WO 2016042441, Mankind Research Centre, Silodosin, New patent

PATENTS Comments Off

Apr 012016

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%.

Mankind Pharma: Formulating Strategy To Enter The Big League

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

New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

PATENTS Comments Off

Apr 012016

Acitretin

PDT PATENT US4105681

WO-2016042573

Process for preparation of acitretin

Emcure Pharmaceuticals Ltd

EMCURE PHARMACEUTICALS LIMITED [IN/IN]; an Indian company at EMCURE HOUSE, T-184, MIDC., Bhosari, Pune – 411 026 Maharashtra (IN)

GURJAR MUKUND KESHAV; (IN).
JOSHI SHASHIKANT GANGARAM; (IN).
BADHE SACHIN ARVIND; (IN).
KAMBLE MANGESH GORAKHANATH; (IN).
MEHTA SAMIT SATISH; (IN)

The present invention Provides a process for preparation of {(2E, 4E, 6E, 8E) -9- (4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6 , 8} tetraenoate, acitretin year intermediate of formula (VI) with trans isomer ≥97%, comprenant of Reacting 3-formyl-Crotonic acid butyl ester of formula (V) Substantially free of impurities, with 5- (4-methoxy- 2,3,6-trimethylphenyl) -3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV) and isolating resulting compound of formula (VI) Treating the filtrate with iodine for isomerization of the Undesired cis intermediate and finally Obtaining acitretin (I), with trans isomer Desired ≥97%.

Samit Satish Mehta holds the position of the President – Research & Development

Acitretin of formula (I), chemically known as (2E,4E,6E,8E)-9-(4-methoxy-2,3,6- trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid, is a second generation retinoid a roved by USFDA in 1996, for the treatment of psoriasis.

Acitretin (I)

The process for preparation of acitretin (I) was first disclosed in US 4,105,681 wherein the intermediate, 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide was reacted with 3-formyl-crotonic acid butyl ester in presence of sodium hydride as base and dimethylformamide as solvent. The resultant ester derivative was obtained with a trans is (E/Z) ratio of around 55:45 which was subjected to hydrolysis in presence of potassium hydroxide and ethyl alcohol to obtain acitretin.

Use of hazardous, highly pyrophoric and moisture sensitive reagent like sodium hydride, along with cumbersome work-up and successive crystallizations to obtain the desired isomer rendered the process unviable for commercial scale.

Indian patent application 729/MUM/2012 discloses use of organic bases such as triethyl amine or pyridine for the reaction of 3-formyl-crotonic acid butyl ester and 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l -triphenyl phosphonium bromide for the synthesis of acitretin. The process utilizes a large excess of the organic base (2.85:1.0) with respect to the reactant phosphonium bromide derivative. Further, there is no mention of the ratio of cis and trans geometric isomers of the product thus obtained either at the intermediate or final stage. The trans: cis (E/Z) ratio of the intermediate significantly impacts the final yield and purity of the product as several purifications and crystallizations are required to obtain the desired trans isomer.

The present inventors have experimentally observed that use of organic base in such large quantities severely hampers the removal of the undesired side product triphenyl phosphonium oxide formed in significant amounts. Also, the intermediate is obtained with a very modest trans: cis (E/Z) ratio.

WO2012/155796 discloses another method wherein alkali metal alkoxides are used as bases in the reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl -penta-2,4-diene-l -triphenyl phosphonium bromide with 3-formyl-crotonic acid. The obtained reaction mass, after adjusting pH to 7-8 with acid, is directly subjected to catalytic isomerization using catalysts such as Pd(OAc)₂ or Pd(NH₃)₂Cl_2. The reaction mixture so obtained is quenched with water, neutralized and filtered to get the desired product, which is further recrystallized from ethyl acetate. Although this procedure avoids the hydrolysis step and attempts in-situ isomerization, however the use of expensive, soluble palladium catalyst which cannot be recycled from the reaction mass coupled with lengthy reaction time of 25-30 hours and large solvent volumes make the process unviable.

It may be noted that in the synthesis of acitretin, the key reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl-penta-2 ,4-diene- 1 -triphenylphosphoniumbromide with 3 -formyl crotonic acid or its ester in presence of either strong inorganic bases such as sodium hydride, alkali metal alkoxides or organic bases like triethylamine is common to almost all synthetic routes disclosed in the prior art. Hence, all these routes suffer from the inherent problems of formation of undesired impurities including cis-isomeric compounds and their separation from the desired all-trans product which necessitates various purification methods ranging from column chromatography, multiple crystallizations etc.

Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of acitretin (I) which avoids use of pyrophoric strong bases and provides a robust method which affords acitretin having desired isomeric purity in high yield.

5-(4-methoxy,2,3,6 trimethylphenyl)- 3-formyl crotonic acid butyl glyoxalate L(+) tartaric acid

3-methyl-penta-2,4-dien-1-triphenyl butyl ester (V) dibutyl ester

phosphonium bromide (IV)

Acitretin (I)

Satish Mehta,CEO, Above and here Inspiring the participants

EXAMPLES

Example 1: Preparation of 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II)

Acetone (6000 ml) was added to 4-methoxy-2,3,6 trimethyl benzaldehyde (500.3 g) and the mixture was stirred at 20-30°C. Aqueous solution of sodium hydroxide (134.8 g in 500 ml water) was gradually added to it and the resulting mixture was heated to 45-50°C with continued stirring. After completion of the reaction, as monitored by HPLC, the reaction mass was cooled and acetic acid was added till pH 4.5 to 5.5. Distillation of acetone, followed by addition of cyclohexane to the residue, followed by washing with water, separation and concentration of the organic layer gave 4-(4-methoxy-2,3,6 trimethylphenyl)-but-3-en-2-one of formula (II).

Yield: 80-84%

Example 2: Preparation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene- 1-triphenyl phosphonium bromide (IV)

4-(4-Methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II; 500 g) dissolved in toluene (2000 ml) was gradually added to a mixture of vinyl magnesium bromide (3500 ml; 1 molar solution in THF) and lithium chloride (4.8 g) and stirred at 20-30 C till completion of the reaction as monitored by HPLC. The reaction mixture was quenched with water and concentrated hydrochloric acid was added till the pH was between 3 and 4. The organic layer was separated and concentrated to give residue containing 5-(4-methoxy-2,3,6 trimethylphenyl)-3 -methyl -penta l,4-dien-3-ol (III). Methyl isobutyl ketone (3500 ml) was added to the residue, followed by gradual addition of triphenyl phosphine hydrobromide (745.3 g) at room temperature. The reaction mixture was heated to 50-60°C till completion of the reaction. The reaction mixture was cooled and filtered to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV).

Yield: 1000 g (76%)

Example 3: Preparation of 3-formyl crotonic acid butyl ester (V)

Dibutyl-L- tartrate (500 g) was dissolved in isopropanol (3500 ml) at room temperature, and water (750 ml) was added to it. The reaction mixture was cooled to 15-25°C and sodium metaperiodate (448.5 g) was gradually added to it with stirring. The reaction was continued at 20-30°C till completion of the reaction based on GC analysis. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in toluene (1000 ml), stirred and filtered to obtain the filtrate containing butyl glyoxylate. Propionaldehyde (221.0 g) was added to the filtrate and heated to around 60°C, followed by gradual addition of piperidine (26.4 g, dissolved in toluene). The reaction mixture was further heated and stirred at 110-120°C till completion of the reaction, as monitored by GC. After completion, the reaction mass was cooled, washed with aqueous sulfuric acid, water and finally with aqueous sodium bicarbonate solution. The organic layer was concentrated and the residue was distilled to give 3-formyl crotonic acid butyl ester (V)

Yield: 230-280 g (35-43%)

Example 4. Preparation of butyI{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6,8}tetraenoate (VI)

Sodium carbonate (297. lg), was added to the mixture of 5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl-phosphoniumbromide (IV; 1000 g) in toluene (5000 ml) followed by gradual addition of 3-formyl crotonic acid butyl ester (330 g) at room temperature. The stirred reaction mixture was heated to 60-70°C till completion of the reaction as monitored by HPLC. The reaction mass was cooled, quenched with water. The organic layer was separated, concentrated and n-heptane was added to the residue. The mass was stirred, filtered and 40% aqueous methanol (2000 ml) was added to it with stirring. Layer separation, concentration of the organic layer, and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding followed by filtration gave crop I of butyl {{(2E,4E,6E,8E)— 9-(4-methoxy-2,3,6 trimethyl)phenyl-3,7 dimethyl -nona-2,4,6,8} tetraenoate (VI),.

Yield: 45-50%;

Cis: Trans isomer ratio (2.0:98.0)

The filtrate was concentrated, the residue was dissolved in toluene (2000 ml) and treated with iodine (4.5 g) at room temperature. After completion of the reaction, as monitored by HPLC, the reaction mixture was stirred with aqueous sodium thiosulfate solution. Separation and concentration of the organic layer and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding, gave crop II of butyl {{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8} tetraenoate (VI).

Yield (crop II): 15 to 20%.

Cis: Trans isomer ratio (2.0:98.0)

Total yield (crop I+II): 60-70%.

Example 5: Preparation of acitretin (I)

Aqueous solution of potassium hydroxide (155.2 g in 600 ml water) was added to a solution of butyl {(2E,4E,6E,8E)-9-(4-methoxy-2,3 ,6-trimethyl) phenyl-3 ,7-dimethyl-nona- 2,4,6,8}tetraenoate, VI (300.0 g) in ethanol (1800 ml) at 25-30°C and the reaction mixture was stirred at reflux temperature till completion of the reaction. After completion, as monitored by HPLC, the reaction mixture was quenched with water, and hydrochloric acid was added till pH was between 2.5 and 3.5. The mass was heated at 70°C, stirred, cooled to 40-50°C and filtered. Recrystallization of the resulting solid from tetrahydrofuran gave acitretin (I).

Yield: 154.0 g (60%)

Desired trans isomer: > 98%

India’s hockey stars Sardara Singh and Sandeep Singh with Emcure Pharmaceuticals COO, Arun Khanna

HE Dr. Kenneth Kaunda, First President of Zambia interacting with Mr. A. K. Khanna, COO & ED, Emcure at Emcure booth at AIDS 2012 conference, Washington

Mr. Sunil Mehta is an Executive Director and Senior Director (Projects)

Arun Khanna is the Chief Operating Officer and Executive Director on the Board of Emcure Pharmaceuticals Limited.

//////New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

New patent, Lomitapide mesylate , Zydus Cadila Healthcare Ltd, US 20160083345,

PATENTS Comments Off

Apr 012016

Lomitapide mesylate

Was developed and launched by Aegerion, under license from the University of Pennsylvania (which acquired rights from BMS).

US-20160083345

Sanjay Jagdish DESAI
Brij KHERA
Jagdish Maganlal PATEL
Harshita Bharatkumar SHAH
Arunkumar Shyam Narayan UPADHYAY
Sureshkumar Narbheram AGRAVAT

Polymorphic forms of lomitapide and its salts and processes for their preparation

Zydus Cadila Healthcare Ltd

The present invention relates to various polymorphic forms of lomitapide or its salts and processes for preparation thereof. The present invention provides Lomitapide mesylate in solid amorphous form and process for preparation thereof. The invention also provides an amorphous solid dispersion of lomitapide mesylate. Further, various crystalline forms of lomitapide mesylate like A, B and C and process for preparation thereof are provided. The invention also provides crystalline forms of lomitapide free base, in particular Form I and Form-II and their preparation. The invention further provides compositions comprising various forms of lomitapide and its salts.

A novel amorphous form of lomitapide mesylate (having >98% of purity and 0.5% of residual solvent and particles size D90 of >250 µm, D50 of >100 µm and D10 of >50 µm), a process for it preparation and a composition comprising it is claimed. Also claimed is an amorphous solid dispersion of lomitapide mesylate and a carrier (eg hydroxypropylmethyl cellulose acetate succinate). Further claimed are crystalline forms of lomitapide mesylate (designated ad Forms A, B, C, I, II and free base of lomitapide in amorphous form), processes for their preparation and compositions comprising them. Lomitapide is known to act as a microsomal triglyceride transfer protein inhibitor, useful for treating familial hypercholesterolemia.

Lomitapide is a synthetic lipid-lowering agent for oral administration. It is a microsomal triglyceride transfer protein inhibitor approved as Juxtapid® in US and as Lojuxta® in Europe as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-highdensity lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). The approved drug product is a mesylate salt of lomitapide, chemically known as N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9carboxamide methanesulfonate [“lomitapide mesylate” herein after] and has the structural formula

(MOL) (CDX)

As per the approved label for Juxtapid® (US) “Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane”.

As per Public Assessment Report for Lojuxta® (Europe) “Polymorphism has been observed for lomitapide mesylate. Of the different solid-state forms, hydrates, and solvates identified in the polymorph studies, only 2 desolvated solid-state forms, Form I and Form II, were identified in batches after drying to final drug substance.” The report further states, under the heading Manufacture, that “The final particle size distribution is controlled during the crystallisation step” (emphasis added) suggesting that the approved drug product lomitapide mesylate is a crystalline compound

U.S. Pat. No. 5,712,279 A discloses the lomitapide compound and a process for its preparation. It also discloses a process for preparation of lomitapide monohydrochloride.

U.S. Pat. No. 5,883,109 A discloses lomitapide mesylate specifically but no solid form was disclosed.

The reference article Synthesis and Applications of Isotopically Labelled Compounds, Vol. 8, Pg. 227-230 (2004) discloses the preparation of Deuterium labelled [d₄]BMS-201038, [³H]BMS-201038, [¹⁴C]BMS-201038 wherein BMS-201038 is lomitapide mesylate.

International (PCT) Publication No. WO 2015/121877 A2 discloses lomitapide crystalline Form I and Form II as well as amorphous form of Lomitapide mesylate and processes for their preparation.

There is still a need to provide a novel polymorph of lomitapide or its salts which is suitable for pharmaceutical preparations. Therefore, the present invention provides new crystalline forms of lomitapide free base and lomitapide mesylate. The present invention also provides amorphous form of lomitapide free base and lomitapide mesylate, which is stable and useful for pharmaceutical preparations.

EXAMPLES

Example-1

Preparation of Lomitapide Mesylate

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 10 g lomitapide and 20 mL methanol were added and stirred to obtain a solution. 1.5 g methane sulfonic acid dissolved in 20 mL water was added slowly to the above solution under stirring. The reaction mixture was stirred till maximum salt formation was achieved. 50 mL water was added to the mixture, stirred for 15-20 min, filtered and washed with water. The product was dried further to obtain lomitapide mesylate.

EXAMPLE 2

Preparation of Amorphous Form of Lomitapide Mesylate

10 g lomitapide mesylate, 50 mL acetone and 150 mL ethyl acetate were heated in a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel at 50-55° C. and stirred to obtain clear solution. The solution was subjected to spray drying in JISL Mini spray drier LSD-48 with feed pump running at 30-35 rpm, inlet temperature 50-55° C., out let temperature 45-50° C., aspiration rate 1200-1300 rpm, hot air supply 1.8-2.2 Kg/cm²and vacuum for conveying the dry product 80 mmHg. The product was collected from cyclone and characterized to an amorphous form by x-ray powder diffraction. The product was further dried to obtain the amorphous form of lomitapide mesylate

/////////////New patent, Lomitapide mesylate , Zydus Cadila Healthcare Ltd, US 20160083345, Amorphous

Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

spectroscopy, SYNTHESIS Comments Off

Mar 312016

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC00157B, Paper

Hamideh Ahankar, Ali Ramazani, Katarzyna Slepokura, Tadeusz Lis, Sang Woo Joo
In this study, we reported a simple and efficient route for the one-pot sonochemical synthesis of substituted 3-pyrrolin-2-ones by citric acid as an additive.

Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

The ultrasound-promoted one-pot multicomponent synthesis of substituted 3-pyrrolin-2-ones using citric acid as a green additive in a green solvent is reported. Citric acid catalyzed the reaction efficiently without the need for any other harmful organic reagents. Clean reaction profile, easy work-up procedure, excellent yields and short reaction times are some remarkable features of this method. The utilization of ultrasound irradiation makes this method potentially very useful, fast, clean and convenient.

Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

Hamideh Ahankar,^a Ali Ramazani,*^a Katarzyna Ślepokura,^b Tadeusz Lis^b and Sang Woo Joo*^c

*Corresponding authors

^aDepartment of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran
E-mail: aliramazani@gmail.com

^bFaculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland

^cSchool of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
E-mail: swjoo@yu.ac.kr

Green Chem., 2016, Advance Article

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00157B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract
DOI: 10.1039/C6GC00157B

Ethyl 4-hydroxy-5-oxo-1,2-diphenyl-2,5-dihydro-1H-pyrrole-3-carboxylate

ethyl 4-hydroxy-5-oxo-1,2-diphenyl-2,5-dihydro-1H-pyrrole-3-carboxylate

//////Synthesis, pyrrolidinone derivatives, aniline, aldehyde, diethyl acetylenedicarboxylate, ethanolic citric acid solution, ultrasound irradiation

Tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE)

Phase 3 drug, Uncategorized Comments Off

Mar 312016

Gly-Pro-Glu

Synonym: GPE, Glycyl-prolyl-glutamic acid, (1-3)IGF-1

Pfizer (Originator)
Neuren Pharmaceuticals (Originator)

Glypromate; glycine-proline-glutamate (neuroprotectant), Neuren

CAS Number 32302-76-4
Empirical Formula C₁₂H₁₉N₃O₆
Molecular Weight 301.30
Psychiatric Disorders (Not Specified)
Neurologic Drugs (Miscellaneous)
Cognition Disorders, Treatment of
Antiepileptic Drugs
Antidepressants Biochem/physiol Actions

Gly-Pro-Glu is a neuroprotective compound and the N-terminal tripeptide of IGF-1. Gly-Pro-Glu is neuroprotective after central administration in animal models of neurodegenerative processes, such as Huntington’s, Parkinson’s, Alzheimer’s diseases, and varies acute brain injury animal models. The neuroprotective activity is not related to its affinity to glutamate receptor. Findings indicate that GPE mimics insulin-like growth factor I effects on the somatostatin system through a mechanism independent of β-amyloid clearance that involves modulation of calcium and glycogen synthase kinase 3β signaling.

GPE is a naturally occurring peptide fragment which had been in phase III clinical trials at Neuren Pharmaceuticals for use as prophylactic neuroprotection for patients undergoing coronary artery bypass graft (CABG) and valvuloplasty surgery. Although clinical evaluation in Australia continues, phase III trials evaluating the compound in the U.S. were discontinued based on negative results. The compound is found in normal brain tissue and, when injected intravenously, has been shown to act by multiple pathways to protect brain tissue from injury. The drug was originally developed by Pfizer, but rights were transferred to Neuren pursuant to a proprietary agreement between the companies.

When amino acids join together (forming short groups called polypeptides, or much longer chains called proteins) the amine group of one amino acid joins with the carboxyl group of the next, making a peptide bond. These bonds don’t ionise at different pHs, but can be hydrolised — broken — reforming the amino acids. GPE is formed from the amino acids glycine, proline and glutamic acid:

This tripeptide has 3 pH-sensitive groups, each with its own pK_a. What the university chemists needed to do was work out what form GPE is in when it is active in the brain, what parts of the molecule are critical to its effectiveness, and how to ‘tweak’ the molecule (by changing the side chains) so that it will remain in the brain for longer than the naturally-occurring substance. They also needed to make sure the final compound passes through the blood-brain barrier (that prevents most substances in the blood from entering and affecting the brain). If possible, they also wanted a compound that could be taken in pill form without being broken down in the stomach. It was also essential that the compound was safe for people to take!

Neuren Pharmaceuticals

After initial work on GPE at the university, the research was passed to a spin-off research group called Neuren Pharmaceuticals Ltd, which takes compounds discovered by the University of Auckland and develops them into medicines. Neuren developed GPE intoGlypromate® and are working with researchers in the US (including the US Military, who have a keen interest in a medicine that will reduce brain damage after head injuries) to test the compound on patients. There is considerable interest in Glypromate® world-wide, because at present there is nothing that reduces cell death after brain injuries. The chances of winning a race are pretty high when you’re the only competitor!Glypromate® is being tested on heart-bypass patients because up to 70% of bypass patients are affected mentally after their surgery. It’s thought that tiny clots form after the heart is restarted, and that these travel to the brain and cause mini-strokes. Unlike naturally-occurring strokes, or the brain damage caused by accident or war, the bypass surgery is planned, so before and after tests can be done on the patients to see exactly what effect the treatment has. Early results look very promising.

Glypromate is just one of the compounds Neuren is working on. Others may develop into treatments for Multiple Sclerosis, Parkinson’s Disease or Alzheimer’s Disease as well as various kinds of cancer. The company’s links with overseas research groups mean that compounds developed in New Zealand are able to be tested in the US and gain the FDA approval which will allow them to be used in most countries in the world.

The tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE) is a naturally occurring peptide, which is proteolytically cleaved from insulin-like growth factor-1 (IGF-1). IGF-1 is a potent neurotrophic factor produced endogenously in damaged regions of the brain. It has been postulated that some of the neuroprotective actions of IGF-1 are mediated by GPE although the precise mechanism of action remains unclear. GPE has a different mode of action to IGF-1 as GPE does not bind to the IGF-1 receptor. Rather, GPE has been shown to bind with low affinity to the N-methyl-D-aspartate (NMDA) receptor and also elicit a biological response via other mechanisms. GPE facilitates the release of dopamine through interaction with the NMDA receptor but GPE stimulated acetylcholine release is via an unknown, non-NMDA pathway.

It has been demonstrated that GPE can act as a neuronal rescue agent following brain injury or disease, including hypoxic-ischemic brain injury, NMDA challenge, chemical toxins and in animal models of Parkinson’s and Alzheimer’s disease. Analogs of GPE are thus of interest in the development of novel pharmaceutical agents for the treatment of central nervous system (CNS) injuries and neurodegenerative disorders among others.

CURRENT STATUS

Neuren Pharmaceuticals was developing Glypromate (glycine-proline glutamate), a naturally occurring small-molecule neuroprotectant derived from IGF-1 which inhibits caspase III dependent apoptosis, for the potential treatment of neurodegenerative diseases by iv infusion. By June 2008, a phase III trial had begun . However, in December 2008, the company discontinued further development of the drug after it failed to show an observable effect [972907]. In November 2005, the company was seeking to outlicense the drug [771417].

Neuren is also investigating the Glypromate analog, NNZ-2566 for similar indications.

In August 2006, Neuren expected Glypromate to be eligible for Orphan Drug status for neurodegenerative diseases and planned to apply for Fast Track status for the drug.

SYDNEY, Australia, Sept. 4 /PRNewswire-FirstCall/ — Neuren Pharmaceuticals today announced that physicians from Madigan Army Medical Center (Madigan) in Tacoma, Washington, will conduct an investigator- initiated Phase 2 trial to determine the safety and efficacy of Glypromate(R) in reducing brain injury caused by out of hospital cardiac arrest. The trial will start in mid-2007 and will be managed by The Henry M. Jackson Foundation for the Advancement of Military Medicine (Jackson Foundation) in consultation with the clinical investigators at Madigan.

The proposed study will be an investigator-initiated study which means that the Investigational New Drug (IND) application will be submitted to the FDA by the Army investigators rather than by Neuren. Neuren will provide the drug product as well as access to preclinical, clinical and regulatory documents related to Glypromate(R). The Company’s only financial commitment will be compensation to the Jackson Foundation for administrative costs incurred in coordinating the study. Neuren will retain all commercial rights to Glypromate(R) in these indications.

Cardiac arrest involves the sudden, complete cessation of heart function and circulation leading rapidly to neurological and other organ system damage. Among patients who survive, the consequences of neurological damage resulting from lack of blood flow and oxygen to the brain represent the primary adverse outcomes. This occurs in up to 80% of survivors and causes cognitive impairment such as occurs in patients undergoing major cardiac surgery, the focus for Neuren’s upcoming Phase 3 study with Glypromate(R). However recovery without residual neurological damage after cardiac arrest is rare.

There are no drugs approved to reduce the neurological damage caused by cardiac arrest. Neuren believes that Glypromate(R) for this indication will be eligible for Orphan Drug designation. Orphan Drug designation provides for a period of market exclusivity following approval as well as possible access to US government grants. In addition, because of the serious nature of neurological impairment resulting from cardiac arrest and the lack of available drug therapy, Neuren intends to apply for Fast Track designation which provides for accelerated clinical development and review.

While the Army’s investigator-initiated trial will focus on out of hospital cardiac arrest, if this trial is successful, Neuren, the Jackson Foundation and the Army investigators are considering additional trials of Glypromate(R) to reduce brain damage resulting from related conditions including in-hospital cardiac arrest and treatment of patients with ventricular fibrillation, the heart rhythm disturbance associated with more than 75% of cardiac arrests.

Under the agreement, the Jackson Foundation will provide support to the Army investigators in clinical trial preparations, protocol development, obtaining human subjects clearance, coordination of patient enrolment, data management and analysis, and preparation of study reports.

Mr David Clarke, CEO of Neuren said: “This is a very important development for Neuren in that it reflects a growing appreciation of the potential for Glypromate(R) to reduce neurological damage. It also, of course, reinforces the value and strength of Neuren’s relationship with the US Army physicians and scientists. Cardiac arrest is a devastating clinical event and one for which a drug to reduce the neurological consequences is clearly needed. The addition of this trial will now give Neuren a very strong and cost effective portfolio of clinical trials in 2007 — a Phase 3 and a Phase 2 for Glypromate(R) and the two Phase 2 trials with NNZ-2566.”

Approximately 300,000 deaths result from cardiac arrest in the US each year, making cardiac arrest one of the leading causes of death. According to the American Heart Association, each year approximately 160,000 people in the US experience sudden cardiac arrest outside of a hospital or in a hospital emergency department.

Neuren estimates that the number of patients in the US that could be treated for out of hospital cardiac arrest and related indications is approximately 400,000 which could represent a potential market of US$800 million.

About Madigan Army Medical Center

Madigan Army Medical Center, located in Tacoma, Washington, is one of the major US Army medical centers, providing clinical care to over 120,000 active, reserve and retired military personnel and dependents. The hospital has a medical staff of more than 1,000 with 200 physicians and nurses in training. Madigan’s Department of Clinical Investigations, which is dedicated to writing, performing, and regulating clinical research, is conducting approximately 200 clinical trials across a wide spectrum of indications from Phase I to IV.

About the Jackson Foundation

The Jackson Foundation is a private, not-for-profit organisation that supports the US military in conducting medical research and clinical trials and has established relationships with more than 160 military medical organisations worldwide. It was founded in 1983, in part, to foster cooperative relationships between the military medical community and the private sector, including pharmaceutical sponsors. The Jackson Foundation manages Phase I – IV clinical trials utilizing an established network of military medical centers across the United States.

About Glypromate(R)

Glypromate(R) is a peptide fragment of IGF-1 and is being developed by Neuren as a potential therapeutic candidate for diseases caused by some forms of chronic or acute brain injury. Glypromate(R) has been shown to act by multiple pathways to protect brain tissue from injury. Neuren has successfully completed a Phase I safety study and a Phase IIa safety and pharmacokinetics study and plans to initiate a Phase III study in late 2006.

About Neuren Pharmaceuticals

Neuren Pharmaceuticals is a biotechnology company developing novel therapeutics in the fields of brain injury and diseases and metabolic disorders. The Neuren portfolio consists of six product families, targeting markets with large unmet needs and limited competition. Neuren has three lead candidates, Glypromate(R) andNNZ-2566, presently in the clinic in development to treat a range of acute neurological conditions, and NNZ-2591, in preclinical development for Parkinson’s and other chronic conditions. Neuren has commercial and development partnerships with the US Army Walter Reed Army Institute of Research, Metabolic Pharmaceuticals,UCLA Medical Center and the National Trauma Research Institute in Melbourne.

For more information, please visit Neuren’s website at http://www.neurenpharma.com

Company David Clarke CEO of Neuren T: 1800 259 181 (Australia) T: +64 9 3 367 7167 ext 82308 (New Zealand) M: +64 21 988 052 Media and investor relations Rebecca Piercy Buchan Consulting T: +61 9827 2800 M: +61 422 916 422

CONTACT: David Clarke, CEO of Neuren, 1-800-259-181(Australia), or
+64-9-3-367-7167 ext 82308 (New Zealand), or +64-21-988-052 (mobile); or
Media and investor relations – Rebecca Piercy of Buchan Consulting,
+61-9827-2800, +61-422-916-422 (mobile)

Web site: http://www.neurenpharma.com/

REFERENCES

1 EP 0366638

2 WO 2005042000

3 WO 2008153929

4 WO 2009033805

5 WO 2009033806

Synthesis off isotopically labelled glycyl-L-prolyl-L-glutamic acid (Glypromate(R)) and derivatives
J Label Compd Radiopharm 2006, 49(6): 571

An efficient fmoc solid-phase synthesis of an amphiphile of the neuroprotective agent glycyl-prolyl-glutamic acid
Synlett (Stuttgart) 2014, 25(15): 2221

Intracellular pathways activated by Insulin-like growth factor 1 and its derivates
40th Annu Meet Soc Neurosci (November 13-17, San Diego) 2010, Abst 167.13

EP2667715A1 *	Jan 27, 2012	Dec 4, 2013	Neuren Pharmaceuticals Limited	Treatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
EP2667715A4 *	Jan 27, 2012	Jul 23, 2014	Neuren Pharmaceuticals Ltd	Treatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
US8940732	Jan 15, 2010	Jan 27, 2015	Massachusetts Institute Of Technology	Diagnosis of autism spectrum disorders and its treatment with an antagonist or inhibitor of the 5-HT2c receptor signaling pathway
US9212204	Jan 26, 2015	Dec 15, 2015	Neuren Pharmaceuticals Limited

WO2005042000A1 *	22 Oct 2004	12 May 2005	David Charles Batchelor	Neuroprotective effects of gly-pro-glu following intravenous infusion
WO2005097161A2 *	30 Mar 2005	20 Oct 2005	Peter D Gluckman	Gpe and g-2mepe, caffeine and alkanol for treatment of cns injury
WO2006127702A2 *	23 May 2006	30 Nov 2006	Neuren Pharmaceuticals Ltd	Analogs of glycyl-prolyl-glutamate
EP0366638A2 *	24 Oct 1989	2 May 1990	KabiGen AB	Neuromodulatory peptide
US20020151522 *	13 Mar 2002	17 Oct 2002	Tajrena Alexi	Regulation of weight

Reference
1	*	ALONSO DE DIEGO, SERGIO A. ET AL: “New Gly-Pro-Glu (GPE) analogues: Expedite solid-phase synthesis and biological activity” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 5, 2006, – 1392 page 1396, XP002527092
2	*	SARA V R ET AL: “IDENTIFICATION OF GLY-PRO-GLU (GPE), THE AMINOTERMINAL TRIPEPTIDE OF INSULIN-LIKE GROWTH FACTOR 1 WHICH IS TRUNCATED IN BRAIN, AS A NOVEL NEUROACTIVE PEPTIDE” BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 165, no. 2, 15 December 1989 (1989-12-15), pages 766-771, XP000992688 ISSN: 0006-291X

//////Gly-Pro-Glu, GPE, Glycyl-prolyl-glutamic acid, 32302-76-4, Tripeptide, Glycyl-L-Prolyl-L-Glutamate, Glypromate®, (1-3)IGF-1 , PHASE 3, Glypromate, glycine-proline-glutamate, neuroprotectant, Neuren

Neuren’s NNZ-2566 shows clinical benefit in Rett syndrome trial

FRAXA Research Foundation Logo

Promising results in Phase 2 clinical trial

by Michael Tranfaglia, MD
FRAXA Medical Director

This isn’t a Fragile X trial, but the Neuren compound, NNZ-2566, that is in trials now for Fragile X has shown significant positive effects in a Phase 2 trial for Rett syndrome.

The results of the trial are interesting, in that improvement was seen a Rett syndrome-specific rating scale compared to placebo, and there was also improvement noted on the CGI-I (Clinical Global Impression of Improvement) and Caregiver Top 3 Concerns. However, there was no effect seen on ABC scores (Aberrant Behavior Checklist) compared to placebo. Many in the Fragile X field have noted the inadequacies of the ABC; indeed, it was never designed or intended to be an outcome measure for clinical trials. In this case, a Rett-specific rating scale called the Motor-Behavior Assessment (MBA) showed a statistically significant and clinically meaningful treatment effect at the highest dose of the Neuren compound compared to placebo.

This is great news for those of us in the Fragile X community for several reasons:

It shows that this compound really does something—it seems to have useful properties in actual patients, and that’s not trivial.
It demonstrates that disease-specific symptoms can improve significantly on the drug, and that improvement can be measured in a relatively short clinical trial.
It shows that a drug can have beneficial effects on core features of a genetically based developmental disorder, even if the more general rating scales (like the ABC) show no change.

–
This last point is strongly reminiscent of the experience of many families and clinicians in recent Fragile X clinical trials, where the drugs showed no advantage compared to placebo based on rating scales, but genuine improvement was noted in many subjects, with significant deterioration upon discontinuation of the drugs. Thus the calls for improved rating scales which can “capture” these core, disease-specific therapeutic effects. The NeurenFragile X trial is using some Fragile X-specific outcome measures which will hopefully lead to similar positive results.

The fact that this result is good news for Neuren also means that the company should remain financially viable for longer, so that they can continue the development of this compound for a number of indications—more “shots on goal”.

Of course, the usual caveats apply: this was a small study, and these results need to be replicated in a larger Phase 3 trial. Still, there’s a realistic possibility that we may see a similar result in Fragile X!

LY 2922470

phase 1, Uncategorized Comments Off

Mar 292016

LY 2922470

as per WO2013025424A1

Figure imgf000004_0001

LY 2922470

Picture credit….Bethany Halford

(3S)-3-[4-[[5-[(8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]thiophen-2-yl]methoxy]phenyl]hex-4-ynoic acid

Benzenepropanoic acid, 4-[[5-[(3,4-dihydro-8-methoxy-1(2H)-quinolinyl)methyl]-2-thienyl]methoxy]-β-1-propyn-1-yl-, (βS)-

Glucose Lowering Agents, Signal Transduction Modulators

CAS	1423018-12-5
Molecular Formula:	C₂₈H₂₉NO₄S

Molecular Weight:	475.59916 g/mol

https://clinicaltrials.gov/ct2/show/NCT01867216

Phase I Type 2 diabetes mellitus

Eli Lilly

Eli Lilly And Company

Antihyperglycaemics

28 Jan 2014 Eli Lilly completes a phase I trial in Type-2 diabetes mellitus in USA (NCT01867216)
30 Jun 2013 Phase-I clinical trials in Type-2 diabetes mellitus in USA (PO)
14 Jun 2013 Eli Lilly plans a phase I trial for Type-2 diabetes mellitus in USA (NCT01867216)

PATENT

WO 2013025424

https://www.google.com/patents/US20130045990?cl=de

Also published as	CA2843474A1, CA2843474C, CN103687856A, CN103687856B, EP2744806A1, US8431706, WO2013025424A1, Less «
Inventors	Chafiq Hamdouchi
Original Assignee	Eli Lilly And Company

Figure US20130045990A1-20130221-C00001

Figure US20130045990A1-20130221-C00004

Figure US20130045990A1-20130221-C00005

Preparation 18-Methoxyquinoline

Add potassium hydroxide (435 g, 7.76 mol) to a solution of 8-hydroxy quinoline (250 g, 1.724 mol) in THF (10 L) at ambient temperature and stir. Add methyl iodide (435 g, 2.58 mol) dropwise and stir overnight. Filter the reaction mixture and wash the solid with THF (2 L). Concentrate the solution to dryness; add water; extract with dichloromethane (2×3 L); combine the organic layers; and wash with brine. Collect the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a red oil, which solidifies on standing, to give the title compound (281 g, 102%), which can be used without further purification. ESI (m/z) 160(M+H).

Preparation 2

8-Methoxy-1,2,3,4-tetrahydroquinoline

Add sodium cyanoborohydride (505 g, 8.11 mol) in EtOH (1 L) to a solution of 8-methoxy quinoline (425 g, 2.673 mol) in EtOH (9 L), and stir. Cool the reaction mixture to an internal temperature of 0° C. and add HCl (35%, 1.12 L, 10.962 mol) dropwise over 60 min so that the internal temperature did not rise above 20° C. Allow the reaction mixture to warm to ambient temperature and then heat to reflux for 2.5 hours. Cool to ambient temperature and stir overnight. Add ammonium hydroxide (25%, 1 L); dilute with water (15 L); and extract the mixture with dichloromethane (3×10 L). Combine the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a residue. Purify the residue by silica gel flash chromatography, eluting with ethyl acetate: hexane (1:10) to give the title compound (357 g, 82%). ESI (m/z) 164(M+H).

Preparation 3

Methyl-5-methylthiophene-2-carboxylate

Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5-methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0° C. and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).

Preparation 4

Methyl 5-(bromomethyl)thiophene-2-carboxylate

Add freshly recrystallised NBS (323.8 g, 1.81 mol) to a solution of methyl-5-methylthiophene-2-carboxylate (258 g, 1.65 mol) in chloroform (2.6 L) at room temperature, and stir. Add benzoyl peroxide (3.99 g, 0.016 mol) and heat the reaction mixture to reflux for 7 hours. Cool the reaction mixture to ambient temperature and filter through diatomaceous earth. Wash the filter cake with chloroform (250 ml). Collect the organic layers and remove the solvent to give the title compound (388 g, 100%), which is used without further purification. ESI (m/z) 236(M+H).

Preparation 5

Methyl-5-[8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]thiophene-2-carboxylate

Add methyl-5-(bromoethyl)thiophene-2-carboxylate (432.5 g, 1.84 mol) in EtOH (500 ml) to a solution of 8-methoxy-1,2,3,4-tetrahydroquinoline (300 g 1.84 mol) in EtOH (1 L) and stir. Add DIPEA (641 ml, 3.67 mol) dropwise and stir at room temperature overnight. After completion of the reaction, remove the EtOH in vacuo, and add water (5 L). Extract the aqueous with EtOAc (3×3 L); combine the organic layers; and dry over sodium sulfate. Filter the solution and concentrate under reduced pressure to give a residue. Purify the residue by silica gel flash chromatography eluting with ethyl acetate: hexane (6:94) to give the title compound (325 g, 56%). ESI (m/z) 318(M+H).

Preparation 6

[5-[(8-Methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methanol

Add DIBAL-H (1 M in toluene 2.7 L, 2.66 mol) slowly via a cannula over a period of 1.5 h to a stirred solution of methyl-5-(8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophene-2-carboxylate (281 g, 0.886 mol) in THF (4 L) at −70° C. Monitor the reaction via thin layer chromatography (TLC) for completion. After completion of the reaction, allow the reaction mixture to warm to 20° C. and add a saturated solution of ammonium chloride. Add a solution of sodium potassium tartrate (1.3 Kg in 5 L of water), and stir overnight. Separate the organic layer; extract the aqueous phase with EtOAc (2×5 L); then combine the organic layers; and dry the combined organic layers over sodium sulfate. Remove the solids by filtration. Remove the solvent from the filtrate under reduced pressure to give the title compound as a white solid (252 g, 98%). ESI (m/z) 290(M+H).

Preparation 7

Ethyl(3S)-3-[4-[[5-[(8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methoxy]phenyl]hex-4-ynoate

Add tributylphosphine (50% solution in EtOAc, 543 ml, 1.34 mol) to a solution of ADDP (282.5 g, 1.5 eq) in THF (3 L) and cool the mixture to an internal temperature of 0° C., then stir for 15 minutes. Add (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (173.5 g, 0.747 mol) in THF (3 L) dropwise over 15 min; then add 5-((8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophene-2-yl)methanol (216 g, 0747 mol) in THF (5 L) dropwise. Allow the reaction mixture to warm to ambient temperature and stir overnight. Filter the reaction mixture through diatomaceous earth and wash the filter cake with ethyl acetate (2 L). Concentrate the organic filtrate to dryness. Add water (4 L); extract with ethyl acetate (3×5 L); combine the organic layers; and dry the combined organic layers over sodium sulfate. Remove the solids by filtration and concentrate under reduced pressure to give an oil. Purify the residue by silica gel flash chromatography by eluting with ethyl acetate: hexane (6:94) to give the title compound (167 g, 44%). ESI (m/z) 504(M+H).

Example 1

(3S)-3-[4-[[5-[(8-Methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methoxy]phenyl]hex-4-ynoic acid

Add a solution of potassium hydroxide (49.76 g, 0.88 mol) in water (372 ml) to a solution of (S)-ethyl-3-(4-((5-8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophen-2-yl)methoxy) phenyl)hex-4-ynoate (149 g, 0.296 mol) in EtOH (1.49 L) at room temperature and stir overnight. Concentrate the reaction mixture to dryness and add water (1.3 L). Extract the resulting solution with EtOAc (2×300 ml) and separate. Adjust the pH of the aqueous layer to pH=6 with 2 N HCl. Collect the resulting solids. Recrystallise the solids from hot MeOH (298 ml, 2 vol) to give the title compound (91 g, 65%). ESI (m/z) 476(M+H).

Abstract

GPR40 agonists for the treatment of type 2 diabetes: From the laboratory to the patient
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 260

Presenter

Chafiq Hamdouchi

Senior Research Advisor at Eli Lilly and Company

https://www.linkedin.com/in/chafiq-hamdouchi-4988126

Summary

Dr. Hamdouchi earned his bachelor’s degree and doctorate in organic chemistry from Louis Pasteur University, Strasbourg-France.
Following two postdoctoral fellowships, sponsored by the National Science Foundation-USA and Ministerio de Educación y Ciencia-Spain, he joined Eli Lilly and Company in 1995.
Throughout his 20 years of career at Lilly, he has contributed to a sustainable drug discovery portfolio from preclinical hypothesis to clinical proof-of-concept that spans the oncology, neuroscience and endocrinology therapeutic areas. He has led multidisciplinary (chemistry, pharmacology, ADMET, PK, medical) scientific teams in USA, Europe and Asia to deliver a number of compounds that achieved first human dose.
He is a co-inventor of six innovative molecules being pursued in clinical development for the treatment of Diabetes, Cancer and Neurodegenerative Diseases.
He has an extensive patent and publication record and deep experience in conducting drug discovery and development in Asia through effective partnership and mentorship.

SEE AT…………ONE ORGANIC CHEMIST ONE DAY BLOG

LINK……http://oneorganichemistoneday.blogspot.in/2016/03/chafiq-hamdouchi-senior-research.html

Patent ID	Date	Patent Title
US8431706	2013-04-30	1,2,3,4-tetrahydroqinoline derivative useful for the treatment of diabetes

References

GPR40 agonists for the treatment of type 2 diabetes: From the laboratory to the patient
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 260

//////Phase 1, LY2922470, LY 2922470, Eli Lilly, Type 2 diabetes mellitus, 1423018-12-5, Chafiq Hamdouchi

CC#CC(CC(=O)O)C1=CC=C(C=C1)OCC2=CC=C(S2)CN3CCCC4=C3C(=CC=C4)OC

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THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.

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PF 06650833

Uncategorized Comments Off

Mar 292016

Picture credit….Bethany Halford

PF 06650833

MFC18H20FN3O4, MW361.37

1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide

6-Isoquinolinecarboxamide, 1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-2-pyrrolidinyl]methoxy]-7-methoxy-

CAS 1817626-54-2

WO 2015150995

1st disclosures is @pfizer‘s on inflammatory disease treatment targeting IRAK4

$PFE IRAK4 inhibitor

Phase I Lupus vulgaris

01 Feb 2016 Pfizer completes a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02609139)
01 Nov 2015 Pfizer initiates a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02609139)
01 Jun 2015 Pfizer completes a phase I trial for Lupus (In volunteers) in USA (PO) (NCT02224651)

Compounds useful for the treatment of autoimmune and inflammatory diseases associated with lnterleukin-1 Receptor Associated Kinase (IRAK) and more particularly compounds that modulate the function of IRAK4.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified in tyrosine and serine/threonine kinases. Inappropriate activity arising from dysregulation of certain kinases by a variety of mechanisms is believed to underlie the causes of many diseases, including but not limited to, cancer, cardiovascular diseases, allergies, asthma, respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases. As such, potent and selective inhibitors of kinases are sought as potential treatments for a variety of human diseases.

There is considerable interest in targeting the innate immune system in the treatment of autoimmune diseases and sterile inflammation. Receptors of the innate immune system provide the first line of defense against bacterial and viral insults. These receptors recognize bacterial and viral products as well as pro-inflammatory cytokines and thereby initiate a signaling cascade that ultimately results in the up-regulation of inflammatory cytokines such as TNFa, IL6, and interferons. Recently it has become apparent that self-generated ligands such as nucleic acids and products of inflammation such as high-mobility group protein B1 (HMGB1) and Advanced Glycated End-products (AGE) are ligands for Toll-like receptors (TLRs) which are key receptors of the innate immune system (O’Neill 2003, Kanzler et al 2007, Wagner 2006). This demonstrates the role of TLRs in the initiation and perpetuation of inflammation due to autoimmunity.

lnterleukin-1 receptor associated kinase 4 (I RAK4) is a ubiquitously expressed serine/threonine kinase involved in the regulation of innate immunity (Suzuki & Saito 2006). IRAK4 is responsible for initiating signaling from TLRs and members of the I L- 1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice were reported to cause reductions in TLR and IL-1 induced pro-inflammatory cytokines (Kawagoe et al 2007; Fraczek et al. 2008; Kim et al. 2007). IRAK4 kinase-dead knock-in mice have also been shown to be resistant to induced joint inflammation in the antigen-induced-arthritis (AIA) and serum transfer-induced (K/BxN) arthritis models (Koziczak-Holbro 2009). Likewise, humans deficient in IRAK4 also appear to display the inability to respond to challenge by Toll ligands and IL-1 (Hernandez & Bastian 2006). However, the immunodeficient phenotype of IRAK4-null individuals is narrowly restricted to challenge by gram positive bacteria, but not gram negative bacteria, viruses or fungi. This gram positive sensitivity also lessens with age, implying redundant or compensating mechanisms for innate immunity in the absence of IRAK4 (Lavine et al 2007).

These data indicate that inhibitors of IRAK4 kinase activity should have therapeutic value in treating cytokine driven autoimmune diseases while having minimal immunosuppressive side effects. Additional recent studies suggest that targeting IRAK4 may be useful in other inflammatory pathologies such as atherosclerosis and diffuse large B-cell lymphoma (Rekhter et al 2008; Ngo et al 2011). Therefore, inhibitors of IRAK4 kinase activity are potential therapeutics for a wide variety of diseases including but not limited to autoimmunity, inflammation, cardiovascular diseases, cancer, and metabolic diseases. See the following references for additional information: N. Suzuki and T. Saito, Trends in Immunology, 2006, 27, 566. T. Kawagoe, S. Sato, A. Jung, M. Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi and S. Akira, Journal of Experimental Medicine, 2007, 204, 1013. J. Fraczek, T. W. Kim, H. Xiao, J. Yao, Q. Wen, Y. Li, J.-L. Casanova, J. Pryjma and X. Li, Journal of Biological Chemistry, 2008, 283, 31697. T. W. Kim, K. Staschke, K. Bulek, J. Yao, K. Peters, K.-H. Oh, Y. Vandenburg, H. Xiao, W. Qian, T. Hamilton, B. Min, G. Sen, R. Gilmour and X. Li, Journal of Experimental Medicine, 2007, 204, 1025. M. Koziczak-Holbro, A. Littlewood- Evans,

B. Pollinger, J. Kovarik, J. Dawson, G. Zenke, C. Burkhart, M. Muller and H. Gram, Arthritis & Rheumatism, 2009, 60, 1661. M. Hernandez and J. F. Bastian, Current Allergy and Asthma Reports, 2006, 6, 468. E. Lavine, R. Somech, J. Y. Zhang, A. Puel, X. Bossuyt, C. Picard, J. L. Casanova and C. M. Roifman, Journal of Allergy and Clinical Immunology, 2007, 120, 948. M. Rekhter, K. Staschke, T. Estridge, P. Rutherford, N. Jackson, D. Gifford-Moore, P. Foxworthy,

C. Reidy, X.-d. Huang, M. Kalbfleisch, K. Hui, M.S. Kuo, R. Gilmour and C. J. Vlahos, Biochemical and Biophysical Research Communications, 2008, 367, 642. O’Neill, L. A. (2003). “Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases.” Curr Opin Pharmacol 3(4): 396. Kanzler, H et al. (2007) “Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists.” Nature Medicine 13:552. Wagner, H. (2006) “Endogenous TLR ligands and autoimmunity” /Advances in Immunol 91 : 159. Ngo, V. N. et al. (2011) “Oncogenically active MyD88 mutations in human lymphoma” Nature 470: 115.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015150995&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Preparation 1 : 1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1) Step 1. Synthesis of methyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9. CD.

To a solution of 3-hydroxy-4-iodobenzoic acid (CAS 58123-77-6, C12) (10800 g, 40.9 moles) in DMF (65 L) was added K₂C0₃ (25398 g, 184 moles), followed by the slow addition of dimethyl sulfate (11352 g, 90 moles). This mixture was heated to about 50 °C for over night. The reaction mixture was cooled to about 25 °C, diluted with EtOAc (50 L) and filtered through a plug of Celite®. The solid was thoroughly washed with EtOAc (10 L X 3). The combined EtOAc filtrates were poured into water. After stirring for about 30 min, the EtOAc layer was separated and it was further washed sequentially with water, 1 M NaOH and brine. The EtOAc layer was separated, dried over Na₂S0₄, filtered and concentrated to provide the title compound C1. Yield: 11750 g (98%).

Step 2. Synthesis of (4-iodo-3-methoxyphenyl)methanol (CAS 244257-61-2, C2).

To a solution of compound C1 (11750 g, 40.2 moles) in THF (35 L) was added NaBH₄ (7645 g, 201.09 moles) and refluxed. While refluxing, MeOH (25 L) was slowly added into the reaction mixture at a rate of about 1 L per hour. After completion of the reaction, it was poured into a solution of cold dilute HCI. Once the excess of NaBH₄was quenched, the solution was filtered and extracted with EtOAc (2.5 L X 3). The combined EtOAc extracts were washed sequentially with water, brine and dried over Na₂S0₄. The solvent was evaporated under reduced pressure and the resulting crude material was treated with MTBE. The resulting solid was filtered and filtrate was washed with water, brine, dried over Na₂S0 , and filtered. The solvent was evaporated under reduced pressure to provide the title compound C2. Yield: 9900 g (93%).

Step 3. Synthesis of 4-iodo-3-methoxybenzaldehyde (CAS 121404-83-9, C3).

To a solution of compound C2 (9900 g, 34.5 moles) in CHCI₃ (186 L), was added manganese dioxide (18000 g, 207 moles) and the resulting mixture was refluxed for about 16 h. The mixture was cooled to about 25 °C and filtered through a Celite pad, which was then washed thoroughly with CHCI₃. The CHCI₃ was evaporated under reduced pressure to provide the title compound C3. Yield: 9330 g (95%). ¹ H NMR (400 MHz, CDCI₃): δ 9.95 (s, 1 H), 7.99 (d, 1 H), 7.14 (dd, 1 H), 3.95 (s, 3 H).

Step 3. Synthesis of 6-iodo-7-methoxyisoquinoline (CAS 244257-63-4. C4).

To a solution of compound C3 (9300 g, 35 moles) in toluene (60 L) was added amino acetaldehyde dimethyl acetal (5590 g, 53 moles) and the mixture was refluxed for about 4 h, while removing the liberated water by the use of a Dean – Stark water separator. The reaction mixture was cooled to about 0 °C, after which trifluoroacetic anhydride (22305 g, 106 moles) followed by BF₃-Et₂0 (15080 g, 106 moles) were added, keeping internal temperature below 5 °C. The reaction mixture was stirred at about 25 °C for about 16 h and quenched by pouring into a mixture of ice and ammonium hydroxide. The product was extracted with EtOAc (10 L X 3), and the combined EtOAc extracts were washed sequentially with water and brine. The combined EtOAc extracts were dried over Na₂S0₄, filtered, and concentrated to afford a dark tan colored residue. This was treated with a mixture of MTBE and hexane (1 :1 v/v, 30 L), followed by 6 M HCI (9 L), with stirring. The precipitated solid was filtered and washed with MTBE. The solid was suspended in EtOAc (5 L) and made alkaline with ammonium hydroxide. The EtOAc layer was separated, washed with brine, dried over Na₂S0₄, filtered, and concentrated to afford crude compound C4 as a brown solid. HPLC (230 nm) showed it to be about 83% pure.

The crude material (1000 g) was taken in AcOH (2.5 L) and stirred for about 90 min at about 25 °C. The solid was filtered and washed with AcOH (500 ml_). The filtrate was neutralized with saturated aqueous Na₂C0₃ solution. The resulting precipitated solid was filtered, washed with water (4 L), and oven dried at about 70 – 75 °C for about 5 h to afford about 780 g of pure C4. Similarly, the remaining crude C4 (4 kg) was purified to provide the title compound C4. Yield: 4300 g (42%). ¹H NMR (400 MHz, CDCI₃): δ 9.15 (s, 1 H), 8.45 (d, 1 H), 8.35 (s, 1 H), 7.45 (d, 1 H), 7.15 (s, 1 H) 4.00 (s, 3 H).

Step 4. Synthesis of 7-methoxyisoquinoline-6-carbonitrile (C5).

To a solution of compound C4 (4300 g , 15 moles) in DMSO (39 L) was added copper(l) cyanide (2954 g, 33 moles) and the mixture was heated to about 120 °C for about 3 h. The reaction mixture was quenched by pouring into a mixture of ice and ammonium hydroxide (40 L) and filtered. The filtrate was extracted with EtOAc (10 L X 2). While stirring, the solid residue was again treated with ammonium hydroxide solution (10 L) and EtOAc (10 L). After filtration, the precipitated material was repeatedly washed with a mixture of MeOH and CHCI₃ (1 :9, v/v) several times and the combined extracts were washed with brine. The extracts were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The resulting crude material was triturated with hexane to provide the title compound C5. Yield: 2250 g (87%). ¹H NMR (400 MHz, CDCI₃): δ 9.25 (br. s, 1 H), 8.55 (br. s, 1 H), 8.15 (s, 1 H), 7.60 (d, 1 H), 7.30 (s, 1 H), 4.05 (s, 3 H).

A solution of a reactant such as 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile (200 mg, 0.5 mmol) in concentrated H₂SO₄ (1.5 ml.) was warmed to about 55 °C for about two hours, then cooled to about 20 °C. The reaction mixture was added dropwise with vigorous stirring to 7.3 ml_ of ice cold concentrated ammonium hydroxide with cooling in ice. The precipitated solid was filtered and washed with water, heptane, ether, and dried under vacuum. The residue may be used directly for subsequent work, or it may be purified by chromatography or HPLC.

ABSTRACTS

251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 261

//////////PF 06650833, IRAK4 inhibitor, inflammatory disease treatment , PFIZER, 1817626-54-2

N1C([C@H](C([C@H]1COc3c2cc(c(cc2ccn3)C(=O)N)OC)CC)F)=O

NC(=O)c2cc3ccnc(OC[C@H]1NC(=O)[C@@H](F)[C@H]1CC)c3cc2OC

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

amcrasto@gmail.com

P.S

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.

AZD 7594

phase 2, Uncategorized Comments Off

Mar 272016

Picture credit….Bethany Halford

AZD 7594

$AZN‘s asthma candidate

AZ13189620; AZD-7594

Bayer Pharma Aktiengesellschaft, Astrazeneca Ab

Molecular Formula:	C₃₂H₃₂F₂N₄O₆
Molecular Weight:	606.616486 g/mol

3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(oxolan-3-yl)benzamide

Benzamide, 3-[5-[(1R,2S)-2-[(2,2-difluoro-1-oxopropyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]-1H-indazol-1-yl]-N-[(3R)-tetrahydro-3-furanyl]-

Cas 1196509-60-0

AZD-7594 is in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma.

It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).

https://clinicaltrials.gov/ct2/show/NCT02479412

Company	AstraZeneca plc
Description	Inhaled selective glucocorticoid receptor (GCCR) modulator
Molecular Target	Glucocorticoid receptor (GCCR)

Phase II Asthma
Phase I Chronic obstructive pulmonary disease

01 Feb 2016 AstraZeneca completes a phase II trial in Asthma in Bulgaria and Germany (Inhalation) (NCT02479412)
09 Jan 2016 AstraZeneca plans to initiate a phase I trial in Healthy volunteers in USA (IV and PO) (NCT02648438)
01 Jan 2016 Phase-I clinical trials in Chronic obstructive pulmonary disease (In volunteers) in USA (PO, IV, Inhalation) (NCT02648438)

PATENT

http://www.google.com/patents/WO2009142569A1

PATENT

US20100804345

UNWANTED ISOMER

WANTED COMPD

PATENT

WO 2009142571

Example 6

WANTED ISOMER

3-(5- { TC 1 R,2SV2-r(2,2-difluoropropanoyl)aminol- 1 -(2,3-dihydro-l ,4-benzodioxin-6-5 yDpropylioxy) – 1 H-indazol- 1 -ylVN-[(3R)-tetrahydrofuran-3-vnbenzamide. APCI-MS: m/z 607 [MH⁺] ¹H NMR ^OO MHz, DMSOd₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d). LC (method A) rt = 12.03 min LC (method B) rt = 11.13 min Chiral SFC (method B) rt = 4.71 min M.p. = 177 °C

UNWANTED

o 3-(5- { IY 1 R,2S V2-r(2,2-difluoropropanoyl^‘)amino^‘|- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6- yl)propyl]oxy } – 1 H-indazol- 1 -yP-N-IO S)-tetrahydrofuran-3 -yl^“|benzamide

APCI-MS: m/z 607 [MH⁺]

¹H NMR (400 MHz, DMSO-J₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s),

7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H,s m), 5.17 (IH, d), 4.48 (IH, m), 4.24 – 4.11 (5H, m), 3.90 – 3.81 (2H, m), 3.72 (IH, td), 3.61

(IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt = 12.02 min

LC (Method B) rt = 11.12 min

Chiral SFC (method B) rt = 5.10 min o M.p. = 175 ⁰C

PATENT

WO 2011061527

http://www.google.com/patents/WO2011061527A1?cl=en

Intermediate 12

( 1 R,2S)-2-amino- 1 -(2,3 -dihydrobenzo b [ 1 ,41dioxin-6-yl)propan- 1 -ol hydrochloride. (12)

5-6 N HC1 in 2-propanol (8 mL, 40-48 mmol) was added to tert-butyl (lR,2S)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxypropan-2-ylcarbamate (I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at 40°C and stirred for 3 hours. The reaction mixture was allowed to reach r.t. and was concentrated by evaporation. Ether was added and the salt was filtered off and washed with ether. The salt was found to be hygroscopic. Yield 2.10 g (85%)

APCI-MS: m/z 210 [MH⁺-HC1]

1H-NMR (300 MHz, DMSO-^): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93 (brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl (1R,2S)- 1 -(2,3-dihvdrobenzorbl Γ 1 ,41dioxin-6-yl)- 1 -hvdroxypropan-2-ylcarbamate.

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843.

(S)-tert-butyl 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) were stirred at 50°C under argon for 16 hours. The reaction mixture was poured into 1M HC1 (150 mL) and the mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na₂SC”4, filtered and concentrated. The crude product was purified by flash- chromatography on silica using ethyl acetate/hexane (1/2) as eluent. Fractions containing product were combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%) APCI-MS: m/z 236, 210, 192 [MH -tBu-18, MH -BOC, MH -BOC- 18]

1H NMR (300 MHz, DMSO-^): δ 6.80-6.70 (m, 3H), 6.51 (d, IH), 5.17 (d, IH), 4.36 (t, IH),

4.19 (s, 4H), 3.49 (m, IH), 1.31 (s, 9H), 0.93 (d, 3H).

(S)-tert-butyl 1 -(2,3-dihydrobenzo[bl [ 1 ,41dioxin-6-yD- 1 -oxopropan-2-ylcarbamate. (I2b)

A suspension of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of argon and cooled down to -15 to -20°C. Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol), was added keeping the temperature below -10°C. The temperature was allowed to reach 0°C. A freshly prepared solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t. overnight. The reaction mixture was poured into ice cooled IN HC1 (300 mL). TBME (300 mL) was added and the mixture was transferred to a separation funnel. The water phase was back extracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na₂S0₄). The crude product was purified by flash chromatography using TBME /Heptane 1/2 as eluent. Fractions containing the product were combined and solvents were removed by evaporation to give the subtitle compound as a slightly yellow sticky oil/gum. Yield 3.76g

(95%)

APCI-MS: m/z 208 [MH⁺ – BOC]

1H NMR (300 MHz, DMSO-^): δ 7.50 (dd, IH), 7.46 (d, IH), 7.24 (d, IH), 6.97 (d, IH), 4.97 (m, IH), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Intermediate 13

(lR,2S)-2-amino-l-(4H-benzo[dl[l,31dioxin-7- l)propan-l-ol hydrochloride (13)

Tert-butyl ( 1 R,2S)- 1 -(4H-benzo[d] [ 1 ,3]dioxin-7-yl)- 1 -hydroxypropan-2-ylcarbamate (I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL) and 5-6 N HC1 solution in 2- propanol (1.5 mL, 7.5-9 mmol) was added. The mixture was stirred at 50 °C for 1.5 hours. The solvents was removed by evaporation. The residual sticky gum was treated with ethyl acetate and evaporated again to give a solid material that was suspended in acetonitrile and stirred for a few minutes. The solid colourless salt was collected by filtration and was found to be somewhat hygroscopic. The salt was quickly transferred to a dessicator and dried under reduced pressure. Yield 293 mg (92%)

APCI-MS: m/z 210 [MH⁺ -HC1]

1H NMR (300 MHz, DMSO-^) δ 8.07 (3H, s), 7.05 (IH, d), 6.92 (IH, dd), 6.85 (IH, d), 6.03 (IH, d), 5.25 (2H, s), 4.87 (3H, m), 3.42 – 3.29 (IH, m), 0.94 (3H, d).

(4S.5R -5-(4H-benzordiri.31dioxin-7-vn- -methyloxazolidin-2-one (I3a

A mixture of (lR,2S)-2-amino-l-(4H-benzo[d][l,3]dioxin-7-yl)propan-l-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at r.t. for 2 hours. The reaction mixture was concentrated by evaporation and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 10% NaHS0₄, dried over MgS0₄, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)

The relative cis conformation of the product was confirmed by comparing the observed 1H- NMR with the literature values reported for similar cyclised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 and Terahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experiment a strong NOE cross-peak was observed for the doublet at 5.64 with the multiplet at 4.19 ppm. This also confirmed the relative czs-conformation.

APCI-MS: m/z 236 [MH⁺]

1H NMR (400 MHz, CDC1₃) δ 6.99 (d, J= 8.0 Hz, IH), 6.88 (dd, J= 8.0, 1.4 Hz, IH), 6.83 (s, IH), 5.81 (brs,lH), 5.64 (d, J= 8.0 Hz, IH), 5.26 (s, 2H), 4.91 (s, 2H), 4.19 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Tert-butyl ( 1 R,2S)- 1 -(4H-benzord1 Γ 1 ,31dioxin-7-yl)- 1 -hvdroxypropan-2-ylcarbamate (I3b)

A mixture (S)-tert-butyl l-(4H-benzo[d][l,3]dioxin-7-yl)-l-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at 65 °C for 15 hours. The reaction mixture was allowed to cool down, poured into 1M HC1 (50 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with water, brine, dried over MgS0₄, filtered and solvents were removed by evaporation to afford a colourless solid. The crude product was purified by flash chromatography, (solvent A = Heptane, solvent B = EtOAc + 10% MeOH. A gradient of 10%B to 50%B in A was used). The obtained product was crystallised from DCM / heptane to afford the subtitle compound as colourless needles. Yield 414 mg (60%)

APCI-MS: m/z 210 [MH⁺ -BOC]

1H NMR (400 MHz, DMSO- ¾ δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s), 6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t), 3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d). (S)-Tert-butyl 1 -(4H-benzord1 Γ 1 ,31dioxin-7-vD- 1 -oxopropan-2-ylcarbamate (I3c)

7-Bromo-4H-benzo[d][l,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5 mL) and added to magnesium (0.113 g, 4.65 mmol) under a protective atmosphere of argon. One small iodine crystal was added. The coloured solution was heated with an heat gun in short periods to initiate the Grignard formation. When the iodine colour vanished the reaction was allowed to proceed at r.t. for 1.5 hours.

In a separate reaction tube (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2- ylcarbamate (1 g, 4.31 mmol) was suspended in THF (5 mL) and cooled in an ice/acetone bath to below -5 °C. Isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol) was slowly added to form a solution. To this solution was added the above freshly prepared Grignard reagent. The mixture was allowed to reach r.t. and stirred for 4 hours. The reaction mixture was slowly poured into ice-cold 150 mL 1M HC1. Ethyl acetate (150 mL) was added and the mixture was stirred for a few minutes and transferred to a separation funnel. The organic phase was washed with water and brine, dried over MgS04, filtered and concentrated. The obtained crude product was further purified by flash chromatography using a prepacked 70g silica column with a gradient of 10% TBME to 40% TBME in heptane as eluent. The subtitle compound was obtained as a colourless solid. Yield 790 mg (59%>)

APCI-MS: m/z 208 [MH⁺ -BOC]

1H NMR (400 MHz, DMSO-^) δ 7.53 (IH, dd), 7.39 (IH, s), 7.30 (IH, d), 7.22 (IH, d), 5.30 (2H, s), 4.98 (IH, m), 4.95 (2H, s), 1.35 (9H, s), 1.20 (3H, d).

Preparation 4

3-(5-([(lR,2S)-2-[(2,2-difluoropropanoyl)aminol-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy| – 1 H-indazol- 1 -yl)-N-[(3R)-tetrahydrofuran-3-yllbenzamide

TEA (2.0 g, 20.65 mmol) was added to a mixture of 3-(5-((lR,2S)-2-(2,2- difluoropropanamido)- 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)propoxy)-l H-indazol-1 – yl)benzoic acid (14) (3.6 g, 6.70 mmol), (R)-tetrahydrofuran-3 -amine hydrochloride (0.99 g, 8.0 mmol) and HBTU (2.65 g, 6.99 mmol) in DCM (15 mL). The reaction was stirred at r.t. for 3h, then quenched by addition of a mixture of water and ethyl acetate. The mixture was shaken and the organic layer was collected. The water phase was extracted twice with ethyl acetate. The combined organic layers were washed with a small portion of water and dried over magnesium sulphate. The product was purified by flash chromatography (silica, eluent: a gradient of ethyl acetate in heptane). The residue was crystallized by dissolving in refluxing acetonitrile (50 mL) and then allowing to cool to r.t. over night. The solid was collected by filtration, washed with a small volume of acetonitrile and dried at 40°C in vaccum to give the title compound (2.5 g, 61%).

APCI-MS: m/z 607 [MH⁺]

1H NMR (400 MHz, DMSO-d₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt = 12.03 min

LC (method B) rt = 11.13 min

Chiral SFC (method B) rt = 4.71 min

M.p. = 177 °C

Patent ID	Date	Patent Title
US2015080434	2015-03-19	PHENYL AND BENZODIOXINYL SUBSTITUTED INDAZOLES DERIVATIVES
US8916600	2014-12-23	Phenyl and benzodioxinyl substituted indazoles derivatives
US8211930	2012-07-03	Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

REFERENCES

https://www.astrazeneca.com/content/dam/az/press-releases/2014/Q2/Pipeline-table.pdf

////////AZD 7594, AZ13189620, AZD-7594 , phase 2, astrazeneca, 1196509-60-0

c21cc(ccc1n(nc2)c3cc(ccc3)C(=O)NC4COCC4)O[C@H](c5cc6c(cc5)OCCO6)[C@@H](NC(=O)C(F)(F)C)C

CC(C(C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)NC6CCOC6)NC(=O)C(C)(F)F

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

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P.S

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GLPG 1690

Uncategorized Comments Off

Mar 252016

Picture credit….Bethany Halford

GLPG 1690

2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile

5-Thiazolecarbonitrile, 2-[[2-ethyl-6-[4-[2-(3-hydroxy-1-azetidinyl)-2-oxoethyl]-1-piperazinyl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)-

CAS 1628260-79-6

Galapagos

$GLPG compound for treating idiopathic pulmonary fibrosis

Molecular Formula:	C₃₀H₃₃FN₈O₂S
Molecular Weight:	588.698823 g/mol

	Galapagos Nv

Galapagos Nv

http://files.glpg.com/docs/website_1/Poster_ERS_2015_final.pdf

http://www.glpg.com/docs/view/56b360a81f6b2-en

Phase I Idiopathic pulmonary fibrosis

Description	Selective autotaxin (ENPP2; ATX) inhibitor
Molecular Target	Autotaxin (ENPP2) (ATX)

Originator Galapagos NV
Class Anti-inflammatories; Small molecules
Mechanism of Action ENPP2 protein inhibitors

23 Sep 2015 Pharmacodynamics data from a preclinical trial in Indiopathic pulmonary fibrosis released by Galapagos
22 Sep 2015 Pharmacokinetics data from a phase I trial in healthy volunteers released by Galapagos
22 Sep 2015 Updated adverse events data from a phase I trial in healthy volunteers released by Galapagos

GLPG1690

GLPG1690 is a selective autotaxin inhibitor discovered by Galapagos, with potential application in idiopathic pulmonary disease (IPF). In a Phase 1 study in healthy human volunteers, GLPG1690 demonstrated favorable safety and tolerability, as well as a strong pharmacodynamic signal implying target engagement. Galapagos is currently preparing a Phase 2 study in IPF, to be filed for approval before the end of 2015. GLPG1690 is fully proprietary to Galapagos.

March 17, 2015 02:37 ET | Source: Galapagos NV

Fully owned and proprietary clinical asset for pulmonary fibrosis
GLPG1690 acts on autotaxin target
Novel mode of action, originating from Galapagos target discovery engine
Filing for Phase 2 clinical trial in 2015

MECHELEN, Belgium, March 16, 2015 (GLOBE NEWSWIRE) — Galapagos NV (Euronext: GLPG) announced that Janssen Pharmaceutica NV and Galapagos have mutually agreed to terminate the inflammation alliance and option agreements between the companies. Galapagos views the molecules emerging from the alliance as strong additions to its growing proprietary pipeline. Among others, all rights to candidate drug GLPG1690, a selective autotaxin inhibitor, return to Galapagos. Galapagos has successfully completed a First-in-Human Phase 1 trial for GLPG1690 and is preparing a Phase 2 clinical trial in idiopathic pulmonary fibrosis (IPF).

“We are pleased to regain the rights to GLPG1690 to pursue the most suitable clinical application of autotaxin inhibition. There is a large unmet medical need in IPF, and our pre-clinical data with GLPG1690 supports its potential as a competitive and novel approach in this disease area,” said Dr Piet Wigerinck, Chief Scientific Officer of Galapagos. “The alliance with Janssen has been underway since October 2007 and has generated three clinical molecules, two of which are now proprietary Phase 2 assets of Galapagos: GLPG1205 and GLPG1690. This program is a valuable component of our development portfolio, and regaining the rights is a next step in our transformation into a mature biotech company with a proprietary product pipeline.”

Galapagos identified autotaxin as playing a key role in inflammation, using an inflammation assay in its unique target discovery platform. Pharmacology and translational studies published by other parties in the literature since then suggest autotaxin may play a key role in metabolic disease, arthritic pain, oncology, and lung disease.

GLPG1690 is a potent and selective inhibitor of autotaxin. In a Phase 1 study in healthy human volunteers, GLPG1690 demonstrated favorable safety and tolerability, as well as a strong pharmacodynamic signal implying target engagement. Galapagos is currently preparing a Phase 2 study in IPF, to be filed for approval before the end of 2015.

About IPF
Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Pulmonary fibrosis involves scarring of lung tissue and is the cause of shortness of breath. Fibrosis is usually associated with a poor prognosis. The term “idiopathic” is used because the cause of pulmonary fibrosis is still unknown. Estimated incidence of IPF is up to 16.3 per 100,000 persons in the US and 7.4 per 100,000 persons in Europe, with approximately 30,000-35,000 new patients diagnosed with IPF worldwide each year. The goals of treatment in IPF are essentially to reduce the symptoms, slow down disease progression, reduce acute exacerbations, and prolong survival. Approved treatments thus far have improved the overall survival of IPF patients, but unwanted side effects with these treatments are common, presenting an unmet need for effective treatments with safer side effect profiles.

September 22, 2015 01:37 ET | Source: Galapagos NV

MECHELEN, Belgium, Sept. 22, 2015 (GLOBE NEWSWIRE) — Galapagos NV (Euronext & NASDAQ: GLPG) presents pre-clinical and Phase 1 results for autotaxin inhibitor GLPG1690 at the European Respiratory Society Annual Meeting in Amsterdam, Netherlands. Galapagos expects to file an exploratory Phase 2 study in idiopathic pulmonary fibrosis before year end. GLPG1690 has potential application in other pulmonary diseases such as chronic obstructive pulmonary disease (COPD), as supported by the presentation on pre-clinical findings at ERS this year:

“Pharmacological profile and efficacy of GLPG1690, a novel ATX inhibitor for COPD treatment,” poster PA2129 in Poster Discussion Session: “New targets and modalities for the treatment of asthma and COPD” (September 28, 2015; Room D201-202, 10:45 AM – 12:45 PM)

Galapagos is the first to show efficacy of an autotaxin inhibitor in pre-clinical models for COPD and IPF, pointing to novel therapeutic areas for autotaxin inhibition. The poster shows how GLPG1690 acts as a potent inhibitor of mouse and human autotaxin (IC₅₀: 100 -500 nM range). Furthermore, GLPG1690 reduces inflammation in a mouse steroid-resistant tobacco smoke model to a similar extent as a standard therapy for COPD.

Galapagos also presents the topline results with GLPG1690 in Phase 1 in healthy human volunteers: “Favorable human safety, pharmacokinetics and pharmacodynamics of the autotaxin inhibitor GLPG1690, a potential new treatment in COPD,” oral presentation OA484 in session “Advances in the future treatment of COPD” (September 27, 2015; Room 2.1, 10:45 AM – 12:45 PM)

GLPG1690 was safe and well tolerated up to a single oral dose of 1500 mg and up to 1000 mg twice daily for 14 days, with no significant adverse effects on ECGs, vital signs or laboratory parameters. The compound also showed good oral bioavailability with a half-life of 5 hours and a dose-proportional increase in exposure. GLPG1690 showed concentration-dependent reduction of a relevant biomarker (plasma LPA18:2 levels) with a maximum of approximately 90%. At steady state, continuous reduction of this biomarker levels of >60% was observed from 0 to 24 hours. The presentation will also include relevant pre-clinical model data for COPD and IPF with GLPG1690.

Both the presentation and the posters will be made available on the Galapagos website after the conference.

About Galapagos

Galapagos (Euronext & NASDAQ: GLPG) is a clinical-stage biotechnology company specialized in the discovery and development of small molecule medicines with novel modes of action, with a pipeline comprising three Phase 2 programs, two Phase 1 trials, five pre-clinical studies, and 20 discovery small-molecule and antibody programs in cystic fibrosis, inflammation, and other indications. In the field of inflammation, AbbVie and Galapagos signed a collaboration agreement for the development and commercialization of filgotinib. Filgotinib is an orally-available, selective inhibitor of JAK1 for the treatment of rheumatoid arthritis and potentially other inflammatory diseases, currently in Phase 2B studies in RA and in Phase 2 in Crohn’s disease. Galapagos reported good activity and a favorable safety profile in both the DARWIN 1 and 2 trials in RA. AbbVie and Galapagos also signed a collaboration agreement in cystic fibrosis to develop and commercialize molecules that address mutations in the CFTR gene. Potentiator GLPG1837 is currently in a Phase 1 trial, and corrector GLPG2222 is at the pre-clinical candidate stage. GLPG1205, a first-in-class inhibitor of GPR84 and fully-owned by Galapagos, is currently being tested in a Phase 2 proof-of-concept trial in ulcerative colitis patients. GLPG1690, a fully proprietary, first-in-class inhibitor of autotaxin, has shown favorable safety in a Phase 1 trial and is expected to enter Phase 2 in idiopathic pulmonary fibrosis. The Galapagos Group, including fee-for-service subsidiary Fidelta, has approximately 400 employees, operating from its Mechelen, Belgium headquarters and facilities in The Netherlands, France, and Croatia. More info at www.glpg.com

CONTACT

Galapagos NV
Elizabeth Goodwin, Head of Corporate Communications & IR
Tel: +31 6 2291 6240
ir@glpg.com

MECHELEN, Belgium, Feb. 16, 2015 (GLOBE NEWSWIRE) — Galapagos NV (Euronext: GLPG) announced today that GLPG1690, a first-in-class molecule for pulmonary disease, has demonstrated target engagement, a good safety profile, and favorable drug properties in a Phase 1 study. Galapagos is developing GLPG1690 within its alliance with Janssen Pharmaceutica NV.

The aim of the Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral single and multiple ascending doses of GLPG1690. The randomized, double-blind, placebo-controlled, single center study was conducted in 40 healthy volunteers in Belgium. In the first part of the study, single ascending doses were evaluated. In the second part, the new compound was administered daily for 14 days.

GLPG1690 proved to be safe and well-tolerated over a wide dose range in healthy volunteers. Engagement of the thus far undisclosed novel target was confirmed using a relevant biomarker. GLPG1690 displayed a favorable pharmacokinetic and pharmacodynamic profile. The data shown in Phase 1 encourage Galapagos to explore a Phase 2 study design in pulmonary disease.

“GLPG1690 is the first molecule against this target ever to be evaluated clinically, and we are pleased with the outcome of the Phase 1 study,” said Dr Piet Wigerinck, CSO of Galapagos. “Galapagos continues to deliver novel therapeutics from its unique target and drug discovery engine.”

In 2007, Galapagos announced an alliance agreement with Janssen Pharmaceutica NV providing the option to worldwide, commercial licenses to certain Galapagos internal inflammatory disease programs. These programs are based on novel targets for inflammatory disorders that were identified and validated by Galapagos using its proprietary target discovery engine. Subsequent Galapagos research led to the discovery of GLPG1690, a first-in-class molecule that entered the clinic for inflammatory disorders. Galapagos is responsible for execution of Phase 1 and Phase 2A studies with GLPG1690.

SYNTHESIS

INTRODUCTION

relates to compounds that are inhibitors of autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), that is involved in fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases. The present invention also provides methods for the production of a compound of the invention, pharmaceutical compositions comprising a compound of the invention, methods for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering a compound

STAGE 1

STAGE2

STAGE 3

Figure US20140303140A1-20141009-C00040

STAGE4

STAGE 5

FINAL

PATENT

US2014303140

http://www.google.com/patents/US20140303140

1.2.4.4. Illustrative Synthesis of Intermediate Gen-3-e: N-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-N-methylformamide

To a suspension of formamide Gen-2-d (720 g, 2.55 mol, 1 eq.) in 5 L of acetone were added potassium carbonate (1 kg, 7.66 mol, 3 eq.) and methyl iodide (700 g, 4.93 mol, 1.9 eq.). The reaction mixture was heated to 40° C. overnight. Additional methyl iodide (25 g, 0.18 mol, 0.07 eq.) was then introduced and stirring continued for 1 h at 40° C. The reaction mixture was filtered and washed with acetone (2×300 mL) and DCM (2×300 mL). The filtrate was concentrated in vacuo and the residue was partitioned between DCM (3 L) and water (1 L). The aqueous layer was further extracted with DCM. The combined organic layers were then washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The solid was triturated with Et₂O (1 L) at r.t. for 1 h, filtered off and dried to afford Intermediate Gen-3-e.
Rotamer A (Major): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.19 (1H, s), 7.78 (1H, s), 7.15 (1H, s), 3.24 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31 (3H, t)
Rotamer B (Minor): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.49 (1H, s), 7.65 (1H, s), 7.08 (1H, s), 3.36 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31 (3H, t)
LC-MS: MW (calcd): 295 (⁷⁹Br), 297 (⁸¹Br); m/z MW (obsd): 296 (⁷⁹Br M+1), 298 (⁸¹Br M+1)

1.2.5.2. Illustrative Synthesis of Intermediate Gen-4-d: (6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine

Intermediate Gen-3-e (80 g, 270 mmol, 1 eq.) was dissolved in a 1.25 M HCl solution in MeOH (540 mL, 2.5 eq.) and the resulting mixture was refluxed overnight. 270 mL of 1.25 M HCl solution in MeOH were added and heating continued overnight. After 48 h, additional 70 mL of the 1.25 M HCl solution in MeOH were introduced in the reaction mixture. Heating was maintained overnight until conversion was complete. The crude mixture was then concentrated in vacuo and the residue was partitioned between EtOAc (300 mL) and water (700 mL). A saturated NaHCO₃solution was added until pH reached 8-9. The aqueous layer was extracted twice with EtOAc (2×300 mL). The combined organic layers were then washed with brine (200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give Intermediate Gen-4-d (6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine) as a free base.
¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.05 (1H, s), 7.04 (1H, s), 2.84-2.78 (5H, m), 2.60 (3H, s), 1.35 (3H, t)
LC-MS: MW (calcd): 267 (⁷⁹Br), 269 (⁸¹Br); m/z MW (obsd): 268 (⁷⁹Br M+1), 270 (⁸¹Br M+1)

1.2.6.4. Illustrative Synthesis of Intermediate Gen-5-t: 2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

To a solution of amine Gen-4-d (4.4 g, 16.6 mmol, 1 eq.) in THF (44 mL) under argon was slowly added NaH (60% in oil suspension, 2.0 g, 50.0 mmol, 3 eq.). The reaction mixture was heated at 90° C. for 30 min then cooled to 40° C. before adding the chlorothiazole Gen-12-a (4.74 g, 19.9 mmol, 1.2 eq.). The reaction mixture was stirred at 90° C. overnight. After cooling to r.t. the mixture was slowly quenched by addition of water and then diluted with EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic layers were then washed with water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was triturated in Et₂O, filtered and washed with Et₂O and MeCN. Recrystallization was performed in MeCN (180 mL) to afford Intermediate Gen-5-t (2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile).
¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.15 (2H, dd), 7.80 (1H, s), 7.22-7.14 (3H, m), 3.62 (3H, s), 2.77 (2H, q), 2.64 (3H, s), 1.35 (3H, t)
LC-MS: MW (calcd): 469 (⁷⁹Br), 471 (⁸¹Br); m/z MW (obsd): 470 (⁷⁹Br M+1), 472 (⁸¹Br M+1)

1.2.7.1.4. Illustrative Synthesis of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of Intermediate Gen-5-t (24.2 g, 51.5 mmol, 1 eq.) in toluene under argon were successively added N-Boc piperazine (14.4 g, 77.3 mmol, 1.5 eq.), sodium tert-butoxide (9.9 g, 103 mmol, 2 eq.), JohnPhos (1.54 g, 5.15 mmol, 0.1 eq.) and Pd₂(dba)₃(2.36 g, 2.58 mmol, 0.05 eq.). The reaction mixture was heated at 115° C. for 1 h. After cooling to r.t., the crude product was filtered on Celpure® P65 and the residue dissolved in EtOAc and washed with water. The organic layer was further washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (elution with heptane/EtOAc:90/10 to 20/80) to afford the expected product.
¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.16 (2H, dd), 7.17 (2H, app t), 6.99 (2H, bs), 3.62-3.53 (4H, m), 3.60 (3H, s), 3.04-2.93 (4H, m), 2.74 (2H, q), 2.62 (3H, s), 1.47 (9H, s), 1.33 (3H, t).
LC-MS: MW (calcd): 575; m/z MW (obsd): 576 (M+1)

1.2.7.8.4. Illustrative Synthesis of Compound 1: 2-[(2-Ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from intermediate Gen-5-t using Boc-piperazine and method Flb.
To a solution of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) was added a 2 M HCl solution in Et₂O (127 mL, 254 mmol, 6 eq.). The reaction mixture was stirred at r.t. for 3.5 h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. A 2 M NaOH solution was added to the aqueous layer until pH reached 8-9 and further extraction with EtOAc was performed. The combined organic layers were then washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The solid was triturated with heptane (100 mL) at r.t. overnight, filtered off, washed with heptane and Et₂O, and dried to afford the expected compound.
¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.17 (2H, dd), 7.18 (2H, app t), 6.99 (2H, bs), 3.61 (3H, s), 3.09-2.98 (8H, m), 2.75 (2H, q), 2.61 (3H, s), 1.34 (3H, t).
LC-MS: MW (calcd): 475; m/z MW (obsd): 476 (M+1)

1.2.7.14. Illustrative Synthesis of Compound 2: 2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

To a solution of amine compound 1 (12.6 g, 27 mmol, 1 eq.) in 100 mL of MeCN were added potassium carbonate (7.3 g, 53 mmol, 2 eq.) and Gen13-a (5.2 g, 34 mmol, 1.3 eq.). The reaction mixture was refluxed for 5.5 h then cooled to r.t. and stirred for 40 h. The crude product was filtered and washed with MeCN. The collected precipitate was then suspended in 300 mL of water, stirred for 1 h, filtered, and finally washed with water and MeCN. The solid obtained was dried in vacuo for 48 h to afford Compound 2.
¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.12 (2H, m), 7.22-7.13 (2H, m), 6.99 (2H, s), 4.68 (1H, m), 4.43 (1H, dd), 4.26 (1H, dd), 4.14-4.05 (1H, m), 3.88 (1H, dd), 3.61 (3H, s), 3.58-3.52 (1H, m), 3.14-3.02 (6H, m), 2.74 (2H, q), 2.70-2.62 (4H, m), 2.59 (3H, s), 1.33 (3H, t)
LC-MS: MW (calcd): 588; m/z MW (obsd): 589 (M+1)

US9249141	Dec 17, 2014	Feb 2, 2016	Galapagos Nv	Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

1 to 2 of 2

Patent ID	Date	Patent Title
US2015111872	2015-04-23	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
US2014303140	2014-10-09	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

////////////GLPG 1690, idiopathic pulmonary fibrosis, PHASE 1, GALAPAGOS, 1628260-79-6

n12c(c(nc1c(cc(c2)N3CCN(CC3)CC(=O)N4CC(C4)O)C)CC)N(C)c5nc(c(s5)C#N)c6ccc(cc6)F

CCC1=C(N2C=C(C=C(C2=N1)C)N3CCN(CC3)CC(=O)N4CC(C4)O)N(C)C5=NC(=C(S5)C#N)C6=CC=C(C=C6)F

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P.S

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DISCLAIMER

GDC 0853

cancer, phase 1, Uncategorized Comments Off

Mar 252016

Picture credit….Bethany Halford

GDC 0853

GDC-0853; RG 7845

Molecular Formula:	C₃₇H₄₄N₈O₄
Molecular Weight:	664.79646 g/mol

2-[3-(hydroxymethyl)-4-[1-methyl-5-[(7-methyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-one

3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one

3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-1H-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one

2H-Cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one, 2-[1,6-dihydro-3′-(hydroxymethyl)-1-methyl-5-[[5-[(2S)-2-methyl-4-(3-oxetanyl)-1-piperazinyl]-2-pyridinyl]amino]-6-oxo[3,4′-bipyridin]-2′-yl]-3,4,7,8-tetrahydro-7,7-dimethyl-

s ISoMER 1434048-34-6

r iSoMER 1434048-57-3

Phase 1

Patients with Patients with Resistant B-Cell Lymphoma or Chronic Lymphocytic Leukemia..

@genentech‘s Btk inhibitor

https://clinicaltrials.gov/ct2/show/NCT01991184

Bruton tyrosine kinase inhibitor

	Genentech, Inc.

Genentech, Inc.

01 Sep 2015 Phase-I clinical trials in Autoimmune disorders (In volunteers) in USA (PO, Capsule and Tablet) (NCT02699710)
16 Oct 2014 Discontinued – Phase-I for Non-Hodgkin’s lymphoma (Second-line therapy or greater) in USA (unspecified route)
16 Oct 2014 Discontinued – Phase-I for Chronic lymphocytic leukaemia (Second-line therapy or greater) in USA (unspecified route)

BTK inhibitor GDC-0853 An orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, GDC-0853 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival.

Patent

WO 2013067274

https://www.google.co.in/patents/WO2013067274A1?cl=en

part

Example 271a (S)-tert-Butyl 4-(6-(5-Chloro-2-methoxypyridin-3-ylamino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate 271a

Image loading...

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), (S)-tert-butyl 4-(6-amino pyridin-3-yl)-3-methylpiperazine-1-carboxylate 101h (2.04 g, 7.0 mmol), 3-bromo-5-chloro-2-methoxypyridine (2.8 g, 12.6 mmol), Pd₂(dba)₃ (640 mg, 0.70 mmol), XantPhos (404.6 mg, 0.70 mmol), and cesium carbonate (4.56 g, 14.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100 °C for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 271a (1.7 g, 57%) as a yellow solid. MS-ESI: [M+H]⁺ 434.2

Example 271btert-Butyl (3S)-4-(6-{[5-(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-2-methoxypyridin-3-yl] amino}pyridin-3-yl)-3-methylpiperazine-1-carboxylate 271b

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 271a (650 mg, 1.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.79 g, 4.5 mmol), Pd₂(dba)₃ (137.2 mg, 0.15 mmol), P(cy)₃(167.4 mg, 0.60 mmol), Cs₂CO₃ (978 mg, 3.0 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110°C for 16 h. After this time the reaction was cooled to room temperature. Lithium hydroxide monohydrate (1.89 g, 45 mmol) and water (2.0 mL) were added. The resulting mixture was stirred at 45°C for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 271b (290 mg, 27%) as a yellow solid. MS-ESI: [M+H]⁺ 709.3

Example 271c 10-[3-(Hydroxymethyl)-4-[5-({5-[(2S)-2-methylpiperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-9-one 271c

A solution of 271b (286.6 mg, 0.40 mmol) in dioxane/HCl (30 mL) was stirred at 50 °C for 2 h. It was evaporated under reduced pressure to afford 271c (450 mg, crude) as a black solid. MS-ESI: [M+H]⁺ 595.3

Example 271 3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-1H-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one 271

To a solution of 271c (450 mg, 0.75 mmol) in methanol (10 mL) was added oxetan-3-one (162 mg, 2.25 mmol), NaBH₃CN (141.8 mg, 2.25 mmol), and ZnCl₂ (306 mg, 2.25 mmol). The reaction was stirred at room temperature for 3 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with dichloromethane (3 X 10 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 271 (23.0 mg, 8.8%, over two steps) as a yellow solid. MS-ESI: [M+H]⁺651.3. ¹H NMR (500 MHz, CDCl₃) δ 9.76 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 4.5 Hz, 1H), 7.35 (dd, J = 2.5 Hz, 8.5 Hz, 1H), 6.87 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 5.16-5.13 (m, 1H), 4.72-4.69 (m, 5H), 4.54-4.53 (m, 1H), 4.36-4.35 (m, 1H), 4.19-4.17 (m, 2H), 3.89-3.87 (m, 1H), 3.56-3.49 (m, 2H), 3.11-3.09 (m, 2H), 2.60-2.48 (m, overlap, 7H), 2.24-2.21 (m, 1H), 1.29 (s, 6H), 1.02 (d, J = 6.0 Hz, 3H)

Image loading... 271

………………………..

syn of 191 j

is intermediate Image loading... not product, is acid

To a mixture of 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (500 mg, 1.46 mmol), tert-butyl alcohol (20 mL), and dichloromethane (5 mL) was added 2-methyl-2-butene (3066 mg, 43.8 mmol). An aqueous solution (8 mL) of NaClO₂ (263 mg, 2.92 mmol) and NaH₂PO₄·2water (683 mg, 4.38 mmol) was added dropwise at -10°C and the reaction mixture was stirred at -10 °C for overnight. It was concentrated under reduced pressure and the residue was extracted with ethyl acetate (4 × 20 mL). The combined organic extract was dried over MgSO₄ and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 210a (315 mg, 60%) as a pale yellow solid. MS-ESI: [M+H]⁺ 360.1

Example 210b 2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl} -4-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carboxylic Acid 210b

A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 210a (400 mg, 1.1 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (536 mg, 1.1 mmol), PdCl₂(dppf) (81 mg, 0.11 mmol), K₃PO₄ (466 mg, 2.2 mmol), sodium acetate (216 mg, 2.2 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100°C for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 210b as a yellow solid (306 mg, 41%). MS-ESI: [M+H]⁺ 679.3

construction, use your discretion

Example 130a (3S)-tert- utyl 3-methyl-4-(6-nitropyridin-3-yl)piperazine-l-carboxylate 130a

130a

Following the procedures as described for compound lOlg, reaction of 5-bromo-2-nitropyridine (10.5 g, 50 mmol), and (JS)-tert-butyl-3 -methylpiperazine- 1 -carboxylate (10.0 g, 50 mmol) afforded 130a as a yellow solid (8.05 g, 50%). LCMS: [M+H]⁺ 323

Example 130b (3 S)-tert-butyl-4-(6-aminopyridin-3 -yl)-3 -methylpiperazine- 1 -carboxylate 130b

130b

Following the procedures as described for compound lOlh, hydrogenation of 130a (5.8 g) afforded 130bas a brown solid (4.9 g, 96%). LCMS: [M+H]⁺ 293

Example 130c (3 S)-tert-Butyl-4-(6-(5 -bromo- 1 -methyl -2 -oxo- 1,2-dihydropyridin-3 -yl amino) pyridine-3 -yl)-3 -methylpiperazine- 1 -carboxylate 130c

Following the procedures as described for compound lOli, reaction of 130b (4.0 g) and 3,5-dibromo-l-methylpyridin-2(lH)-one (5.5 g) afforded 130c as a yellow solid (5.4 g, 83%). LCMS: [M+H]⁺ 478

Example 130d (3 S)-5 -Bromo- 1 -methyl-3 -(5 -(2-methylpiperazin- 1 -yl)pyridin- 2-ylamino)pyridine-2(lH)-one 130d

Following the procedures as described for compound lOlj, acidic hydrolysis of the Boc group of 130c (3.1 g) afforded 130d as a yellow solid (2.3 g, 95%). LCMS: [M+H]⁺ 380.

Example 130e (3 S)-5 -Bromo- 1 -methyl-3 -(5 -(2 -methyl-4-(ox etan-3-yl)piperazin-l-yl) pyridine -2-ylamino)pyridin-2(lH)-one 130e

Following the procedures as described for compound 101k, reductive amination of 130d (2.35 g) with oxetan-3-one (0.4 mL) afforded 130e as a yellow solid (2.6 g, 98%). LCMS: [M+H]⁺ 434.

Example 13 Of (3S)-l-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-l-yl)pyridin-2-ylamino) -5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 130f

check pyridine ring position

A 100 mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 130e (1.0 g, 1.0 eq., 2.3 mmol), Pin₂B₂ (1.46 g, 2.50 eq., 5.75 mmol), Pd₂(dba)₃ (105 mg, 0.05 eq., 0.125 mmol), X-Phos (93 mg, 0.1 eq., 0.23 mmol), AcOK (676 mg, 3.0 eq., 6.9 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90 °C for 4 hrs, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 3: 1 PE/EA (80 mL) to afford 130f as yellow solid (1.0 g, 90%). MS: [M+H]⁺ 482.

check pyridine ring position, use your discretion

Example 191h ( 3S)-5 -Bromo- 1 -methyl-3 -(5 -(2-methylpiperazin- 1 -yl)pyridin- -ylamino)pyridine-2(lH)-one 191h

Following the procedure described for compound lOlj and starting with (3S)-tert-butyl 4-(6-(5 -bromo- 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3 -ylamino)pyridine-3 -yl)-3 -methyl-piperazine-l-carboxylate 191g (3.1 g, 6.5 mmol) afforded 191h as a yellow solid (2.3 g, 94%). MS-ESI: [M+H]⁺ 378.

Example 1 1 i (S)-5 -Bromo- 1 -methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin- 1 -yl)pyridin-2-ylamino)pyridin-2(lH)-one 191i

A mixture of (5)-5-bromo-l-methyl-3-(5-(2-methylpiperazin-l-yl)pyridin-2-ylamino)pyridin-2(lH)-one 191h (40.0 g, 106 mmol), oxetan-3-one (1 1.4 g, 159 mmol), NaBH₃CN (10.0 g, 159 mmol), and zinc chloride (21.3 g, 159 mmol) in methanol (700 mL) was stirred at 50°C for 5 hours. The mixture was added to water (100 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (200 mL x 3). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40: 1 dichloromethane /methanol to afford 191i (35 g, 73%). MS: [M+H]⁺ 434.

Example 191j (J5)-l-Methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-l-yl)-pyridin- -ylamino) -5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 191j

191 i 191j

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (5)-tert-butyl-4-(6-(5-bromo-l-methyl-2-oxo-l ,2-dihydropyridin-3-ylamino)pyridine-3-yl)-3-methylpiperazine-l-carboxylate 191i (1.0 g, 1.0 eq., 2.3 mmol), Pin₂B₂ (1.46 g, 2.50 eq., 5.75 mmol), Pd₂(dba)₃ (105 mg, 0.05 eq., 0.125 mmol), X-Phos (93 mg, 0.1 eq., 0.23 mmol), potassium acetate (676 mg, 3.0 eq., 6.9 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90°C for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 3 : 1 petroleum ether/ethyl acetate (80 mL) to afford 191j as yellow solid (1.0 g, 90%). MS: [M+H]⁺ 482.

pipeline

http://www.gene.com/medical-professionals/pipeline

Pictrelisib, GDC-0941, RG7321 and GNE0941

Patent ID	Date	Patent Title
US8921353	2014-12-30	Heteroaryl pyridone and aza-pyridone compounds
US2014378432	2014-12-25	HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS
US8716274	2014-05-06	Heteroaryl pyridone and aza-pyridone compounds

//////GDC 0853, genentech, Btk inhibitor, phase 1, Patients with Resistant B-Cell Lymphoma, Chronic Lymphocytic Leukemia, Bruton tyrosine kinase inhibitor, GDC-0853, RG 7845, 1434048-34-6

N1(CCN(CC1C)C2COC2)c3cnc(cc3)NC=4C(N(\C=C(/C=4)c5c(c(ncc5)N6CCn7c(C6=O)cc8CC(Cc78)(C)C)CO)C)=O

CC1CN(CCN1C2=CN=C(C=C2)NC3=CC(=CN(C3=O)C)C4=C(C(=NC=C4)N5CCN6C7=C(CC(C7)(C)C)C=C6C5=O)CO)C8COC8

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

amcrasto@gmail.com

P.S

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.