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Alpelisib, BYL 719

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Alpelisib.pngChemSpider 2D Image | Alpelisib | C19H22F3N5O2S

Alpelisib

(2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide
PDT PAT WO 2010/029082
Chemical Names: Alpelisib; CAS 1217486-61-7; BYL-719; BYL719; UNII-08W5N2C97Q; BYL 719
Molecular Formula: C19H22F3N5O2S
Molecular Weight: 441.473 g/mol
  1. alpelisib
  2. 1217486-61-7
  3. BYL-719
  4. BYL719
  5. UNII-08W5N2C97Q
  6. BYL 719
  7. Alpelisib (BYL719)
  8. (S)-N1-(4-Methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide
  9. NVP-BYL719

Alpelisib is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. Alpelisib specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the 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.

Alpelisib has been used in trials studying the treatment and basic science of Neoplasms, Solid Tumors, BREAST CANCER, 3rd Line GIST, and Rectal Cancer, among others.
str1 str2
Image result for Alpelisib PHARMACODIA
 SYN 2Image result for Alpelisib PHARMACODIA
POLYMORPHS

(S)-pyrrolidine-l,2-dicarboxylic acid 2-amide l-(4-methyl-5-[2-(2,2,2-trifluoro-l,l- dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amidei hereafter referred to as compound I,

Figure imgf000002_0001

is an alpha-selective phosphatidylinositol 3 -kinase (PI3K) inhibitor. Compound I was originally described in WO 2010/029082, wherein the synthesis of its free base form was described. There is a need for additional solid forms of compound I, for use in drug substance and drug product development. It has been found that new solid forms of compound I can be prepared as one or more polymorph forms, including solvate forms. These polymorph forms exhibit new physical properties that may be exploited in order to obtain new pharmacological properties, and that may be utilized in drug substance and drug product development. Summary of the Invention

In one aspect, provided herein is a crystalline form of the compound of formula I, or a solvate of the crystalline form of the compound of formula I, or a salt of the crystalline form of the compound of formula I, or a solvate of a salt of the crystalline form of the compound of formula I. In one embodiment, the crystalline form of the compound of formula I has the polymorph form SA, SB, Sc, or SD.

In another aspect, provided herein is a pharmaceutical composition comprising a crystalline compound of formula I. In one embodiment of the pharmaceutical composition, the crystalline compound of formula I has the polymorph form SA, SB,Sc, or So.

In another aspect, provided herein is a method for the treatment of disorders mediated by PI3K, comprising administering to a patient in need of such treatment an effective amount of a crystalline compound of formula I, particularly SA, SB, SC,or SD .

In yet another aspect, provided herein is the use of a crystalline compound of formula I, particularly SA, SB, SC, or SD, for the preparation of a medicament for the treatment of disorders mediated by PI3K.

In still another aspect, provided herein is a method for the treatment of disorders selected from benign or malignant tumor; a cancer selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease);

pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma;

thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphomas; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; tumor diseases, including solid tumors; a tumor of the neck or head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease; as well as polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler’s syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn’s disease), endocrine opthalmopathy, Grave’s disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma, comprising administering to a patient in need of such treatment an effective amount of the crystalline compound of formula I, particularly polymorph forms SA, SB, SC, or SD-

In another aspect, provided herein is the use of the crystalline compound of formula I, particularly polymorph forms SA, SB, SC, or SD for the preparation of a medicament for the treatment of the disorders listed above. Brief Description of the Drawings

Figure I depicts the X-ray powder diffraction pattern of polymorph form A. Figure II depicts the FT-IR spectrum of polymorph form A. Figure III depicts the differential scanning calorimetry thermogram of polymorph form A. Figure IV depicts the X-ray powder diffraction pattern of polymorph form SA- Figure V depicts the X-ray powder diffraction pattern of polymorph form SB. Figure VI depicts the X-ray powder diffraction pattern of polymorph form Sc. Figure VII depicts the X-ray powder diffraction pattern of polymorph form SD.

Scheme 2. Synthesis of (S)-Pyrrolidine-1.2-dicarboxylic acid 2-amide l-((4-methyl-5-r2- (2,2,2-trifluoro- 1 , 1 -dimethyl-ethyl -pyridin-4-yl1-thiazol-2-yl} -amide)

Figure imgf000028_0001

Example 2: (S)-Pyrrolidine-1.2-dicarboxylic acid 2-amide 1 -((4-methyl-5- 2 -(2,2,2- trifluoro-1 J-dirhethyl-ethylVpyridin-4-yl -thia2ol-2-yll-amide

The title compound is prepared in analogy to the procedure described in Example 1 but with the following modifications. In Step 2.1 (corresponding to Step 1.1 of Example 1), the reaction mixture is stirred for 14 h at reflux. In Step 2.2 (corresponding to Step 1.2 of Example 1), the reaction mixture is stirred for 1 h at 85 °C and extracted with ethyl acetate after being quenched. In step 2.3 (corresponding to Step 1.3 of Example 1), the reaction mixture is stirred for 2.5 h at 120 °C. In Step 2.4 (corresponding to Step 1.4 of Example 1), the reaction mixture is stirred for 1 h at 83 °C and extracted with ethyl acetate after being quenched. In Step 2.5 (corresponding to Step 1.5 of Example 1), the reaction mixture is stirred for 1 h at 65 °C and trituration in methanol is not performed. In Step 2.6

(corresponding to Step 1.6 of Example 1), the crude product is not purified. In Step 2.7 (corresponding to Step 1.7 of Example 1), 3,3,3-trifluoro-2,2-dimethyl-propionyl chloride is used.

Title compound: ESI-MS: 442.0 [M+H]+; tR= 3.02 min (System 1); TLC: Rf = 0.35 (DCM/MeOH, 9: 1).

Example 3: Preparation of Polymorph Form A

(S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-({4-methyl-5-[2-(2,2,2-trifluoro-l,l- dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (10.0 g) was suspended in ethanol/water (85:15 v/v; 75 mL) and the mixture was heated to 75 °C. The solution was clear-filtered into a second flask and the first flask was then washed with ethanol/water (4:6 v/v; 20 mL), followed by water (10 mL). The clear solution was stirred at 75 °C for an additional 30 minutes. The clear solution was then cooled to 2 °C over 2 hours and the obtained thick suspension was stirred at 2 °C for an additional hour. The mixture was then filtered, and the flask and filter cake were washed with ethanol/water (1 :1 v/v; 20 mL), followed by ethyl acetate (10 mL). The wet filter cake was returned to the flask and suspended in ethyl acetate (75 mL). the mixture was heated to 78 °C and was stirred under reflux for 1 hour. During this time, 15 mL ethyl acetate was distilled off. The mixture was then cooled to 2 °C over 2 hours and the suspension was stirred at 2 °C for an additional hour. The mixture was filtered, and the flask and filter cake were washed with cold ethyl acetate (12 mL). The filter cake was then dried under 1-50 mbar vacuum at 50 °C to yield the polymorph form A (7.3 g).

Publication numberPriority datePublication dateAssigneeTitle
WO2010029082A12008-09-102010-03-18Novartis AgOrganic compounds
WO2012016970A1 *2010-08-022012-02-09Novartis AgA crystalline form of (s)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-(4 -methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amide and its use as pi3k inhibitor
KR20070113188A *2004-10-072007-11-28베링거 인겔하임 인터내셔날 게엠베하Thiazolyldihydroindazoles
EP2016075A1 *2006-05-032009-01-21AstraZeneca ABThiazole derivatives and their use as anti-tumour agents
WO2016051374A1 *2014-10-032016-04-07Novartis AgPharmaceutical compositions comprising alpelisib
CN105979947A *2013-12-062016-09-28诺华股份有限公司Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor
 PATENTS
Patent ID

Patent Title

Submitted Date

Granted Date

US9815898 ANTIBODY MOLECULES TO PD-1 AND USES THEREOF
2017-05-15
US2017210733 BENZOXAZEPIN OXAZOLIDINONE COMPOUNDS AND METHODS OF USE
2017-04-07
US2017210804 ANTIBODY MOLECULES TO LAG-3 AND USES THEREOF
2017-03-24
US2017190777 ANTIBODY MOLECULES TO TIM-3 AND USES THEREOF
2017-03-17
US2017166550 BENZOTHIOPHENE-BASED SELECTIVE ESTROGEN RECEPTOR DOWNREGULATORS
2016-12-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2015291606 MERTK-SPECIFIC PYRROLOPYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
US2015291609 MERTK-SPECIFIC PYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
US9603850 MERTK-SPECIFIC PYRAZOLOPYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
US2015259420 ANTIBODY MOLECULES TO LAG-3 AND USES THEREOF
2015-03-13
2015-09-17
US9605070 ANTIBODY MOLECULES TO TIM-3 AND USES THEREOF
2015-01-30
2015-08-06
Patent ID

Patent Title

Submitted Date

Granted Date

US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF
2015-10-13
2016-04-21
US2017209574 COMBINATION THERAPIES
2015-10-02
US2017224836 ANTI-CDH6 ANTIBODY DRUG CONJUGATES
2015-08-07
US2017189409 MEDICAL USE
2015-05-21
US2015320880 ANTIBODY DRUG CONJUGATES
2015-05-20
2015-11-12

/////////////////Alpelisib,  CAS,  1217486-61-7, BYL-719, BYL719, UNII-08W5N2C97Q, BYL 719

CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F

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DR ANTHONY CRASTO

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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

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