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ORGANIC SPECTROSCOPY

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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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Alpelisib, BYL 719


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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Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India

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Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India
Recent Advances in Drug Development

/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas

New 5-​Substituted-​N-​(piperidin-​4-​ylmethyl)​-​1H-​indazole-​3-​carboxamides: Potent Glycogen Synthase Kinase-​3 (GSK-​3) Inhibitors in Model of Mood Disorders


str1

 

CAS 1452582-16-9, 428.47, C23 H26 F2 N4 O2

1H-​Indazole-​3-​carboxamide, 5-​(2,​3-​difluorophenyl)​-​N-​[[1-​(2-​methoxyethyl)​-​4-​piperidinyl]​methyl]​-

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.

1 H-indazole-3-carboxamide compounds acting as glycogen synthase kinase 3 beta (GSK-33) inhibitors and to their use in the treatment of GSK-33-related disorders such as (i) insulin-resistance disorders; (ii) neurodegenerative diseases; (iii) mood disorders; (iv) schizophrenic disorders; (v) cancerous disorders; (vi) inflammation, (vii) substance abuse disorders; (viii) epilepsies; and (ix) neuropathic pain.

Protein kinases constitute a large family of structurally related enzymes, which transfer phosphate groups from high-energy donor molecules (such as adenosine triphosphate, ATP) to specific substrates, usually proteins. After phosphorylation, the substrate undergoes to a functional change, by which kinases can modulate various biological functions.

In general, protein kinases can be divided in several groups, according to the substrate that is phosphorylated. For example, serine/threonine kinase phosphorylates the hydroxyl group on the side chain of serine or threonine aminoacid.

Glycogen synthase kinases 3 (GSK-3) are constitutively active multifunctional enzymes, quite recently discovered, belonging to the serine/threonine kinases group.

Human GSK-3 are encoded by two different and independent genes, which leads to GSK-3a and GSK-33 proteins, with molecular weights of about 51 and 47 kDa, respectively. The two isoforms share nearly identical sequences in their kinase domains, while outside of the kinase domain, their sequences differ substantially (Benedetti et al., Neuroscience Letters, 2004, 368, 123-126). GSK-3a is a multifunctional protein serine kinase and GSK-33 is a serine-threonine kinase.

It has been found that GSK-33 is widely expressed in all tissues, with widespread expression in the adult brain, suggesting a fundamental role in neuronal signaling pathways (Grimes and Jope, Progress in Neurobiology, 2001, 65, 391-426). Interest in glycogen synthase kinases 3 arises from its role in various physiological pathways, such as, for example, metabolism, cell cycle, gene expression, embryonic development oncogenesis and neuroprotection (Geetha et al., British Journal Pharmacology, 2009, 156, 885-898).

GSK-33 was originally identified for its role in the regulation of glycogen synthase for the conversion of glucose to glycogen (Embi et al., Eur J Biochem, 1980, 107, 519-527). GSK-33 showed a high degree of specificity for glycogen synthase.

Type 2 diabetes was the first disease condition implicated with GSK- 3β, due to its negative regulation of several aspects of insulin signaling pathway. In this pathway 3-phosphoinositide-dependent protein kinase 1 (PDK-1 ) activates PKB, which in turn inactivates GSK-33. This inactivation of GSK-33 leads to the dephosphorylation and activation of glycogen synthase, which helps glycogen synthesis (Cohen et al., FEBS Lett, 1997, 410, 3-10). Moreover, selective inhibitors of GSK-33 are expected to enhances insulin signaling in prediabetic insulin- resistant rat skeletal muscle, thus making GSK-33 an attractive target for the treatment of skeletal muscle insulin resistance in the pre-diabetic state (Dokken et al., Am J. Physiol. Endocrinol. Metab., 2005, 288, E1 188-E1 194).

GSK-33 was also found to be a potential drug target in others pathological conditions due to insulin-resistance disorders, such as syndrome X, obesity and polycystic ovary syndrome (Ring DB et al., Diabetes, 2003, 52: 588-595).

It has been found that GSK-33 is involved in the abnormal phosphorylation of pathological tau in Alzheimer’s disease (Hanger et al., Neurosci. Lett, 1992, 147, 58-62; Mazanetz and Fischer, Nat Rev Drug Discov., 2007, 6, 464-479; Hong and Lee, J. Biol. Chem., 1997, 272, 19547- 19553). Moreover, it was proved that early activation of GSK-33, induced by apolipoprotein ApoE4 and β-amyloid, could lead to apoptosis and tau hyperphosphorylation (Cedazo-Minguez et al., Journal of Neurochemistry, 2003, 87, 1 152- 1 164). Among other aspect of Alzheimer’s disease, it was also reported the relevance of activation of GSK-33 at molecular level (Hernandez and Avila, FEBS Letters, 2008, 582, 3848-3854).

Moreover, it was demonstrated that GSK-33 is involved in the genesis and maintenance of neurodegenerative changes associated with Parkinson’s disease (Duka T. et al., The FASEB Journal, 2009; 23, 2820- 2830).

Accordingly to these experimental observations, inhibitors of GSK-33 may find applications in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with tauopathies; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (the involvement of GSK-33 in such deficits and diseases is disclosed in Meijer L. et al., TRENDS Pharm Sci, 2004; 25, 471 -480); dementia, such as, but not limited to, vascular dementia, post-traumatic dementia, dementia caused by meningitis and the like; acute stroke; traumatic injuries; cerebrovascular accidents; brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma (the involvement of GSK-33 in such conditions is disclosed in WO 2010/109005).

The treatment of spinal neurodegenerative disorders, like amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy and neurodegeneration due to spinal cord injury has been also suggested in several studies related to GSK-33 inhibition, such as, for example in Caldero J. et al., “Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord”, Neuroscience. 2010 Feb 17;165(4):1353-69, Leger B. et al., “Atrogin-1 , MuRF1 , and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients”, Muscle Nerve, 2009 Jul; 40(1 ):69-78, and Galimberti D. et al., “GSK33 genetic variability in patients with Multiple Sclerosis”, Neurosci Lett. 201 1 Jun 1 5;497(1 ):46- 8. Furthermore, GSK-33 has been linked to the mood disorders, such as bipolar disorders, depression, and schizophrenia.

Inhibition of GSK-33 may be an important therapeutic target of mood stabilizers, and regulation of GSK-33 may be involved in the therapeutic effects of other drugs used in psychiatry. Dysregulated GSK-33 in mood disorder, bipolar disorder, depression and schizophrenia could have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression and the ability of neurons to respond to stressful, potentially lethal conditions (Jope and Ron, Curr. Drug Targets, 2006, 7, 1421- 1434).

The role of GSK-33 in mood disorder was highlighted by the study of lithium and valproate (Chen et al., J. Neurochem., 1999, 72, 1327- 1330; Klein and Melton, Proc. Natl. Acad. Sci. USA, 1996, 93, 8455-8459), both of which are GSK-33 inhibitors and are used to treat mood disorders. There are also existing reports from the genetic perspective supporting the role of GSK-33 in the disease physiology of bipolar disorder (Gould, Expert. Opin. Ther. Targets, 2006, 10, 377-392).

It was reported a decrease in AKT1 protein levels and its phosphorylation of GSK-33 at Serine-9 in the peripheral lymphocytes and brains of individuals with schizophrenia. Accordingly, this finding supports the proposal that alterations in AKT1 -GSK-33 signaling contribute to schizophrenia pathogenesis (Emamian et al., Nat Genet, 2004, 36, 131- 137).

Additionally, the role of GSK-33 in cancer is a well-accepted phenomenon.

The potential of small molecules that inhibit GSK-33 has been evidenced for some specific cancer treatments (Jia Luo, Cancer Letters, 2009, 273, 194-200). GSK-33 expression and activation are associated with prostate cancer progression (Rinnab et al., Neoplasia, 2008, 10, 624-633) and the inhibition of GSK3b was also proposed as specific target for pancreatic cancer (Garcea et al., Current Cancer Drug Targets, 2007, 7, 209-215) and ovarian cancer (Qi Cao et al., Cell Research, 2006, 16 671 -677). Acute inhibition of GSK-33 in colon-rectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth (Ghosh et al., Clin Cancer Res 2005, 1 1 , 4580-4588).

The identification of a functional role for GSK-33 in MLL-associated leukaemia suggests that GSK-33 inhibition may be a promising therapy that is selective for transformed cells that are dependent on HOX overexpression (Birch et al., Cancer Cell, 2010, 1 7, 529-531 ).

GSK-33 is involved in numerous inflammatory signalling pathways, for example, among others GSK-33 inhibition has been shown to induce secretion of the anti-inflammatory cytokine IL-1 0. According to this finding, GSK-33 inhibitors could be useful to regulate suppression of inflammation (G. Klamer et al., Current Medicinal Chemistry, 2010, 17(26), 2873-2281, Wang et al., Cytokine, 2010, 53, 130-140).

GSK-33 inhibition has been also shown to attenuate cocaine-induced behaviors in mice. The administration of cocaine in mice pretreated with a GSK-33 inhibitor demonstrated that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long- term neuroadaptations produced by repeated cocaine (Cocaine-induced hyperactivity and sensitization are dependent on GSK3, Miller JS et al. Neuropharmacology. 2009 Jun; 56(8):1 1 16-23, Epub 2009 Mar 27).

The role of GSK-33 in the development of several forms of epilepsies has been demonstrated in several studies, which suggest that inhibition of GSK-33 could be a pathway for the treatment of epilepsy (Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy, Lohi H et al., Hum Mol Genet. 2005 Sep 15;14(18):2727-36 and Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease, Purl R et al., J Biol Chem. 2009 Aug 21 ;284(34) 22657-63). The relationship between GSK-33 inhibition and treatment of neuropathic pain has been demonstrated in Mazzardo-Martins L. et al., “Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action”, Neuroscience. 2012 Dec 13;226, and Xiaoping Gu et al., “The Role of Akt/GSK33 Signaling Pathway in Neuropathic Pain in Mice”, Poster A525, Anesthesiology 2012 October 13-17, 2012 Washington.

A review on GSK-33, its function, its therapeutic potential and its possible inhibitors is given in “GSK-33: role in therapeutic landscape and development of modulators” (S. Phukan et al., British Journal of Pharmacology (2010), 160, 1- 19).

WO 2004/014864 discloses 1 H-indazole-3-carboxamide compounds as selective cyclin-dependant kinases (CDK) inhibitors. Such compounds are assumed to be useful in the treatment of cancer, through a mechanism mediated by CDK2, and neurodegenerative diseases, in particular Alzheimer’s disease, through a mechanism mediated by CDK5, and as anti-viral and anti-fungine, through a mechanism mediated by CDK7, CDK8 and CDK9.

Cyclin-dependant kinases (CDKs) are serine/threonine kinases, first discovered for their role in regulating the cell cycle. CDKs are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. Such kinases activate only after their interaction and binding with regulatory subunits, namely cyclins.

Moreover, 1 H-indazole-3-carboxamide compounds were also described as analgesics in the treatment of chronic and neuropathic pain (see, for example, WO 2004/074275 and WO 2004/101 548) and as 5-HT4 receptor antagonists, useful in the treatment of gastrointestinal disorders, central nervous system disorders and cardiovascular disorders (see, for example, WO 1994/101 74).

Patent

WO 2013124158

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.

SEE ENTRY 8

Figure imgf000020_0001

DMSO-de; δ 13.09 (s, 1 H), 8.23-8.42 (m, 2H), 7.72 (dd, J=0.82, 8.69 Hz, 1 H), 7.55 (td, J=1.76, 8.74 Hz, 1 H), 7.24-7.49 (m, 3H), 3.40 (t, J=6.04 Hz, 2H), 3.22 (s, 3H), 3.18 (d, J=6.40 Hz, 2H), 2.84 (d, J=11.53 Hz, 2H), 2.42 (t, J=5.95 Hz, 2H), 1.82- 2.02 (m, 2H), 1.41 -1.71 (m, 3H), 1.06-1.31 (m, 2H)

PAPER

Abstract Image

 

Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01208

Angelini S.p.A., Angelini Research Center, P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy
Drug Discovery and Development Department, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.5b01208
Publication Date (Web): October 20, 2015
*(G.F.) Phone: +390691045265. E-mail: g.furlotti@angelini.it..,
*(A.G.) Phone: +3901071781571. E-mail: Angelo.Reggiani@iit.it.

Angelo Reggiani

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01208

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.

Angelini S.p.A., Angelini Research Center,

 

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