BTI-320 (formerly PAZ320), Soluble mannan polysaccharides from Boston Therapeutics for the treatment of type 2 diabetes in combination with oral agents or insulin

BTI-320 (formerly PAZ320)

PAZ 320

Non-insulin dependent diabetes

Alpha-glucosidase inhibitor; Hydrolase inhibitor; Sucrose alpha-glucosidase inhibitor

Composition of chemically purified (fractionation) soluble mannan polysaccharides from legume's seeds

BTI-320 is in phase II clinical development at Boston Therapeutics for the treatment of type 2 diabetes in combination with oral agents or insulin, and also for the treatment of high-risk patients with pre-diabetes. A chewable tablet formulation is being developed. The product is already available as dietary supplement.

Company	Boston Therapeutics Inc.
Description	Chewable polysaccharide that inhibits alpha glucosidase
Molecular Target
Mechanism of Action	Alpha glucosidase inhibitor
Therapeutic Modality	Macromolecule: Polysaccharide

Latest Stage of Development	Phase II
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes

PATENT

http://www.google.co.in/patents/WO2012061675A1?cl=en

A composition of chemically purified soluble mannans from legumes' seeds (e.g. Ceratonia siliqua, Cæsalpinia spinosa Trigonelle foenum-graecum, and Cyamopsis tetragonolobus) and their use in the assembly of palatable dietary supplements is disclosed herein. The fractionation process provides high-quality physiologically soluble, chemically modified and purified homogeneous size polysaccharide fibers, devoid of natural impurities, for example proteins, alkaloids, glycoalkaloids, and/or environmental impurities including heavy metals, agricultural residues and microbial toxins. This process provides hypoallergenic dietary fibers devoid of any potential allergens, cytotoxins, and gastrointestinal toxins. A sequential process for assembly of the soluble fibers with plurality of molecular weights to create a time controlled dissolution of the functional high and low molecular weight fibers for improving solubility and palatability with improved dietary performance in the oral and gastro-intestinal system is also disclosed herein.

Fig. 1 illustrates a block flow diagram of an embodiment of a method for recovering purified mannan polysaccharides;

Fig. 2 illustrates a chemical structure of a mannan polysaccharide;

Fig. 3 illustrates a block flow diagram of an embodiment of a method for recovering high molecular weight (HMW) purified mannan polysaccharides;

Fig. 4 illustrates a block flow diagram of an embodiment of a method for recovering low molecular weight (LMW) purified mannan polysaccharides;

REFERENCES

https://clinicaltrials.gov/show/NCT02060916

https://clinicaltrials.gov/show/NCT02358668

BTI-320, a nonsystemic novel drug to control glucose uptake into the bloodstream, functions as a competitive inhibitor of sugar hydrolyzing enzymes
75th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 5-9, Boston) 2015, Abst 974-P

Boston Therapeutics' Hong Kong Affiliate Advance Pharmaceutical's BTI-320 Clinical Trial Reaches Mid-Point by Enrolling 30 Patients at the Chinese University of Hong Kong
Boston Therapeutics Press Release 2015, July 08

Insight into the molecular mechanism of action of BTI320, a non-systemic novel drug to control serum glucose levels in individuals with diabetes50th Annu Meet Eur Assoc Study Diabetes (EASD) (September 15-19, Vienna) 2014, Abst 545

////BTI-320, PAZ320, PHASE 2, BTI 320, PAZ 320, Macromolecule,  Polysaccharide, Non-insulin dependent diabetes, Alpha-glucosidase inhibitor,  Hydrolase inhibitor,  Sucrose alpha-glucosidase inhibitor, phase II clinical development,  Boston Therapeutics, Soluble mannan polysaccharides

Composition of chemically purified (fractionation) soluble mannan polysaccharides from legume's seeds

POLYMER OF BELOW

CAS 9036-88-8, 51395-96-1

refractive index :

78.5 ° (C=1.4, H2O)

Ailes;MANNAN;K-41K1;D-Mannan;NSC 174478;NSC 174479;NSC 174481;NSC 307194;NSC 174477;NSC 174473

Chemical name:	1,6-Anhydro-β-D-mannopyranose
Synonyms:	1,6-Anhydro-D-mannose; 1,6-Anhydromannose; Mannosan; NSC 226600;
CAS Number:	14168-65-1
Possible CAS #:	NA
Molecular form.:	C₆H₁₀O₅
Appearance:	White to Pale Beige Solid
Melting Point:	182-184°C
Mol. Weight:	162.14

Summary:
Mannans are major constitutents of hemicelluloses in plant tissue and are polymers composed of β(1→4)-linked mannose and glucose residues. Some contain galactopyranosyl side chains (see a galactomannan).

Slightly galactosylated mannans (4% galactose), considered as linear β(1→4)-D-mannans, have been isolated from the seed endosperm of vegetable ivory nut ( Phytelephas macrocarpa) and date ( Phoenix dactylifera) .

Glycan icon:

Child Classes: a 1,6-α-D-mannan backbone (0), a galactoglucomannan (0), a galactomannan (0), a glucomannan (0), a mannan oligosaccharide (1)

SMILES: C(O)C4(C(O[R1])C(O)C(O)C(OC3(C(O)C(O)C(OC2(C(O)C(O)C(OC1(C(O)C(O)C(O[R2])OC(CO)1))OC(CO)2))OC(CO)3))O4)

CAS:9036-88-8,

BMS 919373

.

Bethany Halford on Twitter: "BMS-919373, from $BMS for ...https://twitter.com/beth_halford/status/634105343719682048

Aug 19, 2015 - BMS-919373, from $BMS for atrial fibrillation #ACSBoston MEDI 1st disclosures @bmsnews pic.twitter.com/y3D4Yv2U7M.

BMS 919373

 CAS 1272353-82-8

C₂₅ H₂₀ N₆ O₂ S, 468.53

3-​Pyridinesulfonamide, 5-​[5-​phenyl-​4-​[(2-​pyridinylmethyl)​amino]​-​2-​quinazolinyl]​-

5-[5-phenyl-4-[[(pyridin-2-yl)methyl]amino]quinazolin-2-yl]pyridine-3-sulfonamide

• Phase IIParoxysmal atrial fibrillation
• Phase IAcute coronary syndromes; Atrial fibrillation
• • 01 Oct 2014Phase-I clinical trials in Atrial fibrillation in Canada (PO) (NCT02153437)
  • 01 Jul 2014Phase-II clinical trials in Paroxysmal atrial fibrillation in Canada (PO) (NCT02156076)
  • 01 Jul 2014Phase-II clinical trials in Paroxysmal atrial fibrillation in USA (PO)
  • https://clinicaltrials.gov/ct2/show/NCT02153437
  • https://clinicaltrials.gov/ct2/show/NCT02156076
•  CAS HCL SALT 1272356-77-0

Company	Bristol-Myers Squibb Co.
Description	IKur antagonist
Molecular Target	Potassium channel Kv1.5 (KCNA5)
Mechanism of Action	Potassium channel Kv1.5 (KCNA5) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I
Standard Indication	Fibrillation
Indication Details	Treat atrial fibrillation

Synthesis

PATENT

WO 2011028741

http://www.google.co.in/patents/WO2011028741A1?cl=en

EXAMPLE 7

5-(5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridine-3-sulfonamide

Step 1. Preparatio -Bromopyridine-3 -sulfonamide

See also U.S. Publication Nos. 2006/217387 and 2006/375834, and J. Org. Chem., 54:389 (1989). A mixture of pyridine-3 -sulfonic acid (10.3 g, 64.8 mmol), phosphorous pentachloride (20.82 g, 100 mmol) and phosphorous oxychloride (10 mL, 109 mmol) was heated to reflux where it stirred for 4h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was evaporated to dryness under reduced pressure to yield a residue. The residue was treated with bromine (6.00 mL, 1 16 mmol) and then heated to reflux where it stirred for 14h. After this time, the reaction mixture was cooled to 0 °C and then a saturated solution of NH₄OH in ¾0 (40 mL) was slowly added. The resulting mixture was allowed to warm to room temperature where it stirred for 30 min. The reaction mixture was then filtered and the filter cake was washed with hexane to afford 5 -bromopyridine-3 -sulfonamide (6.0 g) as an off- white solid. The product was used without further purification. LCMS Method Q: retention time 0.75 min; [M+l] = 237.0.

Step 2. Preparation of pyridine-3-sulfonamide-5-ylboronic acid pinacol ester

See also WO2008/150827 Al and WO2008/144463. A mixture of 5- bromopyridine-3 -sulfonamide (1.5 g, 6.33 mmol), bis(pinacolato)diboron (2.41 g, 9.5 mmol) and potassium acetate (1.86 g, 19.0 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 15 min then (l, l'-bis(diphenylphosphino)- ferrocene)palladium (II) chloride dichloromethane complex (232 mg, 0.317 mmol) was added and the resulting mixture was degassed again with nitrogen for 10 min. At the conclusion of this period, the reaction mixture was heated in a microwave at 120 °C for 45 min. After this time, the reaction mixture was filtered through CELITE® and the filtrate was concentrated under reduced pressure to provide pyridine-3- sulfonamide-5-ylboronic acid pinacol ester (740 mg) as a brown solid. The product was used without further purification. ^XH NMR (400 MHz, DMSO-d₆) δ (ppm): 8.83 (s, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.56-7.74 (bs, 2H), 1.17 (s, 12H).

Step 3. Example 7

To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4- amine (150 mg, 0.43 mmol) in 1,4-dioxane (6 mL) and ¾0 (1 mL) under nitrogen was added pyridine-3-sulfonamide-5-ylboronic acid pinacol ester (185 mg, 0.65 mmol), and potassium carbonate (119 mg, 0.86 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 minutes and then (1, 1'- bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (31 mg, 0.043 mmol) was added. The resulting mixture was again degassed with nitrogen for 10 min. After this time, the mixture was heated to 90 °C where it stirred for 16h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then transferred to a separation funnel. The aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The resulting concentrate was purified by preparative TLC using 5% methanol in dichloromethane to afford Example 7 (50 mg) as a brown solid. 'H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.81 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.24 (d, J= 4.4 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J= 7.6 Hz, 1Η),7.75-7.72 (t, J= 7.6 Hz, 3H), 7.59-7.51 (m, 5H), 7.34 (d, J=7.2 Hz, 2H), 7.24 (t, J=6.4 Hz, 1H), 6.98 (t, J= 3.2 Hz, 1H), 4.77 (d, J= 4.0 Hz, 2H). LCMS Method Q: retention time 1.39 min; [M+l] = 469.0. HPLC Method B: purity 98.1%, retention time = 8.74 min. [00120] Alternatively, Example 7 can be synthesized as follows:

Step 1. Preparation of 5-Bromo-pyridine-3-sulfonyl chloride

PC1₅ (2.95 Kg, 14.16 moles) and POCl₃ (2.45 Kg, 15.98 moles) were added into pyridine-3 -sulfonic acid (1.5 Kg, 9.42 mol) in 10 L RB flask equipped with mechanical stirrer under inert atmosphere. The reaction mass was heated to 120- 125°C where it stirred for 18 h. After this time, the reaction progress was monitored by HPLC, which indicated the reaction was complete. Excess POCI3 was removed under vacuum to give a residue. The residue was cooled to ambient temperature and bromine (1.2 Kg, 7.5 moles) was added. Upon completion of addition, the resulting mixture was heated to 120-125°C where it stirred for 5 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and then poured into ice-water (10 L), and the resulting mixture was extracted with DCM (10.5 Lx2). The DCM extracts were combined and the solvent was removed under vacuum to yield crude product (1.8 Kg, 74.4% yield).

Step 2. Preparation of 5-bromo-N-tert-butylpyridine-3 -sulfonamide

Crude 5 -bromopyridine-3-sulfonyl chloride from step 1 above was dissolved in THF (14 L, 8 vol) and then transferred to a 20 L RB flask equipped with mechanical stirrer under inert atmosphere. The solution was cooled to 0-5°C and tert- butyl amine (1.95 Kg, 26.66 moles) was added at 0-5°C. Upon completion of addition, the reaction mixture was warmed to ambient temperature where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The solvent was evaporated under vacuum to give a thick residue. The residue was dissolved in ethyl acetate (18 L, 12 vol). The organic layer was separated, washed with water (9 L, 5 vol) and then concentrated under vacuum to yield a residue. Hexanes (9 L, 5 vol) were added to the residue and the product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.5 Kg, 54.28% overall yield). ¾ NMR (DMSO-D6, 400 MHz, δ ppm); 8.99 (d, J = 2Hz, 1H), 8.81 (d, J= 2 Hz, 1H), 8.29 (t, J= 2Hz, 1H). [M⁺+l] = 293. Step 3. Preparation of 5-bromo-N-tert-butylpyridine-3 -sulfonamide

5 -Bromo-N-tert-butylpyridine-3 -sulfonamide (1.5 Kg, 5.11 moles) was dissolved in dimethylformamide (7.5 L, 5 vol) and the solution was added to a 20 L glass-lined reactor equipped with mechanical stirrer. The solution was degassed with nitrogen for 30 min. After this time, potassium ferrocyanide trihydrate (867 g, 2.05 moles), sodium carbonate (1.08 Kg, 10.189 moles), copper (I) iodide (73.2 g, 0.374 moles) and dichloro-bis (triphenylphosphine) palladium (II) (71.6 g, 0.102 moles) were added. Upon completion of addition, the reaction mixture was heated to 120- 125°C where it stirred for 4 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and then filtered through a celite bed. Water (18 L, 12 vol) was added into the filtrate and the resulting mixture was extracted with ethyl acetate (7.5L*2). The organic layers were combined, washed with water and then concentrated to yield a thick residue. Hexanes (7.5 L, 5 vol) were added to the residue. The product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.0 Kg, 82.8% yield, 89% purity by HPLC). ¾ NMR (DMSO-D6, 400 MHz, δ ppm); 9.21 - 9.24 (d,d J= 7.2Hz, 3.2Hz, 2H), 8.70-8.71(m,lH), 7.98 (s, lH). [M⁺+l] = 239.2.

Step 4. Preparation of 3-aminobiphenyl-2-carbonitrile

2-Amino-6-bromo-benzonitrile (1.0 Kg, 5.07 moles) and toluene (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer under inert atmosphere. Potassium acetate (996 g, 10.16 moles) and phenylboronic acid (866, 7.10 moles) were added into the solution and the solution was degassed with nitrogen for 30 min. After this time, dichloro-bis (triphenylphosphine) palladium (II) (17.8 g, 0.025 moles) was added to the reaction mixture at ambient temperature. The mixture was heated to 110°C, where it stirred for 17 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was completed. The reaction mixture was filtered through a celite bed. The filtrate was transferred back to the reactor and concentrated hydrochloric acid (-35%, 2 L, 2 vol) was charged to the reactor at ambient temperature. The HCl salt of the title compound precipitated out from the reaction and was collected by filtration. The HCl salt was transferred into the 20 L reactor and then made basic with 10% NaOH solution (pH 8-9). The resulting product was extracted with ethyl acetate (10 L, 10 vol). The ethyl acetate layer was washed with water (5 L, 5 vol) and then the solvent was evaporated under vacuum to give a residue. Hexanes (5 L, 5 vol) were added to the residue at 35-40°C, and the resulting slurry was cooled to ambient temperature. Once at the prescribed temperature, the product was collected by filtration to provide a pale yellow solid (802 g, 81.4%, 99% by HPLC). ^XH NMR (DMSO-D6, 400 MHz, δ ppm); 7.43-7.52 (m, 5H), 7.33-7.37 (m, 1H), 6.83 (d, J=8Hz, 1H), 6.62 (d, J=8Hz, 1H), 6.1 (s, 2H). ES-MS: [M⁺+l] = 194.23.

Step 5. Preparation of 5-(4-amino-5-phenylquinazolin-2-yl)-N-tert-butylpyridine-3-

3-Aminobiphenyl-2-carbonitrile (1028 g, 5.30 moles), 5-bromo-N-tert- butylpyridine-3 -sulfonamide (1440 g, 5.55 moles) and 1,4-dioxane (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. Sodium tert-butoxide (1.275 Kg 12.870 moles) was added to the solution portion-wise at 20- 30°C. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 30-35°C and then poured into water (40 L, 40 vol). The resulting mixture was extracted with DCM (20 L*2). The DCM layers were combined, washed with water (10 L, 10 vol) and then dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue. Isopropyl alcohol (1.2 L, 1.2 vol) was added to the residue at 40°C. The resulting precipitate slurry was cooled to 10-15°C and then stirred for 2 h. After this time, the precipitate was collected by filtration and dried at 50°C for 16 h to yield the product (1.9 Kg, 82.9% yield, 99% purity by HPLC). Ή NMR (DMSO-D6, 400 MHz, δ ppm); 9.72 (s, 1H), 9.11 (s, 2H), 7.83-7.94 (m, 4H), 7.49-7.60 (m, 5H), 7.31 (d,d /=6.8Hz,1.2Hz, 1H). ES-MS: [M⁺+l] = 433.53.

Step 6. Preparation of N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino) quinazolin-2-yl) pyridine-3 -sulfonamide

2-(Chloromethyl) pyridine hydrochloride (564 g, 3.44 moles) and dimethyl acetamide (7L, 7 vol) were added to a 20 L RB flask- 1 equipped with mechanical stirrer under inert atmosphere. The resulting solution was cooled to 0- 5°C and triethylamine (346.3, 3.44 moles) was added at 0-5°C. 5-(4-Amino-5- phenylquinazolin-2-yl)-N-tert-butylpyridine-3-sulfonamide (1.0 Kg. 2.306 moles) and dimethylacetamide (4 L, 4 vol) were added to a separate 20 L RB flask-2 equipped with mechanical stirrer under inert atmosphere. This solution was cooled to 0-5°C and sodium tert-butoxide (884 g, 9.24 moles) was added at 0-5°C. The resulting solution was stirred to affect dissolution and then transferred to the RB flask- 1 at 0- 5°C. Upon completion of addition, the reaction mixture was stirred at 0-5°C for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The reaction mass was poured into water (60 L, 60 vol) with stirring. The crude product was collected by filtration and dried at 60°C for 12 h. After this time, the dried material was dissolved in THF (20 L, 20 vol). Upon dissolution, 6M HC1 in isopropyl alcohol (1 L, 1 vol) was added at 20-25°C. The crude HCL salt of the product was obtained a pale-yellow free flow solid (920 g, 71% yield, 93% purity by HPLC). The crude HC1 salt (1.345 Kg, 2.56moles), methanol (6.7 L, 5 vol) and dichloromethane (13.5 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. The slurry was stirred for 20-30 min at 30°C. After this time, the solvent was distilled to 4 vol with respect to input under vacuum. The resulting slurry was cooled to 20-25°C, where stirred for 2 h. At the conclusion of this period, the slurry was filtered and dried at 50°C for 6 h to yield the product (1.1 Kg, 82% yield, 98% purity by HPLC). ^XH NMR (DMSO- D6, 400 MHz, δ ppm); 9.72 (s, 1H), 9.10-9.14 (m, 2H), 8.39 (s, 1H), 7.92-8.03 (m, 4H), 7.56-7.58 (m, 5H), 7.43-7.49 (m, 3H), 7.1 (bs, 1H), 4.88 (s, 2H), 1.17 (2, 9H).

Step 7. Example 7

N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino) quinazolin-2-yl) pyridine-3 -sulfonamide (1.0 Kg, 1.9 moles) and concentrated hydrochloric acid (7 L, 7 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. The reaction mixture was heated to 90-100°C where it stirred for 1 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 5-10°C and the pH was adjusted to 1.7 to 2.0 using 12% aqueous sodium hydroxide solution. Once at the prescribed pH, the crude HC1 salt of the product was collected by filtration. The HC1 salt filter cake and ethanol (5 L, 5 vol) were added to 10 L glass-lined reactor equipped with a mechanical stirrer. The resulting mixture was made basic to pH 7-8 at 20-25°C using triethyl amine (2.25 Kg, 22.23 moles). Once at the prescribed pH, the basic mixture was stirred for 2 h. After this time, the free base of product was filtered and washed with water (10 L, 10 vol) followed by ethanol (2L, 2 vol). The resulting product was dried at 50-55°C for 8 h to yield Example 7 (644 g, 72% yield, 99.9% purity by HPLC).

^XH NMR (DMSO-D6, 400 MHz, δ ppm); 9.81 (d, J=2.0Hz, 1H), 9.18 (t, J=2Hz, 1H), 9.1 1 (d, J=2Hz, 1H), 8.23 (d, J=4.4Hz, 1H), 7.92-7.94 (m, 1H), 7.83-7.87 (m, 1H), 7.78 (s, 2H), 7.70-7.72 (m, 1H), 7.50-7.59 (m, 5H), 7.31-7.34 (m, 2H), 7.22-7.25 (m, 1H), 6.95 (t, J=4Hz, 1H), 4.76 (d, J=4Hz, 2H). ES-MS: [M⁺+l] = 469.

/////////atrial fibrillation, Potassium channel Kv1.5 (KCNA5) inhibitor, IKur antagonist, Bristol-Myers Squibb Co., BMS 919373, BMS-919373, PHASE 2

NS(=O)(=O)c1cc(cnc1)c4nc2cccc(c2c(NCc3ccccn3)n4)c5ccccc5

Siponimod, BAF-312

Siponimod , BAF-312

FREE FORM

CAS Number:	1230487-00-9
Molecular Weight:	516.59501
Molecular Formula:	C29H35F3N2O3

1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid

1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethylbenzyloxyimino]-ethyl}-2-ethylbenzyl)-azetidine-3-carboxylic acid

a selective modulator of S1P1 and S1P5 receptors, allowing S1P1 receptor-dependent modulation of lymphocyte traffic without producing S1P3 receptor-mediated effects.

Phase III

A sphingosine-1-phosphate receptor modulator potentially for the treatment of multiple sclerosis(MS).

Research Code BAF-312

CAS. 1230487-00-9, 1234627-85-0

Siponimod, (BAF312) is a selective sphingosine-1-phosphatereceptor modulator for oral use that is an investigational drug for multiple sclerosis (MS). It is intended for once-daily oral administration.^[1]
As of January 2016 it is in a phase III clinical trial for secondary progressive MS due to complete Dec 2016.
AF312 is a potent and selective agonist of S1P with EC50 value of 0.39nM for S1P1 receptors and 0.98nM for S1P5 receptors, respectively [1]. BAF312 has shown >1000-fold selectivity for S1P1 versus S1P2, S1P3 and S1P4 receptors [1]. In vitro metabolism studies with liver microsomes have shown that the metabolic clearance of BAF312 is high in rat, low to moderate in monkey and human being, and low in dog and mouse. Moreover, BAF312 has been revealed to dose-dependently reduce peripheral lymphocyte counts in Lewis rats [2].For the detailed information about the solubility of BAF312 in water, the solubility of BAF312 in DMSO, the solubility of BAF312 in PBS buffer, the animal experiment of BAF312 ,the in vivo and in vitro test of BAF312 ,the cell experiment of BAF312 ,the IC50 and EC50 of BAF312

Clinical trials

(June 8, 2009) It is in Phase II trial. “A back-up compound for Fingolimod, BAF 312” is in Phase II studies.^[2] It is being tested for the first time on people having multiple sclerosis. Worldwide 275 patients will participate in this phase II trial the outcome of which is to establish what the optimal dosage of BAF312 is for patients affected with Multiple Sclerosis for use in further trials. In order to identify “the optimal dosage”, participants in group I will be randomly selected to take either placebo, or BAF312 in doses of 0.5 mg/day, 2 mg/day, or 10 mg./day and will be regularly controlled in order to measure and determine the effectiveness, the tolerability and the safety of the dosages.
A phase III trial should run from Dec 2012 to Dec 2016.^[3]

Approvals and indications

None yet

Mechanism of action

Siponimod binds selectively to some of the Sphingosine-1-phosphate receptor forms – including Sphingosine-1-phosphate receptor 1 – found on lymphocytes and other cell types.
This binding inhibits the migration of the lymphocytes to the location of the inflammation (e.g. in MS).
BAF312, may be very similar to Fingolimod but preventing lymphopenia, one of its main side effects, by preventing egress of lymphocytes from lymph nodes. BAF312 may be more selective in the particular sphingosine-1-phosphate receptors (8 in number) that it modulates.^[4] It is selective for the -1 and -5 SIP receptors.^[1]

SYNTHESIS

MAIN

 SYNTHESIS

Paper

http://pubs.acs.org/doi/abs/10.1021/ml300396r

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

Shifeng Pan*†, Nathanael S. Gray†, Wenqi Gao†, Yuan Mi†, Yi Fan†, Xing Wang†, Tove Tuntland†, Jianwei Che†, Sophie Lefebvre†, Yu Chen†, Alan Chu†, Klaus Hinterding‡, Anne Gardin‡, Peter End‡, Peter Heining‡, Christian Bruns‡, Nigel G. Cooke‡, and Barbara Nuesslein-Hildesheim‡

^† Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States

^‡ Novartis Institute for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland

ACS Med. Chem. Lett., 2013, 4 (3), pp 333–337

DOI: 10.1021/ml300396r

Publication Date (Web): January 04, 2013

Copyright © 2013 American Chemical Society

*Tel: 858-812-1621. E-mail: span@gnf.org.

Abstract

A novel series of alkoxyimino derivatives as S1P₁ agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure–activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing–remitting multiple sclerosis.

 PATENT

EP-2990055-A1 / 2016-03-02

MEDICINAL COMPOSITION FOR INHIBITING FORMATION AND/OR ENLARGEMENT OF CEREBRAL ANEURYSM OR SHRINKING SAME

 PATENT

US-9265754-B2 / 2016-02-23

Use of 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid in treating symptoms associated with rett syndrome

PATENT

US-20160046573-A1 / 2016-02-18

IDENTIFYING PATIENT RESPONSE TO S1P RECEPTOR MODULATOR ADMINISTRATION

a fixed dose combination of BAF312 and a CYP2C9 metabolic activity promotor (e.g. rifampin or carbamezipine).

BAF312 is preferably administered at the standard therapeutic dosage. The CYP2C9 metabolic activity promotor is preferably administered at a dosage suitable to upregulate CYP2C9 to a level where a reduced dosage of BAF312 is not considered clinically necessary.

1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid forms

BAF312 (with the INN Siponimod) has the chemical name 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid and has the structure of formula (I) below:

1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid may be administered as a free base, as a pharmaceutically acceptable salt (including polymorphic forms of the salt) or as a prodrug.

Pharmaceutically acceptable salt forms include hydrochloride, malate, oxalate, tartrate and hemifumarate.

In a preferred aspect, 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid is administered as a hemifumarate salt.

PATENT

US-20150175536-A1 / 2015-06-25

HEMIFUMARATE SALT OF 1-[4-[1-(4-CYCLOHEXYL-3-TRIFLUOROMETHYL-BENZYLOXYIMINO)-ETHYL]-2-ETHYL-BENZYL]-AZETIDINE-3-CARBOXYLIC ACID

One particular compound disclosed in WO2004/103306 is 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic acid (Compound I), the structure of which is shown below.

PATENT

EP-2809645-A1 / 2014-12-10

PROCESS FOR PREPARING N-(4-CYCLOHEXYL-3-TRIFLUOROMETHYL-BENZYLOXY)-ACETIMIDIC ACID ETHYL ESTER

PATENT

EP-2379498-B1 / 2015-01-21

POLYMORPHIC FORM OF 1-(4-{1-[(E)-4-CYCLOHEXYL-3-TRIFLUOROMETHYL-BENZYLOXYIMINO]-ETHYL}-2-ETHYL-BENZYL) -AZETIDINE-3-CARBOXYLIC ACID

Example 1 – Preparation of the Crystalline Form A of the free base of 1-(4-{1-[(E)-4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic acid (Compound I)Method

10 g of 1-4-{1-[(E)-4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyldehyde, 4.7 g of 3-azetidine carboxylic acid and methanol (300 mL) are mixed. The resulting mixture is heated to 45 °C over 30 min and stirred at this temperature for 2 h. Then the reaction mixture is cooled to 20-25 °C and a solution of NaBH₃CN (0.73 g) in MeOH (30 mL) is then added over a period of 20 min. The resulting mixture is stirred at room temperature for 1 h. After concentration, the residue is dissolved in EtOAc, (200 mL) and washed with minimum amount of H₂O (20 mL). The organic layer is washed with water (2 x 10 mL) and concentrated to remove as much AcOH as possible. The residue is purified by column chromatography (minimum silica gel was used, 5 cm long by 3 cm diameter) first eluted with EtOAc and then MeOH to give 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid, as a thick oil. The residue is azeotroped with toluene to ca. 30 mL in volume, then heptane (60 mL) is added. The product crystallized after seeding with pure 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid. The suspension is stirred at 20-25 °C for 24 h and filtered. The filter cake is washed with toluene/heptane (1:3, 10 mL) and heptane (20 mL), and dried at 65 °C for 16 h. The product had a melting point of 110°C. ¹H NMR (400 MHz, CD₃OD) δ 7.67 (s, 1 H), 7.60 (m, 2 H), 7.55 (m, 2H), 7.35 (d, J = 8.4 Hz, 1 H), 5.23 (s, 2 H), 4.32 (bs, 2 H), 4.08 (bs, 4 H), 3.38 (m, 1 H), 2.93 (m, 1 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.26 (s, 3 H), 1.83 (m, 5 H), 1.47 (m, 5 H), 1.24 (t, J = 8.4 Hz, 3 H).

PATENT

WO2004/103306

Example 3
1 – (4-[ 1 -(4-Cvclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyll -azetidine-
3-carboxylic acid

To a suspension of MnO₂ (10 eq) in dioxane is added l-(3-ethyl-4-hydroxymethyl- phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with azetidine-3-carboxylic acid (2 eq) and Et₃N (1.5 eq). The resulting mixture is heated at 50°C for 30 minutes. After cooling to room temperature, NaBH₃CN (3 eq) is added in portions. Purification by preparative LCMS results in l-{4-[l- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3- carboxylic acid; Η NMR (400 MHz, CD₃OD) δ 1.24 (t, 3H), 1.30-1.60 (m, 5H), 1.74-1.92 (m, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (m, 1H), 3.68 (m, 1H), 4.32 (m, 4H), 4.51 (s, 2H) 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 5H). MS: (ES⁺): 517.3 (M+l)⁺.

References

• 1Siponimod (BAF312) for the Treatment of Secondary Progressive Multiple Sclerosis: Design of the Phase 3 EXPAND Trial (P07.126)
• 2
• Multiple sclerosis and the pharmaceutical industry/Medicines in development for MS: abpi.org.uk 2009
• 3
• Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)
• 4

WO 2008000419, Hiestand, Peter C; Schnell, Christian, “S1P Receptor modulators for treating multiple sclerosis”^[

/////////BAF-312 , 1230487-00-9, 1234627-85-0 , Siponimod , BAF 312, Phase III , S1P receptor,  S1P₁ agonist,  lymphocytes

N(CC1=CC=C(/C(=N/OCC2=CC=C(C3CCCCC3)C(C(F)(F)F)=C2)/C)C=C1CC)1CC(C(O)=O)C1

P7435 from Piramal Enterprises Mumbai, India

P7435
Piramal Enterprises Mumbai, India
P-7435; P7435-DGAT1, P7435, P 7435

CAS 1210756-48-1,

_C22 H₁₉ F N₄ O₄ S

L-​Valine, N-​[[3-​[4-​[(6-​fluoro-​2-​benzothiazolyl)​amino]​phenyl]​-​5-​isoxazolyl]​carbonyl]​-

Molecular Weight, 454.47

GDAT1 inhibitor

• Phase IDiabetes mellitus; Lipid metabolism disorders

• ClassAntihyperglycaemics; Antihyperlipidaemics; Small molecules
• Mechanism of ActionDiacylglycerol O acyltransferase inhibitors
• 

Company	Piramal Enterprises Ltd.
Description	Diacylglycerol O-acyltransferase-1 (DGAT1) inhibitor
Molecular Target	Diacylglycerol O-acyltransferase-1 (DGAT1)
Mechanism of Action	Diacylglycerol O-acyltransferase-1 (DGAT1) inhibitor
Therapeutic Modality

Latest Stage of Development	Phase I
Standard Indication	Metabolic (unspecified)
Indication Details	Treat metabolic disorders

https://clinicaltrials.gov/ct2/show/NCT01910571
https://clinicaltrials.gov/ct2/show/NCT01764425

• 24 Nov 2014Piramal Enterprises completes a phase I trial in healthy, overweight or obese subjects in USA (NCT01910571)
• 17 Jun 2014Adverse events and pharmacokinetics data from a phase I trial in healthy male volunteers presented at the 74th Annual Scientific Sessions of the American Diabetes Association (ADA-2014)
• 17 Jun 2014Pharmacodynamics data from preclinical studies in Dyslipidaemia and obesity presented at the 74th Annual Scientific Sessions of the American Diabetes Association (ADA-2014)
• 
  
• 
  
• 
  
• 

Chairman Ajay Piramal

Swati Piramal-The Vice Chairperson of Piramal Enterprises Ltd

Nandini Piramal, Executive Director, Piramal Enterprises

Piramal Enterprises gets US FDA approval for P7435 IND

http://www.pharmabiz.com/NewsDetails.aspx?aid=76992&sid=2
Our Bureau, Mumbai
Tuesday, August 06, 2013, 12:25 Hrs  [IST]
Piramal Enterprises Ltd has received US Food and Drug Administration (FDA) approval for its Investigational New Drug (IND) P7435. This is a novel, potent and highly selective, oral diacylglycerolacyltransferase 1 (DGAT1) inhibitor.
P7435 has been developed by the NCE Research Division of PEL for the management of metabolic disorders such as lipid abnormalities and diabetes. It is well-established that increased lipid levels’ (including triglycerides) is one of the major risk factors for cardiovascular disease (CVD). It has been reported by the World Health Organisation, that CVD, is the number one cause of deaths globally, representing approximately 30 per cent of all deaths. Currently, there is a significant medical need for effective and safe drugs for the management of lipid abnormalities and metabolic disorders.
P7435 has demonstrated its lipid lowering potential in various preclinical studies by showing significant reduction in triglyceride levels, glucose and insulin levels,and decrease in food intake and body weight gain -factors which are associated with lipid abnormalities and metabolic disorders.
PEL has established the safety and tolerability of P7435 in a phase I trial recently completed in India. This extension trial in the US will further evaluate the safety and efficacy of P7435 in a larger population.
Dr Swati Piramal, vice chairperson, Piramal Enterprises, said, “The NCE Research division of PEL continues its ambitious diabetes/metabolic disorders programme to discover and develop NCEs to fight against diseases like diabetes and lipid disorders. With P7435 we are looking at addressing a serious need for effective and well-tolerated drugs that treat lipid disorders, which are commonly associated with diabetes and CVDs. Expansion of this trial will allow testing this NCE in a wider population,which is critical to the development of this drug and will provide therapeutic solutions not just to India but also to the rest of the world.”
The NCE Research division of Piramal Enterprises focuses on the discovery and development of innovative small molecule medicines to improve the lives of patients suffering from cancer, metabolic disorders and inflammatory conditions. The key elements of its strategy include capitalizing on Piramal’s strengths, in particular the India advantage, and leveraging external partnerships to achieve high levels of R&D productivity. Piramal’s state-of-the-art Research Centre in Mumbai has comprehensive capabilities spanning target identification all the way through clinical development. Its robust pipeline, including 8 compounds in clinical development, bears testimony to its innovative and rigorous drug discovery process.
PAPER
European Journal of Medicinal Chemistry (2012), 54, 324-342
http://www.sciencedirect.com/science/article/pii/S0223523412003133
PATENT
WO 2010023609
http://www.google.co.in/patents/WO2010023609A1?cl=en
/////////Piramal Enterprises,  Mumbai, India, P-7435, P7435-DGAT1, P7435, P 7435, GDAT1 inhibitor
O=C(O)[C@@H](NC(=O)c1cc(no1)c2ccc(cc2)Nc3nc4ccc(F)cc4s3)C(C)C