New Drug Approvals

Home » Posts tagged 'Parkinson’s disease'

Tag Archives: Parkinson’s disease

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

Blog Stats

  • 2,664,562 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,430 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,430 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

GNE-0877


img

GNE-0877

Maybe  DNL-151 ?

CAS 1374828-69-9
Chemical Formula: C14H16F3N7
Molecular Weight: 339.31895

2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile

Denali Therapeutics Inc, useful for treating Alzheimer’s disease, breast tumor, type I diabetes mellitus and Crohn’s disease

GNE-0877 is a highly potent and selective LRRK2 inhibitor. Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson’s disease therapy.

  • Developer Denali Therapeutics Inc
  • Class Antiparkinsonians; Small molecules
  • Mechanism of Action LRRK2 protein inhibitors
  • Phase I Parkinson’s disease
  • 20 Dec 2017 Denali Therapeutics plans clinical studies for Parkinson’s disease
  • 13 Nov 2017 Phase-I clinical trials in Parkinson’s disease (In volunteers) in Netherlands (unspecified route)
  • 13 Nov 2017 Preclinical trials in Parkinson’s disease in USA (unspecified route) before November 2017

Denali Therapeutics  is developing DNL-151 (phase 1, in July 2019), a lead from a program of small-molecule inhibitors of LRRK2 originally licensed from Genentech, for the treatment of Parkinson’s disease.

Leucine-rich repeat kinase 2 (LRRK2) is a complex signaling protein that is a key therapeutic target, particularly in Parkinson’s disease (PD). Combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment (Christensen, K.V. (2017) Progress in medicinal chemistry 56:37-80). Inhibition of the kinase activity of LRRK2 is under investigation as a possible treatment for Parkinson’s disease (Fuji, R.N. et al (2015) Science Translational Medicine 7(273):ral5;

Taymans, J.M. et al (2016) Current Neuropharmacology 14(3):214-225). A group of LRRK2 kinase inhibitors have been studied (Estrada, A.A. et al (2015) Jour. Med. Chem. 58(17): 6733-6746; Estrada, A.A. et al (2013) Jour. Med. Chem. 57:921-936; Chen, H. et al (2012) Jour. Med. Chem. 55:5536-5545; Estrada, A.A. et al (2015) Jour. Med. Chem. 58:6733-6746; US 8354420; US 8569281; US8791130; US 8796296; US 8802674; US 8809331; US 8815882; US 9145402; US 9212173; US 9212186; WO 2011/151360; WO 2012/062783; and WO 2013/079493.

PATENT

WO2012062783 , assigned to Hoffmann-La Roche , but naming inventors specifically associated with both Genentech and BioFocus (which had an agreement with Genentech for drug discovery programs); the compound was also later identified in J.Med.Chem (57(3), 921-936, 2014) in an article from these two companies, with the lab code GNE-0877. So while this represents the first application in the name of Denali Therapeutics Inc that focuses on this compound, it is likely that it provides the structure of DNL-151 , a lead from a program of small-molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) originally licensed from Genentech, being developed for the oral treatment of Parkinson’s disease, and which had begun phase I trials by December 2017 (when this application was lodged).

PATENT

WO2019104086 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019104086

claiming novel crystalline and amorphous forms of pyrimidinylamino-pyrazole compound, useful for treating Alzheimer’s disease, breast tumor, type I diabetes mellitus and Crohn’s disease.

Novel crystalline and amorphous forms of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (which is substantially pure form) and their anhydrous and solvates such as cyclohexanol solvate (designated as Forms B-D), processes for their preparation and compositions comprising them are claimed. The compound is disclosed to be leucine rich serine threonine kinase 2 inhibitor, useful for treating Gaucher disease, Alzheimer’s disease, motor neurone disease, Parkinson’s disease, prostate tumor, Lewy body dementia, mild cognitive impairment, breast tumor, type I diabetes mellitus and Crohn’s disease.

The present disclosure relates to crystalline polymorph or amorphous forms of a pyrimidinylamino-pyrazole kinase inhibitor, referred to herein as the Formula I compound and having the structure:

FORMULA I COMPOUND

The present disclosure includes polymorphs and amorphous forms of Formula I compound, (CAS Registry Number 1374828-69-9), having the structure:

and named as: 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-lH-pyrazol-l-yl)propanenitrile (WO 2012/062783; US 8815882; US 2012/0157427, each of which are incorporated by reference). As used herein, the Formula I compound includes tautomers, and pharmaceutically acceptable salts or cocrystals thereof. The Formula I compound is the API (Active Pharmaceutical Ingredient) in formulations for use in the treatment of neurodegenerative and other disorders, with pKa when protonated calculated at 6.7 and 2.1.

CRYSTALLIZATION 

Initial polymorph screening experiments were performed using a variety of

crystallization or solid transition methods, including: anti-solvent addition, reverse anti-solvent addition, slow evaporation, slow cooling, slurry at room temperature (RT), slurry at 50 °C, solid vapor diffusion, liquid vapor diffusion, and polymer induced crystallization. By all these methods, the Form A crystal type was identified. Polarized light microscopy (PLM) images of Form A obtained from various polymorph screening methods were collected (Example 5).

Particles obtained via anti-solvent addition showed small size of about 20 to 50 microns (pm) diameter while slow evaporation, slow cooling (except for THF/isooctane), liquid vapor diffusion and polymer-induced crystallization resulted in particles with larger size. Adding isooctane into a dichloromethane (DCM) solution of the Formula I compound produced particles with the most uniform size. Crude Formula I compound crystallized from THF///-heptane and then was micronized. A crystallization procedure was developed to control particle size.

A total of four crystal forms (Forms A, B, C, and D) and an amorphous form E of Formula I compound were prepared, including 3 anhydrates (Form A, C, and D) and one solvate (Form B). Slurry competition experiments indicated that Form D was thermodynamically more stable when the water activity aw< 0.2 at RT, while Form C was more stable when aw> 0.5 at RT. The 24 hrs solubility evaluation showed the solubility of Form A, C and D in FLO at RT was 0.18, 0.14 and 0.11 mg/mL, respectively. DVS (dynamic vapor sorption) results indicated that Form A and D were non-hygroscopic as defined by less than 0.1% reversible water intake in DVS, while Form C was slightly hygroscopic. Certain characterization data and observations of the crystal forms are shown in Table 1.

Table 1 Characterization summary for crystal forms of Formula I compound

Differential Scanning Calorimetry (DSC) analysis of Forms A and C showed that Form C had higher melting point and higher heat of fusion (Table 1), suggesting that the two forms are monotropic with Form C being the more stable form. Competitive slurry experiments with 1 : 1 Form A and C in a variety of solvents always produced Form C confirming that Form C was

more stable than Form A. In accordance with this, Form C was produced even when the crystallization batch was seeded with seeds of Form A.

PATENT

WO-2019126383

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019126383&tab=PCTDESCRIPTION&_cid=P10-JXOARZ-73253-1

Methods of making leucine-rich repeat kinase 2 (LRRK2)-inhibiting, pyrimidinyl-4-aminopyrazole compounds (eg 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- lH-pyrazol-1-yl)propanenitrile), useful for treating LRRK2 mediated diseases such as Parkinson’s disease.

Example 1 Preparation of 2-(4-amino-3 -methyl- liT-pyrazol-l -yl)-2-methylpropanamide 5a

4a 5a

To a 20-L reactor containing dimethyl formamide (4.5 L) was charged 5-methyl-4-nitro-lH-pyrazole la (1.5 kg, 1.0 equiv). The solution was cooled to 0 °C and charged with finely ground K2CO3 (2.45 kg, 1.5 equiv) in three portions over ~l h. Methyl 2-bromo-2-methylpropanoate (3.2 kg, 1.5 equiv) was added dropwise to the mixture and then was allowed to warm to ~25 °C. The reaction mixture was maintained for 16 h and then quenched with water (15 L) and product was extracted with ethyl acetate. The combined organic layer was washed with water, and then with a brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give a light yellow solid. The crude product was purified by crystallization with petroleum ether (15 L), filtered, and dried to give methyl 2-m ethyl -2-(3 -methyl -4-nitro- l//-pyrazol- l -yl)propanoate 3a (2.25 kg, >99% purity by HPLC, 84 % yield) as an off-white solid. ¾ NMR (400 MHz, CDCb) 8.28 (s, 1H), 3.74 (s, 3H), 2.53 (s, 3H), 1.85 (s, 6H).

Methanol (23 L) and 2-methyl-2-(3-methyl-4-nitro-lif-pyrazol-l-yl)propanoate 3a (2.25 kg, 1.0 equiv) were charged into a 50-L reactor and cooled to approximately -20 °C. Ammonia gas was purged over a period of 5 h and then the reaction mixture warmed to 25 °C. After 16 h, the reaction mixture was concentrated under reduced pressure (~50 °C) to give the crude product. Ethyl acetate (23 L) was charged and the solution agitated in the presence of charcoal (0.1 w/w) and Celite® (0.1 w/w) at 45 °C. The mixture was filtered and concentrated under reduced pressure, and then the solid was slurried in methyl tert-butyl ether (MTBE, 11.3 L) at RT for 2 h. Filtration and drying at ~45 °C gave 2-m ethyl -2-(3 -m ethyl -4-ni tro- 1 //-pyrazol – 1 -yl)propanamide 4a (1.94 kg, >99% purity by HPLC, 92% yield).

Methanol (5 L) and 2-m ethyl-2-(3 -methyl -4-nitro-lif-pyrazol-l-yl)propanamide 4a (0.5 kg) were charged into a 10-L autoclave under nitrogen atmosphere, followed by slow addition of 10 % (50% wet) Pd/C (50 g). Hydrogen was charged (8.0 kg pressure/l 13 psi) and the reaction mixture agitated at 25 °C until complete. The mixture was filtered, concentrated under reduced

pressure and then slurried in MTBE (2.5 L) for 2 h at 25 °C. Filtration and drying under reduced pressure (45 °C) gave 2-(4-amino-3-methyl- l//-pyrazol- l -yl)-2-methyl propanamide 5a (0.43 kg, >99% purity by HPLC, 99% yield).

Example 2 Preparation of 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-lH-pyrazol-l-yl)-2-methylpropanamide 7a

DCM

Into a first reactor was charged /-BuOH (or alternatively 2-propanol) (15.5 vol) and 2-(4-amino-3 -methyl- li7-pyrazol-l-yl)-2-methylpropanamide 5a (15 kg), followed by zinc chloride (13.5 kg, 1.2 equiv) at room temperature and the suspension agitated ~2 h. Into a second reactor was charged dichloromethane (DCM, 26.6 vol) and 2,4-dichloro-5-trifluoromethyl pyrimidine 6a (19.6 kg, 1.1 equiv) and then cooled to 0 °C. The contents from first reactor were added portion-wise to the second reactor. After addition, the reaction mixture was agitated at 0 °C for ~l h and then Et3N (9.2 kg, 1.1 equiv) was slowly charged. After agitation for 1 h, the temperature was increased to 25 °C and monitored for consumption of starting material. The reaction mixture was quenched with 5% aqueous NaHCO, and then filtered over Celite®. The DCM layer was removed and the aqueous layer was back-extracted with DCM (3x). The combined organics were washed with water, dried (Na2S04), and concentrated. Methanol (2.5 vol) was charged and the solution was heated to reflux for 1 h, then cooled to 0 °C. After 1 h, the solids were filtered and dried under reduced pressure to give 2-(4-((4-chloro-5-(tri fluoromethyl)pyri mi din-2-yl)amino)-3 -methyl – l//-pyrazol- l -yl)-2-methyl propanamide 7a

(31.2 kg (wet weight)). 1H NMR (600 MHz, DMSO-de) 10.05 (br. s., 1H), 8.71 (d, J= 11 Hz, 1H), 7.95 (app. d, 1H), 7.18 (br. s., 1H), 6.78 (br. s., 1H), 2.14 (s, 3H), 1.67 (s, 6H).

Example 3 Preparation of 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- lH-pyrazol- 1 -yl)propanamide 8a

A reactor was charged with anhydrous tetrahydrofuran (THF, 10 vol) and 2-(4-((4-chloro-5-(trifl uoromethyl )pyrimi din-2-yl)amino)-3 -methyl – l //-pyrazol- l -yl)-2-methylpropanamide 7a (21 kg) at room temperature with agitation. A solution of 2M

methylamine in THF (3.6 vol) was slowly charged to the reactor at 25 °C and maintained for ~3 h. The reaction mixture was diluted with 0.5 w/w aqueous sodium bicarbonate solution (10 w/w), and extracted with ethyl acetate (EtOAc, 4.5 w/w). The aqueous layer was extracted with EtOAc (4x), the organics were combined and then washed with H20 (7 w/w). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. «-Heptane (3 w/v) was added to the residue, agitated, filtered and dried under reduced pressure to give 2-m ethyl -2-(3 -methyl -4-((4-(methyl ami no)-5-(trifl uoromethyl )pyri mi din-2-yl)amino)- l //-pyrazol-1 -yl)propanamide 8a (19.15 kg, 93% yield). ¾ NMR (600 MHz, DMSO-d6) 8.85 (m, 1H), 8.10 (s, 1H), 8.00 (m, 1H), 7.16 (br. s., 1H), 6.94 (m, 1H), 6.61 (br. s., 1H), 2.90 (d, J = 4.3 Hz, 3H), 2.18 (br. s., 3H), 1.65 (s, 6H).

Example 4 Preparation of 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- lH-pyrazol- 1 -yl)propanenitrile 9a

To a reactor was charged 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifl uoromethyl )pyri mi din-2-yl)amino)- l //-pyrazol- l -yl)propan amide 8a (15 kg, 1 equiv) at room temperature followed by EtOAc (2 vol) and 6.7 vol T3P (50% w/w in EtOAc). The reaction mixture was heated to 75 °C over 1 h and then agitated for 16 h until consumption of starting material. The reaction mixture was cooled between -10 to -15 °C then added drop-wise 5N aqueous NaOH (7 vol) resulting in pH 8-9. The layers were separated and the aqueous layer back-extracted with EtOAc (2 x 4 vol). The combined organic extracts were washed with 5 %

aqueous NaHCO, solution, and then distilled to azeotropically remove water. The organics were further concentrated, charged with «-heptane (2 vol) and agitated for 1 h at room temperature. The solids were filtered, rinsed with «-heptane (0.5 vol) and then dried under vacuum (<50 °C). The dried solids were dissolved in EtOAc (1.5 vol) at 55 °C, and then «-heptane (3 vol) was slowly added followed by 5-10% of 9a seeds. To the mixture was slowly added «-heptane (7 vol) at 55 °C, agitated for 1 h, cooled to room temperature and then maintained for 16 h. The suspension was further cooled between 0-5 °C, agitated for 1 hour, filtered, and then rinsed the filter with chilled 1 :6.5 EtOAc/«-heptane (1 vol). The product was dried under vacuum at 50 °C to give 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1 //-pyrazol – 1 -yl )propaneni tri 1 e 9a (9.5 kg, first crop), 67% yield). ‘H NMR (600 MHz, DMSO-d6) 8.14 (s, 1H), 8.13 (br. s., 1H), 7.12 (br. s., 1H), 5.72 (br. s, 1H), 3.00 (d, J= 4.6 Hz, 3H),

2.23 (s, 3H), 1.96 (s, 3H).

Example 5 Preparation of methyl 2-(4-amino-3-methyl-lH-pyrazol-l-yl)-2-methylpropanoate 10a

Following the procedure of Example 1, a mixture of methanol and methyl 2-methyl-2-(3-methyl-4-nitro-lH-pyrazol-l-yl)propanoate 3a (0.5 kg) was charged into an autoclave under nitrogen atmosphere, followed by slow addition of 10 % (50% wet) Pd/C. Hydrogen was charged under pressure and the reaction mixture agitated at 25 °C until complete. The mixture was filtered, concentrated under reduced pressure and then slurried in MTBE for 2 h at 25 °C. Filtration and drying under reduced pressure gave methyl 2-(4-amino-3-methyl-lH-pyrazol-l-yl)-2-methylpropanoate 10a (LC-MS, M+l=l98).

Example 6 Preparation of methyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3 -methyl- lH-pyrazol- 1 -yl)-2-methylpropanoate 11a

Following the procedure of Example 2, a mixture of methyl 2-(4-amino-3-methyl-lH-pyrazol-l-yl)-2-methylpropanoate 10a and DIPEA (1.2 equiv) in /-BuOH was warmed to 80 °C. Then a solution of 2,4-dichloro-5-trifluoromethyl pyrimidine 6a in /-BuOH was added slowly drop wise at 80 °C. After 15 minutes, LCMS showed the reaction was complete, including later eluting 59.9% of product ester 11a, earlier eluting 31.8% of undesired regioisomer (ester), and no starting material 10a. After completion of reaction, the mixture was cooled to room temperature and a solid was precipitated. The solid precipitate was filtered and dried to give methyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimi din-2 -yl)amino)-3-methyl-lH-pyrazol-l-yl)-2-methylpropanoate 11a (LC-MS, M+l=378).

PAPER

J.Med.Chem (57(3), 921-936, 2014

https://pubs.acs.org/doi/full/10.1021/jm401654j

2-Methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (11)

A solution of 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide (34, 250 mg, 0.7 mmol) in POCl3 (5 mL) was stirred at 90 °C for 1 h. The POCl3 was removed by evaporation. The mixture was then slowly poured onto ice (10 mL). The pH of the solution was adjusted to 8 with saturated sodium carbonate. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by recrystallization to give 11 (100 mg, 42% yield) as a white solid. 1H NMR (300 MHz, DMSO) δ 9.18 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.10 (s, 1H), 2.91 (d, 3H), 2.22 (s, 3H), 1.94 (s, 6H). HRMS (ES) m/z: [M + H]+ calcd for C14H16F3N7H+, 340.1492; found, 340.1484.
Scheme 2

Scheme 2. Synthesis of N-Alkyl Pyrazole Analoguesa

aReagents and conditions: (a) NaH, methyl 2-bromo-2-methylpropanoate, DMF, 70%; (b) LiOH, THF-H2O, 90%; (c) (i) (COCl)2, CH2Cl2, (ii) R-NH2, THF; (d) Pd/C, H2, MeOH; (e) 26, Et3N, n-BuOH, 120 °C; (f) 26, TFA, 2-methoxyethanol, 70 °C; (g) POCl3, 90 °C, 42%.

GNE-9605

product image (CAS 1536200-31-3)

CAS № 1536200-31-3

Molecular Formula
C17H20ClF4N7O
Formula Weight
449.8

GNE-9065 is an orally bioavailable and potent inhibitor of leucine-rich repeat kinase 2 (LRRK2; IC50 = 18.7 nM).1 It is selective for LRRK2 over 178 kinases, inhibiting only TAK1-TAB1 >50% at a concentration of 0.1 μM. GNE-9065 (10 and 50 mg/kg) inhibits LRRK2 Ser1292 autophosphorylation in BAC transgenic mice expressing human LRRK2 protein with the G2019S mutation found in families with autosomal Parkinson’s disease.

CNC1=C(C(F)(F)F)C=NC(NC2=C(Cl)N([C@H]3CCN(C4COC4)C[C@@H]3F)N=C2)=N1

N2-(5-Chloro-1-((trans)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (20)

A mixture of (±)-(trans)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine (53, 2.2 g, 3.9 mmol), iron dust (1.6 g, 29 mmol), and ammonium chloride (1.5 g, 29 mmol) in ethanol (20 mL) was stirred at 90 °C for 30 min. The reaction was filtered and concentrated. The residue was sonicated with 100 mL of EtOAc for 5 min. The mixture was filtered to remove all insoluble solids. The filtrate was then concentrated to give crude (±)- (trans)-4-(5-chloro-4-amino-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine (1.9 g).
To a mixture of the crude (±)-(trans)-4-(5-chloro-4-amino-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine (1.9 g) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (26, 1.5 g, 6.9 mmol) in 2-methoxyethanol (25 mL) was added TFA (0.60 mL, 7.7 mmol). The reaction was stirred at 90 °C for 15 min. The mixture was then diluted with saturated sodium bicarbonate and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC, chiral SFC, and recrystallized in isopropanol to give 20 (0.70 g, 40% yield). 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.00 (s, 1H), 5.03 4.79 (m, 1H), 4.56 (m, 1H), 4.46 (m, 2H), 3.68–3.51 (m, 1H), 3.26–3.12 (m, 1H), 2.92–2.73 (m, 3H), 2.54 (s, 2H), 2.20–1.88 (m, 3H). HRMS (ES) m/z: [M + H]+ calcd for C17H20ClF4N7OH+, 450.1427; found, 450.1418.
Scheme 8

Scheme 8. Synthesis of Inhibitor 20a

aReagents and conditions: (a) (±)-(cis)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, PPh3, diisopropyl azodicarboxylate, THF; (b) TFA, DCM, 58% over two steps; (c) oxetan-3-one, DIPEA, NaBH(OAc)3, acetic acid, DCE, 85%; (d) LiHMDS then C2Cl6, THF, −78 °C, 65%; (e) iron dust, NH4Cl, EtOH, 90 °C; (f) 26, TFA, 2-methoxyethanol, 90 °C, 40%, two steps.

REFERENCES

1: Estrada AA, Chan BK, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chen H, Dominguez SL, Dotson J, Drummond J, Flagella M, Fuji R, Gill A, Halladay J, Harris SF, Heffron TP, Kleinheinz T, Lee DW, Pichon CE, Liu X, Lyssikatos JP, Medhurst AD, Moffat JG, Nash K, Scearce-Levie K, Sheng Z, Shore DG, Wong S, Zhang S, Zhang X, Zhu H, Sweeney ZK. Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors. J Med Chem. 2014 Jan 15. [Epub ahead of print] PubMed PMID: 24354345.

/////////////DNL-151, DNL 151, DNL151, Alzheimer’s disease, breast tumor, type I diabetes mellitus,  Crohn’s disease, phase 1, Parkinson’s disease, GNE0877, GNE 0877, GNE-0877, GNE-9605, GNE 9605, GNE9605, Genentech

CC(N1N=C(C)C(NC2=NC=C(C(F)(F)F)C(NC)=N2)=C1)(C)C#N

TOZADENANT


Image result for TOZADENANT

Tozadenant

RO-449351
SYN-115

  • Molecular Formula C19H26N4O4S
  • Average mass 406.499 Da

A2 (3); A2a-(3); RO4494351; RO4494351-000; RO4494351-002; SYN-115

Phase III clinical trials at Biotie Therapies for the treatment of Parkinson’s disease as an adjunctive therapy with levodopa

1-Piperidinecarboxamide, 4-hydroxy-N-[4-methoxy-7-(4-morpholinyl)-2-benzothiazolyl]-4-methyl-
4-Hydroxy-N-[4-methoxy-7-(4-morpholinyl)-1,3-benzothiazol-2-yl]-4-methyl-1-piperidinecarboxamide
4-Hydroxy-N-[4-methoxy-7-(4-morpholinyl)-2-benzothiazolyl]-4-methyl-1-piperidinecarboxamide
4-Hydroxy-4-methyl-piperidine-1-carboxylic acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
CAS 870070-55-6
  • Originator Roche
  • Developer Acorda Therapeutics
  • Class Amides; Antiparkinsonians; Benzothiazoles; Carboxylic acids; Morpholines; Piperidines; Small molecules
  • Mechanism of Action Adenosine A2A receptor antagonists

Highest Development Phases

  • Phase III Parkinson’s disease
  • Phase I Liver disorders

Most Recent Events

  • 30 Jun 2017 Biotie Therapies plans a phase I trial in Healthy volunteers in Canada (NCT03200080)
  • 30 Jun 2017 Phase-I clinical trials in Liver disorders (In volunteers) in USA (PO) (NCT03212313)
  • 27 Apr 2017 Acorda Therapeutics initiates enrolment in a phase III trial for Parkinson’s disease in Germany (EudraCT2016-003961-25)(NCT03051607)

Biotie Therapies Holding , under license from Roche , is developing tozadenant (phase 3, as of August 2017) for the treatment of Parkinson’s disease.

SYN-115, a potent and selective adenosine A2A receptor antagonist, is in phase III clinical trials at Biotie Therapeutics for the treatment of Parkinson’s disease, as an adjunjunctive therapy with levodopa. Phase 0 trials were are underway at the National Institute on Drug Abuse (NIDA) for the treatment of cocaine dependency, but no recent development has been reported.

The A2A receptor modulates the production of dopamine, glutamine and serotonin in several brain regions. In preclinical studies, antagonism of the A2A receptor resulted in increases in dopamine levels, which gave rise to the reversal of motor deficits.

Originally developed at Roche, SYN-115 was acquired by Synosia in 2007, in addition to four other drug candidates with potential for the treatment of central nervous system (CNS) disorders. Under the terms of the agreement, Synosia was responsible for clinical development and in some cases commercialization, while Roche retained the right to opt-in to two preselected programs.

In 2010, the compound was licensed to UCB by Synosia Therapeutics for development and commercialization worldwide.

In February 2011, Synosia (previously Synosis Therapeutics) was acquired by Biotie Therapeutics, and in 2014, Biotie regained global rights from UCB.

Image result for TOZADENANT

TOZADENANT.png

Image result for TOZADENANT

Figure

Representative examples of A2AAdoR antagonists.

Tozadenant, also known as 4-hydroxy-N-(4-methoxy-7-(4-morpholinyl)benzo[d]thiazol-2-yl)-4-methylpiperidine-l-carboxamide or SYN115, is an adenosine A2A receptor antagonist. The A2A receptor modulates the production of

dopamine, glutamine and serotonin in several brain regions. In preclinical studies, antagonism of the A2A receptor resulted in increases in dopamine levels, which gave rise to the reversal of motor deficits.

Tozadenant is currently phase III clinical trials for the treatment of Parkinson’s disease as an adjunctive therapy with levodopa. It has also been explored for the treatment of cocaine dependency.

Inventors Alexander FlohrJean-Luc MoreauSonia PoliClaus RiemerLucinda Steward
Original Assignee Alexander FlohrJean-Luc MoreauPoli Sonia MClaus RiemerLucinda Steward

(F. Hoffmann-La Roche AG)

Image result

Claus Riemer

Claus Riemer

Expert Scientist
Roche , Basel · Department of Medicinal Chemistry

Sonia Poli

Sonia Poli

PhD
Chief Scientific Officer – CSO
Addex Therapeutics , Genève · R&D
PhD
Principal Scientist

PAPER

Fredriksson, KaiLottmann, PhilipHinz, SonjaOnila, IounutShymanets, AliakseiHarteneck, ChristianMüller, Christa E.Griesinger, ChristianExner, Thomas E. – Angewandte Chemie – International Edition, 2017, vol. 56, 21, pg. 5750 – 5754, Angew. Chem., 2017, vol. 129, pg. 5844 – 5848,5

PAPER

Mancel, ValérieMathy, François-XavierBoulanger, PierreEnglish, StephenCroft, MarieKenney, ChristopherKnott, TarraStockis, ArmelBani, Massimo – Xenobiotica, 2017, vol. 47,  8, pg. 705 – 718

Paper

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation

Drug Discovery Facility, Advinus Therapeutics Ltd., Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
J. Med. Chem.201760 (2), pp 681–694
DOI: 10.1021/acs.jmedchem.6b01584
* Phone: +91 20 66539600. Fax: +91 20 66539620. E-mail: sujay.basu@advinus.com.
Abstract Image

Patent

https://www.google.com/patents/US20050261289

  • Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzyme A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
  • [0003]
    The adenosine receptors have been classified as A1, A2A, A2B and A3receptors, belonging to the family of G protein-coupled receptors. Activation of aderosine receptors by adenosine initiates signal transduction mechanisms. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtypes has been classically characterized by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The A1and Areceptors, coupled with Gproteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A2A and A2Breceptors couple to Gproteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A1receptor system activates phospholipase C and modulates both potassium and calcium ion channels. The Asubtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and activates calcium ion channels.
  • [0004]
    The Areceptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A2Areceptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) was cloned from human and mouse and shows 45% homology with the human Aand A2A receptors. The Areceptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
  • [0005]
    The Aand A2A receptor subtypes are proposed to play complementary roles in adenosine’s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A1) or increase the oxygen supply (A2A) and so reinstate the balance of energy supply: demand within the tissue. The actions of both subtypes is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischemia, hypotension and seizure activity.
  • [0006]
    Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat Areceptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the Areceptor plays a role in mediating asthmatic attacks and other allergic responses.
  • [0007]
    Adenosine is a neurotransmitter able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington’s disease), Alzheimer’s disease, depression, schizophrenia, or addiction. An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A1agonists mimic the central inhibitory effects of adenosine and may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Furthermore, adenosine antagonists have proven to be effective as cognition enhancers. Selective A2A antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer’s disease, and of neurodegenerative disorders, e.g. stroke. Adenosine A2A receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, and cannabinoids). Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder).
  • [0008]
    An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). By acting at the Areceptor, adenosine Aagonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating influence of A2Areceptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A2Aantagonists may be of therapeutic benefit in situations in which an enhanced anti-adrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A2A Areceptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias.
  • [0009]
    Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds which antagonize the renal affects of adenosine have potential as renal protective agents. Furthermore, adenosine Aand/or A2Bantagonists may be useful in the treatment of asthma and other allergic responses or and in the treatment of diabetes mellitus and obesity.
  • [0010]

    Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:

      • Bioorganic & Medicinal Chemistry, 6, (1998), 619-641,
      • Bioorganic & Medicinal Chemistry, 6, (1998), 707-719,
      • J. Med. Chem., (1998), 41, 2835-2845,
      • J. Med. Chem., (1998), 41, 3186-3201,
      • J. Med. Chem., (1998), 41, 2126-2133,
      • J. Med. Chem., (1999), 42, 706-721,
      • J. Med. Chem., (1996), 39, 1164-1171,
      • Arch. Pharm. Med. Chem., 332, 39-41, (1999),
      • Am. J. Physiol., 276, H1113-1116, (1999) or
      • Naunyn Schmied, Arch. Pharmacol. 362,375-381, (2000)
    EXAMPLE 14-Hydroxy-4-methyl-piperidine-1-carboxylic acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (I)

  • [0065]
    To a solution of (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid phenyl ester (3.2 g, 8.3 mmol) and N-ethyl-diisopropyl-amine (4.4 ml, 25 mmol) in trichloromethane (50 ml) is added a solution of 4-hydroxy-4-methyl-piperidine in trichloromethane (3 ml) and tetrahydrofurane (3 ml) and the resulting mixture heated to reflux for 1 h. The reaction mixture is then cooled to ambient temperature and extracted with saturated aqueous sodium carbonate (15 ml) and water (2×5 ml). Final drying with magnesium sulphate and evaporation of the solvent and recrystallization from ethanol afforded the title compound as white crystals (78% yield), mp 236° C. MS: m/e=407(M+H+).

Figure US20050261289A1-20051124-C00013

Figure US20050261289A1-20051124-C00012Figure US20050261289A1-20051124-C00011

PATENT

WO-2017136375

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017136375&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated forms of tozadenant are claimed. Also claimed are compositions comprising them and method of modulating the activity of adenosine A2A receptor (ADORA2A), useful for treating Parkinson’s diseases. Represents new area of patenting to be seen from CoNCERT Pharmaceuticals on tozadenant. ISR draws attention towards WO2016204939 , claiming controlled-release tozadenant formulations.

This invention relates to deuterated forms of morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an adenosine A2A receptor antagonist.

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co- administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.

Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Patent ID

Patent Title

Submitted Date

Granted Date

US2016367560 Methods for Treating Parkinson’s Disease 2016-06-17
US9534052 Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer’s disease 2016-07-16 2017-01-03
US9512225 Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer’s disease 2016-06-22 2016-12-06
US9512227 Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer’s disease 2016-07-05 2016-12-06
Patent ID

Patent Title

Submitted Date

Granted Date

US2016000909 REDUCING SYSTEMIC REGULATORY T CELL LEVELS OR ACTIVITY FOR TREATMENT OF DISEASE AND INJURY OF THE CNS 2015-07-13 2016-01-07
US2016008463 REDUCING SYSTEMIC REGULATORY T CELL LEVELS OR ACTIVITY FOR TREATMENT OF DISEASE AND INJURY OF THE CNS 2015-09-10 2016-01-14
US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF 2015-10-13 2016-04-21
US9394365 Reducing systemic regulatory T cell levels or activity for treatment of alzheimer’s disease 2015-12-02 2016-07-19
US2017029508 Reducing Systemic Regulatory T Cell Levels or Activity for Treatment of Disease and Injury of the CNS 2016-09-10
Patent ID

Patent Title

Submitted Date

Granted Date

US7368446 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide 2005-11-24 2008-05-06
US8168785 BENZOTHIAZOLE DERIVATIVES 2010-12-23 2012-05-01
US2009082341 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide FOR THE TREATMENT OF POST-TRAUMATIC STRESS DISORDER 2008-07-23 2009-03-26
US2013317019 A2A Antagonists as Cognition and Motor Function Enhancers 2011-11-04 2013-11-28
US9387212 Methods for Treating Parkinson’s Disease 2013-04-19 2015-06-11

///////////////TOZADENANT, phase III,  clinical trials,  Parkinson’s disease ,  adjunctive therapy,  levodopa, RO-449351, SYN-115

CC1(CCN(CC1)C(=O)NC2=NC3=C(C=CC(=C3S2)N4CCOCC4)OC)O

FDA approves drug Xadago (Safinamide, сафинамид , سافيناميد , 沙非胺 , ) to treat Parkinson’s disease


ChemSpider 2D Image | Safinamide | C17H19FN2O2

Safinamide

  • Molecular Formula C17H19FN2O2
  • Average mass 302.343 Da
(2S)-2-[[[4-[(3-Fluorophenyl)methoxy]phenyl]methyl]amino]propanamide
133865-89-1 ,
сафинамид ,
سافيناميد 
沙非胺 
EMD-1195686, ZP-034, FCE-28073(R-isomer), PNU-151774E, NW-1015, FCE-26743
CAS   202825-46-5 (mesylate) SEE BELOW

str1

(+)-(S)-2-[[p-[(m-fluorobenzyl)oxy]benzyl]amino]propionamide monomethanesulfonate

Propanamide, 2-[[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino]-, (2S)-, methanesulfonate

Molecular Weight 398.45
Formula C17H19FN2O2 ● CH4O3S

CAS 202825-46-5 (Safinamide Mesylate)

Safinamide is a white to off-white, non-hygroscopic crystalline solid. It shows pH dependent solubility in aqueous buffers due to the secondary amine moiety, being soluble at acidic pH and practically insoluble at neutral pH.

It is freely soluble in de-ionized water, methanol and DMSO but practically insoluble in non-polar organic solvents.

Safinamide is chiral and possesses a single stereogenic centre.

Three crystalline forms are known. The anhydrous form selected for commercialisation is the most thermodynamically stable form, whilst the others are either not physiologically relevant or have very similar dissolution profiles. SOURCE EMA

Safinamide methanesulfonate was approved by European Medicine Agency (EMA) on Feb 22, 2015. It was developed by Newron and Zambon, then marketed as Xadago® by Zambon in EU.

FDA approved March 21, 2017,

STR1

Safinamide is a unique molecule with a novel dual mechanism of action based on the enhancement of the dopaminergic function (through potent reversible inhibition of MAO-B and of dopamine uptake) and inhibition of the excessive release of glutamate. It is indicated for the treatment of Parkinson’s disease (PD).

Xadago® is available as film-coated tablet for oral use, containing Eq. 50 mg/100 mg of free Safinamide. The recommended dose is 50 mg or 100 mg once daily.

SYNTHESIS WILL BE UPDATED…………..
03/21/2017
The U.S. Food and Drug Administration today approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

March 21, 2017, Release

The U.S. Food and Drug Administration today approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

“Parkinson’s is a relentless disease without a cure,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, though it can occur earlier, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement – such as eating, writing, and shaving. Early symptoms of the disease are subtle and occur gradually. In some people, Parkinson’s disease progresses more quickly than in others.

The efficacy of Xadago in treating Parkinson’s disease was shown in a clinical trial of 645 participants who were also taking levodopa and were experiencing “off” time. Those receiving Xadago experienced more beneficial “on” time, a time when Parkinson’s symptoms are reduced, without troublesome uncontrolled involuntary movement (dyskinesia), compared to those receiving a placebo. The increase in “on” time was accompanied by a reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment.

In another clinical trial of 549 participants, the participants adding Xadago to their levodopa treatment had more “on” time without troublesome uncontrolled involuntary movement compared to those taking a placebo, and also had better scores on a measure of motor function assessed during “on” time than before treatment.

Certain patients should not take Xadago. These include patients who have severe liver problems, or who take a medicine used to treat a cough or cold called dextromethorphan. It also should not be taken by patients who take another medicine called a monoamine oxidase inhibitor (MAOI) because it may cause a sudden severe increase in blood pressure, or by those who take an opioid drug, St. John’s wort, certain antidepressants (such as serotonin-norepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines), or cyclobenzaprine, because it may cause a life-threatening reaction called serotonin syndrome.

The most common adverse reactions observed in patients taking Xadago were uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia).

Serious, but less common, risks include the following: exacerbated high blood pressure (hypertension); serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs; falling asleep during activities of daily living; hallucinations and psychotic behavior; problems with impulse control/compulsive behaviors; withdrawal-emergent hyperpyrexia (fever) and confusion; and retinal pathology.

The FDA granted approval of Xadago to Newron Pharmaceuticals.

Safinamide (INN; brand name Xadago) is a drug indicated for the treatment of Parkinson’s disease with monoamine oxidase B inhibiting and other methods of action.[2] It was approved in Europe in February 2015,[3] and in the United States on March 21, 2017[4]. It has also been tested for the use in patients with restless legs syndrome (RLS), but no study results have been published.

Image result for SAFINAMIDE SYNTHESIS

Medical uses

Safinamide has been approved by the European Medicines Agency for the treatment of adult patients with idiopathic Parkinson’s disease as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs in patients with mid-to-late-stage fluctuating disease.[5]

Contraindications

Safinamide is contraindicated in patients with severe liver impairment, with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis and other disorders of the retina. Combination with other monoamine oxidase (MAO) inhibitors and pethidine is also contraindicated.[6]

Adverse effects

Common adverse events in clinical trials (in more than 1% of patients) included nausea, dizziness, tiredness, sleeplessness, orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide and placebo treated patients.[6][7]

In experiments with rats (but not in those with monkeys), retinopathies have been observed.[1][8]

Overdose

Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a singe patient was suspected to have overdosed for a month; symptoms were confusion, drowsiness and mydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available.[6]

Interactions

As a MAO inhibitor, safinamide can theoretically cause hypertensive crises, serotonin syndrome and other severe side effects when combined with other MAO inhibitors or with drugs that are known to interact with MAO inhibitors, such as pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants. An interaction with tyramine, a substance found in various foods, could be expected by the same reasoning but has been excluded in studies.[6]

Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexat, and diclofenac; a study with the latter has shown no clinical relevance.[9] A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan.[1] There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.[6]

Pharmacology

Mechanisms of action

Like the older antiparkinson drugs selegiline and rasagiline, safinamide is a selective monoamine oxidase B inhibitor, reducing degradation of dopamine; in contrast to the other two, its action is reversible. Safinamide also inhibits glutamate release[7][10] and dopamine reuptake.[11] Additionally, it blocks sodium and calcium channels,[10][12] the relevance of which for its antiparkinson action is however unknown.[6]

Pharmacokinetics

Safinamide is absorbed quickly and nearly completely from the gut and reaches highest blood plasma concentrations after 1.8 to 2.8 hours. There is no relevant first-pass metabolism; total bioavailability is 95%. The substance is bound to plasma proteins to 88–90%.[6]

The metabolism is not well understood. The principal step is mediated by amidases which have not been identified, and produces safinamide acid (NW-1153). Other relevant metabolites are O-debenzylated safinamide (NW-1199),[9] the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter.[6][13] In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies.[6]

Safinamide is eliminated, mainly (>90%) in form of its metabolites, via the kidney, with an elimination half-life of 20 to 30 hours. Only 1.5% are found in the stool.[6]

Metabolism pathways of safinamide.[9][13] Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide.

History

The compound was originally discovered at Farmitalia-Carlo Erba, which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998.[14] In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed company Newron Pharmaceuticals, which developed the drug until it was sold to Merck KGaA in 2006.[15]

In 2007, a Phase III clinical trial was started, scheduled to run until 2011.[16] In October 2011 Merck, now Merck-Serono, announced that they would give all rights to develop the compound back to Newron because they wanted to prioritise other projects and had corrected their estimates for safinamide’s market potential downwards.[17]

The US Food and Drug Administration (FDA) refused to file Newron’s application in 2014 on formal grounds.[18] Newron re-applied in December 2014.[19] In spring 2015, the European Medicines Agency (EMA) approved the drug. Safinamide is the first antiparkinson medication to be approved for ten years.[8]

Research

Potential additional uses might be restless legs syndrome (RLS) and epilepsy.[20] They were being tested in Phase II trials in 2008, but no results are available.

str1

(+)-(S)-2-[[p-[(m-fluorobenzyl)oxy]benzyl]amino]propionamide monomethanesulfonate

Propanamide, 2-[[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino]-, (2S)-, methanesulfonate

Molecular Weight 398.45
Formula C17H19FN2O2 ● CH4O3S

CAS 202825-46-5 (Safinamide Mesylate)

Safinamide is a white to off-white, non-hygroscopic crystalline solid. It shows pH dependent solubility in aqueous buffers due to the secondary amine moiety, being soluble at acidic pH and practically insoluble at neutral pH.

It is freely soluble in de-ionized water, methanol and DMSO but practically insoluble in non-polar organic solvents.

Safinamide is chiral and possesses a single stereogenic centre.

Three crystalline forms are known. The anhydrous form selected for commercialisation is the most thermodynamically stable form, whilst the others are either not physiologically relevant or have very similar dissolution profiles.SOURCE EMA

Safinamide methanesulfonate was approved by European Medicine Agency (EMA) on Feb 22, 2015. It was developed by Newron and Zambon, then marketed as Xadago® by Zambon in EU.

FDA approved March 21, 2017

Safinamide is a unique molecule with a novel dual mechanism of action based on the enhancement of the dopaminergic function (through potent reversible inhibition of MAO-B and of dopamine uptake) and inhibition of the excessive release of glutamate. It is indicated for the treatment of Parkinson’s disease (PD).

Xadago® is available as film-coated tablet for oral use, containing Eq. 50 mg/100 mg of free Safinamide. The recommended dose is 50 mg or 100 mg once daily.

SYNTHESIS

Safinamide has been obtained by reductocondensation of 4-(3-fluorobenzyloxy)benzaldehyde (I) with L-alaninamide (II) by means of sodium cyanoborohydride in methanol.EP 0400495; EP 0426816; JP 1992500215; US 5236957; US 5391577; US 5502079; WO 9014334

CLIP

http://pubs.rsc.org/en/content/articlehtml/2016/sc/c6sc00197aImage result for SAFINAMIDE SYNTHESIS

image file: c6sc00197a-s2.tif

Scheme 2 Synthesis and isolation of [18F]safinamide, [18F]FMT, and [18F]mFBG.

PATENT

WO2009074478A1

Safinamide (NW- 1015, FCE-26743A, PNU- 151774E) is a sodium channel blocker, a calcium channel modulator, a monoamino oxidase B (MAO-B) inhibitor, a glutamate release inhibitor and a dopamine metabolism modulator. Safinamide is useful in the treatment of CNS disorders, in particular of epilepsy, Parkinson’s disease, Alzheimer’s disease, depression, restless legs syndrome and migraine (WO 90/ 14334, WO 2004/089353, WO 2005/ 102300 and WO 2004/062655). Ralfinamide (NW- 1029, FCE-26742A, PNU-0154339E) is a sodium channel blocker useful in the treatment of pain conditions, including chronic pain and neuropathic pain, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders (WO 99/35125, WO 03/020273, WO 2004/062655, WO 2005/018627, WO 2005/070405, WO 2005/ 102300).

In particular, safinamide is specifically described in WO 90/ 14334. Safinamide, its R-enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and the use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents are specifically claimed in WO 90/ 14334. Ralfinamide is specifically described in WO 90/ 14334. Ralfinamide, its R- enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and their use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agent are comprised by the claims of WO 90/ 14334.

Moreover, the use as analgesics of safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures and their salts with pharmaceutically acceptable acids is claimed in WO 99/035125. WO 2006/027052 A2 specifically discloses and claims the use of the single R-enantiomer of ralfinamide i.e., (R)-2-[4-(2- fluorobenzyloxy)benzylamino]propanamide (I’b), and its salts with pharmaceutically acceptable acids as a selective sodium and calcium channel modulator for the selective treatment of pathological affections wherein sodium or calcium channel mechanism(s) play(s) a pathological role, including pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissue, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, and urogenital disorders, wherein the therapeutical activity of said compound is substantially free from any MAO inhibitory side effect or exhibits significantly reduced MAO inhibitory side effect.

It has now been discovered that the large scale preparations of safinamide and ralfinamide according to the methods described in the prior art, contain two undesired impurities, i.e., respectively, (S)-2-[3-(3- fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (Ha) and (S)- 2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (lib), and their salt, in particular the respective methanesulfonates (lie) and (Hd)

Figure imgf000004_0001

(Ha) (lib)

The same situation occurs with the preparation according the prior art methods for the R-enantiomers (I’a) and (I’b) of, respectively, safinamide and ralfinamide, the respective racemic mixtures (Ia, I’a) and (Ib, I’b), and the salts thereof with pharmaceutically acceptable acids, (I’c), (I’d) and the respective racemic mixtures (Ic, I’c) and (Id, I’d) in particular the methanesulfonates, which result to be contaminated by the respective R isomers (Il’a), (Il’b), (II’c), and (Il’d) of the above identified impurities (Ha), (lib), (lie) and (Hd) or the respective racemic mixtures (Ha, Il’a), (lib, Il’b), (Hc, II’c) and (Hd, Il’d).

PATENT

WO2014178083A1.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by bradykinesia, rigidity, resting tremor, and ataxia. These symptoms are caused by decreased dopamine release in the striatum. Clinically, PD is defined by presence of Lewy bodies, intracellular neuronal inclusions in the substantia nigra and at other sites in the brain. Estimated prevalence of this disease is 100 to 200 per 100,000 population including males and females across the entire age group. Current treatment for PD comprises dopaminergic medications that include levodopa, dopamine agonists (DAs), monoamine oxidase-B (MAO-B) inhibitors. Figure 1 provides few examples of pharmaceutically important benzyloxy-benzylamine derivatives. Many of these benzyl oxy-benzylamines with various amine functions were studied and has been patented as sodium channel blockers. Among them, safinamide ((5)-N2– {4-[3- fluorobenzyl)oxy] benzyl}- alaninamide methanesulfonate) is a noted example which is under phase III clinical trials for treatment of Parkinson’s disease. Its mechanism of action is manifold which comprise MAO-B and dopamine uptake inhibition. Further, safinamide is believed to block voltage-dependent sodium channels, modulates calcium channels and reduction of glutamate release in the central nervous system. WOl 998003472 discloses serinamide, glycinamide, alaninamide and phenylalaninamide derivatives of a compound (I). These compounds (I) are useful for the treatment of neurological diseases.

EP2474521 discloses high purity degree (S)-2-[4-(3-fluorobenzyloxy)- benzylamino]propanamide (safinamide) or (S)-2-[4-(2-fluorobenzyloxy)- benzylamino]propanamide (ralfinamide) or a salt thereof with a pharmaceutically acceptable acid with a content of the respective impurity (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propanamide or (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide.

US2009149544 relates to novel alpha- aminoamide derivatives, their pharmaceutically acceptable salts, solvates, and hydrates thereof. The application also provides compositions comprising a compound and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of monoamine oxidase type B (MAO-B) and/or a sodium (Na.sup.+) channel blocker, and/or a calcium (Ca.sup.2+) channel modulator.

The strategy employed in the art to prepare benzyloxy-benzylamine derivatives including safinamide or its analogue ralfinamide is chiral pool approach starting from L-alaniriamide and reductively aminating with 4-(3-fluorobenzyloxy) benzaldehyde. Although this method is very simple and straightforward, it suffers from several serious drawbacks, such as need to use toxic reagents such as sodium cyanoborohydride and further formation of toxic by-products such as hydrogen cyanide and sodium cyanide and other toxic impurities in large-scale production Importantly, the possibility of generating a range of safinamide analogues by means of the chiral-pool approach is limited in terms of the structure and stereochemistry of the products because of inadequacies in the availability of D-alaninamide and its analogues

Hence, the developments of newer methods for the preparation of compounds of formula (I) comprising safinamide and related analogues are highly desirable

Example 2: Synthesis of (R)-l-(benzyIoxy)propan-2-ol [(R)-compound 3]

To a solution of (7? benzyl glycidyl ether [fR)-compound 2] (4 g, 24.4 mmol) in dry THF (10 mL) at 0 °C, a pre-cooled solution of lithium aluminium hydride (1.4 g, 36.6 mmol) in anhydrous THF (10 mL) was added slowly with stirring under nitrogen. After 60 min, the reaction mixture was quenched with 1 ml of water and 1 ml of 15 % NaOH solution and the content was stirred for 15 min. The inorganic precipitate was filtered, washed with ethyl acetate and the solvent evaporated under reduced pressure. The residue was purified by a short filtration column to afford (-fl)-compound 3 as a colorless oil (3.8 g, 95%); [a]22D = -14.5 (c 2, CHC13); IR (CHC13): vmax3418, 3087, 3063, 3030, 2963, 2924, 1952, 1873, 1600, 1495, 1454, 1363, 1244, 1099, 1028, 918, 808, 698 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.13 (d, J = 6.3 Hz, 3H), 2.5 (bs, 1H), 3.23-3.32 (dd, J = 9.8, 1.3 Hz, 1H), 3.43-3.49 (dd, J = 9.45, 3.2 Hz, 1H), 3.91-4.03 (m, 1H), 4.55 (s, 2H), 7.25-7.37 (m, 5H); I3C NMR (50 MHz, CDC13): 5C 137.8 (C), 128.3 (CH, 2 carbons), 127.7 (CH, 3 carbons), 75.7 (CH2), 73.2 (CH2), 66.4 (CH), 18.6 (CH3); MS: m/z 189 [M+Na]+.

Example 3: Synthesis of (S)-((2-azidopropoxy)methyl)benzene [(S)- compound 4]

To a stirred solution of secondary alcohol ( )-compound 3 (3 g, 18.1 mmol) in dry dichloromethane (25 mL), Et3N (3.1 mL, 21.7 mmol) at 0 °C was added, followed by drop wise addition of mesyl chloride (1.8 mL, 21.7 mmol). The reaction mixture was stirred at 0°C for 2 hours, subsequently at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction (indicated by TLC), the reaction mixture was diluted with dichloromethane and washed with a saturated solution of sodium bicarbonate (30 mL) and water (2 x 10 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the O-mesyl compound (4.3 g; crude).

To a solution of the crude 0-mesyl compound (4 g, 16.37 mmol) in dry DMF (10 mL), sodium azide (1.6 g, 24.55 mmol) was added and the reaction mixture was heated at 60°C for 6 hours under nitrogen atmosphere. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield (¾)-compound 4 as a colorless oil. (2.8 g; 89%); [a]22D = +6.1 (c 1.3, CHC13); IR (CHC13): vmax 3394, 3032, 2977, 2864, 2500, 2104, 1724, 1641 , 1496, 1454, 1363, 1269, 1 101 , 913, 698 αη ‘,Ή NMR (200 MHz, CDC13): δΗ 1.20 (d, J = 6.7 Hz, 3H), 3.39-3.54 (m, 2H), 3.61-3.77 (m, 1H), 4.57 (s, 2H), 7.25-7.39 (m, 5H); 13C NMR (50 MHz, CDC13): 5C 137.8 (C), 128.4 (CH, 2 carbons), 127.7 (CH), 127.5 (CH, 2 carbons), 73.7 (CH2), 73.2 (CH2), 56.9 (CH), 16.1 (CH3);MS: m/z 214 [M+Na]+.

Example 4: Synthesis of (S)-N-(l-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [(S)- compound 5]

To a solution of ^-compound 4 (2.5 g, 13.1 mmol) in methanol (15 mL), trifluoroacetic acid (2 mL) and palladium hydroxide on activated carbon (0.05 g, 10-20 wt %) were added and the reaction mixture was stirred under hydrogen (60 psi) for 8 hours. After completion of the reaction (indicated by TLC), the catalyst was filtered over a plug of celite and the solvent was evaporated under reduced pressure to half of its volume which was basified with 2.5 M methanolic NaOH. Evaporation of the remaining solvent under reduced pressure was done followed by filtration of the residue through a short bed of basic alumina (eluent; MeOH) to obtain the amino alcohol as a pale brown oil (0.94 g, crude) which was subjected to the next reaction without further purification.

To a solution of amino alcohol (0.9 g, 1 1.98 mmol) in dry dichloromethane (5 mL), 2-nitrobenzenesulfonylchloride (3.2 g, 14.37 mmol) in dichloromethane (8 mL) and triethylamine (2.6 mL, 17.97 mmol) at 0 °C were slowly added under nitrogen atmosphere. The solution was stirred for 2 hours. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with dichloromethane (2 x 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 60:40) to yield (S)- compound 5 as a pale yellow oil (2.33 g, 75% ); [a]22D = +80.2 (c 2.1, CHClj); IR (CHC13): vmax 3546, 3367, 3022, 2883, 2401, 1594, 1542, 1412, 1362, 1216, 1170, 1 125, 1059, 971, 854, 668 cm“1; ]H NMR (200 MHz, CDC13): δΗ 1.13 (d, J = 6.5 Hz, 3H), 2.16 (bs, 1H), 3.45-3.70 (m, 3H), 5.61 (d, J = 6.6 Hz, 1H), 7.73-7.80 (m, 2H), 7.86-7.91 (m, 1H), 8.13-8.22 (m, 1H); 13C NMR (50 MHz, CDC13): 5C 147.8 (C), 134.4 (C), 133.7 (CH), 133.0 (CH), 130.9 (CH), 125.5 (CH), 66.2 (CH2), 52.5 (CH), 17.8 (CH3); MS: m/z 283 [M+Na]+.

Example 5: Synthesis of l-fluoro-3-(iodomethyl)benzene ( compound 7)

To a stirred solution of triphenyl phosphine (4.15 g, 15.85 mmol), imidazole (1.1 g, 15.85 mmol) in dry dichloromethane (20 mL), iodine (4.8 g, 19.02 mmol) at 0°C was added and the solution was stirred for 5 min. To this, 3-fluoro benzyl alcohol (compound 6) (2 g, 15.85 mmol) dissolved in dichloromethane (5 mL) was added drop wise over 10 min and the stirring was continued for 1 hour with exclusion of light. After completion of the reaction (indicated by TLC), the reaction mixture was quenched by addition of an aqueous Na2S203 solution (15 mL), then extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield compound 7 as a colorless oil (3.5 g, 95% ); (IR (CHC13): vmax 3460, 3060, 2965, 1695, 1613, 1593, 1482, 1446, 1259, 1 156, 1068, 944, 871, 782, 736, 686 cm“1 ; Ή NMR (200 MHz, CDC13): δΗ 4.42 (s, 2H), 6.89-6.99 (m, 1H), 7.05-7.17 (m, 2H), 7.21-7,29 (m, 1H); 13C NMR (50 MHz, CDC13): 6C 165.0 (C), 141.6 (C), 130.2 (CH), 124.4 (CH), 1 15.9 (CH), 1 14.7 (CH), 3.9 (C¾).

Example 6: Synthesis of (4-((3-flurobenzyl)oxy)phenyl)methanol (compound 8)

To a stirred solution of 4-(hydroxymethyl)phenol (1.57 g, 12.7 mmol) and K2C03 (8.8 g, 63.55 mmol) in dry acetonitrile (25 mL), compound 7 (3 g, 12.7 mmol) in acetonitrile was slowly added and the reaction mixture was heated at 70°C for 6 hours. After completion of the reaction (indicated by TLC), water (20 mL) was added to the reaction mixture, then extracted with ethylacetate (3 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 70:30) to yield compound 8 as a colorless solid (2.7 g, 91% ); mp 63-65 °C; IR (CHC13): vmax 3422, 3017, 1612, 1512, 1489, 1381, 1216, 1 174, 1020, 829, 668 cm“1; Ή NMR (200 MHz, CDC13): δΗ 4.61 (s, 2H), 5.06 (s, 2H), 6.91-6.98 (m, 2H), 7.00-7.06 (m, 1H), 7.12-7.20 (m, 2H), 7.25-7.37 (m, 3H); 13C NMR (50 MHz, CDC13): 5C 165.4 (C), 160.5 (C), 158.0 (C), 139.6 (C), 133.5 (CH), 130.2 (CH), 128.7 (CH, 2 carbons), 122.7 (CH), 1 14.8 (CH, 2 carbons), 1 13.9 (CH), 69.1 (CH2), 64.9 (CH2); MS: m/z 255 [M+Na]+.

Example 7: Synthesis of l-fluoro-3-((4-(iodomethyl)phenoxy)methyI)benzene (compound 9)

To a stirred solution of triphenyl phosphine (2.82 g, 10.8 mmol), imidazole (0.73 g, 10.76 mmol) in dry dichloromethane (20 mL), iodine (3.27 g, 12.9 mmol) at 0 °C was added and the solution was stirred for 5 min. To this, compound 8 (2.5 g, 10.8 mmol) dissolved in dichloromethane (5 mL) was added drop wise over 10 min and the stirring was continued for 1 hour with exclusion of light. After completion of the reaction (indicated by TLC), the reaction mixture was quenched by addition of an aqueous Na2S203 solution (15 mL), then extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield compound 9 as a colorless oil (3.4 g, 93%); IR (CHC13): vmax 3503, 3033, 2925, 2089, 1607, 1509, 1488, 1381, 1301, 1250, 1 155, 1079, 944, 869, 776, 684 cm“1; 1H NMR (200 MHz, CDC13): δΗ 4.47 (s, 2H), 5.04 (s, 2H), 6.85-6.91 (m, 2H), 6.96-7.02 (m, 1H), 7.05-7.12 (m, 1H), 7.16-7.20 (m, 1H), 7.29-7.40 (m, 3H).

,3C NMR (50 MHz, CDC13): 6C 165.4 (C), 160.5 (C), 158.1 (C), 131.9 (C), 130.2 (CH), 130.1 (CH, 2 carbons), 122.7 (CH), 1 15.1 (CH, 2 carbons), 1 14.7 (CH), 1 13.9 (CH), 69.2 (CH2), 6.33 (CH2).

Example 8: Synthesis of (S)-N-(4-((3-flurobenzyl)oxy)benzyl)-N-(l-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [(S)-compound 10]

To a stirred solution of (^-compound 5 (1 g, 3.8 mmol) and K2C03 (2.65 g, 19.2 mmol) in dry acetonitrile (25 mL), compound 9 (1.84 g, 5.4 mmol) in acetonitrile was slowly added and the reaction mixture was heated at 70°C for 72 hours. After completion of the reaction (indicated by TLC), water (20 mL) was added to the reaction mixture, then extracted with ethylacetate (3 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 80:20) to yield (¾)-compound 10 as a colorless oil (1.46 g, 80% ); [a]22D = +5.4 (c 1.5, CHC13); IR (CHC13): vmax 3445, 3020, 2928, 2400, 1613, 1544, 1512, 1453, 1371, 1216, 1 162, 1029, 852, 668 cm“1; 1H NMR (200 MHz, CDC13): δΗ 1.07 (d, J = 6.9 Hz, 3H), 1.91 (t, J = 5.2 Hz, 1H), 3.41-3.53 (m, 2H), 4.05-4.22 (m, 1H), 4.37-4.57 (m, 2H), 5.02 (m, 2H), 6.87 (d, J = 8.53 Hz, 2H), 6.97-7.12 (m, 2H), 7.20 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.47-7.67 (m, 3H), 7.89 (d, J = 8.09 Hz, 1H); 13C NMR (50 MHz, CDC13): 6C 165.5 (C), 160.6 (C), 158.4 (C), 147.7 (C), 139.6 (C), 134.1 (C), 133.4 (CH), 131.6 (CH), 131.4 (CH), 130.3 (CH), 129.7 (CH, 2 carbons), 124.1 (CH), 122.8 (CH), 115.1 (CH), 114. 9 (CH, 2 carbons), 114.0 (CH), 69.2 (CH2), 64.3 (CH2), 56.2 (CH), 46.9 (CH2), 15.4 (CH3); MS: m/z 497 [M+Na]+.

Example 9: Synthesis of (S)-2-(N-(4-((3-fluorobenzyl)oxy)benzyl)-2-nitrophenylsulfonamido) propanoic acid [(S)-compound 11]

A mixture of (S compound 10 (1.25 g, 2.6 mmol), TEMPO (0.028 g, 0.18 mmol), acetonitrile (20 mL), and sodium phosphate buffer (16 mL, 0.67 M, pH 6.7) was heated to 35°C. Next, sodium chlorite (0.47 g dissolved in 2 mL water, 7.9 mmol) and diluted bleach (4-6%, 0.09 mL diluted in 1 mL water) were added simultaneously over 1 hour. The reaction mixture was stirred at 35°C until the reaction was complete (3 hours, TLC), then cooled to room temperature. Water (30 mL) was added and the pH adjusted to 8 with 2 M NaOH. The reaction was quenched by pouring it into ice cold Na2S03 solution maintained at <20°C. After stirring for 30 min at room temperature, ethyl acetate (20 mL) was added and the stirring was continued for an additional 15 min. The organic layer was separated and discarded. More ethyl acetate (20 mL) was added, and the aqueous layer was acidified with 1 M HC1 to pH 3-4. The organic layer was separated, washed with water (2 x 15 mL), brine and concentrated under reduced pressure to afford the carboxylic acid (S -compound 1 1 (1.1 g, 85%); [ ]22ο = -20.4 (c 1.1, CHC13); IR (CHC13): vmax 3398, 3095, 1718, 1612, 1591, 1543, 1512, 1489, 1457, 1371, 1303, 1251, 1163, 1059, 900, 852, 831 , 778, 684 cm“1; 1H NMR (200 MHz, CDC13): 8H 1.44 (d, J = 7.3 Hz, 3H), 4.23 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.82-4.90 (q, J = 7.4 Hz, 1H), 4.92 (s, 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.89-7.01 (m, 2H), 7.07-7.13 (m, 3H), 7.18-7.33 (m, 2H), 7.43-7.55 (m, 3H), 8.81 (bs, 1H); 13C NMR (50 MHz, CDC13): 5C 176.5 (CO), 165. 0 (C), 158.0 (C), 147.4 (C), 139.4 (C), 134.1 (C), 133.2 (CH), 131.4 (CH), 130.3 (CH), 129.9 (CH, 2 carbons), 128.4 (C), 124.1

(CH), 122.6 (CH), 1 15.0 (CH), 114.6 (CH, 2 carbons), 1 14.3 (CH), 1 13.8 (CH) 69.1 (CH2), 56.1 (CH), 49.0 (CH2), 16.8 (CH3); MS: m/z 51 1 [M+Na .

Example 10: Synthesis of (S)-2-(N-(4-((3-fluorobenzyI)oxy)benzyl)-2-nitrophenylsulfonamido) propanamide [(S)- compound 12]

To a solution of carboxylic acid (¾)-compound 1 1 (1 g, 2.04 mmol) and triethyl amine (0.34 mL, 2.4 mmol) in dry THF (20 mL), ethyl chloroformate (0.21 mL, 2.2 mmol) at 0 °C was added under nitrogen atmosphere. After 1 hour, ammonium hydroxide (25% w/v aqueous solution, 1.4 mL, 10.2 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, potassium carbonate (0.29 g, 2.1 mmol) was added and the reaction mixture was filtered, and washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/EtOAc, 50:50) to obtain sulfonamide (Sj-compound 12 as a colorless oil (0.9 g, 91%); [a]22D = -32.1 (c 1.2, CHC13); IR (CHC13): vmax 3472, 1961 , 161 1, 1592, 1542, 1511, 1449, 1371, 1304, 1243, 1 163, 1060, 1029, 895, 852, 684 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.43 (d, J = 7.1 Hz, 3H), 4.44 (d, J = 15.4 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.60-4.71 (q, J= 7.0 Hz, 1 H), 5.01 (s, 2H), 5.50 (bs, 1H), 6.31 (bs, 1H), 6.78 (d, J = 8.71 Hz, 2H), 6.98-7.1 1 (m, 2H), 7.15-7.22 (m, 3H), 7.31-7.45 (m, 2H), 7.59-7.64 (m, 3H);13C NMR (50 MHz, CDC13): 5C 172.3 (CO), 165.5 (C), 158.2 (C), 147.5 (C), 139.6 (C), 139.4 (C), 133.6 (CH), 131.7 (CH), 130.5 (CH, 2 carbons),130.3 (CH), 128.1 (C), 124.2 (CH), 122.7 (CH), 1 15.1 (CH), 1 14.7 (CH, 2 carbons),1 14.4 (CH), 1 13.9 (CH), 69.0 (CH2), 55.7 (CH), 48.3 (CH2), 14.9 (CH3); MS: m/z 510 [M+Na]+.

Example 11: Synthesis of (S)-2-((4-((3-fluorobenzyl)oxy) benzyl) amino) propanamide [(S)-compound of formula I]

To a solution of sulfonamide (S)- compound 12 (0.8 g, 1.64 mmol), potassium carbonate (0.56 g, 4.9 mmol) in dry DMF (10 mL), thiophenol (0.2 mL, 1.9 mmol) was added. The reaction mixture was vigorously stirred for 6 hours. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with ethylacetate (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 60:40) to yield (S) -compound of formula I as a colorless solid (0.43 g, 86% ); mp 207-09 °C; [a]22D = +3.89 (c 1.55, CHC13); IR (CHC13): vmax 3341, 2970, 2927, 2853, 1648, 1592, 1512, 1489, 1445, 1406, 1384, 1254, 1176, 1 137, 1030, 953, 928, 829, 680 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.34 (d, J = 6.9 Hz, 3H), 2.49 (bs, 2H), 3.19-3.30 (q, J = 6.8 Hz, 1H), 3.63-3.78 (dd, J = 19.4, 3.9 Hz, 2H), 5.05 (s, 2H), 5.85 (bs, 1H), 6.95 (d, J = 8.7 Hz, 2H), 7.00-7.06 (m, 1H), 7.13-7.24 (m, 4H), 7.29-7.40 (m, 1H). 13C NMR (50 MHz, CDC13): 8C 178.3 (CO), 165.4 (C), 157.7 (C), 139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 carbons), 122.7 (CH), 1 14.9 (CH, 2 carbons), 1 14.6 (CH), 1 13.9 (CH), 69.2 (CH2), 57.5 (CH), 51.9 (CH2), 19.6 (CH3); MS: m/z 302 [M]+, 325 [M+Na]+.

Example 12: Synthesis of (S)-Safinamide mesylate

To a stirred solution of (^-compound of formula I (0.1 g, 0.33 mmol) in ethylacetate (3 mL) at 70°C, methanesulfonic acid (0.02 mL, 0.33 mmol) was added and the reaction mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 35°C and the stirring was continued for additional 1 hour. The solvent was evaporated under reduced pressure and the residue was filtered through a short bed of basic alumina [eluent: EtOAc/MeOH; (95:5)] to obtain safinamide mesylate as a white solid (0.11 g, 90%); mp 209-10 °C [lit.7mp 210]; [a]22D = +9.6 (c 1.1, AcOH); {lit.7 [a] D = +12.9 (c 1.1, AcOH)} ee >98% [The ee of safinamide mesylate was determined by chiral HPLC analysis; Chiralcel OD-RH (150 x 4.6 mm) column; eluent:

Methanol/ Acetonitrile/Buffer-TEAP, pH 3 (20: 10:70); flow rate 0.5 mL/min (780 psi); detector: 224 nm] [f¾)-isomer tR = 1 1.55 min, (SJ-isomer tR = 12.94 min].

PAPERS

Synthesis2014, 46, 1751-1756.

N2-{4-[(3-Fluorobenzyl)oxy]benzyl}-L-alaninamide [(S)-14] BASE FORM
PhSH (0.2 mL, 1.9 mmol) was added to a solution of sulfonamide (S)-13 (0.8 g, 1.64 mmol) and K2CO3 (0.56 g, 4.9 mmol) in anhyd DMF (10 mL), and the mixture was vigorously stirred for 6 h. When the reaction was complete (TLC), H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (2 × 10), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography [silica gel, PE–EtOAc(60:40)] to give a colorless solid; yield: 0.43 g (86%); mp 207–09 °C;

[α]D22 +3.89 (c 1.55, CHCl3).
IR (CHCl3): 3341, 2970, 2927, 2853, 1648, 1592, 1512, 1489, 1445,1406, 1384, 1254, 1176, 1137, 1030, 953, 928, 829, 680 cm–1.

1H NMR (200 MHz, CDCl3): δH = 1.34 (d, J = 6.9 Hz, 3 H), 2.49 (brs, 2 H), 3.19–3.30 (q, J = 6.8 Hz, 1 H), 3.71 (dd, J = 19.4, 3.9 Hz, 2H), 5.05 (s, 2 H), 5.85 (br s, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.00–7.06 (m, 1 H), 7.13–7.24 (m, 4 H), 7.29–7.40 (m, 1 H).

13C NMR (50 MHz, CDCl3): δC = 178.3 (CO), 165.4 (C), 157.7 (C),139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 C), 122.7 (CH), 114.9 (CH, 2 C), 114.6 (CH), 113.9 (CH), 69.2 (CH2), 57.5 (CH),51.9 (CH2), 19.6 (CH3).

MS: m/z = 302 [M]+, 325 [M + Na]+.

(S)-Safinamide Mesylate (1)
MsOH (0.02 mL, 0.33 mmol) was added to a stirred solution of sulfonamide (S)-14 (0.1 g, 0.33 mmol) in EtOAc (3 mL) at 70 °C, and the mixture was stirred for 2 h. The temperature was then lowered to 35 °C, and the mixture was stirred for an additional 1 h. The solvent was evaporated under reduced pressure and the residue was filtered
through a short bed of basic alumina with elution by EtOAc–MeOH; (95:5) to give a white solid; yield: 0.11 g (90%);

mp 209–210 °C [Lit.7a 210 °C];

[α]D22 +9.6 (c 1.1, AcOH); {Lit.7 [α]D22+12.9 (c 1.1, AcOH)}.
Chiral HPLC: column: Chiralcel OD-RH (150 × 4.6 mm); eluent:MeOH–MeCN–buffer-TEAP (pH 3) (20:10:70); flow rate: 0.5mL/min (780 psi); detector: 224 nm [(R)-isomer: tR = 11.55 min;
(S)-isomer: tR = 12.94 min]; ee >98%.

7a) Pevarello, P.; Bonsignori, A.; Dostert, P.;
Heidempergher, F.; Pinciroli, V.; Colombo, M.; McArthur,
R. A.; Salvati, P.; Post, C.; Fariello, R. G.; Varasi, M. J. Med.
Chem. 1998, 41, 579.

PAPER

Chin. J. Pharmas.2012, 43, 161-163.

…………….BASE

…………MESYLATE

PAPER

J. Med. Chem. 2007, 50, 4909-4916.

(S)-2-[6-(3-Fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide (21). The title compound was obtained using the same procedure described for the synthesis of (R)-2-[6-(3-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]propionamide, starting from 6-(3-fluorobenzyloxy)-1,2,3,4-tetrahydroisoquinoline (0.24 g, 0.95 mmol) and (R)-2-amino-1-methyl-2-oxoethyl-2-nitrobenzenesulfonate (0.52 g, 1.9 mmol). After column chromatography
purification using 99:1 DCM/MeOH as eluent, 0.075 g (24% yield) of the title compound was obtained as a pure white solid. Mp 153- 154 °C. 1H NMR (CDCl3) ä 1.35 (d, 3H, J ) 7.0), 2.67-2.97 (m, 4H), 3.28 (q, 1H, J ) 7.0), 3.64 (d, 1H, J ) 14.2), 3.77 (d, 1H, J ) 14.2), 5.05 (s, 2H), 5.36 (br, 1H), 6.74 (d, 1H, J ) 2.5), 6.79 (dd, 1H, J ) 8.5, 2.5), 6.97 (d, 1H, J ) 8.5), 6.99-7.06 (m, 1H), 7.06-7.24 (m, 3H), 7.30-7.40 (m, 1H).

J. Med. Chem.1998, 41, 579-590.

Molecules 21 00793 g001 1024

References

  1. “Summary of the risk management plan (RMP) for Xadago (safinamide)” (PDF). European Medicines Agency. January 2015.
  2.  Fariello, RG (2007). “Safinamide”. Neurotherapeutics. 4 (1): 110–116. doi:10.1016/j.nurt.2006.11.011. PMID 17199024.
  3.  “EPAR Summary for the Public for Xadago” (PDF). European Medicines Agency. February 2015.
  4.  “After an odyssey of setbacks, FDA finally green-lights Newron’s Parkinson’s drug Xadago”. endpts.com. Retrieved 2017-03-21.
  5.  Lawrence, Janna (2015-01-19). “Safinamide recommended for approval as Parkinson’s disease therapy”. The Pharmaceutical Journal. Royal Pharmaceutical Society. Retrieved 2015-01-19.
  6.  Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  7.  H. Spreitzer (14 April 2014). “Neue Wirkstoffe – Safinamid”. Österreichische Apothekerzeitung (in German) (8/2014): 30.
  8. Klement, A (18 July 2016). “Xadago”. Österreichische Apothekerzeitung (in German) (15/2016): 10.
  9.  “Summary of Product Characteristics for Xadago” (PDF). European Medicines Agency. 24 February 2015.
  10. ^ Jump up to:a b Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, RG (2006). “Safinamide: From molecular targets to a new anti-Parkinson drug”. Neurology. 67 (7 Suppl 2): S18–23. doi:10.1212/wnl.67.7_suppl_2.s18. PMID 17030736.
  11.  Merck Serono: Vielversprechende Daten zur kognitiven Wirkung von Safinamid bei Parkinson im Frühstadium. (German) 8 June 2007.
  12.  Pevarello, P; Bonsignori, A; Caccia, C; Amici, R; Salvati, P; Fariello, RG; McArthur, RA; Varasi, M (1999). “Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants”. Bioorganic & Medicinal Chemistry Letters. 9 (17): 2521–2524. doi:10.1016/s0960-894x(99)00415-1.
  13. ^ Jump up to:a b Krösser, Sonja; Marquet, Anne; Gallemann, Dieter; Wolna, Peter; Fauchoux, Nicolas; Hermann, Robert; Johne, Andreas (2012). “Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects”. Biopharmaceutics & Drug Disposition. 33 (9): 550. doi:10.1002/bdd.1822. PMID 23097240.
  14. Jump up^ Pevarello, P; Bonsignori, A; Dostert, P; Heidempergher, F; Pinciroli, V; Colombo, M; McArthur, RA; Varasi, M (1998). “Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives”. Journal of Medicinal Chemistry. 41 (4): 579–590. doi:10.1021/jm970599m. PMID 9484507.
  15. Jump up^ “Wichtigste Ergebnisse der Langzeitstudie mit Safinamid als Begleittherapie zu Levodopa bei Parkinson im fortgeschrittenen Stadium” [Major results from the long-term study of safinamide as add-on to levodopa for late-stage Parkinson] (in German). Merck KGaA. 4 November 2010.
  16. Jump up^ Study of Safinamide in Early Parkinson’s Disease as Add-on to Dopamine Agonist (MOTION)
  17. Jump up^ Merck Returns Rights for Safinamide to Newron, 21 October 2011.
  18. Jump up^ “Information about FDA Refusal to File” (PDF). Newron. 29 July 2014.
  19.  “Information about FDA re-application” (PDF). Newron. 29 December 2014.
  20.  Chazot, PL (2007). “Drug evaluation: Safinamide for the treatment of Parkinson’s disease, epilepsy and restless legs syndrome”. Current Opinion in Investigational Drugs. 8 (7): 570–579. PMID 17659477.
Safinamide
Safinamide.svg
Clinical data
Trade names Xadago
AHFS/Drugs.com UK Drug Information
Pregnancy
category
  • Fetal malformations in animal studies[1]
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • UK:POM (Prescription only)
Pharmacokinetic data
Bioavailability 95%
Protein binding 88–90%
Metabolism Amidases, glucuronidation
Biological half-life 20–30 hrs
Excretion 76% renal, 1.5% faeces
Identifiers
Synonyms EMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
CAS Number
PubChemCID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.120.167
Chemical and physical data
Formula C17H19FN2O2
Molar mass 302.34 g/mol
3D model (Jmol)

//////////Xadago, safinamide,  Newron Pharmaceuticals, FDA 2017, Parkinson’s disease, 133865-89-1 , сафинамид , سافيناميد沙非胺, EMD-1195686, ZP-034, FCE-28073(R-isomer), PNU-151774E, NW-1015, FCE-26743

C[C@H](NCC1=CC=C(OCC2=CC=CC(F)=C2)C=C1)C(N)=O

Opicapone


STR1

Image result for Opicapone

Opicapone

2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide

BIA-9-1067; ONO-2370; BIA-91067
CAS No.923287-50-7

MF C15H10Cl2N4O6
MW: 411.9977

TRADE NAME (Ongentys®)

Approved EU 2016-06-24 BIAL PORTELA

PORTELA & CA. S.A. [PT/PT]; Av. Da Siderurgia Nacional, P-4745-457 S. Mamede do Coronado (PT)

LEARMONTH, David Alexander; (PT).
KISS, Laszlo Erno; (PT).
LEAL PALMA, Pedro Nuno; (PT).
DOS SANTOS FERREIRA, Humberto; (PT).
ARAÚJO SOARES DA SILVA, Patrício Manuel Vieira; (PT)

MOA:Catechol-O-methyl transferase (COMT) inhibitor

Indication:Parkinson’s disease (PD)

A COMT inhibitor used as adjunctive therapy for parkinson’s disease.

STR1

Opicapone was approved by European Medicine Agency (EMA) on Jun 24, 2016. It was developed and marketed as Ongentys® by Bial – Portela in EU.

Opicapone is a selective and reversible COMT inhibitor, used as adjunctive therapy for Parkinson’s disease.

Ongentys® is available as hard capsules, containing 25 mg and 50 mg of opicapone. The recommended dose is 50 mg, taken once a day at bedtime, at least one hour before or after levodopa combination medicines.

Catechol-O-methyltransferase (COMTa) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine to catecholic substrates such as endogenous catechol neurotransmitters(2)and xenobiotics including (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (l-Dopa), the gold standard drug for treatment of Parkinson’s disease (PD). Coadministration of a peripheral amino acid decarboxylase (AADC) inhibitor prevents breakdown of l-Dopa in the periphery by blocking enzymatic decarboxylation, and inhibition of COMT further improves its bioavailability by reducing the formation of 3-O-methyl-l-Dopa (3-OMD).

Abbreviations: COMT, catechol-O-methyltransferase; PD, Parkinson’s disease; AADC, amino acid decarboxylase; SAR, structure−activity relationship; ADMET, absorption, distribution, metabolism, excretion, toxicity; l-Dopa, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid; 3-OMD, 3-O-methyl-l-Dopa.

“First-generation” COMT inhibitors such as pyrogallol, tropolone, and gallic acid are poorly selective and have poor efficacy in vivo. “Second-generation” inhibitors are exemplified by tolcapone 1, entacapone 2,(13) and nebicapone (BIA 3-202) 3 . Structure−activity (SAR) studies exploring the position of the nitro group and various side-chain substituents have been reported. Subtle differences in the mode of COMT inhibition by 1are thought to be relevant in terms of efficacy. Entacapone 2 is a short-acting,peripherally selective inhibitor which is taken concomitantly with every dose of l-Dopa. Albeit the most widely marketed COMT inhibitor, the clinical efficacy of 2 has been questioned. Tolcapone 1 is a more potent, longer acting but nonselective inhibitor of both cerebral and peripheral COMT. Unlike2, clinical use of 1 is severely restricted due to its elevated hepatotoxicity risk, postulated to occur through uncoupling of oxidative phosphorylation. Nebicapone 3 possesses a longer duration of peripheral COMT inhibition than 2 and more limited access to the brain than 1, but due to limited clinical experience, firm conclusions concerning safety have not yet been established. Undoubtedly therefore, a requirement exists for improved COMT inhibitors to address the unmet medical needs of many PD patients.
Figure

 Chemical structures of tolcapone 1, entacapone 2, and nebicapone 3.

ChemSpider 2D Image | Opicapone | C15H10Cl2N4O6

Opicapone

A preferred method of treatment of Parkinson’s disease is the administration of a combination of levodopa and a peripherally selective aromatic amino acid decarboxylase inhibitor (AADCI) together with a catechol-O-methyltransferase (COMT) inhibitor. The currently employed COMT inhibitors are tolcapone and entacapone. However, some authorities believe that each of these COMT inhibitors have residual problems relating to pharmacokinetic or pharmacodynamic properties, or to clinical efficiency or safety. Hence, not all patients get most benefit from their levodopa/AADCI/COMT inhibitor therapy.

Favoured new COMT inhibitors were disclosed in L. E. Kiss et al, J. Med. Chem., 2010, 53, 3396-3411 (D1), WO 2007/013830 (D2) and WO 2007/117165 (D3) which are believed to have particularly desirable properties so that patients can benefit from enhanced therapy.

D1, D2 and D3 also disclosed methods of preparing the new COMT inhibitors. Those processes, although effective, would benefit from an increase in yields. Other benefits which would be appropriate include those selected from reduction in number of process steps, reduction in number of unit operations, reduction of cycle-times, increased space yield, increased safety, easier to handle reagents/reactants and/or increase in purity of the COMT inhibitor, especially when manufacture of larger quantities are envisaged. A process has now been discovered that proceeds via a new intermediate which is suitable for manufacture of commercially useful quantities of a particularly apt COMT inhibitor in good yield. Additional benefits occur such as those selected from a reduced number of process steps and number of unit operations, reduced cycle-times, increased space yield, increased safety, with easier to handle reagents/reactants, improved impurity profile and/or good purity.

CLINICAL

https://clinicaltrials.gov/show/NCT01851850

SYN1

Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

Laboratory of Chemistry
Laboratory of Pharmacology
Department of Research and Development, BIAL, À Avenida da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal
J. Med. Chem., 2010, 53 (8), pp 3396–3411
*To whom correspondence should be addressed. E-mail: Psoares.silva@bial.com. Phone: +351-22-9866100. Fax: +351-22-9866192.
Abstract Image
Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to l-Dopa therapy of Parkinson’s disease
2,5-Dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (37d). Compound 37d was synthesized by a similar procedure as described for 37a. Compound 36d (500 mg, 0.84 mmol) was reacted with BBr3 (1.05 g, 4.21 mmol) in dichloromethane (5 mL) at -78°C. Recrystallization from dichloromethane-ethanol afforded 37d (284 mg, 82%) as a yellow solid.
STR1
NMR (DMSO-d6):
1H : 11.07 (2H, br, OH), 8.11 (1H, d, J = 2 Hz, H6), 7.73 (1H, d, J = 2 Hz, H2), 2.66 (3H, s, H15),2.24 (3H, s, H14).
13C : 175.2 (C7), 164.5 (C8), 150.4 (C12), 148.7 (C3), 146.3 (C4), 139.4 (C13), 137.8 (C5), 134.1(C10), 131.1 (C11), 122.7 (C9), 116.6 (C2), 115.7 (C6), 112.7 (C1), 17.9 (C14), 16.5 (C15).
Elemental Analysis:
(C15H10Cl2N4O6) C, H, N, S: Calc: C, 43.60; H, 2.44; N, 13.56; Found: C, 44; H, 2.3; N, 13.6.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007013830&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

LEARMONTH, David Alexander; (PT).
KISS, Laszlo Erno; (PT).
LEAL PALMA, Pedro Nuno; (PT).
DOS SANTOS FERREIRA, Humberto; (PT).
ARAÚJO SOARES DA SILVA, Patrício Manuel Vieira; (PT)

PATENT

The present invention in one aspect provides 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4,oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene and salts thereof, that is the compound of the formula (I):

and salts thereof.

Most aptly the compound of formula (I) is unsalted. However, salts of the hydroxy group with metal ions such as the alkali or alkaline earth metals, particularly the sodium and potassium salts are provided as well as those of highly basic organic compounds such as guanidine or the like.

Particularly suitably the compound of formula (I) or its salt is provided in a form suitable for use as a chemical intermediate. This may be, for example, in a form at least 50% pure, in crystalline form, in solid form or in an organic solvent or the like.

The compound of formula (I) is useful as an intermediate in the preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol i.e. the compound of formula II):

The compound of formula (II) may also be referred to as opicapone or 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-[1,2,4]-oxadiazole-3-yl)-4,6-dimethylpyridine-1-oxide. Opicapone has been found to be more potent than tolcapone in inhibiting liver COMT both at 3 hours and 6 hours post oral administration to rats [ED50 in mg/kg, opicapone 0.87 at 3 hours and 1.12 at 6 hours as compared to tolcapone 1.28 at 3 hours and 2.08 at 6 hours]. Opicapone at a dose of 3 mg/kg was found to be more effective at inhibiting rat liver COMT with nearly complete inhibition occurring 2 to 6 hours post oral administration with only about 90% of enzyme activity recovered after 72 hours while tolcapone provided shorter duration of activity with about 84% recovery after only 9 hours. Both opicapone and tolcapone inhibit human recombinant S-COMT but opicapone has an inhibitory constant of 16pM being 10 fold lower than that for tolcapone. With respect to the desirable property of avoiding inhibition of COMT in the brain, opicapone following oral administration to the rat was found to be devoid of effect whereas tolcapone inhibited about 50% of enzyme activity over a period of 8 hours post administration.

Preparation 1

Cyanoacetamide (280g) was reacted with acetyl acetone (352.9g) in methanol (1015g) and morpholine (14.9g). The reaction was stirred under reflux at 65 °C until the reaction appeared complete. The resulting product suspension was filtered, washed with methanol and dried to provide the desired product about 97% yield.

Preparation 2

The product of Preparation 1 (159g) was suspended in acetonitrile (749.5g) and cooled to 0-5°C. Sulfuryl chloride (178.9g) was added and the reaction mixture warmed to room temperature and stirred until the reaction appeared complete.

The resulting suspension is cooled to 0-5°C and filtered. The solid was washed with acetonitrile, ethyl acetate and heptane. The product was then dried under vacuum at 50°C to yield the desired product (82%).

Preparation 3

Phosphoryl chloride (973.2g), tetramethylammonium chloride (67.3g) and compound of Preparation 2 (227.1g) were added to dichloromethane (500g). The suspension was heated to 85°C and stirred for 5 hours. Excess of phosphoryl chloride was removed by distillation in vacuo. The reaction mixture was cooled below 30°C and diluted with dichloromethane. The resulting solution was added to water (1350g) at room temperature and stirred for 30 minutes. The lower organic phase was separate and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with water and then treated with charcoal. The charcoal was filtered and a solvent swap to heptane was performed by distillation at atmospheric pressure. The solution was filtered at 50°C and then cooled to 30°C. On further cooling to 0°C

crystals were obtained. These were isolated by filtration, washed twice with heptane. After drying at 50°C the desired product was obtained typically at 88-91 % .

The above process was repeated with a reduction in dichloromethane during crystallisation and adding some methanol. The resulting plate-like crystals were more easily transferred for subsequent use.

Preparation 4a

Product of Preparation 3 (68.6g) and 1,10-phenanthroline monohydrate (0.9g) were suspended in methanol (240g) at room temperature. Water (518g) and a hydroxylamine solution (50% in water, 80.9g), were added and the mixture heated to 70-80°C and stirred for 5-6 hours. Water was added at 70-80 °C and the solution held for 1 hour to induce crystallization. Crystallization was completed by cooling to 15°C over 8 hours. The product was filtered off and washed twice with water and dried at 50°C under vacuum. The product was an off white to light yellow and the yield was 87.9% .

Preparation 4b

A suspension of 2,5-Dichloro-4,6-dimethyl-nicotinonitrile (45.0 kg) and 50% hydroxylamine (59.2 kg) in the presence of catalytic amount of 1,10-phenanthroline monohydrate (0.680 kg) in methanol / water (214 kg/362 kg) is heated to 70-80°C. The mixture is agitated at 70-80°C. Water (353 kg) is added slowly into the resulting solution while the temperature is maintained at > 79°C. The solution is cooled to 75 °C with stirring resulting in crystallization of (Z)-2,5-dichloro-N’-hydroxy-4,6-

dimethylnicotinimidamide. The suspension is further cooled to 20 °C, the solid is filtered off and the wet cake is washed with water (160 kg). (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide is dried under vacuum at max. 60°C until residual water level is max 0.15% (KF).

Example 1a

Preparation of 4-hydroxy-5-methoxy-3 nitrobenzoic acid

Vanillic acid (75g) was suspended in acetic acid (788g). The suspension was cooled to 10°C to 15°C and nitric acid (49g or 65% solution) was added over three hours at a rate which kept temperature between 10°C and 20°C. The resulting yellow orange was stirred for a further one hour at 18°C to 23°C. The suspension was filtered off, washed with acetic acid, then a mixture of acetic acid and water (1/2) and then water. Yield of 53% of a 87.9% pure product was obtained.

The above crude product was suspended in acetic acid and warmed to 105°C to 110°C until an orange brown solution is obtained. The solution was transferred to the crystallization vessel via a charcoal filter (or polish filtration) at a temperature above 85°C (optional step). The solution was then cooled to 80°C to 85°C. The mixture was stirred for one hour at 70°C to 80°C (optionally at 75°C) during which crystallization occurred. The product suspension was cooled to 20°C to 25°C for 17 hours or stirred for at least 12h at 20°C to 25 °C. The product suspension was filtered and washed with acetic acid, then acetic acid/ water (1/2) and finally water. The product was dried under vacuum at 50°C to 55°C. The yield of 70% corresponds to an overall yield of 44% for both parts of this preparation. The purity of the product assayed at 99.7% .

The preceding crystallization step is optional and the solution may be transferred to the crystallization vessel via polish filtration instead of via a charcoal filter.

The post crystallization suspension may be stirred for at least 12 hours at 20° C to 25 °C as an alternative to 17 hours.

Example 1b

Preparation of 4-hydroxy-5-methoxy-3 nitrobenzoic acid

A reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50°C in around 75 minutes. Temperature was set to 16°C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours.

The suspension was centrifuged whilst washed with 25 kg of acetic acid, 50 liter deionised water and 25 kg of acetic acid again. The wet crystalline material was suspended in 165 kg of acetic acid and heated at 91°C until complete dissolution. The solution was then cooled to 19.8°C and the mixture was allowed to stir for 1 hr. Centrifugation and washing with 15.2 kg acetic and 40 liter of deionised water was performed. The wet material was then dried in tray vacuum drier between 40-50°C until constant weight, for 72 hours. The dry material weight was 28.7 kg. The calculated yield was 45.4%.

Example 1c

Preparation of 4-h droxy-5-methoxy-3 nitrobenzoic acid

A suspension of vanillic acid (68.8 kg) in acetic acid (720 kg) is cooled to 17°C before an excess of a 65% nitric acid (44.0 kg) is added. After complete dosage of nitric acid the suspension is stirred for 2 hours. The suspension is filtered off and the wet cake is successively washed with acetic acid (80.0 kg), acetic acid/water (1:2 w/w – 105 kg) and finally water (80 kg – if necessary repeat). The solid is dried at 52°C for NMT 12 hours prior going to next step.

A suspension of the crude solid (650 kg) in acetic acid is warmed to 105 °C and stirred until complete dissolution of the crude solid. After polish filtration, the solution is cooled to 20°C over 3h resulting in crystallization and the suspension is stirred for 2h at 20°C. The solid is filtered off and the wet cake is successively washed with acetic acid (80 kg), acetic acid/water (1:2 w/w – 105 kg) and finally water (193 kg – if necessary repeat). 4-hydroxy-5-methoxy-3 nitrobenzoic acid pure is dried under vacuum at max. 55 °C until max 0.5% w/w residual acetic acid and max 0.2% w/w water is reached.

Example 2a

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoic acid

The process of Example la was scaled up to employ vanillic acid (375g) in acetic acid (3940g) to which was added nitric acid (65%, 245g) at 12°C over 3 hours followed by stirring for one hour. The overall yield was 40% of a 99.9% pure product.

Example 2b

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoic acid

Vanillic acid methyl ester (33g) and sodium nitrite (0.625g) are charged. Water (158mL) and 1,4-dioxane (158mL) are added at room temperature. The reaction mixture is heated to 40 °C. Nitric acid (65%) (15.75g) is added in the course of three hours and the resulting mixture is stirred for 4h after addition. The reaction mixture is sampled for completion.

The water/nitric-acid/dioxane azeotrope is distilled off in vacuum at 40 °C. The resulting product suspension is quenched by addition of sodium hydroxide solution (50% , 33.2 mL) and then stirred for 16h. The quench mixture is sampled for completion.

Then, HCl (18,5%, 70.2mL.) is added until the pH is below 1. The product is filtered off and washed with water (27.9mL). The product is then dried in vacuum at 50 °C. The overall yield was 81 % of a 97.3 % pure product.

Example 3a

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in dioxane (approx 4.5 vol) was treated with thionyl chloride (1.5 eq) and heated to 80°C. A clear solution formed at approximately 75 °C. The mixture was stirred for 3 hours at 80°C. Unreacted thionyl chloride was distilled off and after distillation the residue was cooled to 10°C.

Example 3 b

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in DCM (approx 3.4 vol) is treated with thionyl chloride (1.0 – 1.2 eq, for example 1.1 eq) and catalytic amount (0.011 eq) of DMF and the mixture is stirred for 16 h at 40°C. DCM is distilled off (approx 2.7 vol) and the residue is diluted with THF (approx 1.8 vol). The excess of thionylchloride is distilled off with THF/DCM and the residue after distillation is cooled to 10°C.

Example 3c

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0 – 1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10°C.

The amount of DCM may be approx 3.4 as an alternative to approx 4.5 vol.

The catalytic amount of DMF may be about 0.011 eq as an alternative to 0.0055 eq.

Example 3d

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

In a reactor 68 kg dichloromethane, 20 kg 5-nitro- vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2°C.

The mixture was heated to 40°C until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40°C then the mixture was cooled to 20-25 °C and the distillation was continued until dry under vacuum at 40°C.

The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in

Example 4d.

Example 3e

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of product of example 1C (4-hydroxy-5-methoxy-3 nitrobenzoic acid -160g, 1eq) in 1,4-dioxane (720mL, 4.5vol) is treated with thionyl chloride (169.8g, 103.7mL,1.5eq) and heated to 80°C. A clear solution is formed at approx. 75 °C. The mixture is stirred at 80 °C (3 hours). Unreacted thionyl chloride is distilled off and the residue after distillation is cooled to 10°C.

Example 4a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In this example the compound of formula (IV) is reacted with the compound of formula (V) to produce the compound of the formula (III).

Compound of formula (V) (1.24 eq) was suspended in 1,4-dioxane (approximately 4.5 vol) and the suspension cooled to 10°C. The acyl chloride (compound of formula (IV)) solution of Example 3a in 1,4-dioxane was added slowly maintaining the temperature below 20°C. A clear orange solution was formed. After complete addition, the reaction mixture was stirred at 20°C for one hour. Pyridine (approximately 8eq) was added and the reaction mixture heated slowly to 115°C. The mixture was stirred for 6 hours at 115°C and then cooled to 20°C.

The dioxane/pyridine was distilled off under vacuum at 70°C. The residue was kept at 80°C and ethanol (approx 8 vol) added to induce crystallization. The resulting yellow suspension was cooled to 0°C and stirred for two hours. The product was filtered off and washed with ethanol (2.5 vol) water (3.8 vol) and ethanol 2.5 vol). The product was dried under vacuum at 50 °C. Typical yields for this process are 82 to 85%.

In an optional variant, methanol was employed in place of ethanol to induce crystallization.

Example 4b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a different reactor, compound of formula (V) (1.1 eq) is dissolved in DM Ac (approx 5.8 vol) and the solution is cooled to 5°C. The benzoyl chloride solution of Example 3b in THF/DCM is then added slowly maintaining the temperature below 10°C. After complete addition, the reaction mixture is stirred at 20 ±5°C. Pyridine (1.3 to 1.6 eq, for example 1.5 eq) is charged and the reaction mixture is heated slowly to 110±5°C removing low boiling components by distillation. The mixture is stirred for additional 3 h at 110±5°C.

In a further reactor, concentrated HCl (23.8 eq) is diluted with water (approx. 8.5 vol) and cooled to 10 °C. The reaction mixture in pyridine is dosed slowly to diluted hydrochloric acid. After complete addition, the resulting suspension is stirred for additional 2 h and the solid is filtered off. The crude solid is washed once with water and pre-dried on funnel.

The crude solid is suspended in DCM (approx. 28.6 vol) and the suspension is heated to 40°C to reach a clear solution. Resulting solution is cooled to 20°C and extracted with water. After phase separation, the aqueous phase is re-extracted with DCM and combined organic phase are washed once with water. DCM is distilled off under vacuum followed by addition of ethanol. Resulting suspension is further distilled to reduce the amount of DCM, then cooled to 5°C and stirred for additional 2 h. Finally, the product is filtered off, washed once with cold ethanol and dried under vacuum at 45°C.

Example 4c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a second reactor, compound of formula (V) (1.1 eq) is dissolved in DMAc (approx. 7 vol) and the solution is cooled to 5°C. The benzoyl chloride solution of Example 3c in THF/DCM is added slowly maintaining the temperature below 10 °C. After complete addition, the reaction mixture is stirred at 20 ± 5°C for 30 min. Pyridine (6.9 to 7.3 eq, for example 7.14 eq) is charged and the reaction mixture is heated slowly to 110°C removing low boiling components by distillation. The mixture is stirred for additional 4 h at 110°C and cooled to 20°C.

In a third reactor an emulsion of diluted hydrochloric acid (prepared from cone. HCl (19.6 eq) and approx. 7.6 vol distilled water) and DCM (approx. 25.5 vol) is cooled to about 15 °C before the reaction mixture in pyridine is dosed slowly to the emulsion. After complete addition, the organic phase is separated and washed with water before DCM is distilled off under vacuum followed by addition of ethanol. The resulting suspension is further distilled to reduce the amount of DCM, then cooled to 5°C and stirred for additional 2 h.

Finally, the product is filtered off, washed once with cold ethanol and dried under vacuum at 45 °C.

Example 4d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

140 kg Ν,Ν-dimethyl acetamide was charged into the reactor. 24.2 kg of amidoxime of Preparation 4 was dissolved in N,N-dimethyl acetamide while stirring at 21°C. The solution was cooled to 5-10°C. The THF solution of Example 3d was introduced slowly into the reaction mixture, 1.5-2 hrs, while the internal temperature was maintained at max. 9.5°C by external cooling. When the addition was complete the external cooling

was stopped. The internal temperature was allowed to raise to 21 °C in an hour. After stirring for 30 minutes, pyridine 53.0 kg was added to the mixture, while the temperature was in the range of 22.4°C – 20.6°C. Heating was started and the internal temperature raised to 105-115°C. The mixture started to reflux for 3h while the internal temperature managed to 113°C by partial distillation of some THF. The reaction mixture was then cooled and introduced to a mixture of 220 kg concentrated HCl and 170 kg of deionised water while the internal temperature was maintained between 14-16°C. The reactor was rinsed with 10 kg of Ν,Ν-dimethylacetamide and 20 kg deionised water. The rinse liquid was run to the mixture. The suspension was then further cooled to 5-10°C and stirred for 1.5-2.0 hours. The product was centrifuged and was washed 80 kg deionised water. Crude wet weight of the product was 88.6 kg.

The crude wet product, was dissolved in 460 kg (340 L) dichloromethane at max 40°C. When dissolved the temperature was set to 20-30°C and 120 kg deionised water was added. The organic phase was separated, the inorganic phase was extracted with 80 kg dichloromethane. The organic phase of 460 kg, was then washed with 200 kg deionised water and the phases were separated. The inorganic phase was extracted with the 80 kg dichloromethane and the organic phases were unified. The organic phase obtained so was concentrated in vacuum at 35°C to 200-240 Liter, then 260 kg ethanol 96% was continuously added and the evaporation was continued to a final 200-240 liter volume. Then the mixture was cooled to 5-10°C and was allowed to stir for 3 hrs. Centrifuging, washing with 20 kg ethanol resulted in 35.4 kg wet product. Vacuum drying for 16 hours at 45°C gave 34.09 kg dry product. The yield was 79.9%.

Example 4e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a second vessel, (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotiriimidamide (201.2g, 1.24eq) is suspended in 1,4-dioxane (720mL, 4.5vol) and the suspension is cooled to 10°C. The residue of example 3e in 1,4-dioxane is added slowly maintaining the temperature below 20°C. A clear orange solution is formed. After complete addition, the reaction mixture is stirred at 20°C for 1 hour. Pyridine (483.7mL, 8eq) is then charged and the reaction mixture is heated slowly to 115°C. The mixture is stirred at 115°C for 6 hours. The solution is then cooled to 20°C. Dioxane/pyridine is distilled off.

After distillation, the pit is kept at 80 °C and ethanol (1.28L, 8vol) is added at this temperature to induce crystallization. The resulting yellow suspension is cooled to 75 °C and stirred for 1h at this temperature to allow crystal growth. The product suspension is then cooled to 0 °C and stirred for 2h at this temperature. The product is filtered off and washed subsequently with ethanol (400mL, 2.5vol), water (608mL, 3.8vol) and ethanol (400mL, 2.5vol). The product is dried under vacuum at 50°C until LOD is max 1% w/w.

Example 4f

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

A mixture of compound of formula (V) (11.7g, 50 mmol, 1.25eq), methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10g, 40 mmol, leq) and a catalytic amount of p-toluenesulfonic acid (0.76g, 4mmol, 0.1eq) in dimethyl acetamide was heated to 80°C. The reaction was followed by HPLC. After 23h, 6% of conversion was obtained.

Example 4g

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-y1]-2-hydroxy-3-methoxy-1-nitrobenzene

A mixture of compound of formula (V) (11.7g, 50 mmol, 1.25eq), methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10g, 40 mmol, 1eq) and a catalytic amount of aluminum chloride (0.53g, 4mmol, 0.1eq) in dimethyl acetamide was heated to 80°C. The reaction was followed by HPLC. After 20h, 10% of conversion was obtained.

Example 5a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

A solution of the product of Example 4a (24g) was dissolved in dichloromethane (388g) at 20-40°C. The yellow solution was cooled to 5°C and urea hydrogen-peroxide (UHP) (17.6g) and trifluoroacetic acid anhydride (37g) added and stirring continued for 12hr at 5°C. The reaction mixture was warmed to room temperature over one hour and stirring continued for a further five hours. The precipitate that formed was filtered off and washed with dichloromethane. The combined filtrates were diluted further with dichloromethane, all washed and concentrated at atmospheric pressure. Toluene was added and the resulting suspension concentrated under vacuum, to remove residual dichloromethane. Further toluene was added and the mixture checked to ensure less than 0.5% dichloromethane and less than 0.1% water was present. Formic acid was added to provide a 10-12% formic acid in toluene mixture. The resulting suspension was warmed to 90°C and stirred until complete dissolution of solid. Crude product was obtained by cooling the solution to 5-10°C until crystallization commenced. The suspension was agitated at 5-10°C until crystallization appeared complete. The solid was filtered off, washed with toluene and dried under a stream of nitrogen.

The crude product was suspended in 10-12% wt/wt solution of formic acid in toluene and warmed to 90°C until dissolution of the solid. The solution was cooled to 5°C and stirred at 5°C until crystallisation occurred. The solid was obtained by filtration and washed with toluene. This recrystallization was repeated until the product tested as containing less than 0.1 % of starting material. The pure product was dried under vacuum at 50°C.

Example 5b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4b (24g) in DCM (388g) at 20-40°C the yellow solution is cooled to 5°C before the temperature controlled addition of urea hydrogen peroxide complex (UHP)(17.6) and trifluoroacetic anhydride (TFAA) (37g). After addition of TFAA is complete stirring is continued for 12h at 5°C before the reaction mixture is warmed to room temperature (RT) within 1 h and stirring is continued for additional 5 h. The precipitate formed during the reaction is filtered and washed with DCM on the funnel filter. The combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure. DCM is replaced by toluene (170g) and the resulting suspension is concentrated again under vacuum to remove surplus DCM. Distillates are replaced by fresh toluene as before and the mixture is analyzed for residual water and DCM (Residual DCM after solvent switch max. 0.5%; residual water after solvent switch max. 0.1 %). Formic acid (24g) is charged resulting in an approx. 10-12 % w/w formic acid in toluene solvent mixture The resulting suspension is warmed to 90°C and stirred until compete dissolution of the solid is achieved. The crude product is crystallized by cooling of this solution to 5-10°C and subsequent agitation of the resulting suspension at 5-10°C. The solid is filtered of washed with toluene and then dried in a stream of nitrogen gas.

The crude product so obtained is suspended in an approx. 10-12 %w/w solution (176g) of formic acid in toluene. The suspension is warmed to 90°C and stirred until all product is dissolved. After cooling of this solution to 5°C and subsequent stirring at 5°C, crude product is isolated by filtration and subsequent washing of the wet product with toluene.

The re-crystallization of crude product is repeated (2 or more times). The pure product (11.8g) is dried at 50°C under vacuum.

Example 5c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4c (24g) in DCM (388g) at 20-40°C the yellow solution is cooled to 5°C prior to the temperature controlled addition of urea hydrogen peroxide complex (UHP) (17.6g) and trifluoroacetic acid anhydride (TFAA) (37g). After addition of TFAA is complete stirring is continued for 12h at 5°C before the reaction mixture is warmed to RT within 1 h and stirring is continued for additional 5 h. The precipitate formed during the reaction is filtered and the filter cake is washed with DCM. The combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure. DCM is replaced by toluene (170g) and the resulting suspension is concentrated again in vacuum in order to remove surplus DCM and water. Distillates are replaced by fresh toluene followed by addition of formic acid (24g). The resulting suspension is warmed to 80°C and stirring is continued in order to dissolve the solid. The product is crystallized by cooling of this solution to 5°C and subsequent agitation of the resulting suspension at 5°C. The solid is filtered, washed with toluene and then dried in a stream of nitrogen gas.

The product is suspended in a formic acid / toluene (18g/158g) mixture followed by warming of the reaction mixture to 80°C. After dissolution of the product the solution is cooled to 5°C whereby the product precipitates. After additional stirring at 5°C the suspension is filtered and the filter cake is washed with toluene.

The re-crystallization of the product is repeated. The product is used as a wet material in the next process step (12.1g product obtained if dried at max. 60°C).

Example 5d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yI]-2-hydroxy-3-mefhoxy-1-nitrobenzene

550 kg (420 L) Dichloromethane was charged into a reactor. 34 kg of product of example 4d was added to in a short period at 20°C internal temperature. The solution was cooled to 6.5°C then 24.9 kg urea hydrogen peroxide complex (UHP) was added over a period of 20-40 minutes between 5-10°C. Stirring was continued for additional 20 minutes between 6.5-7.5°C. Trifluoroacetic anhydride, 53 kg, was administered into the reaction mixture, starting and maintaining the temperature at 6-7°C over a period of 2-3 hours. When the administration was complete the mixture was stirred for additional 30 minutes. Then the internal temperature was allowed to rise to a maximum of 25°C over a period of 1.5 hours. The internal temperature was maintained between 20-25°C and the mixture was allowed to react for additional 18-20 hrs. The reaction mixture was centrifuged and the fuge was washed with 45 kg dichloromethane. To the separated dichloromethane solution 460 kg (350 L) dichloromethane and 190 kg deionised water was added. The mixture was stirred for 10 minutes and the phases were separated for 30 minutes. The organic phase was washed again with 2×190 kg deionised water and separated as previously. Evaporation of the unified organic solution at max 35 °C under vacuum was done to a final volume of 100-120 L. Then a total of 105 kg acetonitrile was administered into the system while the distillation was continued to keep the volume at 100-120 L. When complete an additional 170 kg (220 L) acetonitrile was added to the mixture at normal pressure. This suspension was heated to 70-80°C at normal pressure while dichloromethane was distilled off continuously. The mixture was then kept stirred for an hour. The suspension was cooled to 20-25°C and was stirred for an additional 30 minutes. The suspension was then centrifuged and was washed with 30 kg acetonitrile. The wet material, 29.7 kg, was vacuum dried for 16 hrs at 30°C. Dried product yield was 81.5%.

27.7 kg product, 240 kg toluene and 29.2 kg formic acid was charged into reactor then heated to 90°C for complete dissolution for 1 hour. Then the solution was cooled to 7°C and then the suspension was kept at 7°C for additional 2 hrs. If necessary seeding was applied with 3-5 grams of pure product. The suspension was then centrifuged for 1 hour whilst washing with 28 kg cold toluene. The product was suspended in 225 kg toluene and 27.2 kg formic acid was charged. The mixture then was heated to 90°C for complete dissolution for 1 hour. Then the solution was cooled to 20-25 °C, then the suspension was kept between 15-25°C for additional 2 hrs, seeded if necessary. The suspension then was centrifuged for 60 minutes whilst washed with 28 kg cold toluene. The recrystallization process may be repeated 2-3 more times.

Drying for 24 hrs at 38-41°C under vacuum was conducted until constant weight. This resulted in 16.34 kg (58.8%) dry material.

Example 5e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4e (150g) in DCM (2.43kg) at reflux, the yellow solution is cooled to 5°C prior to the temperature controlled addition of carbamide peroxide (UHP – urea hydrogen peroxide) ( 110g) and trifluoroacetic acid anhydride (TFAA) (155.1 ml in 4 portions within 2 hours). The mixture is stirred for 12h at 5°C then the reaction mixture is warmed to 25 °C over 1.5 hours and stirred for 5 hours. The precipitate formed during the reaction is filtered and the filter cake is washed with DCM (0.36 kg). The combined filtrates are warmed to 30°C and diluted with water (300g). 10% sodium hydroxide is added until pH= 4 is reached. The biphasic system is stirred for 10 minutes at 30°C and the mixture is then allowed to separate. The organic layer is then successively washed with a mixture water (750g) and 10% sodium hydroxide (7.5g) (until pH=4), 3.2% HCl solution (300g). DCM is distilled at atmospheric pressure and then replaced by toluene (1035g) applying vacuum (150mbar) and keeping internal temperature at 45°C. Formic acid (300g) and toluene (900g) are added keeping the internal temperature above 40°C. The resulting solution is distilled under vacuum (150 mbar, 45°C internal temperature) until distillation ceases. After seeding at 45°C, the slurry is stirred for 1 hour at 45°C then is cooled to 5°C over 2 hours. The suspension is stirred for at least 2 hours at 5°C and then filtered. The wet cake is washed with toluene (195g) and dried in a stream of nitrogen gas (Chemical purity of crude product min. 92 % area).

A suspension of crude product in formic acid (388g, 2wt) is warmed to 55°C and stirred until complete dissolution of the crude product. Toluene (1242g, 6.4wt) is added maintaining the internal temperature above 50 °C. The reaction is stirred at 150mBar and internal temperature 45 °C until distillation ceases. The vacuum and distillation is stopped and then seed is added at 45°C. The slurry is stirred for 1 hour at 45°C and cooled to 5°C in 2 hours. The resulting suspension is stirred for at least 2 hours at 5°C then filtered. The wet cake is washed with toluene (260g, 1.34wt). The wet cake is collected and charged into the reactor. This procedure is repeated at least twice until 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-y1]-2-hydroxy-3-methoxy-1-nitrobenzene level max is 0.1 % (a/a) prior to dry at 25°C max under vacuum.

Example 6

Example 5a was repeated on a larger scale employing product of Example 3 (82g), dichloromethane (1325g), urea peroxide (60.1g) and trifuoroacetic acid anhydride

(128g).

Example 7a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

(Π)

Product of Example 6 (15g) was suspended in N-methyl pyrrolidone (NMP) (131.5g) and cooled to 5°C. Aluminium chloride (6.2g) and pyridine (12g) were added while maintaining the temperature at 5°C. After the addition of pyridine was complete the reaction mixture was warmed to 60 °C and maintained for 2 hours. After confirmation that less than 0.5 starting material remained, the reaction mixture was cooled, and aqueous HCl (water 233g, HCl 123g, 37%) added. The resulting yellow solid was isolated by suction filtration. The resulting wet product was washed with water and propan-2-ol (67g) and dried under vacuum.

Optionally, the crude product was suspended in ethanol (492g) and warmed to reflux. The suspension was stirred for 1 hour under reflux and then cooled to room temperature. The solid was obtained by filtration, washed with ethanol and dried under vacuum at 50°C. A typical yield of 85% was achieved.

If desired either the final ethanol crystallised material or the initially produced product after washing with propan-2-ol may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-y1)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

An approx. 11 % w/w suspension of the product of example 5b (20g) in NMP (150g) is cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (8g) and pyridine (15.3g). After addition of pyridine is complete the reaction mixture is warmed to 60°C followed by additional 2 h reaction time. After complete conversion of the product of example 5b the reaction mixture is cooled before an aqueous diluted hydrochloric acid (water 293g, HCl 177g, 34%) is dosed. By addition of the hydrochloric acid, crude product precipitates from the NMP/water matrix as a yellow solid which is isolated by suction filtration. The resulting wet product is washed with water and 2-propanol in a replacement wash followed by drying of the wet crude product under vacuum.

The crude product is suspended in ethanol (282g) followed by warming of the mixture to reflux. The suspension is stirred for 1 h at reflux conditions followed by cooling to room temperature. The product is isolated by filtration of the suspension. The wet product is washed with ethanol and subsequently dried in vacuo at approx 50°C (typically weight corrected yield was 85%).

The product (20g) is suspended in formic acid (725g) before the resulting suspension is warmed to max. 67°C. Stirring is continued until complete dissolution of the product is achieved. The hot solution is filtered and the filtrate is cooled to 40 – 45°C before the product is precipitated first by concentration of the solution to approx. 40% (v/v) of its original volume followed by addition of the anti solvent 2-propanol (390g). After addition of 2-propanol is finished the resulting suspension is kept at 55-60°C for crystal ripening followed by cooling to RT and filtration. The filter cake is washed with 2-propanol followed by drying of the material at max. 58°C until loss on drying (LOD) max. 0.5% . Typically, a yield of 97-98% was obtained.

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

A suspension of the product of example 5c (20g) or of example 6 (20g) in NMP (153g) is cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (8.2g) and pyridine (15.4g). After addition of pyridine is complete the reaction mixture is warmed to 60°C followed by additional 3 h reaction time. After complete conversion of the product of example 5c or of example 6 the crude product is

precipitated by a temperature controlled addition of an aqueous hydrochloric acid solution (water 296g, HCl 179g, 34%). Filtration of the solid followed by washing of the wet filter cake with water and 2-propanol yields a crude product wet material which is immediately dissolved in formic acid (536g). After polish filtration the filtrate is concentrated under vacuum followed by addition of the anti-solvent 2-propanol (318g). After aging of the resulting suspension at 55-60°C the suspension is cooled to RT and filtered. The wet filter cake is washed with 2-propanol. The wet product is dried under vacuum at max. 58°C until LOD max. 0.5%. The yield was in the range of 70-95%

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

132 kg (147 L) N-methylpyrrolidone was charged into a 1000 L reactor. 16.3 kg of product of example 5d was then added. The suspension was cooled to 5-7°C and 6.5 kg of sublimed aluminium chloride was added in portions keeping the internal temperature between 5-10°C. The mixture was stirred for 10 minutes then 12.6 kg pyridine was added maintaining the internal temperature between 5-10°C. The mixture was warmed with water in the jacket to 20-25°C and the mixture was stirred for 30 minutes. Then the mixture is heated to 58-62 °C and reacted for around 2 hours. In a separate reactor a mixture of 240.5 kg deionised water and 146.4 kg concentrated HCl was mixed. This was cooled to 15-20°C. The reaction mixture from the demethylation was introduced into the diluted hydrochloric acid between 20-25°C. Optionally, 51.2 kg dichloromethane was added to the suspension, stirred for 30 minutes and was centrifuged, washed with 60 kg deionised water and 20 kg isopropanol. Drying gave 15.9 kg of product.

The product was suspended in 185.3 kg of ethanol. The mixture was then stirred at 78°C for an hour, then cooled to 20-25°C and stirred for 1 hour. The suspension was then centrifuged and the filtercake was washed with 44.5 kg ethanol, 96% . The solid material was dried at 50°C in vacuum in a stainless steel tray drier. 14.35 kg (90.3% yield) dry product was obtained.

A reactor was charged with 317.2 kg formic acid and dry product. The mixture was heated to 65 °C until all the solid dissolves. The hot solution was then filtered to an empty 1000 L reactor, was rinsed with 20 kg formic acid, then the formic acid solution was distilled partially off under vacuum to around 80-100L. 260 kg isopropanol was then introduced at 50-60°C and stirred for 30-35 minutes. The mixture was then cooled to 20-25°C with water in the jacket and was allowed to stir min 2 hours. The suspension was then centrifuged and was washed with 25 kg isopropanol. The wet material was removed from the fuge and was transferred into vacuum tray drier and was dried until constant weight under vacuum at 45-50°C resulting in 13.6 kg product, with a yield of 95.3% .

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

A suspension of product of Example 5e (34.1kg) in N-Methyl pyrrolidone (NMP) (182kg) is warmed to 50 °C until dissolution and then cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (9.8 kg) and pyridine (18.2kg). After addition of pyridine is complete the reaction mixture is warmed to 60°C and stirred for at least 2 hours. The reaction mixture is cooled to 10-16°C (e.g. 11, 13, 15°C) before an aqueous diluted hydrochloric acid (4M solution, 283L) is dosed maintaining the temperature below 25 °C. During the addition of the hydrochloric acid the crude product is precipitated from the NMP/water matrix as a yellow solid. The yellow solid is filtered and subsequently washed with water (179kg), 2-propanol (105kg). The wet solid is dried under vacuum at 55°C.

A suspension of wet product (25.1kg) in formic acid (813kg) is warmed to max. 67°C. The mixture is stirred at 67°C until complete dissolution of the product is achieved. The hot solution is filtered and the filtrate is cooled to 40 – 45°C before the product is precipitated first by concentration of the solution to approx. 40% (v/v) of its original volume followed by addition of the anti solvent 2-propanol (380kg). After addition of 2-propanol the resulting suspension is stirred at 55-60°C for crystal ripening followed by cooling to RT and filtration. The filter cake is washed with 2-propanol (38kg) and then dried at max. 58°C until LOD max. 0.5%). The product may be milled (for example using the method of Example 8).

Example 8

Micronization of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol with MC JETMILL® type 200 milling equipment (micronization through spiral jet mills)

Equipment:

Mill: MC JETMILL® 200

Dosing unit: K-Tron T 35

Cyclone: type 600

Each micronization trial was performed on at least 2 kg of 5-(3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

The following working parameters have been defined for the micronization:

Feed rate range: 24.0-48.0 kg/h (200-400 g/30sec.)

Mill pressure range: 3.0-4.0 bar

Venturi pressure range: 3.0-4.0 bar; preferably the Venturi pressure is the same as the mill pressure

Using the above equipment and working parameters the microparticles of 5-(3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol comply with the following particle size specification (particle size determined by optical microscopy): D10 (EDC) is not less than 4 or 5 μm (for example not less than 5 μm), the D50 (EDC) is 10-45 or 15-30 μm (for example 15-30 μm) and the D95 (EDC) is not more than 60 or 70 μm (for example not more than 60 μm).

Example 9 (Figure 5)

2,5-Dichloro-4,6-dimethyl-nicotinonitrile is reacted with hydroxylamine in the presence of catalytic amounts of 1,10-phenanthroline monohydrate to yield the aldoxime (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide which represents the first coupling partner towards the synthesis of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene. The second coupling partner 5-nitro-vanillic acid pure is synthesized from vanillic acid by nitration with 65 % nitric acid followed by re-crystallization of the crude 5-nitro-vanillic acid intermediate from acetic acid. The convergent assembly of the oxadiazole moiety in 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene is achieved by first activation of 5-nitro-vanillic acid as its acid chloride and subsequent coupling with the aldoxime (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide. Cyclisation of the initially formed coupling product is achieved thermally to give the oxadiazole moiety by elimination of water. The reaction

mixture of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene, after ring closure reaction, is concentrated and product isolated from 1,4-dioxane/ethanol mixture in one step. Oxidation of the pyridine ring to the corresponding aryl-N-oxide (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene) is achieved with trifluoroperoxoacetic acid which is formed in situ from UHP (Urea hydrogen peroxide complex) and trifluoroacetic acid anhydride. Unreacted 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene is subsequently removed from 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene by repeated re-crystallisation from formic acid/toluene. The analogue intermediate 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene pure with a level of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene below 0.10 %area is converted to 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol crude analogue by ether cleavage in the presence of a stoichiometric amount of aluminium chloride and pyridine. After completion of the reaction, the crude product is isolated by precipitation with an aqueous hydrochloric acid followed by dissolution of the precipitate in formic acid. After polish filtration of the resulting solution and partial solvent switch from formic acid to isopropanol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol is crystallized from the resulting formic acid/IPA crystallization matrix and finally optionally milled to the desired particle size.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012107708

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007117165

scheme 1 depicts example how to produce a compound of the general formula IIB from a compound of the general formula IVB:

iii.

HB IVB
Scheme 1. Reagents: i. Piperidine, ethanol, reflux; ii. SO2Cl2, CCl4, reflux; iii. POCI3, 120 0C, 18 h; iv. 50% H2NOH, MeOH-H20, 1.25 mol % 1,10-phenanthroline hydrate.

The following reaction scheme 2 depicts an example how to produce certain compounds of general formula III:

I, R8 = methyl III, R8 = R9 = H
iv.
R9 = H

III, R8 = R9 = benzyl

Scheme 2. Reagents: i. 65 % HNO3, AcOH; ii. 48 % HBr (aq), 140 0C; iii. MeOH, HCl(g); iv. BnBr, K2CO3, CH3CN, reflux; v. 3N NaOH, MeOH/H2O.

The following reaction scheme 3 depicts an example how to produce the compound A, by activation of a compound according to general formula III followed by cyclisation involving condensation with a compound according to formula HB, dehydration and deprotection of the methyl residue protecting the hydroxyl group;

0C

compound A

Cited Patent Filing date Publication date Applicant Title
WO2007013830A1 Jul 26, 2006 Feb 1, 2007 Portela & Ca. S.A. Nitrocatechol derivatives as comt inhibitors
WO2007117165A1 Apr 10, 2007 Oct 18, 2007 Bial – Portela & Ca, S.A. New pharmaceutical compounds
WO2008094053A1 * Oct 10, 2007 Aug 7, 2008 Bial-Portela & Ca, S.A. Dosage regimen for comt inhibitors
WO2012107708A1 * Oct 21, 2011 Aug 16, 2012 Bial – Portela & Ca, S.A. Administration regime for nitrocatechols
US20100168113 * Apr 10, 2007 Jul 1, 2010 David Alexander Learmonth Pharmaceutical Compounds
Reference
1 * [1,2,4]-oxadiazolyl nitrocatechol derivatives“, IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 3 May 2012 (2012-05-03), XP013150541, ISSN: 1533-0001
2 * KISS L E ET AL: “Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase“, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 53, no. 8, 22 April 2010 (2010-04-22), pages 3396 – 3411, XP002594266, ISSN: 0022-2623, [retrieved on 20100324], DOI: 10.1021/JM1001524
3 L. E. KISS ET AL., J. MED. CHEM., vol. 53, 2010, pages 3396 – 3411
4 * RASENACK N ET AL: “MICRON-SIZE DRUG PARTICLES: COMMON AND NOVEL MICRONIZATION TECHNIQUES“, PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, NEW YORK, NY, US, vol. 9, no. 1, 1 January 2004 (2004-01-01), pages 1 – 13, XP009055393, ISSN: 1083-7450, DOI: 10.1081/PDT-120027417

REFERENCES

1: Bicker J, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. A new PAMPA model using an in-house brain lipid extract for screening the blood-brain barrier permeability of drug candidates. Int J Pharm. 2016 Jan 30. pii: S0378-5173(16)30072-2. doi: 10.1016/j.ijpharm.2016.01.074. [Epub ahead of print] PubMed PMID: 26836708.

2: Devos D, Moreau C. Opicapone for motor fluctuations in Parkinson’s disease. Lancet Neurol. 2015 Dec 22. pii: S1474-4422(15)00346-4. doi: 10.1016/S1474-4422(15)00346-4. [Epub ahead of print] PubMed PMID: 26725545.

3: Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P; Bi-Park 1 investigators. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2015 Dec 22. pii: S1474-4422(15)00336-1. doi: 10.1016/S1474-4422(15)00336-1. [Epub ahead of print] PubMed PMID: 26725544.

4: Rascol O, Perez-Lloret S, Ferreira JJ. New treatments for levodopa-induced motor complications. Mov Disord. 2015 Sep 15;30(11):1451-60. doi: 10.1002/mds.26362. Epub 2015 Aug 21. Review. PubMed PMID: 26293004.

5: Gonçalves D, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. Development of a liquid chromatography assay for the determination of opicapone and BIA 9-1079 in rat matrices. Biomed Chromatogr. 2016 Mar;30(3):312-22. doi: 10.1002/bmc.3550. Epub 2015 Aug 17. PubMed PMID: 26147707.

6: Ferreira JJ, Rocha JF, Falcão A, Santos A, Pinto R, Nunes T, Soares-da-Silva P. Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson’s disease. Eur J Neurol. 2015 May;22(5):815-25, e56. doi: 10.1111/ene.12666. Epub 2015 Feb 4. PubMed PMID: 25649051.

7: Bonifácio MJ, Torrão L, Loureiro AI, Palma PN, Wright LC, Soares-da-Silva P. Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat. Br J Pharmacol. 2015 Apr;172(7):1739-52. doi: 10.1111/bph.13020. Epub 2015 Jan 20. PubMed PMID: 25409768; PubMed Central PMCID: PMC4376453.

8: Kiss LE, Soares-da-Silva P. Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility. J Med Chem. 2014 Nov 13;57(21):8692-717. doi: 10.1021/jm500572b. Epub 2014 Sep 2. PubMed PMID: 25080080.

9: Rocha JF, Falcão A, Santos A, Pinto R, Lopes N, Nunes T, Wright LC, Vaz-da-Silva M, Soares-da-Silva P. Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. Eur J Clin Pharmacol. 2014 Sep;70(9):1059-71. doi: 10.1007/s00228-014-1701-2. Epub 2014 Jun 14. PubMed PMID: 24925090.

10: Rocha JF, Santos A, Falcão A, Lopes N, Nunes T, Pinto R, Soares-da-Silva P. Effect of moderate liver impairment on the pharmacokinetics of opicapone. Eur J Clin Pharmacol. 2014 Mar;70(3):279-86. doi: 10.1007/s00228-013-1602-9. Epub 2013 Nov 24. PubMed PMID: 24271646.

11: Bonifácio MJ, Sutcliffe JS, Torrão L, Wright LC, Soares-da-Silva P. Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor. Neuropharmacology. 2014 Feb;77:334-41. doi: 10.1016/j.neuropharm.2013.10.014. Epub 2013 Oct 19. PubMed PMID: 24148813.

12: Gonçalves D, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. An HPLC-DAD method for the simultaneous quantification of opicapone (BIA 9-1067) and its active metabolite in human plasma. Analyst. 2013 Apr 21;138(8):2463-9. doi: 10.1039/c3an36671e. PubMed PMID: 23476919.

13: Rocha JF, Almeida L, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ, Wright LC, Nunes T, Soares-da-Silva P. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013 Nov;76(5):763-75. doi: 10.1111/bcp.12081. PubMed PMID: 23336248; PubMed Central PMCID: PMC3853535.

14: Almeida L, Rocha JF, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ, Wright LC, Nunes T, Soares-da-Silva P. Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7. PubMed PMID: 23248072.

15: Palma PN, Bonifácio MJ, Loureiro AI, Soares-da-Silva P. Computation of the binding affinities of catechol-O-methyltransferase inhibitors: multisubstate relative free energy calculations. J Comput Chem. 2012 Apr 5;33(9):970-86. doi: 10.1002/jcc.22926. Epub 2012 Jan 25. PubMed PMID: 22278964.

16: Gonçalves D, Alves G, Soares-da-Silva P, Falcão A. Bioanalytical chromatographic methods for the determination of catechol-O-methyltransferase inhibitors in rodents and human samples: a review. Anal Chim Acta. 2012 Jan 13;710:17-32. doi: 10.1016/j.aca.2011.10.026. Epub 2011 Oct 20. Review. PubMed PMID: 22123108.

17: Kiss LE, Ferreira HS, Torrão L, Bonifácio MJ, Palma PN, Soares-da-Silva P, Learmonth DA. Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase. J Med Chem. 2010 Apr 22;53(8):3396-411. doi: 10.1021/jm1001524. PubMed PMID: 20334432.

////////BIA-9-1067,  ONO-2370,  BIA-91067, 923287-50-7, Opicapone, Catechol-O-methyl transferase, COMT inhibitor, Parkinson’s disease, PD, BIA 9-1067,  BIA 91067,  BIA-91067,  BIA91067, EU 2016

OC1=CC(C2=NC(C3=C(Cl)[N+]([O-])=C(C)C(Cl)=C3C)=NO2)=CC([N+]([O-])=O)=C1O

Istradefylline


Istradefylline.svg

Istradefylline, KW-6002

(Nouriast®) Approved

A selective adenosine A2A receptor antagonist used to treat Parkinson’s disease.

KW-6002

CAS No. 155270-99-8

Istradefylline; 155270-99-8; KW-6002; KW 6002; 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione; (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione;

Molecular Formula: C20H24N4O4
Molecular Weight: 384.42896 g/mol

Istradefylline (KW-6002) is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.

Istradefylline.png

Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.

Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.

PATENT

US5484920A

http://www.google.co.in/patents/US5484920

PAPER

http://www.sciencedirect.com/science/article/pii/S0960894X13003983

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80°C, ...

Scheme 1.

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80 °C, 2 h, 83%; (ii) sodium nitrite, 50% acetic acid, 60 °C, 15 min, 86%; (iii) sodium dithionite, NH4OH solution (12.5% (w/v)), 60 °C, 30 min, 98%; (iv) SOCl2, toluene, 75 °C, 2 h, 97%; (v) pyridine, DCM, rt, 16 h, 66%; (vi) HMDS, cat. (NH4)2SO4, CH3CN, 160 °C, microwave, 5 h, 100% followed by (vii) MeI, K2CO3, DMF, rt, 2 h, 75%.

Chemical structures of some important adenosine receptor antagonists and their ...

Synthesis

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (2)3

  1. J. Hockemeyer; J. C. Burbiel; C. E. Müller, J. Org. Chem. 2004, 69, 3308.

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione (1.11 g, 3.00 mmol) was taken up in dimethylformamide (15 mL) and potassium carbonate (828 mg, 6.00 mmol). To the milky white mixture was added iodomethane (468 µL, 7.50 mmol) and it was allowed to stir at room temperature for 2 h. The mixture was then filtered and washed with water (100 mL), leaving the title compound 2 as a pale yellow solid which was dried in the oven at 110 °C (863 mg, 75%), mp: 192 °C (lit.3 191 °C). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 – 4.04 (m, 5H), 3.95 (s, 3H), 3.93 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.0 (C), 150.8 (C), 150.4 (C), 150.3 (C), 149.2 (C), 148.2 (C), 138.1 (CH), 128.6 (C), 121.2 (CH), 111.2 (CH), 109.5 (CH), 109.3 (CH), 108.0 (C), 55.98 (CH3), 55.97 (CH3), 38.4 (CH2), 36.3 (CH2), 31.5 (CH3), 13.43 (CH3), 13.39 (CH3). LCMS: m/z (ESI 20 V) 385.2 (MH+, 100).

PATENT

http://www.google.com/patents/CN103254194A?cl=en

Specific synthetic route is as follows:

Figure CN103254194AD00071

the above reaction is a synthetic Parkinson’s disease clinical drug KW-6002 against a yield of 83%.

Example 26 (a new synthetic method for anti-Parkinson’s disease in clinical drug KW-6002):

In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 – two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6

• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187

6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.

Figure CN103254194AD00162

 In contrast, KW-6002 is a new drug to treat Parkinson’s disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:

Figure CN103254194AD00171

The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002’s. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.

PATENT

http://www.google.com/patents/CN104744464A?cl=en

itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 – methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.

Figure CN104744464AD00031

 itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson’s disease patients to improve motor function, for the treatment of Parkinson’s disease and Parkinson’s disease improve early dyskinesia.

The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.

Example 1 Preparation of theophylline itraconazole  Example

Figure CN104744464AD00051

ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen – purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.

References

  1.  Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.

Reference:1. EP0590919A1.

2. US5484920A.

3. US5543415A.

4. J. Org. Chem. 2004, 69, 3308-3318.

5. Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352.

6. Bioorgan. Med. Chem. 2003, 11, 1299-1310.

7. Bioorg. Med. Chem. Lett. 2013, 23, 3427-3433.

8. Chinese Journal of Pharmaceuticals 2010, 41, 241-243.

9. JP0940652A.

10. Org. Biomo. Chem. 2010, 8, 4155-4157.

1. Chem. Commun. 2012, 48, 2864-2866.

2. CN103254194A.

CN104744464A * Nov 15, 2013 Jul 1, 2015 南京华威医药科技开发有限公司 Istradefylline crystal forms
  1. Istradefylline
    Istradefylline.svg
    Systematic (IUPAC) name
    8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
    Identifiers
    CAS Number 155270-99-8 Yes
    ATC code none
    PubChem CID 5311037
    IUPHAR/BPS 5608
    ChemSpider 4470574 Yes
    UNII 2GZ0LIK7T4 Yes
    KEGG D04641 Yes
    ChEMBL CHEMBL431770 Yes
    Chemical data
    Formula C20H24N4O4
    Molar mass 384.429 g/mol

//////Istradefylline, KW-6002, Nouriast®, Approved, A selective adenosine A2A receptor antagonist, Parkinson’s disease,

O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC

PNQ 370 useful in treating Parkinson’s disease from ADVINUS


2016

 

 


PNQ 370

Advinus Therapeutics Ltd

Adenosine A2a receptor antagonist

for treating disease or disorder susceptible to improvement by antagonism of A2A receptor.

Advinus Therapeutics is investigating PNQ-370, presumed to be lead from a series of small molecule therapeutics including PD-2 and PD-3, as adenosine A2a receptor antagonist, for the potential treatment of Parkinson’s disease . In November 2012, this drug was in preclinical development .

KEEP WATCHING THIS POST AS I ARRIVE AT THE STRUCTURE…………..

 

str1

ONE OF THE ABOVE OR SIMILAR

INTRODUCTION

The effects of adenosine are mediated through at least four specific cell membrane receptors so far identified and classified as Ai, A2A, A2B and A3 belonging to G protein-coupled receptor family. The Ai and A3 receptors down-regulate cellular cAMP levels through their coupling to G protein, which inhibit adenylate cyclase. In contrast, A2A and A2B receptors couple to G protein that activate adenylate cyclase and increase intracellular levels of cAMP. Through these receptors, adenosine regulates the wide range of physiological functions.

Advances in understanding the role of adenosine and its receptors in physiology and pathophysiology, as well as new developments in medicinal chemistry of these receptors have identified potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson’s Disease (PD).

Happy new year wishes 2016

Happy New Year from Google!

Happy New Year from Google!

 

 

Movement disorder constitutes a serious health problem, especially among the elderly. These movement disorders can often be the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson’s disease, Huntington’s chorea and Wilson’s disease. Tremor, rigidity, akinesia and postural changes are four classic symptoms of Parkinson’s disease, it is also associated with depression, dementia and overall cognitive decline. Parkinson’s disease has a prevalence of 1 per 1000 of the total population and increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurons in the substantia nigra and the subsequent reductions in the interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson’s disease. About 80% of cells from the substantia nigra can be destroyed before the clinical symptoms of Parkinson’s disease become apparent

PD is a progressive, incurable disorder with no definite preventive treatment, although drugs are available to alleviate the symptoms and/or slow down the progress of the disease. Current therapy is based on dopamine replacement therapy, the most common drug treatments being dopaminomimetic agents, including L-DOPA, a dopamine precursor, as well as direct or indirect dopamine receptor agonists. L-DOPA is the mainstay in the treatment of PD, but because of tolerance problems and a wide range of adverse reactions, including involuntary movements and vomiting, a strong demand for new therapies exists. Among the various strategies, A2A AR blockers are considered a potential approach to treatment of the disease. Within the brain A2A ARs are richly expressed in the striatum, nucleus accumbens, and olfactory tubercle. A coexpression of A2A with D2 dopamine receptors has been reported in the GABAergic striatopallidal neurons where adenosine and dopamine agonists exert antagonistic effects in the regulation of locomotor activity. Activation of A2A ARs in striatopallidal neurons decreases the affinity of D2 receptors for dopamine, antagonizing the effects of D2 receptors.

The negative interaction between A2A and D2 receptors is at the basis of the use of A2A antagonists as a novel therapeutic approach in the treatment of PD. (Pharmacol. Ther. 2005, 105, 267). The recent discovery that the A2A can form functional heteromeric receptor complexes with other Gprote in-coupled receptors such as D2 and the mGlu5 receptors has also suggested new opportunities for the potential of A2A antagonists in PD. (J. Mol. Neurosci. 2005, 26, 209).

A2A knockout (KO) mice transient focal ischemia caused less neuronal damage in comparison to their wild-type (WT) littermates (J. Neurosci. 1999, 19, 9192.). Therefore, it seems that tonic activation of A2A ARs may be responsible for dangerous signal during injury, in contrast to the neuroprotective effects induced by endogenous Al activation. Recently, selective inactivation or reconstitution of A2A ARs in bone-marrow cells revealed their contribution to the development of ischemic brain injury (J.F. Nat. Med. 2004, 10, 1081) Blockade of A2A ARs has recently been implicated in the treatment of movement disorders such as Parkinson’s disease (Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Life Sci. 1994, 55, 61-65).

The potential utility of A2A AR antagonists in the treatment of Parkinson’s disease has been reviewed (CNS drugs, 1998, 10, 31 1-320). One advantage of A2A AR antagonist therapy is that the underlying neurodegenerative disorder may also be treated ((Ann. N. Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 3048). In particular, blockade of A2A AR function confers neuroprotection against MPTP-induced neurotoxicity in mice (Neurosci. 2001, 21, RC143).

Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system manifested by cognitive and memory deterioration, a variety of neuropsychiatric symptoms, behavioral disturbances, and progressive impairment of daily life activities. Recent research suggests that adenosine receptors play important roles in the modulation of cognitive function. Epidemiological studies have found an association between coffee (a nonselective adenosine receptor antagonist) consumption and improved cognitive function in AD patients and in the elderly. Long-term administration of caffeine in transgenic animal models showed a reduced amyloid burden in brain with better cognitive performance.

Advinus’ Pharma Development Bangalore operation, located on a 8-acre campus with 220,000 sq ft of modern facilities, offers end-to-end pre-clinical to early clinical development platform for pharma product development

Antagonists of adenosine A2A receptors mimic these beneficial effects of caffeine on cognitive function. Neuronal cell cultures with amyloid beta in the presence of an A2A receptor antagonist completely prevented amyloid beta-induced neurotoxicity. These findings suggest that the adenosinergic system constitutes a new therapeutic target for AD, and caffeine and A2A receptor antagonists may have promise to manage cognitive dysfunction in AD (Curr Neuropharmacol. 2009 September; 7(3): 207-216).

High expression of A2A ARs has been found in platelets, leukocytes, vascular smooth muscle, and endothelial cells with important implications in the regulation of inflammatory responses. It is now well established that stimulation of the A2A AR in immune cells induces anti-inflammatory effects, mostly due to its ability to increase cAMP levels, which has strong immunosuppressive effects (Trends Immunol. 2005, 26, 299). Stimulation of A2A ARs inhibits neutrophil adherence to the endothelium, degranulation of activated neutrophils and monocytes, plus superoxide anion generation. A2A ARs have been recently defined as sensors and terminators of proinflammatory activities. The strongest evidence for the key role of A2A in inflammation is derived by the elegant study using mice deficient in A2A ARs (Nature 2001, 414, 916).

The state-of-the-art facility in Pune, Advinus Drug Discovery, develops its own drug candidates to out-license them at preclinical or clinical stages

In this model the lack of A2A subtype leads to increased tissue inflammation and damage, thus suggesting a negative and nonredundant regulatory role for the A2A AR. This model permits one to appreciate that adenosinergic regulation of immune cells is fundamental in normal physiological control of inflammation in vivo in spite of the fact that other Gs-protein-coupled receptors and cAMP elevating ligands are present, such as cathecolamines, prostaglandins, dopamine, and histamine (Trends Immunol. 2005, 26, 299). Interestingly, the A2A AR has been demonstrated to be involved in promotion of wound healing and angiogenesis in healing wounds (Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 289, R283).

Moreover, it plays an active role in the pathogenesis of dermal fibrosis, suggesting a role for antagonists as novel therapeutic approach in the treatment and prevention of dermal fibrosis in diseases such as scleroderma (Arthritis Rheum. 2006, 54, 2632) as well as hepatic fibrosis (Br. J. Pharmacol. 2006 Aug; 148(8): 1 144-55). Studies also suggest that A2A receptor antagonists may be beneficial for social memory impairment and hypertension (Behav Brain Res. 2005 Apr 30;159(2):197-205), sepsis (J Immunol. 2006 May 1 ; 176(9): 5616-26), spinal cord injury and neuroprotection (J Neuroinflammation. 201 1 Apr 12;8:31), retinopathy (IVOS, Jan. 2000, vol. 41 (1), 230-243, depression (Neurology. 2003 Dec 9;61(1 1 Suppl 6):S82-7), narcolepsy and other sleep related disorders (Prog Neurobiol. 2007 Dec;83(5):332-47), attention-deficit hyperactivity disorder (ADHD) (Behav Pharmacol. 2009 Mar;20(2): 134-45; Clinical Genetics (2000), 58(1), 31-40 and references therein),

Dr Rashmi Barbhaiya, CEO & Managing Director

… Dr Rashmi Barbhaiya, CEO & Managing Director and Dr Kasim Mookthiar, Chief Scientific Officer and SVP, Drug Discovery, Advinus Therapeutics …

 

Antagonists of the A2A receptor are potentially useful therapies for the treatment of addiction. Major drugs of abuse (opiates, cocaine, ethanol, and the like) either directly or indirectly modulate dopamine signaling in neurons particularly those found in the nucleus accumbens, which contain high levels OfA2A adenosine receptors. Dependence has been shown to be augmented by the adenosine signaling pathway, and it has been shown that administration of an A2A receptor antagonist redues the craving for addictive substances (“The Critical Role of Adenosine A2A Receptors and Gi βγ Subunits in Alcoholism and Addiction: From Cell Biology to Behavior”, by Ivan Diamond and Lina Yao, (The Cell Biology of Addiction, 2006, pp 291-316) and “Adaptations in Adenosine Signaling in Drug Dependence: Therapeutic Implications”, by Stephen P. Hack and Macdonald J. Christie, Critical Review in Neurobiology, Vol. 15, 235-274 (2003)). See also Alcoholism: Clinical and Experimental Research (2007), 31(8), 1302-1307.

A2A receptors may be beneficial for the treatment or prevention of disorders such as a movement disorder, for example, Parkinson’s disease or progressive supernuclear palsy, Restless leg syndrome, nocturnal myoclonus, cerebral ischaemia, Huntington’s disease, multiple system atrophy, corticobasal degeneration, Wilson’s disease or other disorders of basal ganglia which results in dyskinesias, post traumatic stress disorder. See for example WO200013682, WO200012409, WO2009156737, WO20091 1442, WO2008121748, WO2001092264, WO2007038284, WO2008002596, WO20091 1 1449, WO20091 1 1442, WO2008121748, WO2009156737, WO2003022283, WO2005044245, WO2008077557, WO20091 1 1449, WO2009705138, WO20091 1 1442, WO2007035542, WO20080870661, WO2008070529, WO20051 16026, WO2009055548, WO2007133983, WO2010045006, WO2010045015, WO2010045008 WO2009015236.

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9B4D4A1C3A9C0C5ACBBBA119D16D32E2.wapp2nC?docId=WO2012038980&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

centre: Mr Ratan Tata, Chairman, Tata Sons, flanked by Dr Rashmi Barbhaiya (left), Managing Director and CEO, Advinus, and Mr R. Gopalakrishnan, …

ONE EXAMPLE………..

str1

COMPD A1
MF C26 H31 N9 O4
2H-​[1,​2,​4]​Triazolo[5,​1-​i]​purin-​2-​one, 5-​amino-​8-​(2-​furanyl)​-​1,​3-​dihydro-​3-​[2-​[4-​[4-​(2-​methoxyethoxy)​phenyl]​-​1-​piperazinyl]​ethyl]​-​1-​methyl-
mw 533.58
cas 1367365-26-1
Molecular Formula: C26H31N9O4
Molecular Weight: 533.58224 g/mol
SCHEMBL10252679.pngA1

5-amino-8-(furan-2-yl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one

WO2012038980

Example Al :

5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one

 

5-Amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-

5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one

 

Step-1 : 2-[(2,5-Diamino-6-chloro-pyrimidin-4-yI)amino]ethanol

A mixture of 4,6-dichloropyrimidine-2,5-diamine (28g, 156mmol), ethanolamine (18ml, 312mmol) and ethanol (250ml) were heated at 100-1 10 °C for 16 hours. The mixture was cooled and solvent was removed. To the residue methanol (100ml) was added and stirred for 20 minutes. The solid was filtered off to obtain 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (22.0g, 70%).

‘H MR(400MHz, DMSO d6): δ 3.36-3.40 (m, 2H); 3.50-3.54 (m, 2H); 3.88 (bs, 2H); 4.74 (t, J=5.6Hz, 1H); 5.63 (bs, 2H); 6.51 (t, J=5.6Hz, 1H)

Step-2: 2-Amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one

A mixture of 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol obtained in step 1 (l O.Og, 49.26mmol) in acetonitrile (400ml) were cooled to 0 °C. To this reaction mixture K2C03 (20.39gm, 147.7mmol) and 4-nitrophenyl chloroformate (19.8g, 98.52mmol)was added and stirred at 25-27 °C for 24 hours. This reaction mixture was filtered and washed with acetonitrile (300ml) and diethyl ether (300ml) respectively. Solid obtained was dried to obtain crude 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one as a yellow solid. Small amount of crude material was purified by column chromatography to obtain pure product. ‘HNMR(400MHz, DMSO d6): δ 3.61-3.66 (m, 2H); 3.72-3.75 (m, 2H); 4.85 (t, J=6Hz, 1H); 6.60 (s, 2H); 1 1.21 (s, 1 H)

Step-3: 2-Amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one

A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one obtained in step 2 (13g, 56.7mmol) , K2C03 (1 1.5g, 84mmol), methyl iodide (12g, 85.15mmol) and DMF (130ml) were stirred at 25-30 °C for 16 hours. The reaction mixture was concentrated and purified by column chromatography using 60-120 silica gel and 4% methanol in DCM as an eluent to obtain 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one (8g, 58%) as an off white solid.

‘HNMR(400MHz, DMSO d6): δ 3.42 (s, 3H); 3.65 (t, J=5.6Hz, 2H); 3.78 (t, J=5.6Hz, 2H); 4.85 (t, J=5.6Hz, 1H); 6.69 (bs, 2H).

Step-4: 2-Amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyI-purin-8-one

A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one obtained in step 3 (8g, 32.9mmol) , Hydrazine hydrate (16ml ,32.9mmol) and ethanol (300ml) were heated at 100-1 10 °C for 16 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (7g, 89 %) as an off white solid.

‘HNMR(400MHz, DMSO d6): δ 3.37 (s, 3H); 3.58-3.61 (m, 2H); 3.71 (t, J=6Hz, 2H); 4.29 (bs, 2H); 4.87 (t, J=5.6Hz, 1H), 6.00 (bs, 2H); 7.63 (s, 1H).

Step-5: N’-[2-Amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide

2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (4.5g, 18.18mmol) obtained in step 4, 2-furoic acid (2.53g, 22.5mmol), HOBT (2.53g, 18.8 mmol) and N-methylmorpholine were taken in dimethylformamide (40ml). l-Ethyl-3(3′-dimethylaminopropryl)carbodiimide hydrochloride (EDCI.HCl) (5.4g, 28.2mmol) was added to the reaction mixture and stirred at 25-27 °C for 14 hours. The reaction mixture was evaporated and residue was purified by column chromatography to obtain N’-[2-amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide (5.3g, 84%) as an off white solid.

‘HNMR (400MHZ, DMSO d6): δ 3.43 (s, 3H); 3.59-3.63 (m, 2H); 3.74 (t, J=6Hz, 2H); 4.88 (t, J=5.6Hz, 1H); 5.98 (bs, 2H); 6.67 (bs, 1H); 7.25 (d, J=3.2Hz, 1H); 7.90 (s, 1H); 8.35 (s, 1H); 10.28 (s, lH).

Step-6: 5-Amino-8-(2-furyl)-3-(2-hydroxyethyl)-l-methyl-[l^,4]triazolo[5,l-flpurin-2-one

A mixture of N’-[2-amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide obtained in step 5 (5.3g, 15.9mmol), Ν,Ο-bistrimethylsilylacetamide (27ml, 1 1 1.4mmol) and hexamethyldisilazane (83ml, 397mmol) were heated at 1 10-120 °C for 16 hours. The reaction mixture was quenched with methanol (100ml) and water (100ml) and organic volatiles were evaporated. The solid obtained was filtered off and washed with water (30ml) followed by diethyl ether (100ml) to obtain 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-l-methyl-[l,2,4]triazolo[5,l-f]purin-2-one (3.50g, 71%) as an off white solid.

‘HNMR (400MHZ, DMSO d6): δ 3.56 (s, 3H); 3.67-3.70 (m, 2H); 3.84-3.87 (m, 2H); 4.88 (t, J=5.6Hz, 1H); 6.73 (bs, 1H); 7.20 (bs, 1H); 7.79 (bs, 2H); 7.94 (bs, 1H).

Step-7: 2-[5-Amino-8-(2-furyl)-l-methyl-2-oxo-[l,2,4]triazolo[5,l-fJpurin-3-yl]ethyl 4-methylbenzenesulfonate

A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-l -methyl-[l,2,4]triazolo[5, l-fJpurin-2-one obtained in step 6 (3.5g, l lmmol), p-toluene sulphonylchloride (5.2 g, 27mmol) were taken in pyridine (30ml)and stirred at 25-27 °C for 16 hours. To the reaction mixture hexane (100ml) was added and solid obtained was filtered off and washed with water (100ml) followed by hexane (100ml) to obtain 2-[5-amino-8-(2-furyl)-l-methyl-2-oxo-[l,2,4]triazolo[5, l-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1g, 78%) as a brown solid. ‘HNMR (400MHz, DMSO d6): δ 2.02 (s, 3H); 3.49 (s, 3H); 3.99 (t, J=4.8Hz, 2H); 4.71 (t, J=4.8Hz, 2H); 6.73-6.75 (m, 1H); 7.01 (d, J=8Hz, 2H); 7.23 (d, J=3.2Hz, 1H); 7.41 (d, J=8.4Hz, 2H); 7.78 (bs, 2H); 7.96 (d, J=1.2Hz, 1H).

Step-8: : 5-Amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methyl-[l,2,4]triazolo[5,l-f)purin-2-one

A mixture of 2-[5-amino-8-(2-furyl)-l-methyl-2-oxo-[l ,2,4]triazolo[5, l-f]purin-3-yl]ethyl 4-methylbenzenesulfonate obtained in step 7 (0.25g, 0.533mmol), l-[4-(2-Methoxy-ethoxy)-phenyl]-piperazine (0.188g, 0.799mmol) and DIPEA (0.27ml, 1.599mmol) were taken in DMF (5ml) and stirred at 80 °C for 16 hours. To the reaction mixture water (100ml) was added and solid obtained was filtered off. The crude product was purified by column chromatography to obtain 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one (0.135g, 47%) as an off white solid

‘HNMR (400MHz, DMSO d6): δ 2.60 (bs, 4H); 2.68 (t, J=6.4Hz, 2H); 2.96 (bs, 4H); 3.29 (s, 3H); 3.56 (s, 3H); 3.59-3.62 (m, 2H); 3.94-4.00 (m, 4H); 6.71 -6.73 (m, 1H); 6.79-6.86 (m, 4H); 7.19 (dd, J=3.2Hz, 1.2Hz, 1H); 7.80 (bs, 2H); 7.94 (bs, 1H).

 

ANOTHER……..

Example Gl: 5-Amino-l-ethyl-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-[l,2,4]triazolo[5,l-i]purin-2-one

Step-1 : 2-Amino-6-chloro-7-ethyl-9-(2-hydroxyethyl)purin-8-one

(Procedure is same as step-3 in example Al)

‘HNMR (400MHz, DMSO d6): δ 1.21 (t, J=7.2Hz, 3H); 3.64 (s, 2H); 3.78 (t, J=6Hz, 2H);

3.92 (q, J=7.2Hz, 2H); 4.92 (bs, I H); 6.7 (bs, 2H).

Step-2 : 2-Amino-7-ethyl-6-hydrazino-9-(2-hydroxyethyl)purin-8-one

(Procedure is same as step-4 in example Al)

‘ HNMR (400MHz, DMSO d6): δ 1.07 (t, J=6.8Hz, 3H); 3.59 (q, J=6Hz, 2H); 3.72 (t, J=6Hz,

2H); 3.91 (q, J=6.8Hz, 2H); 4.32 (bs, 2H); 4.86 (t, J=5.6Hz, IH); 5.99 (bs, 2H), 7.55 (bs, IH).

Step-3: N’-[2-Amino-7-ethyl-9-(2-hydroxyethyl)-8-oxo-purin-6-yl]furan- 2carbohydrazide (Procedure is same as step-5 in example Al)

Crude product was used in next step

Step-4: 5-Amino-l-ethyI-8-(2-furyl)-3-(2-hydroxyethyl)-[l,2,4]triazolo[5,l-flpurin-2-one

(Procedure is same as step-6 in example Al)

‘H MR (400MHZ, DMSO d6): δ 1.34 (t, J=7.2Hz, 3H); 3.67 (q, J=5.6Hz, 2H); 3.84 (t, J=5.6Hz, 2H); 4.01 (q, J=7.2Hz, 2H); 4.87 (t, J=6Hz, IH); 6.70 (bs, IH); 7.17 (d, J=2.8Hz, I H); 7.18 (bs, 2H); 7.92 (bs, IH).

Step-5: 2-[5-Amino-l-ethyl-8-(2-furyl)-2-oxo-[l,2,4]triazoIo[5,l-f|purin-3-yl]ethyl 4- methylbenzenesulfonate (procedure is same as step-7 in example Al)

lHNMR (400MHz, DMSO d6): δ 1.35 (t, J=7.2Hz, 3H); 2.00 (s, 3H); 3.95-4.00 (m, 4H); 4.47 (bs, 2H); 6.74 (s, IH); 7.00 (d, J=7.6Hz, 2H); 7.22 (s, IH); 7.42 (d, J=7.6Hz, 2H); 7.78 (bs, 2H); 7.97 (bs, IH).

Step-6: 5-Amino-l-ethyl-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyi]piperazin-l- yl]ethyl]-[l,2,4]triazolo[5,l-f]purin-2-one (procedure is same as step-8 in example Al)

HNMR(400MHz, DMSO d6): δ 1.35 (t, J=7.2Hz, 3H); 2.60 (bs, 4H); 2.68 (t, J=6.8Hz, 2H); 2.95 (bs, 4H); 3.28(s, 3H);3.61 (t, J=4.4Hz, 2H); 3.94-4.04 (m, 6H); 6.72 (dd, J=2Hz, 3.6Hz, I H); 6.78-6.85 (m, 4H); 7.19 (d, J=3.2Hz, IH); 7.81(bs, 2H); 7.94 (s, IH).

 

Representative compounds of the present disclosure were tested and had micromolar to nanomolar activity.

 

str1A1 ABOVE

 

str1

A7 ABOVE

str1

A9 ABOVE

str1

A13 ABOVE

 

A31 ‘HNMR (400MHz, DMSO d6): δ 2.62 (bs,4H); 2.68 (t, J=6.8Hz, 2H); 2.85 (bs, 4H); 3.28 (s, 3H); 3.57 (s, 3H); 3.59-3.62 (m, 2H); o 3.95 (t, J=6.8Hz, 2H); 4.01-4.04 (m, 2H);

5-Amino-3-[2-[4-[2-fluoro-4-(2- 6.66-6.68 (m, 1H); 6.72 (dd, J=2 Hz,3.6Hz, methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-8- 1H); 6.79 (dd, J=2.8Hz, 14Hz, 1H); 6.92 (t, (2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f|purin-2- J=9.6Hz, 1H); 7.19 (d, J=3.2Hz, 1 H); 7.93 one (bs, 2H); 7.93-7.94 (m, 1H).

 

 

A31 ABOVE

A32 HNM (400MHz, DMSO d6): δ 2.59 (bs,

4H); 2.68(t, J=6.4Hz, 2H); 3.27(t, J=4.8Hz, 4H); 3.56 (s, 3H); 3.96 (t, J=6.4Hz, 2H);

0 6.72(dd, J=2Hz, 3.6Hz, 1H); 6.99 (d, J=8.8Hz,

4-[4-[2-[5-Amino-8-(2-furyl)-l-methyl-2-oxo- 2H); 7.19 (d, J=3.6Hz, 1H);7.56 (d, J=8.8Hz, [ 1 ,2,4]triazolo[5, 1 -f]purin-3-yl]ethyl]piperazin- 2H); 7.80 (bs, 2H); 7.93 (bs, lH).

l-yl]benzonitrile

 

A32 ABOVE

 

A36 ‘HNMR(400MHz, CDCI3): δ θ.09 (d,

J=4.4Hz, 2H); 0.50 (d, J=6.8Hz, 2H); 0.82- 0.89 (m, 1H); 2.24 (d, J=6.0Hz, 2H): 2.52- 2.72 (m, 8H); 2.80 (t, J=6.4Hz, 2H); 3.76 (s,

5-Amino-3-[2-[4-(cyclopropylmethyl)piperazin- 3H); 4.07 (t, J=6.8Hz, 2H); 5.89 (bs, 2H); l -yl]ethyl]-8-(2-furyl)-l-methyl- 6.61 (bs, 1H); 7.22 (d, J=2.4Hz, 1H); 7.64 (s, [ 1 ,2,4]triazolo[5, 1 -f]purin-2-one 1H).

 

A36 ABOVE

A38 ‘HNMR(400MHz, CDCI3): δ 2.62 . (t,

J=4.4Hz, 4H); 2.79 (t, J=6.4Hz, 2H); 2.81 (s, 6H); 3.22 (t, J=4.4Hz, 4H): 3.77 (s, 3H); 4.06 (t, J=6.8Hz, 2H); 5.74 (bs, 2H); 6.60 (dd,

4-[2-[5-Amino-8-(2-fiiryl)- 1 -methyl-2-oxo- J=2.0Hz, 3.2Hz, 1H); 7.24 (d, J=3.6Hz, 1H);

[ 1 ,2,4]triazolo[5, 1 -f]purin-3-yl]ethyl]-N,N- 7.65 (s, 1H).

dimethy l-piperazine- 1 -sulfonamide

 

 

A38 ABOVE

A39 ‘HNMR(400MHZ, DMSO d6): δ 1.89-1.94

im, 1H); 2.09-2.18 .(m, 1 H); 2.60 (bs, 4H); 2.67 (t, J=6.4Hz, 2H); 2.96 (bs, 4H); 3.56 (s, 3H); 3.69-3.85 (m, 4H); 3.95 (t, J=6.4Hz,

2H); 4.89 (bs, 1H); 6.72 (dd, J=2.0, 3.2Hz,

5-Amino-8-(2-furyl)-l -methyl-3-[2-[4-(4- 1H); 6.78 (d, J=9.2Hz, 2H); 6.85 (d, J=9.2Hz, tetrahydrofuran-3-yloxyphenyl)piperazin- 1 – 2H): 7.20 (d, J=3.2Hz, 1 H); 7.80 (bs, 2H); yl]ethyl]-[l ,2,4]triazolo[5,l-f]purin-2-one

7.93 (s, 1H).

 

A39 ABOVE

A42 ‘HNMR(400MHz, CDCI3): δ

2.26 (s,3H); 2.94-2.97 (m, 6H); 3.72 (s, 2H); 3.75 (s, 3H); 4.17 (t, J=6.4Hz, 2H); 5.74 (bs, 2H); 6.59 (dd, J=1.6Hz, 3.6Hz, 1H);7.13 (s, J=3.6Hz, IH); 7.21-7.24 (m, IH); 7.63 (s,

5-Amino-8-(2-furyl)-l-methyl-3-[2-(3-methyl- IH); 8.20 (bs, IH),

7,8-dihydro-5H- 1 ,6-naphthyridin-6-yl)ethyl]- [ 1 ,2,4]triazolo[5, 1 -f]purin-2-one

 

A42 ABOVE

A57 HNMR(400MHz, DMSO d6): δ 2.95 (t,

J=8Hz, 2H); 3.52 (s, 3H); 3.69 (s, 3H ), 3.97 (t, J=8Hz, 2H); 6.71 (dd, J=2Hz, 3.6Hz, I H );

5-Amino-8-(2-furyl)-3-[2-(4- 6.80 (dd, J=2Hz, 6.8Hz, 2H); 7.10 (d, methoxyphenyl)ethyl]- 1 -methyl- J=8.8Hz, 2H); 7.18 (dd, J=0.8Hz, 3.2Hz, I H );

[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one 7.80 (bs, 2H), 7.94 (dd, J=lHz, 2Hz, I H ).

 

A57 ABOVE

A58 HNMR(400MHz, DMSO d6): δ 2.61 (bs,

4H); 2.68 (bs, 2H); 3.05(bs, 4H); 3.57 (s, 3H ), 3.96 (bs, 2H); 6.72 (bs, IH); 6.92 (d, J=8Hz, 2H); 7.01 (d, J=10Hz, 2H );7.03(d, J=148Hz, IH); 7.19 (bs , 1 H); 7.80 (bs, 2H); 7.94 (s,

5-amino-3-[2-[4-[4- IH).

(difluoromethoxy)phenyl]piperazin-l-yl]ethyl]- 8-(2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fjpurin- 2-one

 

A58 ABOVE

A62 O ‘HNMR (400MHz, DMSO d6): δ 0.66-0.70

(m, 4H); 1.90-1.94 (m, lH); 2.41 (bs, 4H); 2.65 (t, J=6Hz, 2H); 3.38 (bs, 2H); 3.56 (bs, 5H); 3.93 (t, J=6.4 Hz, 2H); 6.71 (bs, 1H );

5-Amino-3-[2-[4- 7.19 (d, J=2.4Hz, 1H); 7.79 (bs, 2H); 7.93 (bs,

(cyclopropanecarbonyl)piperazin- 1 -yl]ethyl]-8- 1H).

(2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fjpurin-2- one

 

A62 ABOVE

A63 ‘HNMR (400MHz, DMSO d6): δ 0.07-0.10

(m, 2H); 0.40-0.44 (m, 2H); 0.88-0.94 (m,lH); 2.21 (d, J=6.4Hz, 2H); 2.41-2.45 (m, 4H); 2.64 (t, J=6.4Hz, 2H); 3.38 (bs,4H); 3.56

5-Amino-3-[2-[4-(2- (s, 3H); 3.93 (t, J=6.4Hz, 2H); 6.72 (dd, cyclopropylacetyl)piperazin-l -yl]ethyl]-8-(2- J=2Hz,3.6 Hz, 1H); 7.19-7.20 (m, 1H); 7.80 fury 1)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fJpurin-2- (bs, 2H); 7.93 (d, J=0.8 Hz, 1H).

one

 

A63 ABOVE

str1

 

C1 ABOVE

E1 ABOVE

 

D3 ABOVE

G1 ABOVE

Image loading...G2

 

Image loading...H2

 

Image loading...M1

 

Image loading...M2

 

Image loading...

M3

Image loading...

M6

 

ETC AS IN TABLE……………..

 

 

 

 

 

Dr Kasim Mookthiar, CSO & Executive VP (Drug Discovery),
Dr Nimish Vachharajani, Senior VP & Head (Pharmaceuticals & Agrochemical Development),

 

 

 

 

 

 

 

 

 

/////////

n21c(nc4c(c1nc(n2)c3occc3)N(C(N4CCN5CCN(CC5)c6ccc(cc6)OCCOC)=O)C)N

CN1C2=C(N=C(N3C2=NC(=N3)C4=CC=CO4)N)N(C1=O)CCN5CCN(CC5)C6=CC=C(C=C6)OCCOC

 

TEVA’S CEP 1347, KT 7515 a MAP3K11 (MLK3) inhibitor potentially for the treatment of Parkinson’s disease.


str1

 

 

 

 

 

 

CEP-1347; KT-7515

(9S,10R,12R)-5-16-Bis[(ethylthio)methyl]-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester

9,12-Epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, 5,16-bis((ethylthio)methyl)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-, methyl ester, (9S-(9alpha,10beta,12alpha))-

METHYL (15S,16S,18S)-10,23-BIS[(ETHYLSULFANYL)METHYL]-15-METHYL-3-OXO-28-OXA-4,14,19-TRIAZAOCTACYCLO[12.11.2.1(1)?,(1)?.0(2),?.0?,(2)?.0?,(1)(3).0(1)?,(2)?.0(2)?,(2)?]OCTACOSA-1(26),2(6),7(27),8(13),9,11,20(25),21,23-NONAENE-16-CARBOPEROXOATE

3,9-Bis(etsm)-K-252a; CEP1347; 3,9-Bis((ethylthio)methyl)-K-252a; AC1L31ZX

3,9-bis[(ethylthio)methyl]-K-252a

Phase III

A MAP3K11 (MLK3) inhibitor potentially for the treatment of Parkinson’s disease.

MW 615.76, MF C33H33N3O5S2
Inhibitor of c-jun N-terminal kinase (JNK) signaling. Rescues motor neurons undergoing apoptosis (EC50 = 20 nM). Blocks Aβ-induced cortical neuron apoptosis (EC50 ~51 nM). Does not inhibit ERK1 activity. Neuroprotective.
Figure

Scheme 1 a

a (a) Ac2O, DMAP, THF, room temperature, 93%; (b) Cl2CHOCH3, TiCl4, CH2Cl2, 66%; (c) NaBH4 CH3OH, CHCl3, 65%; (d) NaOCH3, CH3OH, ClCH2CH2Cl, room temperature, 90%; (e) ROH, CSA, CH2Cl2; (f) RSH, CSA, CH2Cl2.

Inhibitor of c-jun N-terminal kinase (JNK) signaling. Rescues motor neurons undergoing apoptosis (EC50 = 20 nM). Blocks Aβ-induced cortical neuron apoptosis (EC50 ~51 nM). Does not inhibit ERK1 activity. Neuroprotective.

Apoptosis has been proposed as a mechanism of cell death in Alzheimer’s, Huntington’s and Parkinson’s diseases and the occurrence of apoptosis in these disorders suggests a common mechanism.

Events such as oxidative stress, calcium toxicity, mitochondria defects, excitatory toxicity, and deficiency of survival factors are all postulated to play varying roles in the pathogenesis of the diseases.

However, the transcription factor c-jun may play a role in the pathology and cell death processes that occur in Alzheimer’s disease.

Parkinson’s disease (PD) is also a progressive disorder involving the specific degeneration and death of dopamine neurons in the nigrostriatal pathway. In Parkinson’s disease, dopaminergic neurons in the substantia nigra are hypothesized to undergo cell death by apoptotic processes.

The commonality of biochemical events and pathways leading to cell death in these diseases continues to be an area under intense investigation.

The current therapy for PD and AD remains targeting replacement of lost transmitter, but the ultimate objective in neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss.

a novel approach for the treatment of neurodegenerative diseases through the development of kinase inhibitors that block the active cell death process at an early transcriptional independent step in the stress activated kinase cascade.

In particular, preclinical data will be presented on the c-Jun Amino Kinase pathway inhibitor, CEP-1347/KT-7515, with respect to it’s properties that make it a desirable clinical candidate for treatment of various neurodegenerative diseases.

CEP-1347 is also known as KT-7515 and is being developed by Cephalon and Kyowa Hakko for treatment of Parkinson’s disease and cognitive disorders.

It is believed to be a JNK-MAP kinase inhibitor. CEP-1347 has the chemical name 9alpha,12alpha-Epoxy-5,16-bis(ethylsulfanylmethyl)-10beta-hydroxy-9-methyl-1-oxo-2,3,9,10,11,12alpha-hexahydro-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4- i][1,6]benzodiazocine-10-carboxylic acid methyl ester and has the chemical structure as depicted in Formula 7.

 

PATENT

https://google.com/patents/WO2005082920A1?cl=en

The compound with the structure outlined below is presently in clinical trials for Parkinson’s disease (Idrugs, 2003, 6(4), 377-383).

This compound is in the following referred to as Compound I. The chemical name of Compound I is [9S-(9α,10β,12α)]-5,16-Rw[(ethylthio)methyl]-2,3,9,10,l l,12-hexahydro- 10-hydroxy-9-methyl- 1 -oxo-9, 12-epoxy- 1 H-diindolo[l ,2,3 -fg:3 ‘,2’, 1 ‘-kl]ρyrrolo[3,4- i][l,6]benzodiazocine-10-carboxylic acid methyl ester.

The following references relate to Compound I, in particular to methods for its preparation [J.Med. Chem. 1997, 40(12), 1863-1869; Curr. Med. Chem. – Central Nervous System Agents, 2002, 2(2), 143-155] and its potential medical uses, mainly in diseases in the central nervous system (CNS), in particular for treatment of neurodegenerative diseases, e.g. Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, peripheral neuropathy, AIDS dementia, and ear injuries such as noise-induced hearing loss [Progress in Medicinal Chemistry (2002), 40, 23-62; Bioorg. Med. Chem. Lett. 2002,12(2), 147-150; Neuroscience, Oxford, 1998, 86(2), 461-472; J. Neurochemistry (2001), 77(3), 849-863; J. Neuroscience (2000), 20(1), 43-50; J. Neurochemistry (2002), 82(6), 1424-1434; Hearing Research, 2002, 166(1-2), 33-43].

The following patent documents relate to Compound I, including its medical use and synthesis: WO 9402488, WO9749406, US 5621100, EP 0651754 and EP 112 932. By the known methods, Compound I is synthesized in a solid amorphous form. The inventors have now discovered 5 crystalline forms of Compound I (named alpha, beta, gamma, delta and epsilon) thereby providing an opportunity to improve the manufacturing process of Compound I and its pharmaceutical use. There exists a need for crystalline forms, which may exhibit desirable and beneficial chemical and physical properties. There also exists a need for reliable and reproducible methods for the manufacture, purification, and formulation of Compound I to permit its feasible commercialisation.

EXAMPLES

In the following the starting material ” Compound I” may, e.g., be prepared as described by Kaneko M. et al in J. Med. Chem. 1997, 40, 1863-1869.

Example 1. Preparation of crystalline alpha form of Compound I

Method I):

6.0 g amorphous Compound I was dissolved in 30 ml acetone. 0,6 g potassium carbonate was added and the suspension was stirred at room temperature for 1 hour before it was filtered to remove potential minor insoluble impurities and inorganic salts. The filter cake was washed with acetone. The filtrate was then evaporated on a rotary evaporator under reduced pressure at 60°C to a final volume of 10 ml to which 100 ml methanol was added slowly. The product separated as an oil, which almost dissolved on heating to reflux. Subsequently the residual insoluble impurities were removed by filtration. The filtrate was left with stirring at room temperature. A crystalline solid separated and was isolated by filtration. The filter cake was washed with methanol and dried in vacuo at 60°C overnight. Yield 2,83 g (47%), mp=182.4°C (DSC onset value), Weight loss by heating: 0.5%, Elemental analysis: 6.71%N, 63.93%C, 5.48%H, theoretical values corrected for 0.5% H2O: 6.79%N, 64.05%C, 5.43%H. XRPD analysis conforms with the alpha form. Method II):

5 g amorphous Compound I was dissolved in 25 ml acetone by gentle heating. 10 ml Methanol was added very slowly until the solution got turbid. The solution was allowed to cool to room temperature by natural cooling. The suspension was filtered and the filter-cake discarded. During filtration more material precipitated in the filtrate. The filtrate was heated until all material redissolves. Cold methanol was then added to the solution until precipitation was observed. The slightly turbid solution was then heated until all material was in solution. The solution was allowed to cool to room temperature, and the precipitate was removed by filtration. The second filter-cake was discarded. During the filtration some material separated in the filtrate. Heating redissolved the beginning crystallisation in the filtrate. Cold methanol was then added to the solution until precipitation was observed. The suspension was heated until a clear solution was obtained. The solution was allowed to reach room temperature by natural cooling. After a short period of time (15 min) precipitation begun. The precipitated pale yellow product was isolated by filtration and dried in vacuo at 50°C overnight. mp=188.9°C (DSC onset value), Weight loss by heating: 0.3%>, Elemental analysis: 6.53%N, 64.33%C, 5.43%H, theoretical values: 6.82%N, 64.37%C, 5.37%H. XRPD analysis conforms with the alpha form. Method III:

0.5g Compound I in a mixture of isopropyl acetate (10 mL) and water (0.6 mL) was heated to reflux with stirring. The compound was not completely dissolved so isopropyl acetate (10 mL) and water (0.6 mL) were added and heated to reflux. Stirring was stopped and the experiment was allowed to cool to room temperature. The crystalline product obtained were isolated by filtration and dried in vacuo at 40° C. Yield = 0.25g, mp = 183.7°C (DSC onset value). XRPD analysis conforms with the alpha form. Method IV: 0.5g Compound I in a mixture of ethyl acetate (10 mL) and water (0.4 mL) was heated to 70° C with stirring. The experiment was allowed to cool to room temperature. The crystalline product obtained were isolated by filtration and dried in vacuo at 40° C. XRPD analysis conforms with the alpha form.

PATENT

https://www.google.com/patents/US20050261762

 

PATENT

http://www.google.co.ug/patents/EP2004158A2?cl=en

CEP-1347 (KT7515) (Maroney et al. 1998; Roux et al. 2002).

PAPER

Neurotrophic 3,9-bis[(alkylthio)methyl]- and -bis(alkoxymethyl)-K-252a derivatives
J Med Chem 1997, 40(12): 1863

http://pubs.acs.org/doi/full/10.1021/jm970031d

Figure

 


CEP-1347
pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=216326

The synthesis of the title compound used as the starting material was the indolocarbazole alkaloid K-252A (I). Compound (I) was protected as the diacetyl derivative (II) by treatment with Ac2O and DMAP. Formylation of (II) with dichloromethyl methyl ether in the presence of TiCl4 afforded dialdehyde (III), which was further reduced to diol (IV) using NaBH4 in MeOH-CHCl3. Condensation of diol (IV) with ethanethiol in the presence of camphorsulfonic acid furnished the bis-sulfanyl compound (V). The acetyl protecting groups of (V) were finally removed by treatment with sodium methoxide. Alternatively, diol (IV) was first deacetylated by treatment with NaOMe, and the deprotected bis(hydroxymethyl) compound (VI) was then condensed with ethanethiol to produce the title bis-sulfayl compound 8.

3,9-Bis[(ethylthio)methyl]-K-252a (8):

mp 163−165 °C;

IR (KBr) 1725, 1680 cm-1; FAB-MSm/z 615(M+);

1H-NMR (400 MHz, DMSO-d6) δ 1.23 (t, 6H, J = 7.3 Hz), 1.99 (dd, 1H, J = 4.8, 14.1 Hz), 2.132 (s, 3H), 2.489 (q, 2H, J = 7.3 Hz), 2.505 (q, 2H, J = 7.3 Hz), 3.37 (dd, 1H, J = 7.6, 14.1 Hz), 3.92 (s, 3H), 3.94 (s, 2H), 3.98 (s, 2H), 4.95 (d, 1H, J = 17.6 Hz), 5.02 (d, 1H, J = 17.6 Hz), 6.32 (s, 1H), 7.10 (dd, 1H, J = 4.8, 7.6 Hz), 7.450 (m, 2H), 7.84 (d, 1H, J = 8.5 Hz), 7.88 (d, 1H, J = 8.8 Hz), 7.95 (d, 1H, J = 1.0 Hz), 8.60 (s, 1H), 9.13 (d, 1H, J = 0.7 Hz);

HRFAB-MS calcd for C33H33N3O5S2 615.1862, found 615.1869. Anal. (C33H33N3O5S2·0.5H2O) C, H, N.

References

Maroney et al (1998) Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J.Neurosci. 18 104. PMID: 9412490.

Saporito et al (1998) Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis. Neuroscience 86 461. PMID: 9881861.

Bozyczko-Coyne et al (2001) CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J.Neurochem. 77 849. PMID: 11331414.

 

WO1994002488A1 * Jul 26, 1993 Feb 3, 1994 Cephalon Inc BIS-STAUROSPORINE AND K-252a DERIVATIVES
1 * KANEKO M ET AL: “Neurotrophic 3,9-Bis[(alkylthio)methyl]- and -Bis(alkoxymethyl)-K-252a Derivatives” JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 40, no. 12, 1997, pages 1863-1869, XP002128804 ISSN: 0022-2623 cited in the application

 

 

 

 

//////////CEP 1347, KT 7515 ,

CCSCC1=CC2=C(C=C1)N3C4CC(C(O4)(N5C6=C(C=C(C=C6)CSCC)C7=C8CNC(=O)C8=C2C3=C75)C)C(=O)OOC

Health Canada approves NEUPRO (Rotigotine) patch for treatment of Parkinson’s disease and Restless Legs Syndrome


Rotigotine

Novel dosage form represents new treatment for Parkinson’s with efficacy in motor symptoms of the disease

April 2,2013

UCB Canada Inc. announced today that Health Canada has approved NEUPRO® (rotigotine), the first and only non-ergolinic dopamine agonist available in a patch, to treat the signs and symptoms of idiopathic Parkinson’s disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS), also known as Willis-Ekbom disease, in adults.

NEUPRO® is the first new treatment for Parkinson’s disease approved by Health Canada in five years and provides 24-hour delivery of rotigotine through the skin into the blood stream. NEUPRO® has demonstrated efficacy in managing motor symptoms associated with Parkinson’s disease.

“The ability to ensure a steady 24-hour delivery of medication with NEUPRO® may help to reduce debilitating on and off symptoms which many patients experience with Parkinson’s treatments,” says Dr. David Grimes, Director, Parkinson’s Disease and Movement Disorders Clinic at the Ottawa Hospital. “The impact of sustained symptom control in the morning and in the evening can have a substantial effect on a patient’s quality of life.”

UCB Canada Inc. is undertaking all measures required to supply the Canadian market with NEUPRO.

“Parkinson Society Canada is pleased to learn that Canadians living with Parkinson’s now have another treatment option to help manage the symptoms of this chronic disease,” says Joyce Gordon, President and CEO, Parkinson Society Canada. “With innovative therapies such as NEUPRO® and ongoing research into the causes of this disease, we will help to ensure a brighter future and better quality of life for Canadians living with Parkinson’s.”

Although the precise mechanisms of action of NEUPRO® as treatment for PD and RLS are unknown, as a PD treatment, the mechanism of action is thought to be related to increasing the activities of the dopamine receptors within the caudate-putamen, the region of the brain that regulates movement. Similarly, in RLS, the mechanism of action of NEUPRO® is thought to be related to its ability to stimulate dopamine receptors.

Data Demonstrated Significant Symptom Improvement for PD and RLS

The effectiveness of NEUPRO® (rotigotine) in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of four randomized, double-blind placebo-controlled phase 3 trials. A total of seven Canadian trial sites were involved in the international studies. In all trials, patients underwent a weekly titration of NEUPRO® in 2 mg/24 hour increments to the assigned or optimal dose.

In two trials, statistically significant improvements in the combined scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) were observed in early-stage PD patients receiving NEUPRO® compared to patients receiving placebo. The UPDRS is a validated multi-item rating scale intended to evaluate mentation (mental activity), activities of daily living (ADL), motor performance, and complications of therapy. The two trials measured only the ADL and motor performance sections of the UPDRS. The UPDRS contains 13 questions relating to ADL, such as speech, dressing, and cutting food with utensils, and 27 questions related to the cardinal motor symptoms in PD patients—i.e., tremor, rigidity, bradykinesia, and postural instability.

Two trials of NEUPRO® in patients with advanced-stage PD examined change from baseline in “off” time, periods when the effectiveness of medication wears off and PD symptoms return. Statistically significant changes in off-times were observed in advanced-stage PD patients receiving NEUPRO® compared with those who received placebo.

The effectiveness of NEUPRO® in the treatment of Restless Legs Syndrome (RLS) was evaluated in two fixed-dose, randomized, double-blind, placebo-controlled phase 3 trials with maintenance periods of 6 months duration. Patients received NEUPRO® doses ranging from 0.5 mg/24 hours to 3 mg/24 hours, or placebo, once daily. Statistically significant improvements in sum scores on the International RLS Rating Scale (IRLS Scale) and the Clinical Global Impression – Improvement (CGI-I) assessment were observed in RLS patients receiving NEUPRO® compared with those receiving placebo. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The CGI-I is designed to clinically assess RLS symptoms on a 7-point scale.

In clinical trials, treatment emergent adverse events reported in more than 10% of patients treated with NEUPRO® for Parkinson’s disease included nausea, vomiting, dizziness, somnolence, application site reactions and headache.  Treatment emergent adverse events reported in more than 10% of patients treated with NEUPRO® for Restless Legs Syndrome, included nausea, application site reactions, fatigue and headache.

About Parkinson’s disease 
Parkinson’s disease (PD) is a chronic, degenerative neurological disease which affects approximately 100,000 Canadians. PD develops with the loss of nerve cells in the brain that produce a chemical called dopamine. The symptoms of PD can have an impact on many dimensions of patients’ lives. As dopamine levels fall, movement (motor) symptoms—tremors (uncontrollable shaking), rigidity (stiffness or muscle tensing) and bradykinesia (slowness and loss of spontaneous movement) — can progress, along with the underlying symptoms of PD, which are less well recognized and may be under-treated.

About Restless Legs Syndrome 
Restless Legs Syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move to gain relief. Over 80% of people with RLS also have periodic limb movement disorder (PLMD), which causes rhythmic limb movements during sleep. RLS affects between three and 10 per cent of the population to some extent. Some estimates are much higher because RLS is thought to be underdiagnosed, and in some cases, misdiagnosed. Most people with RLS have difficulty falling asleep and staying asleep. Daytime symptoms of RLS, such as inability to sit still and involuntary leg jerks, are increasingly recognized. While the underlying pathophysiology of RLS is not fully understood, it is thought to involve central dopamine systems. Recent neuroimaging data suggest that RLS patients may carry an abnormality in dopamine transport that can be visualized both day and night. RLS can cause exhaustion and daytime fatigue, and may affect work and personal relationships. Patients with moderate-to-severe RLS are often unable to concentrate, have impaired memory, or fail to accomplish daily tasks. These patients may require long-term treatment for their RLS symptoms.

About UCB Canada Inc. 
Inspired by patients and driven by science, UCB Canada Inc. is a biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe auto-immune and central nervous system diseases. For more information, please consult www.ucb.com/worldwide/canada.

Rotigotine (Neupro) is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS) in Europe and the United States. It is formulated as a once-daily transdermal patchwhich provides a slow and constant supply of the drug over the course of 24 hours.

Like other dopamine agonists, rotigotine has been shown to possess antidepressanteffects and may be useful in the treatment of depression as well.

Rotigotine was developed by Aderis Pharmaceuticals. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German pharmaceutical company Schwarz Pharma (today a subsidiary of the Belgian company UCB S.A.).

The drug has been approved by the EMEA for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal treatment of Parkinson’s disease in the United States. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. The patch was reformulated, and was reintroduced in the United States in 2012.

Rotigotine has been authorized as a treatment for restless legs syndrome since August 2008.

Rotigotine is analogous to 7-OH-DPAT and UH-232, all three of which are aminotetralinderivatives. These compounds are similar in structure to dopamine, likely underlying theirpharmacology.

Rotigotine synth.png

Cusack, N. J.; Peck, J. V.; Drugs Future 1993, 18, 1005.

%d bloggers like this: