’s lenvatinib 兰伐替尼 レンバチニブ

 

See synthesis at https://newdrugapprovals.org/2014/08/04/eisais-lenvatinib-%E5%85%B0%E4%BC%90%E6%9B%BF%E5%B0%BC-%E3%83%AC%E3%83%B3%E3%83%90%E3%83%81%E3%83%8B%E3%83%96-to-get-speedy-review-in-europe/

Above post contains SYNTHESIS, spectrocopy predicts, etc

February 13, 2015

Release

The U.S. Food and Drug Administration today granted approval to Lenvima (lenvatinib) to treat patients with progressive, differentiated thyroid cancer (DTC) whose disease progressed despite receiving radioactive iodine therapy (radioactive iodine refractory disease).

The most common type of thyroid cancer, DTC is a cancerous growth of the thyroid gland which is located in the neck and helps regulate the body’s metabolism. The National Cancer Institute estimates that 62,980 Americans were diagnosed with thyroid cancer and 1,890 died from the disease in 2014. Lenvima is a kinase inhibitor, which works by blocking certain proteins from helping cancer cells grow and divide.

“The development of new therapies to assist patients with refractory disease is of high importance to the FDA,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC.”

Lenvima was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that, if approved, would provide significant improvement in safety or effectiveness in the treatment of a serious condition. The drug also received orphan product designation because it is intended to treat a rare disease. Lenvima is being approved approximately two months ahead of the prescription drug user fee goal date of April 14, 2015, the date when the agency was scheduled to complete its review of the application.

Lenvima’s efficacy was demonstrated in 392 participants with progressive, radioactive iodine-refractory DTC who were randomly assigned to receive either Lenvima or a placebo.  Study results showed Lenvima-treated participants lived a median of 18.3 months without their disease progressing (progression-free survival), compared to a median of 3.6 months for participants who received a placebo. Additionally, 65 percent of participants treated with Lenvima saw a reduction in tumor size, compared to the two percent of participants who received a placebo. A majority of participants randomly assigned to receive the placebo were treated with Lenvima upon disease progression.

The most common side effects of Lenvima were high blood pressure (hypertension), fatigue, diarrhea, joint and muscle pain (arthralgia/myalgia), decreased appetite, decreased weight, nausea, inflammation of the lining of the mouth (stomatitis), headache, vomiting, excess protein in the urine (proteinuria), swelling and pain in the palms, hands and/or the soles of the feet (palmar-plantar erythrodysesthesia syndrome), abdominal pain and changes in voice volume or quality (dysphonia).

Lenvima may cause serious side effects, including cardiac failure, blood clot formation (arterial thromboembolic events), liver damage (hepatotoxicity), kidney damage (renal failure and impairment), an opening in the wall of the stomach or intestines (gastrointestinal perforation) or an abnormal connection between two parts of the stomach or intestines (fistula formation), changes in the heart’s electrical activity (QT Interval Prolongation), low levels of calcium in the blood (hypocalcemia), the simultaneous occurrence of headache, confusion, seizures and visual changes (Reversible Posterior Leukoencephalopathy Syndrome), serious bleeding (hemorrhage), risks to an unborn child if a patient becomes pregnant during treatment, and impairing suppression of the production of thyroid-stimulating hormone.

Lenvima is marketed by Woodcliff Lake, New Jersey-based Eisai Inc.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

 amcrasto@gmail.com

09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

 

Eisai’s lenvatinib 兰伐替尼 レンバチニブ to get speedy review in Europe


Lenvatinib skeletal.svg

Lenvatinib

For the treatment of patients with progressive radioiodine-refractory, differentiated thyroid cancer (RR-DTC).

CAS  417716-92-8,
 CAS 857890-39-2 (lenvatinib mesylate)
E 7080, ER-203492-00, E7080, E 7080,
4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide
Molecular Formula: C21H19ClN4O4
Molecular Weight: 426.85296
Eisai Co., Ltd INNOVATOR

European regulators have agreed to undertake an accelerated assessment of Eisai’s lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer.

The drug, which carries Orphan Status in the EU, is to be filed “imminently” and could become the first in a new class of tyrosine kinase inhibitors, the drugmaker said.

Read more at: http://www.pharmatimes.com/Article/14-07-31/Eisai_s_lenvatinib_to_get_speedy_review_in_Europe.aspx#ixzz39OGhRHas

Lenvatinib was granted Orphan Drug Designation for thyroid cancer by the health authorities in Japan in 2012, and in Europe and the U.S in 2013. The first application for marketing authorization of lenvatinib in the world was submitted in Japan on June 2014. Eisai is planning to submit applications for marketing authorization in Europe and the U.S. in the second quarter of fiscal 2014.

Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRalpha, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib a first-in-class treatment, especially given that it simultaneously inhibits the kinase activities of FGFR as well as VEGFR.

Eisai's lenvatinib to get speedy review in Europe

LENVATINIB BASE

COSY PREDICT

COSY  LENVA BASE

Systematic (IUPAC) name
4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide
Clinical data
Legal status Prescription only
Identifiers
CAS number
ATC code None
PubChem CID 9823820
ChemSpider 7999567 Yes
UNII EE083865G2 Yes
Chemical data
Formula C21H19ClN4O4 
Mol. mass 426.853 g/mol

Lenvatinib (E7080) is a multi-kinase inhibitor that is being investigated for the treatment of various types of cancer by Eisai Co. It inhibits both VEGFR2 and VEGFR3 kinases.[1]

The substence was granted orphan drug status for the treatment of various types of thyroid cancer that do not respond toradioiodine; in the US and Japan in 2012 and in Europe in 2013[2] and is now approved for this use.

Clinical trials

Lenvatinib has had promising results from a phase I clinical trial in 2006[3] and is being tested in several phase II trials as of October 2011, for example against hepatocellular carcinoma.[4] After a phase II trial testing the treatment of thyroid cancer has been completed with modestly encouraging results,[5] the manufacturer launched a phase III trial in March 2011.[6]

Chemical structure for Lenvatinib

Lenvatinib Mesilate

Molecular formula: C21H19ClN4O4,CH4O3S =523.0.

CAS: 857890-39-2.

UNII code: 3J78384F61.

About the Lenvatinib (E7080) Phase II Study
The open-label, global, single-arm Phase II study of multi-targeted kinase inhibitor lenvatinib (E7080) in advanced radioiodine (RAI)-refractory differentiated thyroid cancer involved 58 patients with advanced RAI refractory DTC (papillary, follicular or Hurthle Cell) whose disease had progressed during the prior 12 months. (Disease progression was measured using Response Evaluation Criteria in Solid Tumors (RECIST).) The starting dose of lenvatinib was 24 mg once daily in repeated 28 day cycles until disease progression or development of unmanageable toxicities.

2.   About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat or near the trachea. It affects more women than men and usually occurs between the ages of 25 and 65.
The most common types of thyroid cancer, papillary and follicular (including Hurthle Cell), are classified as differentiated thyroid cancer and account for 95 percent of all cases. While most of these are curable with surgery and radioactive iodine treatment, a small percentage of patients do not respond to therapy.

3.   About Lenvatinib (E7080)
Lenvatinib is multi-targeted kinase inhibitor with a unique receptor tyrosine kinase inhibitory profile that was discovered and developed by the Discovery Research team of Eisai’s Oncology Unit using medicinal chemistry technology. As an anti-angiogenic agent, it inhibits tyrosine kinase of the VEGF (Vascular Endothelial Growth Factor) receptor, VEGFR2, and a number of other types of kinase involved in angiogenesis and tumor proliferation in balanced manner. It is a small molecular targeting drug that is currently being studied in a wide array of cancer types.

4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).

However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

[Patent Document 1] WO 02/32872

[Patent Document 2] WO 2004/080462

[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004

………………………..

PATENT

http://www.google.co.in/patents/US8058474

EXAMPLES

Examples will now be described to facilitate understanding of the invention, but the invention is not limited to these examples.

Example 1Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.

1H-NMR (CDCl3): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s)

Example 21-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice and the mixture was stirred overnight at room temperature. Water (400 mL), ethyl acetate (300 mL) and 6N HCl (55 mL) were then added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the title compound (77% yield from 4-amino-3-chlorophenol).

1H-NMR (CDCl3): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8H)

Example 34-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).

1H-NMR (d6-DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz)

Example 44-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).

…………………………

SYNTHESIS

SYN YAOPHA

1H NMR PREDICT

NMR 1H GRAPH NMR 1H VAL

13 C NMR PREDICT

NMR 13C GRAPH NMR 13C VAL

…………………..

PATENT

http://www.google.co.in/patents/US7253286

EX 368

Figure US07253286-20070807-C00838

Example 368

4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as white crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70 mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example 11.

1H-NMR Spectrum (DMSO-d6) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 368-1Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as light brown crystals from 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.745 mmol), by the same procedure as in Production Example 17.

1H-NMR Spectrum (CDCl3) δ (ppm): 4.14 (3H, s), 5.89 (1H, br), 6.50 (1H, d, J=5.6 Hz), 7.16 (2H, dd, J=2.4, 8.8 Hz), 7.22–7.30 (4H, m), 7.44 (2H, m), 7.55 (1H, s), 7.81 (1H, br), 8.31 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s).

……………………

CRYSTALLINE FORM

http://www.google.co.in/patents/US7612208

Preparation Example 1

Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)

Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).

Preparation Example 2Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)

(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.

  • 1H-NMR Spectrum (CDCl3) δ(ppm): 5.12 (1H, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s).
    (2) Preparation of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).

  • 1H-NMR Spectrum (CDCl3) δ(ppm): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8 Hz)
    (3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).

Preparation Example 3Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)

7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).

1H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.

Example 5

A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)

(Preparation Method 1)

In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).

(Preparation Method 2)

In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).

Example 6A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)

A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg)…………MORE IN PATENT

……………………………..

PATENT

https://www.google.com/patents/WO2014098176A1?cl=en

According to the present invention 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide amorphous is excellent in solubility in water.

Example 1 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide manufacture of amorphous amide
4- (3-chloro-4- (cyclopropylamino-carbonyl) amino phenoxy) -7-methoxy-6-quinolinecarboxamide B-type crystals (Patent Document 2) were weighed to 300mg, is placed in a beaker of 200mL volume, it was added tert- butyl alcohol (tBA) 40mL. This was heated to boiling on a hot plate, an appropriate amount of tBA to Compound A is dissolved, water was added 10mL. Then, the weakened heated to the extent that the solution does not boil, to obtain a sample solution. It should be noted, finally the solvent amount I was 60mL. 200mL capacity eggplant type flask (egg-plant shaped flask), and rotated in a state of being immersed in ethanol which had been cooled with dry ice. It was added dropwise a sample solution into the interior of the flask and frozen. After freezing the sample solution total volume, to cover the opening of the flask in wiping cloth, and freeze-dried. We got an amorphous A of 290mg.

Patent Document 2: US Patent Application Publication No. 2007/0117842 Patent specification

Amorphous A 13 C-solid state NMR spectrum in Figure 2, the chemical shifts and I are shown in Table 3.
[Table 3] *: peak of t- butyl alcohol

………………………..

Paper

ACS Medicinal Chemistry Letters (2015), 6(1), 89-94

http://pubs.acs.org/doi/full/10.1021/ml500394m

……………..

Paper

Journal of Pharmaceutical and Biomedical Analysis (2015), 114, 82-87

http://www.sciencedirect.com/science/article/pii/S0731708515002940

KEEP WATCHING WILL BE UPDATED………….most of my posts are updated regularly

References

  1. Matsui, J.; Funahashi, Y.; Uenaka, T.; Watanabe, T.; Tsuruoka, A.; Asada, M. (2008). “Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase”. Clinical Cancer Research 14 (17): 5459–65.doi:10.1158/1078-0432.CCR-07-5270. PMID 18765537.
  2. “Phae III trial shows lenvatinib meets primary endpoint of progression free surival benefit in treatment of radioiodine-refactory differentiated thyroid cancer”. Eisai. 3 February 2014.
  3. Glen, H; D. Boss; T. R. Evans; M. Roelvink; J. M. Saro; P. Bezodis; W. Copalu; A. Das; G. Crosswell; J. H. Schellens (2007). “A phase I dose finding study of E7080 in patients (pts) with advanced malignancies”. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 25 (18S): 14073.
  4. ClinicalTrials.gov NCT00946153 Study of E7080 in Patients With Advanced Hepatocellular Carcinoma (HCC)
  5. Gild, M. L.; Bullock, M.; Robinson, B. G.; Clifton-Bligh, R. (2011). “Multikinase inhibitors: A new option for the treatment of thyroid cancer”. Nature Reviews Endocrinology 7 (10): 617–624.doi:10.1038/nrendo.2011.141. PMID 21862995. edit
  6. ClinicalTrials.gov NCT01321554 A Trial of E7080 in 131I-Refractory Differentiated Thyroid Cancer

UPDATES

EXTRAS……………

Martin Schlumberger et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib(E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). 2014 ASCO Annual Meeting. Abstract Number:LBA6008. Presented June 2, 2014. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA6008). Clinical trial information: NCT01321554.

Bando, Masashi. Quinoline derivative-​containing pharmaceutical composition. PCT Int. Appl. (2011), WO 2011021597 A1

Tomohiro Matsushima, four Nakamura, Kazuhiro Murakami, Atsushi Hoteido, Yusuke Ayat, Naoko Suzuki, Itaru Arimoto, Pinche Hirose, Masaharu Gotoda.Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor. US patent number US7612208  Also published as: CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1 , US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date: Aug 7, 2007 Original Assignee: Eisai Co., Ltd

Funahashi, Yasuhiro et al.Preparation of urea derivatives containing nitrogenous aromatic ring compounds as inhibitors of angiogenesis. US patent number US7253286, Also published as:CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1, US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date:Aug 7, 2007. Original Assignee:Eisai Co., Ltd

Sakaguchi, Takahisa; Tsuruoka, Akihiko. Preparation of amorphous salts of 4-​[3-​chloro-​4-​[(cyclopropylaminocarbonyl)​amino]​phenoxy]​-​7-​methoxy-​6-​quinolinecarboxamide as antitumor agents.  PCT Int. Appl. (2006), WO2006137474 A1 20061228.

Naito, Toshihiko and Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. PCT Int. Appl., WO2005044788, 19 May 2005

Itaru Arimoto et al. Crystal of salt of 4-​[3-​chloro-​4-​(cyclopropylaminocarbonyl)​amino-​phenoxy]​-​7-​methoxy-​6-​quinolinecarboxamide or solvate thereof and processes for producing these. PCT Int. Appl. (2005), WO2005063713 A1 20050714.

10-23-2009
ANTITUMOR AGENT FOR UNDIFFERENTIATED GASTRIC CANCER
10-2-2009
ANTI-TUMOR AGENT FOR MULTIPLE MYELOMA
8-21-2009
ANTITUMOR AGENT FOR THYROID CANCER
8-14-2009
THERAPEUTIC AGENT FOR LIVER FIBROSIS
2-27-2009
USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR
9-5-2008
Medicinal Composition
8-8-2007
Nitrogen-containing aromatic derivatives
5-25-2007
Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
7-21-2006
Nitrogen-containing aromatic derivatives
6-23-2006
Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
11-16-2011
UREA DERIVATIVE AND PROCESS FOR PREPARING THE SAME
8-10-2011
c-Kit kinase inhibitor
7-6-2011
Nitrogen-Containing Aromatic Derivatives
12-24-2010
COMBINED USE OF ANGIOGENESIS INHIBITOR AND TAXANE
9-24-2010
COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND ANTI-TUMOR PLATINUM COMPLEX
4-30-2010
METHOD FOR PREDICTION OF THE EFFICACY OF VASCULARIZATION INHIBITOR
4-16-2010
METHOD FOR ASSAY ON THE EFFECT OF VASCULARIZATION INHIBITOR
3-24-2010
Urea derivative and process for preparing the same
2-26-2010
COMPOSITION FOR TREATMENT OF PANCREATIC CANCER
2-26-2010
COMPOSITION FOR TREATMENT OF UNDIFFERENTIATED GASTRIC CANCER
US7253286 * 18 Apr 2003 7 Aug 2007 Eisai Co., Ltd Nitrogen-containing aromatic derivatives
US20040053908 18 Apr 2003 18 Mar 2004 Yasuhiro Funahashi Nitrogen-containing aromatic derivatives
US20040242506 9 Aug 2002 2 Dec 2004 Barges Causeret Nathalie Claude Marianne Formed from paroxetine hydrochloride and ammonium glycyrrhyzinate by precipitation, spray, vacuum or freeze drying, or evaporation to glass; solid or oil; masks the bitter taste of paroxetine and has a distinctive licorice flavor; antidepressants; Parkinson’s disease
US20040253205 10 Mar 2004 16 Dec 2004 Yuji Yamamoto c-Kit kinase inhibitor
US20070004773 * 22 Jun 2006 4 Jan 2007 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chiloro-4-(cycloproplylaminocarbonyl)aminophenoxy)-7-method-6-quinolinecarboxamide and process for preparing the same
US20070078159 22 Dec 2004 5 Apr 2007 Tomohiro Matsushima Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor
US20070117842 * 22 Apr 2004 24 May 2007 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
EP0297580A1 30 Jun 1988 4 Jan 1989 E.R. SQUIBB & SONS, INC. Amorphous form of aztreonam
JP2001131071A Title not available
JP2005501074A Title not available
JPS6422874U Title not available
WO2002032872A1 19 Oct 2001 25 Apr 2002 Itaru Arimoto Nitrogenous aromatic ring compounds
WO2003013529A1 9 Aug 2002 20 Feb 2003 Barges Causeret Nathalie Claud Paroxetine glycyrrhizinate
WO2004039782A1 29 Oct 2003 13 May 2004 Hirai Naoko QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES INHIBITING AUTOPHOSPHORYLATION OF Flt3 AND MEDICINAL COMPOSITIONS CONTAINING THE SAME
WO2004080462A1 10 Mar 2004 23 Sep 2004 Eisai Co Ltd c-Kit KINASE INHIBITOR
WO2004101526A1 22 Apr 2004 25 Nov 2004 Itaru Arimoto Polymorphous crystal of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-qunolinecarboxamide and method for preparation thereof
WO2005044788A1 8 Nov 2004 19 May 2005 Eisai Co Ltd Urea derivative and process for producing the same
WO2005063713A1 22 Dec 2004 14 Jul 2005 Itaru Arimoto Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
WO2006030826A1 14 Sep 2005 23 Mar 2006 Eisai Co Ltd Medicinal composition

UPDATE………….

1H NMR PREDICT OF LENVATINIB BASE

LEN BASE NMR GRAPH 1H LEN BASE NMR VALUES 1H

hplc real len real nmr

MASS NMR ABMOLE NMR SHIFT
%d bloggers like this: