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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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J-147


ChemSpider 2D Image | N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylene]acetohydrazide | C18H17F3N2O2

J147 structure.png

J-147

N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide

  • Molecular FormulaC18H17F3N2O2
  • Average mass350.335 Da

2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide

Acetic acid, 2,2,2-trifluoro-, 1-(2,4-dimethylphenyl)-2-[(1E)-(3-methoxyphenyl)methylene]hydrazide

N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide
[1146963-51-0]
1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide, 2,2,2-trifluoro-acetic acid
1146963-51-0 [RN] DOUBLE BOND GEOMETRY UNSPECIFIED

FDA UNII Z41H3C5BT9

Abrexa Pharmaceuticals, Dementia, Alzheimer’s type, PHASE1
Blanchette Rockefeller Neurosci Inst (Originator)
Salk Institute for Biological Studies (Originator)

Abrexa Pharmaceuticals is developing the oral curcumin derivative J-147 for the treatment of Alzheimer’s disease. A phase I clinical trial is under way in healthy young and older adults.

The Salk Institute for Biological Studies  and  Abrexa Pharmaceuticals  are developing J-147, a curcumin derivative  CNB-001 , and a 5-lipoxygenase inhibitor, for the oral treatment of Alzheimer’s disease (AD), aging and acute ischemic stroke; in January 2019, a phase I trial for AD was initiated.

J147 is an experimental drug with reported effects against both Alzheimer’s disease and ageing in mouse models of accelerated aging.[1][2][3][4]

The approach that lead to development of the J147 drug was to screen candidate molecules for anti-aging effects, instead of targeting the amyloid plaques. It is contrary to most other approaches to developing drugs against Alzheimer’s disease that target the plaque deposits in the brain.[5]

The J147 drug is also reported to address other biological aging factors, such as preventing the leakage of blood from microvessels in mice brains.[5] The development of J147 follows the chemical pharmacological way, contrary to biological ways that exploit e.g. use of bacteriophages.[6][7]

Enhanced neurogenic activity over J147 in human neural precursor cells has its derivative called CAD-31. CAD-31 is enhancing the use of free fatty acids for energy production by shifting of the metabolic profile of fatty acids toward the production of ketone bodies, a potent source of energy in the brain when glucose levels are low.[8]

The target molecule is a protein called ATP synthase, which is found in the mitochondria.[9]

Image result for J-147

PAPER

Organic & Biomolecular Chemistry (2015), 13(37), 9564-9569

https://pubs.rsc.org/en/content/articlelanding/2015/OB/C5OB01463H#!divAbstract

A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.

Graphical abstract: Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity
http://www.rsc.org/suppdata/c5/ob/c5ob01463h/c5ob01463h1.pdf
Synthesis of (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N’-(3-methoxybenzylidene)- 32 acetohydrazide (3a). To a solution of 3-methoxybenzaldehyde (1a) (0.10 g, 0.7 mmol) in EtOH (10 33 mL) was added (2,4-dimethylphenyl)hydrazine hydrochloride (0.13 g, 0.7 mmol), and the resulting 34 mixture was stirred for 1 h at room temperature (RT). After the reaction, the mixture was concentrated 35 under reduced pressure to yield the corresponding benzylidenehydrazine, which was used for the next 36 step without further purification. The intermediate benzylidenehydrazine was dissolved in CH2Cl2, 37 and the resulting solution was treated with Et3N (0.3 mL, 2.2 mmol). Trifluoroacetic anhydride (0.1 38 mL, 1.1 mmol) was added to this solution in drops at 0 °C. After stirring for 1 h, the mixture was 39 concentrated under reduced pressure, and the residue was purified by column chromatography on 40 silica gel (8:1 = hexanes:ether) to yield 3a (0.12 g, 0.3 mmol, 47% yield) as a yellow solid:
1H NMR 41 (400 MHz, CDCl3) δ 7.29-7.24 (m, 4H), 7.20 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.04 (d, J 42 = 7.9 Hz, 1H), 6.94 (ddd, J = 8.1, 2.2,0.8 Hz, 1H), 3.81 (s, 1H), 2.41 (s, 3H), 2.08 (s, 3H);
13C NMR 43 (100 MHz, CDCl3) δ 160.7, 158.9 (q, J = 36.4 Hz), 155.0, 143.4, 143.1, 142.3, 137.7, 134.4, 130.9, 44 130.8, 130.6, 129.9, 123.5, 123.0, 118.4 (q, J = 287.3 Hz), 113.8, 57.4, 23.5, 19.1;
LC-MS (ESI) m/z found 373.2 [M + Na]+ , calcd for C18H17F3N2O2Na 373.1.

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X12014746

Figure 1. Chemical structures of previously developed [11C]PIB, [18F]Amyvid and [18F]-T808, and newly developed [11C]J147.

Scheme 1. Synthesis of the reference standard J147 (2).

PRODUCT PATENT

WO2009052116

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009052116&tab=PCTDESCRIPTION

PATENT

WO-2019164997

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019164997&tab=PCTDESCRIPTION&_cid=P20-K07KTW-29673-1

A process for preparing crystalline Form II of 2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide (J-147; 98% of purity) comprising the steps of providing a slurry containing saturated amorphous or crystalline Form I of J-147 and mixing the slurry to obtain the crystalline Form II of J147. Also claimed are processes for preparing the crystalline Form I of 2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide. Further claimed are isolation of the crystalline Form II and I of  2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide. The compound is disclosed to be a neurotrophic agent and known to be a Trkb receptor agonist, useful for treating neurodegenerative disease, such as aging and motor neurone disease.

The present disclosure relates to polymorph forms of a pharmaceutical active agent. In particular, the present disclosure relates to polymorph forms of neuroprotective agent 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147).

[0002] 2,2,2 -trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147) is a potent orally active neurotrophic agent discovered during screening for efficacy in cellular models of age-associated pathologies and has a structure given by Formula I:

[0003] J147 is broadly neuroprotective, and exhibited activity in assays indicating distinct neurotoxicity pathways related to aging and neurodegenerative diseases, with EC50 between 10 and 200 nM. It has been indicated to improve memory in normal rodents, and prevent the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

Furthermore, it has displayed neuroprotective, neuroanti-inflammatory, and LTP-enhancing activity.

[0004] The neurotrophic and nootropic effects have been associated with increases in BDNF levels and BDNF responsive proteins. Interestingly, despite this mechanism of action, Jl47’s neuroprotective effects have been observed to be independent of TrkB receptor activation.

J147 has been indicated to reduce soluble Ab40 and Ab42 levels, and it is currently being researched for potential applications in treating ALS.

The Fourier transform infrared (FTIR) spectrum is shown in Figure 4. Based on visual inspection the spectrum is consistent with structure. The Raman spectrum is in agreement with the FTIR spectrum and is shown in Figure 5. The proton NMR data is consistent with the structure of J147 and is shown in Figure 6. The proton NMR data is also shown in tabulated form in Table B below.

Table B 

EXAMPLE OF PREPARATION OF FORM II OF J 147

Batch Process: About 100 kg of crude J147 from its synthetic preparation was evaporated twice from about 80 kg of ethanol. The crude product was taken up in about 48 kg of ethanol and the batch temperature was adjusted to 28 °C. About 37 kg of water was added gradually to the batch. The batch was held at about 30 °C for about 1.7 hours. A sample of the batch was pulled from the reactor and solids precipitated by addition of 45 mL of water. The solids obtained were added back to the batch as seed crystals and the mixture stirred for 40 minutes at 30 °C. An additional about 34 kg of water was added. The batch was held at about 18 °C for about 58 hours and then cooled to about 10 °C for another about 5.5 hours. Analysis of the resultant solids indicated the presence of Form I. Form I was converted to Form II by heating the slurry to about 45 °C for about 16 hours and then cooling back to about 10 °C and holding the batch at this temperature for about 3 hours about 17.7 kg of solid Form II of J147 were recovered by filtration after washing and drying.

CLIP

https://cen.acs.org/articles/90/i31/Tumeric-Derived-Compound-Curcumin-Treat.html

Turmeric-Derived Compound Curcumin May Treat Alzheimer’s

Curry chemical shows promise for treating the memory-robbing disease
Tumeric roots sit on a pile of powered turmeric, both are an intense, warm yellow.
CURRY WONDER
Curcumin, derived from the rootstalk of the turmeric plant, not only gives Indian dishes their color but might treat Alzheimer’s.
Credit: Shutterstock

More than 5 million people in the U.S. currently live with Alzheimer’s disease. And according to the Alz­heimer’s Association, the situation is only going to get worse.

By 2050, the nonprofit estimates, up to 16 million Americans will have the memory-robbing disease. It will cost the U.S. $1.1 trillion annually to care for them unless a successful therapy is found.

Pharmaceutical companies have invested heavily in developing Alzheimer’s drugs, many of which target amyloid-β, a peptide that misfolds and clumps in the brains of patients. But so far, no amyloid-β-targeted medications have been successful. Expectation for the most advanced drugs—bapineu­zumab from Pfizer and Johnson & Johnson and solanezumab from Eli Lilly & Co.—are low on the basis of lackluster data from midstage clinical trials. That sentiment was reinforced last week when bapineuzumab was reported to have failed the first of four Phase III studies.

Even if these late-stage hopefuls do somehow work, they won’t come cheap, says Gregory M. Cole, a neuroscientist at the University of California, Los Angeles. These drugs “would cost patients tens of thousands of dollars per year,” he estimates. That hefty price tag stems from bapineuzumab and solanezumab being costly-to-manufacture monoclonal antibodies against amyloid-β.

“There’s a great need for inexpensive Alzheimer’s treatments,” as well as a backup plan if pharma fails, says Larry W. Baum, a professor in the School of Pharmacy at the Chinese University of Hong Kong. As a result, he says, a great many researchers have turned their attention to less pricy alternatives, such as compounds from plants and other natural sources.

Curcumin, a spice compound derived from the rootstalk of the turmeric plant (Curcuma longa), has stood out among some of the more promising naturally derived candidates.

When administered to mice that develop Alzheimer’s symptoms, curcumin decreases inflammation and reactive oxygen species in the rodents’ brains, researchers have found. The compound also inhibits the aggregation of troublesome amyloid-β strands among the animals’ nerve cells. But the development of curcumin as an Alzheimer’s drug has been stymied, scientists say, both by its low uptake in the body and a lack of funds for effective clinical trials—obstacles researchers are now trying to overcome.

In addition to contributing to curry dishes’ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmeric’s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.

Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcumin’s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.

Molecular structures of Curcumin and J147.

Bharat B. Aggarwal, a professor at the University of Texas M. D. Anderson Cancer Center, says curcumin is an example of a pleiotropic agent: It has a number of different effects and interacts with many targets and biochemical pathways in the body. He and his group have discovered that one important molecule targeted and subsequently suppressed by curcumin is NF-κB, a transcription factor that switches on the body’s inflammatory response when activated (J. Biol. Chem.,DOI: 10.1074/jbc.270.42.24995).

Aside from NF-κB, curcumin seems to interact with several other molecules in the inflammatory pathway, a biological activity that Aggarwal thinks is advantageous. “All chronic diseases are caused by dysregulation of multiple targets,” he says. “Chemists don’t yet know how to design a drug that hits multiple targets.” With curcumin, “Mother Nature has already provided a compound that does so.”

Curcumin’s pleiotropy also brought it to the attention of UCLA’s Cole during the early 1990s while he was searching for possible Alzheimer’s therapeutics. “That was before we knew about amyloid-β” and its full role in Alzheimer’s, he says. “We were working on the disease from an oxidative damage and inflammation point of view—two processes implicated in aging.”

When Cole and his wife, Sally A. Frautschy, also at UCLA, searched the literature for compounds that could tackle both of these age-related processes, curcumin jumped out at them. It also didn’t hurt that the incidence of Alz­heimer’s in India, where large amounts of curcumin are consumed regularly, is lower than in other parts of the developing world (Lancet Neurol., DOI: 10.1016/s1474-4422(08)70169-8).

In 2001, Cole, Frautschy, and colleagues published the first papers that demonstrated curcumin’s potential to treat neurodegenerative disease (Neurobiol. Aging, DOI: 10.1016/s0197-4580(01)00300-1J. Neurosci.2001, 8370). The researchers studied the effects of curcumin on rats that had amyloid-β injected into their brains, as well as mice engineered to develop amyloid brain plaques. In both cases, curcumin suppressed oxidative tissue damage and reduced amyloid-β deposits.

Those results, Cole says, “turned us into curcumin-ologists.”

Although the UCLA team observed that curcumin decreased amyloid plaques in animal models, at the time, the researchers weren’t sure of the molecular mechanism involved.

Soon after the team’s first results were published, Cole recalls, a colleague brought to his attention the structural similarity between curcumin and the dyes used to stain amyloid plaques in diseased brain tissue. When Cole and Frautschy tested the spice compound, they saw that it, too, could stick to aggregated amyloid-β. “We thought, ‘Wow, not only is curcumin an antioxidant and an anti-inflammatory, but it also might be an anti-amyloid drug,’ ” he says.

In 2004, a group in Japan demonstrated that submicromolar concentrations of curcumin in solution could inhibit aggregation of amyloid-β and break up preformed fibrils of the stuff (J. Neurosci. Res., DOI: 10.1002/jnr.20025). Shortly after that, the UCLA team demonstrated the same (J. Biol. Chem., DOI: 10.1074/jbc.m404751200).

As an Alzheimer’s drug, however, it’s unclear how important it is that the spice compound inhibits amyloid-β aggregation, Cole says. “When you have something that’s so pleiotropic,” he adds, “it’s hard to know” which of its modes of action is most effective.

Having multiple targets may be what helps curcumin have such beneficial, neuroprotective effects, says David R. Schubert, a neurobiologist at the Salk Institute for Biological Studies, in La Jolla, Calif. But its pleiotropy can also be a detriment, he contends.

The pharmaceutical world, Schubert says, focuses on designing drugs aimed at hitting single-target molecules with high affinity. “But we don’t really know what ‘the’ target for curcumin is,” he says, “and we get knocked for it on grant requests.”

Another problem with curcumin is poor bioavailability. When ingested, UCLA’s Cole says, the compound gets converted into other molecular forms, such as curcumin glucuronide or curcumin sulfate. It also gets hydrolyzed at the alkaline and neutral pHs present in many areas of the body. Not much of the curcumin gets into the bloodstream, let alone past the blood-brain barrier, in its pure, active form, he adds.

Unfortunately, neither Cole nor Baum at the Chinese University of Hong Kong realized the poor bioavailability until they had each launched a clinical trial of curcumin. So the studies showed no significant difference between Alzheimer’s patients taking the spice compound and those taking a placebo (J. Clin. Psychopharma­col., DOI: 10.1097/jcp.0b013e318160862c).

“But we did show curcumin was safe for patients,” Baum says, finding a silver lining to the blunder. “We didn’t see any adverse effects even at high doses.”

Some researchers, such as Salk’s Schubert, are tackling curcumin’s low bioavailability by modifying the compound to improve its properties. Schubert and his group have come up with a molecule, called J147, that’s a hybrid of curcumin and cyclohexyl-bisphenol A. Like Cole and coworkers, they also came upon the compound not by initially screening for the ability to interact with amyloid-β, but by screening for the ability to alleviate age-related symptoms.

The researchers hit upon J147 by exposing cultured Alzheimer’s nerve cells to a library of compounds and then measuring changes to levels of biomarkers for oxidative stress, inflammation, and nerve growth. J147 performed well in all categories. And when given to mice engineered to accumulate amyloid-β clumps in their brains, the hybrid molecule prevented memory loss and reduced formation of amyloid plaques over time (PLoS One, DOI: 10.1371/journal.pone.0027865).

Other researchers have tackled curcumin’s poor bioavailability by reformulating it. Both Baum and Cole have encapsulated curcumin in nanospheres coated with either polymers or lipids to protect the compound from modification after ingestion. Cole tells C&EN that by packaging the curcumin in this way, he and his group have gotten micromolar quantities of it into the bloodstream of humans. The researchers are now preparing for a small clinical trial to test the formulation on patients with mild cognitive impairment, who are at an increased risk of developing Alzheimer’s.

An early-intervention human study such as this one comes with its own set of challenges, Cole says. People with mild cognitive impairment “have good days and bad days,” he says. A large trial over a long period would be the best way to get any meaningful data, he adds.

Such a trial can cost up to $100 million, a budget big pharma might be able to scrape together but that is far out of reach for academics funded by grants, Cole says. “If you’re down at the level of what an individual investigator can do, you’re running a small trial,” he says, “and even if the result is positive, it might be inconclusive” because of its small size or short duration. That’s one of the reasons the curcumin work is slow-going, Cole contends.

The lack of hard clinical evidence isn’t stopping people from trying curcumin anyway. Various companies are selling the spice compound as a dietary supplement, both in its powdered form and in nanoformulations such as the ones Cole and Baum are working with. Indiana-based Verdure Sciences, for instance, licensed a curcumin nanoformulation from UCLA and sells it under the name Longvida (about $1.00 to $2.00 per capsule, depending on the distributor).

“There’s no proof that it works,” Cole says. “If you want to take it, you’re experimenting on yourself.” And he cautions that correct dosing for this more bioavailable form of curcumin hasn’t yet been established, so there could be safety concerns.

But on the basis of positive e-mails he’s received from caregivers and Alzheimer’s patients who are desperate for options and trying supplements, “I have some hope,” Cole says. “Maybe there’s something to curcumin after all.”

CLIP

J 147 powder

Raw J 147 powder basic Characters

Name: J 147 powder
CAS: 1146963-51-0
Molecular Formula: C18H17F3N2O2
Molecular Weight: 350.3349896
Melt Point: 177-178°C
Storage Temp: 4°C
Color: White or off white powder

Raw J 147 powder in enhance brain function and an extra boost cycle

Names

J 147 powder

J 147 (1146963-51-0) Usage dosage

Using a drug discovery scheme for Alzheimer’s disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J-147 powder, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J 147 powder in human and mouse microsomes and mouse plasma. It is shown that J-147(1146963-51-0) powder is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J 147(1146963-51-0) powder may contribute to its biological activity in animals.
J 147 , derived from the curry spice component curcumin, has low toxicity and actually reverses damage in neurons associated with Alzheimer’s.

J 147 (1146963-51-0) was the mitochondrial protein known as ATP synthase, specifically ATP5A, a subunit of that protein. ATP synthase is involved in the mitochondrial generation of ATP, which cells use for energy.

The researchers demonstrated that by reducing the activity of ATP synthase, they were able to protect neuronal cells from a number of toxicities associated with the aging of the brain. One reason for this neuroprotective effect is thought to be the role of excitotoxicity in neuronal cell damage.

Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivation of receptors for the excitatory neurotransmitter glutamate. Think of it being a bit like a light switch being turned on and off so rapidly that it ends up causing the light bulb to blow.

Recently, the role of ATP synthase inhibition for neuroprotection against excitotoxic damage was demonstrated in a mouse study[4]. The second study showed that mouse models expressing the human form of mutant ATPase inhibitory factor 1 (hIF1), which causes a sustained inhibition of ATP synthase, were more resilient to neuronal death after excitotoxic damage. This data is consistent with this new J 147 powder study, in which an increase in IF1 in the mice reduced the activity of ATP synthase (specifically ATP5A) and was neuroprotective.

Warning on Raw J 147 powder

Data presented here demonstrate that J-147 powder has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J-147 powder to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J-147(1146963-51-0) powder and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J-147 powder was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory.

Further instructions

Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), few have proven effective in the clinic.

“While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says Schubert, senior author of the study.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease–old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J 147(1146963-51-0) powder.

Previously, the team found that J-147 powder could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer’s cases. For everyone else, old age is the primary risk factor, says Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

Raw J-147 powder (1146963-51-0) hplc≥98% | AASraw SARMS powder

References

  1. ^ “Experimental drug targeting Alzheimer’s disease shows anti-aging effects” (Press release). Salk Institute. 12 November 2015. Retrieved November 13, 2015.
  2. ^ Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D (14 December 2011). “A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease”PLoS One6 (12): e27865. doi:10.1371/journal.pone.0027865PMC 3237323PMID 22194796.
  3. ^ Currais A, Goldberg J, Farrokhi C, Chang M, Prior M, Dargusch R, Daugherty D, Armando A, Quehenberger O, Maher P, Schubert D (11 November 2015). “A comprehensive multiomics approach toward understanding the relationship between aging and dementia” (PDF)Aging7 (11): 937–55. doi:10.18632/aging.100838PMC 4694064PMID 26564964.
  4. ^ Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D (May 2013). “The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice”Alzheimer’s Research & Therapy5 (3): 25. doi:10.1186/alzrt179PMC 3706879PMID 23673233.
  5. Jump up to:a b Brian L. Wang (13 November 2015). “Experimental drug targeting Alzheimer’s disease shows anti-aging effects in animal tests”nextbigfuture.com. Retrieved November 16, 2015.
  6. ^ Krishnan R, Tsubery H, Proschitsky MY, Asp E, Lulu M, Gilead S, Gartner M, Waltho JP, Davis PJ, Hounslow AM, Kirschner DA, Inouye H, Myszka DG, Wright J, Solomon B, Fisher RA (2014). “A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies”. Journal of Molecular Biology426: 2500–19. doi:10.1016/j.jmb.2014.04.015PMID 24768993.
  7. ^ Solomon B (October 2008). “Filamentous bacteriophage as a novel therapeutic tool for Alzheimer’s disease treatment”. Journal of Alzheimer’s Disease15 (2): 193–8. PMID 18953108.
  8. ^ Daugherty, D., Goldberg, J., Fischer, W., Dargusch, R., Maher, P., & Schubert, D. (2017). A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimer’s research & therapy, 9(1), 50. https://doi.org/10.1186/s13195-017-0277-3
  9. ^ “Researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer’s disease”. Retrieved 2018-01-30.
J147
J147 structure.png
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C18H17F3N2O2
Molar mass 350.341 g·mol−1
3D model (JSmol)

////////////J-147, J 147, J147, Alzheimer’s disease, neurotrophic agent, The Salk Institute for Biological Studies,  Abrexa Pharmaceuticals, PHASE 1, CURCUMIN

str1

CAS 1417911-00-2

  • Acetic acid, 2,2,2-trifluoro-, 1-(2,4-dimethylphenyl)-2-[[3-(methoxy-11C)phenyl]methylene]hydrazide
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GNE-0877


img

GNE-0877

Maybe  DNL-151 ?

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

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

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

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

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

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

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

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

PATENT

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

PATENT

WO2019104086 ,

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

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

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

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

FORMULA I COMPOUND

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

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

CRYSTALLIZATION 

Initial polymorph screening experiments were performed using a variety of

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

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

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

Table 1 Characterization summary for crystal forms of Formula I compound

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

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

PATENT

WO-2019126383

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

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

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

4a 5a

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

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

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

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

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

DCM

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

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

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

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

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

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

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

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

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

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

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

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

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

PAPER

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

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

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

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

Scheme 2. Synthesis of N-Alkyl Pyrazole Analoguesa

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

GNE-9605

product image (CAS 1536200-31-3)

CAS № 1536200-31-3

Molecular Formula
C17H20ClF4N7O
Formula Weight
449.8

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

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

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

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

Scheme 8. Synthesis of Inhibitor 20a

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

REFERENCES

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

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

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

JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,


2D chemical structure of 1200493-78-2imgChemSpider 2D Image | atabecestat | C18H14FN5OS

Atabecestat, JNJ-54861911

Cas 1200493-78-2

367.40, C18 H14 F N5 O S

2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-
  • N-[3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide
  • Atabecestat
  • атабецестат [Russian] [INN]
    أتابيسيستات [Arabic] [INN]

Atabecestat is a beta-secretase inhibitor drug candidate.

(S)-N-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide

JNJ-54861911
N-{3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-cyano-2-pyridinecarboxamide
2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-

WO 2017111042, 1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Image result

Structure of JNJ54861911.
Credit: Tien Nguyen/C&EN

Presented by: Yuji Koriyama, associate director at Shionogi & Co.

Target: β-site amyloid presursor protein cleaving enzyme 1 (BACE1), an enzyme whose buildup is implicated in Alzheimer’s disease

Disease: Alzheimer’s disease

Reporter’s notes: Presented by Koriyama, who told the audience he was attending the ACS National Meeting for the first time, JNJ-5486911 joins dozens of clinical candidates from many companies in Phase II and III trials to treat Alzheimer’s disease. Researchers started with a hit that inhibited BACE1 with approximately 2,600 nM affinity and advanced the program until finally reaching a compound with roughly 1 nM affinity. The compound is being jointly developed by Shionogi & Co. and Janssen Pharmaceuticals.

  • Originator Shionogi
  • Developer Janssen Research & Development
  • Class Antidementias; Small molecules
  • Mechanism of Action Amyloid precursor protein secretase inhibitors

Highest Development Phases

  • Phase II/III Alzheimer’s disease

Most Recent Events

  • 16 Jul 2017 Pharmacodynamics data from preclinical trials in Alzheimer’s disease presented at the Alzheimer’s Association International Conference (AAIC-2017)
  • 15 Dec 2016 Biomarkers information updated
  • 01 Jun 2016 Janssen Research & Development completes a phase I pharmacokinetic interaction trial in Healthy volunteers in Germany (PO) (NCT02611518)
  • Image result for Janssen Research & Development

SYNTHESIS

PATENTS

WO 2009151098

Applicants: SHIONOGI & CO., LTD. [JP/JP]; 1-8, Doshomachi 3-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP) (For All Designated States Except US).
HORI, Akihiro [JP/JP]; (JP) (For US Only).
YONEZAWA, Shuji [JP/JP]; (JP) (For US Only).
FUJIKOSHI, Chiaki [JP/JP]; (JP) (For US Only).
MATSUMOTO, Sae [JP/JP]; (JP) (For US Only).
KOORIYAMA, Yuuji [JP/JP]; (JP) (For US Only).
UENO, Tatsuhiko [JP/JP]; (JP) (For US Only).
KATO, Terukazu [JP/JP]; (JP) (For US Only)
Inventors: HORI, Akihiro; (JP).
YONEZAWA, Shuji; (JP).
FUJIKOSHI, Chiaki; (JP).
MATSUMOTO, Sae; (JP).
KOORIYAMA, Yuuji; (JP).
UENO, Tatsuhiko; (JP).
KATO, Terukazu; (JP)

PATENT

WO 2011071057

PATENT

WO 2017175855

PATENT

WO 2017111042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017111042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Scheme 1-D
[Chem. 27]

Example 1-4
Preparation of Compound 15
[Chem. 31]

Compound 12 (3.0 g, 20.3 mmol) was dissolved in N-methylpyrrolidone (18 mL), and the solution was cooled to 5°C. Thionyl chloride (3.1 g, 26.1 mmol) was added to obtain a solution of Compound 13.
To a suspension of Compound 11 (5.0 g, 16.8 mmol) in ethyl acetate (50 mL) were added sodium bicarbonate (3.5 g, 42.0 mmol) and water (50 mL), and the mixture was stirred for 5 min at 20°C.
The layers were separated, and the organic layer was concentrated to 10 g under reduced pressure. N-Methylpyrrolidone (5 mL) and 35% hydrochloric acid (0.9 g) were added, and the mixture was cooled to 3°C. The solution of Compound 13 and N-methylpyrrolidone (1.5 mL) were added to obtain a solution of Compound 15.
The solution of Compound 15 was added to a mixture of water (15 mL) and ethyl acetate (10 mL). After stirring the mixture for 1 hour, triethylamine (14.8 g, 14.6 mmol), N-methylpyrrolidone (1.5 mL) and water (5 mL) were added and further stirred for 1 hour. Water (45 mL) was added, and the mixture was stirred for 1 hour, filtered and dried to obtain crystals of Compound 15 (Crystalline Form I, 5.71 g, 92.4%).

Compound 15
1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Example 1-5
To a suspension of Compound 11 (1831 g, 6.2 mol) in ethyl acetate (18L) were added sodium bicarbonate (1293 g, 15.4 mol) and water (18L), and the mixture was stirred for 5 min at 20°C. The layers were separated, and the organic layer was concentrated to 3.8 kg under reduced pressure to obtain a concentrated solution of Compound 14.
Compound 12 (912 g, 6.2 mol) was dissolved in N-methylpyrrolidone (64L), and the solution was cooled to 4°C. Thionyl chloride (951 g, 8.0 mol) was added, and the mixture was stirred for 30 min. The concentrated solution of Compound 14 was added to obtain a solution of Compound 15.
The solution of Compound 15 and N-methylpyrrolidone (1.6 L) were added to water (18 L), and the mixture was stirred for 40 min at 25°C. 24% sodium hydroxide in water (5 kg), sodium bicarbonate (259 g, 3.1 mmol) and water (2.7 L) were added to the mixture. The mixture was stirred for 1 hour, filtered and dried to obtain crystals (metastable Form II) of Compound 15 (1.93 kg, 85.4%).

Example 1-3
Preparation of Compound 11
[Chem. 30]

A suspension of Compound 9 (20.0 g, 29.0 mmol) in N,N-dimethylacetamide (30 mL) was cooled to 5°C. 1,8-diazabicyclo(5,4,0)-7-undecene (39.7 g, 260.8 mmol) was added, and the mixture was stirred for 22 hours. Water (70 mL) was added to afford a solution of Compound 10.

To a mixture of ethyl acetate (200 mL), water (40 mL) and 62% sulfuric acid (12.7 g) was added the solution of Compound 10, and the mixture was cooled to 10°C. 15% sulfuric acid (3.7 g) was added, and the mixture was warmed to 20°C. The layers were separated, and the organic layer was washed with 5% sodium chloride in water (95 g). The layers were separated, and the organic layer was concentrated in vacuo to 42 mL. Ethyl acetate (20 mL) and 50% potassium carbonate in water (20 g) were added, and the mixture was warmed to 40°C. 4-chlorobenzenethiol (6.29 g, 43.5 mmol) and ethyl acetate (11 mL) were added, and the mixture was stirred for 1 hour. After cooling to 20°C, ethyl acetate (100 mL), water (68 mL) and 15% hydrochloric acid (42.6 g) were added. The layers were separated, and ethyl acetate (149 mL) and 20% potassium carbonate in water (40.5 g) were added to the aqueous layer. The layers were separated, and the organic layer was washed with water (100 mL). The layers were separated, and the organic layer was concentrated to 20 mL. Acetic acid (1.7 g, 29.0 mmol) was added, and the mixture was cooled to 5°C and stirred for 90 min, filtered and dried to afford 7.19 g of crystals of Compound 11 (yield: 83.4%, optical purity of (S)-isomer: 100%).

Compound 11
1H-NMR (DMSO-d6) δ: 6.74 (1H, dd, J=11.86, 8.56 Hz), 6.62 (1H, dd, J=6.97, 2.93 Hz), 6.35-6.40 (2H, m), 6.11 (1H, dd, J=9.60, 4.71 Hz), 1.90 (3H, s), 1.49 (3H, s).

The optical purity was determined as follows.
(Sample Preparation)
25 mg of Compound 11 was weighed and dissolved in a solvent to prepare a 50 mL sample solution.

(Method)
Using liquid chromatography, the peak area was determined by automatic integration method for each of (R)- and (S)-isomers of Compound 11.

(Conditions)
Detector: ultraviolet absorptiometer (wave length: 230 nm)
Column: CHIRALCEL OD-RH, φ4.6×150 mm, 5 μm, (Daicel Corporation)
Column Temp.: constant at around 40°C
Mobile Phase: water/acetonitrile (LC grade)/methanol (LC grade)/triethylamine (1320:340:340:1)
Flow Rate: 1.0 mL/min (retention time of Compound 11: about 8 min for (R)-isomer, about 9 min for (S)-isomer)
Time span of measurement: over 15 min from the sample injection
Injection Volume: 10 μL
Sample Cooler Temp.: constant at around 25°C
Autoinjector Rinse Solution: water/acetonitrile (1:1)

http://www.shionogi.co.jp/en/

Image result for HORI, Akihiro SHIONOGI

//////////////JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,Phase III , Alzheimer’s disease, DEMENTIA, Shionogi, Developer,  Janssen Research & Development

C[C@]1(C=CSC(N)=N1)c3cc(NC(=O)c2ccc(C#N)cn2)ccc3F

AD 35


str1

AD 35

IND-120499

MF C24 H27 N3 O3
Molecular Weight, 405.49
Spiro[cyclopropane-1,5′-[5H-1,3]dioxolo[4,5-f]isoindol]-7′(6′H)-one, 6′-[2-[1-(2-pyridinylmethyl)-4-piperidinyl]ethyl]-

6′-[2-[1-(2-Pyridinylmethyl)-4-piperidinyl]ethyl]spiro[cyclopropane-1,5′-[5H-1,3]dioxolo[4,5-f]isoindol]-7′(6’H)-one

1531586-58-9 CAS FREE FORM

1531586-64-7  PHOSPHATE

1531586-62-5  HYDROCHLORIDE

Zhejiang Hisun Pharmaceutical Co Ltd

Image result for Zhejiang Hisun Pharmaceutical Co Ltd

AD-35 is known to be a neuroprotectant, useful for treating Alzheimer’s diseases.

Zhejiang Hisun Pharmaceutical is developing an oral tablet formulation of AD-35, for treating Alzheimers disease . By August 2017, the phase I multiple doses trial had been completed in the US and would be completed in China soon

CAS 1531586-64-7  PHOSPHATE

6′-[2-[1-(Pyridin-2-ylmethyl)piperidin-4-yl]ethyl]spiro[cyclopropane-1,5′-[1,3]dioxolo[4,5-f]isoindol]-7′(6’H)-one phosphate

 Molecular Formula C24 H27 N3 O3 . H3 O4 P
 Molecular Weight 503.4847

With the rapid growth of the elderly population, the number of people suffering from Alzheimer’s disease (Alzheimer’s disease) also will be increased dramatically.Alzheimer’s disease is also known as Alzheimer-type dementia (Alzheimer type dementia), or the Alzheimer type senile dementia (senile dementia of the Alzheimer type). At present, although the prevalence of this disease on a global scale is still unknown, but according to the latest report from the US Alzheimer’s Association (the Alzheimer’s Association), and in 2011 the United States there are about 540 million people suffer from Alcatel the number of Alzheimer’s disease, and in 2050, in the United States suffering from the disease will increase to about 13.5 million. Therefore, the development of better efficacy and fewer side effects of new drugs to treat the disease it is a priority.

Alzheimer’s disease is the most common form of senile dementia, it has become the sixth leading cause of death of Americans, and 65 years and the fifth leading cause of death in Americans over 65 years. Although scientists have this disease carried out extensive and in-depth research, but so far, the exact cause of the disease remains unclear. Alzheimer’s disease is a progressive disease that continues to kill nerve cells, destroying nerve connections in the brain, resulting in brain tissue is damaged, leading to patients gradually lose memory, consciousness and judgment, and cause mood disorders and behavioral disorders in patients.

Alzheimer’s is an irreversible disease, and now there is no any drug can prevent the disease, and no drugs can cure the disease or slow the disease process. Drugs currently used to treat the disease can only alleviate or ameliorate symptoms of the disease. These drugs are FDA approved for use in the United States a total of five, four of which are acetylcholinesterase (acetylcholinesterase) inhibitors. Acetylcholine (acetylcholine) is a neurotransmitter, a chemical released by nerves, if produced in the brain acetylcholine system, i.e. damaged cholinergic system, it can result in associated with Alzheimer’s disease memory disorders; and acetylcholinesterase function is to catalyze the hydrolysis of acetylcholine, acetylcholine is decomposed. Because Alzheimer’s disease is accompanied

Attenuation of acetylcholine activity, thus inhibiting acetylcholinesterase is one way to treat this disease. As described above, in the present 5 treatment of Alzheimer’s disease drugs in clinical use, there are four acetylcholinesterase inhibitors, including acetylcholinesterase inhibitors such as donepezil (donepezil), tacrine (tacrine ), rivastigmine (rivastigmine), and galantamine (galantamine), wherein donepezil (Sugimoto et al US4895841 and 5100901;.. Pathi et al WO 2007077443;. Parthasaradhi et al WO 2005003092;. Dubey et al WO 2005076749; Gutman . et al WO 200009483;… Sugimoto et al J. Med Chem 1995, 38, 481) is a first-line treatment of Alzheimer’s disease drugs. However, donepezil and the other four drugs can only improve the patient’s symptoms, and this is the only improvement of symptoms is short, only lasting about 6-12 months, and the patient response rates to these drugs only about 50% (Alzheimer’s Association, 201 1 Alzheimer ‘Disease Facts and Figures, Alzheimer’s & Dementia, 201 1, 7 (2), 208). The present invention provides a new class of inhibitors of acetylcholinesterase, which is dioxole between a new class of derivatives of benzo, is more effective than donepezil and fewer side effects in the treatment of Alzheimer’s disease drug.

PATENT

WO 2014005421

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014005421&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 42: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropane-5-one (Compound No. 1-29)

To the reaction flask was added 24.3 g (0.069 mol) of compound 11-5, 36.5 g (0.26 mol) of potassium carbonate, 243 ml of ethanol, 6.1 ml (0.044 mole) of triethylamine, heated to about 50 ° C, 0.049 mol) of 2-chloromethylpyridine hydrochloride was maintained at about 50 ° C for 5 hours. The reaction was complete and 750 ml of water was added. The solid was precipitated, filtered and the cake was washed with water and dried to give 17.8 g of compound 1-29. Rate: 63.4%. ‘HNMR (CDC13 . 3 ): [delta] 1.26 (dd, 2H, J = 6.1, 7.6 Hz), 1.35 (brs,. 3 H), 1.49-1.57 (m, 4H), 1.72 (D, 2H, J = 8.6Hz) (T, 2H, J = 7.9 Hz), 3.64 (s, 2H), 6.03 (s, 2H), 2.09 (t, 2H, J = 10.4 Hz), 2.89 (d, 2H, J = 10.7 Hz) , 7.42 (s, 1 H), 7.15 (dd, 1 H, J = 5.2, 6.7 Hz), 7.24 (s, 1 H), 7.41 (d, 1 H, J = 7.7 Hz), 7.64 (td, H, J = 7.6, 1.8 Hz), 8.55 (D,. 1 H, J = 4.2 Hz); the MS (ESI): m / Z 406 [m + H] + .

Example 46: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropane] -5-one hydrochloride (Compound No. 1-33)

To the reaction flask was added 5 g (0.012 mol) of compound 1-29 and 25 ml of ethanol, heated at 50 ° C

(0.012 mol) of concentrated hydrochloric acid was added, and 1 g of activated charcoal was added to decolorize for 20 minutes. The filtrate was cooled to room temperature and 50 ml of isopropyl ether was added dropwise. The solid was precipitated, stirred for 1 hour, The ether cake was washed with ether and dried to give 5 g of compound 1-33 in a yield of 91.7%. Ethanol / isopropyl ether can be re-refined, the yield of about 90%. 1H-NMR is (D 2 0): 51.14 (T, 2 H, J-7.0 Hz), 1.38-1.70 (m,. 7 H), 1.96 (D, 2H, J = 13.3 Hz), 2.99-3.14 (m, H. 4 ), 3.50 (d, 2 H, J = 11.0 Hz), 4.37 (s, 2H), 5.93 (s, 2H), 6.28 (s, 1 H), 6.75 (s, 1 H), 7.47 (dd, J = 7.8, 1.7 Hz), 8.58 (d, 1 H, J = 4.4 Hz), 7.55 (d, 1 H, J = 7.8 Hz), 7.91 (td, ; MS (ESI): m / z 406 [M-Cl] & lt; + & gt ; .

Example 48: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropan-5-one phosphate (Compound I-3S)

To the reaction flask was added 2 g (0.0049 mole) of compound 1-29 and 40 ml of ethanol, stirred at 60 ° C until all dissolved, 0.57 g (0.0049 mole) of 85% phosphoric acid was added, stirred and solidified,

Liter of ethyl acetate, cooled to room temperature, stirred for 1 hour, filtered, and a small amount of ethyl acetate was used to wash the filter cake and dried to give 2.1 g of compound 1-35 in a yield of 84.7%. 1H-NMR (D 2 0): δ 1.10 (t, 2 H, J = 7.2 Hz), 1.33-1.64 (m, 7 H), 1.92 (d, 2 H, J = 13.4 Hz), 2.95-3.09 (m, (S, 1 H), 6.69 (s, 1 H), 7.45 (s, 2 H), 4.34 (s, (d, 1 H, J-7.8 Hz), 7.88 (td, 1 H, J = 7.7, 1.2 Hz), 8.54 (d, 1 H, J = 4.6 Hz).

PATENT

CN 103524515

https://encrypted.google.com/patents/CN103524515B?cl=en

PATENT

CN 105859732

https://www.google.com/patents/CN105859732A?cl=en

Example 14: 6- [2- [l_ (2- pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5 -f] isoindole-7, prepared Γ- cyclopropane] phosphate 5-one (compound I) is

Figure CN105859732AD00182

[0146] Compound was added 2g (4.9 mmol) of formula XI to the reaction flask 50mL, 40mL of ethanol, 60 ~ 70 ° C dissolved by heating, added with stirring square. 57g 85% (4.9mmol) phosphoric acid, and the precipitated solid was added dropwise 40mL of acetic acid ethyl cooled to room temperature, stirred for 1 hour, filtered, the filter cake washed with a small amount of ethyl acetate, dried to give 2.3g white solid (compound I, HPLC purity: 99.8%). Yield: 92.7%, H bandit R (D2O): δ1 · l〇 (t, 2H, J = 7.2Hz), 1.33-1.64 (m, 7H), 1.92 (d, 2H, J = 13.4Hz), 2.95 -3.09 (m, 4H), 3.46 (d, 2H, J = 10.7Hz), 4.34 (s, 2H), 5.89 (s, 2H), 6.20 (s, 1H), 6.69 (s, 1H), 7.45 ( , 7.53 (d, lH, J 7.8Hz dd, lH, J = 5.2,7.4Hz) =), 7.88 (td, lH, J =

PATENT

WO 2017177816

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017177816&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Process for preparing AD-35 and its intermediates – comprising the reaction of a cyano ester with a Grignard reagent, followed by condensation and further manipulative steps.

A novel intermediate of AD-35 is claimed. Also claimed is a processes for preparing 6,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-5-one comprising the reaction of a cyano ester compound in an isopropyl ester (Ti(i-Pr)4)) with a Grignard reagent in the presence of an ethyl magnesium halide. Further claimed are processes for preparing synthon of intermediates. A process for preparing a benzodioxole derivative, particularly AD-35 from intermediates is also claimed.

WO2014005421 reports a class of benzodioxole compounds, which have the activity to inhibit acetylcholinesterase and can be used to treat Alzheimer’s disease. Of these compounds, it is particularly noteworthy that 6- [2- [1- (2-pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxole And [4,5-f] isoindole-7,1′-cyclopropane] -5-one phosphate, codon AD-35, whose chemical structure is as follows:
AD-35 is a weaker acetylcholinesterase inhibitor that inhibits acetylcholinesterase activity in vitro is about one tenth of the activity of donepezil, but the compound exhibits comparable efficacy with donepezil in the Morris water maze test , That is, the effect of improving memory and learning ability is comparable to donepezil. This suggests that the AD-35 is likely to also have the effect of improving memory and learning through other mechanisms in the body. A further study of the rat model of Alzheimer’s disease induced by Aβ 25-35 found that AD-35 significantly inhibited the production and release of proinflammatory cytokines TNF-α and IL-1β, Small Aβ 25-35 on the nerve cell toxicity, effectively protect the nerve cells.
In addition, AD-35 also exhibits a certain ability to chelate transition metal ions such as Cu 2+ in vitro , while Cu 2+ accelerates the formation of Aβ fibers and enhances the toxicity of Aβ to neuronal cells, thereby promoting neuronal cell death , So excessive Cu 2+ in the brain is also considered to be one of the risk factors for Alzheimer’s disease (Sarell et al. J. Biol. Chem. 2010, 285 (53), 41533). From the chemical structure point of view, AD-35 molecules in the piperidine ring and pyridine ring on the two nitrogen atoms constitute a structural unit similar to ethylenediamine, which should be able to explain why this compound to a certain extent Chelating transition metal ions. In terms of the safety of the compounds, the acute toxicity of mice showed that the toxicity of AD-35 was much less than that of donepezil. A newly completed clinical single-dose incremental tolerance test (SAD) showed that the subjects taking 90 mg of AD-35 did not have any adverse effects at once, indicating that the compound was safe.
In summary, the AD-35 is promising to be a small side-effect drug for the treatment of Alzheimer’s disease, and its multiple mechanisms of action are likely to make this compound not only alleviate the symptoms of Alzheimer’s patients , And can delay the process of the disease.
Since the synthesis route of AD-35 and its analogs reported in WO2014005421 is too long, the operation is complicated and the yield is low, and some steps are not suitable for industrial production. Therefore, it is necessary to develop a new process route to overcome the above- Preparation method.
The preferred reaction conditions of the present invention are listed in the following schemes:
Step (1) :
Step (2) :
Step (3) :
Step (4) :
Step (5) :
Step (6) :
Step (7) :
Step (8) :

Specific implementation plan

The following examples are provided for the purpose of further illustrating the invention, but this is not intended to be limiting of the invention.
Reference Example 1: Preparation of the starting material of tert-butyl 4- [2- (p-toluenesulfonyloxy) ethyl] piperidine-1-carboxylate (Formula VIa)

[0103]

[0104]
To a 10 L reaction flask was added 800 g (3.49 mol) of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate, 5 L of dichloromethane, 974 ml of (6.75 mol) of triethylamine and 16 g of 4-dimethyl (3L × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the reaction mixture was washed with anhydrous sodium sulfate , Filtered and the filtrate was concentrated under reduced pressure to give 1360.3 g of compound VIa (HPLC purity: 85%). 1 H NMR (DMSO-d 6 ): δ 0.85-0.93 (m, 2H), 1.38 (s, 9H), 1.42-1.52 (m, 5H), 2.43 (s, 3H), 2.59 (br s, 2H (D, 2H, J = 11.3 Hz), 4.05 (t, 2H, J = 6.1 Hz), 7.50 (d, 2H, J = 8.1 Hz), 7.79 (d, 2H, J = 8.3 Hz) MS (ESI): m / z 383 [M + Na] & lt; + & gt ; .
Reference Example 2: Preparation of the starting material 4- (2-iodoethyl) piperidine-1-carboxylate (Formula VIb)
To a 50 mL reaction flask was added 5 g (13.0 mmol) of tert-butyl 4- [2- (p-toluenesulfonyloxy) ethyl] piperidine-1-carboxylate (Formula VIa), 35 mL of acetone and 2.9 g (19.3 mmol The organic phase was washed with 50 mL of water. The organic phase was collected and the aqueous phase was extracted again with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water and extracted with 50 mL of water and 50 mL of water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give 3.5 g of compound VIb in a yield of 79.5%. 1 H NMR (DMSO-d 6 ): δ 0.97-1.07 (m, 2H), 1.41 (s, 9H), 1.51-1.58 (m, 1H), 1.63-1.66 (m, 2H), 1.73-1.78 (m, 2H), 2.69 (br s, 2H), 3.31 (t, 2H, J = 7.3Hz), 3.96 (d, 2H, J = 10.3Hz); MS (ESI): m / + H] + .
Example 1: Preparation of 6-bromo-1,3-benzodioxole-5-carboxylic acid (Compound II)
To the 2L reaction flask, 100 g (0.60 mol) of piperine, 29 g (0.725 mol) of sodium hydroxide and 1 L of water were successively added, and 150 g (0.84 mol) of N-bromosuccinimide was added thereto, After the reaction was carried out for 45 min, the reaction was monitored by TLC. The reaction solution was concentrated dropwise with concentrated hydrochloric acid to adjust the pH of the reaction solution to 2 to 3, and the solid was precipitated. The ice was cooled, filtered and washed with water to obtain 117.4 g of compound II (HPLC purity: 82%), Yield 79.5%. 1 H NMR (DMSO-d 6 ): δ 6.15 (s, 2H), 7.30 (s, 1H), 7.32 (s, 1H), 13.17 (s, 1H).
Example 2: Preparation of 6-bromo-1,3-benzodioxole-5-carboxylic acid (Compound II)
To the 2L reaction flask, 100 g (0.60 mol) of piperine, 29 g (0.725 mol) of sodium hydroxide and 1 L of water were successively added, and 150 g (0.84 mol) of N-bromosuccinimide was added thereto, After the reaction was complete for 45 min, the reaction was monitored by TLC. After 1 L of ethyl acetate and 40 mL of concentrated hydrochloric acid were added, the mixture was stirred for 20 min. The organic phase was collected, concentrated to dryness, 200 mL of water and 600 mL of petroleum ether, stirred for 1 h, , And 116 g of compound II (HPLC purity: 92.0%) was dried to a yield of 78.9%. & Lt; 1 & gt ; H NMR data with Example 1.
Example 3: Preparation of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (Compound IIIa)
To a 2 L reaction flask was added 117.3 g (0.39 mol) of 6-bromo-1,3-benzodioxole-5-carboxylic acid (II), 585 mL of absolute ethanol, opened with a stirrer, (1.4mol) concentrated sulfuric acid, heating reflux reaction 6h, TLC monitoring reaction is completed. Water was added dropwise, and 1.2 L of water was added dropwise to remove the solid, filtered and washed with water, and dried at 35 to 45C to obtain 124.0 g of compound IIIa (HPLC purity: 85%) in a yield of 93.9%. . 1 H NMR (CDCl3 . 3 ): [delta] 1.39 (T, 3H, J = 7.1Hz), 4.34 (Q, 2H, J = 7.1Hz), 6.04 (S, 2H), 7.07 (S, IH), 7.31 ( s, 1H).
Example 4: Preparation of methyl 6-bromo-1,3-benzodioxole-5-carboxylate (Compound IIIb)
To a 1 L reaction flask was added 50 g (0.30 mol) of 6-bromo-1,3-benzodioxole-5-carboxylic acid (II), 500 mL of anhydrous methanol, opened with a stirrer, 33.3 mL (0.60 mol) of concentrated sulfuric acid was added dropwise and heated under reflux for 6 h. TLC test reaction is completed, ice water cooling, precipitation of solids, dropping 500mL of water, filtration, water washing filter cake, 45 ~ 55 ℃ drying 44.4 g compound IIIb, yield: 84.0%. 1 H NMR (DMSO-d 6 ): δ 3.83 (s, 3H), 6.19 (s, 2H), 7.35 (s, 1H), 7.36 (s, 1H).
Example 5: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVa)
To a 2 L reaction flask was charged 124 g (0.38 mol) of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIa), 990 mL of N, N-dimethylformamide, After opening the stirrer, 33.1 g (0.09 mol) of potassium ferrocyanide and 103.3 g (0.54 mol) of cuprous iodide were added, heated to 120-140C for 5 h, and the TLC reaction was completed. Cooling, dropping water to precipitate a solid, filtering, and washing the filter cake. The filter cake was stirred in 1.9 L of dichloromethane for 30 min, filtered, the filtrate was added with 9 g of activated charcoal, decolorized for 30 min, filtered and the filtrate was concentrated to a small amount. The solid was precipitated, n-hexane was added dropwise, cooled with ice water, filtered and dried to give 82.8 g of compound IVa (HPLC purity: 99.5%), yield: 83.2%. . 1 H NMR (DMSO-D . 6 ): [delta] 1.34 (T, 3H, J = 7.1Hz), 4.33 (Q, 2H, J = 7.1Hz), 6.29 (S, 2H), 7.51 (S, IH), 7.57 (s, 1H).
Example 6: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVa)
To a 50 mL reaction flask was added 3.5 g (12.8 mmol) of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIa), 35 mL of N, N-dimethylformamide , 2.3g (25.7mmol) cuprous cyanide, open stirring, 120 ~ 140 ℃ reaction 30 ~ 60min, TLC detection reaction is completed, cooling, dropping 30mL saturated ammonium chloride aqueous solution, precipitate solid, filter, water washing cake. The filter cake was dissolved in 200 mL of ethyl acetate and washed with saturated aqueous ammonium chloride (30 ml x 2 times). The organic phase was collected and the aqueous phase was extracted again with 100 ml of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered , And concentrated to give 2.0 g of compound IVa in a yield of 62.5%. & Lt; 1 & gt ; H NMR data with Example 5.
Example 7: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVb)
To a 1 L reaction flask was added 40 g (0.15 mol) of methyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIb), 11.4 g (31.0 mmol) of potassium ferrocyanide , 35.2 g (0.18 mol) of cuprous iodide, 240 mL of N, N-dimethylacetamide, 120 to 140 ° C in an oil bath for 2 to 3 hours, and the TLC reaction was completed. After cooling, 480 mL of water was added dropwise, Ice water cooling, filtration, water washing filter cake. Filter cake was dissolved in 500mL ethyl acetate and 200mL tetrahydrofuran mixture, heated to 80 ℃, adding 2g activated carbon, filtered, the filtrate was concentrated to a small amount, precipitation of solid, dropping 200mL petroleum ether, ice water cooling, filtration, petroleum ether washing filter The cake was dried to give 27.7 g of compound IVb in a yield of 87.6%. 1 H NMR (DMSO-d 6 ): δ 3.87 (s, 3H), 6.28 (s, 2H), 7.49 (s, 1H), 7.55 (s, 1H).
Example 8: Preparation of Spiro [6H- [1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -5-one (Compound V)
To a 2 L reaction flask was added 16 g (0.072 mol) of compound of formula IVa, 160 mL of dichloromethane, stirred and dissolved under nitrogen. 24 mL (0.080 mol) of isopropyl tetrafis (4) isopropyl ether was added and cooled to 0 to 20 ° C A solution of 73 mL (0.22 mol) of ethylmagnesium bromide in diethyl ether (3M) was added and the reaction was complete after TLC. Slowly drop the water / tetrahydrofuran solution (64 mL water / 240 mL tetrahydrofuran), heat to 50 ° C, decalcinate with 2 g of activated charcoal and stir for 20 min. Filtration, ethyl acetate washing filter residue, the filtrate 40 ~ 50 ° C concentrated under reduced pressure, add 96mL ethyl acetate and 96mL water, stirring solid precipitation, dropping 290mL n-hexane, ice water cooling, filtration, n-hexane washing cake, Dried to give 11.9 g of compound V (HPLC purity: 70%) in a yield of 80.2%. 1 H NMR (DMSO-d 6 ): δ 1.33-1.41 (m, 4H), 6.11 (s, 2H), 6.86 (s, 1H), 7.09 (s, 1H), 8.53 (s, 1H).
Example 9: Preparation of Spiro [6H- [1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -5-one (Compound V)
To a 500 mL reaction flask was added 10 g (48.8 mmol) of 6-cyano-1,3-benzodioxole-5-carboxylate (IVb), 200 mL of methyl tert-butyl ether, (50.7 mmol) of (IV) isopropyl ester was cooled to 0 to 20 ° C, and 49 mL (0.15 mol) of ethyl magnesium bromide in diethyl ether (3M) was slowly added dropwise. After completion of the drop, the TLC reaction was completed. (10 mL x 2 times), the organic phase was collected and the aqueous phase was extracted again with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the activated charcoal was dried over 100 mL of ethyl acetate and extracted with 250 mL of ethyl acetate. Decolorization, filtration, the filtrate was concentrated to a small amount, dropping petroleum ether, ice water cooling, filtration, petroleum ether washing cake, drying 2.3g compound V, yield: 23.2%. & Lt; 1 & gt ; H NMR data with Example 8.
Example 10: 4- [2- (5-oxospiro [[1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -6 Yl) ethyl] piperidine-1-carboxylate (Compound VIIa)
To a 250 mL reaction flask was added 11.9 g (0.041 mol) of compound of formula V, 84 mL of dimethylsulfoxide, 4 g (0.071 mol) of potassium hydroxide, 27.3 g (0.06 mol) of 4- [2- (p-toluenesulfonyloxy ) Ethyl] piperidine-1-carboxylate (Formula VIa), heated to 55-65 ° C for 3 to 4 hours, and the TLC reaction was completed. (150 mL x 2 times), the aqueous phase was extracted again with 200 mL of ethyl acetate, the organic phase was combined, and 3 g of activated charcoal was added to decolorize, stirred for 30 min, filtered, and the mixture was washed with 300 mL of ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to give compound VIIa. 1 H NMR (CDCl 3 ): δ 1.08-1.19 (m, 2H), 1.28 (dd, 2H, J = 6.2, 7.4 Hz), 1.45 (s, 9H), 1.48-1.57 (m, 5H) (d, 2H, J = 12.7 Hz), 2.69 (t, 2H, J = 11.6 Hz), 3.20 (t, 2H, J = 7.6 Hz), 4.07 (d, 2H, J = 13.1 Hz) , 2H), 6.43 (S, IH), 7.23 (S, IH); the MS (ESI): m / Z 437 [m + of Na] + .
Example 11: 4- [2- (5-oxospiro [[1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -6 Yl) ethyl] piperidine-1-carboxylate (Compound VIIa)
To a 250 mL reaction flask, 6.7 g (33.0 mmol) of compound of formula V, 100 mL of N, N-dimethylformamide, 2.6 g (65.0 mmol) of sodium hydroxide, 14 g (41.3 mmol) of 4- (2-iodoethyl ) Piperidine-1-carboxylic acid tert-butyl ester (VIb), 25-30 ° C for 1.5 h, TLC detection reaction was completed, 100 mL of water and 100 mL of ethyl acetate were added and the organic phase was washed with water (50 mL x 2 times) The organic phase was collected and the aqueous phase was extracted again with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give compound VIIa. & Lt; 1 & gt ; H NMR data with Example 10.
Example 12: 6- [2- (4-Piperidine) ethyl] spiro [[l, 3] dioxolo [4,5-f] isoindole- Propane] -5-one hydrochloride (Compound VIIIa)
To a 100 mL reaction flask was added the compound of formula VIIa obtained in Example 10, 30 mL of ethanol, 45 mL of ethyl acetate, 10.5 mL of concentrated hydrochloric acid. Open the stirrer, 50 ~ 60 ℃ reaction 3h, TLC detection reaction is completed, stop heating, ice water cooling, filtration, ethyl acetate detergent cake, drying, 8.5g off-white solid (compound VIIIa, HPLC purity: 97%) The Yield: 41.4% (calculated based on the amount of compound V in Example 10). 1 H NMR (D 2 O): δ 1.06 (t, 2H, J = 6.7Hz), 1.32-1.46 (m, 6H), 1.60 (m, 1H), 1.91 (d, 2H, J = 13.5Hz) (M, 4H), 3.39 (d, 2H, J = 12.8 Hz), 5.90 (s, 2H), 6.18 (s, 1H), 6.68 (s, 1H); MS (ESI): m / z 315 [M-Cl] + .
Example 13: 6- [2- [1- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7,1′-cyclopropane] -5-one (Compound XI)
A solution of 128.6 g (0.35 mol) of the compound of formula VIIIa, 90 g (0.54 mol) of 2-chloromethylpyridine hydrochloride (formula IXa), 965 mL of water, 26 g of activated carbon and 60 to 65C for 30 minutes were charged into a 2 L reaction flask, , And the residue was washed with 643 ml of water and 215 mL of ethanol. The solution was slowly added with 161 g (1.16 mol) of potassium carbonate. The reaction was carried out at 55 to 65 ° C for 4 to 5 hours. After completion of the TLC reaction, the reaction was cooled, filtered and dried to obtain 137 g of crude The crude product was dissolved in 1.37L ethanol and dissolved at 60-65 ° C. After decontamination with activated charcoal (27.4 g / times x 2 times), 4.11 L of water was added dropwise with stirring, the solid was precipitated, the ice was cooled, filtered, And dried to give 118.9 g of compound XI in 80% yield. 1 H NMR (CDCl 3 ): δ 1.26 (dd, 2H, J = 6.1, 7.6 Hz), 1.35 (br s, 3H), 1.49-1.57 (m, 4H), 1.72 (d, 2H, J = 8.6 (T, 2H, J = 7.9 Hz), 3.64 (s, 2H), 6.03 (s, & lt; RTI ID = 0.0 & gt; 2H), 6.42 (s, 1H), 7.15 (dd, 1H, J = 5.2, 6.7 Hz), 7.24 (s, 1H), 7.41 (d, 1H, J = 7.7 Hz), 7.64 (td, 7.6, 1.8 Hz =), 8.55 (D, IH, J = 4.2Hz); the MS (ESI): m / Z 406 [m + H] + .
Example 14: 6- [2- [1- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7,1′-cyclopropane] -5-one phosphate (Compound I)
To a 50 mL reaction flask was added 2 g (4.9 mmol) of the compound of formula XI, 40 mL of ethanol, dissolved at 60-70 ° C and 0.57 g of 85% (4.9 mmol) of phosphoric acid was added with stirring. The solid was precipitated, 40 mL of ethyl acetate was added dropwise, To room temperature, stirred for 1 hour, filtered, a small amount of ethyl acetate to wash the filter cake, and dried to obtain 2.3 g of a white solid (Compound I, HPLC purity: 99.8%). Yield: 92.7%. 1 H NMR (D 2 O): δ 1.10 (t, 2H, J = 7.2Hz), 1.33-1.64 (m, 7H), 1.92 (d, 2H, J = 13.4Hz), 2.95-3.09 (m, 4H), 3.46 (d, 2H, J = 10.7 Hz), 4.34 (s, 2H), 5.89 (s, 2H), 6.20 (s, 1H), 6.69 (s, 1H), 7.45 (dd, 1H, J = 7.5, 7.4 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.88 (td, 1H, J = 7.7, 1.2 Hz), 8.54 (d, 1H, J = 4.6 Hz)
Multifunctional compound AD-35 improves cognitive impairment and attenuates the production of TNF-alpha and IL-1beta in an alphabeta25-35-induced rat model of alzheimer’s disease
J Alzheimer’s Dis 2017, 56(4): 1403
CN101626688A * Dec 11, 2007 Jan 13, 2010 雷维瓦药品公司 Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors
WO2014005421A1 * Jul 3, 2013 Jan 9, 2014 Zhejiang Hisun Pharmaceutical Co., Ltd. Benzodioxole derivative and preparation method and use thereof
////////////Alzheimers disease, Zhejiang Hisun Pharmaceutical, AD 35, PHASE1, IND-120499
O=C5N(CCC2CCN(Cc1ccccn1)CC2)C3(CC3)c4cc6OCOc6cc45

Xanomeline (LY-246,708; Lumeron, Memcor) ксаномелин , كسانوميلين , 诺美林 ,


Xanomeline.png

Xanomeline (LY-246,708LumeronMemcor)

CAS 131986-45-3

  • Molecular FormulaC14H23N3OS
  • Average mass281.417 Da
ксаномелин كسانوميلين 诺美林 
Hexyloxy-TZTP
5-[4-(Hexyloxy)-1,2,5-thiadiazol-3-yl]-1-méthyl-1,2,3,6-tétrahydropyridine
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist.
Pyridine, 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methyl-
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist. in vitro: Xanomeline had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for a number of other neurotransmitter receptors and uptake sites. In cells stably expressing genetic m1 receptors, xanomeline increased phospholipid hydrolysis in CHO, BHK and A9 L cells to 100, 72 and 55% of the nonselective agonist carbachol. In isolated tissues, xanomeline had high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.006 nM), low affinity for M2 receptors in guinea pig atria (EC50 = 3 microM), was a weak partial agonist in guinea pig ileum and was neither an agonist nor antagonist in guinea pig bladder. Xanomeline produced small increases in striatal acetylcholine levels and did not antagonize the large increases in acetylcholine produced by the nonselective muscarinic agonist oxotremorine, indicating that xanomeline did not block M2 autoreceptors. in vivo: Xanomeline increased striatal levels of dopamine metabolites, presumably by acting at M1 heteroreceptors on dopamine neurons to increase dopamine release. In contrast, xanomeline had only a relatively small effect on acetylcholine levels in brain, indicating that it is devoid of actions at muscarinic autoreceptors. The effects of xanomeline on ex vivo binding and DOPAC levels lasted for about 3 hr and were evident after oral administration. An analog of xanomeline with similar in vivo effects did not inhibit acetylcholinesterase or choline acetyltransferase and inhibited choline uptake only at concentrations much higher than those required to inhibit binding. These data indicate xanomeline is selective agonist for M1 over M2 and M3 receptors in vivo in rat.
Xanomeline (LY-246,708LumeronMemcor) is a muscarinic acetylcholine receptor agonist with reasonable selectivity for the M1 and M4 subtypes,[1][2][3][4] though it is also known to act as a M5 receptor antagonist.[5] It has been studied for the treatment of both Alzheimer’s disease and schizophrenia, particularly the cognitive and negative symptoms,[6] although gastrointestinal side effects led to a high drop-out rate in clinical trials.[7][8] Despite this, xanomeline has been shown to have reasonable efficacy for the treatment of schizophrenia symptoms, and one recent human study found robust improvements in verbal learning and short-term memoryassociated with xanomeline treatment.[9]
Image result for Xanomeline

Xanomeline oxalate

CAS No.:141064-23-5,

Molecular Weight, :371.45,

Molecular Formula, :C16H25N3O5S

5‐[4‐(hexyloxy)‐1,2,5‐thiadiazol‐3‐yl]‐1‐methyl‐1,2,3,6‐tetrahydropyridine; oxalic acid

SEE………..

Title: Xanomeline

CAS Registry Number: 131986-45-3

CAS Name: 3-[4-(Hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine

Molecular Formula: C14H23N3OS

Molecular Weight: 281.42

Percent Composition: C 59.75%, H 8.24%, N 14.93%, O 5.69%, S 11.39%

Literature References: Selective muscarinic M1-receptor agonist.

Prepn: P. Sauerberg, P. H. Olesen, EP384288 (1990 to Ferrosan); eidem,US5043345 (1991 to Novo Nordisk); eidemet al.,J. Med. Chem.35, 2274 (1992).

Prepn of crystalline tartrate: L. M. Osborne et al.,WO9429303 (1994 to Novo Nordisk).

Muscarinic receptor binding study: H. E. Shannon et al.,J. Pharmacol. Exp. Ther.269, 271 (1994). Pharmacology: F. P. Bymaster et al.,ibid. 282.

HPLC determn in plasma: C. L. Hamilton et al.,J. Chromatogr.613, 365 (1993).

Derivative Type: Oxalate

CAS Registry Number: 141064-23-5

Molecular Formula: C14H23N3OS.C2H2O4

Molecular Weight: 371.45

Percent Composition: C 51.74%, H 6.78%, N 11.31%, O 21.54%, S 8.63%

Properties: Crystals from acetone, mp 148°.

Melting point: mp 148°

Derivative Type: (+)-L-Hydrogen tartrate

CAS Registry Number: 152854-19-8

Additional Names: Xanomeline tartrate

Manufacturers’ Codes: LY-246708; NNC-11-0232

Trademarks: Lomeron (Lilly); Memcor (Lilly)

Molecular Formula: C14H23N3OS.C4H6O6

Molecular Weight: 431.50

Percent Composition: C 50.10%, H 6.77%, N 9.74%, O 25.95%, S 7.43%

Properties: Crystals from 2-propanol, mp 95.5°.

Melting point: mp 95.5°

Therap-Cat: Cholinergic; nootropic.

Keywords: Cholinergic; Nootropic.

SYNTHESIS WILL BE UPDATED

Image result for Xanomeline

Image result for Xanomeline

EP 0384288; US 5260311; US 5264444; US 5328925, US 5834495; WO 9429303, EP 0687265; JP 1996507298; WO 9420495
The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Figure

PAPER

Image result for Xanomeline nmr

http://www.mdpi.com/1420-3049/6/3/142/htm

Xanomeline (39) has emerged as one of the most potent unbridged arecoline derivatives. It has higher potency and efficacy for m1 and m4 than for m2, m3 and m5 receptor subtypes [73], binds to the m1receptor subtype uniquely tightly [74,75] and stimulates phosphoinositide hydrolysis in the brain. In cells containing human m1 receptors which are stably expressing amyloid precursor protein (APP), xanomeline (39) stimulates APP release with a potency 1000 greater than carbachol and reduces the secretion of Aβ by 46% [76] (cf 2.6 Central nervous system). In patients with Alzheimer’s disease, it halted cognitive decline and reduced behavioural symptoms such as hallucinations, delusions and vocal outbursts [77,78]. As might be expected there have been numerous attempts to prepare analogues with comparable potency and efficacy. Transplanting the thiadiazole ring of xanomeline to a range of bicyclic amines reduced selectivity [79,80] as did the use of pyrazine analogues (40) [81].

Paper

J Med Chem 1992,35(12),2274-83

see http://pubs.acs.org/doi/pdf/10.1021/jm00090a019

PAPER

Classics in Chemical Neuroscience: Xanomeline

 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
§ Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
ACS Chem. Neurosci.20178 (3), pp 435–443
DOI: 10.1021/acschemneuro.7b00001
Publication Date (Web): January 31, 2017
Copyright © 2017 American Chemical Society

Abstract

Abstract Image

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer’s disease (AD) patients. Despite the compound’s promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound’s unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address xanomeline’s overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.

PAPER

References

  1. Jump up^ Farde L, Suhara T, Halldin C, et al. (1996). “PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man”. Dementia (Basel, Switzerland)7 (4): 187–95. PMID 8835881.
  2. Jump up^ Jakubík J, Michal P, Machová E, Dolezal V (2008). “Importance and prospects for design of selective muscarinic agonists” (PDF). Physiological Research / Academia Scientiarum Bohemoslovaca. 57 Suppl 3: S39–47. PMID 18481916.
  3. Jump up^ Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). “Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice”European Journal of Pharmacology603 (1-3): 147–9. PMID 19111716doi:10.1016/j.ejphar.2008.12.020.
  4. Jump up^ Heinrich JN, Butera JA, Carrick T, et al. (March 2009). “Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists”European Journal of Pharmacology605 (1-3): 53–6. PMID 19168056doi:10.1016/j.ejphar.2008.12.044.
  5. Jump up^ Grant MK, El-Fakahany EE (October 2005). “Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor”The Journal of Pharmacology and Experimental Therapeutics315 (1): 313–9. PMID 16002459doi:10.1124/jpet.105.090134.
  6. Jump up^ Lieberman JA, Javitch JA, Moore H (August 2008). “Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry”The American Journal of Psychiatry165 (8): 931–6. PMID 18676593doi:10.1176/appi.ajp.2008.08050769.
  7. Jump up^ Messer WS (2002). “The utility of muscarinic agonists in the treatment of Alzheimer’s disease”. Journal of Molecular Neuroscience : MN19 (1-2): 187–93. PMID 12212779doi:10.1007/s12031-002-0031-5.
  8. Jump up^ Mirza NR, Peters D, Sparks RG (2003). “Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists”. CNS Drug Reviews9 (2): 159–86. PMID 12847557doi:10.1111/j.1527-3458.2003.tb00247.x.
  9. Jump up^ Shekhar A, Potter WZ, Lightfoot J, et al. (August 2008). “Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia”The American Journal of Psychiatry165 (8): 1033–9. PMID 18593778doi:10.1176/appi.ajp.2008.06091591.
Xanomeline
Xanomeline.png
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.208.938
Chemical and physical data
Formula C14H23N3OS
Molar mass 281.42 g/mol
3D model (JSmol)

///////XanomelineLY 246708, LumeronMemcor, ксаномелин كسانوميلين 诺美林 allosteric modulation, Alzheimer’s disease, antipsychotic,  muscarinic acetylcholine receptors, schizophrenia, 

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

 

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Phone : +91-40-2354-1142, 2354-3311
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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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Banjara Hills,Hyderabad

Banjara Hills, Hyderabad, Telangana
Map of Banjara Hills, Hyderabad
TAJ KRISHNA
SUBWAY RESTAURANT

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

RG-1577, EVT 302, Sembragiline, RO-4602522


 

 

front page image

RG-1577, EVT 302, Sembragiline, RO-4602522

Hoffmann La Roche

CAS 676479-06-4, MW 342.36

  • C19 H19 F N2 O3
  • Acetamide, N-​[(3S)​-​1-​[4-​[(3-​fluorophenyl)​methoxy]​phenyl]​-​5-​oxo-​3-​pyrrolidinyl]​-

UNII-K3W9672PNJ2D chemical structure of 676479-06-4

RG-1577, a selective and reversible monoamine oxidase B inhibitor, for treating AD (phase 2 clinical, as of May 2015).

Family members of the product case for RG-1577 (WO2004026825) hold protection in EU until 2023 and expire in US in 2024 with US154 extension. Follows on from WO2006097197, claiming a process for preparing RG-1577.

Alzheimers Disease is a brain disease that slowly destroys memory and thinking skills, up to loss of the ability to carry out the simplest tasks. It is the most common cause of dementia among older people. Mild Alzheimers Disease manifests itself in memory loss and small changes in other cognitive abilities, e.g getting lost, trouble handling money and managing daily tasks, having some mood and personality changes, etc.

In the stage of Moderate Alzheimers Disease, the control of language, reasoning, sensory processing, and conscious thought are impacted. Memory loss and con usion grow worse, e.g patients have problems recognizing family and friends and become unable to learn new things, etc. hallucinations, delusions, and paranoia may occur. .Severe Alzheimers Disease is the final stage. Patients cannot communicate anymore and are completely dependent.

N-[(3S)-l-[4-[(3-fluorophenyl)methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide has previously been described in the art. 1 WO 2006/097197 2 and WO 2006/0972703 relate to methods for preparing enantiomerically pure 4-pyrrolidinophenylbenzyl ether derivatives.

The processes of the prior art hamper from several drawbacks (e.g. long reaction sequence, low overall yield also due to loss of half of the product in the classical resolution step, the need for a chromatographic purification to remove by-products formed in the Mitsunobu reaction) and are therefore less suitable for the preparation of N-[(3S)-l-[4-[(3-fluorophenyl) methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide on large scale.

 

Most Recent Events

  • 01 Aug 2014Roche completes a phase I trial in volunteers in USA (NCT02104648)
  • 14 May 2014Roche completes enrolment in the MAyflOwer RoAD trial for Alzheimer’s disease (combination therapy, adjunctive treatment) in Australia, Canada, Czech Republic, France, Germany, Italy, Poland, South Korea, Spain, Sweden the United Kingdom and the USA (NCT01677754)
  • 01 Apr 2014Roche initiates enrolment in a phase I trial in healthy volunteers in USA (NCT02104648)

http://www.evotec.com/uploads/media_library/10/2012-09_Evotec_Company_presentation_September_e.pdf

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WO2004026825

http://www.google.com/patents/WO2004026825A1?cl=en

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WO2006097197

http://www.google.com/patents/WO2006097197A1?cl=en

……………………………………………..

PATENT

WO 2015063001

https://patentscope.wipo.int/search/ja/detail.jsf;jsessionid=82F2EFFC078602A9E3061C7CF658B36C.wapp2nA?docId=WO2015063001&recNum=37&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=%E5%85%AC%E9%96%8B%E6%97%A5%EF%BC%88%E6%96%B0%E3%81%97%E3%81%84%E9%A0%86%EF%BC%89&maxRec=57119

Novel, crystalline polymorphic forms A and B of a pyrrolidone derivative ie RG-1577, useful for treating Alzheimer’s disease (AD). Roche and its Japanese subsidiary Chugai, under license from Evotec, which previously licensed the drug from Roche, are developing RG 1577

 

formula 1 via the following routes

In a certain embodiment, present invention relates to a synthesis of a compound of formula he following route A

1

In a certain embodiment, present invention relates to a synthesis of a compound of formula he following route B

In a certain embodiment, present invention relates to a crystalline polymorph of a compound of formula 1.

 

synthesize a compound of formula 1 from a compound of formula 7

 

compound of formula 6 to a compound of formula 7

In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 6 via the intermediate 6a to a compound of formula 7

 

further comprising reacting a compound of formula 3 with a compound of formula 5 to a compound of formula 6

 

 

comprising reacting a compound of formula 2 to a compound of formula 3

2 3

 

In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 10 to a compound of formula 6

 

eacting a compound of formula 9 with a compound of formula 5 to a compound of formula 10

 

In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 8 to a compound of formula 9

 

(lS’)-N-[l-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl-]acetamide (1)

To a suspension of chloride (7) (37.9 g, 100 mmol) in 2-methyltetrahydrofurane (600 ml) was added under vigorous stirring at 0°C 1.65 M potassium ie/t-butoxide in THF (75.5 ml, 125 mmol, ACROS) over 2.5 h. After additional stirring at 0°C for 1 h, the cold suspension was hydrolyzed with 0.1 M HCl (600 ml) and the reaction mixture was stirred at 30°C for 0.5 h. The organic layer was washed with water (300 ml), dried (Na2S04) and filtered. Removal of the solvent by rotary evaporation (50°C/>10 mbar) afforded 32.1 g crystalline residue, which was dissolved in 2-butanone (400 ml) at ca. 95°C and hot filtered. Crystallization, which was induced by seeding and cooling to room temperature and 0°C (4 h) afforded 25.4 g (74.2%) of the titled compound (1) as an off-white, crystalline powder,

Mp. 162-164°C (polymorph B).

Ee >99.8%, [cc]D20 = – 17.8 (DMF; c = 1).

1H NMR (400 MHz, DMSO- 6) δ ppm 1.82 (s, 3H), 2.34 (dd, J1=n. l, J2=3.9, 1H), 2.84 (dd, J/=17.1, J2=8.2, 1H), 3.55 (dd, J/=10.2, J2=3.2, 1H), 4.07 (dd, J/=10.2, J2=6.7, 1H), 4.32-4.41 (m, 1H), 5.13 (s, 2H), 7.02 & 7.55 (d, J=9.1, each 1H), 7.11-7.19 (m, 1H), 7.24-7.31 (m, 1H), 7.40-7.47 (m, 1H), 8.40 (d, J=6.4, 1H).

ESI-MS (m/z) 343 [M+H]+, 365 [M+Na]\. Anal.Calcd for Ci9H19FN203 (342.37): Calcd. C, 66.66; H, 5.59; N, 8.18; F, 5.02; O, 14.02. Found C, 66.76; H, 5.48; N, 8.13; F, 5.03; O, 13.99.

Crystallized (1) form previous step (9.5 g, 0.028 mol) was dissolved in 2-butanone (290 mL) upon heating. The hot solution was filtered over charcoal. The solution was concentrated by removal of 2-butanone (200 mL) by distillation prior to seeded cooling crystallization. Filtration, washing with chilled 2-butanone and drying at 50°C/25 mbar/16h afforded 9.18 g (93.9% corrected yield) of the title compound (1) as a crystalline powder of polymorphic form B with an assay of 100.4 %(w/w) and a purity of 99.97 %(area) (by HPLC).

Alternatively, to a stirred suspension of hydroxyamide (6) (30.0 g, 0.083 mol) in toluene (500 ml) was added at 50°C within 45 minutes thionyl chloride (10.40 g, 0.087 mol) and the resulting mixture was stirred for 3h at 50°C. The mixture was then heated up to 92°C and subsequently stirred at this temperature for 15 h. The Suspension was then cooled to 50°C and toluene was removed by distillation under reduced pressure. The distillation residue was cooled to ambient temperature and treated with N-methylpyrrolidone (210 ml) to obtain an almost clear solution. This solution was then cooled to -10°C and subsequently treated at this temperature within 2h with a solution of potassium iert-butoxide (12.40 g, 0.111 mol) in THF (60 g). The resulting mixture was stirred for another 60 minutes at -10°C, then warmed up to room temperature within 60 minutes and subsequently stirred at room temperature for 6 h. The reaction mixture was quenched with water (150 g) and the pH was adjusted with acetic acid (approx. 1.8 g) to pH 7-8. The mixture was then heated to 30-45°C and THF and toluene were distilled off under reduced pressure (<200 mbar) to obtain a clear NMP/water mixture (400 ml). This mixture was heated to 45°C and 260 mg of seed crystals were added. Water (320 ml) was then added within 3 h whereby the product crystallized. The resulting suspension was cooled to room temperature within 3 h and subsequently stirred at this temperature for 2 h. Filtration and washing of the filter cake with a mixture of water (100 ml) and N-methylpyrrolidone (20 ml) and subsequently only with water (150 ml) afforded after drying (70°C/10 mbar/20 h) 26.2 g (92%) of the title compound (1) as a crystalline powder with an assay of 99.6 %(w/w) and a purity of 99.7 %(area) (by HPLC).

HPLC

Purity (HPLC): Column: XSelect Phenyl Hexyl x2, 150 x 4.6mm, 3.5um. Starting

Pressure: 226 bar; temp.: 50°C. Inj. vol.: 2.0 μΐ^ + wash. Flow: 1.0 ml/min. Det: 204 nm. A: Water + 5% ACN, 77-2% in 7 min., hold for 1 min.; B: 0.1% HCOOH, 18% isocratic; C: MeOH, 5-80% in 7 min., hold for 1 min. Sample prep.: 2 mg/ml ACN. Retention times: β-acid 5.93 min., diacid 6.18 min., cc-acid 6.89 min., diester 6.96 min.

ee determination(HPLC): Column: Chiralpak IA-3 100 x 4.6mm, 3um; 91 bar, 2ml/min; temp.: 30°C. Inj. vol.: 10.0 μL· Det.: 206 nm. A: n-heptane, 80%; B: EtOH, 20%. Sample prep.: 4 mg/ml EtOH. Retention times: D-enantiomer 2.21 min., L-enantiomer 2.71 min

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US 20050065204

EXAMPLE 11

Preparation of (S)-1-(4-Hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic Acid

8.00 g Polyethyleneglycol 6000 was dissolved in 150 mL (100 mM) magnesium acetate buffer pH 6.0 under stirring, and the solution added to a stirred suspension of 10.00 g (42.51 mmol) (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (99.7%) in 40 mL methylcyclohexane. The mixture was heated to 28° C. and the pH readjusted to 6.0 with 2 M NaOH. The reaction was started by adding 33.2 mg Candida cylindraceae cholesterase (16.88 kU/g), and the pH was maintained at 6.0 by the controlled addition of 1.0 M NaOH solution under stirring. After a total consumption of 20.35 mL (20.35 mmol) 1.0 M sodium hydroxide solution (after 17.1 h; 47.9% conversion) the reaction mixture was passed through a sintered glass filter. The filtrate spontaneously separated into an aqueous and an organic phase.The aqueous phase was washed with 2×200 mL ethyl acetate to remove uncleaved ester. The aqueous phase was set to pH 4.0 with 25% sulfuric acid and concentrated in vacuo to a volume of ca. 80 mL (bath 60° C.). The solution was cooled to 1° C. (formation of white precipitate/crystals) and the pH set to 1.5 with 25% sulfuric acid. The precipitate/crystals were stirred overnight at 1° C., filtered off on a sintered glass filter (washed with a minimum amount of water) and dried overnight on high vacuum (RT, 6×10−2 mbar) to give 4.32 g (19.53 mmol; 45.9%) (S)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid. Analysis: HPLC (area A226nm): 99.3%, 0.7% ester. 98.9%ee. The product contains 5.3% water (according to Karl Fischer determination) and 2.1% (w/w) PEG (according to NMR).

 

Company Evotec AG
Description Small molecule monoamine oxidase B (MAO-B) inhibitor
Molecular Target Monoamine oxidase B (MAO-B)
Mechanism of Action Monoamine oxidase B (MAO-B) inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Alzheimer’s disease (AD)
Indication Details Treat Alzheimer’s disease (AD)
Regulatory Designation
Partner

Chugai Pharmaceutical Co. Ltd.; Roche

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Chūō, japan

Map of chuo-ku tokyo

 

A Chūō Line (Rapid) E233 series (right) and A Chūō-Sōbu Line E231 series (June 2007)

Chuo Dori street on a weekend afternoon

Mitsubishi Tanabe And EnVivo in Phase III Trial Of Alzheimer’s Disease Treatment MT-4666


Figure JPOXMLDOC01-appb-C000080

OR

Encenicline (EVP-6124, MT-4666)

EVP-6124 , MT-4666, α7-nAChR agonist, UNII-5FI5376A0X
Chemical Name: (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
Therapy Type: Small Molecule
Target Type: Cholinergic System

CAS : 550999-75-2

C16 H17 Cl N2 O S
Benzo[b]​thiophene-​2-​carboxamide, N-​(3R)​-​1-​azabicyclo[2.2.2]​oct-​3-​yl-​7-​chloro-
(R)​-​7-​Chloro-​N-​(quinuclidin-​3-​yl)​benzo[b]​thiophene-​2-​carboxamide; EVP 6124

Condition(s): Alzheimer’s Disease, Schizophrenia
U.S. FDA Status: Alzheimer’s Disease (Phase 3), Schizophrenia (Phase 3)
Status in Select Countries: Investigational in Japan
Company: FORUM Pharmaceuticals Inc. (was EnVivo Pharmaceuticals), Mitsubishi Tanabe Pharma
Approved for: None  AS ON SEPT 2014

Figure imgb0009

CAS  550999-74-1

Benzo[b]​thiophene-​2-​carboxamide, N-​(3R)​-​1-​azabicyclo[2.2.2]​oct-​3-​yl-​7-​chloro-​, monohydrochloride

(R)​-​7-​Chloro-​N-​(quinuclidin-​3-​yl)​benzo[b]​thiophene-​2-​carboxamide hydrochloride

Mitsubishi Tanabe Pharma  ..Encenicline-hydrochloride (EVP-6124) for Alzheimer’s disease by partner EnVivo Pharmaceuticals. Mitsubishi Tanabe has licensed EVP-6124 from EnVivo and is currently developing the drug under the code MT-4666.

The drug is a new alpha-7 potentiator intended to improve cognition in patients affected with Alzheimer’s disease. The drug is being tested in Phase III COGNITIV clinical trials in two categories: COGNITIV AD in patients with Alzheimer’s disease and COGNITIV CIAS in patients with cognitive impairment associated with schizophrenia.

Alzheimer’s disease affects five million people in the U.S. alone, or one in eight Americans over the age of 65. The disease is the sixth-leading cause of death in the country, with the number of affected patients expected to balloon to nearly triple by 2030. Alzheimer’s disease is a complex neurodegenerative disease that eventually leads to cellular loss and dysfunction in the brain resulting in decline of language skills and reasoning among others.

Phase III of COGNITIV AD clinical trial program involves about 1,600 patients with mild to moderate AD and who are presently receiving stable treatment with or have undergone previous acetylcholinesterase inhibitor treatment. The trials will be placebo-controlled, double-blind, and randomized. Patients in the trial will be randomized to receive either one of two doses of MT-4666 once daily against a placebo to assess safety and efficacy of the drug.

Chemical structure for W-5978

In the news release recently launched by EnVivo, CEO and president Deborah Dunsire said, “We are pleased to advance encenicline into Phase 3 clinical development in Alzheimer’s disease, a significant milestone for our company and promising step forward for patients who desperately need new therapies…Prior clinical studies of encenicline have demonstrated clinically significant improvements in cognitive function in patients with Alzheimer’s disease. For the millions of patients living with AD, we believe encenicline has the potential to make a meaningful difference.”

Encenicline hydrochloride is a partial, selective agonist of the α-7 nicotinic acetylcholine receptor (α7-nAChR). It is being developed for the treatment of cognitive deficits in schizophrenia and Alzheimer’s disease. Cholinergic function declines in Alzheimer’s, and currently approved acetylcholinesterase inhibitor therapies modestly improve cognitive deficits in patients with AD by way of boosting cholinergic transmission. The rationale of selective α7-nAChR agonists is that they will enhance cognition without causing side effects associated with overactivation of other nAChRs such as α4β2, or muscarinic AChRs. In rats, encenicline penetrates the blood-brain barrier and improves memory performance by potentiating the acetylcholine response. Encenicline has been reported to act as a co-agonist with acetylcholine. It sensitizes the α-7 nACh receptor to its natural ligand and renders sub-efficacious doses of AChEI drugs effective in restoring memory function in an object recognition task (Prickaerts et al., 2012).

 Chemical structure for EVP-6124

This compound was originally developed at Bayer Healthcare and then licensed to Envivo Pharmaceuticals, which subsequently licensed development in Asia to Mitsubishi Tanabe Pharma Corporation. Envivo then changed its name to FORUM Pharmaceuticals Inc.

Encenicline is being tested in Alzheimer’s disease and schizophrenia. In Alzheimer’s, an ascending-dose Phase 1/2 study showed 0.1 to 1 mg/day of EVP-6124 to be safe and well-tolerated when given to 49 people with mild to moderate AD for 28 days. No serious side effects were reported. Secondary efficacy endpoints suggested that EVP-6124 given in addition to therapy with the acetyl cholinesterase inhibitors donepezil or rivastigmine appeared to improve attention, verbal fluency, and executive function as measured on  tests in the CogState or NTB batteries (see conference news story). This study has posted results on clinicaltrials.gov.

A 24-week Phase 2 trial conducted in 409 people with mild to moderate Alzheimer’s disease in the United States and Eastern Europe compared 0.3, 1, and 2 mg of EVP-6124 per day to placebo, measuring cognition with ADAS-Cog as the primary outcome plus cognitive, functional, and psychiaric secondary outcomes. EVP 6124 was given as adjunct therapy to donepezil or rivastigmine. This trial was reported to have met its primary and most secondary endpoints, showing that people on the highest dose improved over baseline. EVP-6124 dose-dependently improved measures of attention, verbal and language fluency, and executive function. In this trial, all treatment groups initially improved, possibly due to a placebo effect, but by 12 weeks the groups separated and the placebo and low-dose groups declined (see conference news story). EVP-6124 was well-tolerated.

Mitsubishi Tanabe Pharma Corporation is conducting a Phase 2 trial for the treatment of Alzheimer’s disease in Japan.

In October 2013, two international Phase 3 trials began enrolling what are to be 790 patients in each trial with mild to moderate Alzheimer’s who are already taking an acetylcholinesterase inhibitor. The trials will compare two fixed, undisclosed add-on doses of EVP-6124 to placebo, all given as once-daily tablets for six months, for cognitive benefit as measured by the ADAS-Cog, clinical benefit as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), as well as for safety and tolerability. Called COGNITIV AD, this Phase 3 program is is set to run through 2016.

For schizophrenia, a Phase 1 study comparing 0.3 and 1 mg/day of EVP-6124 to placebo in 28 people with the disease gave preliminary evidence for the compound’s safety, tolerability, and pharmacokinetics in this population. In addition, the compound yielded signals of bioactivity in the brain by way of EEG tests of evoked potentials, a measure of sensory gating affected in this disease. See study results on clinicaltrials.gov.

A subsequent 12-week Phase 2 trial compared 0.3 and 1 mg/day of EVP-6124 to placebo in 317 people with schizophrenia and measured safety and the compound’s efficacy on cognitive function. As presented at the American College of Neuropsychopharmacology meeting held in Hawaii December 2011, EVP 6124 met its primary endpoint of improvement on the CogState overall cognition index. The study also met secondary endpoints, showing improvement in clinical function as assessed by the Schizophrenia Cognition Rating Scale, and a decrease in negative symptoms (See company press release).

Two six-month, 700-patient Phase 3 studies, plus a six-month extention study, are ongoing. For all clinical trials of encenicline, see clincialtrials.gov.

http://www.google.com.ar/patents/WO2014051055A1?cl=pt-PT

Synthesis (hereinafter, the compound of Reference Example 25) carboxamide hydrochloride (Reference Example 25) (R) -7 – chloro-N-(quinuclidin-3 – – yl) benzo [b] thiophene-2:
[First Step]
Synthesis of carboxamide (R) -7 – chloro-N-(quinuclidin-3 – – yl) benzo [b] thiophene-2:

Figure JPOXMLDOC01-appb-C000080

-N, N, N ‘, N’-tetra-7 – chloro-1 – benzothiophene -2 – – o-(yl benzotriazol-1) chloroform solution (210mg, 1.0mmol) of carboxylic acid in (10mL) was added (0.70mL, 4.0mmol) and (570mg, 1.5mmol), diisopropylethylamine methyl hexafluorophosphate, (R) – (200mg, 1.0mmol) amine hydrochloride – quinuclidine-3 was added, and the mixture was stirred at room temperature. 16 hours later, was added distilled water, 1.0N sodium hydroxide solution, and extracted with chloroform. Was washed with saturated brine and the organic layer was concentrated and then dried over anhydrous sodium sulfate. (Fuji Silysia Chemical amine silica gel DM1020, chloroform alone – chloroform / methanol = 90/10) on silica gel column chromatography of the crude product obtained was purified by the title compound; was obtained as a white solid (170mg 53%).
1 H-NMR (400MHz, DMSO-d 6)
δ :1.22-1 .38 (1H, m) ,1.53-1 .62 (2H, m) ,1.75-1 .82 (2H, m) ,2.63-2 .73 (4H , m) ,2.84-2 .94 (1H, m) ,3.07-3 .18 (1H, m) ,3.90-4 .00 (1H, m), 7.49 (1H, dd , J = 7.6,8.0 Hz), 7.59 (1H, d, J = 7.6Hz), 7.96 (1H, d, J = 8.0Hz), 8.31 (1H, s) ,8.62-8 .66 (1H, m).
MS (ESI): 321 [M + H] +

[Second Step]
Synthesis of the compound of Reference Example 25:

Figure JPOXMLDOC01-appb-C000081

Ethyl acetate solution – solution of hydrogen chloride in ethyl acetate (170mg, 0.53mmol) of the (2.0mL) carboxamide – (R) -7 – chloro-N-(quinuclidin-3 – yl) benzo [b] thiophene-2 was added (4.0M, 0.20mL, 0.80mmol), and the mixture was stirred at room temperature. 10 minutes later, by which is filtered off and the resulting solid was washed with ethyl acetate and hexane, and dried, the compound of Reference Example 25; was obtained as a white solid (170mg 90%).
1 H-NMR (400MHz, DMSO-d 6)
δ :1.70-1 .78 (1H, m) ,1.86-1 .94 (2H, m) ,2.10-2 .19 (2H, m) ,3.18-3 .35 (5H , m) ,3.63-3 .72 (1H, m) ,4.27-4 .36 (1H, m), 7.50 (1H, d, J = 7.6,8.0 Hz), 7 .61 (1H, d, J = 7.6Hz), 7.98 (1H, d, J = 8.0Hz), 8.38 (1H, s) ,9.07-9 .10 (1H, m) ,9.80-9 .85 (1H, m).
MS (ESI): 321 [M + H] +

………………………………….

http://www.google.com/patents/EP1461335A1?cl=en

Example 69

N-[(3 R) – 1 – azabicyclo [2.2.2] oct-3-y 1]-7-chloro-1-benzothiophene-2-carboxamide hydrochloride  DESIRED

Figure imgf000124_0001

x HCI

176.2 mg (0.83 mmol) of 7-chloro-l-benzothiophene-2-carboxylic acid, 150 mg (0.75 mmol)

R-3-Aminochinuklidin dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg

(2.71 mmol) of N, N-diisopropylethylamine and 3.0 ml of DMF are reacted according to the general working procedure (variant B). The reaction mixture is purified by preparative HPLC. The product will be in a mixture of 4 M HCl solution in dioxane and methanol, and then concentrated. This gives 175.2 mg

(65.1% of theory) of the title compound.

1H NMR (200 MHz, DMSO-d 6): δ – 10.03 (s, IH, br), 9.17 (d, IH), 8.43 (s, IH), 7.98 (m, IH), 7.63 (m, IH ), 7.52 (dd, IH), 4.33 (m, IH), 3.77-3.10 (m, 6H), 2.28-

2.02 (m, 2H), 1.92 (m, 2H), 1.75 (m, IH) ppm.

HPLC: R t = 4.0 min (Method H)

MS (ESIpos): m / z = 321 (M + H) + (free base).

Example 70

N-[(3 S) – 1-azabicyclo [2.2.2] oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamide hydrochloride  UNDESIRED

Figure imgf000125_0001

x HCI

176.2 mg (0.83 mmol) of 7-chloro-l-benzothiophene-2-carboxylic acid, 150 mg (0.75 mmol) of S-3-Aminochinuklidin dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N, N- diisopropylethylamine and 3.0 ml of DMF are implemented according to the general procedure (Method B). The reaction mixture is purified by preparative HPLC. The product will be in a mixture of 4 M HCl solution in dioxane and methanol, and then concentrated. Obtained 231.9 mg (85.7% of theory) of the title compound. The analytical data are consistent with those of the enantiomeric compound from Example 69.

………………………………………

http://www.google.com.ar/patents/EP2727604A1?cl=en

(Reference Example 3)
Synthesis of (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride (hereinafter referred to as the compound of Reference Example 3):

[First step]Synthesis of 7-Chloro-1-benzothiophene-2-carboxylic acid:

  • [Second step]Synthesis of (R)-7-Chloro-N-(quinuclidine-3-yl)benzo[b]thiophene-2-carboxamide:

  • To a solution (10 mL) of 7-chloro-1-benzothiophene-2-carboxylic acid (210 mg, 1.0 mmol) in chloroform, o-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol) and diisopropylethylamine (0.70 mL, 4.0 mmol) were added. Thereafter, (R)-quinuclidine-3-amine hydrochloride (200 mg, 1.0 mmol) was added thereto, and the resulting mixture was stirred at room temperature. Sixteen hours later, distilled water and 1.0 N aqueous sodium hydroxide solution were added thereto, and the resultant was extracted with chloroform. The organic layer was washed with brine, then dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, Fuji Silysia Chemical Ltd., chloroform alone to chloroform/methanol = 90/10) to obtain the title compound (170 mg; 53%) as a white solid.
    1H-NMR (400 MHz, DMSO-d6)
    δ: 1.22-1.38 (1H, m), 1.53-1.62 (2H, m), 1.75-1.82 (2H, m), 2.63-2.73 (4H, m), 2.84-2.94 (1H, m), 3.07-3.18 (1H, m), 3.90-4.00 (1H, m), 7.49 (1H, dd, J=7.6, 8.0 Hz), 7.59 (1H, d, J=7.6 Hz), 7.96 (1H, d, J=8.0 Hz), 8.31 (1H, s), 8.62-8.66 (1H, m).
    MS (ESI) [M+H]+ 321
  • [Third step]Synthesis of Compound of Reference Example 3:

  • To a solution (2.0 mL) of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide (170 mg, 0.53 mmol) in ethyl acetate, hydrogen chloride-ethyl acetate solution (4.0 M, 0.20 mL, 0.80 mmol) was added, and the resulting mixture was stirred at room temperature. Ten minutes later, the obtained solid was filtered off, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 3 (170 mg; 90%) as a white solid.
    1H-NMR (400 MHz, DMSO-d6)
    δ: 1.70-1.78 (1H, m), 1.86-1.94 (2H, m), 2.10-2.19 (2H, m), 3.18-3.35 (5H, m), 3.63-3.72 (1H, m), 4.27-4.36 (1H, m), 7.50 (1H, d, J=7.6, 8.0 Hz), 7.61 (1H, d, J=7.6 Hz), 7.98 (1H, d, J=8.0 Hz), 8.38 (1H, s), 9.07-9.10 (1H, m), 9.80-9.85 (1H, m).
    MS (ESI) [M+H]+
    321
  • WO1991012254A1 * 15 Feb 1991 17 Aug 1991 Novo Nordisk As Substituted urea compounds and their preparation and use
    WO2004069141A2 * 5 Feb 2004 19 Aug 2004 Strakan Ltd Transdermal granisetron
    WO2004076449A2 * 20 Feb 2004 10 Sep 2004 Jozef Klucik 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
    WO2008019372A2 * 7 Aug 2007 14 Feb 2008 Amr Technology Inc 2-aminobenzoxazole carboxamides as 5ht3 modulators
    WO2008096870A1 * 8 Feb 2008 14 Aug 2008 Astellas Pharma Inc Aza-bridged-ring compound
    JPH0881374A * Title not available

     

    Encenicline hydrochloride [USAN]
    550999-74-1
    2D chemical structure of 550999-74-1
    MW: 357.3032
    2
    Encenicline [USAN]
    550999-75-2
    2D chemical structure of 550999-75-2
    MW: 320.8423
    3
    2D chemical structure of 1350343-61-1
    MW: 375.318

     

    Experimental Drug Seems to Aid Memory in Mice With Alzheimer’s


    //

    TUESDAY May 14, 2013 — An experimental drug improved the memory and brain function in older mice with advanced symptoms of Alzheimer’s disease, according to a new study.

    read this at

    http://www.drugs.com/news/experimental-seems-aid-memory-mice-alzheimer-s-44538.html

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