OSILODROSTAT for Treatment of Cushing’s Syndrome

Phase 3 drug Comments Off

Jul 122016

ChemSpider 2D Image | osilodrostat | C13H10FN3

OSILODROSTAT

LCI 699, LCI 699NX

Novartis Ag INNOVATOR

UNII-5YL4IQ1078, CAS 928134-65-0

Benzonitrile, 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluoro-

4-[(5R)-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile

(R)-4-(6,7-Dihydro-5H-pyrrolo[l,2-c]imidazol-5-yl)-3-fluoro- benzonitrile

CYP11B1 CYP11B2

Molecular FormulaC₁₃H₁₀FN₃
Average mass227.237 Da

Originator Novartis
Class Antihypertensives; Fluorobenzenes; Imidazoles; Nitriles; Pyridines; Small molecules
Mechanism of Action Aldosterone synthase inhibitors

Phase III Cushing syndrome
Phase I Liver disorders
Discontinued Heart failure; Hypertension; Solid tumours

Most Recent Events

27 Feb 2016 Novartis plans the phase III LINC-4 trial for Cushing’s syndrome in Greece, Thailand, Poland, Turkey, Russia, Brazil, Belgium, Spain, Denmark, Switzerland and USA (PO) (NCT02697734)
12 Jun 2015 Novartis plans a phase II trial for Cushing syndrome in Japan (NCT02468193)
01 Apr 2015 Phase-I clinical trials in Liver disorders in USA (PO)

Osilodrostat phosphate
CAS: 1315449-72-9

MF, C13-H10-F-N3.H3-O4-P

MW, 325.2347

LCI 699AZA

An orally active aldosterone-synthase inhibitor.

for Treatment of Cushing’s Syndrome

4-((5R)-6,7-Dihydro-5H-pyrrolo(1,2-c)imidazol-5-yl)-3-fluorobenzonitrile dihydrogen phosphate

Aromatase inhibitor; Cytochrome P450 11B1 inhibitor

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

SYNTHESIS

ACS Medicinal Chemistry Letters, 4(12), 1203-1207; 2013

REMIND ME, amcrasto@gmail.com, +919323115463

Osilodrostat, as modulators of 11-β-hydroxylase, useful for treating a disorder ameliorated 11-β-hydroxylase inhibition eg Cushing’s disease, hypertension, congestive heart failure, metabolic syndrome, liver diseases, cerebrovascular diseases, migraine headaches, osteoporosis or prostate cancer.

Novartis is developing osilodrostat, an inhibitor of aldosterone synthase and aromatase, for treating Cushing’s disease. In July 2016, osilodrostat was reported to be in phase 3 clinical development.

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3mg/kg/day, subcutaneously), osilodrostat (20mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03mg/kg/day; mid-dose, 5/0.1mg/kg/day; or high dose, 20/0.3mg/kg/day), or vehicle for 13weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0-24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. C_max and AUC_0–24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner.

In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.

The somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin- 14 and analogues having somatostatin related activity, e.g. as disclosed by A.S. Dutta in Small Peptides, Vol.19, Elsevier (1993). By “somatostatin analogue” as used herein is meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin- 14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of the native somatostatin- 14 which exhibit a somatostatin related activity, e.g. they bind to at least one of the five somatostatin receptor (SSTR), preferably in the nMolar range. Commonly known somatostatin analogs are octreotide, vapreotide, lanreotide, pasireotide.

Pasireotide, having the chemical structure as follow:

Pasireotide is called cyclo[{4-(NH₂-C₂H₄-NH-CO-0-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)- Phe], wherein Phg means -HN-CH(C₆H5)-CO- and Bzl means benzyl, in free form, in salt or complex form or in protected form.

Cushing’s syndrome is a hormone disorder caused by high levels of Cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce Cortisol or adrenocorticotropic hormone (ACTH) or CRH. Cushing’s disease refers to one specific cause of the syndrome: a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which elevates Cortisol. It is the most common cause of Cushing’s syndrome, responsible for 70% of cases excluding glucocorticoid related cases. The significant decrease of Cortisol levels in Cushing’s disease patients on pasireotide support its potential use as a targeted treatment for Cushing’s disease (Colao et al. N Engl J Med 2012;366:32^12).

Compound A is potent inhibitor of the rate-limiting enzyme 1 1-beta-hydroxylase, the last step in the synthesis of Cortisol. WO 201 1/088188 suggests the potential use of compound A in treating a disease or disorder characterised by increased stress hormone levels and/or decreased androgen hormone levels, including the potential use of compound A in treating heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, Cushing’s syndrome or metabolic syndrome.

Compound A, also called (R)-4-(6,7-Dihydro-5H-pyrrolo[l,2-c]imidazol-5-yl)-3-fluoro- benzonitrile, has formula (II).

Compound A can be synthesized or produced and characterized by methods as described in WO2007/024945.

PRODUCT PATENT

WO2007024945, hold protection in the EU states until August 2026, and expire in the US in March 2029 with US154 extension

PAPER

ACS Medicinal Chemistry Letters (2013), 4(12), 1203-1207.

http://pubs.acs.org/doi/abs/10.1021/ml400324c?source=chemport&journalCode=amclct

Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors

Erik L. Meredith*†, Gary Ksander†, Lauren G. Monovich†, Julien P. N. Papillon†, Qian Liu†, Karl Miranda†, Patrick Morris†, Chang Rao†, Robin Burgis†, Michael Capparelli†, Qi-Ying Hu†, Alok Singh†, Dean F. Rigel‡, Arco Y. Jeng‡, Michael Beil‡, Fumin Fu‡, Chii-Whei Hu‡, and Daniel LaSala‡

^† Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, United States

^‡ Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States

ACS Med. Chem. Lett., 2013, 4 (12), pp 1203–1207

DOI: 10.1021/ml400324c

*(E.L.M.) Tel: 617-871-7586. Fax: 617-871-7045. E-mail: erik.meredith@novartis.com.

Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure–activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing’s syndrome.

PATENT

WO-2016109361

silodrostat (LCI699; 4-[(5R)-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-5-yl]-3-fluoro-benzonitrile; CAS# 928134-65-0). Osilodrostat is a Ι Ι-β-hydroxylase inhibitor.

Osilodrostat is currently under investigation for the treatment of Cushing’s disease, primary aldosteronism, and hypertension. Osilodrostat has also shown promise in treating drug-resistant hypertension, essential hypertension, hypokalemia, hypertension, congestive heart failure, acute heart failure, heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, Cushing’s syndrome, metabolic syndrome, hypercortisolemia, atrial fibrillation, renal failure, chronic renal failure, restenosis, sleep apnea, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heary disease, increased formation of collagen, cardiac or myocardiac fibrosis and/or remodeling following hypertension and endothelial dysfunction, Conn’s disease, cardiovascular diseases, renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, arrythmia, diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertrophic cardiomyopathy, sudden cardia death, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ej ection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, fibrinoid, necrosis of coronary arteries, ectopic ACTH syndrome, change in adrenocortical mass, primary pigmented nodular adrenocortical disease (PPNAD), Carney complex (CNC), anorexia nervosa, chronic alcoholic poisoning, nicotine withdrawal syndrome, cocaine withdrawal syndrome, posttraumatic stress syndrome, cognitive impairment after a stroke or cortisol-induced mineral corticoid excess, ventricular arrythmia, estrogen-dependent disorders, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycyctic ovarian disease, infertility, fibrocystic breast disease, breast cancer, and fibrocystic mastopathy. WO 2013109514; WO 2007024945; and WO 2011064376.

Osilodrostat

Osilodrostat is likely subject to extensive CYP45o-mediated oxidative metabolism. These, as well as other metabolic transformations, occur in part through polymorphically-expressed enzymes, exacerbating interpatient variability. Additionally, some metabolites of osilodrostat derivatives may have undesirable side effects. In order to overcome its short half-life, the drug likely must be taken several times per day, which increases the probability of patient incompliance and discontinuance. Adverse effects associated with osilodrostat include fatigue, nausea, diarrhea, headache, hypokalemia, muscle spasms, vomiting, abdominal discomfort, abdominal pain, arthralgia, arthropod bite, dizziness, increased lipase, and pruritis.

Scheme I

EXAMPLE 1

(R)-4-(6,7-dihvdro-5H-pyrrolo[l,2-elimidazol-5-yl)-3-fluorobenzonitrile

(osilodrostat)

[00144] 4-(bromomethyl)-3-fluorobenzonitrile: 3-Fluoro-4-methylbenzonitrile (40 g, 296 mmol), NBS (63.2 g, 356 mmol) and benzoyl peroxide (3.6 g, 14.8 mmol) were taken up in carbon tetrachloride (490 mL) and refiuxed for 16 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated and purified via flash column chromatography (0-5% EtOAc/hexanes) to give 4-(bromomethyl)-3-fluorobenzonitrile (35.4 g, 56%).

[00145] 2-(l-trityl-lH-imidazol-4-yl)acetic acid: Trityl chloride (40 g, 143.88 mmol, 1.2 equiv) was added to a suspension of (lH-imidazol-4-yl) acetic acid hydrochloride (20 g, 123.02 mmol, 1.0 equiv) in pyridine (200 mL). This was stirred at 50 °C for 16 h. Then the mixture was cooled and concentrated under vacuum and the crude product was purified by recrystallization from ethyl acetate (1000 ml) to afford 42 g (90%) of 2-[l-(triphenylmethyl)-lH-imidazol-4-yl] acetic acid as an off-white solid. LCMS (ESI): m/z = 369.2 [M+H]⁺

Step 2

2 step 2

2-( 1 -trityl- lH-imidazol-4-yl)ethanol : 2-(l-Trityl-lH-imidazol-4-yl) acetic acid (42 g, 114.00 mmol, 1.0 equiv) was suspended in THF (420 mL) and cooled to 0 °C. To this was added BH3 (1M in THF, 228.28 mL, 2.0 equiv). The clear solution obtained was stirred at 0 °C for 60 min, then warmed to room temperature until LCMS indicated completion of the reaction. The solution was cooled again to 0 °C and quenched carefully with water (300 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried over anhydrous Na2S04 and evaporated to give a sticky residue which was taken up in ethanolamine (800 mL) and heated to 90 °C for 2 h. The reaction was transferred to a separatory funnel, diluted with EtOAc (1 L) and washed with water (3 x 600 mL). The organic phase was dried over anhydrous Na2S04 and evaporated afford 35 g (87%) of 2-[l-(triphenylmethyl)-lH-imidazol-4-yl]ethanol as a white solid, which was used in the next step without further purification. LCMS (ESI) : m/z = 355.1 [M+H]⁺.

Step 3

3 step 3 4

4-(2-(tert-butyldimethylsilyloxy)ethyl)-l-trityl-lH-imidazole: 2-(l-Trityl-lH-imidazol-4-yl) ethanol (35 g, 98.75 mmol, 1.00 equiv) was dissolved in DCM (210 mL). To this was added imidazole (19.95 g, 293.05 mmol, 3.00 equiv) and tert-butyldimethylsilylchloride (22.40 g, 149.27 mmol, 1.50 equiv). The mixture was stirred at room temperature until LCMS indicated completion of the reaction. Then the resulting solution was diluted with 500 mL of DCM. The resulting mixture was washed with water (3 x 300 mL). The residue was purified by a silica gel column, eluted with ethyl

acetate/petroleum ether (1 :4) to afford 40 g (77%) of 4-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-l-(triphenylmethyl)-lH-imidazole as a white solid. LCMS (ESI) : m/z = 469.1 [M+H]⁺.

Step 4

4-((5-(2-(tert-butyldimethylsilyloxy )ethylVlH-iniidazol-l -vnmethylV3-fluorobenzonitrile: 4-(2-((tert-Butyldimethylsilanyl)oxy)ethyl)-l rityl-lH-irnidazole (40 g, 85.34 mmol, 1.00 equiv) and 4-(Bromomethyl)-3-fluorobenzonitrile (27.38 g, 127.92 mmol, 1.50 equiv) obtained as a product of step 0, were dissolved in MeCN (480 mL) and DCM (80 mL), and stirred at room temperature for 48 h. Et₂NH (80 mL) and MeOH (480 mL) were then added and the solution was warmed 80 °C for 3 h. The solution was evaporated to dryness and the residue was purified via flash column chromatography (EtOAc/hexanes 1 :5 to EtOAc) to afford 4-((5-(2-((tert-Butyldimethylsilanyl)oxy)ethyl)-lH-imidazol-l -yl)methyl)-3-fluorobenzonitrile (15 g, 50%). ¾ NMR (400 MHz, CDCh) δ: 7.67 (s, 1H), 7.43 (m, 2H), 6.98 (s, 1H), 6.88-6.79 (m, 1H), 5.34 (s, 2H), 3.79 (t, J= 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 0.88 (s, 9H), 0.02 (s, 6H). LCMS (ESI) : m/z = 360.1 [M+H]⁺.

Step 5

5 6

Methyl 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-lH-imidazol-l -yl)-2-(4-cvano-2-fluorophenvDacetate: 4-((5-(2-((tert-Butyldimethylsilanyl)oxy)ethyl)-lH-imidazol-l -yl)methyl)-3-fluorobenzonitrile (15 g, 41.72 mmol, 1.00 equiv) was dissolved in anhydrous THF (150 mL) and stirred at -78 °C, then a THF solution of LiHMDS (75 mL, 1.80 equiv, 1.0 M) was added dropwise over 15 min. After 30 min, methyl cyanoformate (4.3 g, 45.50 mmol, 1.10 equiv) was added dropwise over 10 min and the solution was stirred at -78 °C for 2 h. The excess LiHMDS was quenched with aqueous saturated NH4CI and the mixture was allowed to warm to room temperature. The mixture was then diluted with EtOAc and washed

with aqueous saturated NH4CI (200 mL). The organic layers was dried over anhydrous Na2S04 and evaporated. The crude residue was purified via flash column chromatography (EtOAc/PE 3: 10 to EtOAc) to give methyl 2-(5-(2-((tert-butyldimethylsilanyl)oxy)ethyl)-lH-imidazol-l-yl)-2-(4-cyano-2-fluorophenyl) acetate (15 g, 86%) as a light yellow solid.

¾ NMR (400 MHz, CDCL3) δ: 7.66 (s, 1H), 7.54-7.43 (m, 2H), 7.15 (t, J= 8.0 Hz 1H), 6.93 (s, 1H), 6.47 (s, 1H), 3.88-3.74 (m, 5H), 2.81-2.62 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H) . LCMS (ESI) : m/z = 418.2 [M+H]⁺.

Step 6

Methyl 2-(4-cvano-2-fluorophenyl)-2-(5-(2-hvdroxyethyl)-lH-imidazol-l-yl) acetate: Methyl 2-(5-(2-((tert-butyldimethylsilanyl)oxy)ethyl)-lH-imidazol-l-yl)-2-(4-cyano-2-fiuorophenyl)acetate (15 g, 35.92 mmol, 1.00 equiv) was added to a solution of HCl in 1,4-dioxane (89 mL, 4.0 M, 359.2 mmol) at 0 °C and the mixture was allowed to warm to room temperature and stirred for 2 h. The solution was concentrated to dryness to give the crude alcohol, methyl 2-(4-cyano-2-fluorophenyl )-2-(5-(2 -hydroxy ethyl)-lH-imidazol-l-yl)acetate (10 g, 92%), which was used without further purification. LCMS: m/z = 304.0 [M+H]⁺.

Step 7

7 8

Methyl 2-(4-cvano-2-fluorophenyl)-2-(5-(2-(methylsulfonyloxy)ethyl)-lH-imidazol-l-yl) acetate: The crude methyl 2-(4-cyano-2-fluorophenyl )-2-(5-(2-hydroxyethyl)-lH-imidazol-l-yl)acetate (10 g, 32.97 mmol, 1.00 equiv) was dissolved in DCM (200 mL) and stirred at 0 °C, then Et₃N (20 g, 197.65 mmol, 6.00 equiv) and

methanesulfonyl chloride (4.52 g, 39.67 mmol, 1.20 equiv) were added. After completion of the reaction, the solution was diluted with DCM and washed with aqueous saturated

NaHCC . The organic layer was dried over anhydrous Na2S04, filtered and evaporated to give the crude methyl 2-(4-cyano-2-fluorophenyl)-2-(5-(2-((methylsulfonyl)oxy)ethyl)-lH-imidazol-l-yl)acetate (11.43 g, 91%), which was used in the next step without further purification. LCMS (ESI) : m/z = 382.0 [M+H]⁺.

Step 8

Methyl 5-(4-cvano-2-fluorophenyl)-6.7-dihvdro-5H-pyrrolo[1.2-elimidazole-5-carboxylate: The crude methyl 2-(4-cyano-2 -fluorophenyl )-2-(5-(2- ((methylsulfonyl)oxy)ethyl)-lH-imidazol-l-yl)acetate (11.43 g, 29.97 mmol, 1.00 equiv) was dissolved in MeCN (550 mL) and then K2CO3 (12.44 g, 90.01 mmol, 3.00 equiv), Nal (13.50 g, 90.00 mmol, 3.00 equiv) and Et₃N (9.09 g, 89.83 mmol, 3.00 equiv) were added. The reaction was stirred at 80 °C for 42 h. The mixture was filtered. The solids were washed with DCM. The filtrate was concentrated and purified by flash column chromatography (EtOAc) to give methyl 5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-5-carboxylate (4.2 g, 49% in 3 steps).

[00153] ¾ NMR (400 MHz, CDCb) δ: 7.61 (s, 1H), 7.47-7.47 (m, 2H), 6.88 (s, 1H), 6.79-6.75 (m, 1H), 4.17-4.12 (m, 1H), 3.87 (s, 3H), 3.78-3.70 (m, 1H), 3.08-3.02 (m, 1H), 2.84-2.71 (m, 2H). LCMS (ESI) : m/z = 286.0 [M+H]⁺.

Step 9

4-(6.7-dihvdro-5H-pyrrolo[1.2-elimidazol-5-yl)-3-fluorobenzonitrile: To a 40-mL sealed tube, was placed methyl 5-(4-cyano-2-fluorophenyl)-5H,6H,7H-pyrrolo[l,2-c]imidazole-5-carboxylate (1 g, 3.51 mmol, 1.00 equiv), DMSO (10 mL), water (5 mL). The final reaction mixture was irradiated with microwave radiation for 40 min at 140 °C. The resulting solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with (3 x 20 mL) brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (4: 1) to afford 420 mg (44%) of 5-(4-cyano-2-fluorophenyl)-5H,6H,7H-pyrrolo[l,2-c]irnidazole-5-carboxylic acid as a light yellow solid.

¾ NMR (400 MHz, CDCL₃) δ: 7.55-7.28 (m, 3H), 6.90-6.85 (m, 2H), 5.74-5.71 (m, 1H), 3.25-3.15 (m, 1H), 3.02-2.92 (m, 2H), 2.58-2.50 (m, 1H). LCMS (ESI) : m/z = 228.2 [M+H]⁺.

Step 10

(R)-4-(6 -dihvdro-5H-pyrrolo[1.2-elirnidazol-5-yl)-3-fluorobenzonitrile:

Resolution of the enantiomers of the title compound (300 mg) was performed by chiral HPLC: Column, Chiralpak IA2, 2*25cm, 20um; mobile phase, Phase A: Hex (50%, 0.1% DEA), Phase B: EtOH (50%) ; Detector, UV 254/220 nm to afford the (S)-enantiomer (RT = 17 min) and the (R)-enantiomer (97.6 mg, desired compound) (RT = 21 min).

¾ NMR (400 MHz, DMSO-<4) δ: 7.98-7.95 (m, 1H), 7.70-7.69 (m, 1H), 7.50 (s, 1H), 6.87 (t, J= 8.0 Hz, 1H), 6.70 (s, 1H), 5.79-5.76 (m, 1H), 3.15-3.06 (m, 1H), 2.92-2.74 (m, 2H), 2.48-2.43 (m, 1H). LCMS (ESI) : m/z = 228.1 [M+H]⁺.

PATENT

WO2013/153129

https://www.google.com/patents/WO2013153129A1?cl=en

PATENT

WO2007/024945

http://www.google.co.in/patents/WO2007024945A1?cl=en

PATENT

EP 2815749

Aspect (iii) of the present invention relates to phosphate salt or nitrate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile according to Formula (III)

abbreviated as ‘{drug3}’. In particular, the present invention relates to crystalline form of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3a}’; to crystalline Form A of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3b}’; to crystalline Form B of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3c}’; to crystalline Form C of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3d}’; to crystalline Form D of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3e}’; to crystalline Form E of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3f}’; to crystalline Form F of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3g}’; to crystalline Form G of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3h}’; to crystalline Form H of phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3i}’; and to crystalline form of nitrate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile, abbreviated as ‘{drug3j}’. {drug3a}, {drug3b}, {drug3c}, {drug3d}, {drug3e}, {drug3f}, {drug3g}, {drug3h}, {drug3i}, and {drug3j} are specific forms falling within the definition of {drug3}. Aspect (iii) of the invention is separate from aspects (i), (ii), (iv), (v), (vi), (vii), and (viii) of the invention. Thus, all embodiments of {drug3a}, {drug3b}, {drug3c}, {drug3d}, {drug3e}, {drug3f}, {drug3g}, {drug3h}, {drug3i}, and {drug3j}, respectively, are only related to {drug3}, but neither to {drug1}, nor to {drug2}, nor to {drug4}, nor to {drug5}, nor to {drug6}, nor to {drug7}, nor to {drug8}.

PAPER

Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats

^a Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA
^b Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA
^c Novartis Oncology Development, Basel, Switzerland

doi:10.1016/j.taap.2015.05.004, http://www.sciencedirect.com/science/article/pii/S0041008X15001684

CLIPS

WO2011088188A1 *	Jan 13, 2011	Jul 21, 2011	Novartis Ag	Use of an adrenal hormone-modifying agent

Reference
1	*	BOSCARO M ET AL: “Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial“, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 94, no. 1, January 2009 (2009-01), pages 115-122, XP002698507, ISSN: 0021-972X

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14: Li W, Luo S, Rebello S, Flarakos J, Tse FL. A semi-automated LC-MS/MS method for the determination of LCI699, a steroid 11β-hydroxylase inhibitor, in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jun 1;960:182-93. doi: 10.1016/j.jchromb.2014.04.012. Epub 2014 Apr 30. PubMed PMID: 24814004.

15: Trainer PJ. Next generation medical therapy for Cushing’s syndrome–can we measure a benefit? J Clin Endocrinol Metab. 2014 Apr;99(4):1157-60. doi: 10.1210/jc.2014-1054. PubMed PMID: 24702012.

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18: Schumacher CD, Steele RE, Brunner HR. Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy. J Hypertens. 2013 Oct;31(10):2085-93. doi: 10.1097/HJH.0b013e328363570c. PubMed PMID: 24107737; PubMed Central PMCID: PMC3771574.

19: Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013 Aug;9(8):459-69. doi: 10.1038/nrneph.2013.110. Epub 2013 Jun 18. Review. PubMed PMID: 23774812; PubMed Central PMCID: PMC3922409.

20: van der Pas R, de Herder WW, Hofland LJ, Feelders RA. Recent developments in drug therapy for Cushing’s disease. Drugs. 2013 Jun;73(9):907-18. doi: 10.1007/s40265-013-0067-6. Review. PubMed PMID: 23737437.

///////OSILODROSTAT, Novartis , osilodrostat, an inhibitor of aldosterone synthase and aromatase, treating Cushing’s disease, July 2016, phase 3 clinical development, LCI 699, 928134-65-0, 1315449-72-9, PHASE 3, LCI 699NX, LCI 699AZA, CYP11B1 CYP11B2

c1cc(c(cc1C#N)F)[C@H]2CCc3n2cnc3.OP(=O)(O)O

N#CC1=CC=C([C@H]2CCC3=CN=CN32)C(F)=C1

Supporting Info

Novartis, Torrent drug for diabetes, NVP-LBX192, LBX-192

Uncategorized Comments Off

Jun 192016

Figure US07750020-20100706-C00023

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

R(−) 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

R(−)17c BELOW

Inventors	Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,
Original Assignee	Novartis Ag

Inventors

Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,

Original Assignee

Novartis Ag

Molecular Formula:	C₂₆H₃₃N₅O₄S₂
Molecular Weight:	543.70132 g/mol

LBX192, also known as NVP-LBX192, is a Liver Targeted Glucokinase Activator. LBX192 activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.

SYNTHESIS BY WORLDDRUGTRACKER

54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM

Nathan Hale North (Hilton Third Floor)

Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA

Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen. We will describe our efforts to generate liver selective GK activators which culminated in the discovery of NVP-LBX192 (3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide). This compound activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice.

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Sulfonamide-Thiazolpyridine Derivatives, Glucokinase Activators, Treatment Of Type 2 Diabetes

2009 52 (19) 6142 – 6152
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Journal of Medicinal Chemistry
Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao JP, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang JS, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, Denny IS, Taslimi PM, Vash B, Caplan SL

2010 240th (August 22) Medi-198
Glucokinase activators with improved physicochemicalproperties and off target effects
American Chemical Society National Meeting and Exposition
Kirman LC, Schuster HF, Grondine MS et al

2010 240th (August 22) Medi-197
Investigation of functionally liver selective glucokinase activators
American Chemical Society National Meeting and Exposition
Schuster HF, Kirman LC, Bebernitz GC et al

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]⁺.

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: ¹H NMR (400 MHz, CDCl₃) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]⁺.

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]⁺.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]⁺.

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]⁺.

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

The title G compound, 3-cyclopentyl-2-(4-methyl piperazinyl sulfonyl)phenyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)propionamide (2.8 g, 0.0051 mol) is added to a cooled solution of 10% hydrochloric acid in isopropanol (3.75 mL). The reaction mixture is stirred at 0° C. for 1 h and then at RT for 2 h. The solid is separated, triturated with 10 mL of isopropanol and collected by vacuum filtration and washed with 50 mL of hexane. The solid is dried at 70° C. for 48 h to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride as an off white solid.

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Gregory R. Bebernitz*†, Valerie Beaulieu†, Bethany A. Dale†, Richard Deacon†, Alokesh Duttaroy†, Jiaping Gao†, Melissa S. Grondine†, Ramesh C. Gupta‡, Mesut Kakmak†, Michael Kavana†, Louise C. Kirman†, Jinsheng Liang†, Wieslawa M. Maniara†, Siralee Munshi‡, Sunil S. Nadkarni‡, Herbert F. Schuster†, Travis Stams†, Irene St. Denny†, Paul M. Taslimi†, Brian Vash† and Shari L. Caplan†

^† Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139

^‡ Torrent Research Centre, Village Bhat, Gujarat, India

J. Med. Chem., 2009, 52 (19), pp 6142–6152

DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αK_a = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2

Patent ID	Date	Patent Title
US2015218151	2015-08-06	NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020	2010-07-06	Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

^† Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139

^‡ Torrent Research Centre, Village Bhat, Gujarat, India

J. Med. Chem., 2009, 52 (19), pp 6142–6152

DOI: 10.1021/jm900839k

Publication Date (Web): September 11, 2009

*To whom correspondence should be addressed. Phone: (617) 871 7302. Fax: (617) 871 7042. E-mail: greg.bebernitz@novartis.com.

http://pubs.acs.org/doi/abs/10.1021/jm900839k

https://www.google.com/patents/US7750020

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

Patent ID	Date	Patent Title
US2015218151	2015-08-06	NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020	2010-07-06	Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

Torrent Research Centre, Village Bhat, Gujarat, India

Mr. Samir Mehta, 52, is the Vice Chairman of the USD 2.75 billion Torrent Group and Chairman of Torrent Pharma

Mr. Sudhir Mehta - Executive Chairman

Shri Sudhir Mehta – Chairman Emeritus ::

Dr. Chaitanya Dutt – Director (Research & Development) ::

Born in the year 1950, Dr. Chaitanya Dutt holds an MD in Medicine. He practiced as a consulting physician before joining the company in 1982. Since then he has been associated with the Company. His rich experience spans in the areas of Pharma R&D, clinical research, manufacturing, quality assurance, etc. He is one of the key professionals in the top management team of the Company. He has been instrumental in setting up the Torrent Research Centre (TRC), the research wing of the Company. Under his prudent guidance and leadership, TRC has achieved tremendous progress in the areas of discovery research as well as development work on formulations. He does not hold any directorship in any other company.

///NOVARTIS, DIABETES, Sulfonamide-Thiazolpyridine Derivatives, Glucokinase Activators, Treatment Of Type 2 Diabetes, 866772-52-3, Novartis Molecule, functionally liver selective glucokinase activators, treatment of type 2 diabetes , NVP-LBX192, LBX-192

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

Supporting Info

Novartis Molecule for functionally liver selective glucokinase activators for the treatment of type 2 diabetes

Uncategorized Comments Off

Apr 052016

Figure US07750020-20100706-C00023

2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM

Nathan Hale North (Hilton Third Floor)

Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Molecular Formula:	C₂₆H₃₃N₅O₄S₂
Molecular Weight:	543.70132 g/mol

Sulfonamide-Thiazolpyridine Derivatives, Glucokinase Activators, Treatment Of Type 2 Diabetes

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

^† Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139

^‡ Torrent Research Centre, Village Bhat, Gujarat, India

J. Med. Chem., 2009, 52 (19), pp 6142–6152

DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2

Patent ID	Date	Patent Title
US2015218151	2015-08-06	NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020	2010-07-06	Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

CFG 920, Novartis Scientists team up with Researchers at Aurigene, Bangalore, India,

phase 2, Uncategorized Comments Off

Apr 052016

CFG920,

Inhibitor Of Prostate Cancer With Fewer Cardiac Side Effects

Cas 1260006-20-9

Novartis
Target: CYP17/CYP11B2
Disease: Castration-resistant prostate cancer

MF C14H13ClN4O
MW: 288.0778

Elemental Analysis: C, 58.24; H, 4.54; Cl, 12.28; N, 19.40; O, 5.54

Steroid 17-alpha-hydroxylase inhibitors

CFG920 is a CYP17 inhibitor, is also an orally available inhibitor of the steroid 17-alpha-hydroxylase/C17,20 lyase (CYP17A1 or CYP17), with potential antiandrogen and antineoplastic activities. Upon oral administration, CYP17 inhibitor CFG920 inhibits the enzymatic activity of CYP17A1 in both the testes and adrenal glands, thereby inhibiting androgen production. This may decrease androgen-dependent growth signaling and may inhibit cell proliferation of androgen-dependent tumor cells.

https://clinicaltrials.gov/ct2/show/NCT01647789
NCT01647789: A Study of Oral CFG920 in Patients With Castration Resistant Prostate Cancer2012

09 Nov 2015Adverse events, efficacy and pharmacokinetics data from the phase I part of a phase I/II trial in Prostate cancer (Metastatic disease) presented at the 27th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2015)
29 Jan 2013Phase-I clinical trials in Prostate cancer in Spain (PO)
10 Dec 2012Phase-I clinical trials in Prostate cancer in Canada (PO)

In August 2015, preclinical data were presented at the 250th ACS meeting in Boston, MA. In monkeys, treatment with CFG-920 (3 mg/kg, po) showed good bioavailability with F value of 93%, Tmax of 0.5 h, Cmax of 1382 nM.dn and AUC of 2364 nM.h, while CFG-920 (10 mg/kg, po) showed F value of 183%, Cmax of 1179 nM.dn and Tmax of 1.04 h

Bethany Halford on Twitter: “CFG920 – @Novartis CMOS for …

twitter.com

Bethany Halford on Twitter: “CFG920 – @Novartis CMOS for castration resistant prostate cancer #ACSBoston MEDI 1st disclosures http://t.co/XJJ3tCvpUk”

Novartis is developing CFG-920 (structure shown), an oral CYP17 inhibitor, for the potential treatment of metastatic castration-resistant prostate cancer. In March 2013, a phase I/II trial was initiated and at that time, the study was expected to complete in January 2015; in August 2015, clinical data were presented

2015 250th (August 19) Abs MEDI 341
Discovery of CFG920, a dual CYP17/CYP11B2 inhibitor, for the treatment of castration resistant prostate cancer
American Chemical Society National Meeting and Exposition
Christoph Gaul, Prakash Mistry, Henrik Moebitz, Mark Perrone, Bjoern Gruenenfelder, Nelson Guerreiro, Wolfgang Hackl, Peter Wessels, Estelle Berger, Mark Bock, Saumitra Sengupta, Venkateshwar Rao, Murali Ramachandra, Thomas Antony, Kishore Narayanan, Samiulla Dodheri, Aravind Basavaraju, Shekar Chelur

09338-scitech1-NovartisAcxd

CHEMISTRY COLLABORATORS

Novartis-Aurigene team: (from left) Brahma Reddy V, Thomas Antony, Murali Ramachandra, Venkateshwar Rao G, Wesley Roy Balasubramanian, Kishore Narayanan, Samiulla DS, Aravind AB, and Shekar Chelur. Not pictured: Björn Grünenfelder, Saumitra Sengupta, Nelson Guerreiro, Andrea Gerken, Mark Perrone, Mark Bock, Wolfgang Hackl, Henrik Möbitz, Peter Wessels, Christoph Gaul, Prakash Mistry, and Estelle Marrer.

Credit: Aurigene

Aurigene Discovery Technologies Limited, an independent subsidiary of Dr Reddy’s, CSN Murthy is chief executive officer

Preclinical and clinical studies were performed to evaluate the efficacy of CFG-920, a dual cytochrome P450 (CYP)17 and CYP11B2 dual inhibitor, for the potential treatment of castration resistant prostate cancer. CFG-920 showed potent activity against human CYP17 and CYP11B2 enzymes with IC50 values of 0.023 and 0.034 microM, respectively. In monkeys, treatment with CFG-920 (3 mg/kg, po) showed good bioavailability (93%), Tmax of 0.5 h, Cmax of 1382 nM.dn and AUC of 2364 nM.h, while CFG-920 (10 mg/kg, po) showed F value of 183%, Cmax of 1179 nM.dn and Tmax of 1.04 h. In a phase I, first-in-man study, patients received continuous po dosing of CFG-920 (50 mg, bid) plus prednisone (5 mg) in 28-day cycles. At the time of presentation, CFG-920 was under phase II development.

CFG920

WO 2010149755

Novartis team: (clockwise from left) Wolfgang Hackl, Henrik Möbitz, Peter Wessels, Christoph Gaul, Prakash Mistry, and Estelle Marrer., Credit: Novartis

Prostate cancer is the most commonly occurring cancer in men. Doctors often treat the metastatic stage of the disease by depriving the patient of sex hormones via chemical or surgical castration. But if it progresses far enough, the cancer can survive this therapy, transforming into the castration-resistant form. “Once the cancer becomes castration-resistant, the prognosis is poor,” said Novartis’s Christoph Gaul.

In recent years, CYP17, a bifunctional 17α-hydroxylase/17,20-lyase cytochrome P450 enzyme, has emerged as a target for treating castration-resistant prostate cancer. The enzyme catalyzes the biosynthesis of sex hormones, including testosterone, and blocking it can starve prostate cancer of the androgens it needs to thrive.

Johnson & Johnson’s CYP17 inhibitor, abiraterone acetate (Zytiga), a steroid that binds irreversibly to CYP17, was approved by the Food & Drug Administration in 2011. But Novartis scientists thought they could make a better CYP17 inhibitor, Gaul told C&EN. They teamed up with researchers at Aurigene, in Bangalore, India, and came up with their clinical candidate, CFG920.

Unlike abiraterone, CFG920 isn’t a steroid, and it inhibits CYP17 reversibly. It also reversibly inhibits another cytochrome P450 enzyme, CYP11B2, which is involved in the synthesis of the mineralocorticoids, hormones that regulate cardiac function.

Treating prostate cancer patients by lowering their androgen levels turns out to have negative cardiac side effects: Patients’ lipid metabolism is thrown off and their mineralocorticoid levels jump, leading to increases in blood pressure. Those changes can be stressful for the heart. “If prostate cancer patients don’t die because of the cancer, a lot of times they die because of cardiac disease,” Gaul said.

Because CFG920 also keeps mineralocorticoid levels in check, Novartis is hoping the drug candidate will ameliorate some of the cardiac side effects of inhibiting CYP17. The compound is currently in Phase I clinical trials.

PATENT

WO 2010149755

https://www.google.co.in/patents/WO2010149755A1?cl=en

Example 58

Prύpιn”ation ofI'(2’ChIoroψ}ri(ibi-^’\l)’3’f4’metMψ}τUin’3’yl)-imiJazoliJin’2’θne (5HA)-

Using the same reaction conditions as in Example 14. 1-(4-methyl-pyridin-3-yl)- itnida/olidin-2-onc ().-.!.4b: 600 mg. 3.3898 mmol) uas reacted with 2-chloro-4-iodo- py.idine (974 mg.4.067 mmol). 1 , 4-dioxane (60 mL). copper iodide (65 mg, 0.3398 mmol), /r<w.v-1.2-diamino cycK)hexane (0.12 ml,, 1.0169 mmol) and potassium phosphate (2.15 g, 10.1694 mmol) to afford 810 mg of the product (83% yield).

¹H NMR (C¹DCI₃. 300 Mi l/): 6 8.5-8.4 (m. 211). 8.3 (d. IH), 7.6-7.5 (m, 2H). 7.2 (S. 111). 4.1-3.9 (ni. 4H), 2.35 <s. 3H)

LCVIS puιϊt>: 90.8%. nι-7 – 289.1 (M M)

HPl C: 97.14%

REFERENCES

1: Gomez L, Kovac JR, Lamb DJ. CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids. 2015 Mar;95:80-7. doi: 10.1016/j.steroids.2014.12.021. Epub 2015 Jan 3. Review. PubMed PMID: 25560485; PubMed Central PMCID: PMC4323677.

2: Yin L, Hu Q, Hartmann RW. Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013 Jul 4;14(7):13958-78. doi: 10.3390/ijms140713958. Review. PubMed PMID: 23880851; PubMed Central PMCID: PMC3742227.

///////CFG-920, CYP17 inhibitor (prostate cancer), Novartis, CFG 920, Novartis scientists, team up , researchers , Aurigene, Bangalore, India,

Sonidegib/Erismodegib..Novartis Cancer Drug LDE225 Meets Primary Endpoint in Phase 2

Phase 3 drug Comments Off

Feb 202014

Sonidegib/Erismodegib

CODE DESIGNATION ..LDE225, NVP-LDE-225

Treatment of medulloblastoma PHASE3 2014 FDA FILING

Treatment of advanced basal cell carcinoma PHASE3 2014 FDA FILING

Treatment of SOLID TUMORS..PHASE1 2017 FDA FILING

READMalignant Solid Tumors of Childhood

THERAPEUTIC CLAIM Oncology, Antineoplastics & Adjunctive Therapies

CHEMICAL NAMES

1. [1,1′-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-
methyl-4′-(trifluoromethoxy)-, rel-

2. N-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl}-2-methyl-4′-
(trifluoromethoxy)biphenyl-3-carboxamide

N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide

N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide

MOLECULAR FORMULA C26H26F3N3O3

MOLECULAR WEIGHT 485.5

SPONSOR Novartis Pharma AG

CAS REGISTRY NUMBER 956697-53-3 free form

NOTE… DIPHOSPHATE SALT IS THE DRUG WITH CAS 1218778-77-8

sonidegib – European Medicines Agency READ THIS..

Summary EudraCT Number: 2012-004022-21 Sponsor’s Protocol … READ THIS

Novartis announced that the pivotal trial of the investigational oral compound LDE225 (sonidegib) in advanced basal cell carcinoma met its primary endpoint of demonstrating an objective response rate among patients within six months of treatment. Objective response included complete response (clinically significant tumor response with complete absence of disease) and partial response (clinically significant tumor shrinkage).

Basal cell carcinoma is the most common form of skin cancer, accounting for more than 80% of non-melanoma skin cancers, and can be highly disfiguring and life-threatening if it grows. Worldwide incidence of basal cell carcinoma is rising by 10% each year due to factors such as an aging population and increased ultraviolet exposure. Although basal cell carcinoma rarely metastasizes, once it does, it can be associated with significant morbidity.

“For people living with advanced basal cell carcinoma there are currently limited treatment options,” said Alessandro Riva, president, Novartis Oncology ad interim and global head, Oncology Development and Medical Affairs. “These results demonstrate the potential for LDE225 to offer a treatment option for this patient population, and we look forward to sharing these data with regulatory authorities worldwide.”

Full study results will be presented at a future scientific meeting.

About the Study

The Phase II, randomized, double-blind BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study was designed to assess the safety and efficacy of two oral dose levels of LDE225 (200 mg and 800 mg) in patients with locally advanced or metastatic basal cell carcinoma[4], which are subtypes of advanced basal cell carcinoma.

The primary endpoint was the proportion of patients achieving an objective response rate, defined as a confirmed complete response and partial response as their best overall response per modified RECIST criteria, within six months of starting treatment with LDE225. Key secondary endpoints of the study included assessing the duration of tumor responseand the rate of complete response. Other secondary endpoints included progression-free survival, time to tumor response and overall surviva

Date: February 19, 2013

Source: Novartis

MORE ABOUT SONIDEGIB

Sonidegib (INN) or Erismodegib (USAN), also known as LDE225 is a Hedgehog signalling pathway inhibitor (via smoothened antagonism) being developed as an anticancer agent by Novartis.[1][2] It has been investigated as a potential treatment for:

Pancreatic cancer [3][4][5][6]
Breast cancer [7][8]
Basal cell carcinoma of the skin[9][10][11]
Small cell lung cancer [12]
Medulloblastoma [13][14]
Advanced solid tumours (including ovarian, breast, pancreatic, stomach, oesophageal cancers and glioblastoma multiforme)[15][16][17]
Acute leukaemia [18]
Chronic myeloid leukaemia [19]
Myelofibrosis and Essential thrombocythaemia [20]

NVP-LDE-225, a product candidate developed by Novartis, is in phase III clinical trials for the treatment of medulloblastoma and basal cell carcinoma. Phase II trials are in progress for the treatment of adult patients with relapsed or refractory or untreated elderly patients with acute leukemia.

Early clinical trials are ongoing for the oral treatment of advanced solid tumors, for the treatment of myelofibrosis in combination with ruxolitinib and for the treatment of small cell lung cancer. A phase II clinical trial for the treatment of basal cell carcinomas in Gorlin’s syndrome patients with a cream formulation of NVP-LDE-225 was discontinued in 2011 since the formulation did not demonstrate tumor clearance rate sufficient to support further development.

Dana-Farber Cancer Institute and the Massachusetts General Hospital are conducting phase I clinical trials for the treatment of locally advanced or metastatic pancreatic cancer in combination with chemotherapy. In 2009, orphan drug designation was assigned in the E.U. for the treatment of Gorlin syndrome.

It has demonstrated significant efficacy against melanoma in vitro and in vivo.[21] It also demonstrated efficacy in a mouse model of pancreatic cancer.[22]

NVP-LDE225 Diphosphate salt (Erismodegib, Sonidegib)

Formula Image

Synonym:Erismodegib, Sonidegib

CAS Number:1218778-77-8

Mol. Formula:C26H26F3N3O3 ∙ 2H3PO4

MW:681.5
nmr.http://www.chemietek.com/Files/Line2/Chemietek,%20NVP-LDE225%20[02],%20NMR.pdf
hplc–http://www.chemietek.com/Files/Line3/Chemietek,%20NVP-LDE225%20[02],%20HPLC.pdf

Brief Description:

A potent, selective, and orally bioavailable Smoothened (Hedgehog Signaling Pathway) antagonist, currently in clinical trials. Diphosphate salt offers a much better bioavailability than free base (Ref. a)

a. Pan, S., et al, Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist, ACS Med. Chem. Lett., 2010, 1 (3), pp 130–134.

About LDE225

LDE225 (sonidegib) is an oral, investigational, selective smoothened inhibitor being studied in a variety of cancers. Smoothened (SMO) is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair. LDE225 is currently in clinical development for a variety of diseases including myelofibrosis, leukemia and solid tumors.

Given that LDE225 is an investigational compound, the safety and efficacy profile has not yet been fully established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. Given the uncertainty of clinical trials, there is no guarantee that LDE225 will ever be commercially available anywhere in the world.

Possibility (LDE225) is effective in medulloblastoma relapsed or refractory hedgehog pathway inhibitor sonidegib has been revealed. That the anti-tumor effect was observed in some patients and tolerability in 1/2 test phase.

4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, which was held in San Francisco November 21 to 24 in (WFNO-SNO2013), rice Dana-Farber It was announced by Mark Kieran Mr. Children’s Hospital Cancer Center.

The research group, announced the final results of the Phase 1 trial that target advanced solid cancer in children of sonidegib. 　1 dose increased multi-test phase, was initiated from 372mg/m2 once-daily dosing to target children under the age of 18 more than 12 months. (233mg/m2 group 11 people, 16 people 372mg/m2 group, 11 people group 425mg/m2, 680mg/m2 group 21 women) who participated 59 people, including medulloblastoma 38 patients. 12 median age was (2-17).

Creatine phosphokinase elevation of grade 4 only were seen at 372mg/m2 as dose-limiting toxicity only, and became two recommended dose phase and 680mg/m2. 　Nausea muscle pain creatine kinase rise malaise (22.0%) (15.3%) (15.3%), (13.6%), vomiting side effects were many, was (13.6%). Hypersensitivity vomiting creatine kinase increased (3.4%) (1.7%) (1.7%), rhabdomyolysis side effects of grade 3/4 was (1.7%). 　(One group 372mg/m2, 425mg/m2 group one) complete response was obtained in two people, a strong correlation was found between the activation of the hedgehog pathway and effect.

Phase III clinical trials that target medulloblastoma the activated hedgehog pathway currently are underway.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 136,000 full-time-equivalent associates and operate in more than 140 countries around the world.

Increased levels of Hedgehog signaling are sufficient to initiate cancer formation and are required for tumor survival.

These cancers include, but are not limited to, prostate cancer (“Hedgehog signalling in prostate regeneration, neoplasia and metastasis”, Karhadkar S S, Bova G S, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs J T, Berman D M, Beachy P A., Nature. 2004 Oct. 7; 431(7009):707-12;

“Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling”, Sanchez P, Hernandez A M, Stecca B, Kahler A J, DeGueme A M, Barrett A, Beyna M, Datta M W, Datta S, Ruiz i Altaba A., Proc Natl Acad Sci USA. 2004 Aug. 24; 101(34):12561-6),

breast cancer (“Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer”, Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M., Cancer Res. 2004 Sep. 1; 64(17):6071-4),

medulloblastoma (“Medulloblastoma growth inhibition by hedgehog pathway blockade”, Berman D M, Karhadkar S S, Hallahan A R, Pritchard J I, Eberhart C G, Watkins D N, Chen J K, Cooper M K, Taipale J, Olson J M, Beachy P A., Science. 2002 Aug. 30; 297(5586):1559-61),

basal cell carcinoma (“Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions”, Williams J A, Guicherit O M, Zaharian B I, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter J A, Rubin L L, Wang F Y., Proc Natl Acad Sci USA. 2003 Apr. 15; 100(8):4616-21;

“Activating Smoothened mutations in sporadic basal-cell carcinoma”, Xie J, Murone M, Luoh S M, Ryan A, Gu Q, Zhang C, Bonifas J M, Lam C W, Hynes M, Goddard A, Rosenthal A, Epstein E H Jr, de Sauvage F J., Nature. 1998 Jan. 1; 391(6662):90-2),

pancreatic cancer (“Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis”, Thayer S P, di Magliano M P, Heiser P W, Nielsen C M, Roberts D J, Lauwers G Y, Qi Y P, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw A L, Hebrok M., Nature. 2003 Oct. 23; 425(6960):851-6;

“Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours”, Berman D M, Karhadkar S S, Maitra A, Montes De Oca R, Gerstenblith M R, Briggs K, Parker A R, Shimada Y, Eshleman J R, Watkins D N, Beachy P A., Nature. 2003 Oct. 23; 425(6960):846-51),

and small-cell lung cancer (“Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer”, Watkins D N, Berman D M, Burkholder S G, Wang B, Beachy P A, Baylin S B., Nature. 2003 Mar. 20; 422(6929):313-7).

PATENTS

1 WO 2007131201

2 WO 2008154259

3 WO 2010033481

4 WO 2011009852

5 WO 2011062939

………………………………………

SYNTHESIS

WO2011009852A2

2-Methyl-4′-tr{fluoromethoxy-biphenyl-3-carboxylic acid {6-(cis-2,6-dimethyl- morpholin-4-yl)-pyrid»n-3-yl|-amide:

The following Examples serve to illustrate the invention without limiting the scope thereof, it is understood that the invention is not limited to the embodiments set forth herein, but embraces ali such forms thereof as come within the scope of the disclosure,

Step 1:

To a solution of 2-chloro-5-nitro-pyridine 1 (5.58 g, 35.2 mmoL) and c/s-2,6- dimethylmorpholine (4.05 g, 35.2 mmoL) in anhydrous DMF (30 mi.) was added K2CO3 (9.71 g, 70.4 mnrtoL). The mixture was heated at 50ºC overnight. After concentration, the residue is partitioned between EtOAc and water. The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to give crude product 3 as a yellow solid, after purification by silica gel chromatography, obtained pure product (7.80 g, 93.2%). LC-MS m/z: 238.2 (M+ 1).

Step 2:

The above material 3 (7.3Og. 30.8 mmoL) was hydrogenated in the presence of 10% Pd-C (1.0 g) in MeOH (120 ml) under hydrogen overnight. The suspension was filtered through celite and the filtrate was concentrated to give the crude product 4 (5.92 g) as a dark brown oil which was used directly in the next step without further purification. LC-MS m/z. 208.2 (M+1).

Step 3:

To a solution of 3-bromo-2-methyl benzoic acid (2.71 g, 12.6 mmoL), 6-((2S,6R)-2,6- dimethylmorpholino)pyridin-3-arnine 4 (2.61 g, 12.6 mmoL), and HATU (4.80 g, 12.6 mmoL) in anhydrous DMF (30 mL) was added diisopropylethylamine (6.58 mL, 37.8 mmoL) dropwise. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL), and then extracted with EtOAc (3×120 mL). The organic layer was dried and concentrated to give the crude product. This crude product was then purified by flash column chromatography using 30% EtOAc in hexane as eiuent to give 5 as a white solid (4.23 g, 83.0%). LC-MS m/z: 404.1 (M+1).

Step 4:

A mixture of 4-(trif!uoromethoxy)phenylboronic acid (254 mg, 1.24 mmol), 3-bromo- N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-ylJ-4-methyl-benzamide 5 (250 mg, 0.62mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), Na2CO3 (2.0M aqueous solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL) in a sealed tube was heated at 130ºC overnight. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative mass triggered HPLC (C18 column, etuted with CH3CN-H2O containing 0.05% TFA) to give N-(6-((2S,6R)-2,6-dimethyfmorpholino)pyridin-3-yl)-2-rnethyl- 4′-(trifluoromethoxy)biphenyi-3-carboxamide (183.5 mg, 61.1% yield). LC-MS m/z: 486.2 (M+1).

The resultant crystalline product (Form A) was converted to the amorphous form by dissolving in 3% w/w aqueous ethanol, and the resultant solution spray dried at about 150ºC.

Form B was prepared by heating the amorphous form in an oven at 110ºC for 2 hours. In a further embodiment, the invention relates to a process step or steps, or an intermediate as described herein.

……………………

PAPER

ChemMedChem, 2013 , vol. 8, 8 p. 1261 – 1265

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300217/full

http://onlinelibrary.wiley.com/store/10.1002/cmdc.201300217/asset/supinfo/cmdc_201300217_sm_miscellaneous_information.pdf?v=1&s=702e175bfb44b5a61c41e750695f7f7cd20be83d

Continued optimization provided a novel type of Smoothened (Smo) antagonist based on a pyridazine core. The compound, NVP-LEQ506, currently in phase I clinical trials, combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in rodent tumor models of medulloblastoma. Activity against a Smo mutant conferring resistance observed in a previous clinical trial with a competitor compound suggests additional therapeutic potential.

…………………………..

Links

SYNTHESIS

US20120196849, ENTRY…..95

LC-MS m/z 486.2 (M + 1)

USE SIMILAR METHODOLOGY

EXAMPLESThe present invention is further exemplified, but not limited, by the following example that illustrates the preparation of compounds of Formula I according to the invention.Example 1 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [4-(morpholine-4-sulfonyl)-phenyl]-amide

Step 1: To a solution of 3-iodo-4-methyl-benzoic acid (10.0 g, 38.2 mmol) in methanol (70 ml) is added concentrated sulfuric acid (0.5 ml). The reaction mixture is heated at 70° C. for 48 hours, cooled to room ambient temperature and then concentrated. After that, ethyl acetate (100 ml) and aqueous NaHCO3 (saturated, 100 ml) solution are added to the residue. The organic layer is separated and washed again with aqueous NaHCO3 (saturated, 100 ml) solution. The organic layer is separated, dried over anhydrous Na2SO4 and concentrated to yield 3-iodo-4-methyl-benzoic acid methyl ester 1. It is used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.87 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 3.85 (s, 3H), 3.35 (s, 3H); LC-MS m/z: 277.0 (M+1).

Step 2: To a round-bottom flask containing 3-iodo-4-methyl-benzoic acid methyl ester (1.38 g, 5.00 mmol), 4-cyanophenylboronic acid (1.10 g, 7.48 mmol), palladium acetate (168 mg, 0.748 mmol), 2-(dicyclohexylphosphino)biphenyl (0.526 g, 1.50 mmol) and potassium fluoride (0.870 g, 15.0 mmol) is added anhydrous 1,4-dioxane (15 ml). The flask is purged with argon and sealed. The mixture is stirred at 130° C. for 18 hours, cooled to ambient temperature and then water (20 ml) and ethyl acetate (20 ml) are added. Solid is removed under vacuum filtration. The filtrate is extracted with EtOAc (20 ml×2). The organic layers are combined, washed with aqueous HCl (5%, 20 ml) and saturated NaHCO3 (20 ml). It is dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography (EtOAc/Hexane, gradient) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2; LC-MS m/z: 252.1 (M+1).

Step 3: To a solution of 4′-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2 (2.56 g, 10.3 mmol) in 1,4-dioxane-H2O (1:1 mixture, 20 ml) is added NaOH (1.22 g, 30.2 mmol)). The reaction is stirred at ambient temperature for 24 hours. To this mixture is added aqueous HCl (1 N, 36 ml) and it is then extracted with ethyl acetate (40 ml×3). The organic layers are combined, dried over anhydrous Na2SO4. The solver is removed. The solid obtained is washed with small amount of acetonitrile and air dried to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid 3: 1H NMR (DMSO-d6) δ 7.94 (d, 2H, J=8.0 Hz), 7.84 (dd, 1H, J1=8.4 Hz, J2=1.2 Hz), 7.75 (d, 1H, J=1.2 Hz), 7.61 (d, 2H, J=8.0 Hz), 7.48 (d, 1H, J=8.4 Hz), 2.29 (s, 3 H); LC-MS m/z 238.1 (M+1).

Step 4: To a suspension of 4′-cyano-6-methyl-biphenyl-3-carboxylic acid 3 (40 mg, 0.17 mmol) in anhydrous methylene chloride (5 ml) is added 2 drops of DMF. Then oxalyl chloride (32 mg, 22 μl, 0.25 mmol) is added. The mixture is stirred at ambient temperature until it turns clear. After that, it is concentrated, re-dissolved in anhydrous methylene chloride (3 ml), and added to a solution of 4-(morpholine-4-sulfonyl)-phenylamine (61 mg, 0.25 mmol) and triethylamine (34 mg, 47 μl, 0.33 mmol) in methylene chloride (2 ml). The mixture is stirred for 2 hours, concentrated and the residue is purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [4-(morpholine-4-sulfonyl)-phenyl]-amide: 1H NMR (DMSO-d6) δ 10.64 (s, 1H), 8.07 (d, 2H, J=8.8 Hz), 7.97 (d, 2H, J=8.4 Hz), 7.95 (d, 1H, J=8.8 Hz), 7.89 (s, 1H), 7.43 (d, 2H, J=8.4 Hz), 7.67 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=8.8 Hz), 3.63 (m, 4H), 2.84 (m, 4H) 2.32 (s, 3H); LC-MS m/z: 462.1 (M+1).

Example 2 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide

Step 1: To a solution of 2-chloro-5-nitro-pyridine 4 (2.38 g, 15 mmol.) and cis-2,6-dimethylmorpholine (1.73 g, 15 mmol.) is added K2CO3 (4.14 g, 30 mmol.). The mixture was heated at 50° C. overnight. After concentration, the residue is partitioned between EtOAc and water. The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to give crude product 6 as a yellow solid. The crude product is used directly in next step without further purification. LC-MS m/z: 238.1 (M+1).

Step 2: The above crude material 6 is hydrogenated in the presence of Pd—C (0.2 g) in MeOH (100 mL) under hydrogen over 10 h. The suspension is filtered through celite and the filtrate is concentrated to give the crude product 7 as a dark brown oil which is used directly in the next step without further purification. LC-MS m/z: 208.1 (M+1).

Step 3: To a solution of 3-bromo-4-methyl benzoic acid (108 mg, 0.5 mmol.), 6-(2,6-Dimethyl-morpholin-4-yl)-pyridin-3-ylamine 7 (104 mg, 0.5 mmol.), amd HATU (190 mg, 0.5 mmol.) in dry DMF (5 mL) is added triethylamine (139 uL, 1.0 mmol.) dropwise. The resulting mixture is stirred at room temperature for 2 h. After concentration, the residue is partitioned between EtOAc and water. The organic layer is dried and concentrated to give the crude product. The final compound is purified by flash column chromatography using 50% EtOAc in hexane as eluent to give 8 as a white solid. LC-MS m/z: 404.1 (M+1).

Step 4: A mixture of 4-cyanophenyl boronic acid (18 mg, 0.12 mmol), 3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide 8 (40 mg, 0.1 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), and Na2CO3 (42 mg, 0.4 mmol) in a combined solvent system of toluene (0.2 mL) and water (0.2 mL) and ethanol (0.05 mL) is heated at 140° C. under microwave irradiation for 30 min. The reaction mixture is diluted with EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with brine and concentrated to give the crude product which is purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide. LC-MS m/z: 427.2 (M+1).

USE THIS COMPD IN ABOPVE AND YOU WILL GET SONIDEGIB

4-(Trifluoromethoxy)phenylboronic acid

CAS Number 139301-27-2
Linear Formula CF3OC6H4B(OH)2
Molecular Weight 205.93

CONDENSE WITH …3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamideACS Medicinal Chemistry Letters, 2010 , vol. 1, 3 p. 130 – 134

……………………………………………….

PAPER

ACS Medicinal Chemistry Letters, 2010 , vol. 1, 3 p. 130 – 134

http://pubs.acs.org/doi/full/10.1021/ml1000307

ENTRY 5m

A mixture of 4-(trifluoromethoxy)phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6-(2,6-
dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide E (250 mg, 0.62mmol), Pd(PPh3)4
(36 mg, 0.03 mmol), Na2CO3 (2.0M aqueous solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL)
in a sealed tube was heated at 1300C overnight. The reaction mixture was diluted with EtOAc
and water. The aqueous layer was extracted with EtOAc. The combined organic layer was
washed with brine and concentrated to give the crude product which was then purified by
preparative mass triggered HPLC (C18 column, eluted with CH3CN-H2O containing 0.05% TFA)
to give N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-
(trifluoromethoxy)biphenyl-3-carboxamide (5m, 183.5 mg, 61.1% yield). LC-MS m/z: 486.2 (M+1).
HRMS (m/z): [M+H]+
calcd for C26H27N3O3F3 486.2005; found 486.1986,
1H-NMR (500 MHz, DMSO-d6): δ (ppm) 10.15 (s, 1H), 8.43 (d, 1H), 7.94 (dd, 1H), 7.52-7.43
(m, 5H), 7.38 (m, 1H), 7.33 (m, 1H), 6.86 (d, 1H), 4.06 (d, 2H), 3.62 (m, 2H), 2,34 (m, 2H), 2.22
(s, 3H), 1.16 (d, 6H).

http://pubs.acs.org/doi/suppl/10.1021/ml1000307/suppl_file/ml1000307_si_001.pdf

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ACS Med. Chem. Lett., 2010, 1 (3), pp 130–134.
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sonidegib

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SONIDEGIB

Links

WO2004078163A2	Feb 26, 2004	Sep 16, 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
WO2007113120A1	Mar 22, 2007	Oct 11, 2007	Frank Hoffmann	Stamping apparatus with feed device
WO2007131201A2 *	May 4, 2007	Nov 15, 2007	Irm Llc	Compounds and compositions as hedgehog pathway modulators
WO2008154259A1	Jun 4, 2008	Dec 18, 2008	Irm Llc	Biphenylcarboxamide derivatives as hedgehog pathway modulators