WO 2016042441, Mankind Research Centre, Silodosin, New patent

WO-2016042441

Mankind Research Centre

MANKIND RESEARCH CENTRE [IN/IN]; 191-E, Sector 4-II, IMT-Manesar, Haryana 122050 (IN)

A novel process for the preparation of considerably pure silodosin

GANGWAR, Kuldeep Singh; (IN).
KUMAR, Anil; (IN).
BHASHKAR, Bhuwan; (IN)

The present invention relates to a novel, improved, commercially viable and industrially advantageous process for the preparation of Silodosin of Formula (I), its pharmaceutically acceptable salts or solvates thereof. The invention relates to the preparation of considerably pure Silodosin with high yield.

Silodosin, l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide of Formula (I) is an indoline antidysuric which has a selectively inhibitory effect against urethra smooth muscle constriction, and decreases urethra internal pressure without great influence on blood pressure. Silodosin is available under trade names RAPAFLO^® or UROREC^®. Silodosin was first disclosed in EP 0600675 as a therapeutic agent for the treatment of dysuria associated with benign prostatic hyperplasia, where a process for producing the compound is also disclosed.

Formula (I)

Since, Silodosin is an optically active compound having a complex chemical structure; its synthesis is relatively complex and requires a sequence of multiple steps.

US patent no. 6,310,086, discloses a process for preparing Silodosin analogue compound from reaction of (R)-3-{5-(2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl} propylbenzoate with 2-(2-ethoxyphenoxy)ethyl methanesulfonate and finally isolated as a crude compound which is purified by column chromatography. The said process has a major disadvantage of using column chromatography which is not feasible at plant scale production.

PCT application no. WO 2012147019, discloses the preparation of Silodosin as shown in scheme- 1, wherein the Ν,Ν-dialkyl impurity of Formula (Ila) formed during condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate of Formula (III) with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate of Formula (IV); is removed through preparation of monotartarate salt to give compound of Formula (VI). The compound of Formula (VI) is base hydrolyzed followed by cyano hydrolysis to give crude Silodosin of Formula (VIII) which is then further purified by crystallization to get desired pure Silodosin.

Scheme- 1:

Major drawback of above said reaction process is that multiple isolations and crystallizations are required to get pure Silodosin.

Similarly, US 7,834,193 discloses monooxalate salt represented by Formula Via having 0.9% of dialkyl impurity represented by Formula Ila. The oxalate salt so obtained is subjected to alkaline hydrolysis followed by transformation of the nitrile to an amide.

Formula (Ila)

Similarly, PCT application no. WO 2012147107, discloses the method wherein Silodosin is prepared by condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl} propyl benzoate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate in solvent using base and phase transfer catalyst wherein, dialkyl impurity is formed up to 11%, followed by hydroxyl deprotection in protic solvent using base and phase transfer catalyst which is then subjected to purification to remove N,N-dialkyl impurity represented by Formula (lib) up to 0.6% through the preparation of acetate salt. This process suffers from a serious drawback i.e., accountable formation of dialkyl impurity and even after purification the impurity is reduced to only up to 0.6%. Secondly, the process requires multiple isolations and purifications ensuing into time engulfing workups and purifications and hence incurring solvent wastage. This makes process lengthy, uneconomical and tedious to be performed at plant scale.

Another PCT application no. WO 2012131710, discloses the preparation of Silodosin in which the chiral compound (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) is reacted with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate in isopropyl alcohol using sodium carbonate as base. The reaction is completed in 40-50h and about 9-11% of dimer is formed during condensation. After completion of reaction, it is subjected to hydroxyl deprotection and the crude compound so obtained is purified to remove the Ν,Ν-dialkyl impurity of Formula (lib). The pure compound is then reacted with hydrogen peroxide in dimethyl sulfoxide to give Silodosin. The major drawback of this process is that the process is a multistep process wherein the condensation reaction is long-drawn-out resulting into countable amount of dimer formation during the process.

Thus, the prior art methods of preparing Silodosin require multiple and repeated purifications to synthesize DMF (Drug Master File) grade Silodosin. None of the prior art produces compound of Formula (VI) or (VII) with Ν,Ν-dialkyl impurity of Formula (Ila) or (lib) in an amount less than 0.6% to 0.5% even after purification. Therefore to prepare highly pure Silodosin, there is a need to explore new synthetic schemes that could be more economical and scalable. The present invention provides a novel, improved, commercially viable and industrially advantageous process for the synthesis of Silodosin and its pharmaceutically acceptable salts or solvates thereof. The present invention focus on preparation of highly pure Silodosin in appreciable yields with minimal use of solvents wherein the Silodosin is isolated with purity >99.5% having Ν,Ν-dialkyl impurity less than 0.03% and other individual impurities below 0.1%.

Ramesh Juneja (seated), founder of Mankind Pharma, with brother Rajeev, who is senior director (marketing & sales)

Mankind Pharma Chairman and Founder RC Juneja

In accordance to one embodiment of the present invention, the process of the preparation of Silodosin represented by Formula (I)

comprises the steps of:

a) condensing chiral compound represented by Formula (III)

Formula (III)

wherein, Bz represents to Benzoyl group with compound represented by Formula (IV)

Formula (IV)

wherein, Ms represents to Methanesulfonyl group in presence of base and phase transfer catalyst in an organic solvent to give intermediate represented by Formula (V)

Formula (V)

wherein, n is an integer of 1 and 2 and Bz is as defined above, wherein the compound having n=2 is formed in an amount of less than 5%;

b) optionally isolating compound of Formula (V),

c) without purification converting it to de-protected compound represented by Formula (IX) in an organic solvent;

Formula (IX)

wherein, n is as defined above;

d) optionally isolating compound of Formula (IX), and

e) without purification converting it to compound represented by Formula (X)

Formula (X)

wherein n is as defined above;

f) subjecting compound of Formula (X) to purification by converting to acid salt for removal of Ν,Ν-dialkyl impurity represented by Formula (lie);

Formula (He)

g) hydrolysis of the said acid salt to get Silodosin of Formula (I) with purity >99.5%.

Examples

The invention is explained in detail in the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of Crude Silodosin:

Method A:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Cooled the reaction mass, added de-mineralized water and separated the toluene layer followed by distillation to get crude viscous mass. Added 110ml of dimethyl sulfoxide and a solution of 1.51g (0.0415 mol) of sodium hydroxide dissolved in 8.52ml of water followed by addition of 6.42g (0.0567 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at 20-25°C till completion and added sodium sulfite solution. Extracted the compound in ethylacetate, washed the organic layer with brine solution and concentrated to get 10.2g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.2% as per HPLC.

Method B:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 110ml of dimethyl sulfoxide and added a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10. lg of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.0% as per HPLC

Method C:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 2-3h. Added 100ml of water and 50ml of toluene and stirred the reaction mass at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure. To the crude mass so obtained was added 110ml of dimethyl sulfoxide and a solution of 4.4g of sodium hydroxide dissolved in 10ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.8 g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.1% as per HPLC

Method D:

To the solution of 20g (0.055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 200ml of toluene was added 28.6g (0.165 mol) of dipotassium hydrogen phosphate and 16.4g (0.0522 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 4.0g (0.11 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added de-mineralized water and stirred at room temperature for half an hour. Separated the toluene layer to which was added a solution of 8.8g of sodium hydroxide dissolved in 20ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 200ml of dimethyl sulfoxide and added a solution of 3.9g (0.0976 mol) of sodium hydroxide dissolved in 16ml of water followed by addition of 15g (0.132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 400ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 21. Og of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.8% as per HPLC

Method E:

To the solution of 2g (0.0055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 20ml of was dimethyl sulfoxide was added 2.87g (0.0165 mol) of dipotassium hydrogen phosphate and 1.64g (0.0052 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 0.29g (0.0011 mol) of 16-crown ether and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 0.88g of sodium hydroxide dissolved in 2ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 20ml of dimethyl sulfoxide and a solution of 0.38g (0.0231 mol) of sodium hydroxide dissolved in 1.6ml of water followed by addition of 1.5g (0.0132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 2.1g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.2% as per HPLC

Method F:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was acetonitrile was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.5g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.1% as per HPLC

Method G:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was Dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 4.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10.4g of crude Silodosin.

Ν,Ν-dialkyl impurity is 1.83% as per HPLC

Example 2

Purification of Crude Silodosin:

To the lOg (0.0080 mol) of crude mass of Silodosin was added 110ml of isopropyl alcohol followed by addition of 1.75g of oxalic acid at ambient temperature. Stirred the solution 6-8h and filtered the precipitates. Added ethyl acetate and water in the ratio of 1: 1 to the above solid followed by addition of 5ml of liquor ammonia. Stirred the reaction mass at ambient temperature for 15 min and separated the layers. Concentrated the organic layer to ¼ of its volume and left undisturbed overnight. Filtered the precipitates and recrystallized with ethyl acetate followed by drying under reduced pressure to get 5.1g of pure Silodosin. The amount of impurities and the percent impurity of the Silodosin obtained was as follows:

Ν,Ν-dialkyl impurity: undetectable amount

Other impurities: 0.03 to 0.09%

Silodosin purity: 99.65% (HPLC)

////WO 2016042441, Mankind Research Centre, Silodosin, New patent

RP 6503

phase 1

RP 6503

Mass: 619.1 (M⁺+l). MP: 175-178° C Specific optical rotation (C=l in chloroform, at 25°C) : [a]_D = + 147.16.

A1

RP 6503

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl) ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

(S)-N-[5-[4-amino-1-[1-[5-fluoro-3-(3-fluorophenyl)-4-oxochromen-2-yl]ethyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl]methanesulfonamide

Novartis to develop and commercialize Rhizen’s inhaled dual PI3K-delta gamma inhibitor and related compounds worldwide

The immune pipeline includes ‘dual PI3K inhibitors for various indications’ licensed to Novartis

‘inhaled dual inhibitor’,

Phosphoinositide-3 kinase delta inhibitor; Phosphoinositide-3 kinase gamma inhibitor

WO2011055215A2 and WO2012151525A1 and U.S. Publication Nos. US20110118257 and US20120289496

Rhizen Pharmaceuticals Sa   INNOVATOR

PATENT

http://www.google.com/patents/WO2011055215A2?cl=en

PATENT

http://www.google.com/patents/WO2012151525A1?cl=en

scheme 1A:

Ste -1

Step-2

Scheme 2

SCHEME 3

SCHEME4

List of Intermediates

Intermediate 27: 2-( l -(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin- l – yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To a solution of 3-iodo- l H- pyrazolo[3,4-d]pyrimidin-4-amine (0.800 g, 2.88 mmol) in DMF (5 ml), potassium carbonate (0.398 g, 2.88 mmol) was added and stirred at RT for 30 min. To this mixture intermediate 22 (0.500 g, 1.44 mmol) was added and stirred for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a off-white solid (0.300 g, 38%). Ή-NMR (5 ppm, DMSO-d₆₃, 400 MHz): 8.02 (s, 1 H), 7.94 (s, 1 H), 7.84 (dt, J = 8.4,5.7 Hz, 1H), 7.47 (d, 7 = 8.6 Hz, 1H), 7.29 (m, 3H), 7.09 (dt, 7 = 8.8,2.3 Hz, 1 H), 6.87 (s, 2H), 5.88 (q, 7 = 7.0 Hz, 1H), 1.82 (d, 7 = 7.0 Hz, 3H).

SYNTHESIS

MAIN PART

PATENT

http://www.google.com/patents/WO2015198289A1?cl=en

Prashant Kashinath Bhavar, Swaroop Kumar Venkata Satya VAKKALANKA

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H- chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

compound of formula (Al):

(Al).

The process comprises the steps of:

(a) subjecting (R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one:

to a Mitsunobu reaction with 3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine:

(for example, in the presence of triphenylphosphine and diisopropylazodicarboxylate) to give (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (Intermediate 3):

Intermediate 3;

(b) reducing Intermediate 3, for example with a reducing agent such as Raney Ni, to give (S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl)ethyl)-5-fluoro-3-( -fluorophenyl)-4H-chromen-4-one (Intermediate 4):

Intermediate 4;

The intermediates described herein may be prepared by the methods described in International Publication Nos. WO 11/055215 and WO 12/151525, both of which are hereby incorporated by reference.

Intermediate 1: N-(5-bromo-2-methoxyphenyl)methanesulfonamide:

To a solution of 5-bromo-2-methoxyaniline(1.00 g, 4.94 mmol) in dichloromethane (10 ml), pyridine (0.800 ml, 9.89 mmol) was added and cooled to 0°C. Methane sulphonyl chloride (0.40 ml, 5.19 mmol) was added and stirred for 30 min. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was chromatographed with ethyl acetate : petroleum ether to afford the title compound as a reddish solid (1.20 g, 87%).

Intermediate 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide: Potassium acetate (0.841 g, 8.57 mmol) and bis(pinacolato)diboron (1.190 g, 4.71 mmol) were added to a solution of intermediate 1 (1.20 g, 4.28 mmol) in dioxane (17.5 ml) and the solution was degassed for 30 min.[l, -Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH2Ci2 (0.104 g, 0.128 mmol) was added under nitrogen atmosphere and heated to 80°C. After 2h the

reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as a yellow solid (1.00 g, 71%).^JH-NMR (δ ppm, CDCb, 400 MHz): 7. 91 (d, / = 1.2Hz, 1H), 7. 62 (dd, / = 8.1, 1.2Hz, 1H), 6. 92 (d, / = 8.1Hz, 1H), 6.73 (s, 1H), 3.91 (s, 3H), 2.98 (s, 3H), 1.32 (s, 12H).

Intermediate 3: (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: (S)-2-(l-(4-amino-3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: To a solution of (R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one (0.500 g, 1.64 mmol) in THF (5 ml), 3-(4-methoxy-3-nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (0.564 g, 1.97 mmol) and triphenylphosphine (0.649 g, 2.47 mmol) were added followed by the addition of diisopropylazodicarboxylate (0.50 ml, 2.47 mmol). ((R)-5-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one can be prepared as described for Intermediates 23, 25, and 26 in International Publication No. WO 2012/0151525.). After 4h at room temperature, the mixture was concentrated and the residue was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as a brown solid (0.270 g, 29%). ^JH-NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (s, 1H), 7.83 (m, 1H), 7.63-7.50 (m, 3H), 7.29 (m, 2H), 7.06 (dt, J = 8.7,2.2Hz, 1H), 6.94 (m, 2H), 6.75 (dd, J = 8.1,2.1Hz, 1H), 5.95 (q, J = 7.0Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H), 1.86 (d, J = 7.0 Hz, 3H).

[109] Intermediate 4: (S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one:

(S)-2-(l-(4-amino-3-(3-amino-4-methoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one : To a solution of Intermediate 3 (0.260 g, 0.455 mmol) in ethanol (5 ml), Raney Ni (0.130 g) was added and hydrogeneated at 20psi at 50°C for 24h. The reaction mixture was passed through celitepad and concentrated to afford the title compound as a brown solid (0.150 g, 60%). Mass : 540.8 (M⁺).

Example A

N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

To a solution of 2-(l-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (0.200 g, 0.366 mmol) in DME (2.1 ml) and water (0.67 ml), intermediate 2 (0.179 g, 0.550 mmol) and sodium carbonate (0.116 g, 1.10 mmol) were added and the system was degassed for 30 min. (2-(l-(4-amino-3-iodo-lH^yrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one can be prepared as described for Intermediates 23, 25, and 26 in International Publication No. WO 2012/0151525). Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.059 g, 0.075 mmol) was added and kept under microwave irradiation (microwave power = 100W, temperature = 100 °C) for 45 min. The reaction mixture was Celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a brown solid (0.080 g, 35%). MP: 216-218 °C. ¾-NMR (δ ppm, CDCb, 400 MHz): 8.20 (s, 1H), 7.73 (s, 1H), 7.53 (m, 2H), 7.31 (m, 2H), 7.07-6.73 (m, 6H), 6.07 (q, / = 6.2 Hz, 1H), 3.98 (s, 3H), 3.14 (s, 3H), 2.01 (d, / = 6.0Hz, 3H).

Example Al and A2

Method A

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

and (R)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2- yl)ethyl)-lH-p anesulfonamide

The two enantiomerically pure isomers were separated by preparative SFC (supercritical fluid) conditions from N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide (0.500 g) on a CHIRALPAK AS-H column (250 x 30 mm; 5μπι) using methanol : CO2 (55:45) as the mobile phase at a flow rate of 80g / min.

Example Al (S-isomer): Brown solid (0.247 g). Enantiomeric excess: 97.4%. Retention time: 2.14 min. Mass: 619.1 (M⁺+l). MP: 156-158° C.

Example A2 (R-isomer): Brown solid (0.182 g). Enantiomeric excess: 99.3%. Retention t: 3.43 min. Mass: 619.1 (M⁺+l). MP: 168-171° C.

Method Al

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

and (R)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2- yl)ethyl)-lH-p anesulfonamide

The two enantiomerically pure isomers were separated by preparative SFC (supercritical fluid) conditions from N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methanesulfonamide (15.0 g) on a CHIRALPAK AS-H column (250 x 20 mm; 5μπι) using methanol : CO2 (45:55) as the mobile phase at a flow rate of 120g / min.

Example Al (S-isomer): Enantiomeric excess: 100 %. Retention time: 2.21 min. Mass: 619.1 (M⁺+l). MP: 175-178° C Specific optical rotation (C=l in chloroform, at 25°C) : [a]_D = + 147.16.

Example A2 (R-isomer): Enantiomeric excess: 99.3%. Retention t: 3.72 min. Mass: 619.1 (M⁺+l). MP: 154-157° C. Specific optical rotation (C=l in chloroform, at 25°C) : [a]_D = – 159.54.

Method B

Example Al

(S)-N-(5-(4-amino-l-(l-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)- lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide

To a solution of Intermediate 4 (0.500 g, 0.923 mmol) in dichloromethane (5 ml) cooled to 0°C, pyridine (0.200 ml, 1.84 mmol) was added and stirred for 10 min. Methanesulphonyl chloride (0.100 ml, 0.923 mmol) was added stirred for 30 min. The reaction mixture was quenched with water, extracted with dichloromethane and dried over sodium sulphate. The crude product was column chromatographed with methanol : dichloromethane to afford the title compound as an off-white solid (0.240 g, 42%). MP: 211-213°C. ¾-NMR (δ ppm, DMSO-d6, 400 MHz): 9.15 (s, 1H), 8.06 (s, 1H), 7.83 (m, 1H), 7.49 (m, 4H), 7.28 (m, 4H), 7.08 (dt, / = 8.6, 1.7 Hz, 1H), 6.92 (s, 2H), 5.98 (q, / = 6.9 Hz, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 1.88 (d, / = 7.0 Hz, 3H). Enantiomeric excess: 85.4% as determined by HPLC on a chiralpak AS-3R column, enriched in the fast eluting isomer (retention time = 7.46 min.).

CLIPS

La Chaux-de-Fonds, Switzerland, Sept. 6, 2013  — La Chaux-de-Fonds, Switzerland (6 September 2013): Rhizen Pharmaceuticals S.A. announces a scientific poster presentation on the pre-clinical characterization of its lead calcium release activated channel (CRAC) inhibitor, RP3128, for the treatment of respiratory disorders and an oral presentation on the pharmacological profile of its novel, dual Phosphoinositide-3 kinase (PI3K) delta/gamma inhibitor, RP6503, in the pulmonary disease systems, at the European Respiratory Society Annual Congress (ERS), to be held from 7-11 September 2013, at Barcelona, Spain.

RP6503 is a novel, potent and selective inhibitor of the delta and gamma isoforms of PI3K. It is to be delivered via the inhalation route and has a long duration of action along with excellent PI3K isoform selectivity, which is expected to result in better safety. RP3128 has been optimized with high potency for CRAC channel inhibition, selectivity over the other voltage gated channels and excellent oral bioavailability. Rhizen intends to move both these compounds to the clinic in 2014.

Details of the presentations:

1.      Abstract of the Poster Presentation: “Pre-clinical characterization of RP3128, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders”

Time and Location- 8 September 2013 between 14.45-16.45 in Room 3.6, at Poster Discussion: New drugs in respiratory medicine, at FIRA BARCELONA, Convention Centre de Gran Via, Barcelona, Spain

2.      Abstract of Oral Presentation: “In vitro and in vivo pharmacological profile of RP6503, a novel dual PI3K delta/gamma inhibitor, in pulmonary disease systems”

Time and Location- 11 September 2013 at 8.45 in Room 3.9; Session 8.30-10.30, at the Oral Presentation: Emerging new targets for the treatment of respiratory diseases, at FIRA BARCELONA, Convention Centre de Gran Via, Barcelona, Spain

CLIPS

La Chaux-de-Fonds, Switzerland , Dec. 09, 2015  — Rhizen Pharmaceuticals S.A. announced today that they have entered into an exclusive, worldwide license agreement with Novartis for the development and commercialization of Rhizen’s, inhaled dual PI3K-delta gamma inhibitor and its closely related compounds for various indications.

Under the terms of the agreement, Rhizen will receive an upfront payment and is eligible to receive development, regulatory and sales milestones payments. In addition Rhizen is also eligible to receive tiered royalties on annual nets sales.

The lead compound is a novel, potent, and selective dual PI3K-delta gamma inhibitor with demonstrated anti-inflammatory and immuno-modulatory activity in pre-clinical systems and models representative of respiratory diseases. With a favorable ADME and PK profile and high therapeutic index in animals, the inhaled dual PI3K-delta gamma inhibitor holds promise in the treatment of human airway disorders.

About Rhizen Pharmaceuticals S.A.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel therapeutics for the treatment of cancer, immune and metabolic disorders. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways. Rhizen is headquartered in La-Chaux-de-Fonds, Switzerland. For additional information, please visit Rhizen’s website, http://www.rhizen.com.

SEE

https://newdrugapprovals.org/2015/12/10/alembic-pharma-advances-1-on-rhizen-novartis-license-agreement/

WO-2015181728 

WO-2015001491 

WO-2014072937 

WO-2014006572 

http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880

///////RP 6503, Novartis, develop, commercialize,  Rhizen, inhaled dual PI3K-delta gamma inhibitor, PHASE 1, RP-6503

c21c(cccc1O/C(=C(\C2=O)c3cc(ccc3)F)C(C)n4c6ncnc(c6c(n4)c5cc(c(cc5)OC)NS(=O)(=O)C)N)F

CC(C1=C(C(=O)C2=C(O1)C=CC=C2F)C3=CC(=CC=C3)F)N4C5=C(C(=N4)C6=CC(=C(C=C6)OC)NS(=O)(=O)C)C(=NC=N5)N

/////

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

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

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

 PATENT

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

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

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

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

PATENT

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

AUNP-12

AUR-012; Aurigene-012; NP-12, Aurigene; PD-1 inhibitor peptide (cancer), Aurigene; PD-1 inhibitor peptide (cancer), Aurigene/ Pierre Fabre; W-014A

Aurigene Discovery Technologies Limited

INNOVATOR

• Programmed Cell Death 1 or PD-1 (also referred to as PDCD1) is a 50 to 55 kD type I membrane glycoprotein (Shinohara T et al, Genomics, 1994, Vol. 23, No. 3, pp. 704-706). PD-1 is a receptor of the CD28 superfamily that negatively regulates T cell antigen receptor signalling by interacting with the specific ligands and is suggested to play a role in the maintenance of self tolerance.
• PD-1 peptide relates to almost every aspect of immune responses including autoimmunity, tumour immunity, infectious immunity, transplantation immunity, allergy and immunological privilege.
• The PD-1 protein’s structure comprise of—

  • • an extracellular IgV domain followed by
    • a transmembrane region and
    • an intracellular tail
• The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. Also, PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, (Y. Agata et al., Int Immunol 8, 765, May 1996) suggesting that compared to CTLA-4 ((Cytotoxic T-Lymphocyte Antigen 4, also known as CD152 (Cluster of differentiation 152) is a protein that also plays an important regulatory role in the immune system), PD-1 more broadly negatively regulates immune responses.
• PD-1 has two ligands, PD-L1 (Programmed Death Ligand for PDCD1L1 or B7-H1) (Freeman G J et al, Journal of Experimental Medicine, 2000, Vol. 19, No. 7, pp. 1027-1034) and PD-L2 (Programmed Death Ligand 2 or PDCD1L2 or B7-DC) (Latchman Y et al, Nature Immunology, 2001, Vol. 2, No. 3, pp. 261-267), which are members of the B7 family. PD-L1 is known to be expressed not only in immune cells, but also in certain kinds of tumour cell lines (such as monocytic leukaemia-derived cell lines, mast cell tumour-derived cell lines, hematoma-derived cell lines, neuroblastoma-derived cell lines, and various mammary tumour-derived cell lines) and in cancer cells derived from diverse human cancer tissues (Latchman Y et al, Nature Immunology, 2001, Vol. 2, No. 3, pp. 261-267) and on almost all murine tumour cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ (Y. Iwai et al., Proc Natl Acad Sci USA 99, 12293, Sep. 17, 2002 and C. Blank et al., Cancer Res 64, 1140, February, 2004). Similarly PD-L2 expression is more restricted and is expressed mainly by dendritic cells and a few tumour cell lines. PD-L2 expression has been verified in Hodgkin’s lymphoma cell lines and others. There is a hypothesis that some of the cancer or tumour cells take advantage from interaction between PD-1 and PD-L1 or PD-L2, for suppressing or intercepting T-cell immune responses to their own (Iwai Y et al, Proceedings of the National Academy of Science of the United States of America, 2002, Vol. 99, No. 19, pp. 12293-12297).
• Tumour cells and virus (including HCV and HIV) infected cells are known to express the ligand for PD-1 (to create Immunosuppression) in order to escape immune surveillance by host T cells. It has been reported that the PD-1 gene is one of genes responsible for autoimmune diseases like systemic lupus erythematosis (Prokunina et al, Nature Genetics, 2002, Vol. 32, No. 4, 666-669). It has also been indicated that PD-1 serves as a regulatory factor for the onset of autoimmune diseases, particularly for peripheral self-tolerance, on the ground that PD-1-deficient mice develop lupus autoimmune diseases, such as glomerulonephritis and arthritis (Nishimura H et al, International Immunology, 1998, Vol. 10, No. 10, pp. 1563-1572; Nishimura H et al, Immunity, 1999, Vol. 11, No. 2, pp. 141-151), and dilated cardiomyopathy-like disease (Nishimura H et al, Science, 2001, Vol. 291, No. 5502, pp. 319-332).
• Hence, in one approach, blocking the interaction of PD-1 with its ligand (PD-L1, PD-L2 or both) may provide an effective way for specific tumour and viral immunotherapy.
• Wood et al in U.S. Pat. No. 6,808,710 discloses method for down modulating an immune response comprising contacting an immune cell expressing PD-1 with an antibody that binds to PD-1, in multivalent form, such that a negative signal is transduced via PD-1 to thereby down modulate the immune response. Such an antibody may be a cross-linked antibody to PD-1 or an immobilized antibody to PD-1.
• Freeman et al in U.S. Pat. No. 6,936,704 and its divisional patent U.S. Pat. No. 7,038,013 discloses isolated nucleic acids molecules, designated B7-4 nucleic acid molecules, which encode novel B7-4 polypeptides, isolated B7-4 proteins, fusion proteins, antigenic peptides and anti-B7-4 antibodies, which co-stimulates T cell proliferation in vitro when the polypeptide is present on a first surface and an antigen or a polyclonal activator that transmits an activating signal via the T-cell receptor is present on a second, different surface.
• There are some reports regarding substances inhibiting immunosuppressive activity of PD-1, or interaction between PD-1 and PD-L1 or PD-L2, as well as the uses thereof. A PD-1 inhibitory antibody or the concept of a PD-1 inhibitory peptide is reported in WO 01/14557, WO 2004/004771, and WO 2004/056875. On the other hand, a PD-L1 inhibitory antibody or a PD-L1 inhibitory peptide is reported in WO 02/079499, WO 03/042402, WO 2002/086083, and WO 2001/039722. A PD-L2 inhibitory antibody or a PD-L2 inhibitory peptide is reported in WO 03/042402 and WO 02/00730.
• WO2007005874 describes isolated human monoclonal antibodies that specifically bind to PD-L1 with high affinity. The disclosure provides methods for treating various diseases including cancer using anti-PD-L1 antibodies.
• US2009/0305950 describes multimers, particularly tetramers of an extracellular domain of PD-1 or PD-L1. The application describes therapeutic peptides.
• Further, the specification mentions that peptides can be used therapeutically to treat disease, e.g., by altering co-stimulation in a patient. An isolated B7-4 or PD-1 protein, or a portion or fragment thereof (or a nucleic acid molecule encoding such a polypeptide), can be used as an immunogen to generate antibodies that bind B7-4 or PD-1 using standard techniques for polyclonal and monoclonal antibody preparation. A full-length B7-4 or PD-1 protein can be used, or alternatively, the invention provides antigenic peptide fragments of B7-4 or PD-1 for use as immunogens. The antigenic peptide of B7-4 or PD-1 comprises at least 8 amino acid residues and encompasses an epitope of B7-4 or PD-1 such that an antibody raised against the peptide forms a specific immune complex with B7-4 or PD-1. Preferably, the antigenic peptide comprises at least 10 amino acid residues, more preferably at least 15 amino acid residues, even more preferably at least amino acid residues, and most preferably at least 30 amino acid residues.
• Freeman et al in U.S. Pat. No. 7,432,059 appears to disclose and claim methods of identifying compounds that up modulate T cell activation in the presence of a PD-1-mediated signal. Diagnostic and treatment methods utilizing compositions of the invention are also provided in the patent.
• Further, Freeman et al in U.S. Pat. No. 7,709,214 appears to cover methods for up regulating an immune response with agents that inhibit the interactions between PD-L2 and PD-1.
• Despite existence of many disclosures as discussed above, however, a significant unmet medical need still exists due to the lack of effective peptides or modified peptides as therapeutic agents as alternatives in the therapeutic area. It is known that synthetic peptides offer certain advantages over antibodies such as ease of production with newer technologies, better purity and lack of contamination by cellular materials, low immunogenicity, improved potency and specificity. Peptides may be more stable and offer better storage properties than antibodies. Moreover, often peptides possess better tissue penetration in comparison with antibodies, which could result in better efficacy. Peptides can also offer definite advantages over small molecule therapeutics counterparts such as lesser degree of toxicity and lower probability of drug-drug interaction.
• The present invention therefore may provide the solution for this unmet medical need by offering novel synthetic peptide and its derivatives which are based on the PD1 ectodomain.

Patent

http://www.google.com/patents/US20110318373

8.

SNTSESFK(SNTSESF)FRVTQLAPKAQIKE-NH2 (SEQ ID NO: 49)

CASTRES, France and BANGALORE, India, February 13, 2014 /PRNewswire/ —

Pierre Fabre, the third largest French pharmaceutical company, and Aurigene, a leading biotech company based in India, today announced that the two companies have entered into a collaborative license, development and commercialization agreement granting Pierre Fabre global Worldwide rights (excluding India) to a new immune checkpoint modulator, AUNP-12.

AUNP-12 offers a breakthrough mechanism of action in the PD-1 pathway compared to other molecules currently in development in the highly promising immune therapy cancer space. AUNP-12 is the only peptide therapeutic in this pathway and could offer more effective and safer combination opportunities with emerging and established treatment regimens.  AUNP-12 will be in development for numerous cancer indications.

Under the terms of this agreement, Aurigene will receive an upfront payment from Pierre Fabre. Aurigene will also receive additional milestone payments based upon the continued development, regulatory progresses and commercialization of AUNP-12.

“We are pleased that Pierre Fabre see the PD-1 program as a strategic asset in their portfolio. Overall, the deal structure, in line with the financial terms that have been seen in this space, demonstrate the importance that Pierre Fabre attach to the program,” said CSN Murthy, CEO, Aurigene.

“The plans that Pierre Fabre have detailed for the development of this differentiated asset highlight the long-term opportunities for this novel cancer therapeutic,” added Murali Ramachandra, Sr VP, Research, Aurigene.

“This agreement, in the field of oncology, is fully consistent with our vision to build Pierre Fabre’s future in prescription drugs, from a combination of cutting-edge internal R&D capabilities and license partnerships with innovative biotech companies like Aurigene,” stated Bertrand Parmentier, CEO, Pierre Fabre.

“With this deal, Pierre-Fabre Pharmaceuticals are reinforcing their portfolio of oncology assets and capitalizing on their proven capabilities in developing biological compounds such as monoclonal antibodies and immuno-conjugates. We have been impressed by the science at Aurigene and encouraged by the differentiated profile reported for AUNP-12,” added Frédéric Duchesne, President, Pierre Fabre Pharmaceuticals.

About immuno-oncology

Immuno-oncology is an emerging field in cancer therapy, where the body’s own immune system is harnessed to fight against cancer. This approach of targeting cancer through immune response has had a breakthrough when robust and sustained responses were obtained only upon blocking the immune checkpoint targets (such as PD-1 and CTLA4). Recent successes in clinical trials performed with such therapies suggest that immunotherapy should be considered alongside surgery, chemotherapy, radiotherapy and targeted therapy as the fifth cornerstone of cancer treatment.

PD-1 (Programmed cell Death 1) is a receptor that negatively regulates T-cell activation by interacting with specific ligands PD-L1 and PD-L2. Tumor cells express these ligands and thereby escape from the action of T-cells.

About AUNP-12

AUNP-12  is a branched 29-amino acid peptide sequence engineered from the PD-L1/ L2 binding domain of PD-1 It blocks the PD-1/PD-L1, PD-1/PD-L2 and PD-L1/CD80 pathways. AUNP-12 is highly effective in antagonizing PD-1 signaling, with desirable in vivo exposure upon subcutaneous dosing. It inhibits tumor growth and metastasis in preclinical models of cancer and is well tolerated with no overt toxicity at any of the tested doses.

About Aurigene

Aurigene is a biotech focused on development of innovative small molecule and peptide therapeutics for Oncology and Inflammation; key focus areas for Aurigene are Immuno-oncology, Epigenetics and the Th17 pathway. Aurigene’s PD-1 program is the first of several peptide-based immune checkpoint programs that are at different stages of Discovery.

Aurigene has partnered with several big pharma and mid-pharma companies in the US and Europe, and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies.

Aurigene’s pre-clinical pipeline includes (1) Selective and pan-BET Bromodomain inhibitors (2) RoR gamma reverse agonists (3) EZH2 inhibitors (4) NAMPT inhibitors and (5) Several immune check point peptide inhibitor programs.

For more information:  http://aurigene.com/

About Pierre Fabre:

Pierre Fabre is a privately-owned health care company created in 1961 by Mr Pierre Fabre. It is the second largest French independent pharmaceutical group with 2013 sales amounting to about €2 billion (yet to be audited) across 140 countries. The company is structured around two divisions: Pharmaceuticals (Prescription drugs, OTC, Oral care) and Dermo-cosmetics. Prescription drugs are organized around four main franchises: oncology, dermatology, women’s health and neuropsychiatry. Pierre Fabre employs some 10 000 people worldwide, including 1 300 in R&D. The company allocates about 20% of its pharmaceuticals sales to R&D and relies on more than 25 years of experience in the discovery, development and global commercialization of innovative drugs in oncology. Pierre Fabre has a long commitment to oncology and immunology with major R&D centers in France: the Pierre Fabre immunology Centre (CIPF) in Saint Julien en Genevois and the Pierre Fabre Research Institute (IRPF) located on the Toulouse-Oncopole campus  which has been officially recognized as a National Center of Excellence for cancer research since 2012.

REFERENCES

http://www.differding.com/data/AUNP_12_A_novel_peptide_therapeutic_targeting_PD_1_immune_checkpoint_pathway_for_cancer_immunotherapy.pdf

Mr. CSN Murthy began his career with ICICI Ventures, India’s first Venture Capital fund. He was subsequently a management consultant to the Pharma and Chemical sectors. Later, he worked in the Business Development and General Management functions in Pharmaceutical companies, including as the Chief Operating Officer of Gland Pharma Ltd. CSN holds a Bachelors degree in Chemical Engineering from the Indian Institute of Technology (IIT), Madras and an MBA from the Indian Institute of Management (IIM), Bangalore.

Dr.Thomas Antony did his Ph.D in Biophysical Chemistry from University of Delhi and had his postdoctoral training at Jawaharlal Nehru University- Delhi, The University of Medicine and Dentistry of New Jersey- USA, and Max Planck Institute for Biophysical Chemistry- Germany. He is the recipient of many research fellowships, including Max Planck Fellowship and Humboldt Research Fellowship.  He has more than 20 years of research experience. Dr.Thomas has published 24 research papers and he is the co-author of three international patents. His core area of expertise is in assay development and screening. At Aurigene, Dr.Thomas leads the Biochemistry and Structural Biology Divisions.  He was the coordinator of Aurigene-University of Malaya collaboration programs.

Dr. Kavitha Nellore obtained her PhD in Bioengineering from Pennsylvania State University, USA.  During this time, she was a fellow of the Huck’s Institute of Life Sciences specializing in Biomolecular Transport Dynamics. She has been at Aurigene for more than a decade, and is currently leading a group of cell biologists at both Bangalore and Kuala Lumpur. At Aurigene, she leads multiple drug discovery programs in the therapeutic areas of inflammation, oncology and immuno-oncology. She plays a key role in target selection as well as validation efforts to add to Aurigene’s pipeline. Kavitha also played a key role in coordinating the Aurigene-University of Malaya collaboration.

To print: Click here or Select File and then Print from your browser's menu

/////////AUNP-12,  Aurigene,  Pierre Fabre Pharmaceuticals, Licensing Agreement,  New Cancer Therapeutic,  Immuno-oncology, AUNP 12, Immune Checkpoint Modulator Targeting the PD-1 Pathway, PEPTIDES

P7435

Piramal Enterprises Mumbai, India

P-7435; P7435-DGAT1, P7435, P 7435

GDAT1 inhibitor

• Phase IDiabetes mellitus; Lipid metabolism disorders

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

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

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

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

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

cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

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

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

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

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

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

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

PATENT

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

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

A. Phenylacetic Acid Ethyl Ester

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

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

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

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

PATENT

EP-1735322-B1

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

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

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

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

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

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

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

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

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

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

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

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

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

////////Dr. Reddy’s Laboratories,  CEO , G V Prasad, India’s top 5 most valuable CEOs

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

CHEMISTRY COLLABORATORS

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

Credit: Aurigene

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

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

CFG920

WO 2010149755

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

Example 58

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

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

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

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

HPl C: 97.14%

REFERENCES

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

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

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

MF C18H22N2O
MW: 282.17321

GDC-0919; NLG-919; RG-6078, GDC0919; GDC-0919; GDC 0919; NLG919; NLG 919; NLG-919; RG6078; RG-6078; RG 6078.

 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol
CAS No.1402836-58-1

GDC-0919, also known as NLG919 and RG6078, is an orally available inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), with potential immunomodulating and antineoplastic activities. Upon administration, NLG919 targets and binds to IDO1, a cytosolic enzyme responsible for the oxidation of the essential amino acid tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, this agent increases tryptophan levels, restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, T-lymphocytes, and causes a reduction in tumor-associated regulatory T-cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may induce a cytotoxic T-lymphocyte (CTL) response against the IDO1-expressing tumor cells

• Originator Lankenau Institute for Medical Research
• Developer Genentech; NewLink Genetics Corporation
• Class Antineoplastics; Small molecules
• Mechanism of Action Immunomodulators; Indoleamine-pyrrole 2,3-dioxygenase inhibitors

Phase I Solid tumours

• 27 Sep 2015 Pharmacokinetics results from a phase-I clinical trial in Solid tumours presented at the European Cancer Congress 2015 (ECC-2015)
• 27 Sep 2015 Positive efficacy and safety results from a phase-I clinical trial in Solid tumours presented at the European Cancer Congress 2015 (ECC-2015)
• 31 Jul 2015 Phase-I clinical trials in Solid tumours (Combination therapy, Late-stage disease, Second-line therapy or greater) in USA (PO) (NCT02471846)

PATENT

http://www.google.com/patents/WO2012142237A1?cl=en

PATENT

Fused Imidazole Derivatives Useful as IDO Inhibitors

13041-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol79 ¹H NMR (a mixture of diastereomers) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m, 1H), 5.36 and 5.46 (two m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.80 (s, 1H)

REFERENCES

Nature Reviews Drug Discovery14,373(2015)doi:10.1038/nrd4658

http://www.ncbi.nlm.nih.gov/pubmed/21517759

http://www.roche.com/irp150128-annex.pdf

/////CRD1152, CRD 1152, CRD-1152, Curadev,  Research Collaboration, Licensing Agreement, Develop,  Cancer Immunotherapeutic, IDO1 and TDO inhibitors

OC(C1CCCCC1)CC(C2=C3C=CC=C2)N4C3=CN=C4

Several candidates….one is…….CRD1152

ONE OF THEM IS CRD 1152

Kynurenine pathway regulators (solid tumors)

Compound 2

CAS1638121-21-7

US159738837

N³-(3-Chloro-4- fluorophenyl) furo[2,3- c]pyridine-2,3- diamine

COMPD 190

CAS 1638118-99-6

US159738837

COMPD248

US159738837

7-Chloro-N3- (3-chloro-4- fluorophenyl) furo[2,3- c]pyridine-2,3- diamine,  166

DMSO-d₆: δ 7.87 (d, J = 5.1 Hz, 1H), 7.25 (s, 2H), 7.16-7.10 (m, 2H), 6.88 (d, J = 5.1 Hz, 1H), 6.59 (dd, J′ = 6.2 Hz, J″ = 2.6 Hz, 1H), 6.48 (dt, J′ = 8.8 Hz, J″ = 6.7 Hz, J′′′ = 3.4 Hz, 1H) M + H] 312

US159738837

OR

N³-(3,4- difluorophenyl)- 7-(pyridin-4- yl)furo[2,3- c]pyridine-2,3- diamine, 184

CD₃CN: δ 8.72 (s, 2H), 8.26 (s, 3H), 7.07-7.03 (m, 2H), 6.47-6.40 (m, 2H), 5.74 (s, 1H), 5.55 (s, 2H) M + H] 339

US159738837

OR

COMPD73

CAS 1638117-85-7

US159738837

Several candidates………..CRD1152

67

66

Hoffmann-La Roche partners with Curadev Pharma Ltd. for IDO1 and TDO inhibitors (April 20, 2015)

Curadev Pharma Pvt Ltd., founded in 2010 and headquartered in New Delhi, announced that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors to treat cancer. The agreement covers the development of CRD1152, the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

IDO1 (indoleamine-2,3-dioxygenase-1) and TDO (tryptophan-2,3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response. Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments, as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev is also eligible for milestones and royalties on any additional products resulting from the research collaboration.

NEW DELHI, India, April 20, 2015 /PRNewswire/ —

Curadev Pharma Private Ltd. today announced that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors. The agreement covers the development of the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response.

Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan – to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

“We are very excited to be working with the global leader in oncology with their unrivalled expertise in clinical development,” said Arjun Surya, PhD, Chief Scientific Officer, Curadev. “The collaboration acknowledges our focused research efforts on patient-critical drug targets that have yielded a drug candidate that could make a significant difference in the development of novel treatments for patients suffering from cancer.”

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization to further extend Curadev’s findings, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments based on achievement of certain predetermined events and sales levels as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev would also be eligible for milestones and royalties on any additional products resulting from the research collaboration. Roche will fund future research, development, manufacturing and commercialization costs and will also provide additional research funding to Curadev for support of the research collaboration.

About Curadev

Headquartered in New Delhi, India, Curadev Pharma Private Limited was founded in 2010 by a team of professionals from the pharmaceutical and biotech sectors with the mission to improve human health and enhance the quality of human life by accelerating the discovery and delivery of new drugs. Curadev focuses on the creation and out-licensing of pre-IND assets and IND packages for drug development.

For further information:

Curadev Partnering

Manish Tandon – VP and Chief Financial Officer, manish@curadev.in

PATENT

US20160046596) INHIBITORS OF THE KYNURENINE PATHWAY

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159738837&recNum=2&maxRec=17&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28curadev%29&tab=PCTDescription

Monali Banerjee
Sandip Middya
Ritesh Shrivastava
Sushil Raina
Arjun Surya
Dharmendra B. Yadav
Veejendra K. Yadav
Kamal Kishore Kapoor
Aranapakam Venkatesan
Roger A. Smith
Scott K. Thompson

ONE ………….Example 2

Synthesis of N³-(3-Chloro-4-fluoro-phenyl)-furo[2,3-c]pyridine-2,3-diamine (Compound 2)

Step 1: 3-Methoxymethoxy-pyridine

Step 2: 3-Methoxymethoxy-pyridine-4-carbaldehyde

Step 3: 3-Hydroxy-pyridine-4-carbaldehyde

Step 4: 4-{[3-Chloro-4-fluoro-phenylimino]-methyl}-pyridin-3-ol

Step 5: N³-(3-Chloro-4-fluoro-phenyl)-furo[2,3-c]pyridine-2,3-diamine

writeup

///////CRD1152, CRD-1152, CRD 1152, CURADEV PHARMA PRIVATE LTD, ROCHE, IDO1 and TDO inhibitors, COLLABORATION, CANCER, indoleamine-2,3-dioxygenase-1, Hoffmann-La Roche, kynurenine pathway regulators, solid tumors

.

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

• 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

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

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.

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

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

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,

//////////

Dear Readers
I am on  editorial board ……… Editorial Board member for our Journal of Analytical & Pharmaceutical Research………http://medcraveonline.com/JAPLR/editorial-board

This is possible with your cooperation and support

read…….http://medcraveonline.com/JAPLR/JAPLR-02-00010.pdf
http://medcraveonline.com/JAPLR/JAPLR-02-00011.pdf

Tackling the Challenges with Poorly Soluble Drugs
http://medcraveonline.com/JAPLR/JAPLR-01-00001.pdf

GDC-0084
CAS#: 1382979-44-3
Chemical Formula: C18H22N8O2
Exact Mass: 382.1866

Synonym: RG7666; RG-7666; RG 7666; GDC-0084; GDC0084; GDC 0084.

IUPAC/Chemical Name: 5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine

• Originator Genentech
• Class Antineoplastics; Small molecules
• Mechanism of Action 1 Phosphatidylinositol 3 kinase inhibitors

• 28 Jan 2015 Discontinued – Phase-I for Glioma in Spain (unspecified route)
• 28 Jan 2015 Discontinued – Phase-I for Glioma in USA (unspecified route)
• 01 Jan 2015 Genentech completes a phase I trial in Glioma in USA and Spain (NCT01547546)

GDC-0084, also known as RG7666, is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. PI3K inhibitor GDC-0084 specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in the inhibition of both cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis.

http://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.6b00005

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

//////GDC-0084

NC1=NC=C(C2=NC(N3CCOCC3)=C4N=C(C(C)(C)OCC5)N5C4=N2)C=N1

5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine GDC-0084 

mp 211 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 2H), 7.03 (s, 2H), 4.32–4.17 (m, 4H), 4.17–4.04 (m, 4H), 3.84–3.65 (m, 4H), 1.58 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ 163.8, 157.6, 154.2, 152.5, 151.3, 151.0, 120.3, 117.3, 73.7, 66.2, 57.8, 45.2, 41.5, 27.3. HRMS [M + H]+calcd for C18H22N8O2 383.1938; found 383.1945.

1. The Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of Class I Phosphoinositide 3-Kinases (PI3K) and mTOR.

   Heffron, T.; Ndubaku, C.; Salphati, L.; Alicke, B.; Cheong, J.;Drobnick, J.; Edgar, K.; Gould, S.; Lee, L.; Lesnick, J.; Lewis, C.; Nonomiya, J.; Pang, j.; Plise, E.; Sideris,S.; Wallin, J.; Wang, L.; Zhang, X.; Olivero, A. ACS Med. Chem. Lett. 2016, , DOI: 10.1021/acsmedchemlett.6b00005

2. 3.

   (a) Purine Derivatives Useful as PI3 Kinase Inhibitors. Goldsmith, P.; Hancox, T. C.; Hudson, A.; Pegg, N. A.; Kulagowski, J. J.; Nadin, A. J.; Price, S. PCT Int. Appl. WO 2009053716 A1 Apr 30, 2009.

   (b) Preparation of Purine Derivatives with PI3K Inhibitory Activity and Methods of Use Thereof. Castanedo, G.; Chuckowree,I.; Folkes, A.; Sutherlin, D. P.; Wan, N. C. PCT Int. Appl. WO 2009146406 A1 Dec 3, 2009

DS 2330

a trans compd

4-[2-(4-{[2-({3-[(trans-4-carboxy-cyclohexyl)(ethyl)sulfocarbamoyl]benzoyl}amino)-5-(piperidin-1-yl)benzoyl]amino}phenyl)ethyl]benzoic acid,

4- [2- (4 – {[2 – ({3 – [(trans-4-carboxy-cyclohexyl) (ethyl) sulfur carbamoyl] benzoyl} amino) -5- (piperidin-1-yl) benzoyl] amino} phenyl) ethyl] benzoate

• Originator Daiichi Sankyo Inc
• Class Hyperphosphataemia therapies

useful for treating hyperphosphatemia, DS-2330, a phosphorous lowering agent, being developed by Daiichi Sankyo, for treating hyperphosphatemia in chronic kidney disease. In April 2016, DS-2330 was reported to be in phase 1 clinical development.

• Phase IHyperphosphataemia

• 31 Oct 2015Phase-I clinical trials in Hyperphosphataemia in USA (unspecified route)

SEE  WO2015108038,

PATENT

WO2014175317

http://www.google.com/patents/EP2990400A1?cl=en

PATENT

WO-2016047613

he problem is to provide a pharmaceutical for the prevention or treatment of hyperphosphatemia. The solution is a salt of a compound including formula (I), or a crystal of a hydrate thereof.

[Formula 7] crystal of disodium salt trihydrate of (α crystal)

REFERENCES

http://www.daiichisankyo.com/media_investors/investor_relations/ir_calendar/files/005280/Presentation%20Material.pdf

////////////DS 2330, DS-2330, DAIICHI SANKYO, phase 1

O=C(O)[C@@H]1CC[C@H](CC1)N(CC)S(=O)(=O)c2cccc(c2)C(=O)Nc5ccc(cc5C(=O)Nc4ccc(CCc3ccc(cc3)C(=O)O)cc4)N6CCCCC6

OR

O=C(O)[C@@H]1CC[C@H](CC1)N(CC)S(=O)(=O)c2cccc(c2)C(=O)Nc5ccc(cc5C(=O)Nc4ccc(CCc3ccc(cc3)C(=O)O)cc4)N6CCCCC6

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Debio 1142

Jak2 tyrosine kinase inhibitor; Src tyrosine kinase inhibitor

N-[4-methyl-3-[2-[4-(4-methylpiperazin-1-yl)anilino]-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide

Debiopharm S.A., Aurigene Discovery Technologies Ltd.

ALLISTER Andrès MC, Maximilien Murone,Saumitra Sengupta, Shankar Jayaram Shetty

https://www.google.co.in/patents/WO2011101806A1?cl=en

Bicyclic compounds and their uses as dual c-src / jak inhibitors

Apr. 14 /PR Newswire/ –Debiopharm and Aurigene Sign Agreement for the Development and Commercialisation of Debio 1142, a Novel Inhibitor of an Undisclosed Oncology Pathway

LAUSANNE, Switzerland and BANGALORE, India, April 14, 2011 /PRNewswire/ — Debiopharm Group(TM) (Debiopharm), a global biopharmaceutical development specialist that focuses on serious medical conditions and particularly oncology, and Aurigene Discovery Technologies Ltd (Aurigene), a Bangalore-based drug discovery company, signed on March 23, 2011 an option and exclusive worldwide license agreement concerning the development and commercialisation of Debio 1142, a novel inhibitor of an undisclosed oncology pathway.

“We are very excited about this new collaboration with Aurigene. Their business model offers a one stop solution for structure guided drug design, lead optimisation and preclinical work. The Debio 1142 project aims at developing inhibitors targeting a key oncology pathway, which plays essential roles in various solid tumours, including resistance to chemotherapy” said Dr Rolland-Yves Mauvernay, president and founder of Debiopharm S.A.

“Coming as it does after a successful collaboration programme we already had with Debiopharm, and as a continuation of our close to 5 year association, the relationship between Debiopharm and Aurigene demonstrates the strategic fit between organisations with complimentary scientific skills. We are happy that we have the opportunity to continue to work with Debiopharm, in a unique business model that has been tailor-made to meet each partners’ needs” added CSN Murthy, CEO of Aurigene.

About Debiopharm Group

Debiopharm Group(TM) (Debiopharm) is a Swiss-based global biopharmaceutical group of companies with a focus on the development of prescription drugs that target unmet medical needs. The group in-licenses, develops and/or co-develops promising biological and small molecule drug candidates having reached clinical development phases I, II or III as well as earlier stage candidates. It develops its products for global registration and maximum commercial potential. The products are out-licensed to pharmaceutical partners for sales and marketing. Debiopharm Group is also active in the field of companion diagnostics with a view to progressing in the area of personalised medicine. Debiopharm independently funds the worldwide development of all of its products while providing expertise in pre-clinical and clinical trials, manufacturing, drug delivery and formulation, and regulatory affairs. For more information on Debiopharm Group(TM), please visit: http://www.debiopharm.com.

About Aurigene

Aurigene Discovery Technologies Limited is a Bangalore-based biotech focused on collaborative drug discovery with pharmaceutical and biotech companies on a risk-sharing basis. Aurigene has fully integrated drug discovery infrastructure, from Target to IND, along with strong in house structural biology and fragment based drug design capabilities. The company is engaged in over 20 discovery collaborations with US and European large and mid-pharma companies in Oncology, Inflammatory disorders and anti-infectives. For more information on Aurigene, please visit: http://www.aurigene.com.

PATENT

WO 2011101806

http://www.google.co.in/patents/WO2011101806A1?cl=en

PAPER

Journal of Chemical and Pharmaceutical Research (2014), 6(4), 1146-1152

http://jocpr.com/vol6-iss4-2014/JCPR-2014-6-4-1146-1152.pdf

REFERENCES

INDIAN PATENTS

7554/CHENP/2012

415/CHE/2010

https://www.debiopharm.com/our-business/pipeline.html

http://www.giiresearch.com/report/labd315710-debiopharm-international-sa-product-pipeline.html

///////////Debio 1142, Jak2 tyrosine kinase inhibitor,  Src tyrosine kinase inhibitor, Debio-1142, Debiopharm S.A.,  Aurigene Discovery Technologies Ltd, 1332328-01-4

c21cnc(nc1CCN(C2=O)c3c(ccc(c3)NC(=O)c4cc(ccc4)C(F)(F)F)C)Nc5ccc(cc5)N6CCN(CC6)C

Many diseases in humans and animals are caused by excessive accumulated metals, such as iron. Among such diseases, excess iron is accumulated in various tissues, which is called iron overload disorders, formerly known as siderosis Haemorrhagic. Excess iron has the following sources: 1) long-term blood transfusion; 2) the gastrointestinal system absorbing excess iron, because stimulated by diseases such as anemia. It is necessary to repeat transfusion for some patients with severe anemia, for example, β-thalassemia, as well as other anemia requiring transfusion therapy. Excessive iron absorption from the gastrointestinal tract usually occurs in hemochromatosis patients and in anemia patients who do not require blood transfusion, such as thalassemia intermedia. If iron overload disease is not treated, it will result in severe tissue damage, especially the liver, heart and endocrine organs, and ultimately lead to death. Iron chelators can remove and clear excess iron from such organs, relieve symptoms and reduce the corresponding mortality.

Desferrioxamine (DFO) is an effective iron chelator for a long time. However, in the treatment of the diseases mentioned above, the biggest disadvantage regarding DFO and its salts is its poor oral absorption capability. So, administration is achieved with a slow injection method (8∼12h/day), patients need to wear a portable drug delivery device during treatment, such as mounting the syringe on a mechanical pressing device. This method is inconvenient, and also expensive, which largely limits the utilization of DFO, especially for thalassemia-prone areas, such as Mediterranean, Middle East, and India &South East Asia, it plays no role in treatment of malaria in world-wide and sickle cell anemia in some African countries, which is a very serious problem to the populations there.

UK Patent No. 2, 13, 807, US Patent No. 4, 585, 780 and other scientific research have reported the treatment of iron overload symptoms by using 3-hydroxypyridin-4-one derivatives, especially in some pathological symptoms, such as thalassemia, sickle cell anemia, aplastic anemia in children, and idiopathic hemochromatosis, usually, treatment of the first three diseases includes frequent regular blood transfusion. 3-Hydroxypyridin-4-one derivatives, especially CP20 (commercial named Ferriprox) is employed to treat systemic iron overload disorders, and also to treat certain diseases associated with local iron overload distribution, although such patients do not show symptoms of systemic iron overload, i.e. inhibition free radical mediated reactions caused by excess iron ions in certain neurodegenerative diseases and cancer diseases. A serious limitation of CP20 is that the hydroxyl group at 3′ position is vulnerable to glycosylation, which reduces the half-life of this compound (approximately 2∼3 h). So it requires a high dosage, which is associated with obvious side effects.

EP0120669 discloses compounds with a 3-hydroxypyrid-4-one in which the H attached to the N atom is substituted by an aliphatic acyl group, or an aliphatic hydrocarbon group, these groups can be further substituted, but not by aromatic groups and their use against illnesses related to iron overload. Molenda et al. disclose in Journal of Medicinal Chemistry 1994, 37, pages 4363-4370 chiral 3-hydroxy-pyridin-4-one compound 6 as enhancing iron excretion.

US Patent No. 6, 465, 604 described a series of 3,5-diphenyl-1,2,4-triazole compounds, wherein including Exjade (commercial name), which has strong affinity to Fe(III), However, its active groups contain two negatively charged oxygen ions and a carboxyl group; it is a tridentate ligand while chelating Fe(III), which forms a Fe-L₂ type complex, possessing three unit negative charges itself, that is bad for their discharge from cells/tissues. Moreover, one of the active groups is a nitrogen atom with a lone pair of electrons, Exjade may have a negative effect on the balance of Zn(II) in vivo, at the same time because it has two phenolic hydroxyl groups in different positions (forming intramolecular hydrogen bonds structure similar to cis/trans isomerization), it can be complexed to several zinc ions to form high molecular weight polymers complexes, which is not conducive to its discharge from the cells either.

Absorption, distribution, metabolism and excretion of chiral medicines are largely related to the 3D structures of their chiral centers. For drug absorption, chiral compounds entering cells via active transport mechanism are usually carried by special transport proteins, their recognition of enantiomers can be different, resulting in different absorption of enantiomers. For drug distribution, the binding effects of plasma protein and tissues are also somewhat stereoselective, leading to different in vivo distribution of enantiomers; for stereoselective of drug metabolism refers to when the substrate is biotransformated, the pathway and speed of enantiomer metabolism by biological systems can be different. One enantiomer may show ascendant metabolism, and therefore it is of great significance to the indicators including drug transformation and in vivo half-life. Glomerular filtration, tubular secretion and reabsorption of chiral drugs to clear the chiral drugs, having stereoselectivity, while the glomerular filtration rate is closely related to drug’s selectivity to binding plasma protein, so discharge style of enantiomers (urine / feces percentage) and the rate is also different.

Therefore, the qualitative difference of the interactions of a pair of enantiomers with various binding sites may exist or not, and the quantitive difference may exist (strong or weak), which results in the different activities between enantiomers. Thus the selection of optical enantiomers for medical use, requires a comprehensive study of metabolic activity, toxicology and pharmacokinetic properties etc. Thus the chiral nature of the 3-hydroxypyridin-4-one derivatives described in this patent has an important role on in vivo iron chelation.

The effectiveness of many oral 3-hydroxy-4-one derivatives drugs are subject to metabolic reaction of the 3-hydroxy moiety, which may be quickly glycosylated (see Reaction I). The hydroxypyridone after glycosylation loses the ability to chelate Fe(III). We can effectively inhibit glycosylation reaction by introducing hydroxyl groups to alkyl substituted residues on the pyridine ring. In addition, the partition coefficient of 3-hydroxy-pyridin-4-one derivatives has a great impact on the in vivo distribution and toxic effects. We have introduced various alkyl groups to the chiral point of the compound, in order to modify their lipophilicity, i.e. a phenyl group connected to the chiral point in compound IV-b while in IV-a it is a methyl group, and thus compound IV-b is relatively more lipophilic, and easier to penetrate through cell membranes of various tissues and critical barriers such as the blood-brain barrier and the placental barrier, thus affecting its in vivo distribution. Thus increase of hydroxyl groups can affect the intestinal absorption capacity, by introducing a large alkyl group, intestinal absorption of 3-hydroxy-pyridin-4-one derivatives can be enhanced.

Reaction I

scheme is as follows:

PATENT

CN 102190644

http://www.google.com/patents/CN102190644B?cl=en