New Drug Approvals

Home » Posts tagged 'novartis' (Page 2)

Tag Archives: novartis

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

Blog Stats

  • 2,595,028 hits

Flag and hits

Flag Counter

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

Join 2,400 other followers

Follow New Drug Approvals on WordPress.com

Categories

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 2,400 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 →

Categories

Flag Counter
Advertisements

RP 6503, Novartis to develop and commercialize Rhizen’s inhaled dual PI3K-delta gamma inhibitor


 

str1

 

RP 6503

phase 1
str1

 

RP 6503

Molecular Formula: C30H24F2N6O5S
Molecular Weight: 618.610566 g/mol

Mass: 619.1 (M++l). MP: 175-178° C Specific optical rotation (C=l in chloroform, at 25°C) : [a]D = + 147.16.

A1

RP 6503

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl) ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

(S)-N-[5-[4-amino-1-[1-[5-fluoro-3-(3-fluorophenyl)-4-oxochromen-2-yl]ethyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl]methanesulfonamide

 

 

Novartis to develop and commercialize Rhizen’s inhaled dual PI3K-delta gamma inhibitor and related compounds worldwide

The immune pipeline includes ‘dual PI3K inhibitors for various indications’ licensed to Novartis

‘inhaled dual inhibitor’,

Phosphoinositide-3 kinase delta inhibitor; Phosphoinositide-3 kinase gamma inhibitor

WO2011055215A2 and WO2012151525A1 and U.S. Publication Nos. US20110118257 and US20120289496

Rhizen Pharmaceuticals Sa   INNOVATOR

 Incozen Therapeutics Pvt. Ltd., Rhizen Pharmaceuticals Sa

PATENT

http://www.google.com/patents/WO2011055215A2?cl=en

PATENT

http://www.google.com/patents/WO2012151525A1?cl=en

 

scheme 1A:

Ste -1

Step-2

Scheme 2

 

SCHEME 3

SCHEME4

List of Intermediates

 

STR3

 

Intermediate 27: 2-( l -(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin- l – yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To a solution of 3-iodo- l H- pyrazolo[3,4-d]pyrimidin-4-amine (0.800 g, 2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) was added and stirred at RT for 30 min. To this mixture intermediate 22 (0.500 g, 1.44 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a off-white solid (0.300 g, 38%). Ή-NMR (5 ppm, DMSO-d63, 400 MHz): 8.02 (s, 1 H), 7.94 (s, 1 H), 7.84 (dt, J = 8.4,5.7 Hz, 1H), 7.47 (d, 7 = 8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, 7 = 8.8,2.3 Hz, 1 H), 6.87 (s, 2H), 5.88 (q, 7 = 7.0 Hz, 1H), 1.82 (d, 7 = 7.0 Hz, 3H).

SYNTHESIS

STR2

 

 

MAIN PART

str1

PATENT

http://www.google.com/patents/WO2015198289A1?cl=en

Prashant Kashinath Bhavar, Swaroop Kumar Venkata Satya VAKKALANKA

 

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H- chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

front page image

compound of formula (Al):

(Al).

The process comprises the steps of:

(a) subjecting (R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one:

to a Mitsunobu reaction with 3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine:

(for example, in the presence of triphenylphosphine and diisopropylazodicarboxylate) to give (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (Intermediate 3):

Intermediate 3;

(b) reducing Intermediate 3, for example with a reducing agent such as Raney Ni, to give (S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)ethyl)-5-fluoro-3-( -fluorophenyl)-4H-chromen-4-one (Intermediate 4):

Intermediate 4;

The intermediates described herein may be prepared by the methods described in International Publication Nos. WO 11/055215 and WO 12/151525, both of which are hereby incorporated by reference.

Intermediate 1: N-(5-bromo-2-methoxyphenyl)methanesulfonamide:

To a solution of 5-bromo-2-methoxyaniline(1.00 g, 4.94 mmol) in dichloromethane (10 ml), pyridine (0.800 ml, 9.89 mmol) was added and cooled to 0°C. Methane sulphonyl chloride (0.40 ml, 5.19 mmol) was added and stirred for 30 min. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was chromatographed with ethyl acetate : petroleum ether to afford the title compound as a reddish solid (1.20 g, 87%).

Intermediate 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide: Potassium acetate (0.841 g, 8.57 mmol) and bis(pinacolato)diboron (1.190 g, 4.71 mmol) were added to a solution of intermediate 1 (1.20 g, 4.28 mmol) in dioxane (17.5 ml) and the solution was degassed for 30 min.[l, -Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH2Ci2 (0.104 g, 0.128 mmol) was added under nitrogen atmosphere and heated to 80°C. After 2h the

reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as a yellow solid (1.00 g, 71%).JH-NMR (δ ppm, CDCb, 400 MHz): 7. 91 (d, / = 1.2Hz, 1H), 7. 62 (dd, / = 8.1, 1.2Hz, 1H), 6. 92 (d, / = 8.1Hz, 1H), 6.73 (s, 1H), 3.91 (s, 3H), 2.98 (s, 3H), 1.32 (s, 12H).

Intermediate 3: (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To a solution of (R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one (0.500 g, 1.64 mmol) in THF (5 ml), 3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (0.564 g, 1.97 mmol) and triphenylphosphine (0.649 g, 2.47 mmol) were added followed by the addition of diisopropylazodicarboxylate (0.50 ml, 2.47 mmol). ((R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one can be prepared as described for Intermediates 23, 25, and 26 in International Publication No. WO 2012/0151525.). After 4h at room temperature, the mixture was concentrated and the residue was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as a brown solid (0.270 g, 29%). JH-NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (s, 1H), 7.83 (m, 1H), 7.63-7.50 (m, 3H), 7.29 (m, 2H), 7.06 (dt, J = 8.7,2.2Hz, 1H), 6.94 (m, 2H), 6.75 (dd, J = 8.1,2.1Hz, 1H), 5.95 (q, J = 7.0Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H), 1.86 (d, J = 7.0 Hz, 3H).

[109] Intermediate 4: (S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:

(S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one : To a solution of Intermediate 3 (0.260 g, 0.455 mmol) in ethanol (5 ml), Raney Ni (0.130 g) was added and hydrogeneated at 20psi at 50°C for 24h. The reaction mixture was passed through celitepad and concentrated to afford the title compound as a brown solid (0.150 g, 60%). Mass : 540.8 (M+).

Example A

N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

To a solution of 2-(l-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (0.200 g, 0.366 mmol) in DME (2.1 ml) and water (0.67 ml), intermediate 2 (0.179 g, 0.550 mmol) and sodium carbonate (0.116 g, 1.10 mmol) were added and the system was degassed for 30 min. (2-(l-(4-amino-3-iodo-lH^yrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one can be prepared as described for Intermediates 23, 25, and 26 in International Publication No. WO 2012/0151525). Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.059 g, 0.075 mmol) was added and kept under microwave irradiation (microwave power = 100W, temperature = 100 °C) for 45 min. The reaction mixture was Celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a brown solid (0.080 g, 35%). MP: 216-218 °C. ¾-NMR (δ ppm, CDCb, 400 MHz): 8.20 (s, 1H), 7.73 (s, 1H), 7.53 (m, 2H), 7.31 (m, 2H), 7.07-6.73 (m, 6H), 6.07 (q, / = 6.2 Hz, 1H), 3.98 (s, 3H), 3.14 (s, 3H), 2.01 (d, / = 6.0Hz, 3H).

Example Al and A2

Method A

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

and (R)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2- yl)ethyl)-lH-p anesulfonamide

The two enantiomerically pure isomers were separated by preparative SFC (supercritical fluid) conditions from N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide (0.500 g) on a CHIRALPAK AS-H column (250 x 30 mm; 5μπι) using methanol : CO2 (55:45) as the mobile phase at a flow rate of 80g / min.

Example Al (S-isomer): Brown solid (0.247 g). Enantiomeric excess: 97.4%. Retention time: 2.14 min. Mass: 619.1 (M++l). MP: 156-158° C.

Example A2 (R-isomer): Brown solid (0.182 g). Enantiomeric excess: 99.3%. Retention t: 3.43 min. Mass: 619.1 (M++l). MP: 168-171° C.

Method Al

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

and (R)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2- yl)ethyl)-lH-p anesulfonamide

The two enantiomerically pure isomers were separated by preparative SFC (supercritical fluid) conditions from N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methanesulfonamide (15.0 g) on a CHIRALPAK AS-H column (250 x 20 mm; 5μπι) using methanol : CO2 (45:55) as the mobile phase at a flow rate of 120g / min.

Example Al (S-isomer): Enantiomeric excess: 100 %. Retention time: 2.21 min. Mass: 619.1 (M++l). MP: 175-178° C Specific optical rotation (C=l in chloroform, at 25°C) : [a]D = + 147.16.

Example A2 (R-isomer): Enantiomeric excess: 99.3%. Retention t: 3.72 min. Mass: 619.1 (M++l). MP: 154-157° C. Specific optical rotation (C=l in chloroform, at 25°C) : [a]D = – 159.54.

Method B

Example Al

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

To a solution of Intermediate 4 (0.500 g, 0.923 mmol) in dichloromethane (5 ml) cooled to 0°C, pyridine (0.200 ml, 1.84 mmol) was added and stirred for 10 min. Methanesulphonyl chloride (0.100 ml, 0.923 mmol) was added stirred for 30 min. The reaction mixture was quenched with water, extracted with dichloromethane and dried over sodium sulphate. The crude product was column chromatographed with methanol : dichloromethane to afford the title compound as an off-white solid (0.240 g, 42%). MP: 211-213°C. ¾-NMR (δ ppm, DMSO-d6, 400 MHz): 9.15 (s, 1H), 8.06 (s, 1H), 7.83 (m, 1H), 7.49 (m, 4H), 7.28 (m, 4H), 7.08 (dt, / = 8.6, 1.7 Hz, 1H), 6.92 (s, 2H), 5.98 (q, / = 6.9 Hz, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 1.88 (d, / = 7.0 Hz, 3H). Enantiomeric excess: 85.4% as determined by HPLC on a chiralpak AS-3R column, enriched in the fast eluting isomer (retention time = 7.46 min.).

 

 

str1

CLIPS

La Chaux-de-Fonds, Switzerland, Sept. 6, 2013  — La Chaux-de-Fonds, Switzerland (6 September 2013): Rhizen Pharmaceuticals S.A. announces a scientific poster presentation on the pre-clinical characterization of its lead calcium release activated channel (CRAC) inhibitor, RP3128, for the treatment of respiratory disorders and an oral presentation on the pharmacological profile of its novel, dual Phosphoinositide-3 kinase (PI3K) delta/gamma inhibitor, RP6503, in the pulmonary disease systems, at the European Respiratory Society Annual Congress (ERS), to be held from 7-11 September 2013, at Barcelona, Spain.

RP6503 is a novel, potent and selective inhibitor of the delta and gamma isoforms of PI3K. It is to be delivered via the inhalation route and has a long duration of action along with excellent PI3K isoform selectivity, which is expected to result in better safety. RP3128 has been optimized with high potency for CRAC channel inhibition, selectivity over the other voltage gated channels and excellent oral bioavailability. Rhizen intends to move both these compounds to the clinic in 2014.

Details of the presentations:

1.      Abstract of the Poster Presentation: “Pre-clinical characterization of RP3128, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders”

Time and Location- 8 September 2013 between 14.45-16.45 in Room 3.6, at Poster Discussion: New drugs in respiratory medicine, at FIRA BARCELONA, Convention Centre de Gran Via, Barcelona, Spain

2.      Abstract of Oral Presentation: “In vitro and in vivo pharmacological profile of RP6503, a novel dual PI3K delta/gamma inhibitor, in pulmonary disease systems”

Time and Location- 11 September 2013 at 8.45 in Room 3.9; Session 8.30-10.30, at the Oral Presentation: Emerging new targets for the treatment of respiratory diseases, at FIRA BARCELONA, Convention Centre de Gran Via, Barcelona, Spain

CLIPS

La Chaux-de-Fonds, Switzerland , Dec. 09, 2015  — Rhizen Pharmaceuticals S.A. announced today that they have entered into an exclusive, worldwide license agreement with Novartis for the development and commercialization of Rhizen’s, inhaled dual PI3K-delta gamma inhibitor and its closely related compounds for various indications.

Under the terms of the agreement, Rhizen will receive an upfront payment and is eligible to receive development, regulatory and sales milestones payments. In addition Rhizen is also eligible to receive tiered royalties on annual nets sales.

The lead compound is a novel, potent, and selective dual PI3K-delta gamma inhibitor with demonstrated anti-inflammatory and immuno-modulatory activity in pre-clinical systems and models representative of respiratory diseases. With a favorable ADME and PK profile and high therapeutic index in animals, the inhaled dual PI3K-delta gamma inhibitor holds promise in the treatment of human airway disorders.

About Rhizen Pharmaceuticals S.A.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel therapeutics for the treatment of cancer, immune and metabolic disorders. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways. Rhizen is headquartered in La-Chaux-de-Fonds, Switzerland. For additional information, please visit Rhizen’s website, http://www.rhizen.com.

SEE

https://newdrugapprovals.org/2015/12/10/alembic-pharma-advances-1-on-rhizen-novartis-license-agreement/

 

WO-2015181728 

WO-2015001491 

WO-2014072937 

WO-2014006572 

http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880

WO2011055215A2 Nov 3, 2010 May 12, 2011 Incozen Therapeutics Pvt. Ltd. Novel kinase modulators
WO2012008302A1 Jun 28, 2011 Jan 19, 2012 National University Corporation Tottori University Method for preparing novel hipsc by means of mirna introduction
WO2012121953A1 Feb 29, 2012 Sep 13, 2012 The Trustees Of Columbia University In The City Of New York Methods and pharmaceutical compositions for treating lymphoid malignancy
WO2012151525A1 May 4, 2012 Nov 8, 2012 Rhizen Pharmaceuticals Sa Novel compounds as modulators of protein kinases
WO2013164801A1 May 3, 2013 Nov 7, 2013 Rhizen Pharmaceuticals Sa Process for preparation of optically pure and optionally substituted 2- (1 -hydroxy- alkyl) – chromen – 4 – one derivatives and their use in preparing pharmaceuticals
US20110118257 May 19, 2011 Rhizen Pharmaceuticals Sa Novel kinase modulators
US20120289496 May 4, 2012 Nov 15, 2012 Rhizen Pharmaceuticals Sa Novel compounds as modulators of protein kinases

///////RP 6503, Novartis, develop, commercialize,  Rhizen, inhaled dual PI3K-delta gamma inhibitor, PHASE 1, RP-6503

c21c(cccc1O/C(=C(\C2=O)c3cc(ccc3)F)C(C)n4c6ncnc(c6c(n4)c5cc(c(cc5)OC)NS(=O)(=O)C)N)F

CC(C1=C(C(=O)C2=C(O1)C=CC=C2F)C3=CC(=CC=C3)F)N4C5=C(C(=N4)C6=CC(=C(C=C6)OC)NS(=O)(=O)C)C(=NC=N5)N

str1

/////

Advertisements

RP 6530, Tenalisib


img

str1RP 6530

(S)-2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (Compound A1 is RP 6530).

str1

RP 6530

CID 86291103.png

 

RP 6530, RP6530, RP-6530

Tenalisib

RP6530-1401, NCI-2015-01804, 124584, NCT02567656

(S)-2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

3-(3-fluorophenyl)-2-[(1S)-1-(7H-purin-6-ylamino)propyl]chromen-4-one

MW415.4, C23H18FN5O2

CAS 1639417-53-0, 1693773-94-2

RP6530 demonstrated high potency against PI3Kδ (IC50 =24.5 nM) and γ (IC50 = 33.2 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. Cellular potency was confirmed in target-specific assays, namely anti-FcεR1-(EC50=37.8 nM) or fMLP (EC50 = 39.0 nM) induced CD63 expression in human whole blood basophils, LPS induced CD19+ cell proliferation in human whole blood (EC50=250 nM), and LPS induced CD45R+ cell proliferation in mouse whole blood (EC50=101 nM).
A PI3K inhibitor potentially for the treatment of hematologic malignancies.

An inhibitor of phosphoinositide-3 kinase (PI3K) δ/γ isoforms and anti-cellular proliferation agent for treatment of hematol. malignancies

Rhizen Pharmaceuticals is developing RP-6530, a PI3K delta and gamma dual inhibitor, for the potential oral treatment of cancer and inflammation  In November 2013, a phase I trial in patients with hematologic malignancies was initiated in Italy ]\. In September 2015, a phase I/Ib study was initiated in the US, in patients with relapsed and refractory T-cell lymphoma. At that time, the study was expected to complete in December 2016

PATENTS……..WO 11/055215 ,  WO 12/151525.

Inventors

 Inventors Meyyappan Muthuppalaniappan, Srikant Viswanadha, Govindarajulu Babu, Swaroop Kumar V.S. Vakkalanka,
Incozen Therapeutics Pvt. Ltd., Rhizen Pharmaceuticals Sa
  • Antineoplastics; Small molecules
  • Mechanism of Action Phosphatidylinositol 3 kinase delta inhibitors; Phosphatidylinositol 3 kinase gamma inhibitors
  • Phase I Haematological malignancies
  • Preclinical Multiple myeloma
Swaroop K. V. S. Vakkalanka,
COMPANY Rhizen Pharmaceuticals Sa

https://clinicaltrials.gov/ct2/show/NCT02017613

PI3K delta/gamma inhibitor RP6530 An orally active, highly selective, small molecule inhibitor of the delta and gamma isoforms of phosphoinositide-3 kinase (PI3K) with potential immunomodulating and antineoplastic activities. Upon administration, PI3K delta/gamma inhibitor RP6530 inhibits the PI3K delta and gamma isoforms and prevents the activation of the PI3K/AKT-mediated signaling pathway. This may lead to a reduction in cellular proliferation in PI3K delta/gamma-expressing tumor cells. In addition, this agent modulates inflammatory responses through various mechanisms, including the inhibition of both the release of reactive oxygen species (ROS) from neutrophils and tumor necrosis factor (TNF)-alpha activity. Unlike other isoforms of PI3K, the delta and gamma isoforms are overexpressed primarily in hematologic malignancies and in inflammatory and autoimmune diseases. By selectively targeting these isoforms, PI3K signaling in normal, non-neoplastic cells is minimally impacted or not affected at all, which minimizes the side effect profile for this agent. Check for active clinical trials using this agent. (NCI Thesaurus)

Company Rhizen Pharmaceuticals S.A.
Description Dual phosphoinositide 3-kinase (PI3K) delta and gamma inhibitor
Molecular Target Phosphoinositide 3-kinase (PI3K) delta ; Phosphoinositide 3-kinase (PI3K) gamma
Mechanism of Action Phosphoinositide 3-kinase (PI3K) delta inhibitor; Phosphoinositide 3-kinase (PI3K) gamma inhibitor
Therapeutic Modality Small molecule

 

 

str1

str1

Dual PI3Kδ/γ Inhibition By RP6530 Induces Apoptosis and Cytotoxicity In B-Lymphoma Cells

RP6530 is a potent and selective dual PI3Kδ/γ inhibitor that inhibited growth of B-cell lymphoma cell lines with a concomitant reduction in the downstream biomarker, pAKT. Additionally, the compound showed cytotoxicity in a panel of lymphoma primary cells. Findings provide a rationale for future clinical trials in B-cell malignancies.

PI3K Dual Inhibitor (RP-6530)


Therapeutic Area Respiratory , Oncology – Liquid Tumors , Rheumatology Molecule Type Small Molecule
Indication Peripheral T-cell lymphoma (PTCL) , Non-Hodgkins Lymphoma , Asthma , Chronic Obstructive Pulmonary Disease (COPD) , Rheumatoid Arthritis
Development Phase Phase I Rt. of Administration Oral

Description

Rhizen is developing dual PI3K gamma/delta inhibitors for liquid tumors and inflammatory conditions.

Mechanism of Action

While alpha and beta isoforms are ubiquitous in their distribution, expression of delta and gamma is restricted to circulating hematogenous cells and endothelial cells. Unlike PI3K-alpha or beta, mice lacking expression of gamma or delta do not show any adverse phenotype indicating that targeting of these specific isoforms would not result in overt toxicity. Dual delta/gamma inhibition is strongly implicated as an intervention strategy in allergic and non-allergic inflammation of the airways and other autoimmune diseases. Scientific evidence for PI3K-delta and gamma involvement in various cellular processes underlying asthma and COPD stems from inhibitor studies and gene-targeting approaches. Also, resistance to conventional therapies such as corticosteroids in several COPD patients has been attributed to an up-regulation of the PI3K delta/gamma pathway. Disruption of PI3K-delta/gamma signalling therefore provides a novel strategy aimed at counteracting the immuno-inflammatory response. Due to the pivotal role played by PI3K-delta and gamma in mediating inflammatory cell functionality such as leukocyte migration and activation, and mast cell degranulation, blocking these isoforms may also be an effective strategy for the treatment of rheumatoid arthritis as well.

Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the delta and gamma isoforms would be expected to attenuate the progression of immune response encountered in airway inflammation and rheumatoid arthritis.

https://i1.wp.com/www.rhizen.com/images/backgrounds/pi3k%20delta%20gamma%20ii.png

Clinical Trials

Rhizen has identified an orally active Lead Molecule, RP-6530, that has an excellent pre-clinical profile. RP-6530 is currently in non-GLP Tox studies and is expected to enter Clinical Development in H2 2013.

In December 2013, Rhizen announced the start of a Phase I clinical trial. The study entitled A Phase-I, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual PI3K delta /gamma inhibitor, in patients with Relapsed or Refractory Hematologic Malignancies is designed primarily to establish the safety and tolerability of RP6530. Secondary objectives include clinical efficacy assessment and biomarker response to allow dose determination and potential patient stratification in subsequent expansion studies.

Partners by Region

Rhizen’s pipeline consists of internally discovered (with 100% IP ownership) novel small molecule programs aimed at high value markets of Oncology, Immuno-inflammtion and Metabolic Disorders. Rhizen has been successful in securing critical IP space in these areas and efforts are on for further expansion in to several indications. Rhizen seeks partnerships to unlock the potential of these valuable assets for further development from global pharmaceutical partners. At present global rights on all programs are available and Rhizen is flexible to consider suitable business models for licensing/collaboration.

In 2012, Rhizen announced a joint venture collaboration with TG Therapeutics for global development and commercialization of Rhizen’s Novel Selective PI3K Kinase Inhibitors. The selected lead RP5264 (hereafter, to be developed as TGR-1202) is an orally available, small molecule, PI3K specific inhibitor currently being positioned for the treatment of haematological malignancies.

PATENT

WO2014195888, DUAL SELECTIVE PI3 DELTA AND GAMMA KINASE INHIBITORS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014195888Intermediates

Intermediate 1: 3-(3-fluorophenyl)-2-(l-hydroxypropyl)-4H-chromen-4-one: To a solution of 2-(l-bromopropyl)-3-(3-fluorophenyl)-4H-chromen-4-one1 (8.80 g, 24.36 mmol ) in DMSO (85 ml), n-butanol (5 ml) was added and heated to 120° C for 3h. The reaction mixture was cooled to room temperature (RT), quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (2.10 g, 29 %) which was used without further purification in next step.

Intermediate 2: 3-(3-fluorophenyl)-2-propionyl-4H-chromen-4-one: DMSO (1.90 ml, 26.82 mmol) was added to dichloromethane (70 ml) and cooled to -78°C. Oxalyl chloride (1.14 ml, 13.41 mmol) was then added. After 10 minutes, intermediate 1 (2.00 g, 6.70 mmol) in dichloromethane (20 ml) was added dropwise and stirred for 20 min. Triethylamine (7 ml) was added and stirred for lh. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow liquid (1.20 g, 60%) which was used as such in next step.

Intermediate 3: (+)/(-)-3-(3-fluorophenyl)-2-(l-hydroxypropyl)-4H-chromen-4-one :

To a solution of intermediate 2 (0.600 g, 2.02 mmol) in DMF (7.65 ml) under nitrogen purging, formic acid : trietylamine 5 : 2 azeotrope (1.80 ml) was added followed by [(S,S)tethTsDpenRuCl] (3.0 mg). The reaction mixture was heated at 80°C for 1.5 hours under continuous nitrogen purging. The reaction mixture was quenched with water, extected with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (0.450 g, 74%). Mass: 299.0 (M+).

Enantiomeric excess: 78%, enriched in the late eluting isomer (retention time: 9.72 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 4: (+)/(-)-3-(3-fluorophenyl)-2-(l-hydroxypropyl)-4H-chromen-4-one :

The title compound was obtained as yellow solid (0.500 g, 83%) by using a procedure similar to the one described for intermediate 3, using intermediate 2 (0.600 g, 2.02 mmol), DMF (7.65 ml), formic acid : trietylamine 5 : 2 azeotrope (1.80 ml) and [(R,R)tethTsDpenRuCl] (3.0 mg). Mass: 298.9 (M+). Enantiomeric excess: 74.8%, enriched in the fast eluting isomer (retention time: 8.52 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 5: (R)-3-(3-fluorophenyl)-2-(l-hydroxypropyl)-4H-chromen-4-one:

Step 1 : (R)-2-(l-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one: To 2-(3-fluorophenyl)-l-(2-hydroxyphenyl)ethanone (2.15 g, 9.36 mmol ), in dichloromethane ( 20 ml), HATU (4.27 g, 11.23 mmol), R-(+)2-benzyloxybutyric acid (2.00 g, 10.29 mmol) were added and stirred for lOmin, then triethylamine (14.0 ml, 101.1 mmol) was added dropwise and stirred at RT for 24h. The reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as yellow solid (1.65 g, 45%). JH-NMR (δ ppm, CDC13, 400 MHz): 8.24 (dd, / = 7.9,1.5 Hz, 1H), 7.74 (dt, / = 7.1,1.7 Hz, 1H), 7.58 (dd, / = 8.3,0.4 Hz, 1H), 7.44-7.06 (m, 10H), 4.51 (d, / = 7.8 Hz, 1H), 4.34 (d, / = 7.8 Hz, 1H), 4.25 (dd, / = 7.8,6.2 Hz, 1H), 2.17-1.90 (m, 2H), 0.95 (t, / = 7.5 Hz, 3H). Mass: 389.0 (M+).

Step 2: (R)-3-(3-fluorophenyl)-2-(l-hydroxypropyl)-4H-chromen-4-one : To (R)-2-(l-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (1.50 g, 3.86 mmol) in dichloromethane (15 ml) cooled to 0°C and aluminium chloride (1.00 g, 7.72 mmol) was added portion wise and stirred at RT for 6h. The reaction mixture was quenched with 2N HC1 solution, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as yellow solid (0.552 g, 48%).‘ JH-NMR (δ ppm, CDC13, 400 MHz): 8.24 (dd, / = 8.0,1.6 Hz, 1H), 7.72 (m, , 1H), 7.52 (dd, / = 8.4,0.5 Hz, 1H), 7.44 (m, 2H), 7.12-7.01(m,3H), 4.49 (t, / = 7.0 Hz, 1H), 1.94 (m, 2H), 0.93 (t, / = 7.5 Hz, 3H). Mass: (299.0(M+). Purity: 96.93%.

25[a] D -14.73 (c = 1, CHCI3). Enantiomeric excess: 85.92%, enriched in the fast eluting isomer (retention time: 8.57 min.) as determined by HPLC on a chiralpak AS-3R column.

Compound A

(RS)- 2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 1 (2.50 g, 8.41 mmol) in THF (25 ml), tert-butyl 9-trityl-9H-purin-6-ylcarbamate (4.81 g, 10.09 mmol) and triphenylphosphine (3.31 g, 12.62 mmol) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate (2.5 ml, 12.62 mmol) was added and stirred at RT for 2h. The reaction mixture was concentrated and column chromatographed with ethyl acetate : petroleum ether to afford a yellow coloured intermediate. To the intermediate, dichloromethane (65 ml) and trifluoroacetic acid (7.9 ml) were added and the resulting mixture was stirred at RT for 12 h. The reaction mixture was then basified with aqueous sodium bicarbonate solution, extracted with dichloromethane and dried over sodium sulphate. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale-brown solid (1.05 g, 30 %). MP: 148-150°C. Mass: 415.6 (M+).

Compound Al

(S)-2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

Method A: To a solution of intermediate 3 (0.250 g, 0.838 mmol) in THF (5ml), tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.479 g, 1.00 mmol) and triphenylphosphine (0.329 g, 1.25 mmol) were added and the resulting mixture was stirred at RT for 5 min. Diisopropylazodicarboxylate (0.25 ml, 1.25 mmol) was then added and stirred at RT for 12 h. The reaction mixture was concentrated and column chromatographed with ethyl acetate: pet.ether to afford the yellow coloured intermediate. To the intermediate in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) was added stirred at RT for 12 h. The reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with dichloromethane and dried over sodium sulphate. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as an off-white solid (0.015 g, 4 %). MP: 137-140°C. JH-NMR (δ ppm, DMSO- , 400 MHz): 12.94 (s, 1H), 8.12-8.10 (m, 4H), 7.84-7.80 (m, 1H), 7.61 (d, / = 8.3 Hz, 1H), 7.50-7.41 (m, 2H), 7.28-7.18 (m, 3H), 5.20-5.06 (m, 1H), 2.10-1.90 (m, 2H), 0.84 (t, / = 3.7 Hz, 3H). Enantiomeric excess: 77.4% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 7.90 min.).

Method B : To a solution of intermediate 5 (2.60 g, 8.68 mmol) in THF (52 ml), tert-butyl 9-trityl-9H-purin-6-ylcarbamate (4.96 g, 10.42 mmol) and triphenylphosphine (2.76 g, 13.03 mmol) were added and the resulting mixture was stirred at RT for 5 min. Dusopropylazodicarboxylate (0.25 ml, 1.25 mmol) was then added and stirred at RT for 12 h. The reaction mixture was concentrated and column chromatographed with ethyl acetate: petroleum ether to afford the yellow coloured intermediate. To the intermediate in dichloromethane (55 ml), trifluoroacetic acid (14.2 ml) was added and stirred at RT for 12 h. The reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with dichloromethane and dried over sodium sulphate. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale-yellow solid (1.00 g, 27 %). MP: 168-170°C. Mass: 416.5(M++1) Enantiomeric excess: 86.5% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 7.90 min.).

Method C : The title compound was separated by preparative SFC conditions from Compound A (1.090 g) on a CHIRALPAK AY-H column (250 x 30 mm; 5μπι) using methanol : C(¾ (35:65) as the mobile phase at a flow rate of 80 g / min. Off-white solid (0.378 g). e.e. 100%. Rt: 2.37 min. Mass: 416.1(M++1). MP: 149-152°C.

PATENT
WO 2011055215

Scheme 1A

 

CAUTION        ethyl compd below, NOT THE PRODUCT

Example 47

(S)-2-(l-(9H-purin-6-yIamino) ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

[428] To a solution of intermediate 65 (2.0g, 8.68 mmoles) in dichloromethane (20ml), triethylamine (3.6ml, 26.06 mmoles) was added followed by N-Boc-Alanine (1.97g, 10.42 mmoles). To this mixture HATU (6.6g, 17.37 mmoles) was added and stirred at RT for 12h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the isoflavone intermediate (1.70g). To a solution of this intermediate (1.7g) in dichloromethane (20ml), trifluoroacetic acid (3 ml) was added and stirred at RT for 2h. The reaction mixture was concentrated, basified with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the amine intermediate (0.641 g). To a solution of this amine intermediate (0.30g, 1.05 mmoles) in tert-butanol (6ml), N, N- diisopropylethylamine (0.36ml, 2.17 mmoles) and 6-bromopurine (0.168g, 0.847 mmoles) were added and refluxed for 24h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: ethyl acetate to afford the title compound as off-white solid (0.041g, 10% yield). MP: 135-138 °C. Ή-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.95(s,lH), 8.15(t, / = 6.8Hz, 1H), 8.11(s, 1H), 8.08(s, 1H), 8.03(d, J = 7.8 Hz, 1H), 7.81(t ,J = 7.3Hz, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.49 (t, J = 7.3Hz, 2H), 7.25(m,3H), 5.19(br m, 1H), 1.56(d, J = 6.9Hz,3H). Mass: 402.18(M+ +1).

PATENT
WO 2012151525

Scheme 1

Base

This scheme provides a synthetic route for the preparation of compound of formula wherein all the variables are as described herein in above

15 14 10 12 12a

 CONFERENCE PROCEEDINGS

Abstract 2704: RP6530, a dual PI3K δ/γ inhibitor, potentiates ruxolitinib activity in the JAK2-V617F mutant erythroleukemia cell lines

  1. Swaroop Vakkalanka1,
  2. Seeta Nyayapathy2, and
  3. Srikant Viswanadha2

Author Affiliations

  1. 1Rhizen Pharmaceuticals SA, Fritz-Courvoisier 40, Switzerland;
  2. 2Incozen Therapeutics Pvt. Ltd., Hyderabad, India.
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

Abstract

Background: Myelofibrosis (MF) represents a life-threatening neoplasm that manifests particularly in the elderly population and is characterized by bone marrow fibrosis and extramedullary hematopoeisis. While ruxolitinib, a JAK1/2 inhibitor, has recently been approved by the USFDA for its disease modifying potential in MF patients, it is still not considered as a curative option. Targeting another kinase such as PI3K, downstream of JAK, could therefore be a more efficient way of treating myelofibrotic neoplasms. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor that demonstrated high potency against PI3Kδ (IC50 = 25 nM) and γ (IC50 = 33 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. The objective of this study was to evaluate the effect of a combination of ruxolitinib and RP6530 in the JAK2-V617F mutant Human Erythroleukemia (HEL) cell line.

Methods: Passive resistance was conferred by incubating HEL cells with increasing concentrations of ruxolitinib over an 8-10-week period. Endogenous JAK2, PI3Kδ, PI3Kδ, and pAKT were estimated by Western Blotting. RP6530, ruxolitinib, and the combination of RP6530 + Ruxolitinib were tested for their effect on viability and apoptosis. Cell viability was assessed by a MTT assay. Induction of apoptosis was analyzed by Annexin V/PI staining.

Results: Resistance to ruxolitinib was confirmed by a right-ward shift in EC50 of ruxolitinib in a HEL cell proliferation assay (0.82 μM Vs. 12.2 μM). Endogeous pAKT expression was 3.7-fold higher in HEL-RR compared to HEL-RS cells indicating activation of the AKT signaling pathway. While single-agent activity of RP6530 was modest (33-46% inhibition @ 10 μM) in both HEL-RS and HEL-RR cells, addition of 10 μM RP6530 to ruxolitinib was synergistic resulting in a near-complete inhibition of proliferation (>90% for HEL-RS and >70% for HEL-RR). While the order of addition did not affect the potency of RP6530, addition of 5 μM RP6530, 4 h prior to the addition of ruxolitinib resulted in a significant reduction in EC50 of ruxolitinib (5.8 μM) in HEL-RR cells. On lines with cell proliferation data, incubation of 10 μM RP6530 with ruxolitinib for 72 h increased the percent of apoptotic cells (55% in HEL-RS and 37% in HEL-RR) compared to either agent alone (16-27% in HEL-RS and 17-21% in HEL-RR).

Conclusions: Ruxolitinib resistance in the V617F JAK-2 mutant HEL cells is accompanied by an increase in pAKT expression. Inhibition of pAKT via the addition of RP6530, a dual PI3K δ/γ inhibitor, resulted in a reversal of ruxolitinib resistance. Complementary activity was also observed in HEL-RS cells indicating that a combination of ruxolitinib and RP6530 could have a positive bearing on the clinical outcome in MF patients.

Citation Format: Swaroop Vakkalanka, Seeta Nyayapathy, Srikant Viswanadha. RP6530, a dual PI3K δ/γ inhibitor, potentiates ruxolitinib activity in the JAK2-V617F mutant erythroleukemia cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2704. doi:10.1158/1538-7445.AM2015-2704

REFERENCES
December 2014, data were presented at the 56th ASH Meeting in San Francisco, CA.
April 2015, preclinical data were presented at the 106th AACR Meeting in Philadelphia, PA. RP-6530 had GI50 values of 17,028 and 22,014 nM, respectively
December 2013, preclinical data were presented at the 55th ASH Meeting in New Orleans, LA.
June 2013, preclinical data were presented at the 18th Annual EHA Congress in Stockholm, Sweden. RP-6530 inhibited PI3K delta and gamma isoforms with IC50 values of 24.5 and 33.2 nM, respectively.
  • 01 Sep 2015 Phase-I clinical trials in Haematological malignancies (Second-line therapy or greater) in USA (PO) (NCT02567656)
  • 18 Nov 2014 Preclinical trials in Multiple myeloma in Switzerland (PO) prior to November 2014
  • 18 Nov 2014 Early research in Multiple myeloma in Switzerland (PO) prior to November 2014
WO2011055215A2 Nov 3, 2010 May 12, 2011 Incozen Therapeutics Pvt. Ltd. Novel kinase modulators
WO2012151525A1 May 4, 2012 Nov 8, 2012 Rhizen Pharmaceuticals Sa Novel compounds as modulators of protein kinases
WO2013164801A1 May 3, 2013 Nov 7, 2013 Rhizen Pharmaceuticals Sa Process for preparation of optically pure and optionally substituted 2- (1 -hydroxy- alkyl) – chromen – 4 – one derivatives and their use in preparing pharmaceuticals
US20110118257 May 19, 2011 Rhizen Pharmaceuticals Sa Novel kinase modulators
US20120289496 May 4, 2012 Nov 15, 2012 Rhizen Pharmaceuticals Sa Novel compounds as modulators of protein kinases
WO 2014195888
WO 2011055215

WO2015175966

WO2015051252

  • BC Innovations, Therapeutics
    Indication Target/marker/pathway Summary Licensing status Publication and contact information Cardiovascular disease Intimal hyperplasia Phosphoinositide 3-kinase-g (PI3Kg) Rodent studies suggest inhibiting …
  • BC Innovations, Targets & Mechanisms
    Targets & Mechanisms: PI3K inhibition: solid immunotherapy Table 1. A peek at PI3K inhibitors. According to a study in Nature by Ali et al., inhibition of phosphoinositide 3-kinase-d (PI3Kd) or the PI3K catalytic …
  • Week in Review, Clinical Status
    Rhizen Pharmaceuticals S.A., La Chaux-de-Fonds, Switzerland Product: RP6530 Business: Cancer Molecular target: Phosphoinositide 3-kinase (PI3K) delta; Phosphoinositide 3-kinase (PI3K) gamma Description: Dual …
  • Week in Review, Preclinical Results
    Rhizen Pharmaceuticals S.A., La Chaux-de-Fonds, Switzerland Product: RP6530 Business: Cancer Indication: Treat B cell lymphoma In vitro, 2-7 M RP6530 led to a >50% dose-dependent inhibition in growth of immortalized …

/////

c1cccc4c1C(/C(=C(/[C@H](CC)Nc3c2c(ncn2)ncn3)O4)c5cc(ccc5)F)=O

CCC(C1=C(C(=O)C2=CC=CC=C2O1)C3=CC(=CC=C3)F)NC4=NC=NC5=C4NC=N5

Alembic Pharma advances 1% on Rhizen-Novartis license agreement


 

India Infoline News Service | Mumbai | December 10, 2015 11:32 IST

Swiss subsidiary Rhizen Pharmaceuticals S.A. entered into an exclusive, worldwide license agreement with Novartis for the development and commercialization of Rhizen’s, inhaled dual Pl3K-delta gamma inhibitor and its closely related compounds for various indications.

read

http://www.indiainfoline.com/article/news-top-story/alembic-pharma-advances-1-on-rhizen-novartis-license-agreement-115121000318_1.html

Rhizen Pharmaceuticals Announces Exclusive Worldwide License Agreement for the Development and Commercialization of a Dual PI3K-delta gamma Inhibitor

  | Source: Rhizen Pharmaceuticals SA

La Chaux-de-Fonds, Switzerland , Dec. 09, 2015 (GLOBE NEWSWIRE) — Rhizen Pharmaceuticals S.A. announced today that they have entered into an exclusive, worldwide license agreement with Novartis for the development and commercialization of Rhizen’s, inhaled dual PI3K-delta gamma inhibitor and its closely related compounds for various indications.

Under the terms of the agreement, Rhizen will receive an upfront payment and is eligible to receive development, regulatory and sales milestones payments. In addition Rhizen is also eligible to receive tiered royalties on annual nets sales.

The lead compound is a novel, potent, and selective dual PI3K-delta gamma inhibitor with demonstrated anti-inflammatory and immuno-modulatory activity in pre-clinical systems and models representative of respiratory diseases. With a favorable ADME and PK profile and high therapeutic index in animals, the inhaled dual PI3K-delta gamma inhibitor holds promise in the treatment of human airway disorders.

About Rhizen Pharmaceuticals S.A.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel therapeutics for the treatment of cancer, immune and metabolic disorders. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways. Rhizen is headquartered in La-Chaux-de-Fonds, Switzerland. For additional information, please visit Rhizen’s website, www.rhizen.com.

info@rhizen.com

 

SEE………https://newdrugapprovals.org/2016/04/02/rp-6503-novartis-to-develop-and-commercialize-rhizens-inhaled-dual-pi3k-delta-gamma-inhibitor/

str1

RP 6503

 

 

//////

LIK 066, Licogliflozin diprolinate


imgf000135_0001XFJAMQQAAMJFGB-ZQGJOIPISA-N.png

 

L3

Licogliflozin

LIK 066

Licogliflozin diprolinate

lik 066

LIK-066, a new flozin on the horizon

C23 H28 O7 . 2 C6 H11 N O, 642.7795, 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C…WO2011048112

CAS 1291095-45-8, (1S)​-​1,​5-​anhydro-​1-​C-​[3-​[(2,​3-​dihydro-​1,​4-​benzodioxin-​6-​yl)​methyl]​-​4-​ethylphenyl]​-​D-​glucitol (1:1) WITH L-​Proline, compd.,    1:1 Proline Co-crvstal ,  1:1 Proline Co-crvstal …..WO2011048112

CAS BASE 1291094-73-9, 416.46, C23 H28 O7

(1S)-1,5-Anhydro-1-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-D-glucitol bis[1-[(2S)-pyrrolidin-2-yl]ethanone]

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Sodium glucose transporter-2 inhibitor

SGLT 1/2 inhibitor

Novartis Ag innovator

Clinical trial……..https://clinicaltrials.gov/ct2/show/NCT01915849

https://clinicaltrials.gov/ct2/show/NCT02470403

  • 10 Jun 2015 Novartis initiates enrolment in a phase II trial for Type 2 diabetes mellitus in USA (NCT02470403)
  • 02 Apr 2014 Novartis terminates a phase II trial in Type-2 diabetes mellitus in USA, Poland, Argentina, Hungary, Puerto Rico and South Africa (NCT01824264)
  • 01 Jan 2014 Novartis completes a phase II trial in Type 2 diabetes mellitus in USA (NCT01915849)

 

Licogliflozin, a SGLT-1/2 inhibitor, is in phase II clinical development at Novartis for the treatment of metabolic disorders, for the treatment of heart failure in patients with type 2 diabetes, for the treatment of obesity and for the treatment of polycystic ovary syndrome (PCOS) in overweight and obese women. Phase II trials for the treatment of type 2 diabetes had been discontinued.

EMA/415156/2014 European Medicines Agency decision P/0183/2014 of 24 July 2014 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran3,4,5-triol (2:1) (LIK066) (EMEA-001527-PIP01-13) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

Where name is given

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2017_Vol31-4/en/

l1l2

http://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf?ua=1

SEE ALSO

imgf000135_0001

WO2012140597

 

LIK-066 is in phase II clinical studies at Novartis for the treatment of type 2 diabetes.

In June 2014, the EMA’s PDCO adopted a positive opinion on a pediatric investigation plan (PIP) for LIK-066 for type 2 diabetes

Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition. Glucose level abnormalities can result in serious long-term complications, which include cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage and obesity.

Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus (IDDM), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Type-2 diabetes previously known as adult- onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) – is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin). Chronic hyperglycemia can also lead to onset or progression of glucose toxicity characterized by decrease in insulin secretion from β-cell, insulin sensitivity; as a result diabetes mellitus is self-exacerbated [Diabetes Care, 1990, 13, 610].

Chronic elevation of blood glucose level also leads to damage of blood vessels. In diabetes, the resultant problems are grouped under “microvascular disease” (due to damage of small blood vessels) and “macro vascular disease” (due to damage of the arteries). Examples of microvascular disease include diabetic retinopathy, neuropathy and nephropathy, while examples of macrovascular disease include coronary artery disease, stroke, peripheral vascular disease, and diabetic myonecrosis.

Diabetic retinopathy, characterized by the growth of weakened blood vessels in the retina as well as macular edema (swelling of the macula), can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US. Diabetic neuropathy is characterized by compromised nerve function in the lower extremities. When combined with damaged blood vessels, diabetic neuropathy can lead to diabetic foot. Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic nephropathy is characterized by damage to the kidney, which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of l adult kidney failure worldwide. A high glycemic diet (i.e., a diet that consists of meals that give high postprandial blood sugar) is known to be one of the causative factors contributing to the development of obesity.

Type 2 diabetes is characterized by insulin resistance and/or inadequate insulin secretion in response to elevated glucose level. Therapies for type 2 diabetes are targeted towards increasing insulin sensitivity (such as TZDs), hepatic glucose utilization (such as biguanides), directly modifying insulin levels (such as insulin, insulin analogs, and insulin secretagogues), increasing increttn hormone action (such as exenatide and sitagliptin), or inhibiting glucose absorption from the diet (such as alpha glucosidase inhibitors) [Nature 2001 , 414, 821-827],

Glucose is unable to diffuse across the cell membrane and requires transport proteins. The transport of glucose into epithelial cells is mediated by a secondary active cotransport system, the sodium-D-glucose co-transporter (SGLT), driven by a sodium- gradient generated by the Na+/K+-ATPase. Glucose accumulated in the epithelial cell is further transported into the blood across the membrane by facilitated diffusion through GLUT transporters [Kidney International 2007, 72, S27-S35].

SGLT belongs to the sodium/glucose co-transporter family SLCA5. Two different SGLT isoforms, SGLT1 and SGLT2, have been identified to mediate renal tubular glucose reabsorption in humans [Curr. Opinon in Investigational Drugs (2007): 8(4), 285-292 and references cited herein]. Both of them are characterized by their different substrate affinity. Although both of them show 59% homology in their amino acid sequence, they are functionally different. SGLT1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT2 is found exclusively in the S1 and S2 segments of the renal proximal tubule.

As a consequence, glucose filtered in the glomerulus is reabsorbed into the renal proximal tubular epithelial cells by SGLT2, a low-affinity/high-capacity system, residing on the surface of epithelial cell lining in S1 and S2 tubular segments. Much smaller amounts of glucose are recovered by SGLT1 , as a high-affinity/low-capacity system, on the more distal segment of the proximal tubule. In healthy human, more than 99% of plasma glucose that is filtered in the kidney glomerulus is reabsorbed, resulting in less than 1 % of the total filtered glucose being excreted in urine. It is estimated that 90% of total renal glucose absorption is facilitated by SGLT2; remaining 10 % is likely mediated by SGLT1 [J. Parenter. Enteral Nutr. 2004, 28, 364-371].

SGLT2 was cloned as a candidate sodium glucose co-transporter, and its tissue distribution, substrate specificity, and affinities are reportedly very similar to those of the low-affinity sodium glucose co-transporter in the renal proximal tubule. A drug with a mode of action of SGLT2 inhibition will be a novel and complementary approach to existing classes of medication for diabetes and its associated diseases to meet the patient’s needs for both blood glucose control, while preserving insulin secretion. In addition, SGLT2 inhibitors which lead to loss of excess glucose (and thereby excess calories) may have additional potential for the treatment of obesity.

Indeed small molecule SGLT2 inhibitors have been discovered and the anti-diabetic therapeutic potential of such molecules has been reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin (Diabetes, 2008, 57, 1723-1729)].

SYNTHESIS

imgf000132_0001

imgf000135_0001

PATENT

WO 2011048112

https://www.google.com/patents/WO2011048112A1?cl=en

Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,

Patentscope, Espacenet

Example 61-62:

Figure imgf000135_0001

Ex. 61

Example 61 : Acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester

Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Example 62: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 5 mL of 5% aqueous KHS04 (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.59)

 

H NMR (400 MHz, CD3OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J – 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).

MS (ES) m z 434.2 (M+18).

PICK UP IDEAS FROM HERE

 

Examples 57-58:

Figure imgf000132_0001

Ex. 57 Ex. 58

Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalyl chloride (10.3 mL, 114.74 mmol) at 0 °C followed by D F (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.

Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1 ,4)-dioxane (10.41 g, 76.26 mmol) at 0 °C. To this reaction mixture, AICI3 (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL X 2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL X 2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3- dihydro-benzo[1 ,4]dioxin-6-yl)-methanone (30 g).

1H N R (400 MHz, DMSO-D6): δ 4.29-4.37 (m, 4H), 7.02 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.18-7.19 (m, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H).

Step III: To a stirred solution of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1 ,4]dioxin- 6-yl)-methanone (30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL, 67.42 mmol ) at room temperature. After stirring for 25 min at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (200 mL X 2), water (200 mL), and brine (200 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-2,3- dihydro-benzo[1 ,4]dioxine (26.5 g). H NMR (400 MHz, DMSO-D6): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J = 8.4 Hz, J = 2.0 Hz, H), 6.68 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 8.4 Hz, H), 7.39 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 Hz, J = 2.4 Hz 1 H), 7.67 (d, J = 2.8 Hz, 1 H).

Step IV: To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro- benzo[1 ,4]dioxine (26.5 g, 61.47 mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi in hexanes (42.3 mL, 67.62 mmol) at -78 °C. The reaction mixture was stirred for 1 h, and then transferred to a stirred solution of 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (28.69 g, 61.47 mmol) in toluene (100 mL) at -78 °C. After stirring for 1 h, 0.6 N methanesulfonic acid in methanol (265 mL) was added dropwise and stirred the reaction mixture for 16 h at room temperature. Reaction was quenched by the addition of aq. NaHC03 solution (~75 mL) and extracted with ethyl acetate (250 mL X 3), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran- 3,4,5-triol (28.4 g)

Example 57: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1 ,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate

Step V: To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5- triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1 :1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10 °C. After stirring for 4 h at 10°C, the reaction was quenched with saturated aqueous sodium bicarbonate (~ 100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 X 150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2- [4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification. Example 58: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2!3-dihydro-1,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate Step V: To a stirred solution of (3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[ 1 ,4]dioxin-6-yl methyl)-phenyl]-6-hydroxymethyl-tetrahyd ro-pyran-3,4 , 5-triol (28.4 g, 60.81 mmol) in dichloromethane (300 mL) was added pyridine (40 mL, 486.5 mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg, 6.08 mmol) at room temperature. After stirring for 2 h, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (500ml) and washed with 1 N HCI (200 mL X 2) followed by brine (200ml), then dried over sodium sulfate and

concentrated. The resulting crude compound was dissolved in ethanol (320 mL) at 65 °C and allowed to cool to room temperature while stirring. Light yellow solid formed was filtered and washed with cold ethanol (150 mL) followed by hexane (200 mL) to get acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin- 6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder (22.5 g, purity 98%).

 

 

COCRYSTAL

Example 75: 1:1 Proline Co-crvstal with f2S.3R.4R.5S.6R¾-2-r3-f2.3-Dihvdro- benzori.41dioxin-6-ylmethyl)-4-ethyl-phenvn-6-hvdroxymethyl-tetrahydro-pyran- 3.4.5-triol

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62) was completely amorphous initially but formed a crystalline complex with proline. This was confirmed by powder X-ray diffraction (PXRD) analysis. The stiochiometry of Example 62 and L- proline in the co-crystal prepared by method 1 was found to be 1 :1 by NMR

spectroscopy & HPLC. Characterization data for co-crystals of Example 62 and proline prepared by method 1 is shown in Table 3. Relative intensities of the most prominent powder x-ray diffraction peaks for co-crystals of Example 62 and proline are shown in Table 3A.

Table 3

Table 3A

3.70 15.78 18.36 25.18

9.68 10.68 18.88 36.33

11.07 21.21 20.42 69.29

14.26 14.81 21.18 27.94

14.80 22.97 22.50 12.25

15.40 4 98 23.78 33.08

16.12 8.45 24.56 6.92

16.59 18.78 25.79 21.69

17.31 100.0 27.46 8.90

17.60 20.35 31.97 7.65

17.98 47.20 32.46 5.98

 

1:1 Proline Co-crvstal

Example 77: 1:1 Proline Co-crvstal with (2S.3R.4R.5S.6Ri-2-f3-(2.3-Dihvdro- benzoh .41dioxin-6-ylmethvh-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 2:

1 :1 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1500mg,3.6mmol), L- proline (415mg, 3.6mmol) and ethanol (23 ml_) were added to a 50 mL 3-neck round bottom flask equipped with nitrogen purging, magnetic stirring bar,

thermometer pocket & calcium chloride guard tube and the mixture was stirred at 25-30°C for 30 min., then heat to reflux. A clear solution was observed which was refluxed for 30 min., then slowly cool to 25-30°C causing percipitation. Di- isopropyl ether (DIPE, 23 mL) was added while maintaining the mixture at 25-30°C and stirring continuously for additional one to two hours at the same temperature. The precipitate was collected by filtration using vacuum (Nitrogen atmosphere), and the filter cake was washed with ethanol-DIPE mixture (1 :1 v/v, 10ml) followed by DIPE (23 mL). The product was vacuum dried at 65-70°C for 5-6 hrs.

1:1 Proline Co-crvstal (ΔΗ 53 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig. 1. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 2.

 

2:1 Proline Co-crvstal

Example 78: 2:1 Proline Co-crvstal with f2S.3R.4R.5S.6R>-2-r3-f2.3-Pihvdro-benzof1.41dioxin-6-ylmethvH-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 3: 1 :2 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1 kg) was added to 15 L of ethanol with agitation while maintaining the mixture at 20-25 °C. The mixture was stirred for 10 min at 20-25 °C, then L-proline (537 gm) was added while maintaining the mixture at 20-25 °C. The mixture was stirred at this temperature for 30 min., then heated to reflux and refluxed for 30 min. The mixture was slowly cooled to 25-30°C then stired for 1 hr. DIPE (15 L) was added while maintaining the temperature at 25-30 °C and the mixture was stirred at this temperature for 1 hr. The precipitated product was collected by filtration and the product was washed with DIPE (5 L). The product was air dried at 65-70 °C to yield 1.22 kg

(79%) of a 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C (ΔΗ 85 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig.

3. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 4. Relative

intensities of the most prominent powder x-ray diffraction peaks for the 1 :2 co- crystals of Example 62 and proline are shown in Table 5.

Table 5

lik 066

PATENT

WO 2012140597

http://www.google.co.in/patents/WO2012140597A1?cl=en

. TABLE 2:

Figure imgf000041_0001

Intermediate 2: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-

Figure imgf000049_0001

Intermediate 2

Intermediate 1

Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (Intermediate 1 , 10.0 g, 15.74 mmol) in toluene (200 mL) was added

tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 ml_), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid

(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 ml.) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 ml.) and washed with brine (75 ml_), brine containing 5 ml. of 5% aqueous KHS04 (75 ml_), and brine (20 ml.) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5 g)

1H NMR (400 MHz, CD3OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).

MS (ES) m/z 434.2 (M+18).

Example 3: Synthesis of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester diethyl ester

Figure imgf000059_0002

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- 4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added diethylchlorophosphate (0.27 ml, 1 .9 mmol) at -40°C. After stirring for 1 h at same temperature, reaction was quenched with the addition of 1 N HCI and extracted with ethyl acetate (2 X 10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to give 220 mg of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.07 (t, J = 7.6 Hz, 3H), 1.15 (td J = 7.2, 1.2 Hz, 3H), 1.22 (td, J = 6.8, 0.8 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.36-3.46 (m, 3H), 3.53-3.55 (m, 1 H),3.89 (s, 2H), 3.96-4.11 (m, 5H), 4.17 (s, 4H), 4.18-4.22 (m 1 H), 4.30-4.34 (m, 1 H), 6.52 (d, J = 2.0 Hz, 1 H),6.57 (dd, J = 8.4, 2.4 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15- 7.22(m, 3H). MS (ES) m/z 553.3 (M+1 ).

Example 4: Synthesis of disodium salt of phosphoric acid mono- {(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester

Figure imgf000061_0001
Figure imgf000061_0002

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6- ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di- tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0°C followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to -40 °C and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0°C and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3 X 10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6- [3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro- pyran-2-ylmethyl ester.

To the stirred solution of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion exchange resin (250 mg) and refluxed for overnight. Reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated to give 300 mg of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester. The crude material was taken up for next reaction.

To a solution of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester (300 mg, 0.6 mmol) in methanol (5 ml) was added 1 N sodium bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring at room temperature for 2 h, the volatiles were evaporated under reduced pressure. The resulting solid was triturated with diethyl ether. The resulting residue was purified by preparative HPLC to give 95 mg of disodium salt of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester.

1H NMR (400 MHz, CD3OD): δ 1.06 (t, J = 7.4 Hz, 3H), 2.56 ( q, J = 7.3 Hz, 2H), 3.34- 3.41 (m, 2H), 3.49 (t, J = 8.8 Hz, 1 H), 3.81-3.88 (m, ,3H), 3.92-3.99 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.16 (s, 4H), 4.20-4.25 (m, 1 H), 6.54 (m, 2H), 6.67 (d, J = 7.8 Hz, 1 H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1 ) for phosphoric acid.

 

PATENT

 

SEE  INDIAN PATENT

IN 2009DE02173

Glycoside derivatives and uses thereof

 

REFERENCES

Pediatric investigation plan (PIP) decision: (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2:1) ( LIK066) (EMEA-001527-PIP01-13)
European Medicines Agency (EMA) Web Site 2014, July 24

Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) assessment of LIK066 in healthy subjects and in patients with type 2 diabetes mellitus (T2DM) (NCT01407003)
ClinicalTrials.gov Web Site 2011, August 07

WO2012140597

WO2011048112

IN 2009DE02173

 

WO2001016147A1 24 Aug 2000 8 Mar 2001 Kissei Pharmaceutical Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2001027128A1 2 Oct 2000 19 Apr 2001 Bruce Ellsworth C-aryl glucoside sglt2 inhibitors
WO2001068660A1 15 Mar 2001 20 Sep 2001 Hideki Fujikura Glucopyranosyloxy benzylbenzene derivatives, medicinal compositions containing the same and intermediates for the preparation of the derivatives
WO2001074834A1 29 Mar 2001 11 Oct 2001 Squibb Bristol Myers Co O-aryl glucoside sglt2 inhibitors and method
WO2003020737A1 5 Sep 2002 13 Mar 2003 Squibb Bristol Myers Co O-pyrazole glucoside sglt2 inhibitors and method of use
WO2003043985A1 20 Nov 2002 30 May 2003 Andrew Thomas Bach Heterocyclic compounds and methods of use
WO2004018491A1 21 Aug 2003 4 Mar 2004 Nobuhiko Fushimi Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof
WO2004078163A2 26 Feb 2004 16 Sep 2004 Oern Almarsson Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2004080990A1 12 Mar 2004 23 Sep 2004 Kazuhiro Ikegai C-glycoside derivatives and salts thereof
WO2004099230A1 30 Apr 2004 18 Nov 2004 Eikyu Yoshiteru Monosaccharide compounds
WO2004103995A1 19 May 2004 2 Dec 2004 Gary Michael Ksander N-acyl nitrogen heterocycles as ligands of peroxisome proliferator-activated receptors
WO2005011592A2 29 Jul 2004 10 Feb 2005 Janssen Pharmaceutica Nv Substituted indazole-o-glucosides
WO2005021566A2 20 Aug 2004 10 Mar 2005 Barsoumian Edward Leon Glucopyranosyloxy- pirazoles, drugs containing said compounds the use and production method thereof
WO2005085237A1 3 Mar 2005 15 Sep 2005 Kissei Pharmaceutical Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
WO2005085265A1 3 Mar 2005 15 Sep 2005 Kissei Pharmaceutical Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
WO2006011502A1 27 Jul 2005 2 Feb 2006 Chugai Pharmaceutical Co Ltd Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
WO2006054629A1 17 Nov 2005 26 May 2006 Kissei Pharmaceutical 1-SUBSTITUTED-3-β-D-GLUCOPYRANOSYLATED NITROGENOUS HETERO- CYCLIC COMPOUNDS AND MEDICINES CONTAINING THE SAME
WO2008016132A1 3 Aug 2007 7 Feb 2008 Daiichi Sankyo Co Ltd Benzyl phenyl glucopyranoside derivative
WO2011048112A1 * 19 Oct 2010 28 Apr 2011 Novartis Ag Glycoside derivatives and uses thereof
US20030114390 * 4 Oct 2002 19 Jun 2003 Washburn William N. C-aryl glucoside SGLT2 inhibitors and method
US20040018998 21 Sep 2001 29 Jan 2004 Hideki Fujikura Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same
US20060009400 28 Jun 2005 12 Jan 2006 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US20060019948 15 Jul 2005 26 Jan 2006 Boehringer Ingelheim International Gmbh Methylidene-D-xylopyranosyl- and oxo-D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US20060025349 27 Jul 2005 2 Feb 2006 Boehringer Ingelheim International Gmbh D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture
US20060035841 9 Aug 2005 16 Feb 2006 Boehringer Ingelheim International Gmbh D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture
US20060074031 30 Sep 2005 6 Apr 2006 Boehringer Ingelheim International Gmbh D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US20060293252 14 Aug 2006 28 Dec 2006 Sanofi-Aventis Deutschland Gmbh Novel Thiophene Glycoside Derivatives, Processes for The Preparation, Medicaments Comprising These Compounds, and The Use Thereof
US20080027014 26 Jul 2007 31 Jan 2008 Tanabe Seiyaku Co., Ltd. Novel SGLT inhibitors
Citing Patent Filing date Publication date Applicant Title
WO2015032272A1 * 19 Aug 2014 12 Mar 2015 Jiangsu Hansoh Pharmaceutical Co., Ltd. C-aryl glucoside derivative, preparation method for same, and medical applications thereof
US9034921 1 Jun 2012 19 May 2015 Green Cross Corporation Diphenylmethane derivatives as SGLT2 inhibitors

 

 

INVENTORS OF LIK 066

Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,

BEBERNITZ, Gregory, Raymond; (US).
BOCK, Mark, G.; (US).
REDDY, Dumbala Srinivas; (IN).
HAJARE, Atul Kashinath; (IN).
VYAVAHARE, Vinod; (IN).
BHOSALE, Sandeep Bhausaheb; (IN).
KURHADE, Suresh Eknath; (IN).
SALUNKHE, Videsh; (IN).
SHAIKH, Nadim, S.; (IN).
BHUNIYA, Debnath; (IN).
PALLE, P., Venkata; (IN).
FENG, Lili; (US).
LIANG, Jessica; (US)

IMG-20140228-WA0002Mark G Bock

BEBERNITZ, Gregory, Raymond….PIC NOT AVAILABLE

Image result for SRINIVASAREDDY NCL

Dr. Srinivasa Reddy

NADEEM SHAIKH

 

Venkata PalleVenkata Palle

 

ONLY FEW…………………….

//////Licogliflozin diprolinate

see……..http://medcheminternational.blogspot.in/2015/11/lik-066-novartis-for-treatment-of-type.html

Ribociclib, рибоциклиб , ريبوسيكليب , 瑞波西利


str0

 

Ribociclib

рибоциклиб ريبوسيكليب 瑞波西利

Ribociclib (LEE 011)
CAS: 1211441-98-3

Chemical Formula: C23H30N8O
Exact Mass: 434.25426

7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

FDA UNII

  • TK8ERE8P56

Current developer:    Novartis /Astex Pharmaceuticals.

Novartis Ag, Astex Therapeutics Ltd.

NMR.http://file.selleckchem.com/downloads/nmr/S744002-LEE011-2-HNMR-Selleck%20.pdf

http://file.selleckchem.com/downloads/hplc/S744002-LEE011-2-HPLC-Selleck.pdf

Ribociclib (LEE011) is an orally available, and highly specific CDK4/6 inhibitor. Phase 3.

CDK4 AND 6
(Cell-free assay)Product Ingredients

NOW FDA APPROVED 2017 since the blog post was written

Kisqali FDA 3/13/2017 To treat postmenopausal women with a type of advanced breast cancer
Drug Trials Snapshot

Image result for RIBOCICLIB

INGREDIENT UNII CAS INCHI KEY
Ribociclib hydrochloride 63YF7YKW7E 1211443-80-9 JZRSIQPIKASMEV-UHFFFAOYSA-N
Ribociclib succinate BG7HLX2919 1374639-75-4 NHANOMFABJQAAH-UHFFFAOYSA-N

 

ChemSpider 2D Image | Ribociclib succinate | C27H36N8O5

RIBOCICLIB SUCCINATE

STRUCTURE ….LINK

sb1

 

 

Ribociclib is in phase III clinical trials by Novatis for the treatment of postmenopausal women with advanced breast cancer.

Phase II clinical trials are also in development for the treatment of liposarcoma, ovarian cancer, fallopian tube cancer, peritoneum cancer, endometrial cancer, and gastrointestinal cancer.

Ribociclib, also known as LEE011, is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation

Orally bioavailable CDK4/6-selective inhibitor that has been tested in Phase III clinical trials for treatment of advanced breast cancer.

CDK full name of cyclin-dependent kinases, there are many other subtypes CDK1-11, capable of binding to cell cycle proteins regulate the cell cycle. Pfizer Palbociclib been submitted for FDA review under phase II clinical data, Novartis Ribociclib (LEE011), Lilly Abemaciclib (LY2835219) the three CDK4 / 6 inhibitors have entered late stage development for the treatment of breast cancer

SYNTHESIS

WO2010020675
US20120115878

WO2010020675

http://www.google.co.in/patents/WO2010020675A1?cl=en

Example 74

7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

Figure imgf000094_0002

Following Buchwald Method B, then General Procedure A, 2-chloro-7-cyclopentyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (300 mg, 1.02 mmol) and 5-piperazin-1- yl-pyridin-2-ylamine (314 mg, 1.13 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2- ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (142 mg, 36%). MS(ESI) m/z 435.3 (M+H)+

POSTER

str1

SYNTHESIS

str1

Image result for RIBOCICLIB joygooo

TAKEN FROM ….http://www.joygooo.com/news_71.htm?pageNum=21

PCT Int Appl, WO2012061156.

US Pat Appl Publ, US20120115878

PCT Int Appl, WO2011130232 5) Brain, Christopher Thomas et al; Preparation of pyrrolopyrimidine Derivatives for Use as CDK4 / 6 inhibitors;. PCT Int Appl, WO2011101409.

PCT Int Appl, WO2011101417. 7) Besong, Gilbert et al;.

PCT Int Appl, WO2010020675.

PCT Int Appl, WO2007140222.

Route 1

Reference:1. WO2012064805A1 / US20120115878A1.

2. WO2010020675A1 / US8415355B2.

3. WO2011130232A1 / US20130035336A1.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-10-17)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02571829 Not yet recruiting Liposarcoma|Soft Tissue Sarcoma Hadassah Medical Organization December 2015 Phase 2
NCT02524119 Not yet recruiting Hepatocellular Carcinoma University of Texas Southwestern Medical Center|Novartis  …more November 2015 Phase 2
NCT02494921 Recruiting Prostate Cancer Rahul Aggarwal|University of California, San Francisco September 2015 Phase 1|Phase 2
NCT02420691 Recruiting Gastrointestinal Cancer M.D. Anderson Cancer Center|Novartis August 2015 Phase 2
NCT02431481 Not yet recruiting Normal Renal Function|Impaired Renal Function Novartis Pharmaceuticals|Novartis August 2015 Phase 1

Protocols from literature

In vitro protocol::

Pharmacologic growth inhibition: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

Cell-cycle analysis: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

Senescence and apoptosis assays: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

In vivo protocol:

Xenograft therapeutic trials: Clin Cancer Res. 2013 Nov 15;19(22):6173-82

Immunohistochemistry of xenografted neuroblastomas.Clin Cancer Res. 2013 Nov 15;19(22):6173-82

Ribociclib (LEE011) is a Me-Too version of palbociclib. Their structures are compared side-by-side as the following:

LEE011 and Palbociclib structure

Ribociclib (LEE011) is currently being developed by Novartis and Astex.  According its  Novartis’s website, LEE011 is a novel, orally available, selective inhibitor of CDK4/6 kinases, which induces complete dephosphorylation of Rb and G1 arrest in cancer cells. In preclinical in vitro and in vivo tumor models, LEE011 has been shown active in cancers harboring aberrations that increase CDK4/6 activity, including those directly linked to the kinases as well as activating alterations in the upstream regulators. First-in-human study of LEE011 in patients with solid tumors and lymphoma is currently ongoing. (source: http://www.novartisoncology.us/research/pipeline/lee011.jsp).

Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance. LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. (Clin Cancer Res. 2013 Nov 15;19(22):6173-82)

  

References

1. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. PubMed PMID: 24045179; PubMed Central PMCID: PMC3844928.

2. Caponigro, Giordano; Stuart, Darrin; Kim, Sunkyu; Loo, Alice; Delach, Scott. Pharmaceutical combinations of a CDK4/6 inhibitor and a B-RAF inhibitor for treatment of proliferative diseases such as cancer. PCT Int. Appl. (2014), WO 2014018725 A1 20140130.

3. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven; Huang, Alan Xizhong; Chen, Yan. Combination therapy comprising a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a phosphatidylinositol 3-kinase (PI3K) inhibitor for use in the treatment of cancer. PCT Int. Appl. (2013), WO 2013006532 A1 20130110

4. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven. Combination of cyclin dependent kinase 4/6 (CDK4/6) inhibitor and fibroblast growth factor receptor (FGFR) kinase inhibitor for the treatment of cancer. PCT Int. Appl. (2013), WO 2013006368 A1 20130110

5. Calienni, John Vincent; Chen, Guang-Pei; Gong, Baoqing; Kapa, Prasad Koteswara; Saxena, Vishal. Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof. U.S. Pat. Appl. Publ. (2012), US 20120115878 A1 20120510.

6. Borland, Maria; Brain, Christopher Thomas; Doshi, Shivang; Kim, Sunkyu; Ma, Jianguo; Murtie, Josh; Zhang, Hong. Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer. PCT Int. Appl. (2011), WO 2011130232 A1 20111020

7. Besong, Gilbert; Brain, Christopher Thomas; Brooks, Clinton A.; Congreve, Miles Stuart; Dagostin, Claudio; He, Guo; Hou, Ying; Howard, Steven; Li, Yue; Lu, Yipin; et al. Preparation of pyrrolopyrimidine compounds as CDK inhibitors. PCT Int. Appl. (2010), WO 2010020675 A1 20100225.

CLIP

Cyclin-dependent kinase inhibitors (14 compounds) under clinical evaluation.

Molecules 19 14366 g002 1024

LEE-011 is one of the most selective inhibitors for CDK4 and CDK6 [59] and is being developed by Astex Pharmaceuticals™ and Novartis. In January 2014 this inhibitor entered phase III clinical trials for the treatment of breast cancer [60]. Due to encouraging results LEE-011 has now become the main competing drug-candidate with Pfizer’s PD0332991 (palbociclib), see Figure 3 [59].

Figure 3. Comparison of Astex/Novartis’ LEE-011 and Pfizer’s PD0332991 structures.

Upon comparison of the chemical structure of Novartis’ LEE-011 and Pfizer’s PD0332991, the similarity is evident. The major difference lies in the bicyclic core since LEE-011 possesses a pyrrolo-pyrimidine and PD0332991 a pyridopyrimidine. The “east” part of the structure is also modified. The structural similarities make their analogous CDKs inhibition profiles (high selectivity for CDK4 and CDK6) quite obvious Moreover, both derivatives are orally administered which is pretty advantageous compared with dinaciclib, which is also in phase III clinical trials but is administered intravenously.

http://www.mdpi.com/1420-3049/19/9/14366/htm

  1. Kurt, S. LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers. Oncol. Times 2014, 36, 39–40. [Google Scholar]
  2. Macmillan Publishers Limited. CDK inhibitors speed ahead. Nat. Rev. Drug Discov. 2014, 13, 323. [Google Scholar] [CrossRef]

 

 

Sources:
1)Rader, JulieAnn et al.;Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma;Clinical Cancer Research (2013), 19(22), 6173-6182

2)Tavares, Francis X. and Strum, Jay C.;Preparation of pyrazinopyrrolopyrimidine derivatives and analogs for use as CDK inhibitors;PCT Int. Appl., WO2012061156

3)Calienni, John Vincent et al.;Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof;U.S. Pat. Appl. Publ., US20120115878

4)Borland, Maria et al;Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer;PCT Int. Appl., WO2011130232

5)Brain, Christopher Thomas et al;Preparation of pyrrolopyrimidine derivatives for use as CDK4/6 inhibitors;PCT Int. Appl., WO2011101409

6)Brain, Christopher Thomas and Perez, Lawrence Blas; Preparation of deuterated pyrrolopyrimidine compounds as inhibitors of CDK4/6 for treating cancer; PCT Int. Appl., WO2011101417

7)Besong, Gilbert et al.;Preparation of pyrrolopyrimidine compounds as CDK inhibitors;PCT Int. Appl., WO2010020675

8)Brain, Christopher Thomas et al.;Preparation of pyrrolopyrimidine compounds as protein kinase inhibitors; PCT Int. Appl., WO2007140222

9)A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease;ClinicalTrials.gov Identifier: NCT01958021

/////////Ribociclib, novartis, LEE011, astex, phase 3,  CDK inhibitors

CN(C)C(=O)c1cc2cnc(nc2n1C3CCCC3)Nc4ccc(cn4)N5CCNCC5

Novartis launches first US ‘biosimilar’ drug at 15 percent discount


Zarxio, filgrastim-sndz

 

Novartis launches first US ‘biosimilar’ drug at 15 percent discount

LONDON/ZURICH: Novartis kicked off a new era in U.S. medicine on Thursday with the launch of the first “biosimilar” copy of a biotechnology drug approved in the United States, at a discount of 15 percent to the original.

The Swiss drugmaker’s generics unit Sandoz said Zarxio, its form of Amgen’s white blood cell-boosting product Neupogen, would increase access to an important treatment by offering a “high-quality, more affordable version”.

U.S. biotech group Amgen had tried to stop the sale of Zarxio, also known as filgrastim-sndz, but the Washington-based appeals court rejected its attempt to block the launch…..http://www.channelnewsasia.com/news/health/novartis-makes-history-wi/2097550.html

On March 6, 2015, FDA approved the first biosimilar under the Biologics Price Competition and Innovation Act (BPCIA), Sandoz’s Zarxio®. Sandoz submitted Zarxio®as a highly similar, not interchangeable biosimilar, for the same indications as the referenced product. The BPCIA was signed into law in March 2010.

FDA designated “filgrastim-sndz” as the placeholder nonproprietary name rather than the innovator’s name, filgrastim. FDA said that this nonproprietary name “should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products. While the FDA has not yet issued draft guidance on how current and future biological [biosimilar?] products marketed in the United States should be named, the agency intends to do so in the near future.”

Accompanying the news release was a document “Biosimilars: More Treatment Options Are on the Way”. The document includes various quotes and paraphrased statements by Leah Christl, Ph.D., Associate Director for Therapeutic Biologics, to help describe to consumers what biosimilar medications are. Below are some quotes and information from that document:

Biologics are medicines that generally come from living organisms, which can include humans, animals and microorganisms such as yeast and bacteria.

. . .

“Biologics are different from conventional medications. Conventional medications—drugs—are generally made from chemicals, or chemically synthesized, and therefore their structure can be relatively easily defined,” explains Christl.

Unlike conventional medications, biologics can’t be made by following a chemical “recipe.” “Biologics come from living organisms which are variable in nature. In addition, they are generally more complex and not as easy to define and characterize,” Christl explains. For that reason, manufacturing biologics is a far more complex process than manufacturing drugs.

Just as it does for drugs, FDA rigorously and thoroughly evaluates a biologic’s safety and effectiveness before granting it licensure (approval). Currently, biologics are among the fastest growing segments of the prescription product market.

. . .

Christl explains that a biosimilar is a type of biologic that is highly similar to another, already FDA-approved biologic (known as the reference product).

“It is important to note that a biosimilar is not just like a generic drug,” she adds. “Because of the differences in complexity of the structure of the biologic and the process used to make a biologic, biosimilars are not as easy to produce as generics, which are copies of brand name drugs.” A biosimilar is not an exact duplicate of another biologic; rather, a biosimilar is highly similar to the reference product.

Before approving a biosimilar, FDA experts must also first verify that there are no clinically meaningful differences between the biosimilar and its reference product. In other words, it will work the same way as the reference product for its approved indications.

Also, the biosimilar must have the same strength and dosage form (injectable, for example) and route of administration as the reference product. The biosimilar must be manufactured followingCurrent Good Manufacturing Practices.

“Patients can rest assured that they’ll be able to rely upon the safety and effectiveness of an FDA-approved biosimilar, just as they can rely on the reference product that the biosimilar was compared to,” Christl says. Like other biologics, biosimilars generally must be prescribed by a physician.

. . .

“Biosimilars are likely to create greater competition in the medical marketplace,” saysChristl. This could not only increase treatment options for patients, but also lead to less expensive alternatives to comparable products. With an increasing number of biosimilars on the market, consumers may expect to get equally safe and effective treatment, but at lower costs, she says.

Despite the significant achievement for FDA to approve the first biosimilar under the BPCIA, significant questions other than nonproprietary naming remain. First, Sandoz chose not to take advantage of the pre-approval patent exchange mechanism of the BPCIA, which could have addressed possible patent challenges that may prevent Sandoz from marketing Zarxio®until certain patents are invalidated, are found unenforceable, or have expired. Second, because this and other non-interchangeable versions of biosimilars are not expected to have automatic substitution based on the BPCIA, it remains unclear how ready physicians or patients will be to try a biosimilar version over its referenced product. Third, company representatives from Sandoz and other biosimilar manufacturers have not indicated at what price their biosimilar products will be sold, at times suggesting “at parity,” which may cause reimbursement issues. Fourth, many states have enacted rules that include special physician notification provisions, even when interchangeable biosimilars are dispensed to patients. And there are still issues surrounding pharmacovigilance and risk management when there are innovator and corresponding biosimilar versions marketed. Nevertheless, FDA proclaims that more biosimilars are on the way, as additional companies have indicated that they have submitted or FDA has filed their biosimilar applications. Sandoz’s Zarxio® then is just the tip of the iceberg of what is coming with more issues to be resolved along the way.

http://www.fdalife.com/2015/03/06/first-u-s-biosimilar-zarxio-filigrastim-sndz-approved-issues-remain/

 

ZARXIO (filgrastim-sndz) is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology.

ZARXIO is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. ZARXIO has a molecular weight of 18,800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from humanDNA sequence analysis, except for the addition of an N-terminal methioninenecessary for expression in E coli. Because ZARXIO is produced in E coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.

ZARXIO injection is a sterile, clear, colorless to slightly yellowish , preservative-free liquid containing filgrastimsndz at a specific activity of 1.0 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single-use prefilled syringes. The single-use prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-sndz. See table below for product composition of each single-use prefilled syringe.

300 MCG/0.5 ML SYRINGE 480 MCG/0.8 ML SYRINGE
Filgrastim-sndz 300 mcg 480 mcg
Glutamic Acid 0.736 mg 1.178 mg
Polysorbate 80 0.02 mg 0.032 mg
Sorbitol 25 mg 40 mg
Sodium hydroxide q.s. qs.
Water for Injection
USP q.s. ad* ad 0.5 mL ad 0.8 mL

Novartis obtains European approval for Cosentyx to treat psoriasis


Novartis obtains European approval for Cosentyx to treat psoriasis
Swiss drug-maker Novartis has received approval from the European Commission (EC) for its Cosentyx (secukinumab, formerly known as AIN457) to treat moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.SEE

http://www.pharmaceutical-technology.com/news/newsnovartis-obtains-european-approval-for-cosentyx-to-treat-psoriasis-4492415?WT.mc_id=DN_News

PSORIAIS

secukinumab

Secukinumab is a human monoclonal antibody designed for the treatments of uveitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It targets member A from the cytokine family of interleukin 17.[1][2] At present, Novartis Pharma AG, the drug’s developer, plans to market it under the trade name “Cosentyx.” [3] It is highly specific to the human immunoglobulin G1k (IgG1k) subclass.[2]

In July 2014 secukinumab established superiority to placebo and to etanercept for the treatment of chronic plaque psoriasis in Phase III clinical trials.[4] In October 2014, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee unanimously voted to recommend the drug for FDA approval, although this vote in and of itself does not constitute an approval. However, the FDA typically follows recommendations from these committees.[5] In October 2014, Novartis announced that the drug had achieved a primary clinical endpoint in two phase III clinical trials for ankylosing spondylitis.[6] As of 28 October, the relevant FDA committee had not yet responded to these results. In early November 2014, Novartis also released the results of a Phase 3 study on Psoriatic Arthritis that yielded very promising results.[7]

Although the drug was originally intended to treat rheumatoid arthritis, phase II clinical trials for this condition yielded disappointing results.[8] Similarly, while patients in a phase II clinical trial for [psoriatic arthritis] did show improvement over placebo, the improvement did not meet adequate endpoints and Novartis is considering whether to do more research for this condition.[9] Novartis has said that it is targeting approval and release in early 2015 for plaque psoriasis and ankyloding spondylitis indications.

It is also in a phase II clinical trial for Multiple Sclerosis [10] as it has exhibited efficacy in treating experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CAS registry numbers

  • 875356-43-7 (heavy chain)
  • 875356-44-8 (light chain)

References

  1. “Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
  2.  Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
  3.  http://www.medscape.com/viewarticle/835331
  4.  Langley RG, Elewski BE, Mark Lebwohl M, et al., for the ERASURE and FIXTURE Study Groups (July 24, 2014). “Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials”. N Engl J Med 371: 326–338. doi:10.1056/NEJMoa1314258.
  5.  committees.http://www.familypracticenews.com/index.php?id=2934&type=98&tx_ttnews=306073[dead link]
  6. http://inpublic.globenewswire.com/2014/10/23/Novartis+AIN457+secukinumab+meets+primary+endpoint+in+two+Phase+III+studies+in+ankylosing+spondylitis+a+debilitating+joint+condition+of+the+spine+HUG1864939.html
  7.  http://www.medpagetoday.com/MeetingCoverage/ACR/48743
  8.  http://www.medscape.com/viewarticle/806510_6
  9.  http://www.ncbi.nlm.nih.gov/pubmed/23361084
  10. http://clinicaltrials.gov/show/NCT01874340
Secukinumab 
Monoclonal antibody
Type Whole antibody
Source Human
Target IL17A
Clinical data
Legal status
  • Investigational
Identifiers
CAS number  Yes
ATC code L04AC10
DrugBank DB09029
Synonyms AIN457
Chemical data
Formula C6584H10134N1754O2042S44 
Molecular mass 147.94 kDa

Unanimous FDA panel support for Novartis’ secukinumab


Unanimous FDA panel support for Novartis' secukinumab

Unanimous FDA panel support for Novartis’ secukinumab

October 21, 2014

Kevin Grogan

Advisors to the US Food and Drug Administration have voted unanimously to support approval of Novartis’ secukinumab for moderate-to-severe plaque psoriasis.

The agency’s Dermatologic and Ophthalmic Drugs Advisory Committee voted 7-0  in favour of secukinumab, a selective interleukin-17A inhibitor, based on 10 Phase II/III clinical studies which included nearly 4,000 patients. Treatment with the drug has resulted in high rates of clear to almost clear skin at week 12 and it has shown superiority to Amgen’s Enbrel (etanercept), an anti-TNF standard of care.

Buparlisib in phase 3 for Breast tumor; Hematological neoplasm; Solid tumor


Buparlisib

Novartis Ag

5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine.

5-[2,6-Di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine

5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4- trifluoromethylpyridin-2-amine

944396-07-0

Chemical Formula: C18H21F3N6O2

Mass: 410.16781

NVP-BKM-120, BKM-120;

Novartis AG phase 3 for breast cancer

Phosphoinositide 3-kinase inhibitor

Buparlisib, also known as BKM120,  is an orally bioavailable specific oral inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential antineoplastic activity. PI3K inhibitor BKM120 specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate and activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

NVP-BKM-120 is an oral selective phosphatidylinositol 3-kinase (PI3K) inhibitor in phase III clinical development at Novartis for the treatment of breast cancer in combination with fulvestrant in postmenopausal women with hormone receptor-positive HER2-negative locally advanced or metastatic breast cancer which progressed on or after aromatase inhibitor treatment.

Early clinical development at Novartis Oncology, a division of Novartis, is also ongoing for the treatment of solid tumors, advanced endometrial carcinoma, non-small cell lung cancer (NSCLC), bladder cancer, gastrointestinal stromal cancer and for the treatment of metastatic castration-resistant prostate cancer.

Novartis is conducting phase II clinical trials for the treatment of follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma and squamous cell carcinoma of head and neck.

The University of Kansas is evaluating the compound in phase I clinical trials for the treatment of advanced colorectal cancer in combination with irinotecan, while additional phase I trials are ongoing at the Dana-Farber Cancer Institute for the treatment of renal cell carcinoma. The Dana-Farber Cancer Institute is also conducting phase II clinical trials for the oral treatment of recurrent glioblastoma and preclinical studies for the treatment of ovarian cancer. Novartis is also conducting early clinical studies for the treatment of metastatic melanoma

pyrimidine derivative 5-(2,6-Di- 4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine (Compound A, see below), its hydrates, its salts and hydrates and solvates of its salts, to said specific solid forms thereof, to pharmaceutical compositions containing said solid forms, to processes for the preparation of pharmaceutical compositions containing said solid forms, to methods of using said solid forms and to pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, especially humans. Background of the invention

WO 2007/084786 (priority date: January 20, 2006) describes certain pyrimidine derivatives having PI3 inhibiting properties, their use as pharmaceuticals and manufacturing processes thereof. One pyrimidine derivative disclosed in WO 2007/084786 is the selective

phosphatidylinositol 3-kinase inhibitor compound 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4- trifluoromethylpyridin-2-amine, hereinafter referred to as “Compound A” or “the compound of formula A”.

 

Compound A is described in WO 2007/084786 in free form and as the hydrochloric acid salt. The manufacturing process for preparing Compound A is described in Example 10 of this document. The manufacturing processes described therein are, although suitable, regarded as disadvantageous for commercial production.

Due to the high potency of pyrimidine derivatives, in particular PI3K inhibitors, there is a need for improved manufacturing methods of such compounds. In particular there is a need to provide processes that fulfill one or more of the following criteria: scalable, safer; simpler; higher yielding and more economical when compared to known.

…………………………………….

WO 2007084786

http://www.google.com/patents/WO2007084786A1?cl=en

Example 10

Preparation of 4-(“trifluoromethyπ-5-(2,6-dimorpholmoρyrirnidin-4-yπpyridin-2- amine

c

[0388] To a slurry of 2-moφholino-4,6-dichloropyrimidine (prepared as in

Method 22, 2.0 g, 8.54 mmol) in NMP (14 mL), triethylamine (1.43 mL, 10.25 mmol) was added. The heterogeneous mixture was stirred for 15 minutes, then treated with morpholine (0.75 mL, 8.54 mmol). Upon refluxing at 85 0C under argon for 2 hours, the solution was cooled, then added to EtOAc (160 mL). The organic solution was washed with 25 mL of NaHCO3(sat.) (2 x), water (2 x) and brine, dried over Na2SO4, filtered and concentrated. The crude material was dissolved in 200 mL EtOAc and filtered through a SiO2 pad, further eluting with EtOAc, yielding 2.2 g (93%) of 2,4-dimorpholino-6- chloropyrimidine as an off-white solid. LCMS (m/z): 285.0 (MH+), 1H NMR (CDCl3): δ 5.86 (s, IH), 3.71-3.76(m, 12H), 3.52-3.56(m, 4H).

[0389] 4-(trifluoromethyl)-5-(2,6-dimoφholmopyrimidin-4-yl)pyridin-2-amine 8

 

[0390] Argon gas was bubbled through a heterogeneous mixture of 2,4- dimoφholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridm-2-amine (16.5 g, 57.3 mmol) in 1,2- dimethoxyethane and 2M Na23 (3:1) for 20 minutes. 1,1′-

Bis(diphenylphosphino)ferrocene palladium (IT) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 900C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2Cθ3(sat.):NH4θH(conc.) = 5:4:1, then NH4Cl(sat), and brine (2x), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (50- 90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5- (2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid.

LCMS (m/z): 411.3 (MH+);

1H NMR (CDCl3): δ 8.27 (s, IH), 6.78 (s, IH), 5.97 (s, IH), 4.77 (bs, 2H), 3.59-3.80(m, 12H), 3.58-3.61(m, 4H).

…………….

WO2012044727 or equi as below

http://www.google.com/patents/EP2621908A2?cl=en

Example 1: 4,4′-(6-Chloropyrimidine-2,4-diyl)di[morpholine] (3) U 2011/053808

63

 

Prepare a solution of 22 g (0.12 mol) of 2,4,6-trichloropyrimidine 1 , in 95.2 g (110 mL) of toluene and charge it to the 25 mL addition funnel. Charge a nitrogen-flushed 500 mL round bottom 4- neck flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet / outlet with 62.7 g (63 mL, 0.72 mol) of morpholine 2, 95.2 g (110 mL) of toluene and 44 g (44 mL) of water. Add the toluene solution of 1 over 10 minutes. Heat the reaction mixture to 83 ± 3 °C. Stir at 83 ± 3 °C for 2 h. Check the progress of the reaction. Cool to 30 + 3 °C. Transfer the 2-phase mixture to a 1L separatory funnel.

Separate the phases. Wash the organic phase (top) twice with 200 mL (2 x 100 mL) of warm (30 °C) water. Separate the phases after each wash. Transfer the organic (top) phase back to the 500 mL reaction flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet / outlet. Stir and add 50.0 mL of 10.0 N aqueous hydrochloric acid solution. Heat the solution to 53 ± 3 °C and stir for 12 – 18 h. Check the progress of the reaction. Cool to 22 + 3 °C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Transfer the aqueous (bottom) phase to a 500 mL round bottom 4-neck flask equipped with a cooling bath, thermocouple, addition funnel, pH probe, mechanical stirrer and nitrogen inlet / outlet. Stir and cool to 0 ± 3 °C. Add 85.0 g of 25% aqueous sodium hydroxide solution by drops over 30 minutes, maintaining a batch temperature of 10 ± 10 °C throughout the addition. Warm to 20 ± 3 °C and stir for 30 minutes. Isolate the solids by vacuum filtration. Wash the cake with 3 x 100 mL of water. Dry the solids (55°C, 30 mbar) for 24 hours to afford 30.9 g (91.9% yield) of 3 as a white crystalline solid.

Example 2:

4,4′-[6-(4>4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl]di[morpholine] (4)

Charge a nitrogen-flushed 2 L round bottom 4-neck flask that equipped with a condenser, heating mantle, thermocouple, rubber septum, mechanical stirrer and nitrogen inlet / outlet with 100.0 g (0.351 mol) of 4,4′-(6-chloropyrimidine -2,4-diyl)di[morpholine] 3 and 943 g (1200 mL) of acetonitrile. Stir and heat to 60 + 3 °C. Hold this solution at 60 + 3 °C for charge to batch. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 115.9 g (0.457 mol) of bis(pinacolato)- diboron, 51.7 g (0.527 mol) of potassium acetate, 12.9 g (0.014 mol) of tris(dibenzylideneacetone) – dipalladium(O), 7.9 g (0.029 mol) of tricyclohexylphosphine and 393 g (500 mL) of acetonitrile. Stir and heat the slurry to 84 ± 3 °C (reflux). Collect 00 mL of distillate. Transfer the warm 3 acetonitrile solution via peristaltic pump to the 3 L reactor containing the reaction mixture over 30 minutes and continue collecting distillate. Wash the 2 L flask and transfer lines with 79 g (100 mL) of acetonitrile and transfer the wash to the batch. Maintain distillation at 84 ± 3 °C and collect an additional 900 mL of distillate (batch volume ~ 1100 mL). Check the progress of the reaction 2 h from the start of the addition of 3. Cool the reaction mixture to 70 ± 3 °C and charge 693 g (800 mL) of toluene over 1-2 min. The batch will cool upon the addition of the toluene. Further cool the reaction mixture to 50 ± 3 °C. Charge to a clean 1 L flask, 347 g (400 mL) of toluene and warm it to 50 °C. This will be used as the cake wash. Filter the reaction mixture through a 15 g pad of Celite 545. Wash the filter cake with the warm (50 °C) toluene (400 mL) and collect this wash separately from the batch. This wash will be charged to the distillation residue later in the process. Transfer the filtrate back to the 3 L reactor. Concentrate the batch (25 °C to 40 °C internal temperature, 50 mbar) until a batch volume of 250 mL is reached.

Charge toluene cake wash held in reserve (~400 mL) and continue to concentrate the batch (37 °C to 43 °C internal temperature, 50 mbar) until a batch volume of 250 mL is reached. Check for complete removal of acetonitrile using the described Process Steering Control. Warm to 50 °C and stir for 15 min. Add 164 g (240 mL) of heptane over 30 minutes maintaining 50 °C throughout the addition. Stir the resulting suspension for 1 h. Cool the slurry to 23 ± 3 °C over 1 h and hold at this temperature for at least 1 h. Blanket the filtering funnel used for isolation of the product with nitrogen (to avoid moisture) and quickly filter the solids. Wash the filter cake twice with a mixture of 22 g (25 mL) of toluene and 51 g (75 mL) of heptane. Dry the solids at 50 °C, 35 mbar for 16 h to afford 4.4 g (72.7% corrected yield) of 4 as a sandy, beige solid. Example 3: 5-Bromo-4-(trifluoromethyl)pyridin-2-amine (4a)

 

4b 4a

Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to -5 ± 3 °C. Charge a nitrogen- flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet / outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0 ± 3 °C throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20 + 3 °C over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20 ± 3 °C throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp = 25 °C, 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of fert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30 ± 3 °C and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4 x 200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of terf-butyl methyl ether. Partially concentrate (57 ± 3 °C) to a volume of 350 mL. Cool to 50 °C and add 265 g (350 mL) of ferf-butyl methyl ether. Resume the concentration (57 ± 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 265 g (350 mL) of fe/f-butyl methyl ether. Again, resume the concentration (57 ± 3 °C) until a batch volume of 350 mL is reached. Cool to 50 °C and add 103 g (150 mL) of terf-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45 ± 3 °C throughout the addition. Slowly increase the vacuum and concentrate (internal temp = 40 °C to 50 °C) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp = 25 °C to 40 °C) to a batch volume of 500 mL. Stir the resulting suspension at 0 °C for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0 °C) heptane (containing 30 ppm Octastat). Dry the solids (40 °C, 50 mbar) for 16 h to afford 109.8 g (78.0% yield) 4a as an orange solid.

Example 4: 5-(2,6-Di-4-morpholinyl^^yrimidinyl)-^trifluoromethylpyridin-2-ami^ (5)

 

Charge a 500 mL round bottom 3-neck flask that equipped with a thermocouple, mechanical stirrer, nitrogen inlet/outlet and cooling bath with 202.8 g (0.622 mol) of cesium carbonate and 260 g (260 mL) of water. Stir and cool the resulting solution to 22 ± 3 °C. Transfer the solution to the addition funnel. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, pH probe, nitrogen inlet/outlet and 500 mL addition funnel with 50.0 g (0.207 mol) of 5-bromo-4-(trifluoromethyl) pyridin-2-amine 4a, 190.9 g (0.456 mol) of 4,4′-[6-(4,4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidine-2,4-diyl]di[morpholine] 4, 6.75 g (0.0103 mol) of 1,1′-bis(di-ferf-butylphosphino) ferrocene palladium dichloride and 556 g (625 mL) of thf. Stir the slurry at 22 ± 3 °C. Add the aqueous cesium carbonate solution via the addition funnel to the slurry over 1 – 2 min. Stir rapidly (to ensure good mixing), heat to 45 ± 3 °C over 15 min and hold at this temperature for at least 30 minutes. Check for completeness of the reaction. Cool to 22 ± 3 °C. Separate the phases. Partially concentrate the THF (25 °C, 90 mbar) to a volume of 400 mL. Add 654 g (750 mL) of isopropyl acetate, resume the vacuum distillation and concentrate to a volume of 400 mL. Add 610 g (700 mL) of isopropyl acetate, stir and filter the hazy solution through a 25 g pad of Celite. Wash the reactor and filter cake with 87 g (100 mL) of isopropyl acetate and add the wash to the batch. Add 1 L of 0. 25N aqueous N-acetyl-L- cysteine solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Again, add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Charge 34.5 g of Si-Thiol functionalized silica gel and stir the suspension at 60 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Add 1 L of 1 N aqueous hydrochloric acid solution and stir for 15 minutes. Separate the phases and retain the aqueous phase which now contains product. Extract the organic phase again by adding 500 mL of 1N aqueous HCI solution and stirring for 15 minutes. Separate the phases and combine the aqueous extracts. Adjust the pH to 2.3 ± 0.2 by the addition of ~280 mL of 4N aqueous sodium hydroxide solution. Charge 17.2 g of Si-Thiol functionalized silica gel and stir the suspension at 50 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Adjust the pH to 5.0 ± 0.2 by the slow addition of ~75 mL of 4N aqueous sodium hydroxide solution maintaining a batch temperature of 15 ± 3 °C. Stir the slurry for at least 16 h at 22 ± 3 °C to allow the product to completely solidify. Filter the solids and wash the filter cake once with 250 g (250 mL) of water. Dry the solids (50 °C, 35 mbar) for 16 h to obtain 75 g (89% yield) of 5 as a tan solid. Following this procedure, Compound 5 is the hemihydrate polymorph form HA of the Compound of Formula A.

Alternative procedure:

Charge a 500 mL round bottom 3-neck flask that equipped with a thermocouple, mechanical stirrer, nitrogen inlet/outlet and cooling bath with 202.8 g (0.622 mol) of cesium carbonate and 260 g (260 mL) of water. Stir and cool the resulting solution to 22 ± 3 °C. Transfer the solution to the addition funnel. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, pH probe, nitrogen inlet/outlet and 500 mL addition funnel with 50.0 g (0.207 mol) of 5-bromo-4-(trifluoromethyl) pyridin-2-amine 4a, 90.9 g (0.456 mol) of

4,4′[6(4,4,5,5tetramethyl1 ,3,2 dioxaborolan2yl)pyrimidine2,4diyl]di[morpholine] 4, 6.75 g (0.0103 mol) of 1 ,1′-bis(di-fert-butylphosphino) ferrocene palladium dichloride and 556 g (625 mL) of tetrahydrofuran. Stir the slurry at 22 ± 3 °C. Add the aqueous cesium carbonate solution via the addition funnel to the slurry over 1-2 min. Stir rapidly (to ensure good mixing), heat to 45 ± 3 °C over 15 min and hold at this temperature for at least 30 minutes. Check for completeness of the reaction . Cool to 22 + 3 °C. Separate the phases. Partially concentrate the THF (25 C, 90 mbar) to a volume of 400 mL. Add 654 g (750 mL) of isopropyl acetate, resume the vacuum distillation and concentrate to a volume of 400 mL. Add 610 g (700 mL) of isopropyl acetate, stir and filter the hazy solution through a 25 g pad of Celite. Wash the reactor and filter cake with 87 g (100 mL) of isopropyl acetate and add the wash to the batch. Add 1 L of 0.125N aqueous N- acetyl-L-cysteine solution and stir at 60 ± 3 °C for 1 h. Cool to 22 + 3 °C C and drain the aqueous wash. Add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 + 3 °C for 1 h. Cool to 22 + 3 °C and drain the aqueous wash. Again, add 1 L of 0.25N aqueous N- acetyl-L-cysteine pH = 7 solution and stir at 60 + 3 °C for 1 h. Cool to 22 ± 3 °C and drain the aqueous wash. Charge 34.5 g of Si-Thiol functionalized silica gel and stir the suspension at 60 + 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Add 1 L of N aqueous hydrochloric acid solution and stir for 15 minutes. Separate the phases and retain the aqueous phase which now contains product. Extract the organic phase again by adding 500 mL of 1N aqueous hydrochloric acid solution and stirring for 15 minutes. Separate the phases and combine the aqueous extracts. Adjust the pH to 2.3 + 0.2 by the addition of ~280 mL of 4N aqueous sodium hydroxide solution. Charge 17.2 g of Si-Thiol functionalized silica gel and stir the suspension at 50 ± 3 °C for 1 h. Cool to 22 ± 3 °C and filter to remove the silica gel. Adjust the pH to 5.0 ± 0.2 by the slow addition of ~75 mL of 4N aqueous sodium hydroxide solution maintaining a batch temperature of 15 ± 3 °C. Stir the slurry for at least 16 h at 22 ± 3 °C to allow the product to completely solidify. Filter the solids and wash the filter cake once with 250 g (250 mL) of water. Dry the solids (50 °C, 35 mbar) for 16 h to obtain 75 g (89% yield) of 5 as a tan solid. Following this procedure, Compound 5 is the hemihydrate polymorph form HA of the Compound of Formula A.

…………..

WO-2014064058

Improved process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine

Improved process for the preparation of buparlisib, an oral PI3K inhibitor Novartis is developing for the treatment of solid tumors, including breast cancer and hematological tumors. In January 2014, a phase III development was ongoing and Novartis expected to file for regulatory approval for breast cancer in 2015. Buparlisib was originally claimed in WO2007084786, protection for which expires in both the US and Europe in January 2027. Also see WO2012044727 for a more recent process case.

 

Burger, M.T.; Pecchi, S.; Wagman, A.; et al.
Discovery of BKM120, a pan class I PI3 kinase inhibitor in phase I/II clinical trials
240th ACS Natl Meet (August 22-26, Boston) 2010, Abst MEDI 489

Vu, A.T.; Morris, J.; Malhotra, S.V.
Efficient and improved synthesis of a PI3K inhibitor anticancer agent
241st ACS Natl Meet (March 27-30, Anaheim) 2011, Abst ORGN 115

Binimetinib in phase 3 for for the treatment of metastatic or unresectable cutaneous melanoma with NRAS mutations and in combination with LGX-818 in adult patients with BRAF V600


Figure imgf000024_0001

 

 

Binimetinib

5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide
5-(4-Bromo-2-fluorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamic acid 2-hydroxyethyl ester
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide
606143-89-9  CAS
tyrosine kinase inhibitor, antineoplastic

Array BioPharma Inc;PHASE 3 Cancer, ovary (serous)

Novartis PHASE 3 Melanoma

AGARRY-162
ARRY-438162
MEK-162

 

MEK-1 protein kinase inhibitor; MEK-2 protein kinase inhibitor

Liver injury; Melanoma; Noonan syndrome; Ovary tumor; Solid tumor

Growth factor-mediated proliferative signals are transmitted from the extracellular environment to the nucleus through several pathways, including the RAS/RAF/ MEK pathway. The RAS/RAF/MEK kinase signal transduction pathway is activated through initial extracellular binding and stimulation of tyrosine receptor kinases (RTKs) by their respective cognate ligands. Upon autophosphorylation of specific tyrosine residues in the cytosolic domain of RTKs, the Grb2-Sos complex translocates to the plasma membrane, and converts the inactive RAS’GDP to active RAS’GTP. The interaction between the Grb2 docking protein and the activated kinases or the phosphorylated receptor associated proteins is mediated by the Src Homology (SH2) domain of the signaling protein that recognizes specific phosphotyrosine sequences. RAS undergoes a conformational change upon guanosine 5 ‘-triphosphate (GTP) binding and causes the recruitment of RAF- 1 to the cytoplasmic membrane where it is phosphorylated by several kinases and simultaneous disphosphorylated at key residues by protein phosphatase-2B. Activated RAF phosphorylates the mitogen- activated protein kinase kinase (MEK) on two serine residues in the activation loop, which results in the activation of this protein kinase. MEK then phosphorylates and activates extracellular signal-regulated kinase (ERK), allowing its translocation to the nucleus where it phosphorylates transcriptional factors permitting the expression of a variety of genes.

The RAS/RAF/MEK signal transduction pathway is deregulated, often through mutations that result in ectopic protein activation, in roughly 1/3 of human cancers. This deregulation in turn results in a wide array of cellular changes that are integral to the etiology and maintenance of a cancerous phenotype including, but not limited to, the promotion of proliferation and evasion of apoptosis (Dhillon et al., Oncogene, 2007, 26: 3279-3290).

Accordingly, the development of small molecule inhibitors of key members of the RAS/ RAF/ MEK signal transduction pathway has been the subject of intense effort within the pharmaceutical industry and oncology community.

MEK is a major protein in the RAS/ RAF/ MEK pathway, which signals toward cell proliferation and survival, and frequently activated in tumors that have mutations in the RAS or RAF oncogenes or in growth receptor tyrosine kinases. MEK is a key player in the RAS/RAF/MEK pathway as it is downstream of RAS and RAF. Despite being only rarely mutated in cancer (Murugan et al., Cell Cycle, 2009, 8: 2122-2124; Sasaki et al., J. Thorac. Oncol., 2010, 5: 597-600), inhibitors of the MEK1 and MEK2 proteins have also been targeted for small molecule inhibition owing to their central position within the RAS/ RAF/ MEK signal transduction pathway signaling cascade (Fremin and Meloche, J. Hematol.

Oncol., 2010, 3:8). Recently a potent MEK inhibitor failed to demonstrate efficacy in clinical trials in patients with advanced non-small cell lung cancer (Haura et al., Clin. Cancer Res., 2010, 16: 2450-2457). The reason for failure in this trial is not clear.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (hereinafter, “Compound A”) is a benzimidazole compound that is a known potent and selective inhibitor of the MEK1 and MEK2 proteins, and useful in the treatment of hyperproliferative diseases, particularly cancer, in mammals. For example, in a recently published Phase I study of 28 patients suffering from unresectable, locally advanced or metastatic biliary cancer and who had received < 1 prior systemic therapy, oral Compound A treatment (60 mg twice daily) resulted in 1 complete regression, 1 partial regression and 11 stable disease diagnoses after at least 6 weeks of treatment (Finn et al., J. Clin. Oncol. 30, 2012 (Supplement 4, 2012 Gastrointestinal Cancers Symposium, Abstract No. 220). Compound A has also been demonstrated to be effective in the treatment of patients with either BRAFV600 or NRAS-mutant melanoma (Ascierto et al., J. Clin. Oncol. 30, 2012 (Supplement, 2012 ASCO Annual Meeting, Abstract No. 8511).

The compound, as well as a process for its preparation, is disclosed in PCT Pub. No. WO 03/077914

 

MEK-162, a potent, orally active MEK1/2 inhibitor, is in phase III clinical trials at Array BioPharma and licensee Novartis for the treatment of metastatic or unresectable cutaneous melanoma with NRAS mutations and in combination with LGX-818 in adult patients with BRAF V600. Phase III studies are also under way at Array BioPharma for the treatment of low grade serous carcinomas of the ovary, fallopian tube or primary peritoneum following at least one prior platinum-based chemotherapy regimen and no more than three lines of prior chemotherapy regimens. Novartis and Array BioPharma are also conducting phase II clinical studies for the treatment of locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600E mutations; in BRAF mutated melanoma in combination with AMG-479 and for the treatment of Noonan’s syndrome, and in non-small cell lung cancer harboring KRAS or EGFR mutation and in combination with erlotinib. MEK-162 is being evaluated in phase I/II as first line treatment of advanced biliary tract carcinoma and for the treatment of adult patients with mutant or wild-type RAS metastatic colorectal cancer. The product is in early clinical trials at Array Biopharma for the treatment of biliary cancer.

According to Array, MEK-162 may also provide broad therapeutic benefits in the treatment of chronic degenerative diseases. However, a phase II trial for the treatment of stable rheumatoid arthritis (RA) did not meet its primary endpoint. Based on these data, the company focused development of MEK-162 solely in oncology.

In 2010, MEK-162 was licensed to Novartis by Array BioPharma for worldwide development. In 2013, orphan drug designation was assigned in Japan for the treatment of malignant melanoma with NRAS or BRAF V600 mutation.

WO-2014063024 DEALS WITH Preparation, crystalline forms, and formulations comprising binimetinib. Binimetinib is a MEK-1/2 inhibitor originally claimed in WO03077914, which Array and Novartis are developing for the treatment of cancer, including melanoma, low-grade serous ovarian cancer, and other solid tumors, as well as Noonan syndrome hypertrophic cardiomyopathy and hepatic impairment. See also WO2014018725 for the most recent filing on the agent

 

//////////////////////////

WO 03/077914

http://www.google.com/patents/WO2003077914A1?cl=en

 

Schemes 1-4.

Scheme 1

 

Scheme la

Scheme 2

Scheme 3

 

17 18

Scheme 4

25

Scheme 5

General synthetic methods which may be referred to for preparing some of the compounds of the present invention are provided in PCT published application number WO 00/42022 (published July 20, 2000). The foregoing patent application is incorporated herein by reference in its entirety.

 similar ie chloro instead of fluoro

Example 52

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide (lOcc) Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a

3-Chloro-2,4-difluoro-benzoic acid la (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3x). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.

Step B: 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a

Ammonium hydroxide solution (6.88 g, -30% in water, 58.9 mmol) is added to a solution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7 mmol) in water (16 mL) at 0 °C with stirring. Upon completion of the ammonium hydroxide addition the reaction mixture is warmed to room temperature. After 5 hours the reaction mixture is cooled to 0 °C and concentrated HCl is carefully added until the pH of the reaction mixture is near zero. The solid is collected by filtration and washed with water and diethyl ether. The solids are transferred to a round bottom flask as a solution in MeOH and EtOAc and concentrated under reduced pressure to give 2.96 g of a yellow solid. The filtrate is partitioned between diethyl ether and water and the organic layer is washed with brine. The combined organic extracts are dried (Na2SO ) and concentrated under reduced pressure to give 0.65 g of product. Recovered a total of 3.61 g (104%) of pure desired product, that is carried forward without further purification.

Step C: 4~Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a

To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane (9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. After completion of reaction, the reaction mixture is concentrated via rotary evaporation with acetic acid in the trap. The recovered oily solid is triturated with diethyl ether to provide 1.51 g of a yellow solid. The filtrate is concentrated and triturated with diethyl ether to give an additional 0.69 g of yellow solid. A total of 2.20 g (57%) of pure desired product is recovered.

Step D: 4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c

4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0 °C in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH2C12 and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (-) m/z 320.3 (M-l) detected.

Step E: 4, 5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b

4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c (0.50 g, 1.55 mmol) is dissolved into 2:1 EtOH/MeOH (15.5 mL). Saturated aqueous NH4C1 (15 mL), Zn powder (1.02 g, 15.6 mmol), and THF (10 mL) are added. After stirring for 20 hours, the reaction mixture is diluted with CH C12/THF and water. The organic layer is washed with water (3x). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The solids are triturated with ether to give 0.32 g (70%) clean desired product. Step F: 7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c

4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80 °C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3x), saturated NaHCO3, and brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 302.3 (M+l) detected.

Step G: 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g

7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c (0.327 g, 1.08 mmol) is dissolved into DMF (16 mL) and NBS (0.193 g, 1.08 mmol) is added. After one hour, the reaction mixture is quenched by the addition of saturated aqueous NaHSO3. The reaction mixture is then partitioned between EtOAc/THF and water. The organic layer is washed with water and brine. The combined organic extracts are dried (Na2SO ) and concentrated under reduced pressure. The recovered solid is triturated with ether to give 0.225 g (54%) pure desired product. MS ESI (+) m/z 382, 384 (M+, Br pattern) detected.

Step H: 6-(4-Bromo-2-chloro-phenylamino)- 7 -chloro-3H-benzoimidazole-5 -carboxylic acid methyl ester lOdd 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g (0.225 g, 0.591 mmol) is dissolved in DMF (2 mL) and NCS (79 mg, 0.591 mmol) is added. After the NCS is in solution concentrated HCl (0.005 mL, 0.059 mmol) is added. After 2 hours, sodium bicarbonate, water and NaHSO3 are added to the reaction mixture. Solids are filtered and washed with water and ether to give 0.141 g (57%) of clean desired product as a tan solid. MS APCI (-) m/z 414, 416 (M-, Br pattern) detected.

Step I: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester lOdd (0.141 g, 0.34 mmol), potassium carbonate (0.141 g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved in dimethylformamide (3 mL). After 20 hours, the reaction mixture is diluted with EtOAc and washed with water (3x), potassium carbonate, and brine. The organic layer is dried (Na2SO4) and concentrated to a brown oil. The N3 and Nl alkylated regioisomers are separated by flash chromatography (EtOAc). The recovery of the N3 alkylated regioisomer is 20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.

Step J: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid 10 ff

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee (21 mg, 0.048 mmol) is dissolved into 2:1 THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190 mmol) is added. After stirring for 4 hours the reaction is diluted with water and acidified to pH 2 by addition of 1.0 M HCl. The mixture is then extracted with 3:1 EtOAc/THF (3x), dried (Na2SO ) and concentrated to give quantitative yield of desired prodcut as a white solid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected.

Step K: 6-(4-Bromo-2’chloro-phenylamino)- 7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-vinyloxy-ethoxy) -amide lOgg

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid lOff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3x), 10% potassium carbonate (2x), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (-) m/z 497, 501 (M-, Br pattern) detected.

Step L: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide lOcc

Hydrochloric acid (0.78 mL, 1.0 M aqueous solution, 0.78 mmol) is added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H- benzoimidazole-5-carboxylic acid lOgg (2-vinyloxy-ethoxy)-amide (39 mg, 0.078 mmol) in MeOH (1 mL). After one hour, the reaction mixture is neutralized to pH 7 and concentrated under reduced pressure. The solids are dissolved in EtOAc, washed with brine, dried (Na SO4), and concentrated under reduced pressure. Flash chromatography (20:1 CH2Cl2/MeOH) provides 9 mg (23%) of pure product: MS APCI (+) m/z 473, 475 (M+, Br pattern) detected; 1H NMR (400 MHz, CDC13) δ 8.30 (s, IH), 8.08 (s, IH), 7.57

(d, IH), 7.15 (dd, IH), 6.21 (d, IH), 3.97 (s, 3H) 3.86 (m, 2H), 3.57 (m, 2H).

 

actual is below

Example 18

The following compounds are prepared by methods similar to those described in

Example 10 by using methyl ester 8d and the appropriate alkylating agent (Step A) and

the appropriate hydroxylamine (Step C):

/////////////////////

WO2014063024

http://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E10680BCA177F821C7FEFA1AFC44A438.wapp2nA?docId=WO2014063024&recNum=6&maxRec=53841&office=&prevFilter=%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

COMPD A

Example 1. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-

 

Compound 1 Compound 3

 

In an inertized (N2) reaction vessel at internal temperature 20°C and under exclusion of humidity and air, Compound 1 (1.0 eq.) and Compound 2 (1.2 eq.) are reacted in the presence of cesium carbonate (2.4 eq.), tris(dibenzylidenaceton) dipalladium(O) (0.035 eq.) and Xantphos (0.07 eq.) in a mixture of toluene and 1 ,4-dioxane at internal temperature of 99°C. After 8 hours, the mixture is cooled to internal temperature of 60°C.

Subsequently, dimethylformamide (DMF), filter aid (CEFOK) and activated charcoal (EKNS) are added, and the mixture is stirred and cooled to internal temperature of 35 °C. The solids are filtered off and washed with a mixture of dimethylformamide and toluene. To the filtrate, which contains the product Compound 3, is introduced at internal temperature of

25 °C hydrogen chloride gas (CLC) whereupon the HQ salt of Compound 3 crystallizes. The palladium residue mainly remains in solution. After warming to 60 °C and cooling to 0°C, the solids are filtered using a centrifuge and are washed with a mixture of toluene and dimethylformamide.

The damp Compound 3 HC1 salt is charged to a reactor (equipped with pH probe) together with dimethylformamide and is heated to 60°C. By adding a 4 wt% of aqueous tripotassium phosphate solution, the pH is adjusted to a pH range of 6.8-7.6 (with a target of pH 7.2) while Compound 3 crystallizes as free base. After cooling to 22°C and stirring, the solids are filtered using a centrifuge and are washed with drinking water. The moist solids are dried at 50 °C under vacuum to give dry, crude Compound 3.

In order to remove residual palladium, dry, crude Compound 3 is dissolved in dimethylformamide at internal temperature of 60°C and stirred together with Smopex-234 (commercially available from Johnson Matthey) and activated charcoal for 90 minutes. The solids are filtered off at internal temperature of 60°C and are washed with

dimethylformamide. To the filtrate are added drinking water and Compound 3 seed crystals. More drinking water is added while Compound 3 crystallizes. After cooling to internal temperature of 20 °C, the solids are filtered using a centrifuge and are washed with a mixture of deionized water and dimethylformamide and with deionized water. The moist solids are dried at 50°C under vacuum, providing 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3).

 

Example 2. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide

A. “One-pot” Synthesis

 

Compound 3 Intermediate 1

t-Bu-O. /\ ^ H2

(Compound 4)

 

Compound 5

In an inertized reaction vessel at internal temperature 20-25 °C under nitrogen, 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3, 1.0 eq.) is added to a mixture of DMF and THF. To this slurry, a solution of potassium trimethylsilanolate (1.05 eq.) in THF is added to the mixture at internal temperature of 25 °C over a period of about 40 minutes, and the resulting mixture is stirred for about 1 hour, providing a potassium salt solution of Intermediate 1. A THF/methanol mixture is then sequentially distilled off from the mixture at 85-120°C during about 2 hours.

The potassium salt solution is then added to a suspension of CDI (1.25 eq.) and imidazole hydrochloride (1.40 eq.) in THF at internal temperature of 25 °C over a period of about 1 hour. The resulting mixture is then stirred for approximately 1 hour at 50°C, and the following imidazolide intermediate

 

 

The imidazolide intermediate is not further isolated.

Subsequently, 1.2 eq. of 0-(2-tert-butoxyethyl)hydroxylamine (Compound 4, CAS No. 1023742-13-3, available from suppliers such as Huhu Technology, Inc.®) is added over a period of about 30 minutes at 50°C and stirred for 1.5 hours. Demineralized water is then added at 50°C, producing a precipitate. After cooling to 20°C and stirring for about 3-16 hours, the slurry is filtered off, washed with THF/ demineralized water (1 :2) in 2 portions and with demineralized water in three portions, and dried at 50°C / <70 mbar for about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

 

B. A synthesis method with isolation of the intermediate of step a) from the reaction mixture of step a) prior to the reaction of step b)

Alternatively, 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5 -carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) can be made by the synthesis method as shown below. Compound 3, which is a methyl ester, is first converted to a carboxylic acid, which is then isolated by a crystallization to form Compound

6. Compound 6 is then coupled with Compound 4 to form Compound 5 as monohydrate.

The crystallization step in this method removes starting materials such as Compound 1, process impurities, and the dba ligand from the prior catalyst before the coupling reaction with Compound 4, and at the same time maintains the overall yield of the synthesis.

 

 

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-memy acid In an inertized (N2) reaction vessel at internal temperature of 60°C, Compound 3 (1.0 eq.) is dissolved in DMF and stirred with a fiber, which is sold under the trademark

SMOPEX 234, and activated charcoal for the removal of palladium to not more than 100 ppm. The fiber and activated charcoal are removed by filtration at 60°C and washed with DMF.

The filtrate (containing Compound 3) is transferred to a second inertized (N2) reaction vessel and cooled to an internal temperature of 30°C. A thin suspension can form at this point of time. 30% sodium hydroxide (1.1 eq.) and water (for rinsing) are added, and the resulting reaction mixture is vigorously stirred for 3 hours at an internal temperature of 30 °C. The methyl ester is saponified. Conversion is checked by an IPC (HPLC). As soon as the IPC criterion is met, a filter aid, which is sold under the trademark HYFLO, is added. The mixture is stirred for 15 minutes and then filtered at 30°C via a plate filter and polish filter to a third reaction inertized (N2) vessel.

An aqueous HC1 solution 7.5 % is added to the clear filtrate in the third vessel at an internal temperature of 30 °C until a pH value of 8 is reached. Then the solution is seeded at an internal temperature of 30°C with Compound 6, and an aqueous HC1 solution 7.5 % is added under vigorous stirring until a pH value of pH 2.8 is reached. The product gradually crystalizes. The suspension is cooled over 60 min to an internal temperature of 25 °C and

water is added. The suspension is stirred for at least 4 hours at an internal temperature of 25°C.

The resulting solid is collected by centrifugation or filtration. The filter cake is first washed with DMF/water 1 :1 (w/w) and then with water, discharged and dried in a vacuum at 50°C. The water content is controlled by IPC. The crystalline product Compound 6 is discharged as soon as the IPC criterion is met.

 

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid- (2-tert-butoxyethoxy) – amide

An inertized (N2) reaction vessel is charged with Compound 6 (1.0 eq.), DMF, and

THF at room temperature. The suspension is heated to 25 °C under stirring with flow of nitrogen. After CDI (1.13 eq.) is added, the suspension can get thinner and slight evolution of gases can be observed. After the suspension finally becomes a solution, it is then monitored by IPC (HPLC).

As soon as the IPC (HPLC) criterion is met, the reaction mixture is heated to 50°C over 20 minutes and imidazole hydrochloride (0.3 eq.) is added, forming a solution of

Intermediate 2.

To the solution of Intermediate 2, Compound 4 (1.3 eq.) is added over 60 minutes at internal temperature of 50°C under stirring at a speed of 300 rpm with flow of nitrogen. As soon as the IPC (HPLC) criterion is met, the mixture is cooled to 20-25 °C over 30 minutes. The mixture is then stored at ambient temperature overnight under nitrogen without stirring. DMF is added to the mixture followed by heating it to 50 °C over 30 minutes. Complete conversion of Intermediate 2 to Compound 5 is confirmed by IPC (HPLC).

Water is added to the mixture at internal temperature of 50 °C over 20 minutes. Then the solution is seeded with Compound 5. After stirring at 50 °C for 60 minutes, more water is added to the suspension at 50 °C over 90 minutes. After vigorous stirring, the suspension is cooled to 20 °C over 2 hours and filtered. The filter cake is washed twice with THF/water (v/v: 1 :2) at 20 °C, and twice with water at 20 °C. Finally, the filter cake is dried at 50 °C under vacuum to provide 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

 

Example 3. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A)

Compound 5 Compound A

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85 % aqueous solution) at internal temperature 20-25 °C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53 °C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25 °C. The mixture is then heated to internal temperature 35-37°C and diluted with Ethanol- Water (3 :1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30°C. 3 N aqueous potassium hydroxide (ΚΟΗ) is added to the cooled filtrate over a period of 90 minutes until a pH- value of about 8.1 is reached. The suspension is heated to internal temperature 60-63 °C, stirred at this temperature for a period of about 2 hours, cooled to 20-23 °C over a period of about 45 minutes, filtered over a funnel, and dried at 50°C pressure <100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.

 

Example 4. Preparation of Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) In a dry vessel at room temperature, Compound A is added to a premixed solvent solution of methanol/THF/water (35/35/30 w/w). The suspension is heated to internal temperature 53-55°C, and the resulting solution is hot filtered by deep and membrane filtration (via a paper filter and PTFE membrane) at internal temperature 53-56°C. The clear solution is stirred and cooled to 47-48°C, and the seed crystals suspension (i.e., seed crystals of crystallized Compound A in water, 10% m/m) is added (0.2 to 0.5% of crystallized Compound A expected yield mass). After about 20 minutes, water is slowly added within 25 hours (33.3% within 15 hours and 66.6% within 10 hours with at least 10 minute stirring after addition of water) to obtain a final ratio of methanol THF/water (20/20/60 w/w). After the water is added, the suspension is cooled down to internal temperature 3-5 °C within 10 hours and stirred for 0.5 hours. The white suspension is filtered over a sinter glass nutsche (75 ml, diameter = 6 cm, pore 3) suction filter and washed once with ice cold methanol/THF/water (15/15/70 w/w at 2-4 °C), and two times with ice cold water (2-4 °C). Drying takes place in a vacuum oven dryer at 20°C for 10 hours, and then at 40°C for 10 hours, and then at 60°C for at least 12 hours with pressure < lOmbar, providing crystallized Compound A.

Example 5. Pharmaceutical Composition

Crystallized Compound A is formulated as indicated in Table 1 :

Table 1

 

* The weight of the drug substance is taken with reference to the dried substance (100%) on the basis of assayed value. The difference in weight is adjusted by the amount of lactose monohydrate.

** The Opadry II is combined with the sterile water to make a 12% w/w Opadry II (85F) film coat suspension, which is then sprayed onto the core tablet.

*** Removed during processing

 

Upon mixing of the tablet core components, the pharmaceutical composition is converted into a tablet form by direct compression. The formed tablet may be further coated with the tablet coating provided above.

 

%d bloggers like this: