AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Otsuka multi-drug resistant TB drug approved in Europe

 Uncategorized  Comments Off on Otsuka multi-drug resistant TB drug approved in Europe
May 012014
 

Delamanid.svg

Delamanid

Otsuka Pharmaceutical Co has been given the green light to sell its tuberculosis drug Deltyba in Europe.

Read more at: http://www.pharmatimes.com/Article/14-04-30/Otsuka_multi-drug_resistant_TB_drug_approved_in_Europe.aspx#ixzz30Sz3wf2k
Follow us: @PharmaTimes on Twitter

http://newdrugapprovals.org/2014/03/26/delamanid-an-experimental-drug-for-the-treatment-of-multi-drug-resistant-tuberculosis/

 

Delamanid.svg

Delamanid

http://www.ama-assn.org/resources/doc/usan/delamanid.pdf

(2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole

2(R)-Methyl-6-nitro-2-[4-[4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl]phenoxymethyl]-2,3-dihydroimidazo[2,1-b]oxazole

(R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

Imidazo[2,1-b]oxazole, 2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]phenoxy]methyl]-, (2R)-

(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

681492-22-8 cas no

Delamanid, 681492-22-8, Delamanid (JAN/USAN), Delamanid [USAN:INN],UNII-8OOT6M1PC7,
  • OPC 67683
  • OPC-67683
  • UNII-8OOT6M1PC7
Molecular Formula: C25H25F3N4O6
Molecular Weight: 534.48441

CLINICAL TRIALS

Trial Name: A Placebo-Controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-Positive, Multidrug-Resistant Tuberculosis (TB)
Primary Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Trial ID / Reg # / URL: http://clinicaltrials.gov/ct2/show/NCT00685360

Delamanid (USAN, codenamed OPC-67683) is an experimental drug for the treatment of multi-drug-resistant tuberculosis. It works by blocking the synthesis of mycolic acids in Mycobacterium tuberculosis, the organism which causes tuberculosis, thus destabilising its cell wall.[1][2][3]

In phase II clinical trials, the drug was used in combination with standard treatments, such as four or five of the drugs ethambutolisoniazid,pyrazinamiderifampicinaminoglycoside antibiotics, and quinolones. Healing rates (measured as sputum culture conversion) were significantly better in patients who additionally took delamanid.[3][4]

The European Medicines Agency (EMA) recommended conditional marketing authorization for delamanid in adults with multidrug-resistant pulmonary tuberculosis without other treatment options because of resistance or tolerability. The EMA considered the data show that the benefits of delamanid outweigh the risks, but that additional studies were needed on the long-term effectiveness.[5]

Delamanid, an antibiotic active against Mycobacterium tuberculosis strains, has been filed for approval in the E.U. and by Otsuka for the treatment of multidrug-resistant tuberculosis. In 2013, a positive opinion was received in the E.U. for this indication. Phase III trials for treatment of multidrug-resistant tuberculosis are under way in the U.S. Phase II study for the pediatric use is undergone in the Europe.

The drug candidate’s antimycobacterial mechanism of action is via specific inhibition of the synthesis pathway of mycolic acid, which is a cell wall component unique to M. tuberculosis.

In 2008, orphan drug designation was received in Japan for the treatment of pulmonary tuberculosis.

Tuberculosis (TB), an airborne lung infection, still remains a major public health problem worldwide. It is estimated that about 32% of the world population is infected with TB bacillus, and of those, approximately 8.9 million people develop active TB and 1.7 million die as a result annually according to 2004 figures. Human immunodeficiency virus (HIV) infection has been a major contributing factor in the current resurgence of TB. HIV-associated TB is widespread, especially in sub-Saharan Africa, and such an infectious process may further accelerate the resurgence of TB.

Moreover, the recent emergence of multidrug-resistant (MDR) strains ofMycobacterium tuberculosis that are resistant to two major effective drugs, isonicotinic acid hydrazide (INH) and rifampicin (RFP), has further complicated the world situation.

The World Health Organization (WHO) has estimated that if the present conditions remain unchanged, more than 30 million lives will be claimed by TB between 2000 and 2020. As for subsequent drug development, not a single new effective compound has been launched as an antituberculosis agent since the introduction of RFP in 1965, despite the great advances that have been made in drug development technologies.

Although many effective vaccine candidates have been developed, more potent vaccines will not become immediately available. The current therapy consists of an intensive phase with four drugs, INH, RFP, pyrazinamide (PZA), and streptomycin (SM) or ethambutol (EB), administered for 2 months followed by a continuous phase with INH and RFP for 4 months. Thus, there exists an urgent need for the development of potent new antituberculosis agents with low-toxicity profiles that are effective against both drug-susceptible and drug-resistant strains of M. tuberculosis and that are capable of shortening the current duration of therapy.

………………………

US20060094767

(R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole

 

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol

ARE THE INTERMEDIATES

 

Example 1884

Production of (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg, 1.96 mmol) was dissolved in N,N′-dimethylformamide (3 ml), and sodium hydride (86 mg, 2.16 mmol) was added while cooling on ice followed by stirring at 70-75° C. for 20 minutes. The mixture was cooled on ice. To the solution, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg, 2.75 mmol) in N,N′-dimethylformamide (3 ml) was added followed by stirring at 70-75° C. for 20 minutes. The reaction mixture was allowed to return to room temperature, ice water (25 ml) was added, and the resultant solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washed with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1). Recrystallization from ethyl acetate/isopropyl ether gave (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, 33%) as a light yellow powder.

 

…………………………

 

WO 2010021409 AND http://worldwide.espacenet.com/publicationDetails/biblio?CC=IN&NR=203704A1&KC=A1&FT=D

FOR 2, 4 DINITROIMIDAZOLE

…………………………………………

WO2011093529A1

These patent literatures disclose Reaction Schemes A and B below as the processes for producing the aforementioned 2, 3-dihydroimidazo [2, 1-b] oxazole compound.

Reaction Scheme A:

 

Figure imgf000003_0001

wherein R1 is a hydrogen atom or lower-alkyl group; R2 is a substituted pxperidyl group or a substituted piperazinyl group; and X1 is a halogen atom or a nitro group.

Reaction Scheme B:

Figure imgf000004_0001
Figure imgf000004_0002

wherein X2 is a halogen or a group causing a substitution reaction similar to that of a halogen; n is an integer from 1 to 6; and R1, R2 and X1 are the same as in Reaction Scheme A.

An oxazole com ound represented by Formula (la) :

 

Figure imgf000004_0003

, i.e., 2-methyl-6-nitro-2-{4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl }-2, 3- dihydroimidazo [2, 1-b] oxazole (hereunder, this compound may be simply referred to as “Compound la”) is produced, for example, by the method shown in the Reaction Scheme C below (Patent

Literature 3) . In this specification, the term “oxazole compound’ means an oxazole derivative that encompasses compounds that contain an oxazole ring or an oxazoline ring (dihydrooxazole ring) in the molecule.

Reaction Scheme C:

 

Figure imgf000005_0001

 

Figure imgf000005_0002

However, the aforementioned methods are unsatisfactory in terms of the yield of the objective compound. For example, the method of Reaction Scheme C allows the objective oxazole Compound (la) to be obtained from Compound (2a) at a yield as low as 35.9%. Therefore, alternative methods for producing the compound in an industrially advantageous manner are desired. Citation List

Patent Literature

PTL 1: WO2004/033463

PTL 2: WO2004/035547

PTL 3: WO2008/140090

Example 9

Production of (R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

{R) -1- [ – {2 , 3-epoxy-2-methylpropoxy ) phenyl] -4- [4- ( trifluoromethoxy ) phenoxy ] piperidine (10.0 g, 23.6 mmol, optical purity of 94.3%ee), 2-chloro-4-nitroimidazole (4.0 g, 27.2 mmol), sodium acetate (0.4 g, 4.9 mmol), and t- butyl acetate (10 ml) were mixed and stirred at 100°C for 3.5 hours. Methanol (70 ml) was added to the reaction mixture, and then a 25% sodium hydroxide aqueous solution (6.3 g, 39.4 mmol) was added thereto dropwise while cooling with ice. The resulting mixture was stirred at 0°C for 1.5 hours, and further stirred at approximately room

temperature for 40 minutes. Water (15 ml) and ethyl acetate (5 ml) were added thereto, and the mixture was stirred at 45 to 55°C for 1 hour. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml) . Methanol (100 ml) was added to the resulting

crystals, followed by stirring under reflux for 30 minutes. The mixture was cooled to room temperature. The crystals were then collected by filtration and washed with methanol (30 ml) . The resulting crystals were dried under reduced pressure, obtaining 9.3 g of the objective product (yield: 73%) .

Optical purity: 99.4%ee.

 

……………….

Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles
J Med Chem 2006, 49(26): 7854

http://pubs.acs.org/doi/abs/10.1021/jm060957y

(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (19,  DELAMANID).

To a mixture of 27 (127.56 g, 586.56 mmol) and 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28g) (165.70 g, 468.95 mmol) in N,N-dimethylformamide (1600 mL) was added 60% sodium hydride (22.51 g, 562.74 mmol) at 0 °C portionwise. After the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, the reaction mixture was cooled in an ice bath and carefully quenched with ethyl acetate (230 mL) and ice water (50 mL). The thus-obtained mixture was poured into water (3000 mL) and stirred for 30 min. The resulting precipitates were collected by filtration, washed with water, and dried at 60 °C overnight. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture (5/1) as solvent. The appropriate fractions were combined and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (1300 mL)−isopropyl alcohol (150 mL) to afford 19 (119.11 g, 48%) as a pale yellow crystalline powder.

Mp 195−196 °C.

1H NMR (CDCl3) δ 1.77 (3H, s), 1.87−2.16 (4H, m), 2.95−3.05 (2H, m), 3.32−3.41 (2H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.2 Hz), 4.18 (1H, J = 10.2 Hz), 4.36−4.45 (1H, m), 4.49 (1H, d, J = 10.2 Hz), 6.76 (2H, d, J = 6.7 Hz), 6.87−6.94 (4H, m), 7.14 (2H, d, J = 8.6 Hz), 7.55 (1H, s).

[α  −9.9° (c 1.01, CHCl3).

MS (DI) m/z 535 (M+ + 1). Anal. (C25H25F3N4O6) C, H, N.

http://pubs.acs.org/doi/suppl/10.1021/jm060957y/suppl_file/jm060957ysi20061113_095044.pdf

 

References

  1. Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. (2006). “OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis in Vitro and in Mice”PLoS Medicine 3 (11): e466.doi:10.1371/journal.pmed.0030466PMC 1664607PMID 17132069edit
  2.  Skripconoka, V.; Danilovits, M.; Pehme, L.; Tomson, T.; Skenders, G.; Kummik, T.; Cirule, A.; Leimane, V.; Kurve, A.; Levina, K.; Geiter, L. J.; Manissero, D.; Wells, C. D. (2012). “Delamanid Improves Outcomes and Reduces Mortality for Multidrug-Resistant Tuberculosis”European Respiratory Journal41 (6): 1393–1400. doi:10.1183/09031936.00125812PMC 3669462PMID 23018916edit
  3. H. Spreitzer (18 February 2013). “Neue Wirkstoffe – Bedaquilin und Delamanid”. Österreichische Apothekerzeitung (in German) (4/2013): 22.
  4.  Gler, M. T.; Skripconoka, V.; Sanchez-Garavito, E.; Xiao, H.; Cabrera-Rivero, J. L.; Vargas-Vasquez, D. E.; Gao, M.; Awad, M.; Park, S. K.; Shim, T. S.; Suh, G. Y.; Danilovits, M.; Ogata, H.; Kurve, A.; Chang, J.; Suzuki, K.; Tupasi, T.; Koh, W. J.; Seaworth, B.; Geiter, L. J.; Wells, C. D. (2012). “Delamanid for Multidrug-Resistant Pulmonary Tuberculosis”. New England Journal of Medicine 366 (23): 2151–2160. doi:10.1056/NEJMoa1112433.PMID 22670901edit
  5.  Drug Discovery & Development. EMA Recommends Two New Tuberculosis Treatments. November 22, 2013.
  6. Synthesis and antituberculous activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles
    45th Intersci Conf Antimicrob Agents Chemother (ICAAC) (December 16-19, Washington DC) 2005, Abst F-1473
12-28-2006
Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.
Journal of medicinal chemistry
11-1-2006
OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.
PLoS medicine
1-1-2008
New anti-tuberculosis drugs with novel mechanisms of action.
Current medicinal chemistry
11-11-2010
Synthesis and Structure-Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).
Journal of medicinal chemistry
5-1-2012
Tuberculosis: the drug development pipeline at a glance.
European journal of medicinal chemistry
1-12-2012
Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).
Journal of medicinal chemistry
9-11-2009
Pharmaceutical Composition Achieving Excellent Absorbency of Pharmacologically Active Substance
1-16-2009
Sulfonamide Derivatives for the Treatment of Bacterial Infections

 

WO2004033463A1 Oct 10, 2003 Apr 22, 2004 Otsuka Pharma Co Ltd 2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES
WO2004035547A1 Oct 14, 2003 Apr 29, 2004 Otsuka Pharma Co Ltd 1-substituted 4-nitroimidazole compound and process for producing the same
WO2008140090A1 May 7, 2008 Nov 20, 2008 Otsuka Pharma Co Ltd Epoxy compound and method for manufacturing the same
JP2009269859A * Title not available

TB

Figure

It is estimated that a third of the world’s population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains.

From among acid-fast bacteria, human Mycobacterium tuberculosis has been widely known. It is said that the one-third of the human population is infected with this bacterium. In addition to the human Mycobacterium tuberculosis, Mycobacterium africanum and Mycobacterium bovis have also been known to belong to the Mycobacterium tuberoculosis group. These bacteria are known as Mycobacteria having a strong pathogenicity to humans.

Against these tuberculoses, treatment is carried out using three agents, rifampicin, isoniazid, and ethambutol (or streptomycin) that are regarded as first-line agents, or using four agents such as the above three agents and pyrazinamide.

However, since the treatment of tuberculosis requires extremely long-term administration of agents, it might result in poor compliance, and the treatment often ends in failure.

Moreover, in respect of the above agents, it has been reported that: rifampicin causes hepatopathy, flu syndrome, drug allergy, and its concomitant administration with other drugs is contraindicated due to P450-associated enzyme induction; that isoniazid causes peripheral nervous system disorder and induces serious hepatopathy when used in combination with rifampicin; that ethambutol brings on failure of eyesight due to optic nerve disorder; that streptomycin brings on diminution of the hearing faculty due to the 8th cranial nerve disorder; and that pyrazinamide causes adverse reactions such a hepatopathy, gouty attack associated with increase of uric acid level, vomiting (A Clinician’s Guide To Tuberculosis, Michael D. Iseman 2000 by Lippincott Williams & Wilkins, printed in the USA, ISBN 0-7817-1749-3, Tuberculosis, 2nd edition, Fumiyuki Kuze and Takahide Izumi, Igaku-Shoin Ltd., 1992).

Actually, it has been reported that cases where the standard chemotherapy could not be carried out due to the adverse reactions to these agents made up 70% (approximately 23%, 52 cases) of the total cases where administration of the agents was discontinued (the total 228 hospitalized patients who were subject to the research) (Kekkaku, Vol. 74, 77-82, 1999).

In particular, hepatotoxicity, which is induced by rifampicin, isoniazid, and ethambutol out of the 5 agents used in combination for the aforementioned first-line treatment, is known as an adverse reaction that is developed most frequently. At the same time, Mycobacterium tuberculosis resistant to antitubercular agents, multi-drug-resistant Mycobacterium tuberculosis, and the like have been increasing, and the presence of these types of Mycobacterium tuberculosismakes the treatment more difficult.

According to the investigation made by WHO (1996 to 1999), the proportion ofMycobacterium tuberculosis that is resistant to any of the existing antitubercular agents to the total types of Mycobacterium tuberculosis that have been isolated over the world reaches 19%, and it has been published that the proportion of multi-drug-resistant Mycobacterium tuberculosis is 5.1%. The number of carriers infected with such multi-drug-resistant Mycobacterium tuberculosis is estimated to be 60,000,000, and concerns are still rising that multi-drug-resistantMycobacterium tuberculosis will increase in the future (April 2001 as a supplement to the journal Tuberculosis, the “Scientific Blueprint for TB Drug Development.”)

In addition, the major cause of death of AIDS patients is tuberculosis. It has been reported that the number of humans suffering from both tuberculosis and HIV reaches 10,700,000 at the time of year 1997 (Global Alliance for TB drug development). Moreover, it is considered that the mixed infection of tuberculosisand HIV has an at least 30 times higher risk of developing tuberculosis than the ordinary circumstances.

Taking into consideration the aforementioned current situation, the profiles of the desired antitubercular agent is as follows: (1) an agent, which is effective even for multi-drug-resistant Mycobacterium tuberculosis, (2) an agent enabling a short-term chemotherapy, (3) an agent with fewer adverse reactions, (4) an agent showing an efficacy to latent infecting Mycobacterium tuberculosis (i.e., latentMycobacterium tuberculosis), and (5) an orally administrable agent.

Examples of bacteria known to have a pathogenicity to humans include offending bacteria of recently increasing MAC infection (Mycobacterium avium—intracellulare complex infection) such as Mycobacterium avium andMycobacterium intracellulare, and atypical acid-fast bacteria such asMycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium smegmatis, and Mycobacterium aurum.

Nowadays, there are few therapeutic agents effective for these atypical acid-fast bacterial infections. Under the presence circumstances, antitubercular agents such as rifampicin, isoniazid, ethambutol, streptomycin and kanamycin, a newquinolone agent that is a therapeutic agent for common bacterial infections, macrolide antibiotics, aminoglycoside antibiotics, and tetracycline antibiotics are used in combination.

However, when compared with the treatment of common bacterial infections, the treatment of atypical acid-fast bacterial infections requires a long-term administration-of agents, and there have been reported cases where the infection is changed to an intractable one, finally leading to death. To break the afore-mentioned current situation, the development of an agent having a stronger efficacy is desired.

For example, National Publication of International Patent Application No. 11-508270 (WO97/01562) discloses that a 6-nitro-1,2,3,4-tetrahydro[2,1-b]-imidazopyran compound has a bactericidal action in vitro to Mycobacterium tuberculosis (H37Rv strain) and multi-drug-resistant Mycobacterium tuberculosis, and that the above compound has a therapeutic effect to a tuberculosis-infected animal model when it is orally administered and thus useful as antitubercular agent.

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5 Things You Should Know About MERS, The Deadly Virus That’s Now Breaking Out In Saudi Arabia

 Uncategorized  Comments Off on 5 Things You Should Know About MERS, The Deadly Virus That’s Now Breaking Out In Saudi Arabia
Apr 252014
 

The MERS virus.

MERS (Middle Earth Respiratory Virus)

A new spike in cases of a deadly respiratory virus, in Saudi Arabia and the United Arab Emirates, is prompting new fears of an outbreak when the area’s population spikes during the annual Hajj pilgrimage.

The syndrome, called Middle East Respiratory Syndrome (MERS), is caused by a relatively new-to-humans virus that’s a close cousin of SARS, a virus that infected thousands of people worldwide in 2002-2004.

read at

http://www.businessinsider.in/5-Things-You-Should-Know-About-MERS-The-Deadly-Virus-Thats-Now-Breaking-Out-In-Saudi-Arabia/articleshow/34169304.cms

Illustration: http://yvpc.sph.umich.edu/

Read More at inserbia.info/today/2013/06/mers-new-deadly-virus-spreading-from-middle-east/ © InSerbia News

 

 

MERS, koronavirus that is still mysterious

http://medicmagic.net/mers-koronavirus-that-is-still-mysterious.html

 

 

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A highly efficient and recyclable ligand-free protocol for the Suzuki coupling reaction of potassium aryltrifluoroborates in water

 Uncategorized  Comments Off on A highly efficient and recyclable ligand-free protocol for the Suzuki coupling reaction of potassium aryltrifluoroborates in water
Apr 192014
 

A highly efficient and recyclable ligand-free protocol for the Suzuki coupling reaction of potassium aryltrifluoroborates in water

Green Chem., 2014, 16,2185-2189
DOI: 10.1039/C3GC42182A, Paper
Leifang Liu, Yan Dong, Nana Tang
A highly efficient, recyclable and ligand-free protocol was developed for the Suzuki coupling reaction of potassium aryltrifluoroborates in water.
A highly efficient, recyclable and ligand-free protocol was developed for the Suzuki coupling of aryl halides with potassium aryltrifluoroborates in water using Pd(OAc)2 as a catalyst and Na2CO3 as a base in air. The presence of poly(ethylene glycol) (PEG) was crucial to the efficiency of the protocol. A wide range of functional groups were tolerated under the optimized conditions. Furthermore, the protocol could be extended to the Suzuki coupling of heteroaryl halides with potassium phenyltrifluoroborate, delivering the desired products in moderate to excellent yields. After simple workup, Pd(OAc)2–H2O–PEG could be recycled at least eight times without significant loss in activity.
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The role of modern drug discovery in the fight against neglected and tropical diseases

 Uncategorized  Comments Off on The role of modern drug discovery in the fight against neglected and tropical diseases
Apr 192014
 

The role of modern drug discovery in the fight against neglected and tropical diseases

Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00011K, Review Article
Jeremy N. Burrows, Richard L. Elliott, Takushi Kaneko, Charles E. Mowbray, David Waterson
The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate and will require sustained resourcing and focus
Neglected and tropical diseases affect a large proportion of the world’s population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technological investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chemically diverse compound libraries to enable lead discovery remains one of the critical bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
Med. Chem. Commun., 2014, Advance Article

DOI: 10.1039/C4MD00011K

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Boston Scientists Develop New Probiotic Supplement to Manage Weight

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Apr 192014
 
Boston Scientists Develop New Probiotic Supplement to Manage Weight

(Boston) – Healthcare experts continue to regard probiotics as one of the most powerful tools in the management of everything from constipation and bloating to diarrhea and skin health.

Historically, yogurt has been a primary source of probiotics, but yogurt products loaded with sugar have their own health implications for the tens of millions of Americans who are trying to lose weight. Sales of the healthier Greek-style yogurt were up 50% in 2012, showing that Americans are looking for healthier probiotic options. Unfortunately, even most Greek yogurt is loaded with sugar and calories.

So, how is the weight-conscious American supposed to get their probiotics?

http://www.howlifeworks.com/health_beauty/A_Simple_Way_to_Lose_Pounds_and_Relieve_Gas_and_Bloating_458?ag_id=1505&wid=8DC8FAB4-7586-49C7-938A-93851D50A3B9&did=5484&cid=1005&si_id=4193&pubs_source=mpt&pubs_campaign=20140418-1505

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Apr 172014
 

CERC-301 (MK-0657) MK-657, c-6161, AGN-PC-00887R

structure source….http://www.google.com/patents/WO2013156614A1?cl=en    my id is amcrasto@gmail.com

Treat depression; Treat major depressive disorder (MDD); Treat suicidality

808732-98-1 free form, C19 H23 F N4 O2

(-) (3S,4R) – 1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, 

AND

1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, (3S,​4R)​-
(-​)​-​(3S,​4R)​-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate
(3S,4R)-4-methylbenzyl 3-fluor-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate              
cas no of       hydrochloride 808733-06-4
Company Merck & Co. Inc.
Description Small molecule NMDA receptor NR2B subtype (GRIN2B; NR2B) antagonist
Molecular Target NMDA receptor NR2B subtype (GRIN2B) (NR2B) 
Mechanism of Action NMDA receptor antagonist

 

PLEASE NOTE THE + FORM

(+)​-​(3R,​4S)​-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate HAS CAS NO…..808732-99-2 AND ITS HYDROCHLORIDE 808733-07-5

 

also NOTE

1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, (3R,​4S)​-​rel-;
 cis-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate
HAS CAS    NO      808733-05-3                        AND DELETED CAS 1221592-​28-​4

 MY email ID IS amcrasto@gmail.com

 

AGN-PC-00887R, (4-methylphenyl)methyl (3S,4R)-3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate
Molecular Formula: C19H23FN4O2   Molecular Weight: 358.409923

Cerecor is developing the selective NMDA receptor subunit 2B antagonist CERC-301 (MK-0657) for depression.

CERC-301 (formerly MK-0657) is an oral, selective NMDA receptor subunit 2B (NR2B) antagonist in phase II clinical trials as adjunctive treatment for major depressive disorder (MDD) at Cerecor.

The compound had been in early trials at the National Institute of Mental Health (NIMH) for the treatment of major depression and at Merck & Co. for the treatment of Parkinson’s disease; however, no recent development has been reported in either case.

In 2013, the product was acquired by Cerecor from Merck & Co. on a worldwide basis for development and commercialization.

A phase II trial began in November 2013 and later that month, the FDA granted fast track designation for major depressive disorder.

………………………………………………

wo 2004108705 or http://www.google.co.in/patents/EP1648882B1?cl=en

METHODS OF SYNTHESIS

  • Figure imgb0011
    Figure imgb0012
    Figure imgb0013

EXAMPLES 1 AND 2EXAMPLE 1

    • Figure imgb0014

(35,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylateEXAMPLE 2

    • Figure imgb0015

(3R,4S)-4-methylbenzyl 3-fluor-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

Step 1

Preparation of 4-Methylbenzyl 4-oxopiperidine-1-carboxylate:

    • Figure imgb0016
    • 4-Methylbenzyl alcohol (37.6 g, 308 mmol) was added to a solution of 1,1′-carbonyldiimidazole (50.0 g, 308 mmol) in DMF at RT and stirred for 1 h. 4-Piperidone hydrate hydrochloride (commercially available from Sigma-Aldrich, 47.0 g, 308 mmol) was added, resulting in a reaction mixture that was then heated to 50°C and stirred for 15 h. The reaction mixture was diluted with EtOAc and washed with 0.1 M HCl, H2O (four times), and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (step gradient elution: 10%, 25%, 50% EtOAc in hexanes) produced the title compound (42.4 g, 85% yield) as a clear oil.
      1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 3.79 (t, 4 H), 2.45 (br s, 4 H) 2.31 (s, 3 H) ppm;
      HRMS (ES) m/z 248.1281 [(M+H)+; calcd for C14H18NO3: 248.1287];
      Anal. C14H17NO3: C, 68.03; H, 7.05; N, 5.59. Found: C, 68.00; H, 6.93; N, 5.66.

Step 2Preparation of (±)-4-methylbenzyl 3-fluoro-4-oxopiperidine-1-carboxylate:

    • Figure imgb0017
    • A solution of 4-methylbenzyl 4-oxopiperidine-1-carboxylate (21.2 g, 85.7 mmol) and diisopropylethylamine (71.3 mL, 428 mmol) in dichloromethane (425 mL) was cooled to 0 °C and stirred. TBSOTf (29.5 mL, 129 mmol) was added slowly, maintaining the internal temperature below 5 °C. Aqueous NaHCO3 (20 mL) was added and the layers were separated. The organic layer was washed with NaHCO3, H2O (two times), and brine, dried over Na2SO4, filtered and concentrated to give the crude TBS enol ether.
    • The crude TBS enol ether was dissolved in DMF (125 mL) at RT. Selectfluor® reagent (commercially available from Air Products and Chemicals, Inc., 30.4 g, 85.7 mmol) was added and the reaction mixture was stirred for 10 min. The reaction mixture was partitioned between EtOAc and H2O and the organic layer was washed with H2O (three times). The combined aqueous layers were extracted with EtOAc (two times) and the combined organics were dried over Na2SO4, filtered and concentrated. The entire reaction above was repeated and the resulting reaction products were combined to give the title compound (40 g), which was used in the next step without purification. NMR and mass spectral data suggest the ketone functionality in the product exists as a hydrate.
      1H NMR (400 MHz, CDCl3) δ 7.24 (m, 2 H), 7.19 (m, 2 H), 5.18 (s, 2 H), 4.81 (br d, 1 H), 4.50(br d, 1 H), 4.23 (d, 1 H), 3.90 (m, 1 H), 3.60 (m, 1 H), 3.35 (t, 1 H), 2.58 (m, 2 H), 2.35 (s, 3 H) ppm;
      HRMS (ES) m/z 284.1292 [(M+H)+; calcd for C14H18FNO4: 284.1293];
      Anal. C14H18FNO4•1.2H2O: C, 58.61; H, 6.46; N, 4.88. Found: C, 58.28; H, 6.06; N, 4.72.

Step 3Preparation of:

    • Figure imgb0018

(±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate

       and
  • Figure imgb0019

 

(±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate

    • To a solution of (±)-4-methylbenzyl 3-fluoro-4-oxopiperidine-1-carboxylate (40 g, 150 mmol) in toluene (200 mL) at RT was added (carbethoxymethylene)triphenylphosphorane (63.0 g, 181 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography (gradient elution: 10% to 20% EtOAc in hexanes) to give the olefins (±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate and (±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate (41.0 g, 78% yield, 3 steps) as a 3:1 E:Z mixture. This mixture was utilized directly in the next step. A small sample of the mixture was separated by silica gel chromatography for characterization purposes.
      (±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate: white solid, 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2 H), 7.17 (d, 2 H), 5.98 (s, 1 H), 5.11 (s, 2 H), 4.85 (m, 1 H), 4.18 (q, 2 H), 4.08 (br d, 1 H), 3.70 (m, 1 H), 3.55 (m, 1 H) 3.41 (m, 1 H), 3.33, (m, 1 H), 2.63 (br d, 1 H), 2.35 (s, 3 H), 1.29 (t, 3 H) ppm;
      HRMS (ES) m/z 358.1420 [(M+Na)+; calcd for C18H22FNO4Na: 358.1425];
      Anal. C18H22FNO4: C, 64.21; H, 6.58; N, 4.27. Found: C, 64.46; H, 6.61; N, 4.18.
    • (±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate: white solid, 1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 6.41(m, 1 H), 5.82 (s, 1 H), 5.11 (d, 2 H), 4.61 (m, 1H), 4.38 (br d, 1 H), 4.16 (q, 2 H), 3.05-2.95 (m, 1 H), 2.9-2.75 (m, 2 H), 2.33 (s, 3 H), 2.13 (m, 1 H), 1.27 (t, 3 H) ppm;
      HRMS (ES) m/z 358.1422 [(M+Na)+; calcd for C18H22FNO4Na: 358.1425].

Step 4:Preparation of:

    • Figure imgb0020

(±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate

and

    • Figure imgb0021

(±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate

    • [0081]
      To a solution of the olefin mixture from Step 3 (10.0 g, 29.8 mmol) in toluene (160 mL) and CH2Cl2 (120 mL) was added diphenylsilane (5.53 mL, 29.8 mmol) and (R)-BINAP (1.86 g, 2.98 mmol). Sodium t-butoxide (0.29 g, 2.98 mmol) and CuCl (0.30 g, 2.98 mmol) were then added, the reaction mixture was protected from light and stirred for 15 h. Additional portions of diphenylsilane (2.76 mL), NaOtBu (0.29 g) and CuCl (0.30 g) were added and the reaction mixture was stirred at RT for 24h. The mixture was then filtered through celite and concentrated. Purification on silica gel (step gradient elution: 5%, 10%, 15%, 25%, 30% EtOAc in hexanes) gave recovered starting materials (3.5 g, 35% yield), (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (5.0 g, 50% yield) and (±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (1.2 g, 12% yield).
      (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate: clear oil, 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 2 H), 7.15 (d, 2 H), 5.10 (s, 2 H), 4.80-4.20 (m, 3 H), 4.15 (q, 2 H), 3.10-2.73 (m, 2 H), 2.52 (dd, 1 H), 2.35 (s, 3 H), 2.30 (dd, 1 H), 2.10 (m, 1 H), 1.72-1.48 (m, 2 H), 1.29 (t, 3 H) ppm;
      HRMS (ES) m/z 338.1689 [(M+H)+; calcd for C18H25FNO4: 338.1762].
    • (±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate: clear oil, 1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.50-3.95 (m, 3 H), 4.15 (q, 2 H), 2.81 (br t, 2 H), 2.70 (br d, 1 H), 2.35 (s, 3 H), 2.17 (m, 2 H), 1.89 (br d, 1 H), 1.25 (m, 1 H), 1.22 (t, 3 H) ppm;
      HRMS (ES) m/z 338.1699 [(M+H)+; calcd for C18H25FNO4: 338.1762].

Step 5Preparation of (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid:

    • Figure imgb0022
    • To a solution of (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (10.0 g, 29.6 mmol) in THF (50 mL) was added aqueous NaOH (1M, 50 mL). The reaction mixture was stirred at RT for 5 h and then diluted with EtOAc and 1M HCl. The layers were separated and the aqueous extracted with EtOAc twice. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (9.1 g) as a white solid which was used in the next step without further purification.
      1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.79-4.16 (m, 3 H), 3.05-2.75 (m, 2 H), 2.59 (dd, 1 H), 2.36 (dd, 1 H), 2.31 (s, 3 H), 2.20-2.02 (m, 1 H), 1.60 (m, 2 H) ppm;
      HRMS (ES) m/z 310.1457 [(M+H)+; calcd for C16H21FNO4: 310.1449].
      Anal. C16H20FNO4•0.15 H2O: C, 62.13; H, 6.52; N, 4.53. Found: C, 61.55; H, 6.37; N, 4.41.

Step 6Preparation of (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate:

    • Figure imgb0023
    • To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70 °C and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2 : MeOH : NH4OH) for characterization:
      1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.90-4.18 (m, 3 H), 2.95-2.75 (m, 2 H), 2.79 (dd, 1 H), 2.70 (dd, 1 H), 2.35 (s, 3 H), 1.59 (m, 3 H) ppm;
      HRMS (ES) m/z 281.1658 [(M+H)+; calcd for C15H22FN2O2: 281.1660].

Step 7

Preparation of:

    • Figure imgb0024

(3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

and

    • Figure imgb0025

(3R,4S)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

    • Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140 °C and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid.
    • The enantiomers were separated by preparative HPLC on a ChiralPak AD column (5 cm x 50 cm, 20µM) with MeOH:MeCN (15:85, 150 mL/min) as eluant. The HCl salt of Example 1 was prepared by dissolving (3S,4R)-cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 19.3 mmol) in iPrOH (100 mL) at 65 °C. A solution of HCl in iPrOH (1.608 M, 12.6 mL, 20.2 mmol) was added and the solution was slowly cooled to RT over 15 h. Et2O (25 mL) was added, the mixture stirred for 3h, cooled to 0 °C, stirred for 1h and filtered to give (3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate hydrochloride as a white solid (7.0 g, 92% recovery).
    • The hydrochloride salt of (3R,4S)-4-methylbenzyl-3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate was prepared using a similar procedure.

(3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate•HCl:

    • [α]D -36.4° (c 0.17, MeOH);
      Melting Point 149-150 °C;
      1H NMR (400 MHz, CD3OD) δ 8.58 (br s, 2 H), 7.21 (d, 2 H), 7.17 (d, 2 H), 6.99 (t, 1 H), 5.06 (s, 2 H), 4.79 (m, 1 H), 4.42 (t, 1 H), 4.21 (d, 1 H), 3.60 (dd, 1 H), 3.50 (dd, 1 H), 3.15-2.80 (m, 2 H), 2.30 (s, 3 H), 2.10 (m, 1 H), 1.61 (m, 2 H) ppm;
      HRMS (ES) m/z 359.1879 [(M+H)+; calcd for C19H24FN4O2: 359.1878];
      Anal. C19H23FN4O2•HCl•0.2 H2O: C, 57.27; H, 6.17; N, 14.06. Found: C, 57.22; H, 6.37; N, 14.16.

(3R,4S)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate •HCl:

  • [α]D +34.9° (c 0.18, MeOH);
    Melting Point 149-150 °C;
    1H NMR (400 MHz, CD3OD) δ 8.58 (br s, 2 H), 7.21 (d, 2 H), 7.17 (d, 2 H), 6.99 (t, 1 H), 5.06 (s, 2 H), 4.79 (m, 1 H), 4.42 (t, 1 H), 4.21 (d, 1 H), 3.60 (dd, 1 H), 3.50 (dd, 1 H), 3.15-2.80 (m, 2 H), 2.30 (s, 3 H), 2.10 (m, 1 H), 1.61 (m, 2 H) ppm;
    HRMS (ES) m/z 359.1870 [(M+H)+; calcd for C19H24FN4O2: 359.1878].
    Anal. C19H23FN4O2•HCl•0.5H2O: C, 56.50; H, 6.24; N, 13.87. Found: C, 56.68; H, 6.27; N, 13.80.

……………….

WO 2006069287

http://www.google.com/patents/WO2006069287A1?cl=en

Scheme 1:

,

 

Figure imgf000026_0001

4-MeBnOH CDI

 

Figure imgf000026_0002

Scheme 2:

 

Figure imgf000026_0003

R1 X- R1

X” Rhodium metal precursor/

H I iiR2 chiral phosphine ligand |_] p — R:

14 13

Representative Examples include:

EXAMPLE 1

 

Figure imgf000027_0001

Step A:

11 -‘ .OH

A 5 L round bottom flask was charged with THF (1.87 L, KF< 50 ppm) and cooling to -75 °C was begun. When the temperature of THF had reached < – 20 °C, n-BuLi (11 M in hex, 123 mL) was added over 15 minutes in order to keep the solution temperature below -10 C. When the solution reached -35 °C, controlled addition of diisopropylamine (197 mL, KF < 50 ppm) over 15 minutes was carried out so the exotherm did not cause the solution temperature to exceed -16 °C. The solution was then allowed to continue to cool until it reached -75 C. 3-Fluoropyridine (compound 1 from Scheme 1) (125 g, KF < 150 ppm) was then added neat to this solution via addition funnel while maintaining the batch temperature below -70 °C.

Neat DMF (168 mL, KF < 50 ppm) was then added to the batch over 1 hour maintaining the temperature < -70 °C. After confirming complete formation of the aldehyde, the reaction was warmed to 0 C, and H2O (230 mL, 10 eq.) was added. NaBH4 (48.4 g) was then added in two portions over 5 minutes at 0 °C. Addition of concentrated HCl (6 M, 1.17 L) was completed in 1 hour at temperatures between 0- 25°C. The rection batch was then heated to 40 °C and kept at this temperature for 1 hour.

The reaction was then allowed to cool to room temperature. Then, to the aqueous layer 6 M NaOH (747 mL) was slowly added at 0-15 °C to adjust the pH to 12. Approximately 700 mL of H2O was added to dissolve any precipitate in the aqueous layer. The aqueous layer was then extracted with IPAc (1 x 1.275 L, 2 x 800 mL). The organic layer was treated with 20 wt. % Darco-G60 carbon (based on product assay) and the solution was heated to 40 °C for 1 hour followed by filtration over solka floe. After filtration the organic layer was solvent switched from IPAc to IPAc:heptane (15-20% v/v IPAc:heptane). The product crystallized as a white solid. This solution was then cooled to 0 °C for 30 minutes and filtered. An additional 250 mL of heptane was cooled to 0 °C and used to wash the wet cake. Typical Yield = 79% (128.5 g).

Step B:

 

Figure imgf000028_0001

To a 2 L flask under N2 atmosphere were charged compound 2 from Scheme 1 (50.0Ig), acetone (524 mL), and BnBr (50.0 mL). This homogenous solution was heated to reflux for ~ 12 h. The reaction mixture was cooled to room temperature and diluted with heptane (550 mL). The pyridinium salt (compound 3 from Scheme 1) was collected by filtration. The wet cake was then slurry washed at ambient temperature with 25% acetone/heptane (200 mL) and filtered. The wet cake was then dried under vacuum at ambient temperature exposed to the atmosphere, affording a slight-pinkish solid ca. 98% pure by 1 H NMR

Typical Yield – 93% (109.5 g)

Step C:

 

Figure imgf000028_0002

To a 2 L round bottom flask were charged compound 3 from Scheme 1 (100.30 g, 1.00 eq.) and methanol (960 mL). The homogenous solution was then cooled to 100C. The NaBH4 (19.10 g, 1.50 Eq) was added portion wise (using a solid addition funnel) while keeping the temperature < 0 0C. The batch was diluted with IPAc (1.0 L), followed by addition of 1 L 11.25 wt% brine. The resulting mixture was aged 15 min, then allowed to separate into two clear layers. The lower brine layer was removed. The organic stream was then washed with 500 mL 15wt% brine, then allowed to separate into two clear layers. The lower brine layer was removed. The batch was adjusted to roughly 1:1 MeOHrIPAc (c = 100 g/L) and then treated with 25 wt% Ecosorb C-941 at 50 0C in for ~ 2 h. This was then filtered through a plug of celite, while rinsing with 1 : 1 MeOH:IPAc (rinse was roughly 25% of total batch volume). The batch was then concentrated to a residue.

The batch was then dissolved in 5% MeOH in IPAc at ~ 100 g/L (~ 636 mL). The batch was warmed to 50 0C, followed by addition of a solution of 4M HCl in dioxane (1.10 eq)) slowly over ~ 1 h. At this point, the batch was seeded with a small spatula tip full of seed. After complete addition of the HCl solution, the batch was allowed to cool to room temperature slowly overnight. The solids were isolated by filtration. A slurry cake wash was then performed with 5% MeOH/IPAc (200 mL), followed by a displacement wash of 5% MeOH/IPAc (200 mL). The batch was then dried under vacuum at ambient temperature exposed to the atmosphere to afford compound 4 as a white solid (77% yield).

This material, 66.1O g of crude 4, was dissolved in 450 mL MeOH to which was added 450 mL IPAc. This mixture was treated with 25wt% Ecosorb C-941 (16.53 g) and heated to 50 0C for 2 h. The mixture was then filtered through a pad of celite, washing the Ecosorb C-941 with ~ 500 ml 25% MeOH in IPAc. The mixture was then solvent switched on a rotovap to roughly 10% MeOH in IPAc. During the solvent switch, after concentrating to roughly 60% of its original volume, a small spatula tip full of seed was introduced, causing instant crystal growth. This mixture was concentrated until the final volume was ~ 350 mL. The slurry was then isolated, using a slurry wash of- 200 mL 5% MeOH/IPAc. The solids were dried over night under vacuum, exposed to the atmosphere, affording 60.23 g of 4 (70% yield).

Typical Yield = 70% (60.2 g).

Step D:

 

Figure imgf000029_0001

In a N2 atmosphere glovebox, (R,R)-Walphos (SL-W003-1) (60.1 mg, commercially available from Solvias, Inc., Fort Lee, New Jersey 07024) and [(COD)RhCl]2 (20.3 mg) were dissolved in dichloromethane (3 mL, anhydrous, N2 degassed) and aged for 45 min at room temperature. Compound 4 from Scheme 1 (15.0 g) was charged to a 6 oz. glass pressure vessel (Andrews Glass Co., Vineland, NJ) containing a magnetic stir bar. MeOH (69 mL, anhydrous, N2 degassed) was added, followed by the catalyst solution and a dichloromethane (3 mL) rinse.

The reactor was degassed with H2 (40 psig) and immersed in a preheated 50 0C oil bath. After a few minutes, the vessel was further pressurized with H2 to 85 psig and allowed to age for 18.75 h. After this time, the vessel was vented and cooled to room temperature. HPLC analysis indicated >99% conversion of the vinyl fluoride. HPLC analysis indicated 99.3% ee.

The reaction mixture from above was concentrated in vacuo to a dark brown oil, which was then diluted with 50 mL EtOAc, to which was added 50 mL saturated NaHCO3 (aq). This biphasic mixture was stirred at room temperature for 30 min. This mixture was separated, the aqueous layer was extracted 3 x 10 mL EtOAc, then the combined organic layers were dried over Na2SO4 and concentrated in vacuo to a residue, which was purified by column chromatography (1 : 1 EtOAc:hexanes) to afford 9.45 g of free base compound 5 (74.4% isolated yield) as a pale yellow oil.

Typical Yield = 74% (9.5 g).

HC1 HN^>”F

To a 100 mL round bottom flask was charged the free base compound 5 from Example Scheme 1 , (1.00 eq), the Pd(OH)2/C (1.29g), MeOH (23 mL), and 6M HCl (3.89 mL, 1.00 eq.). This mixture was degassed three times, finally filling the vessel with H2 (1 atm, balloon pressure). The reaction was stirred at room temperature for 18 h. The mixture was filtered through a plug of Celite 521, rinsed with 50 mL MeOH, then concentrated to a residue. The residue was redissolved in ~ 150 mL 1 : 1 MeOH:IPAc, then refiltered through a sintered glass funnel to remove inorganics. Theis resulting solution was then solvent switched to roughly 10% MeOH in IPAc, during which spontaneous crystallization of compound 6 from Scheme 1 was observed. The solids were isolated by vacuum, washed twice with ~ 10 mL 10% MeOH in IPAc, then dried under vacuum over night, affording a pale white, crystalline solid.

Typical Yield = 81% (3.2 g).

 

Figure imgf000031_0001

JV,iV -Carbonyldiimidazole, 2.39 g (1.00 eq) was charged to a 50 mL round bottom flask, to which was added the DMF (19.7 ml). Then, the 4- methylbenzyl alcohol (1.80 g 1.00 eq) was added as a solid. This mixture was stirred for 15 min. at room temperature, during which an exotherm was noted (ΔT = +6.1 0C, 18.5 0C to 24.6 0C). The fluoroalcohol HCl salt 6, 2.50 g (1.00 eq) was then added as a solid to this mixture. This was heated to 50 0C for 1O h, and then allowed to cool to room temperature over night. The resulting mixture was diluted with 40 mL EtOAc. This mixture was washed 2 x 25 mL 3M HCl and separated, then 1 x 25 mL 15wt% brine and separated. This was extracted with 1 x 15 mL EtOAc and combined with the previous organic stream. The organic stream was concentrated to a residue and subjected to column chromatography eluting with a gradient (0% to 50% EtOAc in hexanes, TLCs developed in 50% EtOAc:hexanes, visualizing with UV and KMnO4), to afford 3.35 g of a clear colorless oil.

Typical Yield = 81 % (3.4 g).

Step G:

 

Figure imgf000031_0002

A solution of fluoro alcohol compound 7 from Scheme 1 (1.22 g) in CH3CN was cooled to -20 °C and Hunig’s base (2.2 equiv., 1.66 mL) was added. To this, Tf2O – (1.1 equiv., 0.81 mL) was slowly added while maintaining the internal temperature < -10°C. Aqueous NH4OH (15 equiv., 2.7 mL) was then added to the reaction mixture at low temperature (-20°C) and then warmed up to room temperature and aged for Ih. After completion, toluene (15 mL) and 10% NaOH (10 mL) were added and the layers separated. After extraction, the organic layer was washed with H2O (IO mL).

The toluene stream of the amine was dried (-400 μg/mL) and concentrated to 100 g/L. Methanol was then added to obtain an overall solvent composition of toluene/MeOH (95:5), followed by the slow addition of HCl (1.05 equiv, 1.12 ml) at 50 °C. The amine hydrochloride 8 from Scheme 1 crystallized immediately, and the reaction was aged 20 min. The light yellow salt was then filtered and washed with cold toluene (15 mL) to offer amine hydrochloride 8 in 82% as a white crystalline solid.

 

Figure imgf000032_0001

Into a 100-L round bottom flask were charged 1.67 kg amine HCl salt 8 from Scheme 1, 912.4 g chloropyrimidine, 4.6 L of diisopropylethyl amine and 25.78 L ethylene glycol. The resulting slurry gradually became a solution, which was degassed and stirred under a nitrogen atmosphere. The contents were heated to 100 ° C for 12 h. The heat was turned off and the reaction solution slowly cooled to room temperature, which resulted in the formation of a slurry. To the slurry was added 77.3 L water over 1 h period and the slurry was aged at room temperature for 3 h. The mixture was filtered and the cake was washed with additional 80 L. The wet cake was left under nitrogen to dry overnight. After drying, 1.90 kg of an off white solid was collected.

1.77 kg of the above solid was dissolved into 71 L EtOAc and treated with 531 g Darco G-60 carbon at room temperature for 3 h. Filtration through Solka Floe was followed by washing with 2 x 20 L EtOAc. A solvent switch to MeOH under reduced pressure resulted in a slurry, and the final MeOH volume was adjusted to 19 L. The slurry in MeOH was heated to ca. 60 °C. Gradually cooling to room temperature resulted in a slurry, to which 57 L GMP water was added over 1 h with cooling (exothermic mixing, temperature controlled below 30 “C). The mixture was aged at room temperature for 3 h and filtered to collect solid, the cake was washed with 30 L GMP water and left to dry under nitrogen. 1.55 kg dried product was collected. (89% yield).

Typical Yield = 89% (1.55 kg).

………….

European Journal of Medicinal Chemistry (2012), 53, 408-415

http://www.sciencedirect.com/science/article/pii/S0223523412002310

Two diastereoisomeric NR2B NMDA antagonists were radiolabelled with fluorine-18. ► The radiolabelling of 3-[18F]fluoro-1,4-substituted-piperidine pattern was achieved. ► In vitro study showed high specific and selective binding for NR2B NMDAR receptors. ► Bmax/Kd ratios and logD7.4 demonstrated appropriate properties for in vivo imaging.

Full-size image (30 K)

………………………..

Organic & Biomolecular Chemistry (2012), 10(42), 8493-8500

http://pubs.rsc.org/en/content/articlelanding/2012/ob/c2ob26378e#!divAbstract

In order to develop a novel and useful building block for the development of radiotracers forpositron emission tomography (PET), we studied the radiolabelling of 1,4-disubstituted 3-[18F]fluoropiperidines. Indeed, 3-fluoropiperidine became a useful building block in medicinal chemistry for the pharmacomodulation of piperidine-containing compounds. The radiofluorination was studied on substituted piperidines with electron-donating and electron-withdrawing N-substituents. In the instance of electron-donating N-substituents such as benzylor butyl, configuration retention and satisfactory fluoride-18 incorporation yields up to 80% were observed. In the case of electron-withdrawing N-substituents leading to carbamate or amidefunctions, the incorporation yields depend on the 4-susbtitutent (2 to 63%). The radiolabelling of this building block was applied to the automated radiosynthesis of NR2B NMDA receptor antagonists and effected by a commercially available radiochemistry module. The in vivoevaluation of three radiotracers demonstrated minimal brain uptakes incompatible with the imaging of NR2B NMDA receptors in the living brain. Nevertheless, moderate radiometabolism was observed and, in particular, no radiodefluorination was observed which demonstrates the stability of the 3-position of the fluorine-18 atom. In conclusion, the 1,4-disubstituted 3-[18F]fluoropiperidine moiety could be of value in the development of other radiotracers for PET even if the evaluation of the NR2B NMDA receptor antagonists failed to demonstrate satisfactory properties for PET imaging of this receptor.

Graphical abstract: Radiolabelling of 1,4-disubstituted 3-[18F]fluoropiperidines and its application to new radiotracers for NR2B NMDA receptor visualization

…………………….

WO 2013156614

The chemical structure of MK-0657 is as follows

http://www.google.com/patents/WO2013156614A1?cl=en

Figure imgf000012_0001
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Blinged-Out Fat Blob Nanotrucks for Targeted Drug Delivery

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Apr 152014
 

 

Targeted drug delivery is a popular area of research that melds together the disciplines of chemistry, medicine, and materials. The basic idea is to develop ways to give a person adose of medicine and somehow get that medicine to go to exactly the part of the body that needs it most – and preferably nowhere else. An article recently published in JACSdescribes a clever method of antibiotic delivery that involves fat blobs, gold particles, and their interaction with the toxins released by infectious bacteria.

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http://icanhasscience.com/bacteria/blinged-out-fat-blob-nanotrucks-for-targeted-drug-delivery/

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Nanotechnology Drug Delivery Systems: An Insight

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Apr 152014
 

Nanosponge attaches to Human Breast Cancer cells

Nanosponge particle attaches to Human Breast Cancer cells

One of the most important applications of nanotechnology in medicine involves use of nanoparticles to deliver drugs, and other therapeutic substances to specific types of cells (such as cancer cells). Nanosized structures and devices are smaller than human cells which are around 10,000 nm in diameter and similar in size to biomolecules such as enzymes, proteins (hemoglobin is 5 nm in diameter). Due to their small size, nanoparticles can also penetrate the blood-brain barrier which is impervious to most therapeutic and imaging agents.

read at

http://trialx.com/curetalk/2012/10/nanotechnology-drug-delivery-systems-an-insight/

Varun AroraVarun Arora

Nanotech drug delivery

 

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Cabotegravir, GSK 744 IN PHASE 2 FOR HIV INFECTION

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Apr 102014
 

GSK744.svg

Cabotegravir, GSK 744,

(3S,11aR)-N-(2,4-Difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide

 

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http://newdrugapprovals.org/2014/04/10/cabotegravir-gsk-744-in-phase-2-for-hiv-infection/

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LM11A-31-BHS….. (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide

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Apr 082014
 

 

 

LM11A-31-BHS

(2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide

2-Amino-3-methyl-N-[2-(4-morpholinyl)ethyl]-pentanamide dihydrochloride

  • CAS Number 1214672-15-7
  • Empirical Formula C12H25N3O2 · 2HCl
  • Molecular Weight 316.27

LM11A-31 is a non-peptide ligand of the p75 neurotrophin receptor (p75NTR). LM11A-31 blocks pro-NGF induced cell death in neuronal cultures, and protects neuronal cells from the the cytotoxic effects of cisplatin or methotrexate. Oral administration of LM11A-31 promotes the survival of oligodendrocytes and myelinated axons in a mouse spinal cord injury model and improves function in both weight-bearing and non-weight bearing tests.Inhibits death of hippocampal neurons at 100–1,000 pM

http://amcrasto.wix.com/anthony-melvin-crasto/apps/blog/lm11a-31-new-drug-can-help-paralyzed

PharmatrophiX

Figure 2.

 

LM11A-31, C12 H25 N3 O2, Pentanamide, 2-amino-3-methyl-N-[2-(4-morpholinyl)ethyl]- WO 2010102212 TO LONGO FRANK, PUB 10.09.2010 THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

PATENT LINK

http://patentscope.wipo.int/search/en/WO2010102212

Scientists have developed a pill which they claim could help paralyzed people walk again.

The new drug allowed mice with no movement in their lower limbs to walk with ‘well-coordinated steps’ and even to replicate swimming motions, researchers said.

The experimental drug, called LM11A-31, was developed by Professor Frank Longo, of Stanford University, California.

The researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42 day experimental period, the ‘Daily Mail’ reported.

In tests, the experimental medication did not increase pain in the mice and showed no toxic effects on the animals.

It also efficiently crossed the blood brain barrier, which protects the central nervous system from potentially harmful chemicals carried around in the rest of the bloodstream.

An injury to the spinal cord stops the brain controlling the body and this is the first time an oral drug has been shown to provide an effective therapy.

“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” Professor Sung Ok Yoon, of Ohio State University, Columbus, said.

“So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement,” Yoon said.

The small molecule in the study was tested for its ability to prevent the death of cells called oligodendrocytes.

These cells surround and protect axons, long projections of a nerve cell, by wrapping them in a myelin sheath that protect the fibres.

In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously found p75 is linked to the death of these specialised cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

“Because we know oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said.

FULL TEXT – JOURNAL OF NEUROSCIENCE

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death  in Journal of neuroscience, 26(20): 5288-5300; doi: 10.1523/​JNEUROSCI.3547-05.2006 by SM Massa – 2006 – Cited by 51 – Related articles
17 May 2006 – At 5 nm, LM11A-24 and -31 inhibit TUNEL staining to a degree  We further prioritized LM11A31, because preliminary studies

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

Figure 1.

2010 SLIDE PRESENTATION RE P75 (E.G. LM11A31) BY PHARMATROPHIX’S 

investorvillage.com/smbd.asp?mb=160&mn=440341…

3 Nov 2010 – 2010 slide presentation re p75 (e.g. LM11A31) by PharmatrophiX’s founder. Longo is PharmatrophiX’s founder.

The experimental drug was developed by Prof Frank Longo from Stanford UniversityThe experimental drug was developed by Prof Frank Longo from Stanford University

Prof Frank Longo from Stanford University publications

http://med.stanford.edu/profiles/cancer/frdActionServlet?choiceId=showFacPublications&fid=7249&

Patents

1 US2013005731  (A1) ― 2013-01-03

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2013005731A1&KC=A1&FT=D&ND=3&date=20130103&DB=worldwide.espacenet.com&locale=en_EP

2 WO2011150347  (A2) ― 2011-12-01

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2011150347A2&KC=A2&FT=D&ND=3&date=20111201&DB=worldwide.espacenet.com&locale=en_EP

3 US2011230479  (A1) ― 2011-09-22

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2011230479A1&KC=A1&FT=D&ND=3&date=20110922&DB=worldwide.espacenet.com&locale=en_EP

<a href=”http://www.bloglovin.com/blog/4674983/?claim=hj3e8pdf2nd”>Follow my blog with Bloglovin</a>

………………..

http://www.google.com.mx/patents/US7723328

TABLE I
Structures of Compounds 1-6
Compound Name
Figure US07723328-20100525-C00018
Compound 1 (also referred to herein as “LM11A-28”)
Figure US07723328-20100525-C00019
Compound 2 (also referred to herein as “LM11A-7”)
Figure US07723328-20100525-C00020
Compound 3 (also referred to herein as “LM11A-24”, “24”, and “C24”)
Figure US07723328-20100525-C00021
Compound 4 (also referred to herein as “LM11A-31” and “31”)
Figure US07723328-20100525-C00022
Compound 5 (also referred to herein as “LM11A-36”, “36”, and “C36”)
Figure US07723328-20100525-C00023
Compound 6 (also referred to herein as “LM11A-38” and “C38”)
Figure US07723328-20100525-C00024
Compound 7

 

…………………….

http://www.google.co.in/patents/WO2010102212A2?cl=en

Table I. Structures of Compounds i-vii

 

Figure imgf000050_0001
Figure imgf000051_0001

Example 32: Preparation of enantiomerically pure 2-amino-3-methyl-N-(2- morpholino-ethyϊ)-pentanamide

[00332] 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by a method shown in Scheme 4 below. First, 2-aminoethanol (Compound IE) is transformed to its derivative with a leaving group (Compound 2E). Examples of the leaving group include halides and alkoxy or other activated hydroxyl group. Second, Compound 2E reacts with morpholine at a neutral or basic condition to yield 2-morpholinoethanamine (Compound 3E). The aforementioned two steps may also be performed continuously as one step with Compound 2E being generated in situ. For example, Compound 3 E can be prepared from Compound IE directly through a Mitsunobu reaction wherein the hydroxyl group of Compound IE is activated by diethyl azodicarboxylate (DEAD) before morpholine is added. The final product, 2-amino-3-methyl-N-(2-moipholinoethyl)-pentanamide (Compound 5E), can be obtained by coupling 2-morpholinoethanamine with 2-amino-3- methylpentanoic acid (Compound 4E) via a peptide coupling agent. Examples of the peptide coupling agent include l,r-carbonyldiimidazole (CDI), hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1- hydroxybenzo-7-azatriazole (HOAt), and the like. Scheme 4:

H2N^0H — H2N^ / LG , p , .

1 Ot= LG: a leaving group

1E zt

 

Figure imgf000099_0001

[00333] A chiral 2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide (Compound 5E) can be obtained by using the corresponding chiral 2-amino-3- methylpentanoic acid (Compound 4E) in the above coupling step. For example, (2S,3S)-2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide; (2R,3R)-2-amino- 3 -methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3 -methyl-N-(2- moφholinoethyl)-pentanamide; and (2S,3R)-2-ammo-3-methyl-N-(2- morpholinoethyl)-pentanamide can be obtained by using (2S,3S)-2-amino-3- methylpentanoic acid, i.e., L-isoleucine; (2R,3R)-2-amino-3-methylpentanoic acid, i.e., D-isoleucine; (2R,3S)-2-amino-3-methylpentanoic acid, i.e., D-alloisoleucine; and (2S,3R)-2-amino-3-methylpentanoic acid, i.e., L-alloisoleucine, respectively. [00334] The chiral purity, also known as, enantiomeric excess or EE, of a chiral Compound 5E can be determined by any method known to one skilled in the art. For example, a chiral Compound 5E can be hydrolyzed to Compound 3E and the corresponding chiral Compound 4E. Then, the chiral Compound 4E obtained through hydrolysis can be compared with a standard chiral sample of Compound 4E to determine the chiral purity of the chiral Compound 5E. The determination can be conducted by using a chiral HPLC.

……………….

http://www.google.co.in/patents/EP2498782A1?cl=en

Scheme A shows the chemical structures of the present compounds.

 

Figure imgf000013_0001

(2S,3S)-2-amino-3-methyl-/V-(2-mor holinoethyl)pentanamide

 

Figure imgf000013_0002

(2R,3R)-2-amin -3-methyl-A/-(2-morpholinoethyl)pentanamide

 

Figure imgf000013_0003

(2S,3R)-2-amino-3-meth l-A/-(2-morpholinoethyl)pentanamide

 

Figure imgf000013_0004

] Q (2R,3S)-2-amino-3-methyl-/ /-(2-morpholinoethyl)pentanamide

The free base compound of 2-amino-3-niethyl- -(2-morpholinoethyl)-pentanamide can be prepared from isoleucine by synthetic methods known to one skilled in the art.

Standard procedures and chemical transformation and related methods are well known to one skilled in the art, and such methods and procedures have been described, for example, in standard references such as Fiesers’ Reagents for Organic Synthesis, John Wiley and Sons, New York, NY, 2002: Organic Reactions, vols, 1-83, John Wiley and Sons, New York, NY, 2006; March J, and Smith M,, Advanced Organic Chemistry, 6th ed., John Wiley and Sons, New York, NY; and Larock R.C., Comprehensive Organic Transformations, Wiley-VCH Publishers, New York, 1999. All texts and references cited herein are incorporated by reference in their entirety. Other related synthetic methods can be found in U.S. Patent Application Publication Nos. 2006/024072 and 2007/0060526, the contents of which are herein incorporated by reference in their entirety for all purposes. The amorphous dihydrochloride (di-HCl) salt of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by mixing two molar ecjuivalents of HC1 with one molar equivalent of 2-amino- 3-methyl-N-(2-morpholinoethyl)~pentanamide in appropriate solvent(s) and then separating the di-HCl salt from the solvent(s) mixture.

The amorphous di-HCl salt of 2-aniino-3-methyl-N-(2-moi holinoethyl)-pentariamide was analyzed via the methods as described above. The XRD analysis indicated it was amorphous/low ordered as shown in Figure 1 , The DSC thermogram exhibited a broad endotherm with onset temperature 37 °C and peak temperature 74 °C and an enthalpy value of ΔΗ = 80 J/g. The TGA thermogram indicated the di-HCl salt is anhydrous and starts to decompose after about 200°C. An overlay of DSC and TGA thermograms are shown in Figure 2. The moisture sorption-desorpiion isotherm of the di-HC! salt (Figures 3 A and 3 B ) was collected using dynamic vapor sorption (DVS) analysis. The material did not adsorb much moisture from 0% to 20% RH, then it showed steady sorption up to 140 wt% moisture at 95% RH (likely deliquescence). This sample showed rapid desorption from 95% to 70% RH and then continues desorbing at a relatively slower pace to a mass about 5 wt% greater than the original value at 0% RH. This sample shows a small hysteresis between the sorption and desorption phase. O verall this material is quite hygroscopic. The crude solubility of the di-HCl salt in water was >30 mg/niL. The proton N MR spectrum of the amorphous di-HCl salt is shown in Figure 4. Example 2. Preparation of 2-amino-3-methyl- -(2-morpholinoethy[)-pentanamide (free base):

Five grams of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide di-HCl salt was dissolved in 150 mL of ethanol. Sodium bicarbonate (5.3 g), dissolved in 100 mL of HPLC water, was added to this solution. The mixed solution was sonicated for ~10 minutes. This solution was concentrated using a rotovap, and the residue was dissolved in 300 mL of methylene chloride. This solution was passed through a short plug of carbonate bonded silica gel. This solution was concentrated using rotovap and the residue was lyophilized to dry, resulting in 3.6 g of the free base as a white solid. Proton NMR, C-13 NMR and LC/MS confirmed the structure of this material as the free base of 2-amino-3-methyl-N-(2- morpholmoethyl)-pentanamide.

In the process of converting the di-HCl salt to free base, the sample was lyophilized to avoid formation of oil. XRD analysis of the lyophilized free base surprisingly re vealed it was crystalline, as shown in Figure 5. The DSC thermogram exhibited an endotherm with extrapolated onset temperature 51 °C and peak temperature 53 °C and an enthalpy value of Δ¾= 104 J/g. The TGA thermogram shows less than 0.6 wt% loss at 105 °C, suggesting it was solvent free. An overlay of the DSC and TGA thermograms can be seen in Figure 6. The crude solubility of free base in water was >30 mg/mL. The proton NMR was consistent with the free base. The NMR and Raman spectra are shown in Figures 7 and 8A and 8B, respectively. The moisture sorption-desorption isotherm (Figures 9 A and 9B) was collected using dynamic vapor sorption (DVS) analysis. The sample did not adsorb much moisture content from 0% to 45% RH under the experimental conditions. Above 45 %RH the sample appears to adsorb moisture of – 10 wt% from 45% to 50% RH followed by rapid sorption up to 96 wt% moisture at 95% RH. In the desorption phase, the free base shows a rapid desorption from 95% to 80°/» RH, then the sample desorbs at a relatively slow pace to the original weight at 0% RH. The sample may form a hydrate near 45 %>RH, The putative hydrate appears to deliquesce resulting in an amorphous glass by the end of the scan.

……………

new patent

WO-2014052659

Crystalline forms of neurotrophin mimetic compounds and their salts

Type II TNF receptor agonist; NGF receptor modulator

Crystalline forms of (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide (LM11A-31-BHS), useful for the treatment of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis. See WO2011066544 claiming deuterated compounds of LM11A-31-BHS, useful for treating neurodegenerative diseases. PharmatrophiX is investigating the p75 neutrophin receptor ligand, LM11A-31-BHS, for the oral treatment of AD. By March 2013, a phase I trial was planned. The drug was formerly being investigated in collaboration with Elan Corp and the deal was terminated by the fourth quarter of 2010.

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