LIK 066, Licogliflozin diprolinate

Licogliflozin diprolinate

LIK-066, a new flozin on the horizon
C23 H28 O7 . 2 C6 H11 N O, 642.7795, 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C…WO2011048112
CAS 1291095-45-8, (1S)​-​1,​5-​anhydro-​1-​C-​[3-​ [(2,​3-​dihydro-​1,​4-​benzodioxin-​6-​yl)​methyl]​-​4-​ethylphenyl]​-​ D-​glucitol (1:1) WITH L-​Proline, compd.,    1:1 Proline Co-crvstal ,  1:1 Proline Co-crvstal …..…WO2011048112
CAS BASE 1291094-73-9, 416.46, C₂₃ H₂₈ O₇
(1S)-1,5-Anhydro-1-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-D-glucitol bis[1-[(2S)-pyrrolidin-2-yl]ethanone]
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Sodium glucose transporter-2 inhibitor
SGLT 1/2 inhibitor
Novartis Ag innovator
Clinical trial……..https://clinicaltrials.gov/ct2/show/NCT01915849
https://clinicaltrials.gov/ct2/show/NCT02470403

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

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

SEE ALSO

WO2012140597


LIK-066 is in phase II clinical studies at Novartis for the treatment of type 2 diabetes.
In June 2014, the EMA’s PDCO adopted a positive opinion on a pediatric investigation plan (PIP) for LIK-066 for type 2 diabetes
Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition. Glucose level abnormalities can result in serious long-term complications, which include cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage and obesity.

Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus (IDDM), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Type-2 diabetes previously known as adult- onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) – is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin). Chronic hyperglycemia can also lead to onset or progression of glucose toxicity characterized by decrease in insulin secretion from β-cell, insulin sensitivity; as a result diabetes mellitus is self-exacerbated [Diabetes Care, 1990, 13, 610].
Chronic elevation of blood glucose level also leads to damage of blood vessels. In diabetes, the resultant problems are grouped under “microvascular disease” (due to damage of small blood vessels) and “macro vascular disease” (due to damage of the arteries). Examples of microvascular disease include diabetic retinopathy, neuropathy and nephropathy, while examples of macrovascular disease include coronary artery disease, stroke, peripheral vascular disease, and diabetic myonecrosis.
Diabetic retinopathy, characterized by the growth of weakened blood vessels in the retina as well as macular edema (swelling of the macula), can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US. Diabetic neuropathy is characterized by compromised nerve function in the lower extremities. When combined with damaged blood vessels, diabetic neuropathy can lead to diabetic foot. Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic nephropathy is characterized by damage to the kidney, which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of l adult kidney failure worldwide. A high glycemic diet (i.e., a diet that consists of meals that give high postprandial blood sugar) is known to be one of the causative factors contributing to the development of obesity.
Type 2 diabetes is characterized by insulin resistance and/or inadequate insulin secretion in response to elevated glucose level. Therapies for type 2 diabetes are targeted towards increasing insulin sensitivity (such as TZDs), hepatic glucose utilization (such as biguanides), directly modifying insulin levels (such as insulin, insulin analogs, and insulin secretagogues), increasing increttn hormone action (such as exenatide and sitagliptin), or inhibiting glucose absorption from the diet (such as alpha glucosidase inhibitors) [Nature 2001 , 414, 821-827],
Glucose is unable to diffuse across the cell membrane and requires transport proteins. The transport of glucose into epithelial cells is mediated by a secondary active cotransport system, the sodium-D-glucose co-transporter (SGLT), driven by a sodium- gradient generated by the Na+/K+-ATPase. Glucose accumulated in the epithelial cell is further transported into the blood across the membrane by facilitated diffusion through GLUT transporters [Kidney International 2007, 72, S27-S35].
SGLT belongs to the sodium/glucose co-transporter family SLCA5. Two different SGLT isoforms, SGLT1 and SGLT2, have been identified to mediate renal tubular glucose reabsorption in humans [Curr. Opinon in Investigational Drugs (2007): 8(4), 285-292 and references cited herein]. Both of them are characterized by their different substrate affinity. Although both of them show 59% homology in their amino acid sequence, they are functionally different. SGLT1 transports glucose as well as galactose, and is expressed both in the kidney and in the intestine, while SGLT2 is found exclusively in the S1 and S2 segments of the renal proximal tubule.
As a consequence, glucose filtered in the glomerulus is reabsorbed into the renal proximal tubular epithelial cells by SGLT2, a low-affinity/high-capacity system, residing on the surface of epithelial cell lining in S1 and S2 tubular segments. Much smaller amounts of glucose are recovered by SGLT1 , as a high-affinity/low-capacity system, on the more distal segment of the proximal tubule. In healthy human, more than 99% of plasma glucose that is filtered in the kidney glomerulus is reabsorbed, resulting in less than 1 % of the total filtered glucose being excreted in urine. It is estimated that 90% of total renal glucose absorption is facilitated by SGLT2; remaining 10 % is likely mediated by SGLT1 [J. Parenter. Enteral Nutr. 2004, 28, 364-371].
SGLT2 was cloned as a candidate sodium glucose co-transporter, and its tissue distribution, substrate specificity, and affinities are reportedly very similar to those of the low-affinity sodium glucose co-transporter in the renal proximal tubule. A drug with a mode of action of SGLT2 inhibition will be a novel and complementary approach to existing classes of medication for diabetes and its associated diseases to meet the patient’s needs for both blood glucose control, while preserving insulin secretion. In addition, SGLT2 inhibitors which lead to loss of excess glucose (and thereby excess calories) may have additional potential for the treatment of obesity.
Indeed small molecule SGLT2 inhibitors have been discovered and the anti-diabetic therapeutic potential of such molecules has been reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin (Diabetes, 2008, 57, 1723-1729)].

SYNTHESIS

PATENT

WO 2011048112
https://www.google.com/patents/WO2011048112A1?cl=en
Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,
Patentscope, Espacenet
Example 61-62:

Ex. 61
Example 61 : Acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester
Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).
Example 62: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 5 mL of 5% aqueous KHS0₄ (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.59)

H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J – 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).
MS (ES) m z 434.2 (M+18).

PICK UP IDEAS FROM HERE

Examples 57-58:

Ex. 57 Ex. 58
Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalyl chloride (10.3 mL, 114.74 mmol) at 0 °C followed by D F (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.
Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1 ,4)-dioxane (10.41 g, 76.26 mmol) at 0 °C. To this reaction mixture, AICI₃ (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL X 2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL X 2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3- dihydro-benzo[1 ,4]dioxin-6-yl)-methanone (30 g).
¹H N R (400 MHz, DMSO-D₆): δ 4.29-4.37 (m, 4H), 7.02 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.18-7.19 (m, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H).
Step III: To a stirred solution of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1 ,4]dioxin- 6-yl)-methanone (30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL, 67.42 mmol ) at room temperature. After stirring for 25 min at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (200 mL X 2), water (200 mL), and brine (200 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-2,3- dihydro-benzo[1 ,4]dioxine (26.5 g). H NMR (400 MHz, DMSO-D₆): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J = 8.4 Hz, J = 2.0 Hz, H), 6.68 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 8.4 Hz, H), 7.39 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 Hz, J = 2.4 Hz 1 H), 7.67 (d, J = 2.8 Hz, 1 H).
Step IV: To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro- benzo[1 ,4]dioxine (26.5 g, 61.47 mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi in hexanes (42.3 mL, 67.62 mmol) at -78 °C. The reaction mixture was stirred for 1 h, and then transferred to a stirred solution of 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (28.69 g, 61.47 mmol) in toluene (100 mL) at -78 °C. After stirring for 1 h, 0.6 N methanesulfonic acid in methanol (265 mL) was added dropwise and stirred the reaction mixture for 16 h at room temperature. Reaction was quenched by the addition of aq. NaHC0₃ solution (~75 mL) and extracted with ethyl acetate (250 mL X 3), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran- 3,4,5-triol (28.4 g)
Example 57: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1 ,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate
Step V: To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5- triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1 :1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10 °C. After stirring for 4 h at 10°C, the reaction was quenched with saturated aqueous sodium bicarbonate (~ 100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 X 150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2- [4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification. Example 58: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2_!3-dihydro-1,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate Step V: To a stirred solution of (3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[ 1 ,4]dioxin-6-yl methyl)-phenyl]-6-hydroxymethyl-tetrahyd ro-pyran-3,4 , 5-triol (28.4 g, 60.81 mmol) in dichloromethane (300 mL) was added pyridine (40 mL, 486.5 mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg, 6.08 mmol) at room temperature. After stirring for 2 h, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (500ml) and washed with 1 N HCI (200 mL X 2) followed by brine (200ml), then dried over sodium sulfate and
concentrated. The resulting crude compound was dissolved in ethanol (320 mL) at 65 °C and allowed to cool to room temperature while stirring. Light yellow solid formed was filtered and washed with cold ethanol (150 mL) followed by hexane (200 mL) to get acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin- 6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder (22.5 g, purity 98%).

COCRYSTAL

Example 75: 1:1 Proline Co-crvstal with f2S.3R.4R.5S.6R¾-2-r3-f2.3-Dihvdro- benzori.41dioxin-6-ylmethyl)-4-ethyl-phenvn-6-hvdroxymethyl-tetrahydro-pyran- 3.4.5-triol
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62) was completely amorphous initially but formed a crystalline complex with proline. This was confirmed by powder X-ray diffraction (PXRD) analysis. The stiochiometry of Example 62 and L- proline in the co-crystal prepared by method 1 was found to be 1 :1 by NMR
spectroscopy & HPLC. Characterization data for co-crystals of Example 62 and proline prepared by method 1 is shown in Table 3. Relative intensities of the most prominent powder x-ray diffraction peaks for co-crystals of Example 62 and proline are shown in Table 3A.
Table 3

Table 3A

3.70 15.78 18.36 25.18
9.68 10.68 18.88 36.33
11.07 21.21 20.42 69.29
14.26 14.81 21.18 27.94
14.80 22.97 22.50 12.25
15.40 4 98 23.78 33.08
16.12 8.45 24.56 6.92
16.59 18.78 25.79 21.69
17.31 100.0 27.46 8.90
17.60 20.35 31.97 7.65
17.98 47.20 32.46 5.98

1:1 Proline Co-crvstal

Example 77: 1:1 Proline Co-crvstal with (2S.3R.4R.5S.6Ri-2-f3-(2.3-Dihvdro- benzoh .41dioxin-6-ylmethvh-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol
Method 2:
1 :1 Co-Crvstals of Example 62 with L-Proline
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1500mg,3.6mmol), L- proline (415mg, 3.6mmol) and ethanol (23 ml_) were added to a 50 mL 3-neck round bottom flask equipped with nitrogen purging, magnetic stirring bar,
thermometer pocket & calcium chloride guard tube and the mixture was stirred at 25-30°C for 30 min., then heat to reflux. A clear solution was observed which was refluxed for 30 min., then slowly cool to 25-30°C causing percipitation. Di- isopropyl ether (DIPE, 23 mL) was added while maintaining the mixture at 25-30°C and stirring continuously for additional one to two hours at the same temperature. The precipitate was collected by filtration using vacuum (Nitrogen atmosphere), and the filter cake was washed with ethanol-DIPE mixture (1 :1 v/v, 10ml) followed by DIPE (23 mL). The product was vacuum dried at 65-70°C for 5-6 hrs.
1:1 Proline Co-crvstal (ΔΗ 53 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig. 1. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 2.

2:1 Proline Co-crvstal

Example 78: 2:1 Proline Co-crvstal with f2S.3R.4R.5S.6R>-2-r3-f2.3-Pihvdro-benzof1.41dioxin-6-ylmethvH-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol
Method 3: 1 :2 Co-Crvstals of Example 62 with L-Proline
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1 kg) was added to 15 L of ethanol with agitation while maintaining the mixture at 20-25 °C. The mixture was stirred for 10 min at 20-25 °C, then L-proline (537 gm) was added while maintaining the mixture at 20-25 °C. The mixture was stirred at this temperature for 30 min., then heated to reflux and refluxed for 30 min. The mixture was slowly cooled to 25-30°C then stired for 1 hr. DIPE (15 L) was added while maintaining the temperature at 25-30 °C and the mixture was stirred at this temperature for 1 hr. The precipitated product was collected by filtration and the product was washed with DIPE (5 L). The product was air dried at 65-70 °C to yield 1.22 kg
(79%) of a 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C (ΔΗ 85 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig.
3. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 4. Relative
intensities of the most prominent powder x-ray diffraction peaks for the 1 :2 co- crystals of Example 62 and proline are shown in Table 5.
Table 5

PATENT

WO 2012140597
http://www.google.co.in/patents/WO2012140597A1?cl=en
. TABLE 2:

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

Intermediate 2
Intermediate 1
Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (Intermediate 1 , 10.0 g, 15.74 mmol) in toluene (200 mL) was added
tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 ml_), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).
Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 ml.) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 ml.) and washed with brine (75 ml_), brine containing 5 ml. of 5% aqueous KHS0₄ (75 ml_), and brine (20 ml.) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5 g)
¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.34- 3.50 (m, 4H), 3.68 (dd, J = 12.0, 5.6 Hz, 1 H), 3.85-3.91 (m, 3H), 4.08 (d, J = 9.6 Hz, 1 H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d, J = 8.4 Hz, 1 H), 7.15-7.25 (m, 3H).
MS (ES) m/z 434.2 (M+18).
Example 3: Synthesis of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester diethyl ester

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

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6- ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di- tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0°C followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to -40 °C and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0°C and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3 X 10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6- [3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro- pyran-2-ylmethyl ester.
To the stirred solution of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion exchange resin (250 mg) and refluxed for overnight. Reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated to give 300 mg of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester. The crude material was taken up for next reaction.
To a solution of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester (300 mg, 0.6 mmol) in methanol (5 ml) was added 1 N sodium bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring at room temperature for 2 h, the volatiles were evaporated under reduced pressure. The resulting solid was triturated with diethyl ether. The resulting residue was purified by preparative HPLC to give 95 mg of disodium salt of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester.
¹H NMR (400 MHz, CD₃OD): δ 1.06 (t, J = 7.4 Hz, 3H), 2.56 ( q, J = 7.3 Hz, 2H), 3.34- 3.41 (m, 2H), 3.49 (t, J = 8.8 Hz, 1 H), 3.81-3.88 (m, ,3H), 3.92-3.99 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.16 (s, 4H), 4.20-4.25 (m, 1 H), 6.54 (m, 2H), 6.67 (d, J = 7.8 Hz, 1 H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1 ) for phosphoric acid.

PATENT

SEE  INDIAN PATENT
IN 2009DE02173
Glycoside derivatives and uses thereof

REFERENCES

Pediatric investigation plan (PIP) decision: (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2:1) ( LIK066) (EMEA-001527-PIP01-13)
European Medicines Agency (EMA) Web Site 2014, July 24
Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) assessment of LIK066 in healthy subjects and in patients with type 2 diabetes mellitus (T2DM) (NCT01407003)
ClinicalTrials.gov Web Site 2011, August 07
WO2012140597
WO2011048112
IN 2009DE02173

WO2001016147A1	24 Aug 2000	8 Mar 2001	Kissei Pharmaceutical	Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
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WO2001068660A1	15 Mar 2001	20 Sep 2001	Hideki Fujikura	Glucopyranosyloxy benzylbenzene derivatives, medicinal compositions containing the same and intermediates for the preparation of the derivatives
WO2001074834A1	29 Mar 2001	11 Oct 2001	Squibb Bristol Myers Co	O-aryl glucoside sglt2 inhibitors and method
WO2003020737A1	5 Sep 2002	13 Mar 2003	Squibb Bristol Myers Co	O-pyrazole glucoside sglt2 inhibitors and method of use
WO2003043985A1	20 Nov 2002	30 May 2003	Andrew Thomas Bach	Heterocyclic compounds and methods of use
WO2004018491A1	21 Aug 2003	4 Mar 2004	Nobuhiko Fushimi	Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof
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WO2004080990A1	12 Mar 2004	23 Sep 2004	Kazuhiro Ikegai	C-glycoside derivatives and salts thereof
WO2004099230A1	30 Apr 2004	18 Nov 2004	Eikyu Yoshiteru	Monosaccharide compounds
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WO2006054629A1	17 Nov 2005	26 May 2006	Kissei Pharmaceutical	1-SUBSTITUTED-3-β-D-GLUCOPYRANOSYLATED NITROGENOUS HETERO- CYCLIC COMPOUNDS AND MEDICINES CONTAINING THE SAME
WO2008016132A1	3 Aug 2007	7 Feb 2008	Daiichi Sankyo Co Ltd	Benzyl phenyl glucopyranoside derivative
WO2011048112A1 *	19 Oct 2010	28 Apr 2011	Novartis Ag	Glycoside derivatives and uses thereof
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Citing Patent	Filing date	Publication date	Applicant	Title
WO2015032272A1 *	19 Aug 2014	12 Mar 2015	Jiangsu Hansoh Pharmaceutical Co., Ltd.	C-aryl glucoside derivative, preparation method for same, and medical applications thereof
US9034921	1 Jun 2012	19 May 2015	Green Cross Corporation	Diphenylmethane derivatives as SGLT2 inhibitors

INVENTORS OF LIK 066
Gregory Raymond Bebernitz, Mark G. Bock, Dumbala Srinivas Reddy, Atul Kashinath Hajare, Vinod Vyavahare, Sandeep Bhausaheb Bhosale, Suresh Eknath Kurhade, Videsh Salunkhe, Nadim S. Shaikh, Debnath Bhuniya, P. Venkata Palle, Lili Feng, Jessica Liang,

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

Mark G Bock
BEBERNITZ, Gregory, Raymond….PIC NOT AVAILABLE





Dr. Srinivasa Reddy
NADEEM SHAIKH

Venkata Palle

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

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) 

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.

................................

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

Reference

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25. MORE REF

sonidegib

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Rubin AI, Chen EH, Ratner D (2005). Current Concepts: Basal-Cell Carcinoma. N Engl J Med; 353:2262-9.

ClinicalTrials.gov. “A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (BOLT)” Available at:http://clinicaltrials.gov/ct2/show/NCT01327053?term=%22LDE225%22+and+%22BOLT%22&rank=1. Accessed on February 14, 2014.

National Cancer Institute Dictionary of Cancer Terms. “Complete Response.” Available at: http://www.cancer.gov/dictionary?CdrID=45652 . Accessed on February 14, 2014.

 National Cancer Institute Dictionary of Cancer Terms. “Partial Response.” Available at: http://www.cancer.gov/dictionary?CdrID=45819 . Accessed on February 14, 2014.

Wong C S M, Strange R C, Lear J T (2003). Basal cell carcinoma. BMJ; 327:794-798.

 Copcu E, Aktas A. Simultaneous two organ metastases of the giant basal cell carcinoma of the skin. Int Semin Surg Oncol. 2005;2:1-6. Available at:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC544837/ . Accessed on February 14, 2014.

 Skin Cancer Foundation. “Basal Cell Carcinoma Treatment Options.” Available athttp://www.skincancer.org/skin-cancer-information/basal-cell-carcinoma/bcc-treatment-options . Accessed on February 14, 2014.

Stuetz A, et al. LDE225, a specific smoothened inhibitor, for the topical treatment of nevoid basal cell carcinoma syndrome (Gorlin’s syndrome). Melanoma Research. 2010; 20:e40. Available at:http://journals.lww.com/melanomaresearch/Fulltext/2010/06001/FC24_LDE225,_a_specific_smoothened_inhibitor,_for.87.aspx#FC24_LDE225%2C_a_specific_smoothened_inhibitor%2C_for.87.aspx?s=2&_suid=139234380607909969110518506816.

Novartis.com. “The Pipeline of Novartis Oncology: LDE225.” Available at:http://www.novartisoncology.com/research-innovation/pipeline.jsp #. Accessed on February 14, 2014.

 Children’s Medical Research Center, Children’s Memorial Hospital/Northwestern University Feinberg School of Medicine. “The Sonic hedgehog/patched/gli signal transduction pathway.” Available at http://www.childrensmrc.org/iannaccone/gli/ . Accessed on February 14, 2014.

 Gupta S, Takebe N, LoRusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010 July; 2(4): 237-250. Available at:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126020/ . Accessed on February 14, 2014.

SONIDEGIB

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

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