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ETAMICASTAT

April 12, 2016 6:40 am / Leave a comment

Etamicastat HCl salt
CAS: 677773-32-9 (HCl salt)

CAS 760173-05-5 (free base).
Chemical Formula: C14H16ClF2N3OS
Molecular Weight: 347.8088

Synonym: BIA 5-453; BIA5-453; BIA-5-453; Etamicastat

IUPAC/Chemical Name: (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydro-2H-imidazole-2-thione hydrochloride

5-(2-Aminoethyl)-1-((3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl)-1,3-dihydro-2h-imidazole-2-thione

R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride,

PHASE 2, Treatment of Heart Failure Therapy, Hypertension

Bial-Portela and C^a, S.A

is a novel peripherally selective dopamine β-hydroxylase (DBH) inhibitor being developed by Bial-Portela and C^a, S.A. for treatment of hypertension and congestive heart failure.(1) The compound was shown to be well tolerated in healthy volunteers.

Etamicastat, also known as BIA 5-453, is a potent, reversible, peripherally selective dopamine β-hydroxylase inhibitor (DBH inhibitor). Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases blood pressure, although does not prevent the development of hypertension in the spontaneously hypertensive rat.

^aReagents and conditions: a) Boc₂O, EtOH, rt, 2 h; b) TBDMS-Cl, Et₃N, DMAP, DCM, rt, 18 h; c) Dess–Martin periodinane, DCM, rt, 1 h; d) 2, KSCN, AcOH, EtOAc, reflux, 7 h; e) 2 N HCl, EtOAc, rt, 2 h.

Paper

Development of the Asymmetric Hydrogenation Step for Multikilogram Production of Etamicastat

Alexandre Beliaev^*

Laboratory of Chemistry, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00041

Publication Date (Web): March 21, 2016

*Tel: 351-22-9866100. Fax: 351-22-9866192. E-mail: alexander.beliaev@bial.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00041

The asymmetric hydrogenation of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate is a key step in the manufacturing route to etamicastat. A development of this step including the ruthenium or rhodium catalyst screening and the influence of the catalyst preparation (isolated, preformed in solution or in situ), solvent, temperature, pressure, additive, and concentration on the performance of the given ligand was discussed. Scale-up experiments for the best catalysts under optimized conditions were described.

PAPER

Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase
J Med Chem 2006, 49(3): 1191

PATENT

WO 2015038022

in the processes .

(J?) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3-yl) -1, 3-dihydroimidazole-2 -thione hydrochloride (the compound of formula 1, below) is a potent, non-toxic and peripherally selective inhibitor of ϋβΗ, which can be used for treatment of certain cardiovascular disorders. Compound 1 is disclosed in WO2004/033447 , along with processes for its preparation.

The process disclosed in WO2004/033447 involves the reaction of ( R) – 6 , 8 -difluorochroman-3 -ylamine hydrochloride (the structure of ( R) -6, 8-difluorochroman-3 -ylamine is shown below as compound QA) , [4 – ( tert-butyldimethylsilanyloxy) -3 -oxobutyl] carbamic acid tert-butyl ester and potassium thiocyanate .

(R) -6 , 8-difluorochroman- 3 -ylamine (compound QA) is a key intermediate in the synthesis of compound 1. The stereochemistry at the carbon atom to which the amine is attached gives rise to the stereochemistry of compound 1, so it is advantageous that compound QA is present in as pure enantiomeric form as possible. In other words, the (R) -enantiomer of compound QA should be in predominance, with little or no (S) enantiomer present. Thus, the process for preparing compound QA will advantageously produce compound QA with as high enantiomeric excess (ee) as possible.

Advantageous processes for preparing, for example, the compound of formula QA have now been found. In one aspect, the processes involve a biotransformation step. In another aspect, the processes involve chemical transformation. The processes may also be employed in the preparation of similar precursors useful in the production of other peripherally-selective inhibitors of dopamine -β -hydroxylase .

WO2008/136695 discloses a compound of formula YA, its (R) or (S) enantiomer, a mixture of its (R) and (S) enantiomers, or pharmaceutically acceptable salts thereof.

The (R) -enantiomer of the compound of formula YA has been found to be a potent dopamines-hydroxylase inhibitor having high potency and significantly reduced brain access.

As disclosed in WO2008/136695 , the compound of formula YA may be prepared by reacting the compound of formula 1 with benzaldehyde under reductive alkylation conditions. In particular, (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) – 1 , 3 -dihydroimidazole-2 -thione and benzaldehyde may be reacted in the presence of a solvent or mixture of solvents, and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride .

The compound of formula W may be prepared using a process as disclosed herein from the nitro chromene compound M.

The compound of formula WA may also be prepared using a process comprising bromination of 2 , 4 -difluorophenol to give bromophenol, alkylation of bromophenol with 4 -chloro-3 -oxo butanoate to give ketone followed by cyclization and decarboxylation to produce compound WA.

According to an aspect of the present invention, there is provided the following 2 -part synthetic route from the starting material 2 , 4 -difluorophenol to (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) -1 , 3 -dihydroimidazole-2 – thione

hydrochloride :

Part (1)

Preferred reagents and conditions:

a) HMTA, CF₃COOH, 115°C, 18 hours

b) CH₂CHCN, DABCO, DMF, water, 70°C, 16 hours

c) H₂S0₄, AcOH, 100°C, 1 hour

d) NaClO, NaOH, MeOH, 25°C, 24 hours

e) (R) -C3 -TunePhosRu (acac) 2 S/C 3000, 30 bar H₂, MeOH, 80°C, 20 hours

f) Water, 2-propanol, reflux to 20°C

g) 40% KOH, MeOH, reflux, 24 hours

h) L-tartaric acid, ethanol, water, RT, 1 hour

Part (2)

Preferred reagents and conditions

a’) methyl vinyl ketone, t-BuONa, EtOAc, EtOH, 40-50°C, 2-3 hours

Br₂, MeOH, 20-25°C, 5 hours

water, reflux, 1 hour

KOH, AcOH, reflux, 1 hour

HCl, water, 2-propanol, 75 °C, 4 hours

KSCN, AcOH, 100°C, 2-4 hours

NaHC0₃, water, EtOH

NaBH₄, 2-propanol, THF, water, 20-25°C, 16 hours

HCl, 2-propanol, water, reflux, 1-2 hours

The ( R ) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3 -yl) -1,3-dihydroimidazole-2 – thione hydrochloride

EXAMPLES

Example 1

Nitro chromene synthesis

To 3 , 5-difluoro-2-hydroxybenzaldehyde (lOg, 63mmol, leq) , di-n-butylamine (4.1g, 32mmol, 0.5eq) , phtalic anhydride (18.7g, 126mmol, 2eq) in toluene (500mL) was added nitroethanol (5.75g, 63mmol, leq) . The round bottomed flask fitted with a dean stark apparatus was refluxed for 18h. The mixture was cooled and nitroethanol (5.75g, 63mmol, leq) was added. The resulting reaction mixture was then reflux for 12h. After cooling, the solution was evaporated down to approximately 150mL and purified over silica gel (eluent ethyl acetate : hexane 1:1) this gave several fractions that contained only the product by TLC, these was evaporated under reduced pressure to yield 1.8g which was 100% pure by HPLC aera. Several more fractions were collected containing a mixture of product and starting material. These were combined and washed with 2% NaOH solution (2x50mL) to remove starting material. The organic layer was washed with water (50mL) , dried over sodium sulfate and evaporated under reduced pressure to give 2.49g of brown solid ( 100% pure by HPLC aera) . More fractions were collected. These were combined, washed with 2% NaOH solution (3xl00mL) , water (lOOmL) and dried over sodium sulfate. This was then filtered and evaporated down in vacuum to yield 6.14g of a brown solid which was 91.3% pure by HPLC aera. 6 , 8 -difluoro-3 -nitro-2H-chromene (9.90g, 73.4%) was obtained as a brown solid.

Example 2

Nitro chromene synthesis with column purification

To a solution of isobenzofuran-1 , 3 -dione (4,68 g, 31,6 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (2,5 g, 15,81 mmol) in Toluene (25 ml) was added 2 -nitroethanol (2,88 g, 31,6 mmol). The resulting mixture was heated to reflux overnight (Dean stark) .

The reaction conversion was checked by TLC (eluent PE/EtOAc 9:1) . A yellow spot was observed and corresponds to the expected product .

Reaction was cooled to room temperature and a plug of silica gel was performed. A pale brown solid (3.9g) was obtained. “””H-NMR showed presence of product and starting material. The solid was dissolved in diethylether and the organic layer was washed with aqueous sodium carbonate, dried over Na₂S0₄, filtered and concentrated under reduced pressure. A pale brown solid (1.7g,) was obtained. The ¹H-NMR was indicated no starting material but still polymer from nitroethanol and residue of phtalic anhydride. A second silica plug (eluent: PE/EtOAc 95:5) was done. A pale yellow solid (1.5g) was obtained. ¹H-NMR of solid showed only product and polymer. The solid was recrystallized from methanol/water . A pale yellow solid (1.05g, 31.2%) was obtained.

Example 3

Nitro chromene synthesis without column purification

To a solution of isobenzofuran- 1 , 3 -dione (18,74 g, 127 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (10 g, 63,3 mmol) in Toluene (100 ml) was added 2 -nitroethanol (6,86 ml, 95 mmol) . The resulting mixture was heated to reflux for 24h (Dean stark) .

The reaction conversion was checked by HPLC and by ¹H-NMR. Only 50% conversion was obtained.

The reaction mixture was cooled to room temperature and diluted with DCM (lOOmL) and 1M NaOH solution (200mL) .

The biphasic system was stirred for 30 minutes and then separated (very difficult to see phase separation) . The aqueous layer was washed with DCM (50mL) and the combined organic layers were washed twice with water (2x50ml) , dried over sodium sulfate. The filtered organic layer was concentrated under reduced pressure. To the residue was added methanol (50mL) . The methanol was then removed by distillation under reduced pressure. A brown solution precipitated when most of the methanol was removed. More methanol was added and more solid crushed out then few drops of water was added to increase the product precipitation. The brown slurry was stirred for 30 minutes and filtered. The brown solid was washed with methanol/water (1:9, 5mL) and dried in a vacuum oven at 40°C for 12h.6, 8-difluoro-3 -nitro-2H-chroraene (4,9 g, 22,99 mmol,) was obtained as brown solid in 36.3% yield.

HPLC showed a purity of 98% and ¹H-NMR confirmed the structure and purity around 95%

Example 4

Reduction of nitro chromene to nitro-alkane (racemic mixture)

To a suspension of 6 , 8 -difluoro-3 -nitro-2H-chromene (213mg, 0,999 mmol) and silica (0,8 g, 0,999 mmol) in a mixture of CHC1₃ (10 ml) and IPA (3,4 ml) at 0°C was added portion wise sodium borohydride (95 mg, 2,498 mmol). The resulting mixture was stirred at 0°C for 45 minutes. Reaction conversion was checked by HPLC. 1 mL of acetic acid was added at 0°C and the resulting mixture was stirred for 30 minutes at room temperature. The slurry was filtered and the silica was washed with DCM. The filtrate was diluted with ethyl acetate and water and the biphasic system was separated. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgS0₄, filtered and concentrated under reduced pressure.

6 , 8-difluoro-3 -nitrochroman (196mg, 0,911 mmol, 91 % yield) was obtained as a pale yellow oil.

Example 5

Preparation of 6 , 8 -difluorochroman-3 -one from nitro chromene

A solution of 6, 8-difluoro-3 -nitro-2H-chromene (lOOmg, 0,469 mmol) in acetic acid (0.5 ml) is added slowly to a stirred slurry of iron (262 mg, 4,69 mmol) in acetic acid (1 ml) at 60.deg. C. The reaction mixture is stirred at 60. °C for 2 hour then allowed to cool to room temperature and stirred overnight. The reaction mixture is poured onto ice-water (30 ml) and filtered through Celite. The solid was wash with dichloromethane (DCM) (50 ml) . The organic portion is separated and washed with water (2 x 30 ml) and brine (30 ml) , dried over MgS0₄, filtered and concentrated in vacuo to give a brown oil. 6,8-difluorochroman-3 -one (75 mg, 0,407 mmol, 87 % yield) was obtained as a brown oil.

Example 6

Preparation of 6 , 8-difluorochroman-3 -one from methyl 6,8-difluoro-2H-chromen-3 -yl-carbamate

Methanol (1000m ml) was added to a slurry of methyl fluoro-2H-chromen-3 -yl -carbamate (250 g, 1.037 mol) hydrogen chloride 6N (2000 ml, 12 mol) at room temperature. The resulting mixture was reflux and stirred for 2 hours. Reaction monitored by HPLC.

Reaction was not complete but was stopped in order to avoid degradation of the product. The yellow solution was cooled to room temperature. A slurry (two type of solid) was observed and diluted with diethyl ether (300mL) . The resulting slurry was stirred at 5°C for 1 hour then filtered. The yellow solid was washed with water. The resulting wet yellow solid was suspended in diethylether (400mL) and petroleum ether (PE) (400mL) was added. Slight yellow solid was stirred at room temperature overnight, filtered and washed with PE (300mL) , dried in a vacuum oven at 30 °C for 4h. The wet sample was checked by NMR. No starting material was detected. A pale yellow solid (72.5g, solid 1) was obtained. The mother liquors were concentrated to dryness. A yellow solid was obtained, suspended in diethyl ether and PE. The slurry was then stirred for 4 hours, filtered, washed with PE . A dark yellow solid (4.5g, solid 2) was obtained. Solid 1 (2g) was diluted in DCM and washed with water (pH =6). The organic layer was then dried over Na₂S0₄, filtered, concentrated to dryness. A crystalline pale yellow solid (1.9g, solid 3) was obtained. NMR showed the same purity for solid 3 as for solid 1. The remaining part of solid 1 was then diluted in DCM. The resulting organic layer was washed with water, dried over Na₂S0₄, filtered and then concentrated to dryness. Slight yellow crystalline solid (68.5g, solid 4) was obtained. NMR confirmed high quality material.

Loss on Drying (LOD) : 1.03% .

Example 7

Biotransformation: Transaminases

Codexis transaminases ATA-025, ATA-251 and ATA-P2-A07 recognized 6 , 8 -difluorochroman-3 -one as the substrate and produced the corresponding 6 , 8 -difluorochroman-3 -amine .

PATENT

WO 2004033447

WO 2008094056

WO 2008143540

WO 2009064210

WO2013002660

References

1: Igreja B, Wright LC, Soares-da-Silva P. Sustained high blood pressure reduction with etamicastat, a peripheral selective dopamine β-hydroxylase inhibitor. J Am Soc Hypertens. 2015 Dec 19. pii: S1933-1711(15)00838-4. doi: 10.1016/j.jash.2015.12.011. [Epub ahead of print] PubMed PMID: 26803288.

2: Loureiro AI, Bonifácio MJ, Fernandes-Lopes C, Pires N, Igreja B, Wright LC, Soares-da-Silva P. Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat. Xenobiotica. 2015;45(9):828-39. doi: 10.3109/00498254.2015.1018985. Epub 2015 Jun 10. PubMed PMID: 25915108.

3: Loureiro AI, Soares-da-Silva P. Distribution and pharmacokinetics of etamicastat and its N-acetylated metabolite (BIA 5-961) in dog and monkey. Xenobiotica. 2015;45(10):903-11. doi: 10.3109/00498254.2015.1024780. Epub 2015 Apr 14. PubMed PMID: 25869244.

4: Pires NM, Igreja B, Moura E, Wright LC, Serrão MP, Soares-da-Silva P. Blood pressure decrease in spontaneously hypertensive rats folowing renal denervation or dopamine β-hydroxylase inhibition with etamicastat. Hypertens Res. 2015 Sep;38(9):605-12. doi: 10.1038/hr.2015.50. Epub 2015 Apr 9. PubMed PMID: 25854989.

5: Bonifácio MJ, Sousa F, Neves M, Palma N, Igreja B, Pires NM, Wright LC, Soares-da-Silva P. Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: comparison with nepicastat. Eur J Pharmacol. 2015 Mar 15;751:50-8. doi: 10.1016/j.ejphar.2015.01.034. Epub 2015 Jan 29. PubMed PMID: 25641750.

6: Pires NM, Loureiro AI, Igreja B, Lacroix P, Soares-da-Silva P. Cardiovascular safety pharmacology profile of etamicastat, a novel peripheral selective dopamine-β-hydroxylase inhibitor. Eur J Pharmacol. 2015 Mar 5;750:98-107. doi: 10.1016/j.ejphar.2015.01.035. Epub 2015 Jan 30. PubMed PMID: 25641747.

7: Igreja B, Pires NM, Bonifácio MJ, Loureiro AI, Fernandes-Lopes C, Wright LC, Soares-da-Silva P. Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat. Hypertens Res. 2015 Jan;38(1):30-8. doi: 10.1038/hr.2014.143. Epub 2014 Oct 9. PubMed PMID: 25298210.

8: Loureiro AI, Bonifácio MJ, Fernandes-Lopes C, Igreja B, Wright LC, Soares-da-Silva P. Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat. Eur J Pharmacol. 2014 Oct 5;740:285-94. doi: 10.1016/j.ejphar.2014.07.027. Epub 2014 Jul 21. PubMed PMID: 25058908.

9: Almeida L, Nunes T, Costa R, Rocha JF, Vaz-da-Silva M, Soares-da-Silva P. Etamicastat, a novel dopamine β-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension. Clin Ther. 2013 Dec;35(12):1983-96. doi: 10.1016/j.clinthera.2013.10.012. Epub 2013 Dec 2. PubMed PMID: 24296323.

10: Loureiro AI, Rocha JF, Fernandes-Lopes C, Nunes T, Wright LC, Almeida L, Soares-da-Silva P. Human disposition, metabolism and excretion of etamicastat, a reversible, peripherally selective dopamine β-hydroxylase inhibitor. Br J Clin Pharmacol. 2014 Jun;77(6):1017-26. doi: 10.1111/bcp.12274. PubMed PMID: 24168152; PubMed Central PMCID: PMC4093927.

11: Loureiro AI, Fernandes-Lopes C, Bonifácio MJ, Wright LC, Soares-da-Silva P. N-acetylation of etamicastat, a reversible dopamine-β-hydroxylase inhibitor. Drug Metab Dispos. 2013 Dec;41(12):2081-6. doi: 10.1124/dmd.113.053736. Epub 2013 Sep 6. PubMed PMID: 24013186.

12: Nunes T, Rocha JF, Vaz-da-Silva M, Falcão A, Almeida L, Soares-da-Silva P. Pharmacokinetics and tolerability of etamicastat following single and repeated administration in elderly versus young healthy male subjects: an open-label, single-center, parallel-group study. Clin Ther. 2011 Jun;33(6):776-91. doi: 10.1016/j.clinthera.2011.05.048. PubMed PMID: 21704242.

13: Vaz-da-Silva M, Nunes T, Rocha JF, Falcão A, Almeida L, Soares-da-Silva P. Effect of food on the pharmacokinetic profile of etamicastat (BIA 5-453). Drugs R D. 2011;11(2):127-36. doi: 10.2165/11587080-000000000-00000. PubMed PMID: 21548660; PubMed Central PMCID: PMC3585837.

14: Rocha JF, Vaz-Da-Silva M, Nunes T, Igreja B, Loureiro AI, Bonifácio MJ, Wright LC, Falcão A, Almeida L, Soares-Da-Silva P. Single-dose tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5-453), a new dopamine β-hydroxylase inhibitor, in healthy subjects. J Clin Pharmacol. 2012 Feb;52(2):156-70. doi: 10.1177/0091270010390805. PubMed PMID: 21343348.

15: Nunes T, Rocha JF, Vaz-da-Silva M, Igreja B, Wright LC, Falcão A, Almeida L, Soares-da-Silva P. Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-β-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects. Drugs R D. 2010;10(4):225-42. doi: 10.2165/11586310-000000000-00000. PubMed PMID: 21171669; PubMed Central PMCID: PMC3585840.

16: Beliaev A, Learmonth DA, Soares-da-Silva P. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase. J Med Chem. 2006 Feb 9;49(3):1191-7. PubMed PMID: 16451083.

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
WO1995007284A1 *	Aug 29, 1994	Mar 16, 1995	Smithkline Beecham Plc	Phosphinic acid derivatives with anti-hyper glycemic and/or anti-obesity activity
WO2006044293A2 *	Oct 11, 2005	Apr 27, 2006	Pharmacopeia Drug Discovery, Inc.	Bicyclic compounds as selective melanin concentrating hormone receptor antagonists for the treatment of obesity and related disorders
WO2012007548A1 *	Jul 14, 2011	Jan 19, 2012	Dsm Ip Assets B.V.	(r)-selective amination
WO2013002660A2 *	Jun 29, 2012	Jan 3, 2013	BIAL – PORTELA & Cª, S.A.	Process
GR1005093B *				Title not available

Reference
1	*	AL NEIRABEYEH M. ET AL.: “Methoxy and hydroxy derivatives of 3,4-dihydro-3-(di-n-propylamino)-2H-1-benzopyrans: new synthesis and dopaminergic activity“, EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 26, no. 5, 1991, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS; FR, pages 497 – 504, XP023870436, ISSN: 0223-5234, DOI: 10.1016/0223-5234(91)90145-D
2	*	BELIAEV, A. ET AL.: “Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine ß-Hydroxylase Inhibitor“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, no. 16, 2012, American Chemical Society, Washington; US, pages 704 – 709, XP002731798, DOI: 10.1021/op300012d
3	*	BOYE, S. ET AL.: “N,N-Disubstituted aminomethyl benzofuran derivatives: synthesis and preliminary binding evaluation“, BIOORGANIC & MEDICINAL CHEMISTRY, no. 7, 1999, ELSEVIER SCIENCE LTD; GB, pages 335 – 341, XP002731795, ISSN: 0968-0896, DOI: 10.1016/S0968-0896(98)00239-9
4	*	COMOY, C. ET AL.: “3-Amino-3,4-dihydro-2H-1-benzopyran Derivatives as 5-HT1A Receptor Ligandsand Potential Anxiolytic Agents. 2. Synthesis and QuantitativeStructure-Activity Relationship Studies of Spiro[pyrrolidine- andpiperidine-2,3′(2’H)-benzopyrans]“, JOURNAL OF MEDICINAL CHEMISTRY., vol. 39, no. 21, 1996, AMERICAN CHEMICAL SOCIETY. WASHINGTON; US, pages 4285 – 4298, XP002731797, ISSN: 0022-2623, DOI: 10.1021/JM950861W
5	*	SHIN, C. ET AL.: “Total Synthesis of Bistratamide G, a Metabolite of the PhilippinesAscidian Lissoclinum bistratum, from Dehydrotripeptides“, CHEMISTRY LETTERS, vol. 33, no. 6, 2004, Chemical Society of Japan, Tokyo; JP, pages 664 – 665, XP002731799, ISSN: 0366-7022, DOI: 10.1246/cl.2004.664
6	*	VASSE, J. L. ET AL.: “New efficient conditions for the reduction with NADH models“, SYNLETT, October 1998 (1998-10-01), THIEME INTERNATIONAL, STUTTGART; DE, pages 1144 – 1146, XP002731796, ISSN: 0936-5214, DOI: 10.1055/s-1998-1876
7	*	XIAO, G.-Q. ET AL.: “3-Nitro-2H-chromenes as a New Class of Inhibitors against Thioredoxin Reductase and Proliferation of Cancer Cells“, ARCHIV DER PHARMAZIE, no. 345, 2012, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM; DE, pages 767 – 770, XP002731794, ISSN: 0365-6233, DOI: 10.1002/ardp.201200121

////////Etamicastat, BIA-5-453 , PHASE 2, Treatment, Heart Failure Therapy, Hypertension, Bial-Portela and C^a, S.A

SMILES Code: FC1=CC(F)=C(OC[C@H](N2C(CCN)=CNC2=S)C3)C3=C1.[H]Cl

c1c(cc(c2c1C[C@H](CO2)n3c(c[nH]c3=S)CCN)F)F

LIK 066, Licogliflozin diprolinate

November 16, 2015 7:56 am / 1 Comment on LIK 066, Licogliflozin diprolinate

Licogliflozin

LIK 066

Licogliflozin diprolinate

LIK-066, a new flozin on the horizon

C23 H28 O7 . 2 C6 H11 N O, 642.7795, 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C…WO2011048112

CAS 1291095-45-8, (1S)-1,5-anhydro-1-C-[3-[(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-ethylphenyl]-D-glucitol (1:1) WITH L-Proline, compd., 1:1 Proline Co-crvstal , 1:1 Proline Co-crvstal …..…WO2011048112

CAS BASE 1291094-73-9, 416.46, C₂₃ H₂₈ O₇

(1S)-1,5-Anhydro-1-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-D-glucitol bis[1-[(2S)-pyrrolidin-2-yl]ethanone]

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Sodium glucose transporter-2 inhibitor

SGLT 1/2 inhibitor

Novartis Ag innovator

Clinical trial……..https://clinicaltrials.gov/ct2/show/NCT01915849

https://clinicaltrials.gov/ct2/show/NCT02470403

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

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

EMA/415156/2014 European Medicines Agency decision P/0183/2014 of 24 July 2014 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran3,4,5-triol (2:1) (LIK066) (EMEA-001527-PIP01-13) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

Where name is given

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2017_Vol31-4/en/

http://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf?ua=1

SYNTHESIS

PATENT

WO 2011048112

https://www.google.com/patents/WO2011048112A1?cl=en

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

Patentscope, Espacenet

Example 61-62:

Ex. 61

Example 61 : Acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester

Step I: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Example 62: (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 5 mL of 5% aqueous KHS0₄ (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.59)

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

MS (ES) m z 434.2 (M+18).

PICK UP IDEAS FROM HERE

Examples 57-58:

Ex. 57 Ex. 58

Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalyl chloride (10.3 mL, 114.74 mmol) at 0 °C followed by D F (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.

Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1 ,4)-dioxane (10.41 g, 76.26 mmol) at 0 °C. To this reaction mixture, AICI₃ (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL X 2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL X 2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3- dihydro-benzo[1 ,4]dioxin-6-yl)-methanone (30 g).

¹H N R (400 MHz, DMSO-D₆): δ 4.29-4.37 (m, 4H), 7.02 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.18-7.19 (m, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H).

Step III: To a stirred solution of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1 ,4]dioxin- 6-yl)-methanone (30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL, 67.42 mmol ) at room temperature. After stirring for 25 min at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (200 mL X 2), water (200 mL), and brine (200 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-2,3- dihydro-benzo[1 ,4]dioxine (26.5 g). H NMR (400 MHz, DMSO-D₆): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J = 8.4 Hz, J = 2.0 Hz, H), 6.68 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 8.4 Hz, H), 7.39 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 Hz, J = 2.4 Hz 1 H), 7.67 (d, J = 2.8 Hz, 1 H).

Step IV: To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro- benzo[1 ,4]dioxine (26.5 g, 61.47 mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi in hexanes (42.3 mL, 67.62 mmol) at -78 °C. The reaction mixture was stirred for 1 h, and then transferred to a stirred solution of 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone (28.69 g, 61.47 mmol) in toluene (100 mL) at -78 °C. After stirring for 1 h, 0.6 N methanesulfonic acid in methanol (265 mL) was added dropwise and stirred the reaction mixture for 16 h at room temperature. Reaction was quenched by the addition of aq. NaHC0₃ solution (~75 mL) and extracted with ethyl acetate (250 mL X 3), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish (3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran- 3,4,5-triol (28.4 g)

Example 57: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1 ,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate

Step V: To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5- triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1 :1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10 °C. After stirring for 4 h at 10°C, the reaction was quenched with saturated aqueous sodium bicarbonate (~ 100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 X 150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2- [4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification. Example 58: [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2_!3-dihydro-1,4- benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate Step V: To a stirred solution of (3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro- benzo[ 1 ,4]dioxin-6-yl methyl)-phenyl]-6-hydroxymethyl-tetrahyd ro-pyran-3,4 , 5-triol (28.4 g, 60.81 mmol) in dichloromethane (300 mL) was added pyridine (40 mL, 486.5 mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg, 6.08 mmol) at room temperature. After stirring for 2 h, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (500ml) and washed with 1 N HCI (200 mL X 2) followed by brine (200ml), then dried over sodium sulfate and

concentrated. The resulting crude compound was dissolved in ethanol (320 mL) at 65 °C and allowed to cool to room temperature while stirring. Light yellow solid formed was filtered and washed with cold ethanol (150 mL) followed by hexane (200 mL) to get acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin- 6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder (22.5 g, purity 98%).

COCRYSTAL

Example 75: 1:1 Proline Co-crvstal with f2S.3R.4R.5S.6R¾-2-r3-f2.3-Dihvdro- benzori.41dioxin-6-ylmethyl)-4-ethyl-phenvn-6-hvdroxymethyl-tetrahydro-pyran- 3.4.5-triol

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62) was completely amorphous initially but formed a crystalline complex with proline. This was confirmed by powder X-ray diffraction (PXRD) analysis. The stiochiometry of Example 62 and L- proline in the co-crystal prepared by method 1 was found to be 1 :1 by NMR

spectroscopy & HPLC. Characterization data for co-crystals of Example 62 and proline prepared by method 1 is shown in Table 3. Relative intensities of the most prominent powder x-ray diffraction peaks for co-crystals of Example 62 and proline are shown in Table 3A.

Table 3

Table 3A

3.70 15.78 18.36 25.18

9.68 10.68 18.88 36.33

11.07 21.21 20.42 69.29

14.26 14.81 21.18 27.94

14.80 22.97 22.50 12.25

15.40 4 98 23.78 33.08

16.12 8.45 24.56 6.92

16.59 18.78 25.79 21.69

17.31 100.0 27.46 8.90

17.60 20.35 31.97 7.65

17.98 47.20 32.46 5.98

1:1 Proline Co-crvstal

Example 77: 1:1 Proline Co-crvstal with (2S.3R.4R.5S.6Ri-2-f3-(2.3-Dihvdro- benzoh .41dioxin-6-ylmethvh-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 2:

1 :1 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1500mg,3.6mmol), L- proline (415mg, 3.6mmol) and ethanol (23 ml_) were added to a 50 mL 3-neck round bottom flask equipped with nitrogen purging, magnetic stirring bar,

thermometer pocket & calcium chloride guard tube and the mixture was stirred at 25-30°C for 30 min., then heat to reflux. A clear solution was observed which was refluxed for 30 min., then slowly cool to 25-30°C causing percipitation. Di- isopropyl ether (DIPE, 23 mL) was added while maintaining the mixture at 25-30°C and stirring continuously for additional one to two hours at the same temperature. The precipitate was collected by filtration using vacuum (Nitrogen atmosphere), and the filter cake was washed with ethanol-DIPE mixture (1 :1 v/v, 10ml) followed by DIPE (23 mL). The product was vacuum dried at 65-70°C for 5-6 hrs.

1:1 Proline Co-crvstal (ΔΗ 53 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig. 1. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 2.

2:1 Proline Co-crvstal

Example 78: 2:1 Proline Co-crvstal with f2S.3R.4R.5S.6R>-2-r3-f2.3-Pihvdro-benzof1.41dioxin-6-ylmethvH-4-ethyl-phenvn-6-hvdroxymethyl-tetrahvdro-pyran- 3.4.5-triol

Method 3: 1 :2 Co-Crvstals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example 62, 1 kg) was added to 15 L of ethanol with agitation while maintaining the mixture at 20-25 °C. The mixture was stirred for 10 min at 20-25 °C, then L-proline (537 gm) was added while maintaining the mixture at 20-25 °C. The mixture was stirred at this temperature for 30 min., then heated to reflux and refluxed for 30 min. The mixture was slowly cooled to 25-30°C then stired for 1 hr. DIPE (15 L) was added while maintaining the temperature at 25-30 °C and the mixture was stirred at this temperature for 1 hr. The precipitated product was collected by filtration and the product was washed with DIPE (5 L). The product was air dried at 65-70 °C to yield 1.22 kg

(79%) of a 1 :2 co-crystal of Example 62 : L-proline. A melting point 176°C (ΔΗ 85 J/g) was observed by differential scanning calorimetry (DSC) and is shown in Fig.

3. A powder X-ray diffraction (PXRD) spectrum is shown in Fig. 4. Relative

intensities of the most prominent powder x-ray diffraction peaks for the 1 :2 co- crystals of Example 62 and proline are shown in Table 5.

Table 5

PATENT

WO 2012140597

http://www.google.co.in/patents/WO2012140597A1?cl=en

. TABLE 2:

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

Intermediate 2

Intermediate 1

tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2 X 200 ml_), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid

(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).

Step II: To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 ml.) was added lithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 ml.) and washed with brine (75 ml_), brine containing 5 ml. of 5% aqueous KHS0₄ (75 ml_), and brine (20 ml.) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5 g)

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

MS (ES) m/z 434.2 (M+18).

Example 3: Synthesis of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester diethyl ester

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

Example 4: Synthesis of disodium salt of phosphoric acid mono- {(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]- 3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester

To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1 ,4]dioxin-6- ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di- tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0°C followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to -40 °C and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0°C and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3 X 10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6- [3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro- pyran-2-ylmethyl ester.

To the stirred solution of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion exchange resin (250 mg) and refluxed for overnight. Reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated to give 300 mg of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl- phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester. The crude material was taken up for next reaction.

To a solution of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro- benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester (300 mg, 0.6 mmol) in methanol (5 ml) was added 1 N sodium bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring at room temperature for 2 h, the volatiles were evaporated under reduced pressure. The resulting solid was triturated with diethyl ether. The resulting residue was purified by preparative HPLC to give 95 mg of disodium salt of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3- dihydro-benzo[1 ,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2- ylmethyl} ester.

¹H NMR (400 MHz, CD₃OD): δ 1.06 (t, J = 7.4 Hz, 3H), 2.56 ( q, J = 7.3 Hz, 2H), 3.34- 3.41 (m, 2H), 3.49 (t, J = 8.8 Hz, 1 H), 3.81-3.88 (m, ,3H), 3.92-3.99 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.16 (s, 4H), 4.20-4.25 (m, 1 H), 6.54 (m, 2H), 6.67 (d, J = 7.8 Hz, 1 H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1 ) for phosphoric acid.

PATENT

SEE INDIAN PATENT

IN 2009DE02173

Glycoside derivatives and uses thereof

REFERENCES

Pediatric investigation plan (PIP) decision: (S)-Pyrrolidine-2-carboxylic acid compound with (2S,3R,4R,5S,6R)-2-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2:1) ( LIK066) (EMEA-001527-PIP01-13)
European Medicines Agency (EMA) Web Site 2014, July 24

Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) assessment of LIK066 in healthy subjects and in patients with type 2 diabetes mellitus (T2DM) (NCT01407003)
ClinicalTrials.gov Web Site 2011, August 07

WO2012140597

WO2011048112

IN 2009DE02173

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Citing Patent	Filing date	Publication date	Applicant	Title
WO2015032272A1 *	19 Aug 2014	12 Mar 2015	Jiangsu Hansoh Pharmaceutical Co., Ltd.	C-aryl glucoside derivative, preparation method for same, and medical applications thereof
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INVENTORS OF LIK 066

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

Mark G Bock

BEBERNITZ, Gregory, Raymond….PIC NOT AVAILABLE

Image result for SRINIVASAREDDY NCL

Dr. Srinivasa Reddy

NADEEM SHAIKH

Venkata Palle

ONLY FEW…………………….

//////Licogliflozin diprolinate

see……..http://medcheminternational.blogspot.in/2015/11/lik-066-novartis-for-treatment-of-type.html

FDA approves new treatment for HIV

November 6, 2015 12:54 am / Leave a comment

FDA approves new treatment for HIV

11/05/2015 12:53 PM EST

The U.S. Food and Drug Administration today approved Genvoya (a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

November 5, 2015

Release

The CDC estimates that 1.2 million persons ages 13 years and older are living with HIV infection, and that more than another 150,000 persons in this age range have HIV but are unaware of their infection. Over the past decade, the number of people living with HIV has increased, while the annual number of new HIV infections has remained relatively stable.

“Today’s approval of a fixed dose combination containing a new form of tenofovir provides another effective, once daily complete regimen for patients with HIV-1 infection,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Genvoya is approved for use in HIV-infected adults and children ages 12 years and older weighing at least 35 kilograms (77 pounds) who have never taken HIV therapy (treatment-naïve) and HIV-infected adults whose HIV-1 virus is currently suppressed. While Genvoya is not recommended for patients with severe renal impairment, those with moderate renal impairment can take Genvoya.

Genvoya’s safety and efficacy in adults were evaluated in 3,171 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Genvoya or another FDA approved HIV treatment. Results showed Genvoya was effective in reducing viral loads and comparable to the other treatment regimens.

Genvoya contains a new form of tenofovir that has not been previously approved. This new form of tenofovir provides lower levels of drug in the bloodstream, but higher levels within the cells where HIV-1 replicates. It was developed to help reduce some drug side effects. Genvoya appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir containing regimens based on laboratory measures. Patients receiving Genvoya experienced greater increases in serum lipids (total cholesterol and low-density lipoprotein) than patients receiving other treatment regimens in the studies.

Genvoya carries a Boxed Warning alerting patients and health care providers that the drug can cause a buildup of lactic acid in the blood and severe liver problems, both of which can be fatal. The Boxed Warning also states that Genvoya is not approved to treat chronic hepatitis B virus infection. The most common side effect associated with Genvoya is nausea. Serious side effects include new or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome). Health care providers are advised to monitor patients for kidney and bone side effects. Genvoya should not be given with other antiretroviral products and may have drug interactions with a number of other commonly used medications.

Genvoya is marketed by Gilead Sciences Inc. based in Foster City, California.

/////////

BMS-582949 in phase 2 for Treatment of Antipsoriatics , Rheumatoid arthritis

July 8, 2014 5:09 am / Leave a comment

BMS 582949, PS-540446

UNII-CR743OME9E

CAS 623152-17-0

4-[5-(N-Cyclopropylcarbamoyl)-2-methylphenylamino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide

Bristol-Myers Squibb Company
M.Wt: 406.48
Cas : 623152-17-0 Formula: C22H26N6O2

BMS-582949 had been in phase II clinical trials at Bristol-Myers Squibb for the oral treatment of moderate to severe psoriasis and for the treatment of rheumatoid arthritis (RA) in combination with methotrexate and for the treatment of inflammation in atherosclerotic plaque. However, no recent development has been reported for this research.

…………………..

http://www.google.com/patents/WO2012031057A1?cl=en

The present invention generally relates to a method of treating resistant rheumatic disease, such as refractory rheumatoid arthritis, with a therapeutically effective amount of a dual action p38 inhibitor that is safe and well-tolerated. A dual action p38 kinase inhibitor is a compound that inhibits both activation of p38 kinase and p38 kinase activity in cells.

A large number of cytokines participate in the inflammatory response, including IL- 1 , IL-6, IL-8 and TNF-a. Overproduction of cytokines such as IL-1 and TNF-a are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer’s disease, and congestive heart failure, among others. See e.g., Henry et al., Drugs Fut. , 24: 1345- 1354 ( 1999); Salituro et al., Curr. Med. Ckem., 6:807-823 (1999)]. Important mediators of proinflammatory cytokines such as TNFct and IL-1 β,. as well as cellular responses to such cytokines production, are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. See e.g., Schieven, G.L., “The biology of p38 kinase: a central role in inflammation”, Current Topics in Medicinal Chemistry, 5 :921 – 928 (2005). Accordingly, modulation of p38 kinase may be useful in the treatment of inflammatory disease including rheumatic diseases such as rheumatoid arthritis (RA).

Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-a for use in treating inflammatory diseases are disclosed in U.S. Patent Nos.

6,277,989 and 6, 130,235 to Scios, Inc; U.S. Patent. Nos. 6, 147,080 and 5,945,41 8 to Vertex Pharmaceuticals Inc; U.S. Patent Nos. 6,251 ,914, 5,977, 103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Patent Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01 /27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoHne derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors). Other compounds that inhibit p38 kinase are pyrrolotriazine aniline compounds, information on these compounds is disclosed in U.S. Patent Nos. 6,670,357; 6,867,300; 7,034, 151 ; 7, 160,883; 7,21 1,666; 7,253, 167; and U.S. Publication Nos. 2003/023283 1 (published Dec. 18, 2003); 2004/0229877 (published Nov. 1 8, 2004); 2005/0043306 (published Feb. 24, 2005; 2006/0003967 (published Jan. 5, 2006); 2006/0030708 (published Feb. 9, 2006); 2006/0041 124 (published Feb. 23, 2006); 2006/0229449 (published Oct. 12, 2006); 2006/0235020 (published Oct. 19, 2006); and 2007/0213300 (published Sept 13, 2007).

In particular, WO 2003/090912 (U.S. Patent Nos. 7, 160,883, 7,388,009, p38 inhibitor, BMS-582949 (Example 7,

including processes of making and uses thereof.

……………………

http://www.google.com/patents/WO2003090912A9?cl=en

Examples 4-22

Compounds having the formula (Id), above, wherein R₄ has the values listed in the following Table, were prepared following the same procedure described for Example 3, using the appropriate amine in place of ra-butylamine.

…………………………

WO 2006020904

http://www.google.com.br/patents/WO2006020904A1?cl=en

EXAMPLE IA St

Part a.

A solution of Example 1 (0.86 g, 2.20 mmol, 1.0 eq.) in THF (4.0 mL) and 1 N aqueous NaOH (9.0 mL, 4.1 eq.) was stirred at 6O⁰C overnight. After cooling to RT, the reaction mixture was concentrated in vacuo but not to dryness. To the solution at O⁰C was added 1 N aqueous hydrochloric acid until it was acidic and the precipitate was collected and dried to afford crude Example IA acid (0.51 g, 64.0 % yield). HPLC Ret. t. = 2.400 min.; LC/MS (M+H) ⁺ = 366.06⁺. The filtrate was then extracted with EtOAc (3x) and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give Example IA acid (0.035 g, 4.4 % yield). Part b.

A solution of Part a. acid (0.026 g, 0.071 mmol, 1.0 eq.), EDC (0.021 g, 0.11 mmol, 1.5 eq.), HOBt (0.015 g, 0.11 mmol, 1.5 eq), ^-propylamine (0.015 mL, 0.15 mmol, 2.1 eq.) and DIPEA (0.040 mL, 0.23 mmol, 3.2 eq.) in DMF (0.20 mL) was shaken at RT overnight. Water (1 mL) was added and the precipitate collected by filtration, washed with water, and dried to give Example IA amide (0.021 g, 70% yield); HPLC Ret. t. = 2.883 min.; LC/MS (M+H)⁺ = 421.18 ⁺.

EJiAMPLE 2 Direct Aminolysis Procedure

n-Buli/THF

Ester Compound I or Hexyllithium/THF

,NH₉

1. Aminolysis with hexyllithium

To a dried 100 ml flask was added THF (10 ml) under nitrogen, which was then cooled to -10⁰C. Hexyllithium (2.3 M in hexane, 6.5 ml, 15.0 mmol) was added slowly (exothermic, temperature was up to 5°C), followed by dropwise addition of propylamine (1.01 g, 1.4 ml, 17.1 mmol) at such a rate to maintain the temperature below 5°C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (exothermic, T<5°C). After being stirred at 0⁰C for 20 minutes, the mixture was allowed to warm to room temperature and stirred for 5 hours. Ester compound I was <0.1 AP at this point by HPLC analysis. The mixture was cooled to -5⁰C. Acetic acid (2 ml) was added slowly to maintain the temperature <10°C. The resulting thick slurry was stirred at room temperature for 20 minutes, and then solvents were exchanged with DMF (15 ml) on a rotavapor. To the resulting yellow slurry, water (15 ml) was added slowly to keep T<25°C. During the addition of water, the slurry became a clear solution, and a new slurry was formed. The slurry was stirred at room temperature for overnight. In the morning the slurry was filtered and the solid was washed with DMF/water (1:1, 5 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for 24 hours to afford 0.90 g of amide product II (yield: 87.2%) as a white solid. HPLC: 99.70 AP.

2. Aminolysis with n-butyllithium

To a dried 100 ml of flask was added THF (10 ml) under nitrogen and then cooled to -10⁰C. n-Butyllithium (2.5 M in hexane, 6.0 ml, 15.0 mmol) was added slowly, followed by dropwise addition of propylamine (0.98 g, 16.5 mmol) at such a rate to keep the temperature below 0⁰C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (T<5°C). After being stirred at O⁰C for 30 minutes, the mixture was allowed to warm to room temperature and stirred for overnight (~22h, Note 1). Compound I was not detected at this point by HPLC analysis. The mixture was cooled to -7°C. Acetic acid (2 ml) was added dropwise to maintain the temperature <10°C. The resulting thick slurry was stirred at 5⁰C for 2 hours and at room temperature for 20 minutes, followed by evaporation on a rotavapor to give a wet yellow solid. To this solid was added acetone (10 ml) and water (20 ml). The slurry was stirred at room temperature for one and half hours. Filtration gave a white solid. This solid was washed with 35% acetone in water (10 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for the weekend to afford 0.94g of amide product II (yield: 91.0%) as a white solid. HPLC: 99.76 AP. Note 1: Compound I was -0.056 AP at 2.5 hours.

……………………

WO 2003090912

http://www.google.com/patents/WO2003090912A1?cl=en

……………………..

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38a MAP kinase inhibitor for the treatment of inflammatory diseases
J Med Chem 2010, 53(18): 6629

http://pubs.acs.org/doi/abs/10.1021/jm100540x

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp² character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

Abstract Image

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (7k)

A mixture of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid (6b) (2.16 g, 5.91 mmol), n-propylamine (1.0 mL, 12.2 mmol), BOP (3.40 g, 7.69 mmol), and N-methylmorpholine (2.5 mL, 22.7 mmol) in DMF (10 mL) was stirred at 50 °C for 3 h. The mixture was poured into a mixture prepared from saturated NaHCO₃ solution (60 mL) and water (60 mL). The precipitating product was collected by suction filtration was washed with water. This crude product was suspended into ethyl acetate (100 mL) and stirred at 70 °C for 1 h. Upon cooling to rt, the title compound (2.07 g, 86% yield) was collected as a white solid by suction filtration; 98% purity by HPLC. LCMS (EI)

m/z Calcd for C₂₂H₂₆N₆O₂ (M + H)⁺ = 407.21. Found: 407.22.

¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J = 3.6 Hz, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 3.20 (m, 2H), 2.87 (m, 1H), 2.82 (s, 3H), 2.25 (s, 3H), 1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.68 (m, 2H), 0.59 (m, 2H).

¹³C NMR (125 MHz, DMSO-d₆) δ 167.3, 164.45, 155.3, 148.7, 138.8, 137.1, 133.0, 130.6, 127.2, 125.8, 119.6, 118.8, 114.4, 113.3, 41.0, 23.6, 23.1, 18.5, 12.1, 12.0, 6.2.

EXAMPLE 3

Direct Aminolysis

Ester Compound I

Amide Product II

Method A:

A solution of n-propylamine (6.5 eq) in THF (20 ml/g of ester compound I) was cooled to — 5°C and was slowly treated with 2.5 M solution of n-butyllithium (6.1 eq). The mixture was stirred for 10 minutes. At the end of the period, a slurry of ester compound I (1 eq) in THF (14 ml/g of ester compound I) was cannulated into the performed Li-NHPr solution. The reaction mixture was warmed to 25°C and stirred till all of ester compound I was consumed (~ 3 hours). After the reaction was judged to be completed by HPLC, the reaction mixture was cooled to ~0°C and was slowly treated with acetic acid (5 ml/g of ester compound I). The slurry was then warmed to -2O⁰C and was stirred for 1 hour. At the end of the period, the solvent was distilled under vacuum to the minimum volume and the concentrated slurry was diluted with a solution of acetone (10 ml/g of ester compound I) and water (20 ml/g of ester compound I). The slurry was stirred for 1 hour and was cooled to ~5°C. The slurry was filtered and the cake was washed with acetone (5 ml/g of ester compound I). The cake was dried to give the amide product II (typically in 85% yield and 99 AP).

Method B:

A solution of n-propylamine (20 eq) in 2,2,2-trifmoroethanol (10 ml/g of ester compound I) was slowly treated with 2.5 M solution of n-butyllithium (1.5 eq). The mixture was stirred for 5 minutes. At the end of the period, the starting material, ester compound I, was added and the reaction mixture was warmed to 90⁰C. The reaction mixture was held at 90⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then analyzed by HPLC. Typically, analysis indicated there was only 1.57 AP of starting material left.

Method C:

A solution of n-propylamine (2 eq) in methylene chloride (10 ml/g of ester compound I) at 20⁰C was slowly treated with 2.0 M solution of trimethylaluminum (4 eq) in hexanes. The mixture was stirred for 15 minutes. At the end of the period, the starting material, ester compound 1 (1 eq), was added and the reaction mixture was warmed to 60⁰C. The reaction mixture was held at 60⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then slowly quenched with aqueous HCl solution and analyzed by HPLC. Typically, analysis indicated there was 96.8AP of amide compound II product with 0.03 AP of the dipropylamide impurity.

…………………………………….

WO2003090912A1 *	15 abr. 2003	6 nov. 2003	Squibb Bristol Myers Co	Pyrrolo-triazine aniline compounds useful as kinase inhibitors

Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor.

Liu C, Lin J, Everlof G, Gesenberg C, Zhang H, Marathe PH, Malley M, Galella MA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

Bioorg Med Chem Lett. 2013 May 15;23(10):3028-33. doi: 10.1016/j.bmcl.2013.03.022. Epub 2013 Mar 15.

Methods: implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing.

Freebern WJ, Bigwarfe TJ, Price KD, Haggerty HG.

J Immunotoxicol. 2013 Jan-Mar;10(1):106-17. doi: 10.3109/1547691X.2012.736427. Epub 2012 Nov 23.

Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.

Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, Dyckman AJ, Li T, Wityak J, Gillooly KM, Pitt S, Shen DR, Zhang RF, McIntyre KW, Salter-Cid L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, Sack JS, Kiefer SE, Kish KF, Newitt JA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

J Med Chem. 2010 Sep 23;53(18):6629-39. doi: 10.1021/jm100540x.

BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857.

Norman P.

Expert Opin Ther Pat. 2009 Aug;19(8):1165-8. doi: 10.1517/13543770902816160.

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US20060235020	Apr 4, 2006	Oct 19, 2006	Soojin Kim	Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein
US20070213300	Mar 6, 2007	Sep 13, 2007	Bristol-Myers Squibb Company	Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors

Animation of nanoparticles for drug delivery in cancer treatment

April 14, 2014 2:19 pm / Leave a comment

Animation of nanoparticles for drug delivery in cancer treatment

read at

http://www.nanobotmodels.com/node/69

FDA Approves Perjeta for Neoadjuvant Breast Cancer Treatment

October 1, 2013 3:30 am / 2 Comments on FDA Approves Perjeta for Neoadjuvant Breast Cancer Treatment

The structure of HER2 and pertuzumab

pertuzumab

Sept. 30, 2013 — The U.S. Food and Drug Administration today granted accelerated approval to Perjeta (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Perjeta is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

Perjeta was approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer. HER2-positive breast cancers have increased amounts of the HER2 protein that contributes to cancer cell growth and survival

cut paste of my old article

he European Medicines Agency (EMA) has approved Roche’s PERJETA (pertuzumab) for patients with previously untreated HER2-positive metastatic breast cancer (mBC)

MARCH 5, 2013 8:59 AM / 4 COMMENTS /

The structure of HER2 and pertuzumab

march 4, 2013

The European Medicines Agency (EMA) has approved Roche’s PERJETATM (pertuzumab) RG1273 for patients with previously untreated HER2-positive metastatic breast cancer (mBC). PERJETA is approved in combination with Herceptin® (trastuzumab) and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease\

The European approval comes after the Phase III CLEOPATRA trial showed that the combination of PERJETA, Herceptin and chemotherapy provided patients with a median of 6.1 months longer without their disease worsening or death (progression-free survival, PFS) and provided a 34 percent reduction in the risk of death (overall survival) compared to Herceptin and chemotherapy alone.

Herceptin was the first monoclonal antibody developed for the treatment of HER2-positive breast cancer and has increased survival times for patients so that they are now the same as for patients with HER2-negative breast cancer. Before Herceptin treatment, shorter survival outcomes were expected for patients diagnosed with HER2-positive breast cancer, compared to patients with HER2-negative disease.(1) In the CLEOPATRA study, PERJETA in combination with Herceptin and chemotherapy has shown the extension of survival times for patients with this aggressive disease even further than Herceptin

About PERJETA

PERJETA is designed specifically to prevent the HER2 receptor from pairing (dimerising) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of PERJETA to HER2 may also signal the body’s immune system to destroy the cancer cells. The combination of PERJETA, Herceptin and chemotherapy is thought to provide a more comprehensive blockade of HER signalling pathways.

Pertuzumab (also called 2C4, trade name Perjeta) is a monoclonal antibody. The first of its class in a line of agents called “HER dimerization inhibitors”. By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth.^[1] Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer on June 8, 2012.^[2] Pertuzumab was developed at Genentech and is now owned by Roche which acquired Genentech in 2009.

Clinical trials

Early clinical trials of pertuzumab in prostate, breast, and ovarian cancers have been met with limited success.^[3]

The dosage of pertuzumab used in the pivotal phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial was as follows: IV 840 mg loading dose followed by IV 420 mg every three weeks.^[4]

The pharmacokinetics of intravenous pertuzumab appear to be unaffected by age and no drug-drug interaction has been reported with docetaxel. The pharmacokinetics and pharmacodynamics of pertuzumab were summarized in a Feb 2012 review by Gillian Keating.^[4]

The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects in the randomized, double-blind, multinational, phase III CLEOPATRA trial.^[5]

Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breast cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).^[4]

References

de Bono, Johann S.; Bellmunt, J; Attard, G; Droz, JP; Miller, K; Flechon, A; Sternberg, C; Parker, C et al. (20 January 2007). “Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer”. Journal of Clinical Oncology 25 (3): 257–262.doi:10.1200/JCO.2006.07.0888. PMID 17235043.
“FDA Approves Perjeta (Pertuzumab) for People With HER2-Positive Metastatic Breast Cancer” (Press release). Genentech. Retrieved 2012-06-09.
Genentech press release – May 15, 2005
Keating GM. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer. Drugs 2012 Feb 12; 72 (3): 353-60.Link text
Baselga J, Cortés J, Kim SB, and the CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012 Jan 12; 366 (2): 109-19. Link text

About the CLEOPATRA study

CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, phase III, randomised, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of PERJETA combined with Herceptin and docetaxel chemotherapy compared to Herceptin and chemotherapy plus placebo in 808 people with previously untreated HER2-positive mBC or that had returned after prior therapy in the adjuvant (after surgery) or neoadjuvant (before surgery) setting.

In CLEOPATRA, the most common adverse reactions (rate greater than 30 percent) seen with the combination of PERJETA, Herceptin and chemotherapy were diarrhoea, hair loss, low white blood cell count with or without fever, upset stomach, fatigue, rash and peripheral neuropathy (numbness, tingling or damage to the nerves). The most common Grade 3–4 adverse events (rate greater than 2 percent) were low white blood cell count with or without fever, decrease in a certain type of white blood cell, diarrhoea, damage to the nerves, decrease in red blood cell count, weakness and fatigue.

About breast cancer

Breast cancer is the most common cancer among women worldwide.(4) Each year, about 1.4 million new cases of breast cancer are diagnosed worldwide, and over 450,000 women will die of the disease annually.(4) In HER2-positive breast cancer, increased quantities of the human epidermal growth factor receptor 2 (HER2) are present on the surface of the tumour cells. This is known as “HER2 positivity” and affects approximately 15-20 percent of women with breast cancer.(5) HER2-positive cancer is a particularly aggressive form of breast cancer.

Simeprevir has been approved in Japan for the treatment of genotype 1 chronic hepatitis C infection

September 28, 2013 1:55 am / Leave a comment

simeprevir

CAS number	923604-59-5
Formula	C38H47N5O7S2
Weight	749.93908

Stockholm, Sweden — Medivir AB (OMX: MVIR) today reports that Janssen Pharmaceutical R&D Ireland (Janssen) has been informed by the Japanese Ministry of Health, Labour and Welfare (MHLW) that simeprevir has been approved for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.

read all at

http://www.pharmalive.com/japan-approves-simeprevir

Hepatitis C virus (HCV) infections affect approximately 3 percent of the worldwide population and often lead to cirrhosis and hepatocellular carcinoma. The standard therapy of pegylated- interferon and ribavirin induces serious side effects and provides viral eradication in less than 50% of patients. Combination therapy of HCV including ribavirin and interferonare currently is the approved therapy for HCV. Unfortunately, such combination therapy also produces side effects and is often poorly tolerated, resulting in major clinical challenges in a significant proportion of patients. Numerous direct acting agents (DAAs) have been or are being developed for treatment of HCV, such as telaprevir and boceprevir (both received MA approved in 2011 for use with interferon and ribavirin based therapy), however direct acting agents are linked to increased toxicity of treatment, the emergence of resistance, and to date do not provide a standard of care which is interferon free. The combination of direct acting agents can also result in drug-drug interactions. To date, no HCV therapy has been approved which is interferon free. There is therefore a need for new combination therapies which have reduced side effects, and interferon free, have a reduced emergence of resistance, reduced treatment periods and/or and enhanced cure rates.

Simeprevir (formerly TMC435) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byMedivir and Johnson & Johnson‘s pharmaceutical division Janssen Pharmaceutica and is currently in Phase III clinical trials.^[1]

Simeprevir is a hepatitis C virus protease inhibitor.^[2]

Simeprevir is being tested in combination regimens with pegylated interferon alfa-2a and ribavirin,^[3] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir^[4] and sofosbuvir ^[5]

Food and Drug Administration (FDA) has granted Priority Review to the New Drug Application (NDA) for simeprevir (TMC435). Simeprevir is an investigational NS3/4A protease inhibitor taken orally (150 mg capsule) once a day along with pegylated interferon and ribavirin for genotype 1 chronic hepatitis C virus (HCV) infection in adult patients with compensated liver disease (meaning the liver is heavily scarred but still functional).

“Hepatitis C is a complex disease and Janssen is committed to working with the HCV community, caregivers, and health care systems to address this global epidemic,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “We are pleased that the FDA has granted simeprevir Priority Review, as it is a significant step forward in making this therapy available to physicians and their hepatitis C patients.”

The FDA grants Priority Review to medicines that may offer major advances in care or provide a treatment option where no adequate therapy exists. Under the Prescription Drug User Fee Act, FDA review will begin approximately 60 days after receipt of the application and will aim to be completed within six months from when the review period begins.

The regulatory submission for simeprevir is supported in part by data from three pivotal Phase 3 studies: QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. Janssen also recently submitted simeprevir for marketing authorization to regulatory authorities in Japan and Europe.

“Medivir Announces That Simeprevir (TMC435) Data Will Be Presented at the Upcoming AASLD Meeting”. Yahoo News. October 1, 2012. Retrieved November 6, 2012.
Lin, TI; Lenz, O; Fanning, G; Verbinnen, T; Delouvroy, F; Scholliers, A; Vermeiren, K; Rosenquist, A et al. (2009). “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor”. Antimicrobial agents and chemotherapy 53 (4): 1377–85. doi:10.1128/AAC.01058-08. PMC 2663092. PMID 19171797. |displayauthors= suggested (help)
“Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks”. hivandhepatitis.com. December 27, 2012.
Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.

IUPAC standard name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – ({7-methoxy-8-methyl-2-[4 – (propan-2-yl) -1,3-thiazol-2 -yl] quinolin-4-yl} oxy)-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
IUPAC traditional name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – {[2 – (4-isopropyl-1 ,3-thiazol-2-yl)-7-methoxy-8-methylquinolin-4- yl] oxy}-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
Aliases
TMC435
TMC435350

,,,,,,,,,,,,,

NS3/4A protease inhibitors

Ciluprevir (BILN 2061) Boehringer Ingelheim

Boceprevir (SCH503034) Merck

Telaprevir (VX-950) Vertex

Danoprevir (RG7227) Roche

simeprevir /TMC435 Tibotec / Medivir

Vaniprevir (MK-7009) Merck

Bl 201335 Boehringer Ingelheim

BMS-650032 Bristol-Myers Squibb

GS-9256 Gilead

ABT-450 Abbott / Enanta

Narlaprevir (SCH900518) Merck

PHX1766 Phenomix

ACH-1625 Achillion

IDX320 Idenix

MK-5172 Merck

VX-985 Vertex Drug name Company

GS-9451 Gilead

Telaprevir

Accordin to http://en.wikipedia.Org/wiki/File:Telaprevir.svg, Teaprevir has the structure

Systematic lUPAC Name: (1 S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2- carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-/\/-[(3S)-1-(cyclopropylamino)-1 ,2- dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1/-/-cyclopenta[c]pyrrole-1-carboxamide

Telaprevir may be administered in a unit dose of, for example between about 250 and about l OOOmg, such as about 750mg/kg. Typically once, twice, three or four times daily, such as three times daily for the duration of the pre-treatment period and/or combination treatment period.

Boceprevir

Accordin to http://en.wikipedia.0rg/wiki/File:B0ceprevir.svg, Boceprevir has the structure:

Systematic lUPAC Name: (1 R,2S,5S)-N-[(2≡)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-dimethylbutanoyl}- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide

Boceprevir may be administered in a unit dose of, for example between about 250 and about 1000mg, such as about 800mg/kg. Typically once, twice, three or four times daily, such as three times daily for the duration of the pre-treatment period and/or combination treatment period.

Compound 1: miR-122 inhibitor

As reported in Young et al., JACS 2010, 132, 7976-7981) (hereby incorporated by reference), it is possible to assay for small molecule inhibitors of miR122 and small molecule are known, such as those illustrated below:

» {7.02 ± 1.40) If (4. S3 * 0.45)

The numerical values refer to luciferase expression due to miR-122 deprepression, and values greater than 1 indicate miR-122 inhibition.

Merck Announces FDA Acceptance of New Drug Application for Investigational Fertility Treatment

September 10, 2013 1:03 am / 1 Comment on Merck Announces FDA Acceptance of New Drug Application for Investigational Fertility Treatment

corifollitropin alfa

WHITEHOUSE STATION, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the New Drug Application (NDA) for its investigational fertility treatment, corifollitropin alfa, has been accepted for standard review by the U.S. Food and Drug Administration (FDA). Merck is seeking FDA approval of corifollitropin alfa for Controlled Ovarian Stimulation (COS) in women participating in assisted reproductive technology.

If approved, corifollitropin alfa would be the first sustained follicular stimulant for use in a fertility treatment regimen.

read all at

http://www.pharmalive.com/fda-accepts-mercks-fertility-treatment-nda

Corifollitropin alfa

Merck received approval on February 15, 2010 from the European Commission for ELONVA (corifollitropin alfa) a long lasting single injection fusion protein lacking LH activity. Only one injection is required for the first seven days, replacing the first seven daily injections of conventional FSH. Initial results demonstrates similar pregnancy rates as daily recombinant FSH injections.^[7]^[8]

ref 7 N. P. Koper, R. Boostanfar, P. Devroey, B. C. Fauser, P. C. IJzerman-Boon, B. M. J. L. Mannaerts. Global ClinicalDevelopment, Organon, Part of Schering-Plough Corporation, Oss, Netherlands; Huntington Reproductive Center, Tarzana, CA; Center of Reproductive Medicine, Dutch-speaking Free University, Brussels, Belgium; University Medical Center Utrecht, Utrecht, Netherlands; Biometrics, NV Organon, Part of Schering-Plough Corporation, Oss, Netherlands. “Corifollitropin alfa demonstrates similar pregnancy rates as compared to daily recombinant FSH treatment in a controlled ovarian stimulation regimen for IVF/ICSI.” Fertility and Sterility, 90:page S75.
ref 8 ^ Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC, 2009. “A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.” Human Reproduction, 2009, August 14, [Epub ahead of print]. PMID 19684043.

In May2013, MSD launched ELONVA® (corifollitropin alfa injection) – a new treatment for fertility, – in Singapore. Approved for controlled ovarian stimulation in combination with a GnRH antagonist for the development of multiple follicles, Corifollitropin alfa injection is the first sustained follicle stimulant. A single subcutaneous injection of the recommended dose of corifollitropin alfa injection may replace the first seven injections of any
Findings showed that other failed repeated treatments may lead to depression, anxiety, sexua conventional daily recombinant follicle stimulating hormone (rFSH) preparation in a controlled ovarian stimulation treatment cycle. Simplified fertility treatment with Elonva not only helps to reduce the emotional and physical burden of fertility, it may also reduce dropout rates and potentially improve the overall chances of pregnancy.

l anxiety/difficulty, relationship problems with partner, family and friends, increased sense of self-blame and guilt, particularly for the partner experiencing fertility problem. ”By reducing the number of daily injections, the
availability of corifollitropin alfa injection is a positive step towards helping reduce the burden of fertility treatment for women experiencing difficulty conceiving. Simplifying fertility treatment with new modalities of treatment and new medication may encourage more infertile couple to embark
on treatment earlier when the wife’s age is younger and ovarian reserve better.” said Dr Loh Seong Feei, Medical Director of Thomson Fertility Centre

	DR ANTHONY MELVIN CR… on LANSOPRAZOLE
	DR ANTHONY MELVIN CR… on Molnupiravir, EIDD 2801
	shivkr2 on JBI-802 BY JUBILANT
	DR ANTHONY MELVIN CR… on MAX 40279
	بروكتان proctan : مك… on Oat Straw (Avena sativa) helpf…

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Development of the Asymmetric Hydrogenation Step for Multikilogram Production of Etamicastat

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simeprevir

Stockholm, Sweden — Medivir AB (OMX: MVIR) today reports that Janssen Pharmaceutical R&D Ireland (Janssen) has been informed by the Japanese Ministry of Health, Labour and Welfare (MHLW) that simeprevir has been approved for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.

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