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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

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SUVN-G3031, from Suven Life Sciences Ltd


STR1

.2HCl

SUVN-G3031

N-[4-(1-cyclobutyl piperidin-4-yloxy)-phenyl]-2-(morpholin-4-yl) acet amide dihydrochloride

N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride

4-​Morpholineacetamide, N-​[4-​[(1-​cyclobutyl-​4-​piperidinyl)​oxy]​phenyl]​-​, hydrochloride (1:2)
MF C21 H31 N3 O3 . 2 Cl H,
CAS 1394808-20-8
STR1

SUVN-G3031

Base

Cas 1394808-82-2

MF C21 H31 N3 O3, 373.49
4-​Morpholineacetamide, N-​[4-​[(1-​cyclobutyl-​4-​piperidinyl)​oxy]​phenyl]​-

SUVN-G3031 (in phase I)

Suven Life Sciences Limited, IN 2011CH00520

  • Phase I Cognition disorders  associated with Alzheimer disease patients.

https://clinicaltrials.gov/ct2/show/NCT02342041

Useful for treating cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, obesity, schizophrenia, eating disorders and pain.

Histamine H3 receptor antagonists

Neuropsychotherapeutics; Nootropics

Suven Life Sciences is developing, Histamine H3 receptor antagonists, SUVN-G3031 (in phase I)

  • 13 Jul 2015Suven Life Sciences has patent protection for SUVN G3031 in China and South Africa
  • 16 Mar 2015SUVN G3031 is available for licensing as of 16 Mar 2015. http://www.suven.com/
  • 16 Mar 2015Suven Life Sciences receives patents for SUVN G3031 in USA and New Zealand

STR1

H 3 receptors play a critical role as neuromodulators through their widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of both histamine and other neurotransmitters including acetylcholine from cholinergic neurons. Currently, several H 3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder.

Histamine H3 receptor is a G-protein coupled receptor (GPCR) and one out of the four receptors of Histamine family. Histamine H3 receptor is identified in 1983 and its cloning and characterization were done in 1999. Histamine H3 receptor is expressed to a larger extent in central nervous system and lesser extent in the peripheral nervous system.

Literature evidence suggests that Histamine H3 receptor ligands can be used in treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1 166-1181), dementia (Drug News Perspective, 2010, 23(2), 99-103), attention deficit hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, 33, 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) and pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37).

Patent publications WO 2007/137955, US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 2009/100120, WO 2009/121812 and WO 2009/135842 disclosed series of compounds as ligands at Histamine H3 receptors. While some Histamine H3 receptor ligands have been disclosed, no compound till date is launched in market in this area of research, and there still exists a need and scope to discover new drugs with novel chemical structures for treatment of disorders affected by Histamine H3 receptors.

Suven Life completes Phase 1 studies for SUVN- G3031 for Schizophrenia – Cognitive Impairment

Drugmaker Suven Life Science, which is mostly into researching for new molecules used for ailments of the central nervous system, has completed the single ascending dose (SAD) studies for SUVN- G3031, which is likely to be used for cognitive dysfunction associated with Alzheimer’s and schizophrenia.

The phase-1 study was said to be designed to evaluate safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy volunteers. It was found that the tolerability of SUVN-G3031 up to the highest dose administered in SAD study was ‘excellent’ with ‘no serious adverse events’. The drug candidate was demonstrated for one-day dosing.

OLD CLIPS

SUVN-G3031 for Cognition in Alzheimer’s Disease commenced Phase 1 Clinical Trial in USA under US-IND 123179

HYDERABAD, INDIA (Nov 03, 2014) – Suven Life Sciences today informed that their NCE SUVN-3031 has commenced Phase 1 clinical trial in USA. SUVN-G3031 – A potent, selective, brain penetrant and orally active Histamine H3 antagonist for the treatment of cognitive dysfunction associated with Alzheimer’s Disease / Schizophrenia has completed all the pre-clinical, safety and early toxicological studies, GLP toxicological studies and was submitted forInvestigational New Drug Application {IND) to conduct Phase 1 clinical trial with the indication for Cognition in Alzheimer’s Disease under 505(1) of the Federal Food, Drug and Cosmetic Act (FDCA) which was assigned an IND number 123179.

Based on the IND “A Single Center, Double-blind, Placebo-controlled, Randomized, Phase 1 Study to Evaluate the safety, Tolerability, and Pharmacokinetics of SUVN-G3031 after Single Ascending Doses and Multiple Ascending Doses in Healthy Male Subjects” for Cognition in Alzheimer’s Disease is underway in USA

“We are very pleased that the second compound from our pipeline of molecules in CNS has moved into clinical trial that is being developed for cognitive disorders in Alzheimer’s and Schizophrenia with high unmet medical need which has huge market potential globally” says Venkat Jasti, CEO of Suven.

Suven Life Science is a biopharmaceutical company focused on discovering, developing and commercializing novel pharmaceutical products, which are first in class or best in class CNS therapies through the use of GPCR targets. The Company has eleven (11) internally-discovered therapeutic drug candidates currently in pre-clinical stage of development targeting conditions such as ADHD, dementia, major depressive disorder (MDD), Huntington’s disease, Parkinson’s disease and obesity in addition to this Phase 1 developmental candidate SUVN-G301 and Phase 2 a (PoC) ready SUVN-502 for Alzheimer’s disease and Schizophrenia.

SYNTHESIS

STR1

PATENT

WO2012114348

OR SEE

https://www.google.com/patents/US20140135304?cl=en22

PATENT

WO2014030170

Scheme I as shown below.

Figure imgf000006_0001

PATENT

WO-2016027275

process for large scale production of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (I).

 

N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(moφholin-4-yl) acetamide dihydrochloride, is a promising pharmaceutical agent, which is potent and selective Histamine ¾ receptor ligand intended for the symptomatic treatment of cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, sleep apnea, obesity, schizophrenia, eating disorders and pain. N-[4-(l-Cyclobutyl piperidin-4-yloxy) phehyl]-2-(morpholin-4-yl) acetamide dihydrochloride and its synthesis is disclosed by Ramakrishna et al. in WO20121 14348.

Currently N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride has completed preclinical studies and is ready to enter human clinical trials. The demand for N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride as a drug substance has increased substantially with the advent of its clinical testing. The future need for much larger amounts is projected due to the intended commercialization of N-[4-( 1 -Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride.

For the person skilled in art, it is a well known fact that various parameters will change during the manufacture of a compound on a large scale when compared to the synthetic procedures followed in laboratory. Therefore, there is a need to establish and optimize large scale manufacturing process. The process for the preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride disclosed in WO20121 14348 was proved to be unsatisfactory for adaptation to the large scale manufacturing. Hence it is highly desirable to establish optimized manufacturing process of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2 -(morpholin-4-yl) acetamide dihydrochloride of formula (I), which is amenable to the large scale manufacturing of the compound.

Example 1: Preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(raorpholin-4-yl) acetamide dihydrochloride

Step (i): Preparation of l-cycIobutylpiperidin-4-ol

Ethylene dichloride (235 L) was charged into the reactor at 20-25 °C followed by 4-hydroxy piperidine (9.5 Kg, 93.92 M). The mass was stirred for ~ 15 minutes to obtain a clear, solution. Then cyclobutanone (7.9 Kg, 1 12.71 M) was charged into the reactor at 20-25 °C and stirred the mass for 90 minutes at the same temperature. The mass was cooled to 15-20 °C and started lot wise addition of sodium triacetoxy borohydride (39.9 Kg, 188.26 M) maintaining the mass temperature below 25 °C in ~ 110 minutes. After completion of addition, the mass was stirred for 30 minutes at ~ 20 °C. The mass temperature was raised to 25-30 °C and maintained at the same temperature for ~ 13.1 hours, while monitoring the progress of the reaction by Thin Layer Chromatography (TLC). After completion of the reaction, water (1 12 L) was charged into the reactor at 25-30 °C. The mass was then cooled to 15-20 °C and pH of the reaction mass was adjusted to 13.0-13.5 with a solution of aqueous sodium hydroxide (24.6 Kg of sodium hydroxide dissolved in 106 L of demineralised water (DM water) maintaining the mass

temperature below 20 °C in about 1 hour 20 minutes. In the meanwhile, nutsche filter with hyflow bed (using 4.75 Kg hyflow and 47.5 L DM water) was made ready for filtration of dirt and sodium acetate salt, for the purpose of clean layer separations during extraction of the product. The reaction mass was filtered through nutsche and the nutsche was washed with 23.75 L of ethylene dichloride. The filtrate containing the product was collected into clean and dedicated containers. The combined filtrate and washings were transferred to a reactor, stirred 15 minutes and settled for 15 minutes at 25-30 °C. The bottom organic layer (containing the product) was collected in dedicated containers and the mass was dried over anhydrous sodium sulfate (9.5 Kg). The supernatant, clean, dry organic layer was taken in a reactor and solvent was removed by distillation under vacuum maintaining mass temperature below 50 °C. The residual crude mass was cooled to 25-30 °C.

2nd extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (DCM) (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 3 rd extraction.

3 rd extraction of the aqueous layer: The aqueous layer separated as above was takenin a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 4th extraction.

4th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 5th extraction.

5th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer

(containing product) was separated into dedicated containers. The aqueous layer was collected in dedicated containers and kept aside.

The organic layer obtained from second extraction to fifth extraction was combined and dried over anhydrous sodium sulfate (13.5 Kg). The supernatant, clean, dry organic layer was taken in the reactor, containing the crude product obtained from first extraction, and solvent was removed by distillation under reduced pressure (>500 mm Hg) maintaining mass temperature below 50 °C. The residual mass was cooled to 25-30 °C and collected the technical product (14.36 Kg).

Yield: 98.49 %;

Ή-NMR (δ ppm, CDC13): 1.55 – 1.69 (5H, m), 1.83 – 2.02 (8H, m), 2.65 – 2.69 (3H, m), 3.66 – 3.70 (1H, m);

Mass (m/z): 156.2 (M+H)+.

Step (ii): Preparation of 4-(l-cyclobutylpiperidin-4-yIoxy)-l-nitrobenzene

Tetrahydrofuran (THF) (43.2 L) was charged into a Stainless steel reactor (SS reactor) at 25-30 °C under nitrogen atmosphere followed by addition of sodium hydride (5.22 Kg) maintaining mass temperature at 25-30 °C under nitrogen atmosphere. The contents were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised to 35-40 °C.

THF (56.7 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere by the addition of above obtained step (i) material (13.5 Kg, 86.96 M). The mass was stirred for 15 minutes at 25-30 °C to obtain a clear solution. The resulting solution was added to the above reactor containing sodium hydride in THF, maintaining the mass temperature of the main reactor at 35-40 °C over a period of ~ 45 minutes under nitrogen atmosphere. The resulting mass was further stirred for 90 minutes at 35-40 °C.

In the meanwhile THF (35.8 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere, followed by the addition of 4-fluoro-l-nitrobenzene (14.72 Kg, 104.32 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C to obtain a clear solution. The clear solution, thus obtained, was slowly transferred to the main reactor in ~ 45 minutes maintaining the mass temperature of the main reactor at 35-40 °C. The temperature of the reaction mass was further maintained at 35-40 °C for 5 hours under stirring and under nitrogen atmosphere, while monitoring the progress of the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 15-20 °C.

. Charged water (675 L) into another SS reactor under nitrogen atmosphere. The contents of the reactor were cooled to 5-10 °C. Then the reaction mass from the main reactor was transferred carefully to this reactor containing water, maintaining the mass temperature below 20 °C in ~ 45 minutes. The resulting mass was further stirred for 30 minutes maintaining the temperature at 15-20 °C. The solid mass was centrifuged and the mother liquors were collected in dedicated containers. The cake on the centrifuge was washed with water (2 x 135 L) and spin dried to obtain technical product (19.80 Kg).

Purity: 99.5 %.

Purification: Dissolved the technical product obtained as above (19.80 Kg) in ~ 200 L of 10 % aqueous acetic acid solution (~ 20.59 Kg acetic acid diluted with 180 L with water) at 25-30 °C.

1st toluene extraction: Stirred 15 minutes and then charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated, The top organic layer containing the impurities was kept aside in a dedicated container.

2nd toluene extraction: The lower aqueous product layer was taken into the reactor again and charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.

3rd toluene extraction: The lower aqueous product layer was taken again into the reactor and charged toluene (25 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.

The aqueous product layer was charged into the reactor at 25-30 °C. The mass was cooled to 10 – 15 °C. pH of the reaction mass was adjusted to 1 1.5 -12.0; with 20 % w/v aqueous sodium hydroxide solution (prepared by dissolving 15.44 Kg sodium hydroxide flakes in 69.3 L of DM water) while maintaining mass temperature at 10-15 °C for 1.45 hours. The resulting mass was stirred for 15 minutes at 25-30 °C at pH 11.55. The solids that separated were centrifuged. The cake was washed with (40 L x 2) DM water and the product was spin dried (19.9 Kg), Yield: 53.56 %

Purity: 99.52 %.

Ή-NMR (δ ppm, CDC13): 1.58 – 1.73 (2H, m), 1.84 – 1.93 (4H, m), 2.02 – 2.06 (4H, m), 2.19 (2H, s), 2.62 (2H, s), 2.71 – 2.76 (1H, m), 4.45 (1H, s), 6.93 – 6.95 (2H, d, J = 9.07 Hz), 8.18 – 8.20 (2H, d, J = 9.02 Hz);

Mass (m/z): 277.2 (M+H)+.

The aqueous layer (obtained after eentrifuging and washing the product) was collected in dedicated containers for isolation of the second crop.

Step (iii): Preparation of 4-(l-cyclobutylpiperidin-4-yloxy) aniline

The reaction was done in a SS reactor under nitrogen blanket. DM Water

(33.59 L) was charged into a SS reactor at 25-30 °C followed by iron powder (10.43 Kg, 186.75 M, 1 :4 ratio) under stirring. Then ammonium chloride (11.5 Kg, 215 M) was charged at 25-30 °C and stirred the contents for 15 minutes at 25-30 °C. The mass temperature was raised slowly to 95- 100 °C and maintained at that temperature (95-100 °C).for.^.90 minutes. The mass was cooled to 75-80 °C.

In the meanwhile, ethyl alcohol (128.7 L) was charged into another reactor at 25-30 °C, followed by addition above obtained compound (19.9 Kg). The contents were stirred for 15 minutes and then raised the mass temperature to 50-55 °C, where by a clear solution was obtained. The mass was slowly transferred to the main reactor, containing the activated iron powder at 78-80 °C over a period of ~ 70 minutes. The mass was further stirred for 3 hours, while maintaining the mass temperature at 75-80 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 25-30 °C and filtered through nutsche, containing hyflow bed. The filtrate was collected into dedicated containers. The bed was washed with 3 x 32.18 L of ethyl alcohol and collected the washings into dedicated containers. The combined filtrate was charged into a clean SS reactor at 25-30 °C. All the volatiles are distilled off under reduced pressure (> 500 mm Hg) maintaining the mass temperature below 55 °C. The residual mass was cooled to 25-30 °C and charged DM water (32.18 L). The pH of the reaction mass was adjusted to 9.0 – 10.0 with 91 L of sodium carbonate solution (prepared by dissolving 21.5 Kg of sodium carbonate in 80 L of DM water), while maintaining the mass temperature at 25-30 °C. Final pH is 9.14. The solid mass, separated in the reactor, was cehtrifuged and collected the filtrate in dedicated containers. The product was spin dried (20.34 Kg).

Ethylacetate (EtOAc) (80 L) was charged into a clean SS reactor at 25-30 °C followed by the wet cake (20.34 Kg) obtained above. The mass was stirred for 15 minutes at 25-30 °C. Then added DM water (32 L) and further stirred the mass for 15 minutes and settled for 15 minutes. The aqueous layer was separated and collected in dedicated containers.

The organic layer containing the product was filtered through nutsche filter through hyflow bed (formed with 5.15 Kg hyflow and 26 L water) and filtrate was collected in dedicated containers. The bed was washed with EtOAc (13 L). The combined organic layer and EtOAc washings were charged into a clean SS reactor. Charged 20 L DM water, stirred for 15 minutes and settled for 15 minutes at 25-30 °C. The aqueous layer is separated and the organic layer was dried over anhydrous sodium sulfate (20 Kg).

The clean, dried organic layer was charged into a reactor at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) below 50 °C (Solvent recovered: 70 L). The residual product was cooled to 25-30 °C and unloaded into dedicated containers (12.30 Kg) and sent for complete analysis. Weight of the product: 12.3 Kg (wet with solvent EtOAc: 9.1 %),

Yield (on dry basis): 9.7.5 %;

Purity: 97.79 %;

IR (cm-‘): 3424, 3345, 2943, 1627, 1509, 1229, 1 168, 1044, 821 ;

1H-NMR (5 ppm, DMSO): 1.49 – 1.61 (4H, m), 1.71 – 1.83 (4H, m), 1.92 – 1.97 (5H, m), 2.52 – 2.53 (2H, m), 3.99 – 4.04 (1 H, m), 4.59 (2H, bs), 6.46 – 6.48 (2H, d, J = 8.60 Hz), 6.61 – 6.63 (2H, d, J = 8.66 Hz);

Mass (m/z): 247.4 (M+H)+.

Step (iv): Preparation of 2-chloro-N-[4-(l-cycIobutyI piperidin-4-yloxy).

phenyl] acetamide

The reaction was done in a SS reactor under nitrogen blanket. THF (89.6

L) was charged into a Glass reactor (GLR) at 25-30 °C followed by addition of above obtained material (1 1.2 Kg on dry basis, 45.46 M). The contents were stirred 15 minutes. Then charged anhydrous potassium carbonate (K2C03) powder (12.54 Kg, 90.73 M) into the reactor and stirred the mass for 15 minutes at 25-30 °C. The reaction mass was cooled to -10 to -5 °C by circulating brine in the jacket. Then a solution of chloroacetylchloride (6.72 Kg, 59.5 M) dissolved in THF (44.8 L) was slowly introduced into the reactor through a holding tank, under nitrogen atmosphere, in ~ 2.5 hours maintaining the mass temperature at -10 to -5 °C. The reaction mass was further maintained under stirring at -10 to -5 °C for another 2 hours while monitoring the progress of the reaction by TLC.

After completion of the reaction, slow addition of chilled DM water (186 L) through the addition funnel started at -10 to -5 °C. Towards the end of addition of DM water (addition time 45 minutes), it was so adjusted that the mass temperature reached 10-15 °C. After completion of addition of DM water the mass temperature was raised to 25-30 °C.

1st extraction: Ethyl acetate (1 12 L) charged into the reactor at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer was collected in dedicated containers.

2nd extraction: The aqueous layer obtained as above was charged into the reactor followed by EtOAc (1 12 L) at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer and the aqueous layer were collected in dedicated containers.

The combined organic layer, obtained from the above extractions, was charged into a clean GLR followed by the addition of 116 L of brine solution (prepared by dissolving 33.6 Kg sodium chloride in 1 12 L DM water) at 25-30 °C. The mass was stirred for 30 minutes and settled for 30 minutes at 25-30 °C. The aqueous layer was separated and collected in dedicated containers. The organic product layer was dried over anhydrous sodium sulfate (22.4 Kg). The volume of the organic layer was 360 L. The organic layer obtained as above was charged into a clean GLR at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C (volume of recovered solvent; 178 L). The mass was cooled to 25-30 °C. Solid mass separated in the reactor.

Recrystallization

Isopropanol (72.8 L) was charged into the reactor containing the solids (~ 13.5 Kg) at 25-30 °C, followed by methanol (~ 58.2 L) at 25-30 °C. Stirred the reaction mass at 25-30 °C for 30 minutes. The mass temperature was raised slowly to reflux temperature and maintained at reflux till a clear solution is obtained (~ 30 minutes). Then the mass was cooled to 25-30 °C and stirred the mass for 60 minutes. The mass was further cooled to -12 -15 °C, stirred for 30 minutes and centrifuged the material. The cake on the centrifuge was washed with 2 x 7 L isopropanol (25-30 °C) and spin dried thoroughly.

The wet cake (1 1.2 Kg) was dried in a vacuum tray drier (VTD) for ~ 4 hours at 40-50 °C to obtain crystallized product (9.7 Kg).

Yield: 66.12 %;

Purity (by HPLC): 99.56 %; – IR (cm-1): 3307, 3278, 2951, 1670.43, 1612, 1554.69, 1508.4/1240.28, 1 171.81 , 1047.39, 953.84, 832.32;

1H-NMR (δ ppm, DMSO): 1.53 – 1.61 (4H, m), 1.72 – 1.74 (2H, m), 1.87 – 1.99 (6H, m), 2.49 – 2.53 (2H, m), 2.64 – 2.68 (1H, m), 4.19 (2H, s), 4.24 – 4.29 (1H, m), 6.88 – 6.90 (2H, d, J = 8.96 Hz), 7.44 – 7.46 (2H, d, J = 8.96 Hz), 10.12 (1H, s); …. . . .. ÷.

Mass (m/z): 323.3, 325.2 (M+H)+.

Mother liquor obtained, after recrystallization and centrifuging the product, was processed for isolating second crop.

Step (v): Preparation of N-[4-(l-cycIoburyl piperidin-4-yIoxy) phenyI]-2-(morphoIin-4-yl) acetamide

Acetonitrile (1.41 L) was charged into the GLR at 25-30 °C under nitrogen atmosphere, followed by addition of the above obtained material (9.4 Kg, 29.11 M). Then, charged anhydrous K2C03 granules (6.0 Kg, 43.41 M) into the reactor at 25-30 °C. Stirred the reaction mass in the reactor for 10 minutes and charged morpholine (3.3 Kg, 37.88 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised slowly to reflux (80-82 °C) and maintained at reflux for 4 hours while monitoring the progress of the reaction every two hours by HPLC.

Analysis of the sample by HPLC after 4 hours reflux: 89.61 % product and 8.83 % starting material (SM).

Charged morpholine (253 grams) and K2C03 (400 grams) and further refiuxed. Analysis by of the sample at 7.5 hours: 92.8 % product and 5.63 % SM. So charged morpholine (506 grams), K2C03 (810 grams) and acetonitrile (30 L) and heated the mass at reflux for another five hours. Analysis of the sample at 12.5 hours: 96.78 % product and 2.06 % SM. Again charged K2C03 (820 grams), morpholine (255 gm) and acetonitrile (40 L) and maintained the mass under reflux. Analysis of the sample at 19.5 hours: 97.52 % product and 0.9 % SM. The reaction mass was cooled to 30-35 °C and filtered solids through nutsche at 30-35 °C. The cake on the nutsche was washed with 15 L acetonitrile; Mother liquors (~ 210 L filtrate) were taken back into the main reactor (GLR) and kept under stirring at 30 – 35 °C, while workup of the solid cake (22.4 Kg), containing the product along with salts, was going on in another reactor.

Wet weight of cake: 22.4 Kg (contained ~ 23 % product).

Charged 30 L water into another reactor followed by the wet cake obtained after nutsche filtration (22.4 Kg). Stirred the mass for 30 minutes and charged EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes. The organic layer containing the product was collected in dedicated containers. pH of the aqueous mother liquors was found to be 10.05 on pH meter.

2nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.

3nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (40 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.

The combined organic layer was dried over sodium sulfate (9.4 Kg) and the clean organic layer was taken for distillation under reduced pressure (> 500 mm Hg) at 50-55 °C. The mass was cooled to 25-30 °C. Added 23.5 L of acetonitrile and stirred well.

Part of the reaction mass (65 L of acetonitrile solution) from GLR was unloaded and charged into the above reaction mass at 25-30 °C and stirred 30 minutes, whereby a clear solution was obtained. The mass was transferred to the main reactor. Washing was given to this reactor with 20 L fresh acetonitrile at 40-45 °C and again transferred to the main reactor and stirred 15 minutes before sampling.

The final, uniformly mixed reaction mass was sampled from the main GLR and analyzed. HPLC: 99.09 % product and 0.31 % SM. So charged morpholine (510 grams) and K2C03 (825 grams) and the mass was heated to reflux and further maintained the mass at reflux temperature for 2 hours. A sample was analyzed after 2 hours reflux. Starting material was absent (product purity: 99.24 %).

The reflux was further continued for another 2 hours and then cooled the mass temperature to 30-35 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg), maintaining mass temperature below 55 °C.

1st Extraction: Charged DM water (23.5 L) to the residual mass at 25-30 °C. Stirred the mass for 15 minutes and charged ethyl acetate (80 L). A clear solution was obtained. Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers. 2ndExtraction: The aqueous layer obtained as above (pH was found to be 9.9 on meter) was charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.

3nd Extraction: The aqueous layer obtained as above was once again charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.

Brine washing: The combined organic layer was taken in the reactor and charged

~ 35 L brine solution (prepared by dissolving 9.4 Kg sodium chloride in 28.2 L DM water). The mass was stirred for 15 minutes and settled for 30 minutes.

Layers separated and collected aqueous layer in dedicated containers.

The organic product layer was dried over anhydrous sodium sulfate (18.8

Kg). Total volume of the organic layer was 185 L. The solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C. Solid mass (Step-5 material) separated in reactor.

Yield: Quantitative; 5

Purity: 99.51 %;

1H-NMR (CDC13, δ ppm): 1.65 – 2.04 (12H, m), 2.61 – 2.63 (6H, m), 2.69 – 2.77 (1H, m), 3.12 (2H, s), 3.76 – 3.78 (4H, m), 4.26 – 4.27 (1H, m), 6.87 – 6.89 (2H, d, J = 8.82 Hz), 7.43 – 7.45 (2H, d, J – 8.80 Hz), 8.91 (1H, s);

Mass (m/z): 374.4 (M+H)+.

Step (vi): Preparation of N-[4-(l-CyclobutyI piperidin-4 yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride

Charged isopropyl alcohol (75 L) into the reactor containing step (v) product. The reaction mass temperature was raised to 50-55 °C and stirred for 30 minutes to obtain a clear solution. The mass was cooled to 25 °C before starting the addition of isopropanolic hydrochloride (Isopropanolic HC1).

Isopropanolic HC1 (16.2 L, 16.1 % w/v) was diluted with isopropanol (8 L) and charged into a holding tank. Isopropanolic HC1 in the holding tank was transferred slowly into the reactor in 90 minutes, maintaining mass temperature ~ 22 – 28 °C (now and then giving jerks with brine in the reactor jacket). The resulting mass was further stirred under maintenance at 25-30 °C for 6 hours. The mass was centrifuged; the cake on the centrifuge was washed with fresh isopropanol, 16 L (for slurry wash) + 5.5 L (for spray wash) and spin dried to obtain 20.26 Kg of wet product. Purity: 99.37 %. The material was unloaded into trays and dried in a VTD at 50 – 60 °C for 16 hours.

Final weight: 12.62 Kg;

Yield: 97 %;

Ή-NMR (δ ppm, DMSO): 1.65 – 2.0 (4H, m), 2.13 – 2.19 (4H, m), 2.33 – 2.48 (2H, m), 2.8 – 3.42 (6H, m), 3.67 – 3.92 (6H, m), 4.16 (2H, s), 4.49 – 4.70 (2H, m), 6.97 – 7.03 (2H, m), 7.51 – 7.54 (2H, m), 10.54 (1H, bs), 10.73 (1H, bs), 1 1.01 (lH, bs);

Mass (m/z): 374.4 (M+H)+.

Step (vii): Recrystallization of N-[4-(l-CycIobutyl piperidin-4-yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride

The reaction was done in a GLR reactor under nitrogen blanket. Methanol (24.8 L) was charged into a GLR followed by addition of above obtained technical material (6.2 Kg, 13.89 M) at 25-30 °C. The mass was stirred for 30 minutes to obtain a clear solution. Filtered the mass through nutsche and washed the nutsche with methanol (6.2 L). The filtrate and washing were charged into a clean GLR at 25-30 °C.

The contents of the reactor were heated to 62-63 °C, where a gentle reflux of methanol started. Addition of isopropanol (31 L) through the addition tank started at this temperature of ~ 62 °C. Addition of isopropanol was completed in one hour, while maintaining mass temperature at 62-63 °C. The mass was allowed to cool on its own to room temperature by applying air in the jacket. Solids were separated in the reactor at 48 °C in 3 hours. The mass was allowed to cool to ~ 35 °C on its own. The mass was further cooled to ~ 15 – 20 °C in 2 hours (brine jerks given to the reactor jacket) and the temperature was maintained at ~ 15 – 20 °C for 15 minutes.

The mass was centrifuged. The wet cake on the filter was washed with isopropanol (slurry wash) using 9 L isopropanol at 25-30 °C. The mass was spin dried in the centrifuge for 1 hour, unloaded (wet weight: 5.0 Kg) taken to vacuum tray drier and dried at 50-60 °C for 12 hours.

Weight of the product: 4.20 Kg;

Yield: 67.7 %;

HPLC purity (gradient): 99.71 %;

Any other impurity: < 0.1 %;

Salt content (di HC1): 16.16 %;

Melting Range: 247.0 – 249.5 °C;

DSC (2 °C / min, onset): 246.41 °C

TGA (5 °C / min): 0.45 %

Chemical Assay (% w/w): 101.53 %;

IR (cm“1): 3280, 3085, 2935, 2498, 1689, 1604, 1552, 1505, 1235, 1 120 and 830. Ή-NMR (δ ppm, DMSO): 1.62 – 2.0 (4H, m), 2.12 – 2.16 (4H, m), 2.37 – 2.42

(2H, m), 2.78 – 2.91 (2H, m), 3.16 – 3.60 (6H, m), 3.66 – 3.91 (5H, m), 4.17 (2H, s), 4.47 – 4.70 (1 H, m), 6.96 – 7.03 (2H, m), 7.52 – 7.56 (2H, m), 10.69 (1H, bs),

10.86 – 10.89 (1H, bd), 1 1.36 – 1 1.37 (1 H, bd);

Mass (m/z): 374.4 (M+H)+.

13C-NMR (DMSO, δ ppm): 13.48, 13.61, 24.94, 25.10, 25.98, 27.89, 43.85, 47.06,

52.00, 57.08, 58.16, 63.38, 67.29, 71.20, 1 16.33, 1 17.07, 121.36, 132.02, 132.24,

153.03, 153.37, 162.43.

 

SCHEME 1

Step (i): coupling of 4-hydroxy piperidine of formula (1) with cyclobutanone of formula (2) in presence of sodium triacetoxy borohydride in a suitable solvent to obtain l-cyclobutylpiperidin-4-ol of formula (3). The solvent used in the reaction can be selected from halohydrocarbons, preferably ethylene dichloride. This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 12 hours to 14 hours, preferably from a period of 13 hours to 13.5 hours.

Step (ii): coupling of 1 -cyclobutylpiperidin-4-ol of formula (3) with 4-fluoro-l-nitrobenzene of formula (4) in a suitable solvent and base to obtain 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5). The solvent used in the reaction can be selected from ethers, preferably tetrahydrofuran. The base used in the reaction can be selected from alkali metal hydrides, preferably sodium hydride. This reaction is carried out at temperature of 30 °C to 45 °C, preferably 35 °C to 40 °C. The duration of the reaction may range from 5 hours to 6 hours, preferably from a period of 5.5 hours to 6 hours.

Step (iii): reduction of 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5) using ammonium chloride and iron powder, in a suitable solvent to obtain 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6). The solvent used in the reaction can be selected from aqueous alcohols, preferably aqueous ethyl alcohol. This reaction is carried out at temperature of 70 °C to 85 °C, preferably 75 °C to 80 °C. The duration of the reaction may range from 3 hours to 5 hours, preferably for a period of 4 hours.

Step (iv): reaction of 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6) with chloroacetylchloride of formula (7) in a suitable solvent and base to obtain 2-chloro-N-[4-(l-cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8). The solvent used in reaction can be selected from ethers, preferably tetrahydrofuran. The base used in reaction can be selected from alkali metal carbonates, preferably potassium carbonate. This reaction is carried out at a temperature of -10 °C to 0 °C, preferably -10 °C to -5 °C. The duration of the reaction may range from 4.5 to 5.5 hours, preferably for a period of 5 hours.

Step (v): reaction of 2-chloro-N-[4-(l -cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8) with morpholine of formula (9) in a suitable solvent and base to obtain N-[4-(l-cyclobutyl piperidin^-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10). The solvent used in the reaction can be selected from nitrile solvents, preferably acetonitrile. The base used in the reaction can be selected from alkalimetal carbonates, preferably potassium carbonate. This reaction is carried out at temperature of 75 °C to 85 °C, preferably 80 °C to 82 °C. The duration of the reaction may range from 20 hours to 30 hours, preferably for a period of 24 hours to 26 hours.

Step (vi): converting N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10) in presence of isopropanolic hydrochloride and isopropanol to N-[4-(l-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11). This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 7 hours to 8.5 hours, preferably from a period of 7.5 hours to 8 hours.

Step (vii): recrystallization of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11) in presence of isopropanol and methanol to obtain N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride of formula (I). This reaction is carried out at a temperature of 58 °C to 63 °C, preferably 62 °C to 63 °C. The duration of the reaction may range from 4 hours to 5 hours, preferably for a period of 4.5 hours.

SUVEN Life Sciences Ltd

REFERENCES

https://www.nia.nih.gov/alzheimers/clinical-trials/suvn-g3031-safety-tolerability-and-pharmacokinetics

http://www.alzheimersanddementia.com/article/S1552-5260(14)01286-2/abstract

http://suven.com/news_Apr2015_13.htm

 

///////SUVN-G3031, HISTAMINE H3 RECEPTOR ANTAGONIST, TREATMENT OF COGNITIVE DEFICITS, SUVN G3031, PHASE 1, SUVEN

O=C(CN1CCOCC1)Nc4ccc(OC2CCN(CC2)C3CCC3)cc4

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SUVN-502, From Suven Life Sciences Ltd


STR1

SUVN-502

CAS OF MONOHYDRATE  MESYLATE 1791396-45-6

CAS  MESYLATE 1791396-46-7

1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate

l-{(2-BROMOPHE YL) SULFONYLJ-5-METHOXY-3- [(4-METHYL-l-PIPERAZINYL) METHYLJ-1H-INDOLE DIMESYLATE MONOHYDRATE

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate

MF OF DIMESYLATE – C21 H24 Br N3 O3 S . 2 C H4 O3 S

Serotonin 6 receptor antagonists

 

 

 

STR1

……………..BASE form of SUVN-502

1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole

CAS  OF BASE 701205-60-9, 478.40, C21 H24 Br N3 O3 S

1H-​Indole, 1-​[(2-​bromophenyl)​sulfonyl]​-​5-​methoxy-​3-​[(4-​methyl-​1-​piperazinyl)​methyl]​-​, methanesulfonate (1:2)

5-HT 6 receptor antagonist

SUVN-502 (in phase II)

https://www.clinicaltrials.gov/ct2/show/NCT02580305

Suven Life Sciences Ltd

 

 

IN 2013CH05537

Used as 5-HT 6 receptor antagonist for treating Alzheimer’s disease, attention deficit hyperactivity disorder, Parkinson’s disease and schizophrenia.

SUVN-502

SUVN-502 is a pure 5-HT6 receptor antagonist with >1200-fold selectivity over 5-HT2A receptor with a superior profile that differentiates from competitor 5-HT6 antagonists. SUVN-502 has an excellent human pharmacokinetics for once a day treatment.

The Phase 2A trial is designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of SUVN-502 for the treatment of moderate Alzheimer’s Disease (AD).This trial is expected to enrol 537 patients and the primary objective of the study is to evaluate the efficacy of a serotonin receptor subtype 6 (5-HT6) antagonist, SUVN-502, at daily doses of 50 mg or 100 mg compared to placebo, as adjunct treatment in subjects with moderate Alzheimer’s disease (Mini-Mental State Examination [MMSE] score of 12 to 20) currently treated with the acetylcholinesterase inhibitor, Donepezil Hydrochloride (HCl) and the N-methyl-D-aspartic acid (NMDA) antagonist, MemantineHCl. Efficacy will be assessed by the 11-item Alzheimer’s Disease Assessment Scale for Cognitive Behaviour (ADAScog-11) after 26 weeks of treatment. The trial is likely to complete by end of second quarter 2017, subject to the achievement of estimated 12 months’ enrolment goal in USA.

Secondary objectives of this POC study are to further evaluate the efficacy of these treatments usingClinical Dementia Rating (CDR) Scale, Sum of Boxes (CDR-SB), MMSE, Alzheimer’s Disease Co-operative Study Activity of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI) 12 item and Cornell Scale for Depression and Dementia (C-SDD).

This study is being coordinated by Dr. Jeffrey Cummings, MD, Director, Cleveland Clinic Lou RuvoCenter for Brain Health, Las Vegas, NV, USA.

Prior to the initiation of Phase 2A study, SUVN-502 has successfully undergone two phase 1 studies in Switzerland and USA on 122 healthy young and elderly male populations with no major adverse events and no serious adverse events.

5-HT6 receptor is one of the potential therapeutic target for the development of cognitive enhancers for the treatment of Alzheimer’s disease (AD) and schizophrenia. 5-HT6 receptor is localized exclusively in central nervous system, in areas important for learning and memory. In recent years several studies (Brain Research, 1997, 746, 207-219; Journal of

Neuroscience, 1998, 18(15), 5901-5907; International Review of Neurobiology Volume 96, 201 1 , 27-47 & Annual Reviews in Pharmacology and Toxicology, 2000, 40, 319-334a) have reported that 5-HT6 receptor antagonists show beneficial effect on cognition in animal models.

 

PATENT

WO2015083179

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083179

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate of formula (I) of the present invention is illustrated by the Sc eme-1 as given below:

Mannich Adduct

Scheme-1

Example 1: Preparation of l-[(2-bromophenyI)suIfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole dimesylate monohydrate

Step (i) & (u): Preparation of 5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole

Step (i):

1-Methylpiperazine (15 Kg, 0.15 Kg Mole) was charged into a reactor. The mass was cooled to 5 °C – 10 °C. Demineralised water (12 Kg) was added to the above mass slowly, maintaining the mass temperature 10 °C – 20 °C, over a period of 30 minutes. Then added acetic acid (6.16 Kg, 0.103 Kg Mole) to the above mass in 30 minutes, maintaining the mass temperature at 10 °C – 20 °C. The mass was further stirred for another 15 – 20 minutes at 10 °C – 20 °C and aqueous formaldehyde solution (15.67 Kg, 30 % w/v, 0.1567 Kg Mole) was added in 60 minutes maintaining the mass temperature at 15 °C – 20 °C. The resultant thick, red colored reaction mass was stirred for another 2 hours at 20 °C – 30 °C to obtain the mannich adduct.

Step (ii):

Simultaneously in a separate reactor 125 Kg of methanol was charged at 25 °C – 35 °C. 5-methoxyindole (20 Kg, 0.1359 Kg Mole) was added and the mass was stirred to obtain a clear solution. The mass was cooled to 8 °C – 10 °C in 1.5 hours by circulating brine in the reactor jacket. The Mannich adduct, prepared as above, was charged into the reactor containing cooled methanolic solution of 5-methoxyindole from an addition tank over a period of 50 – 60 minutes, while maintaining the temperature of the reaction mass at 8 °C – 16 °C. After completion of addition, the mass temperature was allowed to rise to 20 °C – 35 °C. Then the reaction mass was further stirred for 3 hours at 20 °C – 35 °C. After completion of the reaction (thin layer chromtography), the reaction mass was discharged into clean and dry containers.

Another reactor was charged with 400 L of demineralised water followed by the addition of 20 Kg of lye solution at 20 °C – 35 °C. The content was cooled to 10 °C – 15 °C under stirring. The above reaction mass in the containers was added to the reactor, maintaining the mass temperature at 10 °C – 15 °C in 30 – 40 minutes. The final pH of the solution was adjusted to 9 – 12, if necessary by adding some more lye solution. Then the product was extracted with ethyl acetate (1 x 260 L & 4 x 160 L) maintaining the mass temperature at 10 °C – 15 °C during the entire operations. The pH of aqueous layer was adjusted to 9 – 12 before each extraction.

The combined organic layer was washed with (2 x 170 Kg) of brine solution (the brine solution was prepared by adding 95 Kg of vacuum salt to 245 Kg of demineralised water) at 20 °C – 35 °C. The total organic extracts, obtained after the brine washing, were dried over 35 Kg of anhydrous sodium sulfate under stirring for 30 minutes at 20 °C – 35 °C.

The organic layer was filtered and charged into another clean reactor. The solvent was removed totally under 500 – 600 mm of Hg vacuum, at 20 °C – 45 °C.

The residual mass, thus obtained, was cooled to room temperature and charged 60 L toluene and stirred the contents at 20 °C – 45 °C for 15 minutes. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C. The operation was repeated again by the addition of 60 L toluene and stirring the contents at 20 °C – 45 °C for 15 min. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C again to ensure total removal of ethylacetate to avoid losses during recrystallization step. The residual technical product, 5-methoxy-3-[(4-methyl-l- piperazinyl)methyl]-lH-indole, thus obtained, was recrystallized twice, as per the details given below, to obtain the product of desired purity.

Step (Hi): Crystallization of 5-methoxy-3-[(4-methyI-l-piperazinyl)methyl]-lH-indoIe

Charged 61 Kg of toluene into the above reactor which contains the technical product, 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole. The contents were heated to 85 °C – 95 °C and maintained for an hour at 85 °C – 95 °C. The clear solution, thus obtained, was allowed to cool to 30 °C – 40 °C by circulating room temperature water in the reactor jacket. The mass was further cooled to 10 °C – 15 °C and maintained for 3 hours at the same temperature. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 18 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 20 L of n-hexane and sucked dry to obtain 22.7 Kg of crystalline material.

Step (iv): Recrystallization of 5-methoxy-3-[(4-methyI-l-piperazinyI)methyl]-lH-indole

Charged 40 Kg of toluene into a reactor followed by the addition of the 5-methoxy- 3-[(4-methyl-l-piperazinyl)methyl]-l H-indole (22.7 Kg) obtained in the first crystallization step under stirring. The contents were heated to 95 °C – 105 °C and maintained for 2 hours to obtain a clear solution. The mass was allowed to cool to 35 °C -40 °C by circulating room temperature water in the jacket. It was further cooled to 10 °C -15 °C and maintained for 3 hours at 10 °C – 15 °C. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 8 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 15 L of n-hexane and sucked dry. The material was further dried in tray driers at 20 °C – 25 °C to obtain the title product, as off white crystalline powder.

Weight of the crystallized material: 19.95 Kg;

Yield (based on 5-methoxyindole charged): 56.6 %;

HPLC purity: 99.74 %;

Total impurities: 0.26 %;

Assay: 100.6 %;

Moisture content: 0.24 %;

Melting range (°C): 139 – 140.6;

IR spectra (cm“1): 3125, 2951, 1875, 1622, 1585, 1492, 1351, 1288, 1215, 1059, 930, 654; Ή – NMR (CDCI3, δ ppm): 2.30 (3H, s), 2.5 (8H, bs), 3.71 (2H, s), 3.86 (3H, s), 6.83 -6.86 (1H, dd, J = 8.81, 2.7 Hz), 7.01 (1H, d, J = 2.06 Hz), 7.18 – 7.20 (2H, m), 8.91 (1H, s); 13C – NMR (CDCI3, δ ppm): 45.89, 52.79, 53.39, 55.1 1, 55.83, 101.3, 1 1 1.39, 11 1.75, 1 11.81, 124.88, 128.45, 131.48, 153.77;

Mass [M+H]+: 260.3.

Step (v): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyI]-lH-indoIe

Tetrahydrofuran (85.78 Kg) was charged into a reactor at 20 °C – 35 °C. Then charged the crystallized 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole (21.5 Kg, 0.0829 Kg Mole) into the reactor at 20 – 35 °C and stirred the mass well. The mass was cooled to 10 °C – 20 °C with chilled water in the jacket. Charged powdered potassium hydroxide (16.1 1 Kg) to the above suspension at 10 °C – 20 °C in 10 minutes under stirring. Slight exotherm was observed. Mass temperature rose from 15.1 °C to 16.3 °C. The mass was further stirred for 60 minutes at 10 °C – 20 °C. A solution of 2-bromobenzenesulfonyl chloride (27.71 Kg, 0.1084 Kg Mole) in 41.72 Kg tetrahydrofuran was added through addition tank at a constant rate in 60 minutes at 10 °C – 30 °C. The reaction was exothermic and the mass temperature went up from 16 °C to 30 °C. Then removed the chilled water from the jacket and stirred the mass for 3 hours at 25 °C – 35 °C. As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by thin layer chromatography (Eiuent system: Chloroform and Methanol in 8:2 ratio and the product is relatively non-polar). Since thin layer chromatography shows the presence of starting material (5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole), another lot of 2-bromo benzenesulfonyl chloride (4.5 Kg, 0.0176 Kg Mole) dissolved in 13.71 Kg tetrahydrofuran was added to the reaction mass at 30 °C in 25 minutes. No exotherm observed. The reaction mass was further stirred for 60 minutes at 30 °C – 35 °C. Since the starting material was absent as per thin layer chromatography, it was taken for further workup.

In the mean while charged 360 L demineralised water into another reactor and cooled the contents to 10 °C – 15 °C. The above reaction mass was quenched into chilled water in 60 minutes (mass temperature was 12.1 °C). The pH of the reaction mass was adjusted to ~ 9.5 with an aqueous solution of potassium hydroxide. The product was extracted with (4 x 155 L) ethyl acetate maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction. The combined organic layer was taken for extraction of the product into aqueous acetic acid. . j

Acetic acid (8.69 Kg, 0.1448 Kg mole) was dissolved in 137 L of demineralised water and cooled the mass to 10 °C – 15 °C. Charged the above organic extracts into it and stirred for 30 minutes at 10 °C – 15 °C. The mass was allowed to settle for 20 minutes and separated the bottom aqueous acetic acid extract containing the product into a fresh clean reactor.

Further, the extraction and separation process with fresh aqueous acetic acid solution was repeated thrice using 3 x 145 Kg of aqueous acetic acid solution (prepared by dissolving 25.74 Kg, 0.429 Kg Mole of acetic acid in 412 L of demineralised water) following the similar procedure mentioned above, maintaining mass temperature at 10 °C -15 °C. The combined aqueous acetic acid extracts (containing the product) were taken into the reactor. It was washed with 44 L of ethyl acetate by stirring the mass at 10 °C – 15 °C for 15 minutes, followed by 15 minutes settling. The aqueous product layer was separated. The pH of the aqueous solution was found to be 4.5. The mass was cooled to 10 °C – 15 °C and the pH of the solution was adjusted to ~ 9.5 with chilled caustic lye solution (31 Kg). The product was extracted with (4 x 155 L) of ethyl acetate, maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction.

The organic layer was washed with (2 x 1 12 Kg) brine solution (prepared from 51.6 Kg vacuum salt and 175 L water) at 10 °C – 15 °C. The organic layer was dried over 32 Kg of anhydrous sodium sulfate at 20 °C – 35 °C and filtered into another clean reactor.

Solvent was removed under 500 – 600 mm Hg by circulating 50 °C – 55 °C water in the jacket of the reactor.

To the residual mass in the reactor after solvent removal, charged 36 L of methanol followed by 72 L of isopropanol. The reaction mass was heated to reflux temperature (65 °C – 75 °C). At mass temperature ~ 70 °C a clear solution was obtained. The mass was allowed to cool to 35 – 45 °C with room temperature water circulation in the reactor jacket. Further, it was cooled to 15 °C – 20 °C by circulating brine in the jacket and maintained under stirring for 2 hours at 15 °C – 20 °C. The solids were filtered through nutsche and sucked well under vacuum. The cake was washed with 36 L of isopropanol (15 °C – 20 °C) and sucked well. The wet solid material (37.76 Kg) was taken in tray drier and air dried at 25 °C – 35 °C for 60 minutes. Further, it was dried at 40 °C – 45 °C for 6 hours to obtain 32.64 Kg of the title product.

Overall Yield: 82.3 % (based on Mannich base charged);

HPLC purity: 99.36 %;

Single major impurity: 0.29 %;

Total impurities: 0.64 %;

Assay: 100.5 %;

Loss on drying at 105 °C: 0.21 %;

Melting range (°C): 128.1 – 129.2;

IR spectra (cm‘1): 2931, 2786, 1607, 1474, 1369, 1222, 1 178, 1032, 737, 597;

Ή – NMR (CDC13, δ ppm): 2.29 (3H, s), 2.32 – 2.50 (8H, bs), 3.62 (2H, s), 3.83 (3H, s),

6.83 – 6.86 (1H, dd, J = 8.98, 2.46 Hz), 7.19 – 7.20 (1H, d, J = 2.42 Hz), 7.36 – 7.40 (1 H, dt,

J.= 7.68, 1.56 Hz), 7.45 – 7.47 (1H, t, J = 7.50 Hz), 7.53 – 7.55 (1H, d, J = 9.00, Hz), 7.64 – 7.66 (2H, m), 8.03 – 8.05 (1H, dd, J = 7.89, 1.54 Hz);

13C – NMR (CDCI3, δ ppm): 45.94, 53.07, 53.33, 55.17, 55.60, 103.28, 1 13.20, 1 13.69,

117.83, 120.42, 127.05, 127.69, 129.57, 131.16, 131.57, 134.48, 135.90, 138.09, 156.12;

Mass [M+Hf: 478.1, 480.1.

Step (vi): Preparation of l-[(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyI-l-piperazinyl)methyI]-lH-indoIe dimesylate

Charged 182.5 Kg of absolute ethanol into a reactor at 20 °C – 35 °C. Then charged l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole -(obtained in the above step, 32.02 Kg, 0.067 Kg Mole) under stirring in a single lot at 20 °C – 35 °C (mass temperature), added methanesulfonic acid (13.9 Kg, 0.1446 Kg Mole) slowly to the above reaction mass from a holding tank in 60 minutes, maintaining mass temperature at 20 °C – 35 °C. No clear solution was obtained at any stage. The mass became thick, but stirrable. The reaction mass was stirred for 24 hours maintaining mass temperature between 25 °C – 30 °C. The mass was filtered through nutsche under nitrogen atmosphere and it was sucked well. The cake, thus obtained, was washed thoroughly with 48 L of ethyl alcohol (slurry wash), sucked well and the cake was again washed with 18 L of ethyl alcohol (spray wash) followed by washing with n-hexane (27 L). It was sucked dry to obtain 70.23 Kg wet cake. The wet cake was taken in a tray drier and dried at 20 °C – 35 °C for 10 hours to obtain 49.43 Kg product (LOD: ~ 9.57 %).

Weight of product on dry basis: 44.65 Kg

Yield of salt: Quantitative (based on l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methy 1- 1 -piperaziny l)methy 1]- 1 H- indo le charged) ;

HPLC purity: 99.69 %;

Total impurities: 0.31 %;

Salt content: 27.39 %.

Step (vii): Preparation of l-[(2-bromop enyl)sulfonyI]-5-methoxyr3-[(4-methyI-l-piperazinyl)methyl]-lH-indole dimesylate monohydrate

Charged 415 Kg of aqueous ethanol (95 % ethanol & 5 % water) into a reactor, followed by the addition of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate (44.65 Kg, 0.0666 Kg Mole, obtained from the above step) at 20 °C – 35 °C. In the meanwhile carbon slurry was prepared separately by adding 6.7 Kg of carbon powder into 18 Kg of aqueous ethanol (95 % ethanol & 5 % water). Then the carbon slurry was transferred to the reactor and the reaction mass was heated at 75 °C – 80 °C by circulating 80 °C – 90 °C hot water in the reactor jacket for 45 minutes. The mass was filtered hot into another clean reactor, washed the carbon bed with 54.25 Kg of aqueous ethanol (95% ethanol & 5% water) at 75 °C – 80 °C. The contents of the reactor were heated at reflux temperature (76 PC – 78 °C) for 30 minutes to obtain a clear solution. The mass was allowed to cool on its own to 45 °C in 10 hours by applying compressed air in the reactor jacket. It was further cooled to 10 °C – 15 °C with chilled water circulated in the jacket and maintained under stirring for 3 hours. Filtered the crystalline material through a centrifuge and the material on the centrifuge was washed with 18.6 Kg of aqueous ethanol (95 % ethanol & 5 % water) (10 °C – 15 °C) and spin dried. The whole material was air dried in a tray drier for 14 hours at 20 °C – 35 °C. The material was milled, sieved and collected in poly bag to obtain 37.7 Kg of the title product. The uniform material was sampled for analysis.

Weight of dry product: 37.7 Kg;

Yield of salt: 82.2 %;

HPLC purity: 99.7 %;

Single impurity: 0.3 %;

Assay: 99.9 %;

Moisture content: 2.61 %;

Salt content (Dimesylate) 27.56 %;

Melting range (°C): 218.0 – 220.0;

IR spectra (cm“1): 3148, 3012, 161 1, 1590, 1471, 1446, 1439, 1382, 1220, 1 194, 1 180, 1045, 775, 596;

Ή – NMR (D20, δ ppm): 2.65 (6H, s), 2.89 (3H, s), 3.52 (8H, bs), 3.70 (3H, s), 4.46 (2H, s), 6.75 – 6.78 (1H, dd, J = 9.07, 2.02 Hz), 7.10 – 7.1 1 (1H, d, J = 1.9 Hz), 7.32 – 7.38 (2H, m), 7.44 – 7.47 (1H, t, J = 7.6 Hz), 7.54 – 7.56 (1H, dd, J = 7.79 Hz), 8.04 (1H, s), 8.14 -8.16 (lH, d, J = 7.94 Hz);

, C – NMR (δ ppm): 38.42, 42.79, 48.19, 50.35, 55.80, 102.57, 108.20, 113.72, 114.07, 1 19.62, 128.25, 128.56, 130.17, 131.80, 132.15, 135.28, 135.95, 156.21 ;

Mass [M+H]+: 478, 480.

 

PATENT………on metabolite and not the drug

caution……….drug has a methyl

WO-2016027276

Suven Life Sciences Ltd is developing l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- l -piperazinyl)methyl]-lH-indole dimesylate monohydrate, which is a selective 5-HT6 receptor antagonists intended for the symptomatic treatment of AD and other disorders of memory and cognition like attention deficient hyperactivity, parkinson’s and schizophrenia. 1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole, and its pharmaceutically acceptable salts were disclosed by Ramakrishna et al. in WO 2004/048330. l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate;monohydrate has already completed Phase 1 clinical trials. Based on phase I clinical trials results, we confirmed l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -piperazinyl)methyl]-lH-indole of formula (I) as an active metabolite of l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- 1 -piperazinyl)methyl]- 1 H-indoIe dimesylate monohydrate in human volunteers.

The development and understanding of the metabolism of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate is desirable for progression of science and necessary step in the commercialization of this compound. Therefore, there is a need to understand regarding metabolism and metabolites of l-t(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate.

In order to improve pharmaceutical properties and efficacy of active metabolite, we performed salt selection program for l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. Based on the results obtained, dimesylate dihydrate salt of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole of formula (Π) is selected for further development along with the compound of formula (I).

 

l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. NOTE THE DRUG IS WITH A METHYL

 

 

SCHEME 1

SCHEME2

Example 1: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indo

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

Step (i):

Demineralized water (DM water) (660 mL) and N-Boc piperazine ( 150.0 grams, 0.8034 moles) were charged into a 2 Litres three necked round bottomed flask provided with a mechanical stirrer and a thermometer pocket. The mass was stirred for 10 minutes at 25 °C, to obtain a clear solution. Then acetic acid (32.5 mL, 0.5416 moles) was added to the above mass while maintaining the mass temperature at ~ 25 °C in 10 minutes. After completion of addition, the clear solution was stirred at 25 °C for 30 minutes.

To the above stirred mass at 25 °C, aqueous formaldehyde solution (81 mL, 30 % w/v, 0.81 moles) was added slowly through an addition funnel over a period of 30 minutes maintaining the mass temperature below 25 °C. During the addition, white slurry mass was formed. The resultant white slurry mass was stirred for another 1 hour at 25 – 30 °C. Methanol (MeOH) (300 mL) was added to the above mass to obtain a clear solution. The solution was further stirred for 30 minutes at 25 °C to obtain Mannich adduct.

Step (ii):

5-Methoxyindole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1

Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC13, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 ( 1 H, d, J = 0.96 Hz), 7.19 (1 H, d, J = 2.24 Hz), 7.24 – 7.26 (1H, d), 8.04 (1H, bs);

Mass [M+H]+: 346.2.

Step (iii): Purification of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

n-Hexane (1.25 Litres) was taken in 2 Litres four necked round bottom flask equipped with thermometer pocket and mechanical stirrer and charged the above obtained technical compound (270.9 grams). The mass was stirred for 1 hour at 25 °C. The product was filtered through Buckner funnel under vacuum. The compound was washed with n-hexane (2 x 125 mL), sucked well and air dried at 25 °C for 20 hours to obtain 240.0 grams of above title compound. Yield: 96 %;

Purity: 97.09 %;

Ή – NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1H, d, J = 1 .57 Hz), 7.19 ( 1 H, d, J = 2.2 Hz), 7.23 – 7.25 (l H, d, J = 8.77 Hz), 8.25 (lH, bs); –

Mass [M+H]+: 346.2.

Step (iv): Preparation of l-[(2-BromophenyI)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yl)methyI]-lH-indole

Tetrahydrofuran (THF) (4.6 Litres) was charged into a reactor at 25 °C, followed by the addition of powdered potassium hydroxide (860.6 grams, 85 %, 13.06 moles) at 25 °C under stirring. THF (3 Litres) was charged into a 5 Litres, three necked round bottom flask, provided with a mechanical stirrer and thermometer pocket. 3-[(l -t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-lH-indole (obtained in above step) (1287.7 grams, 3.7324 moles) was charged into the flask at 25 °C and stirred the mass well for complete dissolution. Then the clear 3-[(l-t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-l H-indole solution, prepared as above, was slowly transferred to the reactor containing potassium hydroxide under stirring, maintaining the mass temperature below 25 °C. After completion of the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2-bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar. The starting material was absent as per TLC. A second lot of 2-bromophenylsuIfonyl chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction, The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was found to be 1 1.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC13, 5 ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1H, m), 7.64

– 7.66 (2H, m), 8.06 – 8.08 (1H, d, J = 7.76 Hz);

Mass [M+Hf : 564.3, 566.4.

The organic layer.was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yI)methyI]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1.6 Litres + 0.8 Litres). It was sucked well and air dried at 40 – 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Cream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (lH, dd, J = 8.34, 2.09 Hz), 7.19 (1 H, d, J = 2.0 Hz), 7.36 – 7.40 (1 H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7.56 Hz), 7.52 – 7.55 (1 H, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 ( 1H, d, J = 7.87 Hz); Mass: [M+H]+: 564.3, 566.3.

Step (vi): Preparation of l-((2-bromophenyl)snlfonyI]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dihydrochloride

S

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-t-butyloxycarbonyl-l -piperazinyl)methyl]-lH-indole (20.2 grams, 0.03578 M, obtained in the above step) was suspended in 250 mL of absoliite ethanol at 25 °C and then added 20 mL of 30 % (w/w) aqueous hydrochloric acid drop wise under stirring over a period of 30 minutes, whereby a clear solution was obtained. The reaction was exothermic and temperature went upto 38 °C. The mass was further heated at reflux for 4 hours. During this period solids separated. The mass was stirred for another 2 hours at reflux. The progress of the reaction was monitored by thin layer chromtography. After completion of the reaction, the mass was cooled to 25 °C and filtered the solids under suction. The solid on the filter was washed with 30 mL of absolute ethanol and the mass was dried under rotavacuum at 40 – 45 °C for 1 hour to obtain l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[( 1 -piperazinyl)methyl]- 1 H-indole dihydrochloride (19.28 grams).

Purity: 99.8 %,

Mass: [M+H]+: 464.2, 466.2.

Step (vii): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole

The above obtained compound (19.09 grams) was suspended in demineralised water (300 mL) and cooled to 15 – 20 °C. The mass was basified to pH 10.5 to 1 1.0 by adding 40 % (w/w) lye solution, maintaining mass temperature below 20 °C under nitrogen atmosphere. The product was extracted with (2 x 150 mL) ethylacetate. The combined organic layer was washed with (100 mL) saturated brine solution, dried over anhydrous sodium sulfate and

solvent removed under rotavacuum at 40 – 45 °C to obtain the title compound (15.91 grams).

Yield: 96. 4 %

Purity: 99.89 %,

DSC (5 °C / minutes): 99.6 °C;

TGA (5 °C / minutes): 0.76 %;

Ή – NMR (CDCI3, δ ppm): 1.85 (1H, s), 2.44 (4H, bs), 2.86 – 2.88 (4H, t), 3.59 (2H, s), 3.76 (3H, s), 6.82 – 6.84 (lH, dd, J = 9.0, 2.45 Hz), 7.20 – 7.21 (1H, d, J = 2.28 Hz), 7.33 – 7.37 (1H, dt, J = 7.48 Hz), 7.41 – 7.44 (1 H, t), 7.52 – 7.54 (1H, d, J = 7.65 Hz), 7.62 – 7.64 (2H, m), 8.01 – 8.03 (1H, dd, J = 7.98, 1.15 Hz);

Mass: [M+H]+: 464.2, 466.2.

Example 2: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-in

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyl]-5-methoxy-lH-indoIe

Step (i):

Demineralized water (DM water) (660 mL) and N-Boc piperazine ( 150.0 grams, 0.8034 moles) were charged into a 2 Litres three necked round bottomed flask provided with a mechanical stirrer and a thermometer pocket. The mass was stirred for 10 minutes at 25 °C, to obtain a clear solution. Then acetic acid (32.5 mL, 0.5416 moles) was added to the above mass while maintaining the mass temperature at ~ 25 °C in 10 minutes. After completion of addition, the clear solution was stirred at 25 °C for 30 minutes.

To the above stirred mass at 25 °C, aqueous formaldehyde solution (81 mL, 30 % w/v, 0.81 moles) was added slowly through an addition funnel over a period of 30 minutes maintaining the mass temperature below 25 °C. During the addition, white slurry mass was formed. The resultant white slurry mass was stirred for another 1 hour at 25 – 30 °C. Methanol (MeOH) (300 mL) was added to the above mass to obtain a clear solution. The solution was further stirred for 30 minutes at 25 °C to obtain Mannich adduct.

Step (ii):

5-Methoxy indole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1 Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC13, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 (1Ή, d, J = 0.96 Hz), 7.19 (1H, d, J = 2.24 Hz), 7.24 – 7.26 (1 H, d), 8.04 (1H, bs);

Mass [M+H]+: 346.2.

Step (iii): Purification of 3-[(l-t-ButyloxycarbonyI piperazin-4-yl)methyl]-5-methoxy-lH-indole

n-Hexane (1.25 Litres) was taken in 2 Litres four necked round bottom flask equipped with thermometer pocket and mechanical stirrer and charged the above obtained technical compound (270.9 grams). The mass was stirred for 1 hour at 25 °C. The product was filtered through Buckner funnel under vacuum. The compound was washed with n-hexane (2 x 125 mL), sucked well and air dried at 25 °C for 20 hours to obtain 240.0 grams of above title compound. Yield: 96 %;

Purity: 97.09 %;

Ή – N R (CDC13, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (lH,jdd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1 H, d, J = 1.57 Hz), 7.19 ( 1H, d, J = 2.2 Hz),

7.23 – 7.25 (1H, d, J = 8.77 Hz), 8.25 (1H, bs);

Mass [M+H]+: 346.2.

Step (iv): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl pipera

Tetrahydrofuran (THF) (4.6 Litres) was charged into a reactor at 25 °C, followed by the addition of powdered potassium hydroxide (860.6 grams, 85 %, 13.06 moles) at 25 °C under stirring. THF (3 Litres) was charged into a 5 Litres, three necked round bottom flask, provided with a mechanical stirrer and thermometer pocket. 3-[( 1 -t-Butyloxycarbonyl piperazin-4-yl)methyl]-5-methoxy-lH-indole (obtained in above step) (1287.7 grams, 3.7324 moles) was charged into the flask at 25 °C and stirred the mass well for complete dissolution. Then the clear 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyl]-5-methoxy-l H-indole solution, prepared as above, was slowly transferred to the reactor containing potassium hydroxide under stirring, maintaining the mass temperature below 25 °C. After completion of

the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2- bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar, The starting material was absent as per TLC. A second lot of 2-bromophenylsulfony] chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction. The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was 11.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC , δ ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1 H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1 H, m), 7.64 – 7.66 (2H, m), 8.06 – 8.08 (1 H, d, J = 7.76 Hz);

, Mass [M+H : 564.3, 566.4.

The organic layer was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-BromophenyI)suIfonyl]-5-methoxy-3-[(l-t- butyloxycarbonyl piperazin-4-yl)methyl]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and

methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1 .6 Litres + 0.8 Litres). It was sucked well and air dried at 40

– 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Gream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDQlj, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (1H, dd, J =.8.34* 2.09 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.36 – 7.40 (1H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7÷56 Hz), 7.52 – 7.55 (lH, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 (1 H, d, J = 7.87 Hz); Mass: [M+H]+: 564.3, 566.3.

Step (vi): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl)-l

9

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -t-butyIoxycarbonyl piperazin-4-yl)methyl]-lH-indole (obtained in the above step, 1540 grams, 2.73 mole) was dissolved in acetone (30.8 Litres) and charged into a glass lined reactor. The temperature of the reaction mass was raised to reflux temperature (56 °C). Methanesulfonic acid (920 grams, 9.57 moles) diluted with acetone (6 Litres) was added to the above mass at reflux temperature, slowly over a period of 30 minutes, through an addition funnel. During addition vigorous reflux was observed. The reaction mass was a clear solution before and after the addition of methanesulfonic acid solution. After stirring for ~ 90 minutes at reflux, thick mass of solids separated out. The progress of the reaction was monitored by TLC. The reaction was completed in 4 hours. Then the mass was cooled to 25 °C and further stirred for two hours at 25 °C. The product was filtered through nutsche filter under vacuum. The product on the nutsche filter was washed with acetone (8 Litres). The material was unloaded into trays and air dried at 30-35 °C for 4 hours in a tray drier. Weight of the product: 1.61 Kg (off white with pinkish tinge).

Yield: 90 %;

Salt content (dimesylate): 32.1 % w/w;

Purity: 99.97 %;

Ή – NMR (D20, 5 ppm): 2.64 (6H, s), 3.48 (4H, bs), 3.53 (4H, bs), 3.70 (3H, s), 4.50 (2H, s), 6.75 – 6.78 (1H, dd, J = 8.97, 1.92 Hz), 7.11 (1H, d, J = 1.78 Hz), 7.32 – 7.34 ( 1H, t, J = 9.28 Hz), 7.34 – 7.38 (lH, t, J = 7.63 Hz), 7.44 – 7.48 ( 1H, d, 3 = 7.76 Hz), 7.54 – 7.56 (2H, d, J = 7.85 Hz), 8.06 (1H, s), 8.15 – 8.17 (2H, d, J = 7.87 Hz);

Mass: [M+H]+: 464.2, 466.2.

Step (vii): Preparation of l-{(2-Bromophenyl)suIfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-l

Acetone (24.15 L) was taken in a Glass Lined Reactor at 25-30 °C, followed by l-[(2-Bromo phenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dimesylate (obtained in the above step) (1.61 Kg) and the resulting mass was stirred To obtain slurry. DM water (4.0 L) was added to the reactor and then the mass temperature was raised to reflux temperature (56.0-57.5 °C). A clear solution was obtained at reflux. It was maintained for 15 minutes. The mass was cooled to 45-50 °C and added activated carbon (161 grams) to the mass and stirred the mass for 45 minutes at reflux temperature: It was filtered hot into another reactor, which was maintained at 50 °C. The clear filtrate was allowed to cool on its own, under nitrogen

blanket. Solids separated when the mass temperature was ~ 44 °C. The mass was allowed to cool to room temperature (30-35 °C) and then it was further cooled at 10-12 °C for 2 hours. The product was centrifuged, washed with acetone (5 L) and sucked well. The wet product (weight: 1.5 Kg) was spread into trays and dried in a tray drier at 40-45 °C for 7.5 hours, till organic volatile impurities are below the allowable limits. Weight of the dry product obtained: 1.3 Kg. Yield: – 76.5 %

Purity: 99.98 %;

Melting range (°C): 203.8 – 205.3;

Salt content (Dimesylate): 28.26 %;

Moisture Content: 5.2 %;

TGA: 4.9 %; ,

Ή – NMR (D20, δ ppm): 2.65 (6H, s), 3.48 (8H, bm), 3.71 (3H, s), 4.48 (2H, s), 6.77 – 6.80 (1H, dd, J = 9.18, 2.24 Hz), 7.12 – 7.13 (1 H, d, J = 2.12 Hz), 7.35 – 7.37 (1H, d, J = 9.06 Hz), 7.37 – 7.41 (1 H, t, J = 7.98 Hz), 7.46 – 7.50 (1 H, t, J = 7.66 Hz), 7.57 – 7.58 (1 H, d, J = 7.86 Hz), 8.06 ( 1H, s), 8.17 – 8.20 (1H, dd, J = 7.95, 0.87 Hz),

Mass [M+H]+: 464.2, 466.1 ;

 

PATENT

WO 2004/048330

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004048330

 

REFERENCES

http://www.avarx.com/search/showOpportunityDetails?asset_id=2424
Phase II
Alzheimer’s disease; Schizophrenia
Phase I
Attention-deficit hyperactivity disorder; Cognition disorders; Parkinson’s disease

05 Jan 2016
Suven Life Sciences has patent protection for chemical entities targeting serotonin receptors for the treatment of neurodegenerative disorders in Canada, Africa and South Korea
11 Dec 2015
Suven Life Sciences receives patent allowance for chemical entities targeting serotonin receptors in Eurasia, Europe, Israel and Macau
01 Oct 2015
Phase-II clinical trials in Schizophrenia in USA (PO)

////////

Brc1ccccc1S(=O)(=O)n4cc(CN2CCN(C)CC2)c3cc(ccc34)OC

SUVN-D4010 from Suven Life Sciences Ltd


str1

1H-​Indazole, 3-​[5-​[1-​(3-​methoxypropyl)​-​4-​piperidinyl]​-​1,​3,​4-​oxadiazol-​2-​yl]​-​1-​(1-​methylethyl)​-

CAS BASE  1428862-32-1, C21 H29 N5 O2, 383.49

str1

SUVN-D4010

C21 H29 N5 O2 . C2 H2 O4

1H-​Indazole, 3-​[5-​[1-​(3-​methoxypropyl)​-​4-​piperidinyl]​-​1,​3,​4-​oxadiazol-​2-​yl]​-​1-​(1-​methylethyl)​-​, ethanedioate (1:1)

1-isopropyl-3-{5-[1-(3-methoxypropyl)-piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3>4]oxadiazol-2-yl}-lH-indazole oxalate salt

SUVN-1004028; SUVN-D-1208045; SUVN-D1003019; SUVN-D1104010; SUVN-D1108121;

l-ISOPROPYL-3-{5-[l-(3-METHOXYPROPYL) PIPERIDIN-4-YL]-[l,3,4]OXADIAZOL-2-YL}-1H-INDAZOLE OXALATE

OXALATE CAS  1428862-33-2

IN 2011CH03203, WO2013042135, WO 2015092804,

In phase I, for treating cognitive dysfunction associated with Alzheimer’s disease, schizophrenia and neurological diseases.

Suven Life Sciences Limited, Phase I Alzheimer’s disease; Schizophrenia

https://www.clinicaltrials.gov/ct2/show/NCT02575482

  • Class Antidementias
  • Mechanism of Action Serotonin 4 receptor agonists

Used as 5-HT4 receptor agonist for treating Alzheimer’s disease, cognitive disorders, Attention deficit hyperactivity disorder, Parkinson’s and schizophrenia

  • 05 Jan 2016Suven Life Sciences has patent protection for chemical entities targeting serotonin receptors for the treatment of neurodegenerative disorders in Canada, Africa and South Korea
  • 11 Dec 2015Suven Life Sciences receives patent allowance for chemical entities targeting serotonin receptors in Eurasia, Europe, Israel and Macau
  • 02 Nov 2015SUVN D4010 is available for licensing as of 02 Nov 2015. http://www.suven.com

SUVN-D4010 for Cognition in Alzheimer’s disease commenced Phase 1 Clinical Trial in USA under US-IND 126099

HYDERABAD, INDIA (Sept 02, 2015)  – Suven Life Sciences today informed that their NCE SUVN-D4010 has commenced Phase 1 clinical trial in USA. SUVN-D4010 is a potent, selective, brain penetrant and orally active 5-HT4 receptor partial agonist for the treatment of cognitive dysfunction associated with Alzheimer’s disease and other dementias. Suven submitted Investigational New Drug Application (IND) to US FDA to conduct Phase-1 clinical trial for Cognition in Alzheimer’s Disease, under 505(1) of the Federal Food, Drug and Cosmetic Act (FDCA) which was assigned an IND number 126099.

Based on the IND# 126099, “A Single Center, Double-blind, Placebo-controlled, Randomized, Phase 1 Study to Evaluate the safety, Tolerability, and Pharmacokinetics of SUVN-D4010 after Single Ascending Doses and Multiple Ascending Doses in Healthy Male Subjects” for Cognition in Alzheimer’s Disease is underway in USA

“We are very pleased that the third compound from our pipeline of molecules in CNS has moved into clinical trial that is being developed for cognitive disorders in Alzheimer’s and Schizophrenia, a high unmet medical need which has huge market potential globally” says Venkat Jasti, CEO of Suven.

Suven Life Science is a biopharmaceutical company focused on discovering, developing and commercializing novel pharmaceutical products, which are first in class or best in class CNS therapies through the use of GPCR targets.Suven has 3 clinical stage compounds, a Phase 2 initiated candidate SUVN-502, Phase 1 completed candidate SUVN-G3031 and Phase 1 initiated candidate SUVN-D4010 for Alzheimer’s disease and Schizophrenia. In addition to that the Company has ten (10) internally-discovered therapeutic drug candidates currently in pre-clinical stage of development targeting conditions such as ADHD, dementia, depression, Huntington’s disease, Parkinson’s disease and pain

SUVEN Life Sciences Ltd

Alzheimer’s disease (AD) is a neurodegenerative disorder of advanced age characterized by loss of memory, accumulation of amyloid beta protein (Αβ) deposits and decreased levels of the neurotransmitter acetylcholine. Approximately forty percent of AD patients suffer from significant depression. 5-HT4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment for AD and may offer improved clinical efficacy and/or tolerability relative to acetylcholine esterase inhibitors. 5-HT4 receptor agonists also have antidepressant like properties (Expert Review of Neurotherapeutics, 2007, 7, 1357-1374; Experimental Neurology, 2007, 203(1), 274- 278; Neuroscience & Medicine, 201 1 , 2, 87 – 92; Schizophrenia Bulletin, 2007, 33 (5), 1 100 – 1 1 19).

1 -Isopropyl-3 – { 5 – [ 1 -(3 -methoxypropyl) piperidin-4-yl] – [ 1 ,3 ,4]oxadiazol-2-y 1 } -1 H-indazole oxalate of formula (I) is a promising pharmaceutical agent, which is a potent, selective and orally bioavailable 5-HT4 receptor partial agonist intended for both disease modifying and symptomatic treatment of Alzheimer’s disease and other disorders of memory and cognition like Attention deficient hyperactivity,

Parkinson’s and Schizophrenia. . In addition to the pro-cognitive effects, the compound also demonstrated dose dependent antidepressant like effects in the mouse forced swim test. l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate and its synthesis is disclosed by Ramakrishna et al. in WO2013042135.

At present, l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) has completed preclinical studies and is ready to enter human clinical trials. The demand for l-Isopropyl-3-{ 5- [ 1 -(3 -methoxypropyl) piperidin-4-yl]- [ 1 ,3 ,4]oxadiazol-2-yl } – 1 H-indazole oxalate of formula (I) as a drug substance would be increased substantially with the advent of its human clinical trials. The future need for much larger amounts is projected due to the intended commercialization of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4]oxadiazol-2-yl}-lH-indazole oxalate of formula (I).

For the person skilled in art, it is a well known fact that various parameters will change during the manufacturing of a compound on a large scale when compared to the synthetic procedures followed in laboratory. Therefore, there is a need to establish and optimize large scale manufacturing process. The process for the preparation of l -Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) which was disclosed in WO2013042135 had been proved to be unsatisfactory for the large scale synthesis. Eventually, it is highly desirable to establish optimized manufacturing process for l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) which is amenable to the large scale preparation.

PATENT

WO2013042135

http://www.google.com/patents/WO2013042135A1?cl=en

Example 3: Preparation of l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3>4]oxadiazol-2-yl}-lH-indazole oxalate salt

Step (i): Preparation of l-isopropyI-3-{5-[l-(3-methoxy propyl) piperidin-4-yI]- [l,3,4]oxadiazol-2-yl}-lH-indazo!e

To the mixture of l-isopropyl-lH-indazole-3-carboxylic acid hydrazide (15.0 grams, 68.8 mmol) and l-(3-Methoxy propyl)-piperidine-4-carboxylic acid hydrochloride (20.9 grams, 88.2 mmol, obtained in preparation 7) cooled at 0 °C was added phosphoryl chloride (130 mL). The reaction temperature was gradually raised to 100 °C and stirred was 2 hours. Upon completion of the reaction, it was cooled to 0 °C and triturated with hexanes (3 x 250 mL). The crude product was basified with aqueous sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3,4]oxadiazol-2-yl}-lH-indazole (15.78 grams)

Yield: 59 %.

Ή – NMR (CDCb): δ 8.35 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (t, J *= 7.0 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 5.05-4.90 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.35 (s, 3H), 3.15-2.97 (m, 3H), 2.48 (t, J = 7.3 Hz, 2H), 2.26-2.02 (m, 6H), 1.88-1.75 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H);

Mass (m/z): 384.5 (M+H)+.

Step (ii): Preparation of l-Isopropyl-3-{5-[l-(3-methoxy-propyl)-piperidin-4-yl]- [l,3,4]oxadiazoI-2-yl}-lH-indazole oxalate salt

To a stirred solution of l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3,4]oxadiazol-2-yl}-lH-indazole (12.55 grams, 32.7 mmol, obtained in the above step) in 2-propanol (200 mL), oxalic acid (4.12 grams, 32.7 mmol) was added. After stirring at room temperature for 1 hour the reaction was further diluted with 2-propanol and refluxed for 2 hours. The crystalline product which was precipitated after cooling the reaction mixture to room temperature was filtered, dried under vacuum to obtain 1- isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH- indazole oxalate salt (16.4 grams)

Yield: 88 %

Ή – NMR (DMSO-d6): δ 8.18 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 5.23 – 5.10 (m, 1H), 3.50 – 3.40 (m, 3H), 3.37 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 3.10 -2.96 (m, 4H), 2.35 – 2.25 (m, 2H), 2.18-2.02 (m, 2H), 1.94 – 1.85 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H);

Mass (m/z): 384.3 (M+H)+.

 

 

Patent

WO2016027277

The large scale manufacturing process for preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4]oxadiazol-2-yl}-lH-indazole oxalate of

Scheme-1

Preparation 1: Preparation of l-Isopropyl-lH-indazoIe-3-carboxylic acid

To a stirred solution of dimethylformamide (DMF) (50 L) at 25 °C to 30 °C under nitrogen atmosphere, sodium tert-butoxide (6.0 Kg, 62.43 mols) was added over a period of 15 minutes. The reaction mixture was stirred for 10 minutes after which it was cooled to 0 °C to 5 °C. A solution of indazole-3-carboxylic acid (4.0 Kg, 24.67 mols) in DMF (50 L) was added slowly into the reactor over a period of 45 minutes, maintaining the reaction mass temperature at 0 °C to 5 °C. The cooling was removed and the reaction temperature was gradually raised to 25 °C to 30 °C over a period of 30 minutes. After stirring at this temperature for 1 hour the reaction mixture was cooled to 0 °C and isopropyl iodide (6.32 Kg, 37.18 mo!s) was added over a period of 30 minutes. The cooling was removed and the reaction temperature was allowed to rise to 25 °C to 30 °C. After 17 hours of stirring, the HPLC analysis of the reaction mixture revealed <10 % of indazole-7-carboxylic acid remaining. The reaction mass was diluted cautiously with water (200 L) and washed with ethylacetate (2 x 100 L). The resultant aqueous layer was acidified to 4.0 – 4.5 pH with aqueous hydrochloride solution (6.0 N, 21.5 L) and extracted with ethylacetate (2 x 144 L). The combined organic layer was washed with water (2 x 100 L), brine solution (200 L) and dried over anhydrous sodium sulfate (4.0 Kg). The filtered organic layer was subjected to solvent removal under reduced pressure (> 500 mm of Mercury) at 50 °C to 60 °C to obtain a crude mass. The obtained crude mass was diluted with dichloromethane (DCM) (28.0 L) and was stirred for 15 minutes. The solids precipitated (un-reacted indazole-7-carboxylic acid) were filtered through nutsche filter and the filter bed was washed once with DCM (8.0 L). The combined filtrate was distilled under reduced pressure (> 500 mm of Mercury) at 45 °C to 55 °C to obtain a crude mass which was stirred with ether (7.0 L) for 30 minutes and filtered through nutsche filter to obtain the wet solid which was dried further in vacuum oven under reduced pressure (> 500 mm of Mercury) at 45 °C to 55 °C to obtain above titled compound (3.0 Kg) as an off-white crystalline powder.

Yield: 59.5 %;

Purity: 99.86 %;

IR (cm-‘): 2980, 1729, 1682, 1487, 1287, 1203, 1 170, 1 127, 1085, 754;

Ή-NMR (δ ppm, CDC13): 8.27 (d, J= 8.1 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), .7.46 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 5.01 – 4.95 (m, 1H), 1 .68 (d, J = 6.65 Hz, 6H);

Mass (m/z): 205.1 (M+H)+.

Preparation 2: Preparation of l-(3-Methoxypropyl) piperidine-4-carboxyIic acid hydrazide

Step (i): Preparation of Ethyl 1 -(3-methoxj propyl) piperidine-4-carboxylate

To a stirred solution of acetonitrile (97.5 L) under nitrogen atmosphere at 25 °C to 30 °C, ethyl isonipecotate (6.5 Kg, 41.35 mols) was added. The contents were stirred for 10 minutes after which potassium carbonate powder (7.35 Kg, 53.2 mols) and l-Bromo-3-methoxy propane (6.89 Kg, 45.0 mols) were sequentially added. The reaction mixture was gradually heated to reflux (82 °C – 85 °C) over a period of 30 minutes and was maintained at this temperature for 7 hours. At this time, the TLC revealed complete consumption of ethylisonipecotate. The volatiles were distilled off under reduced pressure (> 500 mm of Mercury) at 50 °C to 60 °C. The crude mass was cooled to 25 °C to 30 °C and was diluted with water (71.5 L) and DCM (136.5 L). After stirring the contents the two layers were separated. The organic layer was washed with water (71.5 L), dried over anhydrous sodium sulfate (6.5 Kg) and the volatiles were removed under reduced pressure (> 500 mm of Mercury) at 50 °C to 55 °C to obtain the desired product (9.3 Kg) as pale yellow colored liquid.

Yield: 98 %;

Purity: 98.8 %;

IR (cm‘): 2949, 1732, 1449, 1376, 1 179, 11 19, 1048;

Ή-NMR (6 ppm, CDC13): 4.06 (q, J = 7.1 Hz, 2H), 3.37 – 3.34 (t, J – 6.4 Hz, 2H), 3.27 (s, 3H), 2.83 – 2.80 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.22 – 2.18 (m, 1H), 1.96 – 1.94 (m, 2H), 1.85 – 1.82 (m, 2H), 1.74 -1.68 (m, 4H), 1.19 (t, J= 7.04 Hz, 3H);

Mass (m/z): 230.4 (M+H)+.

Step (ii): Preparation of l-(3-Methoxypropyl) piperidine-4-carboxylic acid hydrazide

To a stirred solution of methanol (38 L) under nitrogen atmosphere at 25 °C to 30 °C, ethyl l-(3-methoxypropyl) piperidine-4-carboxylate (5.0 Kg, 21.8 mols, obtained in above step) was added. After stirring the reaction mixture for 15 minutes, hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added over a period of 15 minutes. The reaction mixture was gradually heated to reflux (70 °C) over 30 minutes and continued stirring for 4 hours. Additional amount of hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added and the stirring continued for another 4 hours. Another installment of hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added and the stirring was continued for 16 hours at 70 °C, upon which the Thin Layer Chromatography (TLC) reveals < 5 % of ester. The volatiles were distilled off under reduced pressure (> 500 mm of Mercury) at 60 °C until syrupy mass appeared. After cooling syrypy mass to room temperature (25 °C – 30 °C), it was diluted with DCM (38.0 L) and was stirred for 15 minutes. The observed two layers were then separated. The organic layer was dried over anhydrous sodium sulfate (5.0 Kg) and the solvent was evaporated under reduced pressure (> 500 mm of Mercury) at 55 °C until dryness. The solid product which was separated was cooled to 25 °C to 30 °C, diluted with hexanes (15.0 L) and the resultant slurry was filtered at nutsche filter. The filter bed was washed once with hexanes (15.0 L) and ethylacetate (2 x 10.0 L). The product cake was vacuum dried and the solid material thus separated was further dried in vacuum oven under reduced pressure (> 500 mm of Mercury) at 50 °C for 6 hours to obtain the above titled compound (4.1 Kg) as an off-white crystalline powder.

Yield: 87 %;

Purity: 99.79 %;

IR (cm-‘): 3290, 3212, 2948, 2930, 1637, 1530, 1378, 1 124, 1 1 13, 986, 948, 789, 693;

Ή-NMR (δ ppm, CDC13): 6.83 (s, 1H), 3.86 (bs, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.99 – 2.96 (m, 2H), 2.42 (t, J= 7.44 Hz, 2H), 2.1 1 – 1.96 (m, 3H), 1.82 – 1.73 (m, 6H);

Mass (m/z): 216.3 (M+H)+.

Example 1: Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yI]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate

Step (i): Preparation of N-[l-(3-Methoxypropyl) piperidine-4-carbonyI] ‘-(l-isopropyI-lH-indazole-3-carbonyl) hydrazine

To a stirred solution of 1 ,2-dichloroethane (19.8 L) under nitrogen atmosphere at 25 °C to 30 °C, l -isopropyl-lH-indazole-3-carboxylic acid (3.0 Kg, 14.69 moles, obtained in preparation 1 ) was added and the reaction mixture was stirred for 15 minutes for complete dissolution. Thionyl chloride (3.6 Kg, 30.25 mols) was then added to the reaction mixture by maintaining its temperature below 30 °C over a period of 15 minutes. The reaction temperature was then gradually raised to 75 °C over a period of 30 minutes and was stirred for 2 hours at that temperature. The TLC revealed complete conversion of acid to acid chloride. The solvent 1,2-dichloroethane and excess thionyl chloride was removed under reduced pressure (> 500 mm of Mercury) below 60 °C temperature. The obtained residual mass was cooled to 25 °C to 30 °C, and diluted with DCM (15.6 L). The contents were further cooled to 0 °C to 5 °C. A solution of l-(3-Methoxypropyl) piperidine-4-carboxylic acid hydrazide (3.0 Kg, 1 3.94 mols, obtained in the preparation 2) in DCM (18.0 L) was added to the reaction mass over a period of 30 minutes. The reaction temperature was then gradually raised to 25 °C to 30 °C and the reaction mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC which showed absence of hydrazide (< 1.0 %). The reaction mixture was then diluted with water (30.0 L), stirred for 15 minutes and the two layers were separated. The aqueous layer was washed with DCM (1 x 30.0 L), cooled to 0 °C to 5 °C and cautiously basified to pH 7.6 with aqueous sodium bicarbonate solution (10 % w/v, 46.5 L). The basified aqueous layer was then extracted with DCM (2 x 30.0 L). The combined organic layer was dried over anhydrous sodium sulfate (6.0 Kg) and the solvent was removed under reduced pressure (> 500 mm of Mercury) below 55 °C. The residue was then cooled to 25 °C – 30 °C and diluted with solvent hexane (9.0 L). The slurry, thus obtained, was centrifuged at room temperature under nitrogen atmosphere and the wet product cake was washed with hexanes (6.0 L). The wet product was then dried in oven at 55 °C -60 °C until loss on drying was < 1.0 % to obtain the above titled compound (4.4 Kg) as an off white crystalline powder.

Yield: 74.5 %;

Purity: 98.75 %;

IR (cm-1): 3506, 3233, 2943, 1703, 1637, 1523, 1487, 1 195, 1 1 16, 750;

Ή-NMR (δ ppm, CDC13): 9.35 (bs, 1H), 8.70 (bs, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.90 -4.85 (m, 1H), 3.40 (t, J = 6.4 Hz, 2H), 3.33 (s, 3H), 2.94 – 2.85 (m, 2H), 2.39 -2.31 (m, 3H), 1.92 – 1.88 (m, 4H), 1.76 – 1.65 (m, 4H), 1.59 (d, J = 6.6 Hz, 6H); Mass (m/z): 402.2 (M+H)+.

Step (ii): Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3»4]oxadiazol-2-yl}-lH-indazole

To a stirred solution of 1 ,2-dichloroethane (60 L) under nitrogen atmosphere at 25 °C to 30 °C, N-[l-(3-methoxypropyl) piperidine-4-carbonyl] N’-(l -isopropyl-1 H-indazole-3-carbonyl) hydrazine (3.0 Kg, 7.47 mols, obtainted in above step) was added and the contents were stirred for 15 minutes afterwhich, thionyl chloride (1.77 Kg, 15.0 mols) was added over 15 minutes time. The reaction mixture temperature was then gradually raised to 79 °C – 83 °C over a period of 30 minutes at which the reaction mixture starts refluxing. Upon completion of 9 hours, the reaction mass showed complete consumption of starting material when checked by TLC. The excess thionyl chloride and solvent 1,2-dichloroethane were distilled off under reduced pressure (> 500 mm of Mercury) below 60 °C. The reaction mass was cooled to 25 °C – 30 °C, diluted with water (39.0 L) and solvent ether (19.5 L). The resulting mass was stirred for 15 minutes and the two layers were separated. The pH of the aqueous layer was adjusted to 9 – 10 by adding an aqueous solution of sodium hydroxide (2.5N, 3.0 L). The basified aqueous layer was then extracted with DCM (2 x 54.0 L). The combined organic layer was washed with cold (5 °C – 10 °C) aqueous sodium hydroxide solution (0.6 N, 54.0 L), dried over anhydrous sodium sulfate (6.0 Kg) and the solvent was removed under reduced pressure (> 500 mm of Mercury) below 55 °C, which yielded above titled compound (2.6 Kg) as brown colored syrupy mass.

Yield: 90.5 %;

Purity: 99.3 %;

IR (cm“1): 3054, 2946, 2808, 1599, 1563, 1462, 1389, 121 1, 1 120, 1069, 999, 749; Ή-NMR (6 ppm, CDC13): 8.34 (d, J = 8.12 Hz, 1H), 7.53 (d, J – 8.44 Hz, 1H), 7.45 (t, J = 7.58 Hz, 1H), 7.32 (t, J = 7.44 Hz, 1H), 4.98 – 4.93 (m, 1H), 3.44 (t, J = 6.44 Hz, 2H), 3.03 – 3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54 Hz, 2H), 2.20 -2.02 (m, 6H), 1.80 (t, J= 7.27 Hz, 2H), 1.66 (d, J= 6.72 Hz, 6H);

Mass (m/z): 384.3 (M+H)+.

Step (iii): Purification of l-Isopropyl-3-{5-[l-(3-methoxypropyI) piperidin-4-yl]-[l,3.4]oxadiazoI-2-yl}-lH-indazole

The above obtained crude step (ii) product was dissolved in a stirring aqueous acetic acid solution (10 % w/v, 26.0 L) and washed with ethylacetate (2 x 26.0 L). The resultant aqueous layer pH was adjusted to 9.0 – 10.0 by adding an aqueous sodium hydroxide solution (0.5N, 52.0 L). The basified aqueous layer was extracted with solvent ether (2 x 26.0 L) and the combined organic layer was dried over anhydrous sodium sulfate (3.0 Kg). The volatiles were removed under reduced pressure (> 500 mm of Mercury) below 55 °C to obtain a brown colored syrupy mass (2.19 Kg).

Yield: 84 %;

Purity: 99.72 %;

IR (cm“1): 3054, 2978, 2946, 2808, 2772, 1599, 1563, 1462, 1389, 1 194, 1 177, 1 120, 1069, 999, 749;

Ή-NMR (δ ppm, CDC13): 8.34 (d, J = 8.12 Hz, 1H), 7.53 (d, J = 8.44 Hz, 1H), 7.45 (t, J = 7.58 Hz, 1H), 7.32 (t, J = 7.44 Hz, l H), 4.98 – 4.93 (m, 1H), 3.44 (t, J = 6.44 Hz, 2H), 3.03 – 3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54 Hz, 2H), 2.20 -2.02 (m, 6H), 1.80 (t, J= 7.27 Hz, 2H), 1.66 (d, J = 6.72 Hz, 6H);

Mass (m/z): 384.4 (M+H)+.

Step (iv): Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yI]-[l,3,4]oxadiazol-2-yi}-lH-indazole oxalate

To a stirred solution of isopropanol (60.8 L) under nitrogen atmosphere at 25 °C -30 °C, l-isopropyl-3-{5-[l -(3-methoxypropyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole (6.08 Kg, 15.86 mols, obtained in step (iii) was added, followed by oxalic acid (1.46 Kg, 16.2 mols) addition. The reaction mixture was stirred for 2 hours and solid product that is precipitated was filtered through nutsche filter under nitrogen atmosphere. The wet product bed was washed with isopropanol (10.0 L) and solvent ether (60.8 L) to obtain a technical grade product.

IR (cm“1): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1 192, 1 1 14, 992, 750;

Ή-NMR (δ ppm, DMSO-d6): 10.72, (bs, 2H), 8.16 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1H), 5.20 – 5.07 (m, 1H), 3.55 – 3.43 (m, 3H), 3.36 (t, J = 5.9 Hz, 2H), 3.21 (s, 3H), 3.1 8 – 2.98 (m, 4H), 2.40 – 2.30 (m, 2H), 2.26-2.12 (m, 2H), 1.96 – 1.85 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H)+.

Step (v): Recrystallization of l-Isopropyl-3-{5-[l-(3-methoxypropyI) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate

The above obtained product was suspended in a mixture of isopropanol (35.26 L) and water (7.3 L) and refluxed (76 °C) for 4 hours until complete dissolution. The homogenous solution thus obtained was gradually cooled to 25 °C – 30 °C and maintained at this temperature under slow stirring for 16 hours. The precipitated oxalate salt was centrifuged under nitrogen atmosphere. The product cake was washed with isopropanol (15.0 L) and ether (60.8 L). The suction dried product was then dried in vacuum oven at 25 °C – 30 °C for 2 hours and at 65 °C for 1 hour to obtain above titled compound (4.24 Kg) as light cream colored crystalline material.

Yield: 60 %;

Purity: 99.92 %;

Salt content (oxalate salt): 20.37 %;

Heavy metals: < 20 ppm;

IR (cm-1): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1 192, 1 1 14, 992, 750;

1H-NMR (δ ppm, DMSO-d6): 10.72, (bs, 2H), 8.16 (d, J- 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 5.20 – 5.07 (m, 1H), 3.55 – 3.43 (m, 3H), 3.36 (t, J = 5.9 Hz, 2H), 3.21 (s, 3H), 3.18 – 2.98 (m, 4H), 2.40 – 2.30 (m, 2H), 2.26-2.12 (m, 2H), 1.96 – 1.85 (m, 2H), 1.53 (d, J= 6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H)+.

 

REFERENCES

http://www.sciencedirect.com/science/article/pii/S1552526014012874

http://www.suven.com/news_Sep2015_02.htm

SUVN-D4010: Novel 5-HT4 receptor partial agonist for the treatment of Alzheimer’s disease
45th Annu Meet Soc Neurosci (October 17-21, Chicago) 2015, Abst 54.08

SEE BELOW

Characterization of SUVN-D1104010: A potent, selective and orallyactive 5-HT4 receptor partial agonist
Alzheimer’s Assoc Int Conf (AAIC) (July 14-19, Vancouver) 2012, Abst P2-392

SUVN-D1104010 displayed IC50 values > 45 and > 10 mcM for cytochrome P450 3A4 and 2D6, respectively. In dog, rat and human liver microsome preparations, it showed respective stabilities of 64, 26 and 26%. It displayed rat brain, rat plasma and human plasma protein binding values of 94, 89 and 93%, respectively. For parmacokinetic studies, the agent was administered to male Wistar rats (1 mg/kg i.v.; 3 mg/kg p.o.) and male Beagle dogs (1 mg/kg i.v. and p.o.). Following intravenous administration, the rats showed AUC(0-24 h), t1/2, MRT Last, Cl and Vdss values of 245 ng·h/mL, 1.1 hours, 1.1 hours, 67 mL/min/kg and 5.3 L/kg, respectively. Following intravenous administration to dogs, these respective values were 951 ng·h/mL, 6 hours, 3.9 hours, 18 mL/min/kg and 5.1 L/kg. Following oral administration to rats, the respective values were 136 ng·h/mL, 0.42 hours, 222 hours, 1.4 mL/min/kg and 1.4 L/kg. For dogs, these respective values were 179 ng·h/mL, 0.58 hours, 711 hours, 4.6 mL/min/kg and 4.0 L/kg. Oral bioavailabilty values in rats and dogs were 30 and 72%, respectively. The brain penetration profile was studied 1 hour after the administration of 1, 3 and 10 mg/kg p.o. in rats. Plasma, cerebrospinal fluid (CSF), whole brain samples were collected and drug concentrations were analyzed by liquid chromatography – mass spectrometry. Dosing at 1, 3 and 10 mg/kg p.o. was associated with respective plasma concentrations of 42, 136 and 537 nM; respective brain concentrations of 120, 352 and 1674 nM; respective CSF concentrations of 7, 18 and 90 nM; ratios of CSF concentrations over Ki values of 0.3, 0.8 and 3.8; ratios of brain concentrations over Ki values of 5, 5 and 70; and ratios of brain over plasma concentrations of 2.8, 2.5 and 3. Further studies included in vivo receptor occupancy (brain 5-HT4 receptor) analysis. The drug showed dose-dependent occupancy in the rat striatum and gained ready access to the brain. An ED50 of 2.75 mg/kg p.o. was noted. Brain cortical soluble amyloid precursor protein alpha (sAPPalpha) levels were assessed in male C57BL6 mice injected with 1-10 mg/kg s.c. and sacrificed 30/60 minutes later. Results were compared to vehicle-treated mice. At 3 and 10 mg/kg doses, significant increases in sAPPalpha levels were noted (P values < 0.05 and < 0.01, respectively) using ELISA. To study changes in CSF beta-amyloid levels, Wistar rats were administered the drug orally at 0.03-3 mg/kg and 2 hours later, CSF was collected and analyzed for beta-amyloid protein 42 (Abeta42) and 40 (Abeta40) by ELISA. The drug induced a decrease of 19-35% in Abeta42 levels and a decrease of 20-38% in Abeta40 levels in rat CSF at a dose of 0.1 mg/kg (P < 0.01). Toxicity studies are currently under way.

March 16, 2015

Drug firm Suven Life Sciences has been granted a patent each by the US and New Zealand for a drug used in the treatment of neuro-degenerative diseases.

The patents are valid until 2030 and 2031, respectively, Suven Life Sciences said in a filing to the BSE.

Commenting on the development, Suven Life CEO Venkat Jasti said: “We are very pleased by the grant of these patents to Suven for our pipeline of molecules in CNS arena that are being developed for cognitive disorders with high unmet medical need with huge market potential globally.”

SUVEN, Chief executive and chairman Venkat Jasti

The company has “secured patents in USA and New Zealand to one of their new chemical entity (NCE) for CNS therapy through new mechanism of action – H3 Inverse agonist…,” Suven Life Sciences said.

With these new patents, Suven has a total of 20 granted patents from US and 23 granted patents from New Zealand.

“These granted patents are exclusive intellectual property of Suven and are achieved through the internal discovery research efforts.

“Products out of these inventions may be out-licensed at various phases of clinical development like at Phase-I or Phase-II,” Suven said.

Pdf Link: Suven Life Sciences secures 2 (two) Product Patents for their NCE’s through New mechanism of action – H3 Inverse Agonist in USA & New Zealand

http://www.bseindia.com/xml-data/corpfiling/AttachLive/suven_life_sciences_ltd_160315.pdf

Suven Life Sciences secures 2 (two) Product Patents for their NCE’s through New mechanism of action – H3 Inverse Agonist in USA & New Zealand HYDERABAD, INDIA (March 16, 2015) – Suven Life Sciences Ltd (Suven) announced today that they secured patents in USA (us 8912179) and New Zealand (614567) to one of their New Chemical Entity (NCE) for CNS therapy through new mechanism of action – H3 Inverse agonist and these patents are valid until 2030 and 2031 respectively. The granted claims of the patent include the class of selective H3 ligands discovered by Suven and are being developed as therapeutic agents and are useful in the treatment of cognitive impairment associated with neurodegenerative disorders

 

Suven Life Sciences Ltd.
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Avenue – 7, Road No. 5, Banjara Hills,
Hyderabad-500 034, Telangana, INDIA

Phone : +91-40-2354-1142, 2354-3311
Fax     : +91~40~2354-1152
Email id: info@suven.com

 

INDIAN PATENT

 

  • Nirogi, Ramakrishna; Shinde, Anil Karbhari; Kambhampati, Ramasastri; Namala, Rambabu; Dwarampudi, Adi Reddy; Kota, Laxman; Gampa, Murlimohan; Kodru, Padmavathi; Tiriveedhi, Taraka Naga Vinaykumar; Kandikere, Vishwottam Nagaraj; et al
  • From Indian Pat. Appl. (2012), IN 2010CH02551

 

 

 

PATENT

http://www.google.com/patents/US8912179

The present invention relates to heterocyclyl compounds of formula (I) and their pharmaceutically acceptable salts, its process of preparation and compositions containing them, for the treatment of various disorders that are related to Histamine H3 receptors.

Figure imgf000003_0001
ONE EXAMPLE
EXAMPLE 1
Example 1
Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one tartrate
Step (i): Preparation of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester

1-Cyclobutyl-piperidin-4-ol (1.6 grams, 10 mmol) in tetrahydrofuran (20 mL) was treated with cooled and stirred suspension of sodium hydride (0.9 grams, 18 mmol) in tetrahydrofuran (20 mL) slowly over a period of 30 minutes; the reaction mixture was stirred for 1 hour. A solution of 2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (3 grams, 9 mmol, obtained in preparation 1) in tetrahydrofuran (30 mL) was added drop wise over a period of 15 minutes and refluxed the reaction for 6 hours. Reaction mass was quenched with ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethylacetate/n-hexane, 1/1) to obtain the title compound (2.0 grams).

1H-NMR (δ ppm): 1.48 (9H, s), 1.65-1.72 (2H, m), 1.85-1.92 (4H, m), 2.01-2.07 (4H, m), 2.18-2.19 (2H, m), 2.57 (2H, m), 2.62-2.66 (2H, m), 2.71-2.75 (1H, m), 3.70 (2H, m), 4.43 (2H, m), 4.93 (1H, m);

Mass (m/z): 394.2 (M+H)+.

Step (ii): Preparation of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridineA solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (2.0 grams, 5 mmol, obtained in above step) in dichloromethane (30 mL) was treated with trifluroacetic acid (5.0 mL, 50 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of reaction, the reaction mass was quenched into ice cold water and adjust pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL), combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum to obtain the title compound (1.3 grams).

1H-NMR (δ ppm): 1.68-1.74 (2H, m), 1.85-1.93 (4H, m), 2.06 (4H, m), 2.19 (2H, m), 2.60-2.61 (4H, m), 2.73-2.80 (1H, m), 2.90-3.10 (1H, m), 3.13-3.16 (2H, m), 3.85 (2H, s), 4.90-4.93 (1H, m);

Mass (m/z): 294.2 (M+H)+.

Step (iii): Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-oneA solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (1.3 grams, 4 mmol, obtained in above step) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (30 mL) was cooled to 0° C. Propionylchloride (0.4 mL, 5 mmol) in dichloromethane (5 mL) was added drop wise over a period of 15 minutes and stirred the reaction for 30 minutes. Reaction mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 gram).

1H-NMR (δ ppm): 1.17-1.21 (3H, m), 1.65-1.72 (5H, m), 1.87-1.91 (4H, m), 2.01-2.07 (4H, m), 2.22 (1H, m), 2.38-2.45 (2H, m), 2.45 (1H, m), 2.68-2.76 (3H, m), 3.72-3.74 (1H, m), 4.47-4.62 (2H, m), 4.92-4.94 (1H, m).

Mass (m/z): 350.4 (M+H)+.

Step (iv): Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one tartrateA solution of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one (0.8 grams, 2.3 mmol, obtained in above step) in methanol (10 mL) was treated with L(+)-Tartaric acid (0.34 grams, 2.3 mmol) at 0° C. Stirred the reaction mass for about 1 hour and the solvent was evaporated under vacuum to dryness. The solids were washed with diethyl ether and dried under vacuum to obtain the title compound (1.1 grams).

1H-NMR (δ ppm): 1.12-1.20 (3H, m), 1.82-1.87 (2H, m), 2.16-2.32 (7H, m), 2.45-2.55 (2H, m), 2.63-2.66 (3H, m), 2.72 (1H, m), 3.20 (2H, m), 3.47-3.50 (1H, m), 3.66-3.70 (1H, m), 3.81-3.88 (2H, m), 4.45 (2H, s), 4.60 (2H, s), 5.18 (5H, m);

Mass (m/z): 350.4 (M+H)+.

Publication number US8912179 B2
Publication type Grant
Application number US 13/818,152
PCT number PCT/IN2010/000740
Publication date Dec 16, 2014
Filing date Nov 15, 2010
Priority date Sep 2, 2010
Also published as CA2812970A1, 4 More »
Inventors Ramakrishna Nirogi, Anil Karbhari Shinde,Ramasastri Kambhampati, Rambabu Namala,Adi Reddy Dwarampudi, Laxman Kota,Murlimohan Gampa, Padmavathi Kodru,Taraka Naga Vinaykumar Tiriveedhi,Vishwottam Nagaraj Kandikere, Nageshwara Rao Muddana, Ramanatha Shrikantha Saralaya, Pradeep Jayarajan, Dhanalakshmi Shanmuganathan, Ishtiyaque Ahmad,Venkateswarlu Jasti, Less «
Original Assignee Suven Life Sciences Limited
Export Citation BiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet

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CC(C)n4nc(c1nnc(o1)C2CCN(CCCOC)CC2)c3ccccc34

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