IVERMECTIN

MK933

22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b

70288-86-7  71827-03-7

C₄₈H₇₄O_14, 875.09

Ivermectin is a macrocyclic lactone derived from Streptomyces avermitilis with antiparasitic activity. Ivermectin exerts its anthelmintic effect via activating glutamate-gated chloridechannels expressed on nematode neurons and pharyngeal muscle cells. Distinct from the channel opening induced by endogenous glutamate transmitter, ivermectin-activated channels open very slowly but essentially irreversibly. As a result, neurons or muscle cells remain at either hyperpolarisation or depolarization state, thereby resulting in paralysis and death of the parasites. Ivermectin does not readily pass the mammal blood-brain barrier to the central nervous system where glutamate-gated chloride channels locate, hence the hosts are relatively resistant to the effects of this agent.

This drug, ivermectin, was developed by William C. Campbell of Drew University and Satoshi Ōmura of Japan’s Kitasato University. They were awarded the Nobel Prize in Physiology or Medicine. Originally, the drug was used to treat parasites in livestock and pets before becoming the mainstay of the global campaigns to combat lymphatic filariasis and onchocerciasis.

A workhorse of a drug that a few weeks ago earned its developers a Nobel prize for its success in treating multiple tropical diseases is showing early promise as a novel and desperately needed tool for interrupting malaria transmission, according to new findings presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting.

At ASTMH annual meeting, new studies explore advances in using ivermectin in ‘mass drug administration’ campaigns to reduce infections in Africa and slow spread of drug resistance in Asia…http://www.pharmpro.com/news/2015/10/nobel-prize-winning-drug-could-also-fight-malaria?et_cid=4908183&et_rid=577220619&type=cta

http://www.forbes.com/sites/zackomalleygreenburg/2015/10/27/the-13-top-earning-dead-celebrities-of-2015/

This new finding was presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting by researchers from Colorado State University.

Ivermectin has been used for decades, given once per year as a part of Mass Drug Administration (MDA) programs, to reduce the disabling worm infections onchocerciasis, which causes river blindness, and filariasis, the cause of the hugely swollen legs (elephantiasis). Merck has generously donated the entire supply of drug; other companies have followed suit with different drugs for other neglected tropical diseases.

Ivermectin (22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b) is a broad-spectrum antiparasitic drug in theavermectin family. It is sold under brand names Heartgard, Sklice^[1] and Stromectol^[2] in the United States, Ivomecworldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT^[3] in Nepal by Alive Pharmaceutical and Ivextermin Mexico by Valeant Pharmaceuticals International. In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. While in development, it was assigned the code MK-933 by Merck.^[4]

It is taken internally or used topically, depending on the treated condition.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basichealth system.^[5]

It is a drug for the treatment of Onchocerciasis.

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

Medical uses

Ivermectin is a broad-spectrum antiparasitic agent, traditionally against parasitic worms. It is mainly used in humans in the treatment of onchocerciasis (river blindness), but is also effective against other worm infestations (such as strongyloidiasis,ascariasis, trichuriasis, filariasis and enterobiasis), and some epidermal parasitic skin diseases, including scabies.

Ivermectin is currently being used to help eliminate river blindness (onchocerciasis) in the Americas, and to stop transmissionof lymphatic filariasis and onchocerciasis around the world in programs sponsored by the Carter Center using ivermectin donated by Merck.^[6][7][8] The disease is endemic in 30 African countries, six Latin American countries, and Yemen, according to studies conducted by the World Health Organization.^[9] The drug rapidly kills microfilariae, but not the adult worms. A single oral dose of ivermectin, taken annually for the 10- to 15-year lifespan of the adult worms, is all that is needed to protect the individual from onchocerciasis.^[10]

An Ivermectin cream called Soolantra has been approved by the FDA for treatment of rosacea.^[11][12]

SOOLANTRA (ivermectin) cream, 1% is a white to pale yellow hydrophilic cream. Each gram of SOOLANTRA cream contains 10 mg of ivermectin. It is intended for topical use.

Ivermectin is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones.

Ivermectin is a mixture containing not less than 95.0 % and not more than 102.0 % of 5-O-demethyl-22,23-dihydroavermectin A1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b or H2B1a and H2B1b, respectively; and the ratio (calculated by area percentage) of component H2B1a/(H2B1a + H2B1b)) is not less than 90.0 %.

The respective empirical formulas of H2B1a and H2B1b are C₄₈H₇₄O₁₄and C₄₇H₇₂O₁₄ with molecular weights of 875.10 and 861.07 respectively.

The structural formulas are:

Component H2B1a: R = C2H5, Component H2B1b: R = CH3.SOOLANTRA cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.

River blindness?

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

The infection is associated with a nematode worm Onchocerca volvulus, which are transmitted by Simulium blackflies which live and breed near fast-flowing streams and rivers. The worms carry parasitic Wolbachia bacteria. The bite of the flies enables the worm larvae to enter the human’s body; after maturing into adults, followed by breeding, the larvae (microfilariae) formed move towards the skin, and release the bacteria when they die. The bacteria trigger an immune response which leads to lesions on the eye and possible blindness (the “river blindness”).

Left: the Simulium fly (from http://flipper.diff.org/app/items/6730). Right: Simplified life cycle of Onchocerciasis volvulus, modified from the original at: http://emedicine.medscape.com/article/224309-overview#a0104.

Arthropod

More recent evidence supports its use against parasitic arthropods and insects:

• Mites such as scabies:^[13][14][15] It is usually limited to cases that prove to be resistant to topical treatments or that present in an advanced state (such as Norwegian scabies).^[15]

• Lice:^[16][17] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.^[18] After a single, 10-minute application of this formulation on dry hair, 78% of subjects were found to be free of lice after two weeks.^[19] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.^[20]

• Bed bugs:^[21] Early research shows that the drug kills bed bugs when taken by humans at normal doses. The drug enters the human bloodstream and if the bedbugs bite during that time, they will die in a few days.

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);^[22] and those who are breastfeeding, and have a hepatic or renal disease.^[23]

Side effects

The main concern is neurotoxicity, which in most mammalian species may manifest as central nervous system depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses.

Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin.

Since drugs that inhibit CYP3A4 enzymes often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, and glucocorticoids such as dexamethasone, lidocaine, and the benzodiazepines.^[24]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.^[25]

Pharmacology

Pharmacodynamics

Ivermectin and other avermectins (insecticides most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission.

The drug binds and activates glutamate-gated chloride channels (GluCls).^[26] GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion channelspresent in neurons and myocytes.

Pharmacokinetics

Ivermectin can be given either by mouth or injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,^[27] (the MDR1 gene mutation affects function of this protein). Crossing may still become significant if ivermectin is given at high doses (in which case, brain levels peak 2–5 hr after administration). In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences.

Ecotoxicity

Field studies have demonstrated the dung of animals treated with ivermectin supports a significantly reduced diversity of invertebrates, and the dung persists longer.^[28]

History

The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by Satoshi Ōmura of Kitasato University, Tokyo and William C. Campbell of the Merck Institute for Therapeutic research. Ōmura identified avermectin from the bacterium Streptomyces avermitilis. Campbell purified avermectin from cultures obtained from Ōmura and led efforts leading to the discovery of ivermectin, a derivative of greater potency and lower toxicity.^[29] Ivermectin was introduced in 1981.^[30] Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, “the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases”.^[31]

It started with the avermectins. In 1974, a group of researchers headed by Professor Satoshi Ōmura of the Kitasato Institute, isolated an organism with promising antimicrobial properties in a soil sample (sample OS-3153) picked up near a golf course at Kawana, Ito City, Shizuoka Prefecture, Japan. This was passed on to researchers at the Merck, Sharpe and Dohme (MSD) research laboratories in the USA, who isolated a small family of natural products that became known as avermectins. For many years, scientists have looked in soil samples for the source of potential medicines, like the tetracyclines or streptomycin . There are 8 avermectins, molecules with closely related structures. They are made by fermentation from the bacterium Streptomyces avermitilis.

Professor Satoshi Ōmura

The 8 different avermectins, with the differences between them shown in the table below.

The avermectins proved to be have biocidal activity against a wide range of parasites – such as roundworms, lungworms, mites, lice and arachnids; one of these parasites is the tick Rhipicephalus (Boophilus) microplus, one of the most important cattle parasites in tropical regions. Those with the -CH=CH- function are the more active; the most potent was Avermectin B₁, occurring as an 80:20 mixture of the similar molecules B_1a and B_1b, particularly the B_1a component. Commercially it is known as Abamectin.

Veterinary use

In veterinary medicine ivermectin is used against many intestinal worms (but not tapeworms), most mites, and some lice. Despite this, it is not effective for eliminating ticks, flies, flukes, or fleas. It is effective against larval heartworms, but not against adult heartworms, though it may shorten their lives. The dose of the medicine must be very accurately measured as it is very toxic in over-dosage. It is sometimes administered in combination with other medications to treat a broad spectrum of animal parasites. Some dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), though, have a high incidence of a certain mutation within the MDR1 gene (coding for P-glycoprotein); affected animals are particularly sensitive to the toxic effects of ivermectin.^[32][33] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.^[34] A 0.01% ivermectin topical preparation for treating ear mites in cats (Acarexx) is available.

Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated.

IVERMECTIN

Chlorotris(triphenylphosphine)rhodium(I), [RhCl(PPh₃)₃]

http://www.chm.bris.ac.uk/motm/wilcat/wilcath.htm

Such selectivity found an important application in the synthesis of Ivermectin (MectizanTM). Avermectin is a naturally-occurring molecule with anthelmintic and insecticidal properties; selectively reducing one double bond using Wilkinson’s catalyst afforded Ivermectin. The resultant small change in molecular shape makes Ivermectin a much more effective drug to combat onchocerciasis (river blindness), a disease which affects many millions of people, mainly in poor African communities.

You need to add just two hydrogen atoms to reduce a C=C bond in avermectin.

Notes and references

External links

• Stromectol
• The Carter Center River Blindness (Onchocerciasis) Control Program
• Mectizan Donation Program
• American NGDO Treating River Blindness
• MERCK. 25 Years: The MECTIZAN® Donation Program
• Trinity College Dublin. Prof William Campbell – The Story of Ivermectin
• “IVERMECTIN- ivermectin tablet (NDC Code(s): 42799-806-01)”. DailyMed. November 2014. Retrieved 2015-09-09

Bibliography

• Chapman and Hall Combined Chemical Dictionary compound code number CMD99-Y (Ivermectin); CLF13-X (Avermectin).
• The World Health Organisation page on Onchocerciasis
• “Organic Chemists Fighting Blindness” – the Mectizan story from the RSC Organic Division
• A. Crump and K. Otoguro, Trends in Parasitology, 2005, 21, 126-132. (Ōmura’s work)
• Nobel committee’s announcement.

Avermectin

• R. W. Burg, B. M. Miller, E. E. Baker, J. Birnbaum, S. A. Currie, R. Hartman, Y.-L. Kong, R. L. Monaghan, G. Olson, I. Putter, J. B. Tunac, H. Wallick, E. O. Stapley, R. Oiwa, and S. Ōmura, Antimicrob. Agents Chemother., 1979, 15, 361-367 (production of avermectins)
• T. W. Miller, L. Chaiet, D. J. Cole, L. J. Cole, J. E. Flor, R. T. Goegelman, V. P. Gullo, H. Joshua, A. J. Kempf, W. R. Krellwitz, R. L. Monaghan, R. E. Ormond, K. E. Wilson, G. Albers-Schönberg and I. Putter., Antimicrob. Agents Chemother., 1979, 15, 368-371 (isolation of avermectins)
• J. R. Egerton, D. A. Ostlind, L. S. Blair, C. H. Eary, D. Suhayda, S. Cifelli, R. F. Riek and W. C. Campbell, Antimicrob. Agents Chemother., 1979, 15, 372-378 (efficacy of avermectins)
• M. H. Fisher, Pure Appl. Chem., 1990, 62, 1231-1240 (avermectin review)
• Y. J. Yoon, E.-S. Kim, Y.-S. Hwang and C.-Y. Choi, Appl. Microbiol. Biotechnol., 2004, 63, 626–634 (biosynthesis)

Ivermectin

• J. C. Chabala, H. Mrozik, R. L. Tolman, P. Eskola, A. Lusi, L. H. Peterson, M. F. Woods, M. H. Fisher and W. C. Campbell, J. Med. Chem., 1980, 23, 1134-1136 (synth)
• W. C. Campbell, M. H. Fisher, E. O. Stapley, G. Albers-Schönberg and T. A. Jacob, Science, 1983, 221, 823–828 (ivermectin as a new antiparasitic agent)
• S. Ōmura and A. Crump, Nat. Rev. Microbiol., 2004, 2, 984-989. (“The life and times of ivermectin – a success story”).
• K. Collins, Perspect. Biol. Med., 2004, 47, 100-109. (History of the Merck Mectizan donation program)
• A. D. Hopkins, Eye, 2005, 19, 1057–1066 (improvements upon ivermectin treatment)
• T. G. Geary, Trends in Parasitology, 2005, 21, 530–532 (20 years of ivermectin)
• S. Ōmura, Int. J. Antimicrob. Ag., 2008, 31, 91–98 (25 years of Ivermectin)
• A. G. Canga, A. M. S. Prieto, M. J. D. Liébana, N. F. Martínez, M. S.Vega and J. J. G. Vieitez, Vet. J., 2009, 179, 25–37 (pharmacokinetics and metabolism of ivermectin in domestic animal species)
• A. Crump and S. Ōmura, Proc. Jpn. Acad., Ser. B., 2011, 87, 13-28 (ivermectin review)
• I. Farrell, Education in Chemistry, November 2013. (“One in the eye for river blindness”), online.
• The Mectizan donation program
• Colombia eliminates river blindness

Doramectin

• K. Stutzman-Engwall, S. Conlon, R. Fedechko, H. McArthur, K. Pekrun, Y. Chen, S. Jenne, C. La, N. Trinh, S. Kim, Y.-X. Zhang, R. Fox, C. Gustafsson and A. Krebber, Metabolic Engineering, 2005, 7, 27–37 (synth.)
• J.-B. Wang, H.-X. Pan and G.-L. Tang, Bioorg. Med. Chem. Lett., 2011, 21, 3320–3323 (synth.)

Ivermectin

Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names	Stromectol
AHFS/Drugs.com	monograph
MedlinePlus	a607069
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral, topical
Pharmacokinetic data
Protein binding	93%
Metabolism	Liver (CYP450)
Biological half-life	18 hours
Excretion	Feces; <1% urine
Identifiers
CAS Registry Number	70288-86-7  71827-03-7
ATC code	D11AX22 P02CF01 QP54AA01QS02QA03
PubChem	CID: 9812710
DrugBank	DB00602
ChemSpider	7988461
UNII	8883YP2R6D
KEGG	D00804
ChEMBL	CHEMBL341047
PDB ligand ID	IVM (PDBe, RCSB PDB)
Chemical data
Formula	C 48H 74O 14 (22,23-dihydroavermectin B1a) C 47H 72O 14 (22,23-dihydroavermectin B1b)
Molecular mass	875.10 g/mol

SIMILAR

Doramectin is a similar molecule, used to treat parasites in animals, such as cattle, horses, sheep and pigs.

/////////////////ivermectin, MALARIA

2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol

Tramadol (marketed as Ultram, and as generics) is an opioid pain medication used to treat moderate to moderately severepain.^[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.^[5]It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin andnorepinephrine.^[6][7]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. Its use is not recommended in women who are breastfeeding or those who are at risk of suicide.^[1]

Tramadol is marketed as a racemic mixture of both R– and S–stereoisomers.^[2] This is because the two isomers complement each other’s analgesic activity.^[2] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.^[2] Tramadol is metabolised to O-desmethyltramadol, which is a more potent opioid.^[8] It is of the benzenoid class.

Tramadol was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 inWest Germany, and 20 years later it was launched in countries such as the UK, U.S., and Australia.^[7]

Developed (from 1962) by the German company Grünenthal, and is marketed through much of the world under various trade names, including Acugersic (Malaysia), Mabron (some Eastern European countries as well as parts of the Middle and Far East), Ultram (USA), Zaldiar (France and much of Europe, as well as Russia) and Zydol (UK and Ireland).

CONFUSION ON CIS TRANS

There is some confusion within the literature as to what should be called cis and what should be called trans. For purposes of this disclosure, what is referred to herein as the trans form of Tramadol includes the R,R and S,S isomers as shown by the following two structures:

The cis form of Tramadol, as that phrase is used herein, includes the S,R and the R,S isomers which are shown by the following two structures:

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. It is a μ-opioid receptor agonist, like morphine, but much less active. It inhibits reuptake of the neurotransmitters serotonin and norepinephrine, suggesting that it lifts mood and thereby may dull the brain’s perception of pain.

1R,2R-Tramadol	1S,2S-Tramadol

In the body, tramadol undergoes demethylation to several metabolites by a Cytochrome P450 enzyme (CYP2D6) in the liver, the most important of these products being O-desmethyltramadol. O-desmethyltramadol has a much stronger (200x) affinity for the μ-opioid receptor than tramadol, so in effect tramadol is a prodrug.

1R,2R–O-desmethyltramadol	1S,2S–O-desmethyltramadol

Not everyone’s liver works identically. Around 6% of the Caucasian population has a reduced CYP2D6 activity (hence reducing metabolism), so there is a reduced analgesic effect with Tramadol. These people require a dose increase of 30% to get the same pain relief as the norm. A case has been reported of a patient where, following an overdose, their ultrarapid tramadol metabolism led to excessive norepinephrine levels, with near-fatal consequences.

However, it has recently been discovered at relatively high concentrations in the roots of the African peach or pin cushion tree (Nauclea latifolia), which has a long tradition as a folk remedy. As usual, Nature got there first.

The African pin-cushion tree (Nauclea latifolia)

In the area of “legal highs”, a disturbing development is a drug blend known as “Krypton”. This isn’t the noble gas, but a mixture of O-desmethyltramadol withKratom (Mitragyna speciosa, a medicinal plant that originates in SE Asia, seemingly the local equivalent of khat), which contains an alkaloid mitragynine which is also a μ-receptor agonist. Several fatalities have been linked with its use, notably in Sweden.

SYNTHESIS

 
(1R,2R)-Tramadol     (1S,2S)-Tramadol
 
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.^[35] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at thecyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

• (1R,2R)-isomer
• (1S,2S)-isomer
• (1R,2S)-isomer
• (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described^[36] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects^[37] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[38] and in humans.^[39]

Synthesised by chemists at the German company Grünenthal and brought to the market in 1977. It can readily be made by nucleophilic attack of a Grignard or RLi species upon a carbonyl group.

ALSO

Paper

http://www.jmcs.org.mx/PDFS/V49/N4/04-Alvarado.pdf

Tramadol hydrochloride (1). To a solution of 3-bromoanisol 13 (0.823 g, 4.4 mmol) in dry THF (10 mL), 1.75 M n-BuLi (2.5 mL, 4.4 mmol) was added dropwise at -78°C under argon atmosphere. The mixture was stirred at the same temperature during 45 minutes and a solution of 2-dimethylaminomethylcyclohexanone 6a (0.62 g, 4mmol) in dry THF was added dropwise. The resulting mixture was stirred at -78°C for 2 h. and the solvent was removed in vacuo. Water (30 mL) was added and the product was extracted with ethyl ether (3X30 mL). The extracts were dried over sodium sulfate, filtered and evaporated in vacuum. The residue was treated with 5mL of ethyl ether saturated with hydrogen chloride; the ethyl ether was evaporated in vacuo and the resulting solid was purified by crystallization from acetone. Tramadol hydrochloride 1 was obtained as white crystals (0.94 g, 78.6%),

MP 168- 175°C.

IR (KBr): 3410, 3185, 2935, 2826, 2782, 1601, 1249, 702 cm-1;

1H NMR (CDCl3, 300 MHz) δ 1.2-1.9 (10H, m), 2.15 (6H, s), 2.45 (1H, dd, J = 15.1, 4.4 Hz), 3.82 (3H, s), 6.76 (1H, dd, J = 8, 2.4 Hz), 7.04 (1H, d, 7.6 Hz), 7.14 (1H, s), 7.26 (1H, t, 3.9 Hz), 11.4 (1H, bs);

MS (EI): m/z 263 M+ (28), 58 (100).

PATENT

http://www.google.com.ar/patents/WO1999003820A1?cl=en

Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-l-(3- methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic

Tramadol means the racemic mixture of cis-Tramadol as shown by the following chemical structures:

(1 R, 2R) (1S. 2S) cis-Tramadol

Step l Formation of Dimethylaminomethyl Cyclohexanone Hydrochloride

Dimethylaminomethyl Cyclohexanone Hydrochloride

Step 2 Formation of Tramadol Mannich Base

NaOH, Water

Toluene, TBME

Tramadol Mannich Base

Step 3 Formation of Tramadol Base Hydrate

Tramadol Base Hydrate (crude) Step 4 Purification of Tramadol Base Hydrate

Tramadol Base Hydrate (pure)

Step 5 Formation of Tramadol Hydrochloride

Tramadol Hydrochloride

Example 1

To produce the Tramadol base hydrate, a reaction vessel is charged successively with 69 Kg of Magnesium, 400 1 of dry Tetrahydrofuran (THF) and 15 1 of 3- bromoanisole.

With careful heating, the reactor temperature is brought up to ca. 30°C. The Grignard initiates at this point and exotherms to approximately 50°C. A further 5 1 of bromoanisole are added which maintains reflux. 400 1 of THF are then added before the remainder of the bromoanisole. This addition of the remainder of the bromoanisole is carried out slowly so as to sustain a gentle reflux. The reaction is refluxed after complete addition of 3-bromoanisole. The vessel is cooled and Mannich base is added. When addition is complete, the vessel is reheated to reflux for 30 minutes to ensure complete reaction. After cooling to ca. 10°C, 2,300 1 of water are added to quench the reaction. When complete, part of the solvents are distilled under vacuum. Approximately 260 1 of concentrated HC1 is added at a low temperature until a pH of 0 – 1 is reached. This aqueous phase is extracted with toluene. The toluene phases are discarded and ethyl acetate is added to the aqueous phase. 30% Ammonia solution is then charged to reach pH 9 – 10 and the phases are separated. The aqueous phases are extracted again with ethyl acetate and finally all ethyl acetate layers are combined and washed twice with water. Ethyl acetate is then distilled from the reaction solution at atmospheric pressure. Process water is added and the solution cooled to 20°C and seeded. After crystallisation, the vessel is cooled to -5 to 0°C and stirred for one hour.

The product is centrifuged at this temperature and washed with cold ethyl acetate 5 x 50 1. Approximately 310 – 360 Kg of moist cis-Tramadol base hydrate are obtained.

Purification

A reactor vessel is charged successively with cis-Tramadol base hydrate (crude) 200 Kg and ethyl acetate 300 1 and the contents of the vessel heated to 50°C until all solids are in solution. The vessel is then cooled to -5 to 0°C and the product crystallises. Stirring is continued for two hours and the product is then centrifuged and washed with cold ethyl acetate, 2 x 25 1. Approximately 165 – 175 Kg (moist) of cis(+/-) Tramadol base hydrate are obtained from this procedure.

The overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.03%. Analytical data of the base hydrate of cis-Tramadol

Melting point: 79 – 80°C (in comparison cis-Tramadol base anhydrous is an oil). Water content (KF) : 6.52% (= monohydrate) IR-spectrum of the base hydrate of cis-Tramadol (see Fig. 1).

IR-spectrum (=cis-Tramadol base anhydrous, see Fig. 2).

The invention provides a unique process in which a base hydrate of cis-Tramadol is selectively crystallised without impurities. The base hydrate is processed to readily form cis-Tramadol hydrochloride. The process is substantially simpler than known processes and does not require the use of potentially toxic solvents. Thus the process is environmentally friendly.

The base hydrate of cis-Tramadol prepared may also be used in various formulations.

The base hydrate of cis-Tramadol may be formulated in the form of a solid with a slow release profile. For example, slow release pellets may be prepared by coating a suitable core material with a coating, for example, of ethylcellulose/schellack solution (4:1) and suitable pharmaceutical excipients. The pellets have typical average diameter of 0.6 to 1.6 mm. The pellets may be readily converted into gelatine capsules or pressed into tablet form using well-known techniques.

Alternatively the base hydrate of cis-Tramadol may be formulated into effervescent tablets by forming granules of the base hydrate with acidity/taste modifiers and a suitable effervescent base such as sodium hydrogen carbonate /anhydrous sodium carbonate (12:1). The ingredients are typically blended in a mixer /granulator and heated until granulation occurs. The resulting granules may be pressed into tablet form, on cooling. Of particular interest is the use of the base hydrate of cis-Tramadol in a form for parenteral use/injectables. The base hydrate is typically dissolved in water together with suitable excipients (as necessary). The solution is filtered through a membrane to remove solid fibres or particles. The filtered solution may then be filled into ampoules, typically containing 10.0 mg of the active compound. Usually the formulation is prepared for intramuscular injection.

PATENT

http://www.google.com/patents/EP1346978A1?cl=en

• Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
• [0004]

  The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3^rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).
• In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.
• PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.
• More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.
• Therefore, all the known methods require potentially toxic solvents and/or reagents, and multiple steps to produce the desired quality and quantity of tramadol hydrochloride. By contrast, the present invention requires a single step process (or only two steps when tramadol hydrochloride is made via the tramadol (base) monohydrate route) using a natural solvent (ie water) in the absence of carcinogenic solvents (such as the category 1 carcinogen, 1,4-dioxane) to produce pure tramadol hydrochloride, so it is ‘ecofriendly’ and easily commercialized to plant scale without any difficulties.

PATENT

http://www.google.co.in/patents/US6399829

EXAMPLE 8 Hydrochloride Formed without Improvement of the Trans:Cis Ratio

Whether a recrystallization step improves the trans:cis ratio of Tramadol depends upon the solvent composition from which the recrystallization is performed. When the hydrochloride form of Tramadol is produced and then crystallized in the presence of a solvent with a high toluene concentration, the ratio of trans:cis remains essentially unchanged. This is in contrast to the recrystallization from a solvent which has a high acetonitrile concentration as was the case in Examples 5-7.

A 21 mL solution of 1.8 g of HCl gas (bubbled at 5° C.) in acetonitrile (yielding a 2.0 M solution), was added to 10.2 g of Grignard product C (90/10 of trans/cis) in 30 mL of toluene and stirred mechanically for 3 hours. The mixture was filtered and washed with toluene. Drying in vacuo yielded 11.2 g (96% recovery). The resulting hydrochloride had a trans/cis ratio of 92:8, essentially the same trans:cis ratio as did the 10.2 g of Grignard product C.

Recrystallization from 90 mL of acetonitrile yielded 8.83 g, which was 96.6/3.4 of trans/cis by HPLC. Of this, 8.6 g was recrystallized from 75 mL of acetonitrile to give 7.44 g, trans/cis ratio of 99.6/0.4.

This example shows that the formation of the hydrochloride in the presence of a relatively large amount of toluene (here about 60%) and crystallization from toluene-acetonitrile does not improve the trans:cis ratio. As the percentage of toluene present in the mixture of toluene and acetonitrile in a crystallization step is decreased, the trans:cis ratio of the recovered product will increase. Steps in which the hydrochloride is recrystallized from acetonitrile do yield an improved trans:cis ratio.

PATENT

https://www.google.com/patents/EP0831082A1

The synthesis of Tramadol is described in U.S. Patent No. 3,652,589 and in British Patent No. 992,399. The synthesis of Tramadol consists of a Grignard reaction between 2-dimethylaminomethylcyclohexanone and 3-methoxyphenyl magnesium bromide (Equation 1). From the reaction scheme, it is clear that both isomers (RR,SS) (Structure 1) and (RS, SR) (Structure 2) are obtained in variable ratios, depending on the reaction conditions.

The original patents assigned to Gruenenthal GmbH describe the isolation of the (RR,SS) isomer, as follows:

The complex mixture of products containing both isomers of Tramadol obtained from the Grignard reaction is distilled under reduced pressure. The isomers are distilled together at 138-140°C (0.6 mm Hg). The distillate is dissolved in ether and is reacted with gaseous HCl. The resulting mixture of both isomers of Tramadol is precipitated as hydrochlorides and filtered. The resulting mixture contains about 20% of the (RS,SR) isomer. The isomer mixture is then refluxed twice with five volumes of moist dioxane, and filtered. The cake obtained consists of pure (RR,SS) isomer. The residual solution consists of “a mixture of about 20-30% of the cis (i.e. RS,SR), which cannot be further separated by boiling dioxane” [U.S. Patent 3,652,589, Example 2].

Dioxane, used in large quantities in this process, possesses many undesirable properties. It has recently been listed as a Category I carcinogen by OSHA [Kirk & Othmer, 3rd Ed., Vol. 9, p. 386], and it is known to cause CNS depression and liver necrosis [ibid., Vol. 13, p. 267]; in addition, it tends to form hazardous peroxides [ibid., Vol 17, p. 48]. As a result, the concentration of dioxane in the final product has been strictly limited to several ppb’s, and the DAC (1991) restricted the level of dioxane in Tramadol to 0.5 ppm.

A different separation method, described in Israeli Specification No. 103096, takes advantage of the fact that the precipitation of the (RR,SS) isomer of Tramadol from its solution in medium chained alcohols (C₄-C₈) occurs faster than the precipitation of the (RS,SR) isomer, which tends to separate later. The main disadvantage of this method is, that the time interval between the end of separation of the (RR,SS) isomer and the beginning of the (RS,SR) isomer separation is variable, and seems to depend sharply on the composition of the crude mixture. Therefore, variations in the yield and the quality of the product often occur. Furthermore, about 40% of the (RR,SS) isomer does not separate and remains in solution, along with the (RS,SR) isomer. This remaining mixture cannot be further purified by this method.

Another method, described in Israeli Specification No. 116281, relies on the fact that the (RS,SR) isomer of Tramadol undergoes dehydration much faster then the (RR,SS) isomer, when treated with 4-toluenesulfonic acid, or sulfuric acid; furthermore, when the reaction is carried out in an aqueous medium, a certain amount (up to 50%) of the (RS,SR) isomer is converted to the (RR,SS) isomer. This may, of course increase the efficiency of the process.

The unreacted (RR, SS) isomer is then separated from the dehydrated products and from other impurities by simple crystallization.

While further examining the results of the latter process, it was surprisingly found that the hydroxyl group of the (RS,SR) isomer of Tramadol reacts faster than the same group of the (RR,SS) with various reagents. A plausible explanation for this observation can be supplied by comparing the structures of both isomers, and their ability to form hydrogen bonds.

Looking closely at Fig. 1 [(RR,SS) Tramadol hydrochloride] and at Fig. 2 [(RS,SR) Tramadol hydrochloride], one can provide a plausible explanation for the difference in the OH group’s activity, as follows: The proton attached to the nitrogen atom of the protonated (RR,SS) isomer of Tramadol is capable of forming a stable hydrogen bonding with the oxygen atom of the hydroxyl group (see Fig. 1). Thus, any reaction involving protonation of the hydroxyl group (such as dehydration), or any reaction in which the hydroxyl group reacts as a nucleophile (such as a nucleophilic substitution or esterification process) is less favored to occur.

In the (RS,SR) isomer, on the other hand, there is no possible way of forming a stable intramolecular hydrogen bond, and therefore, any of the above-mentioned types of reactions can easily occur, considering the fact that this particular hydroxyl group is tertiary and benzyllic.

The general purification procedure of the present invention consists of reacting a mixture of both geometrical isomers of Tramadol hydrochloride with a potential electrophile under such conditions that the (RS,SR) isomer reacts almost exclusively, while the (RR,SS) isomer remains practically intact. The resulting mixture is evaporated and the resulting solid substance is then recrystallized from isopropanol or any other suitable solvent.

Example 1

11.1 g of a mixture consisting of 77% (RR,SS) Tramadol hydrochloride and 23% of the corresponding (RS,SR) isomer were dissolved in 30 ml DMF. 1.3 g acetic anhydride were added and the reaction mixture was stirred at room temperature for 12 hours. The solvent was partly evaporated under reduced pressure and 15 ml toluene were added. The suspension obtained was filtered and washed with 5 ml toluene. 5.8 g of crystals were obtained, in which the (RR,SS):(RS,SR) isomer ratio was 70:1. The product obtained was crystallized from 12 ml isopropanol and 4 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 2

19.5 g of a mixture consisting of 60.5% (RR,SS) Tramadol hydrochloride and 40.5% of the corresponding (RS,SR) isomer were suspended in 55 ml chlorobenzene. A solution of 4 ml thionyl chloride in 15 ml chlorobenzene was added dropwise for two hours. The suspension was partly evaporated, the residue was filtered and rinsed with toluene, and 8.1 g of crystals were obtained, in which the (RR,SS):(RS, SR) isomer ratio was 14:1. The product obtained was recrystallized from isopropanol, and 6.7 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 3

33.4 g of a mixture consisting of 45% (RR,SS) Tramadol hydrochloride and 55% of the corresponding (RS,SR) isomer was immersed in 50 ml trifluoroacetic acid, 5.2 g of sodium azide was added, and the reaction mixture was stirred for 24 hours. The reaction mixture was then evaporated under reduced pressure, 50 ml water was added, and the solution was brought to pH 12 with solid potassium carbonate. The suspension was extracted with 50 ml toluene, the solvent was evaporated and 25 ml hydrogen chloride solution in isopropanol were added. The solution was cooled and filtered. 9.5 g of crude (RR,SS) Tramadol were obtained, and the crude product was purified by recrystallization from isopropanol.

The hitherto unknown (RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride was isolated from the reaction mixture, recrystallized from isopropanol and characterized as follows:

(RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride

• ms : 288 m⁺
• IR : 2050 cm^-1 (N₃)

• ¹H-NMR (DMSO): 10.42 ppm: (acidic proton); 1H; 7.40-6.90 ppm: (aromatic protons) 4H; 3.79 ppm; (OCH₃ ), 3H; 2.78, 2.42 ppm: NCH₂ ; 2H; 2.58, 2.37 ppm: [N(CH₃ )₂], 6H; 2.30-1.40 ppm: cyclohexane ring protons, 9H.

• ¹³C-NMR (DMSO): 159.74 ppm: C₁; 144.12 ppm: C₅; 130.08 ppm: C₃; 117.36 ppm: C₄; 112.97, 111.35 ppm: C₂, C₆; 69.61 ppm: C₈; 59.29 ppm: C₁₄; 55.21 ppm: C₇; 44.6 ppm: C₁₅; 40.12 ppm: C₁₃; 35.94, 27.02, 23.56, 21.63 ppm: cyclohexane ring carbon nucleii.

AZIDE COMPD

Bibliography

Synthesis of Tramadol

http://www.nioch.nsc.ru/icnpas98/pdf/posters1/156.pdf

• http://www.opioids.com/tramadol/synthesis/index.html
• Patents to Grünenthal G.m.b.H.:- K. Flick and E. Frankus, U.S. Patent 3,652,589, March 28, 1972; Chem. Abs., 1972, 76, 153321; K. Flick and E. Frankus, U.S. Patent. 3,830,934, August 20, 1974; Chem. Abs., (1974), 82, 21817 (synth)
• C. Alvarado, Á. Guzmán, E. Díaz and R. Patiño, J. Mex. Chem. Soc., 49, (2005) 324-327 (synth)
• G. Venkanna, G. Madhusudhan, K. Mukkanti, A. Sankar, V. M. Kumar and S. A. Ali, J. Chem. Pharm. Res., 4 (2012) 4506-4513 (synth)
• A. Boumendjel, G. S.Taïwe, E. N. Bum, T. Chabrol, C. Beney, V. Sinniger, R. Haudecoeur, L. Marcourt, S. Challal, E. F. Queiroz, F. Souard, M. Le Borgne, T. Lomberget, A. Depaulis, C. Lavaud, R. Robins, J.-L. Wolfender, B. Bonaz and M. De Waard, Angew. Chem. Int. Ed., 52 (2013) 11780 –11784 (Tramadol in nature)

Action

• R. B. Raffa, E. Friderichs, W. Reimann, R. P. Shank, E. E. Codd and J. L. Vaught, J. Pharmacol. Exp. Ther., 260 (1992) 275-285 (means of action)
• P. Dayer, L. Collart and J. Desmeules, Drugs (Suppl. 1), (1994) 3-7.
• T. A. Bamigbade, C. Davidson, R. M. Langford and J. A. Stamford, Br. J. Anaesthes., 79 (1997) 352-356. (action of enantiomers)
• P. W. Keeley, G. Foster and L. Whitelaw, BMJ, 321 (2000) 1608 (auditory hallucinations with tramadol)
• U. M. Stamer, F. Musshoff, M. Kobilay, B. Madea, A. Hoeft and F. Stuber, Clin. Pharmacol. Ther., 82 (2007) 41-47 (different CYP2D6 Genotypes and metabolism)
• W. Leppert, Pharmacology, 87 (2011)274–285 (metabolism of tramadol to O-desmethyltramadol by CYP2D6)
• A. Elkalioubie, D. Allorge, L. Robriquet, J.-F. Wiart, A. Garat, F. Broly and F. Fourrier, Eur. J. Clin. Pharmacol., 67 (2011) 855–858 (ultrarapid metabolism of tramadol)
• C. F. Samer, K. I. Lorenzini, V. Rollason, Y. Daali and J. A. Desmeules, Molecular Diagnosis & Therapy, 17 (2013), 165–84 (variations in tramadol response)

Tramadol abuse

• M. K. Wedge, Can. Pharm. J., 142 (2009) 71-73. (tramadol and antidepressants)
• ACMD advice on O-desmethyltramadol
• Y. Progler, J. Res. Med. Sci., 15 (2010) 185-188 (Tramadol abuse and smuggling into Gaza)
• M. M. Fawzi, Egypt. J. Forensic Sci., 1 (2011) 99–102 (Tramadol abuse in Egypt)
• I. Giraudon, K. Lowitz, P. I. Dargan, D. M. Wood and R. C. Dart, Br. J. Clin. Pharmacol., 76, (2013) 823–824 (prescription opioid abuse in the UK)
• C. Stannard, BMJ, 347 (2013) f5108 (tramadol problem)
• N. Hawkes, BMJ, 347 (2013) f5336 (deaths from tramadol and legal highs)
• A. Winstock, J. Bell and R. Borschmann, BMJ 347 (2013) f5599 (monitoring Tramadol abuse)
• S. H. Park, R. C. Wackernah and G. L. Stimmel, J. Pharm. Pract., 27 (2014) 71-78.
• Unemployment in Gaza and Tramadol addiction.

Tramadol in “highs”

• T. Arndt, U. Claussen, B. Güssregen, S. Schröfel, B. Stürzer, A. Werle and G. Wolf, For. Sci. Int., 208 (2011) 47-52. (Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer)
• R. Kronstrand, M. Roman, G. Thelander and A. Eriksson, J. Anal. Toxicol., 35 (2011) 242–247. (fatalities from mitragynine and O-desmethyltramadol combinations in Krypton herbal mixture)
• C. D. Rosenbaum, S. P. Carreiro and K. M. Babu, J. Med. Toxicol., 8 (2012) 15-32 (review of herbal marijuana alternatives, including Kratom)

Tramadol in cycling

• Michael Barry, “Shadows on the Road: Life at the Heart of the Peloton, from US Postal to Team Sky”, Faber 2014.
• Chris Froome, “The Climb: The Autobiography”, Viking, 2014.
• http://cyclingtips.com.au/2014/05/wada-proposes-tramadol-remains-a-monitored-rather-than-a-banned-substance-in-2015/
• Tramadol blamed for crashes
• Tramadol use for pain in cycling

Systematic (IUPAC) name
2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Clinical data
Trade names	Ryzolt, Tramal, Ultram
AHFS/Drugs.com	monograph
MedlinePlus	a695011
Licence data	US FDA:link
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: Class C US: Schedule IV ℞ (Prescription only)
Dependence liability	Present[1]
Routes of administration	Oral, IV, IM, rectal
Pharmacokinetic data
Bioavailability	70–75% (oral), 77% (rectal), 100% (IM)[2]
Protein binding	20%[3]
Metabolism	Liver-mediated demethylation andglucuronidation via CYP2D6 &CYP3A4[2][3]
Biological half-life	6.3 ± 1.4 hr[3]
Excretion	Urine (95%)[4]
Identifiers
CAS Registry Number	27203-92-5
ATC code	N02AX02
PubChem	CID: 33741
DrugBank	DB00193
ChemSpider	31105
UNII	39J1LGJ30J
KEGG	D08623
ChEBI	CHEBI:9648
ChEMBL	CHEMBL1066
Chemical data
Formula	C16H25NO2
Molecular mass	263.4 g/mol

DMF

Tramadol hydrochloride..CEP

SYNOPSIS FOR M. PHARM DISSERTATION

////////TRAMADOL,

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro- 2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections

(S)-3-aminomethylbenzoxaborole; ABX; AN-3365; GSK ‘052; GSK-052; GSK-2251052, GSK2251052, Epetraborole

[(S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy- 1,3-dihydro-2,1-benzoxaborole hydrochloride],

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride

1-Propanol, 3-(((3S)-3-(aminomethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborol-7-yl)oxy)-

AN3365,

MW 237.0614,

cas 1093643-37-8
UNII: 6MC93Z2DF9

Anacor Pharmaceuticals, Inc., INNOVATOR

Glaxosmithkline Llc DEVELOPER

Biomedical Advanced Research and Development Authority (BARDA)

GSK 2251052 • $38.5M over the 1st two years; up to $94M……..http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Press_Releases/FIS%20Slides.pdf

Originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it’s an oxaborole heterocycle that inhibits leucyl tRNA synthetase

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development
Authority (BARDA), a US government preparedness organization ,  The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.

The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).

Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesizedbortezomib, a boronic acid peptide, in 1995.

Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.

Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.

Boron-containing molecules such as benzoxaboroles that are useful as antimicrobials have been described previously, see e.g. “Benzoxaboroles – Old compounds with new applications” Adamczyk-Wozniak, A. et al., Journal of Organometallic Chemistry Volume 694, Issue 22, 15 October 2009, Pages 3533-3541 , and U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, a benzoxaborole has the following structure and substituent numbering system:

Certain benzoxaboroles which are monosubstituted at the 3-, 6-, or 7-position, or disubstituted at the 3-/6- or 3-/7- positions are surprisingly effective antibacterials, and they have been found to bind to the editing domain of LeuRS in association with tRNA^Leu Such compounds have been described in US7, 816,344. Using combinations of certain substituted benzoxaboroles with norvaline and/or other amino acid analogs and their salts to: (a) reduce the rate of resistance that develops; and/or (b) decrease the frequency of resistance that develops; and/or (c) suppress the emergence of resistance, in bacteria exposed to compounds

Epetraborole R-mandelate
1234563-15-5

Epetraborole hydrochloride
1234563-16-6

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets.

Lucy Shapiro is a Professor in the Department of Developmental Biology at Stanford University School of Medicine where she holds the Virginia and D. K. Ludwig Chair in Cancer Research and is the Director of the Beckman Center for Molecular and Genetic Medicine. She is a member of the Scientific Advisory Board of Ludwig Institute for Cancer Research and is a member of the Board of Directors of Pacific Biosciences, Inc. She founded the anti-infectives discovery company, Anacor Pharmaceuticals, and is a member of the Anacor Board of Directors.  Professor Shapiro has been the recipient of multiple honors, including: election to the American Academy of Arts and Sciences, the US National Academy of Sciences, the US Institute of Medicine, the American Academy of Microbiology, and the American Philosophical Society. She was awarded the FASEB Excellence in Science Award, the 2005 Selman Waksman Award from the National Academy of Sciences, the Canadian International 2009 Gairdner Award, the 2009 John Scott Award, the 2010 Abbott Lifetime Achievement Award, the 2012 Horwitz Prize and President Obama awarded her the National Medal of Science in 2012. Her studies of the control of the bacterial cell cycle and the establishment of cell fate has yielded valuable paradigms for understanding the bacterial cell as an integrated system in which the transcriptional circuitry is interwoven with the three-dimensional deployment of key regulatory and morphological proteins, adding a spatial dimension to the systems biology of regulatory networks.

Stephen J. Benkovic

Office:
414 Wartik Laboratory
University Park, PA 16802
Email: sjb1@psu.edu
(814) 865-2882

http://chem.psu.edu/directory/sjb1

Naeja was a three-year-old contract research firm run by Ronald Micetich and his son Christopher Micetich. Based in Edmonton, Alberta, the firm is staffed by chemists and biologists from a variety of nations who have found Canada welcoming to highly educated immigrants.

GSK. Last July, the British firm paid Anacor $15 million and exercised its option to take over development of AN3365. David J. Payne, vice president of GSK’s antibacterial drug discovery unit, lauded the compound, now renamed GSK2251052, as having “the potential to be the first new-class antibacterial to treat serious hospital gram-negative infections in 30 years.” GSK chemists have since developed a stereospecific synthesis for commercial-scale production

david.j.payne@gsk.com

David J. Payne, vice president of GSK’s antibacterial drug discovery unit

David J Payne Dr Payne holds a BSc in Biochemistry from Brunel University, UK, and a PhD and DSc from The Medical School, University of Edinburgh, UK. Dr Payne has 20 years of experience in antibacterial drug discovery and is currently Vice President and Head of the Antibacterial Discovery Performance Unit (DPU) within the Infectious Diseases Centre of Excellence in Drug Discovery (ID CEDD) where he is responsible for GSK’s antibacterial research effort from discovery to clinical proof of concept (up to Phase II clinical trials). At GSK, Dr Payne has played a leading role in redesigning the strategy for antibacterial research and has helped create long-term alliances with innovative biotechnology companies which has expanded GSK’s discovery pipeline. Furthermore, he has created industry-leading partnerships with the Wellcome Trust and the Defense Threat Reduction Agency (US Department of Defense) to accelerate GSK’s antibacterial programmes. To date, Dr Payne has been involved with the progression of a broad diversity of novel mechanism antibacterial agents into development. Dr Payne has authored more than 190 papers and conference presentations.

PATENT

http://www.google.com/patents/US20090227541

General procedure for Chiral Synthesis of 3-aminomethylbenzoxaboroles

4-(3-Aminomethyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyramide acetate salt (A5)

4-[2-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid ethyl ester

• A mixture of 4-(2-bromo-3-formyl-phenoxy)-butyric acid ethyl ester (5.50 g, 17.5 mmol), bis(neopentyl glucolato)diboron (6.80 g, 30.1 mmol), PdCl₂(dppf).CH₂Cl₂ (1.30 g, 1.79 mmol), and KOAc (5.30 g, 54.1 mmol) in anhydrous THF (600 mL) was heated with stirring at 80° C. (bath temp) O/N under an atmosphere of N2. The mixture was then filtered through Celite and concentrated in vacuo to approximately one quarter of the original volume. The resulting precipitate was isolated by filtration. The precipitate was washed with THF and EtOAc and the combined filtrate was concentrated in vacuo to give an oily residue which was used directly in the next reaction without further purification.
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.95 (s, 1H), 7.47-7.39 (m, 2H), 7.09-7.07 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.09-4.01 (m, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 2.53 (t, J=8.0 Hz, 2H), 2.19-2.07 (m, 2H), 1.32-1.22 (m, 3H), 0.98 (s, 6H).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester

• MeNO₂ (1.3 mL, 25 mmol) was added dropwise to a stirred solution of crude 4-[2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid methyl ester (9.4 g), NaOH (1.0 g, 25 mmol) and H₂O (35 mL) in MeCN (90 mL) at rt. The mixture was stirred at rt O/N and then acidified (pH 2) using 4 M HCl. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% EtOAc in hexane) to give the title compound as a yellow oil: yield 2.52 g (45% over 2 steps).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.46-7.42 (m, 1H), 7.07-7.05 (m, 1H), 6.88-6.86 (m, 1H), 5.87 (d, J=8.2 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.29 (dd, J=13.3, 2.7 Hz, 1H), 4.14-3.94 (m, 5H), 2.55-2.44 (m, 2H), 2.02-1.88 (m, 2H), 1.16 (t, J=7.2 Hz, 3H); MS (ESI) m/z=322 (M−1, negative).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid

• A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H₂O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO₄), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.08 (bs, 1H), 9.01 (bs, 1H), 7.46-7.41 (m, 1H), 7.06-7.04 (m, 1H) 6.89-6.87 (m, 1H), 5.70 (dd, J=7.0, 2.3 Hz, 1H), 5.30 (dd, J=13.3, 2.3 Hz, 1H), 4.55 (dd, J=13.6, 4.2 Hz, 1H), 4.03 (t, J=6.6 Hz, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.95-1.89 (m, 2H); MS (ESI) m/z=296 (M+1, positive).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-Benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

4-(2-Benzyloxy propoxy-2-bromobenzaldehyde

• A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N₂. The reaction mixture was cooled to rt and diluted with H₂O and extracted with EtOAc. The organic layer was washed with H₂O then brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.22 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.42-7.20 (m, 5H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 4.52 (s, 2H), 4.16 (t, J=6.2 Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 2.10 (q, J=6.2 Hz, 2H).

4-(2-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

• General procedure 5: 4-(2-benzyloxy propoxy-2-bromobenzaldehyde (4.84 g, 13.9 mmol), B₂pin₂ (5.27 g, 20.8 mmol), KOAc (4.08 g, 41.6 mmol), PdCl₂(dppf).CH₂Cl₂ (811 mg, 8 mol %), and 1,4-dioxane (50 mL). Purification: Biotage (gradient from 2% EtOAc/hexane to 20% EtOAc/hexane): yield 4.0 g (70%).
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.36 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.43-7.14 (m, 6H), 7.01 (dd, J=8.6, 2.7 Hz, 1H), 4.53 (s, 2H), 4.18 (t, J=6.2 Hz, 2H), 3.66 (t, J=6.1 Hz, 2H), 2.11 (q, J=6.1 Hz, 2H), 1.40 (s, 12H).

6-(2-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

• General procedure 8: 4-(2-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.0 g, 7.6 mmol), MeNO₂ (924 mg, 15.1 mmol), NaOH (605 mg, 15.1 mmol), and H₂O (10 mL). Purification: flash chromatography (10% EtOAc/hexane to 40% EtOAc): yield 820 mg (30%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.46 (bs, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.41-7.18 (m, 6H), 7.09 (dd, J=8.6, 2.3 Hz, 1H), 5.71 (dd, J=9.2, 2.5 Hz, 1H), 5.31 (dd, J=13.3, 2.7 Hz, 1H), 4.58-4.40 (m, 3H), 4.08 (t, J=6.2 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 2.08-1.94 (m, 2H).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

• General procedure 13: 6-(2-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (820 mg, 2.29 mmol), 20% Pd(OH)₂ (850 mg, 1 equiv w/w), and AcOH (40 mL). Purification: preparative HPLC: yield 120 mg (22%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.32 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.98 (bs, 1H), 4.04 (t, J=6.2 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.03-2.85 (m, 1H), 2.61 (dd, J=12.9, 7.0 Hz, 1H), 1.89 (s, 3H), 1.97-1.67 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 97.44% (MaxPlot 200-400 nm), 97.77% (220 nm).
• 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

  3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde

  • NaH (2.95 g, 72.4 mmol) was added to an ice-cold solution of 2,3-dihydroxybenzaldehyde (5.0 g, 36 mmol) in anhydrous DMSO (45 mL). Benzyl-3-bromopropyl ether (6.45 mL, 36.2 mmol) was then added and the mixture was stirred at rt for 12 h. The mixture was neutralized using 1 N HCl and then extracted with EtOAc. The organic fraction was washed with H₂O and concentrated in vacuo. The residue was purified by flash chromatography (8:2 hexane/EtOAc) to give the title compound as a brown oil: yield 8.40 g (81%).
  • [0891]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.93 (s, 1H), 7.36-7.23 (m, 6H), 7.20-7.16 (m, 2H), 6.98-6.91 (m, 1H), 4.53 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70 (t, J=6.1 Hz, 2H), 2.19-2.16 (m, 2H).

  3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

  • [0893]
    General procedure 6: 3-(3-benzyloxy-propoxy)-2-hydroxy-benzaldehyde (7.6 g, 26 mmol), pyridine (3.42 mL, 42.5 mmol), Tf₂O (4.60 mL, 27.9 mmol), and CH₂Cl₂ (200 mL): yield 8.60 g (77%).
  • [0894]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.23 (s, 1H), 7.54-7.47 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.36-7.22 (m, 6H), 4.52 (s, 2H), 4.23 (t, J=6.3 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.21-2.17 (m, 2H).
  • [0895]
    General procedure 5: trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (8.0 g, 19 mmol), B₂pin₂ (9.71 g, 38.2 mmol), KOAc (5.71 g, 57.4 mmol), PdCl₂(dppf).CH₂Cl₂ (1.39 g, 1.89 mmol), and anhydrous dioxane (160 mL). Purification: flash chromatography (9:1 hexane/EtOAc): yield 4.80 g (43%)-some pinacol contamination, used without further purification.
  • [0896]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.93 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.24 (m, 5H), 7.08 (d, J=7.8 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.11 (quin, J=6.2 Hz, 2H), 1.43 (s, 12H).

  7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

  • General procedure 8: 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol), MeNO₂ (16.6 g, 273 mmol), NaOH (3.64 g, 83 mmol), H₂O (180 mL), and THF (50 mL). Purification: flash chromatography (1:1 hexane/EtOAc). A47 was isolated as a light yellow oil: yield 15.9 g (50%).
  • ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).

  Alternative synthesis of 3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

  • General procedure 13: A47 (0.50 g, 1.4 mmol), 20% Pd(OH)₂/C (0.5 g, 1:1 w/w), AcOH (20 mL), and H₂O (0.24 mL). The filtrate was concentrated and treated with 4 N HCl to give the title compound as a colorless solid: yield 0.22 g (47%).
  • ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.42 (t, J=7.8 Hz, 1H), 6.97-6.90 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.20 (dd, J=9.2, 2.5 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 3.40 (dd, J=13.3, 2.7 Hz, 1H), 2.68 (dd, J=13.1, 9.2 Hz, 1H), 1.88-1.78 (m, 2H); MS (ESI): m/z=238 (M+1, positive).

3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

Synthesis of 3-(3-Benzyloxy-propoxy)-2-bromo-benzaldehyde (C)

• To a 5° C. solution of compound A (15.0 g, 0.075 mol), B (12.0 ml, 0.075 mol) and triphenylphosphine (19.6 g, 0.075 mol) in 200 ml of anhydrous THF was added DIAD (14.8 ml, 0.075 mol) drop by drop over a period of 15 minutes. The resulting solution was warmed to room temperature over a period of 5 h and the solvent was evaporated in vacuo. The residue was dissolved in 150 ml of EtOAc and the organic layer washed with water, brine and dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) generating 13.0 g (50% yield) of C [3-(3-benzyloxy-propoxy)-2-bromo-benzaldehyde].
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.41 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.32-7.25 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 4.54 (s, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.19-2.14 (m, 2H).

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (D)

• Compound C (8.9 g, 0.025 mol), KOAc (7.5 g, 0.076 mol), and bis(pinacolato)diboron (12.9 g, 0.051 mol) were dissolved in 50 ml of dry DMF and degassed for 30 minutes. To this was added PdCl₂(dppf).DCM (0.56 g, 0.76 mmol) and the contents were again degassed for 10 minutes and then heated to 90° C. for 4 h. An additional quantity of PdCl₂(dppf).DCM (0.2 g, 0.27 mmol) was added and heating was continued for an additional 2 h. The reaction was cooled to RT, filtered through celite and the solvent evaporated in vacuo. The residue was dissolved in DCM, washed with brine and the organic layer dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) provided 5.4 g (53% yield) of D [3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde].
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 9.91 (s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.32-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.11-2.08 (m, 2H), 1.44 (s, 12H). ESI+MS m/z, 397 (M+H)⁺.

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (E)

• To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
• ¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.49 (t, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.08 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 5.23 (dd, J=13.2, 2.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.47 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.04-2.00 (m, 2H). ESI-MS m/z, 356 [M−H]⁻. HPLC purity: 97.12% (MaxPlot 200-400 nm).

3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A46)
• Compound E (6.0 g, 0.016 mol) was dissolved in 50 ml of glacial acetic acid and to it was added Pd(OH)₂ on Carbon (20% metal content, 50% weight-wet) (5.2 g) and the content set for hydrogenation in a Parr shaker at 45 psi for 2 h. The reaction was checked for completion and the contents were filtered through Celite. The solvent was evaporated under reduced pressure at ambient temperature to yield a gummy material. To this three times was added 15 ml of dry toluene and evaporated yielding a fluffy solid. Purification was accomplished by preparative HPLC (C18 column, using acetonitrile and 0.1% AcOH/water solution) provided 1.5 g (45% yield) of compound A46 [3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol] with 0.33 mol % acetic acid (by HNMR).
• ¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.52 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.29 (dd, J=9.2, 2.4, 1H), 4.12 (t, J=6.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.48 (dd, J=13.2, 2.8 Hz, 1H), 2.80-2.74 (m, 1H), 1.92 (t, J=6.2 Hz, 2H). ESI+MS m/z, 238 [M+H]⁺. HPLC purity: 95.67% (MaxPlot 200-400 nm) and 96.22% (220 single wavelength).

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A49)

(3-Benzyloxy)-1-bromo-propane (2)
• A solution of 1 (160 g, 962.58 mmol) and triphenylphosphine (277.72 g, 1.1 eq, 1058.83 mmol) was dissolved in dichloromethane (800 mL) and cooled to 0° C. (ice/water). A solution of carbon tetrabromide (351.16 g, 1.1 eq, 1058.83 mmol) in dichloromethane (200 mL) was added dropwise and the mixture was left to stir at rt for 18 h. The dichloromethane solvent was evaporated to obtain a white solid. The solid was treated with an excess of hexanes, stirred for 1 h, filtered off and the solvent was evaporated to yield a crude product. The crude product was purified by silica gel column chromatography using 5-10% ethyl acetate and hexane to obtain 2 (199 g, 91%) as a colorless liquid.

3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde (4)

• To a solution of aldehyde 3 (27.47 g, 1 eq, 198.88 mmol) in 0.5 L of anhydrous DMSO was added sodium tertiary-butoxide (42.3 g, 2.2 eq, 440.31 mmol) portionwise. The reaction mixture was stirred at rt for 30 minutes. A brown color solution was formed. The reaction mixture was cooled to 0° C. and added bromide (56 g, 1.2 eq, 244.41 mmol) dropwise. The mixture was stirred at rt O/N. 90% of aldehyde 3 was converted to product. The reaction mixture was acidified to pH-3 and then extracted into EtOAc and washed with water. The organic layer was concentrated, the product was purified on silica gel column (EtOAc:hexane 80:20), to yield as compound 4 (48 g, 84.31% yield) (viscous oil).

Trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (5)

• To an ice cold solution of 4 (48 g, 1.0 eq, 167.72 mmol) in 200 mL of dry DCM was added pyridine (22 mL, 1.62 eq, 272.11 mmol). To the reaction mixture trifluoromethanesulfonic anhydride (33 mL, 1.16 eq, 196.14 mol) was added drop by drop. The mixture was stirred for 3 h at 0° C. The mixture was quenched with 500 mL of 1N HCl. The compound was then extracted into DCM (300 mL) and passed through a small silica gel column and concentrated to give compound 5 (57 g, 82% yield) as a pale yellow thick oil.

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (6)

• Compound 5 (65 g, 1.0 eq, 155.5 mmol), bis(pinacolato)diboron (86.9 g, 2.2 eq, 342.11 mmol), KOAc (45.7 g, 3.0 eq, 466.5 mmol) were mixed together and 600 mL of dioxane was added. The mixture was degassed with N₂ for 30 minutes and PdCl₂(dppf).DCM (5.7 g, 0.05 eq, 7.77 mmol) was added. The resulting slurry was heated to 90° C. overnight. The solvent was evaporated, EtOAc was added and then filtered through a pad of Celite. The organic layer was then washed with water (2×150 mL) and the solvent was evaporated. Column chromatography using 15% EtOAc/hexanes gave compound 6 (37.1 g, 61% yield).

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

• A solution of compound 6 (36 g, 1.0 eq, 90.91 mmol) in 50 mL of THF was cooled to 0° C. Nitromethane (16.6 g, 3.0 eq, 272.72 mmol) was added, followed by an aqueous solution of NaOH (3.64 g in 180 mL of H₂O). The reaction mixture was stirred at room temperature overnight. The starting material disappeared. The cyclization was afforded by adding 1N HCl until the solution was acidified and then extracted into EtOAc. The EtOAc was evaporated and the mixture was triturated with water and decanted. Column chromatography using 50% EtOAc/hexanes gave compound A47 (15.9 g, 50% yield).

(R) and (S) 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

• 4.82 g of (A47) was resolved via chiral HPLC using CHIRALPAK ADH column and CO₂:methanol (86:14) as eluent (25° C. UV detection was monitored at 230 nm. Two peaks, (S)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol and (R)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol were collected and evaporated to yellow oils. Analysis of the pooled fractions using a CHIRALPAK ADH 4.6 mm ID×250 mm analytical column and the same mobile phase provided the (S) enantiomer [0.7 g (29% yield)] with a retention time of 6.11 min and a 98.2% ee. The (R) enantiomer [1.0 g (41% yield)] had a retention time of 8.86 min and a 99.6% ee.

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A49)

• (A47) (550 mg, 1.57 mmol) was dissolved in 15 mL of glacial acetic acid. 280 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 128 mg of the acetate salt of (A49). The acetate salt was treated with 10 mL of 2N HCl and stirred for 3 hours. The material was lyophilized overnight to obtain 93 mg of the hydrochloride salt of (A49) (Yield 22%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.82 (dd, J=13.3, 9.0 Hz, 1H), 1.95-1.83 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 98.74% (MaxPlot 200-400 nm), 98.38% (220 nm); Chiral HPLC=95.14% ee.

OTHER ISOMER

(R)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A50)
• (R)-7-(3-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (0.70 g, 2.0 mmol) was dissolved in 20 mL of glacial acetic acid. 350 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 65 mg of pure compound. After purification, this acetate salt was combined with material from another reaction. This product was treated with 2N HCl (10 mL) and stirred for 3 h at rt. The material was lyophilized overnight to obtain 74 mg of the hydrochloride salt of (A50) (Yield 14%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.83 (dd, J=13.3, 8.6 Hz, 1H), 1.94-1.82 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 99.12% (MaxPlot 200-400 nm), 98.74% (220 nm); Chiral HPLC=98.82% ee.

REFERENCES

https://pubs.acs.org/cen/coverstory/89/8912cover3.html

https://www.yumpu.com/en/document/view/34463506/the-discovery-of-gsk2251052-a-first-in-class-boron-anacor

Anacor

Dr. R. G. Micetich’s research career began in 1963 as a Research Scientist with R & L Molecular Research Ltd. (established by Dr. R. U. Lemieux). This company later became Raylo Chemicals Ltd. Dr. Micetich served as the Research Director (Pharmaceutical Research) of Raylo. During the period from 1963 to 1980 Dr. Micetich’s group was involved in pharmaceutical research and process development work in antibiotics and in NSAI’s (non-steroidal anti-inflammatory agents). This work produced a drug “Mofezolac” – a NSAI which is now marketed in Japan by the Japanese company “Yoshitomi”. Market ~ U.S. $60 million.

In 1980, Dr. R. G. Micetich joined the Faculty of Pharmacy, University of Alberta as an Adjunct Professor working on projects for international big Pharma companies. The work with Taiho Pharmaceutical Company in Japan has produced another drug – a beta-lactamase inhibitor – “TAZOBACTAM” which is now marketed worldwide. This drug now produces annual sales of over US$ 1 billion.

In 1987, Dr. Micetich established a joint venture research company with Taiho, Japan called SynPhar. SynPhar had numerous patents worldwide in various therapeutic areas and many compounds and classes of compounds at various stages of development up to late preclinical.

In view of the significant growth opportunities for SynPhar and in response to the changing international market place for pharmaceuticals, Dr. Micetich acquired and transferred all the assets including intellectual property, equipment and fixtures from SynPhar to NAEJA Pharmaceutical Inc. in 1999. NAEJA is a private Albertan company, founded by the Micetich family which from an initial staff in August 1999 of 40, has grown to 130 and is still growing. NAEJA is a completely self-supporting private company with no venture capital, nor private, nor government funding. The majority of NAEJA employees hold Ph.D.’s. NAEJA has collaborative agreements with pharmaceutical companies around the world. Based on its own intellectual property, NAEJA also has a number of co-development agreements with biotech companies worldwide. Dr. Micetich laid the seeds of foundation for NAEJA and the company continues after his passing, building his legacy.

Dr. R. G. Micetich boasted over 100 publications in well know scientific journals and composed over 100 patents taken out in many countries…………..http://www.bioalberta.com/ron-micetich

more……….

RONALD G. MICETICH (1931-2006): A Scientific Career Ronald Micetich was born in Podanur, Coimbatore (South India). Following receipt of B.Sc. Honors (Chemistry, Loyola College, Madras) and M.A. (Chemistry, Madras University) degrees in India, Ron obtained a Ph.D. (Organic Chemistry, University of Saskatchewan, Canada) in 1962. Ron initiated his interest in microbiology while he was a postdoctoral fellow at the National Research Council of Canada. During the period 1963-1980, Ron held a number of industrial appointments where he rapidly advanced his industrial scientific career (research scientist → associate research director → acting research director → director pharmaceutical / agricultural research) at Raylo Chemicals in Edmonton, Alberta. In 1981 Ron joined the Faculty of Pharmacy & Pharmaceutical Sciences at the University of Alberta as an Adjunct Professor at which time a highly successful drug development program was established with Taiho Pharmaceuticals. This joint industrial collaboration led to the birth of SynPhar with Dr. Micetich as Chairman of the Board, President, CEO and Research Director (1987-1999). Ron, again as Chairman of the Board, CEO and Research Director, established NAEJA (North America, Europe, Japan, Asia) Pharmaceuticals in 1999 with a rollover of assets, including staff, equipment and intellectual property, from SynPhar Laboratories. What began as a full fledged pharmaceutical company with an extensive intellectual property portfolio and a proven track record evolved into an internationally respected pharmaceutical outsource service provider. NAEJA has carved a unique niche in the outsource industry offering extensive discovery experience and expertise. Today, NAEJA has over 120 staff that consists of over 90% scientists holding PhD degrees.,………….see link below

[PDF]RONALD G. MICETICH – University of Alberta – Journal …

https://ejournals.library.ualberta.ca/index.php/JPPS/article/…/4173

by T Yajima – ‎2008

Dr.Muhammed Majeed with Dr. Ronald Micetich, CEO, Naeja Pharmaceuticals, Edmonton Canada’.

////////////GSK 2251052, Epetraborole, Christopher Micetich, Ronald Micetich, Naeja Pharmaceuticals

B1(c2c(cccc2OCCCO)[C@H](O1)CN)O

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C₁₄H₁₀BNO_3, Average mass251.045 Da

Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis

crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis

A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.

Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129

http://www.sciencedirect.com/science/article/pii/S0960894X09002996

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis

http://www.google.co.in/patents/WO2006089067A2?cl=en

http://www.google.com/patents/US20090291917

…………..///////////crisaborole, AN 2728

AN-2718,

2,1-Benzoxaborole, 5-chloro-1,3-dihydro-1-hydroxy-

5-chloro-1,3-dihydro-l-hydroxy-2,1- benzoxaborole

5-Chloro-2,1-benzoxaborol-1(3H)-ol

CAS 174672-06-1
UNII: 810U6C2DGG

MW 168.3864, MF C7 H6 B Cl O2

MP…150-154 °C [WO 9533754]

MP 142-144 °C  [ jmc 2006, 49(15) 447]

M.p. 147- 149 °C. WO2013050591

Anacor Pharmaceuticals Inc,  INNOVATOR

Onychomycosis is a disease of the nail caused by yeast, dermatophytes, or other molds, and represents approximately 50% of all nail disorders. Toenail infection accounts for approximately 80% of onychomycosis incidence, while fingernails are affected in about 20% of the cases. Dermatophytes are the most frequent cause of nail plate invasion, particularly in toenail onychomycosis. Onychomycosis caused by a dermatophyte is termed Tinea unguium. Trichophyton rubrum is by far the most frequently isolated dermatophyte, followed by T. mentagrophytes. Distal subungual onychomycosis is the most common presentation of tinea unguium, with the main site of entry through the hyponychium (the thickened epidermis underneath the free distal end of a nail) progressing in time to involve the nail bed and the nail plate. Discoloration, onycholysis, and accumulation of subungual debris and nail plate dystrophy characterize the disease. The disease adversely affects the quality of life of its victims, with subject complaints ranging from unsightly nails and discomfort with footwear, to more serious complications including secondary bacterial infections.

Many methods are known for the treatment of fungal infections, including the oral and topical use of antibiotics (e.g., nystatin and amphotericin B), imidazole anti-fungal agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole, and non-imidazole fungal agents such as the allylamine derivatives terbinafme and naftifϊne, and the benzylamine butenafine.  However, onychomycosis has proven to be resistant to most treatments. Nail fungal infections reside in an area difficult to access by conventional topical treatment and anti-fungal drugs cannot readily penetrate the nail plate to reach the infection sites under the nail. Therefore, onychomycosis has traditionally been treated by oral administration of anti-fungal drugs; however, clearly this is undesirable due to the potential for side effects of such drugs, in particular those caused by the more potent anti-fungal drugs such as itraconazole and ketoconazole. An alternative method of treatment of onychomycosis is by removal of the nail before treating with a topically active anti-fungal agent; such a method of treatment is equally undesirable. Systemic antimycotic agents require prolonged use and have the potential for significant side effects. Topical agents have usually been of little benefit, primarily because of poor penetration of the anti-fungal agents into and through the nail mass.

• 51. Hui X, Baker SJ, Wester RC, In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci 2007;96(10):2622-31 [CrossRef], [PubMed], [Web of Science ®]
• 55. Mao W, Seiradake E, Crepin T, AN2718 has Broad Spectrum Antifungal Activity Necessary for the Topical Treatment of Skin and Nail Fungal Infections. J Am Acad Dermatol 2007:56(2 Suppl):AB124
• 56. ClinicalTrials.gov. Cumulative Irritation Test. Available from: http://clinicaltrials.gov/ct2/show/NCT00781664 [Cited 11 December 2011]

SYNTHESIS

Reduction of 2-bromo-5-chlorobenzoic acid with BH3/THF in THF gives 2-bromo-5-chlorobenzyl alcohol , which is protected as the methoxymethyl derivative  by treatment with MOM-Cl in the presence of DIEA in CH2Cl2. Metalation and boronylation of aryl bromide either with t-BuLi or BuLi (1,2,3,4) and (i-PrO)3B (4) or B(OMe)3  in THF affords the title compound .

Alternatively, reaction of 3-chlorobenzaldehyde  with p-toluenesulfonylhydrazide in MeOH provides tosyl hydrazone  which undergoes thermal decomposition in the presence of BBr3 and catalytic FeCl3 in refluxing CH2Cl2, followed by heating with aqueous NaOH to produce the title oxaborole compound .

You can construct from this…………….

OH       A

(2-bromo-5-chloro-phenyl)methanol (A)

 B

l-bromo-4-chloro-2-(methoxymethoxymethyl)benzene (B)

 1

5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

PATENT

WO 9533754

https://www.google.com/patents/WO1995033754A1?cl=en

Example 1 Preparation of 5-chloro-1,3-dihydro-l-hydroxy-2,1- benzoxaborole (Method B).

a)

Preparation of 3-chlorobenzaldehyde tosyl hydrazide

A solution of 3-chlorobenzaldehyde (15.56 parts; 0.109M;

Aldrich) in methylated spirits (40 ml) was added slowly at below 10°C to a stirred suspension of p-toluene-sulphonylhydrazide (20.7 parts;

0.108M) in methylated spirits (150 ml). The reaction mass was then stirred at 20 to 25°C for 1 hour and then heated at 60-70°C for 1M hours when the reactants and products dissolved. The solvent was then removed by rotary evaporation and the product was obtained as a solid which was slurried with ether and washed with n-hexane. Yield = 27.2 parts (81.5% theory) mpt 122-3°C. Elemental analysis

Theory 54.5%C; 4.2%H; 9.1%N

Found 54.5%C; 4.3%H; 9.1%N

Proton NMR (CDCl₃:ppm)

8.5, s, 1H(-NH-); 7.9, d, 2H(Tosyl aromatic); 7.7,s, 1H(CH=N); 7.5, s, 1H (aromatic); 7.2-7.4, m, 5H(Tosyl aromatic); 2.3, s, 3H(-CH₃) b) Preparation of title compound

A suspension of anhydrous ferric chloride catalyst (0.75 parts, Fisons) in dry dichloromethane (20 ml) was added at 20 to 25°C simultaneously with boron tribromide (25 parts, 0.1M, Aldrich) in dry dichloromethane (100 mis) to a stirred suspension of the hydrazide from a) above (10.18 part, 0.033M) in dry dichloromethane (160 mis) under a nitrogen blanket. The reactants were then stirred under reflux and the evolved hydrogen bromide trapped under aqueous sodium hydroxide. After 3 hours stirring at reflux, the reactants were allowed to stand at 20- 25°C for 48 hours and then stirred under reflux for a further 4 hours. The reaction mass was then cooled and the solvent removed by rotary evaporation. The solid obtained was then stirred under reflux with 2N sodium hydroxide solution (160 ml) for 3 hours. The brown aqueous suspension was extracted with dichloromethane (50 ml), screened and then acidified to about pH 2 by addition of 2N hydrochloric acid. The solid was filtered, slurried with dichloromethane (400 ml) and then washed with a saturated solution of sodium bicarbonate followed by water.

Yield = 24 parts (43% theory). The solid was slurried in hot

dichloromethane and filtered to give 0.36 parts oxaborole mp 140-45°C. The dichloromethane solution was cooled and the solid filtered giving a further 0.35 parts oxaborole mp 146-8°C. The solids were combined and recrystallised from methylated spirits.

Yield = 0.51 parts (9.2% theory) mp 150-4°C.

Elemental Analysis

Theory 49.8%C, 3.5%H, 21.06%C1

Found 49.5%C, 3.5%H, 21.0%C1

Proton NMR (CDCl₃) ppm

9.3, s, 1H(-OH); 7.5, d, s, d, 3H(aromatic);

5.0, s, 2H(-CH₂-O).

PATENT

WO 2006089067

http://www.google.co.in/patents/WO2006089067A2?cl=en

Analytical data for exemplary compounds of structure I are provided below.

4.2. a 5-Chloro-1.3-dihydro-l -hvdroxy-2J-benzoxaborole (Cl)  M.ρ. 142-15O⁰C. MS (ESI): m/z = 169 (M+l, positive) and 167 (M-I, negative). HPLC (220 nm): 99% purity. ¹H NMR (300 MHz, DMSO-d₆): δ 9.30 (s, IH), 7.71 (d, J = 7.8 Hz, IH), 7.49 (s, IH), 7.38 (d, J = 7.8 Hz, IH) and 4.96 (s, 2H) ppm.

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm0603724?source=chemport

COMPD IS 19d

5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (19d) This compound was made from 18d in the same manner as compound 19b (triturated with hexane, 75% yield):: mp 142-144°C. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 4.96 (s, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 9.30 (s, 1H); ESI-MS m/z 167 (M-H)- ; HPLC purity 99.0%; Anal (C7H6BClO2 ⋅ 0.1H2O) C, H

precursor 18d

2-Bromo-5-chloro-1-(methoxymethoxymethyl)benzene (18d) To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0o C and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was S6 mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88%): 1 H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J = 8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H). 2-Bromo-5-chlorobenzyl alcohol obtained above was dissolved in CH2Cl2 (150 mL) and cooled to 0o C on an ice bath. To this solution under nitrogen were added in sequence i-Pr2NEt (5.4 mL, 31 mmol) and chloromethyl methyl ether (2.0 mL, 26 mmol). The reaction mixture was stirred overnight at room temperature and washed with NaHCO3-saturated water and then brine. The residue after rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 18d (4.67 g, 85%) as a colorless oil: 1 H NMR (300 MHz, DMSO-d6): δ (ppm) 3.30 (s, 3H), 4.53 (s, 2H), 4.71 (s, 2H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (dd, J = 2.4, 0.6 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H).

PATENT

http://www.google.com/patents/WO2013050591A2?cl=en

EXAMPLES Example 1 : Preparation of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

Step 1 : Preparation of (2-bromo-5-chloro-phenyl)methanol (A)

A solution of borane-tetrahydrofuran complex in THF (0.15 L, 1.5 eq) was added dropwise to a solution of 2-bromo-5-chlorobenzoic acid (24 g) in anhydrous tetrahydrofuran (0.24 L) at 0°C and under argon atmosphere. The reaction mixture was stirred at room temperature for 16 h, before being slowly poured onto 0.10 L of a 2N aqueous solution of hydrogen chloride at 0°C. The mixture was stirred for 15 minutes and the volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a IN aqueous solution of sodium hydroxide and then water. After drying over sodium sulfate, filtration and concentration under reduced pressure, the crude product was purified by column chromatography; 23.2 g; M.p. 79-80 °C.

Step 2: Preparation of l-bromo-4-chloro-2-(methoxymethoxymethyl)benzene (B)

(2-bromo-5-chloro-phenyl)methanol (A, 12 g) was dissolved in dichloromethane (0.35 mL) and cooled to 0 °C. Under argon atmosphere, diisopropylethylamine (14 mL, 1.5 eq) and chloromethyl methyl ether (5.0 mL, 1.2 eq) were added. After 1 night of stirring at room temperature, the crude reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried over sodium sulfate and evaporated under reduced pressure. Purification by column chromatography afforded 10.5 g of l-bromo-4-chloro-2- (methoxymethoxymethyl)benzene (B) as an oil.

Step 3: Preparation of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1)

To a solution of (B) (6.0 g) in anhydrous tetrahydrofuran (120 mL) at -78°C was added dropwise a solution of butyllithium in hexane (15.6 mL, 1.1 eq). To the resulting yellow- brown solution trimethyl borate (2.5 mL, 1.0 eq) was injected in one portion and the cooling bath was removed. The mixture was warmed gradually for 30 minutes. After stirring at room temperature for 2 hours, 8.0 ml of a 6N aqueous solution of hydrogen chloride were added and the reaction mixture was left stirring overnight at room temperature. Evaporation of the volatiles gave a residue which was taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate and then evaporated. The crude product was crystallized from ethyl acetate to give 1.4 g of 5-chloro-l-hydroxy-3H-2,l-benzoxaborole (1) as a white powder. Purification of the filtrate by column chromatography afforded 1.2 g more of 1. M.p. 147- 149 °C.

PATENT

http://www.google.fr/patents/WO2010110400A1?cl=en&hl=fr

Reference Example 187
5-chloro-2,1-benzoxazine ball roll -1 (3H) – All

5-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde 8.50g synthesized in Reference Example 185 was dissolved in methanol 100ml, borohydride Sodium 2.40g was added, and after stirring for 30 minutes at room temperature and stirred for 2 hours at 60 ℃. The reaction solution was concentrated, and the organic layer after the layers were separated with ethyl acetate and saturated aqueous ammonium chloride and then concentrated under reduced pressure. The residue was added 100ml of tetrahydrofuran, and 6N hydrochloric acid 60ml, and stirred for 8 hours at room temperature.After the reaction mixture was dried and the organic layer was extracted with ethyl acetate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound 9.6g. ¹ H-NMR (400MHz, _{DMSO-d 6)} ^δ: 4.95 (2H, s), 7.36 (1H, dd, J = 8.0,1.6Hz), 7.47 (1H, s) , 7.70 (1H, d, J = 8.0Hz), 9.28 (1H, s).

PATENT

http://www.google.com/patents/WO2008070257A2?cl=en

5-Fluoro-l,3-dihvdro-l-hvdroxy-2, 1-benzoxaborole (Cl)

1-Hydroxy-dihydrobenzoxaboroles, such as Cl, were synthesized as shown in Scheme 1. The protected o-bromobenzyl alcohol derivative (18), prepared from 16 or 17, was converted into the corresponding phenyl boronic acid. Deprotection of the methoxymethyl ether using hydrochloric acid followed by spontaneous cyclization gave the target compounds.

Scheme 7

Conditions (a) NaBH₄, MeOH, rt (when X = H ), or BH₃-THF, THF, rt (when X = OH), (b) MeOCH₂CI, /-Pr₂NEt, CH₂CI₂, rt, (c) MeMgBr, THF, -78 ⁰C to rt , (d) NBS, AIBN, CCI₄, reflux, (e) NaOAc, DM F, 70 ⁰C, (f) NaOH, MeOH, reflux, (g) n-BuLι, (/-PrO)₃B, THF, -78⁰C to rt, (h) 6N HCI, THF, rt

References

1. Hui, Xiaoying; Journal of Pharmaceutical Sciences 2007, 96(10), Pg2622-2631 
2.  Baker, Stephen J.; Journal of Medicinal Chemistry 2006, 49(15), Pg4447-4450 
3. Austin, Peter William; WO 9533754 A1 1995 CAPLUS

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

http://apisynthesisint.blogspot.in/p/borole-compds.html

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

//////////AN-2718,   Borole, PHASE 2

B1(c2ccc(cc2CO1)Cl)O

SEE           http://www.google.co.in/patents/US20100298257

Example 28

• Chemical Purity Determination by HPLC
• Various HPLC conditions can be used to determine the chemical purity of the compounds disclosed herein. One such example is disclosed above in relation to the thermodynamic aqueous solubility studies. Another example is disclosed below.
• HPLC Conditions:
• • LC: Waters Alliance 2695 Separations Module, Waters 2996 PDA detector and Waters Empower 2 Software (Version 6.00)
  • Column: Phenomenex Luna C18(2); 4.6×50 mm; 3 μm
  • Flow rate: 1.2 mL/min
  • Injection Volume: 10 μL
  • Mobile phase: Solvent A: 95% Water with 5% Methanol and 10 mM Ammonium Acetate; pH˜5.3
  • Gradient Solvent B: MeOH with 10 mM Ammonium Acetate hold at 0% B 3 min
    • 0-47% B 3-4 min
    • hold at 47% B 4-10 min
    • 47%-74% B 10-11 min
    • hold at 74% B 11-13.5 min
    • return to 0% B 13.5-13.6 min
    • hold at 0% B 13.6-15.5 min
• Under these conditions, the purity of 4, R_P-4, and S_P-4 was determined to be ˜99.6, ˜99%, and ˜99.5%, respectively. It is noted that higher purities can be realized by optimizing the methods disclosed above.
• Inspection of the XRPD diffractograms shows that the two crystalline single diastereoisomers gave clearly different XRPD patterns. Additionally, there was a clear difference in the melting point of the two crystalline diastereoisomers, with R_P-4 having a considerably higher onset than S_P-4 (136° C. vs. 94° C.).
• Example 29Additional Separation Methods
• The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, R_P-4 and S_P-4.

• Preparative Method:	Analytical Method:
  Chiralpak AS-H (2 × 25 cm) SN# 07-8656	Chiralpak AS-H (25 ×
  	0.46 cm)
  20% methanol/CO2 (100 bar)	20% methanol/CO2 (100 bar)
  50 ml/min, 220 nm.	3 ml/min, 220 nm.
  Conc.: 260 mg/30 ml methanol,
  inj vol.: 1.5 ml

• The following SFC separation (conditions listed below) yielded adequate separation of a mixture of the diastereomers, R_P-4 and S_P-4.
• Preparative Method:	Analytical Method:
  Chiralpak IA(2 × 15 cm) 802091	Chiralpak IA(15 × 0.46 cm)
  30% isopropanol(0.1% DEA)/CO2,	40% methanol(DEA)/CO2, 100 bar
  100 bar
  60 mL/min, 220 nm.	3 mL/min, 220 nm.
  inj vol.: 2 mL, 20 mg/mL methanol

• TABLE 16
  Summary of results from the batch characterization of RP-4, 4, and SP-4.
  Analysis	RP-4	4	SP-4
  Proton NMR	Single diastereoisomer	1:1 Mixture of	Single diastereoisomer
  		diastereoisomers
  XRPD	Crystalline – different	Amorphous	Crystalline – different
  DSC	from SP-4	Endotherm; 59° C.	from RP-4
  	Endotherm; melt – 136° C.		Endotherm; melt – 94° C.
  TGA	No wt loss,	No wt loss, decomposition	No wt loss,
  	decomposition >240° C.	>240° C.	decomposition >240° C.
  IR	See above	See above	See above
  Aq Solubility	1.58	6.11	5.65
  (mg · ml−1)
  HPLC Purity	96.9%	99.6%	99.5%
  40° C./75% RH	No form change	Deliquescence inside 1.5 h	Deliquescence inside 4.5 h
  25° C./53% RH	—	Deliquescence	No form change
  GVS	Non-hygroscopic up to 90%	—	Non-hygroscopic up to 60%
  	RH		RH

Example 27Thermodynamic Aqueous Solubility
• Aqueous solubility was determined by suspending a sufficient amount of compound in water to give a maximum final concentration of ≧10 mg.ml⁻¹ of the parent free-form of the compound. The suspension was equilibrated at 25° C. for 24 hours then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg.ml⁻¹ in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
• TABLE 14
  HPLC Method Parameters for Solubility Measurements
  Type of method:	Reverse phase with gradient elution
  Column:	Phenomenex Luna, C18 (2) 5 μm 50 × 4.6 mm
  Column Temperature	25
  (° C.):
  Standard Injections (μl):	1, 2, 3, 5, 7, 10
  Test Injections (μl):	1, 2, 3, 10, 20, 50
  Detection:	260, 80
  Wavelength,
  Bandwidth (nm):
  Flow Rate (ml · min−1):	2
  Phase A:	0.1% TFA in water
  Phase B:	0.085% TFA in acetonitrile
  	Time (min)	% Phase A	% Phase B
  Timetable:	0.0	95	5
  	1.0	80	20
  	2.3	5	95
  	3.3	5	95
  	3.5	95	5
  	4.4	95	5

• [0306]
  Analysis was performed under the above-noted conditions on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1.
• TABLE 15
  Aqueous solubility result for RP-4, 4, and SP-4.
  	pH of Unfiltered
  Sample ID	mixture	Solubility/mg · ml−1	Comments
  RP-4	7.12	1.58	Suspension
  4	7.03	6.11	Residual solid
  SP-4	6.88	5.65	Residual solid

READ

http://www.us.edu.pl/uniwersytet/jednostki/wydzialy/chemia/acta/ac14/zrodla/14_AC14.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291777/

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((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4′-​[[[6-​[(2R,​5S)​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​pyridinyl]​carbonyl]​amino]​-​2′-​(trifluoromethoxy)​[1,​1′-​biphenyl]​-​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, Carbamic acid, methyl ester

Carbamic acid, N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4′-​[[[6-​[(2R,​5S)​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​pyridinyl]​carbonyl]​amino]​-​2′-​(trifluoromethoxy)​[1,​1′-​biphenyl]​-​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, methyl ester

CAS 1374883-22-3, 819.87, C₄₁ H₄₈ F₃ N₉ O₆

Theravance, Inc.  INNOVATOR

To treat hepatitis C virus infection

• ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (compound 1):
• Recent estimates place the number of people infected with the hepatitis C virus (HCV) worldwide at more than 170 million, including 3 million people in the United States. The infection rate is thought to be roughly 4 to 5 times that of the human immunodeficiency virus (HIV). While in some individuals, the natural immune response is able to overcome the virus, in the majority of cases, a chronic infection is established, leading to increased risk of developing cirrhosis of the liver and hepatocellular carcinomas. Infection with hepatitis C, therefore, presents a serious public health problem.
  The virus responsible for HCV infection has been identified as a positive-strand RNA virus belonging to the family Flaviviridae. The HCV genome encodes a polyprotein that during the viral lifecycle is cleaved into ten individual proteins, including both structural and non-structural proteins. The six non-structural proteins, denoted as NS2, NS3, NS4A, NS4B, NS5A, and NS5B have been shown to be required for RNA replication. In particular, the NS5A protein appears to play a significant role in viral replication, as well as in modulation of the physiology of the host cell. Effects of NS5A on interferon signaling, regulation of cell growth and apoptosis have also been identified. (Macdonald et al., Journal of General Virology (2004), 85, 2485-2502.) Compounds which inhibit the function of the NS5A protein are expected to provide a useful approach to HCV therapy.
  Commonly-assigned U.S. Provisional Application Nos. 61/410,267, filed on Nov. 4, 2010, 61/444,046, filed on Feb. 17, 2011, and 61/492,267, filed on Jun. 1, 2011, and U.S. application Ser. No. 13/288,216, filed on Nov. 3, 2012 disclose pyridyl-piperazinyl compounds

SYNTHESIS

CLICK ON IMAGES FOR CLEAR VIEW

PATENT

WO-2013/165796

https://www.google.co.in/patents/WO2013165796A1?cl=en

PATENT

http://www.google.com/patents/US20130295048

crystalline compound 1 is advantageously prepared directly from the crude product of the final step of the synthesis of compound 1, illustrated in the following scheme, without purification of the amorphous form.

As described in Example 3 below, ((S)-1-{(S)-2-[4-(4′-{[6-(2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl}-amino]-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2) is reacted with methylaminoformyl chloride to provide a crude product, which is recovered by conventional extraction and drying. The reaction is typically performed in the presence of an excess of base, in an inert diluent such as dichloromethane. Next, methanol is added to the crude product followed by the slow addition of water in a ratio of methanol:water of about 2.5:1 to about 2.7:1 to form a crystallization mixture. Seeds of crystalline compound 1 are added about halfway through the water addition. The crystallization mixture is stirred for a period of several days to form crystalline compound 1. To increase purity, the product can be recrystallized by a similar process: the crystalline compound is dissolved in methanol, water and seeds are added, such that the ratio of methanol to water in the mixture is about 2.5:1, and the mixture is stirred for a period of at least 12 hours to provide crystalline compound 1, which is recovered conventionally

Preparation 1: (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester(a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide
• To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1:4 ethanol:water (2×25 mL) to give the title intermediate as a white solid (3.87 g). Analytical HPLC: Retention time=21.3 min.

(b) (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

• The product of the previous step (3.86 g, 10.2 mmol) (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.62 g, 12.2 mmol) and N,N-diisopropylethylamine (5.32 mL, 30.5) was dissolved in DMSO (12 mL). The reaction mixture heated at 120° C. for 3 h, diluted with EtOAc (100 mL), washed with water, and saturated NH₄Cl, water, and brine. The reaction mixture was evaporated to about 40% volume and 3 M HCl in cyclopentyl methyl ether (4.24 mL, 12.7 mmol) was added slowly. Seeds from a previous run at smaller scale were added and the reaction mixture was stirred for 2 days and filtered to provide the HCl salt of the title intermediate (5.15 g, 83% yield). Analytical HPLC: Retention time=21.1 min.

Preparation 2: (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

• To a solution of ((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.05 g, 6.8 mmol), bis(pinacolato)diboron (1.81 g, 7.1 mmol) and potassium acetate (1.00 g, 10.2 mmol) was added nitrogen sparged toluene (15 mL). The resulting mixture was sparged with nitrogen and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (Pd catalyst) (0.17 g, 0.204 mmol) was added. The reaction mixture was stirred at 90° C. overnight.
• The reaction mixture was cooled to RT and to this mixture was added nitrogen sparged water (7.6 mL), potassium carbonate (5.16 g, 37.3 mmol), and (2S,5R)-4-[5-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (4.35 g, 7.13 mmol). The reaction mixture was stirred at 95° C. overnight.
• Another portion of the Pd catalyst used above (0.08 g, 0.10 mmol) was added to the reaction mixture. After 5 h, the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with water (150 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give a black residue (6.7 g), which was purified by silica gel chromatography (eluted with 50-100% EtOAc/hexane) to provide the title intermediate (5.3 g, 90% yield). Analytical HPLC: Retention time=14.7 min.

Preparation 3: ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

• Acetyl chloride (63.2 mL, 888 mmol) was added to ethanol (360 mL) and stirred at RT for 1 h. To the resulting HCl solution was added a solution of (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (73 g, 84 mmol) in ethanol (360 mL). The reaction mixture was stirred at RT overnight.
• The reaction mixture was concentrated to dryness (124 g crude). Water 500 mL) was added and the mixture was extracted with EtOAc (2×500 mL). The aqueous layer was adjusted to pH 4 with 1:1 NaOH:water. Ethyl acetate (400 mL) and sat. aq. Na₂CO₃ (100 mL) were added and the layers were separated. The organic layer was dried over Na₂SO₄ and evaporated to give the title intermediate (62.8 g; 88% yield). Analytical HPLC: Retention time=10.0 min.

Example 1Amorphous ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

(a) ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tri-HCl

• Acetyl chloride (0.71 mL, 10.0 mmol) was added to ethanol (7 mL) and stirred at RT for 1 h. The resulting HCl solution was added to a solution of (2S,5R)-4-[5-(4′-{2-[(5)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.55 g, 1.8 mmol) in ethanol (7 mL). The reaction mixture was warmed to 35° C. and stirred overnight. The mixture was concentrated to dryness, and chased with DCM to provide the crude tri-HCl salt of the title intermediate (1.57 g) which was used directly in the next step. HPLC method C: Retention time=10.0 min.

(b) Amorphous ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

• To a solution of the product of the previous step (1.57 g crude, ca. 1.80 mmol) and N,N-diisopropylethylamine (3.14 mL, 18.0 mmol) in DCM (24 mL) was slowly added 1 M methylaminoformyl chloride in DMA (1.8 mL). The reaction mixture stirred at RT for 1 h, and then 1 M methylaminoformyl chloride in DMA (1.8 mL) was added. The reaction was quenched with sat. aq. NaHCO₃ and the reaction mixture was stirred for 20 min. The layers were separated and the organic layer was dried and evaporated to give a residue. To the residue was added methanol (15 mL) followed by 2 N LiOH/water (3 mL). The reaction mixture was stirred at RT for 1 h, diluted with water, extracted with DCM (80 mL), dried, and evaporated to give a crude product which was purified by silica gel chromatography (40 g silica, 2-8% MeOH/DCM) to provide the title compound (0.93 g, 63% yield). Analytical HPLC: Retention time=11.0 min.

HPLC

Analytical HPLC Method
• • • Column: Zorbax Bonus-RP 3.5 μm. 4.6×150 mm
    • Column temperature: 35° C.
    • Flow rate: 1.0 mL/min
    • Mobile Phases: A=Water/ACN (98:2)+0.1% TFA
      • B=Water/ACN (10:90)+0.1% TFA,
    • Injection volume: 100-1500 μL
    • Detector wavelength: 214 nm
    • Sample preparation: Dissolve in 1:1 ACN:water
    • Gradient: 29 min total (time (min)/% B): 0.5/10, 24/90, 25/90, 26/10, 29/10

  http://www.google.com/patents/US20130295048

About Theravance Biopharma
The mission of Theravance Biopharma (NASDAQ: TBPH) is to create value from a unique and diverse set of assets: an approved product; a development pipeline of late-stage assets; and a productive research platform designed for long-term growth.

Our pipeline of internally discovered product candidates includes potential best-in-class opportunities in underserved markets in the acute care setting, representing multiple opportunities for value creation. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S., Europe and certain other countries for certain difficult-to-treat infections. Revefenacin (TD-4208) is an investigational long-acting muscarinic antagonist (LAMA) being developed as a potential once-daily, nebulized treatment for COPD. Axelopran (TD-1211) is an investigational potential once-daily, oral treatment for opioid-induced constipation (OIC). Our earlier-stage clinical assets represent novel approaches for potentially treating diseases of the lung and gastrointestinal tract and infectious disease. In addition, we have an economic interest in future payments that may be made by GlaxoSmithKline plc pursuant to its agreements with Theravance, Inc. relating to certain drug development programs, including the combination of fluticasone furoate, umeclidinium and vilanterol (the “Closed Triple”).

With our successful drug discovery and development track record, commercial infrastructure, experienced management team and efficient corporate structure, we believe that we are well positioned to create value for our shareholders and make a difference in the lives of patients.
For more information, please visit www.theravance.com.

THERAVANCE®, the Cross/Star logo, MEDICINES THAT MAKE A DIFFERENCE® and VIBATIV® are registered trademarks of the Theravance Biopharma group of companies.

Journal of Medicinal Chemistry (2014), 57(5), 1643-1672……….

(e)Thalladi, V. R.; Nzerem, J.; Huang, X.; Zhang, W. Crystalline form of a pyridyl-piperazinyl hepatitis C virus inhibitor. World Patent Application WO-2013/165796, November 7, 2013.

PATENT

WO 2012061552

http://www.google.com.ar/patents/WO2012061552A1?cl=en

Preparation 28: ((S)-l-{(S)-2-[4-(4′-{[6-((2_JR,5S)-2,5-Dimethyl-piperazin-l- yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2- yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

A mixture of [(5)-2-methyl-l-((5)-2- {4-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-lH-imidazol-2-yl}-pyrrolidine-l-carbonyl)-propyl]- carbamic acid methyl ester (86 mg, 0.17 mmol) and (25′,5R)-4-[5-(4-bromo-3- trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-l-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol, Preparation 27) was dissolved in 1,4-dioxane (1.8 mL, 23 mmol) and water (0.25 mL, 14 mmol). Cesium carbonate (170 mg, 0.52 mmol) was added. The reaction mixture was sparged with nitrogen and then

tetrakis(triphenylphosphine)palladium(0) (12.1 mg, 0.011 mmol) was added. The reaction mixture was sealed under nitrogen and heated at 95 °C overnight. The reaction mixture was extracted with ethyl acetate/water, the organic layer was dried over sodium sulfate and concentrated to produce an orange oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane (2 mL, 7 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated and evaporated with ethyl acetate (2 x) to produce the HCl salt of the title compound as a yellow solid which was purified by preparative HPLC to provide the tri-TFA salt of the title compound (150 mg, 30 % overall yield), (m/z): [M+H] calcd for

763.35 found 763.7.

Example 29 ((S)-l-{(S)-2-[4-(4′-{[6-((2_JR,5S)-2,5-Dimethyl-4- methylcarbamoyl-piperazin-l-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy- biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)- carbamic a

To a solution of ((5)- l – {(5)-2-[4-(4′- { [6-((2R,55)-2,5-dimethyl-piperazin- l-yl)- pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl]- pyrrolidine- l-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester tri-TFA (1 1.4 mg, 0.01 1 mmol; Preparation 28) and N,N-diisopropylethylamine (18 uL, 0.1 1 mmol) dissolved in DMA (0.4 mL, 4 mmol) was added 1.0 M methyl isocyanate in toluene (10 uL, 0.01 mmol). The reaction mixture was stirred at RT overnight, concentrated, dissolved in 1 : 1 acetic acid:water (1.5 mL) and purified by preparative HPLC to provide the di-TFA salt of the title compound (7.1 mg). (m/z): [M+H]⁺ calcd for C₄₁H₄₈F₃N₉0₆ 820.37 found 820.5.

Alternative synthesis of ((5)-1-{(5)-2-[ -(4′-{[6-((2Λ,ί» 2,5- Dimethyl-4-methylcarbamoyl-piperazin-l-yl)-pyridine-3-carbonyl]-amino}-2′- trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2- methyl-propyl)-carbamic acid methyl ester

(a) N-(^‘4-Bromo-3-trifluoromethoxy-phenyl -6-fluoro-nicotinamide

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1 :4 ethanohwater (2 x 25 mL) to give the title intermediate as a white solid (3.87 g). HPLC method C: Retention time = 21.3 min.

(b) (25^,,5R)-4-r5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl) -pyridin-2-yl1-2,5- dimethyl-piperazin – 1 -carboxylic acid fe/t-butyl ester

The product of the previous step (3.86 g, 10.2 mmol) (2S,5R)-2,5-dimethyl- piperazine-1 -carboxylic acid tert-butyl ester (2.62 g, 12.2 mmol) and N,N- diisopropylethylamine (5.32 mL, 30.5) was dissolved in DMSO (12 mL). The reaction mixture heated at 120 °C for 3 h, diluted with EtOAc (100 mL), washed with water, and saturated NH₄C1, water, and brine. The reaction mixture was evaporated to about 40% volume and 3 M HCl in cyclopentyl methyl ether (4.24 mL, 12.7 mmol) was added slowly. Seeds from a previous run at smaller scale were added and the reaction mixture was stirred for 2 days and filtered to provide the HCl salt of the title intermediate (5.15 g, 83 % yield). HPLC method C: Retention time = 21.1 min (c) (2 .5R)-4 5-(4′-{2 ffl -((5^f)-2-Methoxycarbonylamino-3-methyl-butyrvn- pyiTolidin-2-yl1-lH-imidazol-4-yl}-2-tri

pyridin-2- -2,5-dimethyl-piperazine-l-carboxylic acid fert-butyl ester

To a solution of ((5′)-l-{(5^,)-2-[4-(4-bromo-phenyl)-lH-imidazol-2-yl]- pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.05 g, 6.8 mmol;), bis(pinacolato)diboron (1.81 g, 7.1 mmol) and potassium acetate (1,00 g, 10.2 mmol) was added nitrogen sparged toluene (15 mL). The resulting mixture was sparged with nitrogen and l,l’-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (Pd catalyst) (0.17 g, 0.204 mmol) was added. The reaction mixture was stirred at 90 °C overnight.

The reaction mixture was cooled to RT and to this mixture was added nitrogen sparged water (7.6 mL), potassium carbonate (5.16 g, 37.3 mmol). The reaction mixture was stirred at 95°C overnight.

Another portion of the Pd catalyst used above (0.08 g, 0.10 mmol) was added to the reaction mixture. After 5 h, the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with water (150 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give a black residue (6.7 g), which was purified by silica gel chromatography (eluted with 50-100 % EtOAc/hexane) to provide the title intermediate (5.3 g, 90 % yield). HPLC method C: Retention time = 14.7 min.

(d) (ffl ffl-2 4-(4′ r6-((2R,5^-2,5-Dimethyl-piperazin-l-vn-pyridine-3-carbonyl1- amino}-2′ rifluoromethoxy-biphenyl-4-yl -lH-imidazol-2-yl1-pyrrolidine-l- carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Acetyl chloride (2.57 mL, 36.2 mmol) was added to ethanol (18 mL) and stirred at RT for 1 h. To the resulting HQ solution was added a solution of the product of the previous step (3.90 g, 4.5 mmol) in ethanol (18 mL). The reaction mixture was warmed to 35 °C and stirred overnight. Acetyl chloride (1.28 mL, 18.1 mmol) was added to ethanol (7.8 mL) and stirred for 30 min. The resulting HC1 solution was added to the reaction mixture at 35 °C. The temperature was raised to 40 °C. The mixture was concentrated to dryness chased by dichloromethane to provide the crude tri-HCl salt of the title intermediate (5.4 g) which was used directly in the next step. HPLC method C: Retention time = 10.1 min.

(e) ((^-l- {(^-2-r4-(4′- {r6-((2R.5^-2.5-Dimethyl-4-methylcarbamoyl-piperazin-l-yl)- pyridine-3-carbonyl1-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl1- pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

To a solution of the product of the previous step (5.4 g crude, ca. 3.96 mmol) and N,N-diisopropylethylamine (6.89 mL, 39.6 mmol) in DCM (52 mL) was slowly added 1 M methylaminoformyl chloride in DMA (4.3 mL). The reaction mixture stirred at room temperature for 1 h, and then water (50 mL) was added. The organic layer was washed with saturated NH₄C1 and then brine, dried over Na₂S0₄ and evaporated to give 5.2 g crude product, which was purified by silica gel chromatography (133 g silica, 2 to 8 % methanol/DCM for 15 min then 8 % methanol/DCM for 40 min) to provide the title compound (2.4 g, 74 % yield). HPLC method C: Retention time 1 1.2 min

I AM NOT SURE OF BELOW DATA, It is a cut paste for TD 6450 , NOT ABLE TO CONNECT CAS 1374883-22-3 WITH TD 6450

IF YOU HAVE A STRUCTURE PIC FOR THE SAME MAIL ME amcrasto@gmail.com, call +919323115463

POSTER

50th Annu Meet Eur Assoc Study Liver (EASL) (April 22-26, Vienna) 2015, Abst P0898

http://ilc-congress.eu/abstract_25_04/ILC2015-abstract-book-25-04-Saturday.pdf

P0898

TD-6450,

A NEXT GENERATION ONCE-DAILY NS5A INHIBITOR, HAS POTENT ANTIVIRAL ACTIVITY FOLLOWING A 3-DAY MONOTHERAPY STUDY IN GENOTYPE 1 HCV INFECTION

E. Lawitz1, M. Rodriguez-Torres2, R. Kohler3, A. Amrite3, C. Barnes3, M.L.C. Pecoraro3, J. Budman3, M. McKinnell3, C.B. Washington3. 1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States; 2Fundacion de Investigacion, San Juan, Puerto Rico; 3Theravance Biopharma, South San Francisco, CA, United States

E-mail: cwashington@theravance.com

Background and Aims: TD-6450 is a next generation HCV NS5A inhibitor with superior in vitro potency against resistanceassociated variants (RAVs) encountered with first-generation NS5A inhibitors. This study evaluated the safety, pharmacokinetics (PK) and antiviral activity of TD-6450 following multiple oral doses in HCV patients

Theravance Biopharma Announces Positive Results From Phase 1 Proof-of-Concept Study of TD-6450, an NS5A Inhibitor to Treat Hepatitis C

240 mg Achieved a Median Maximal Viral Load Decline of 4.9 Log10 IU/mL Following Three Daily Doses in Genotype 1a Patients

Theravance Biopharma and Trek Therapeutics Announce Initiation of Phase 2a Trial of TD-6450, an NS5A Inhibitor to Treat Hepatitis C

Study Being Conducted by Trek Therapeutics Following Licensing of Worldwide Rights to Drug Candidate From Theravance Biopharma

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.

SERTINDOLE

Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States.

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.^[4]

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,^[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.^[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.^[12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.^[13] Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.^[14] As of October 2010, the drug has not been approved by the FDA for use in the USA.^[15]

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996,^[12] but its marketing authorization was suspended by the European Medicines Agency in 1998^[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA’s CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.^[17][18]

Synthesis

PAPER

I. V. Sunil Kumar¹, G. S. R. Anjaneyulu¹ and V. Hima Bindu²

¹Research and Development Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
²Institute of Science and Technology, JNTU, Hyderabad-500072, India

Corresponding author email

Associate Editor: N. Sewald

Beilstein J. Org. Chem. 2011, 7, 29–33.

SEE AT http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-5

Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone. Its literature synthesis (Scheme 1) [1-5] involves the copper catalyzed N-arylation of 5-chloroindole (11) with 4-fluorobromobenzene (12). The product, 5-chloro-1-(4-fluorophenyl)indole (13), on treatment with 4-piperidinone hydrochloride monohydrate (14) under acidic conditions affords 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride (15). Reduction of 15 in the presence of platinum oxide yields 5-chloro-1-(4-fluorophenyl)-3-(4-piperdinyl)-1H-indole (9) which on condensation with 1-(2-chloroethyl)imidazolidinone (16) in the presence of a base gives sertindole (1).

During the laboratory optimization of sertindole (1), many process related impurities were identified. The guidelines recommended by ICH state that the acceptable levels for a known and unknown compound (impurity) in the drug should be less than 0.15 and 0.10%, respectively [6]. In order to meet the stringent regulatory requirements, the impurities present in the drug substance must be identified and characterized. Literature reports [5,7-9] include impurities formed due to either over reduction (e.g., 2, 3 and 6) [5,7], incomplete reduction (e.g., 4 and 5) [5,8] or due to incomplete alkylation (e.g., 9 and 10) [5,7]. However, no synthetic details have been reported. In this context, the present study describes identification, synthesis and characterization of impurities formed during sertindole synthesis.

References

• Karamatskos, E; Lambert, M; Mulert, C; Naber, D (November 2012). “Drug safety and efficacy evaluation of sertindole for schizophrenia”. Expert Opinion on Drug Safety 11 (6): 1047–1062. doi:10.1517/14740338.2012.726984. PMID 22992213.
• “PRODUCT INFORMATION SERDOLECT® TABLETS” (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013.
• Juruena, MF; de Sena, EP; de Oliveira, IR (May 2011). “Sertindole in the Management of Schizophrenia” (PDF). Journal of Central Nervous System Disease 3: 75–85. doi:10.4137/JCNSD.S5729. PMC 3663609. PMID 23861640.
• Lewis, R; Bagnall, AM; Leitner, M (Jul 20, 2005). “Sertindole for schizophrenia.”. Cochrane database of systematic reviews (Online) (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMID 16034864.
• Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
• Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.”. Lancet 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
• Roth, BL; Driscol, J (12 January 2011). “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 27 October 2013.
• Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
• http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092
• Zeneca’s Seroquel Nears Market Approval – The Pharma Letter, 16 July 1997
• Abbott Labs Withdraws Sertindole NDA Sertindole – The Pharma Letter, 12 Jan 1998
• “WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole – approval application withdrawn”.
• FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia – Lundbeck press release, 8 Apr 2009
• Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
• [1]
• EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) – National electronic Library for Medicines, NHS
• COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE – European Medicines Agency, 13 Sep 2002
• Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) – MHRA, 2002

Perregaard, J.; Arnt, J.; Boegesoe, K. P.; Hyttel, J.; Sanchez, C. (1992). “Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles”. Journal of Medicinal Chemistry 35 (6): 1092. doi:10.1021/jm00084a014.

Sertindole

Systematic (IUPAC) name
1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Legal status	AU: Prescription Only (S4) approved for marketing in approx. 20 countries
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	75%[1]
Protein binding	99.5%[1]
Metabolism	Hepatic (mostly via CYP2D6 and CYP3A4)[2][3]
Biological half-life	3 days[2]
Excretion	Faecal (the majority), Renal (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Registry Number	106516-24-9
ATC code	N05AE03
PubChem	CID: 60149
IUPHAR/BPS	98
DrugBank	DB06144
ChemSpider	54229
UNII	GVV4Z879SP
KEGG	D00561
ChEBI	CHEBI:9122
ChEMBL	CHEMBL12713
Chemical data
Formula	C24H26ClFN4O
Molecular mass	440.941

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

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SCYX-7158

SCYX-7158 [4-fluoro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c]oxaborol-6-yl-2-trifluoromethyl benzamide]

• C₁₇H₁₄BF₄NO₃
• Average mass 367.103 Da

Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT.

The presence of a boron atom in the heterocyclic core structure has been found essential for trypanocidal activity of orally active series of benzoxaborole-6-carboxamides in murine models of human African trypanosomiasis. SCYX-7158 (Fig. 13) has been identified as an effective, safe and orally active treatment for human African trypanoso-miasis to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011 (21,22)………http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764666/

A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C_max >10 µg/mL and AUC_{0–24 hr} >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment.

Medicinal Chemistry Synthesis of SCYX-7158  SCHEME1

While the original route was eff ective for producing multi-gram quantities of the API, it was not amenable to scale-up. The route started with 2, a relatively expensive aryl boronic acid. This was protected as borocan 3 and halogen-lithium exchange followed by reaction with acetone and subsequent deprotection provided the oxaborole 4. This protection/alkylation/deprotection sequence added two steps to the overall synthesis and the metalation was not reliable. However, the biggest concern in the sequence was nitration of 4 to give 5. This was accomplished by adding a concentrated solution of 4 to cold fuming nitric acid. Besides the signifi cant safety considerations, the reaction did not scale well. Reduction of the nitro group to give aniline 6 was followed by amide formation to provide 1. While this end game was effi cient, the material produced was dark in color. The colored impurities were not removed by crystallization of 1 and furthermore a mixture of two polymorphs was formed under the original conditions.

The process chemistry route to SCYX-7158 is shown in Scheme 2. When considering alternative routes to 1, the readily available and inexpensive methyl 2-bromobenzoate (8) was identifi ed as an attractive starting point. Gratifyingly, treatment of 8 with methylmagnesium bromide aff orded 2-bromocumyl alcohol (9) in high yield using simple operating conditions. Lithiumhalogen exchange followed by reaction with triisopropyl borate and acidic work-up provided benzoxaborole 4, along with cumyl alcohol (10). While this conversion was not completely atom-effi cient, it was easily scalable and several strategies are available to suppress the by-product in the future.

With benzoxaborole 4 in hand, attention turned to the introduction of a nitrogen-linked amide at the C(6) position. This was accomplished using the same nitration/reduction/acylation strategy used in Scheme 1. Yet signifi cant changes to the chemistry were required for safety and reliability reasons. The fi rst task was introduction of the nitrogen. Nitration was demonstrated using acetic anhydride/nitric acid. However, due to slow rates of nitration and potential for accumulation of a reactive intermediate, alternative conditions had to be identifi ed. These limitations were overcome by use of trifl uoroacetic anhydride/nitric acid, which provided a more reactive nitrating intermediate, thus improving the rate of nitration and aff ording a process in which nitric acid was slowly added until 4 was consumed. Full safety assessment of the nitration reaction, including extensive calorimetry studies, demonstrated the safety of this reaction. This process was used to prepare kilogram quantities of 5.

Following reduction of nitrobenzoxaborole 5 to aniline 6 under standard catalytic hydrogenation conditions, acylation with 7 provided the fi nal drug candidate in high chemical yield. Two challenges remained which needed to be addressed through further optimization of the process. The fi rst challenge was color and purity of the API, which derived from a highly colored impurity generated in the nitration reaction which carried through to fi nal product and was not removed by crystallization. The second challenge was to consistently obtain a single polymorph of the API. Both challenges were addressed by isolation of crystalline isopropyl boronate 11 which rejected colored impurities, followed by regeneration of 1 through addition of water and azeotropic removal of isopropanol. This crystallization provided the API as a single polymorph. The API was isolated in good yield, very high purity and was white in color.

REFERENCES

http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001151

• touguia J, Costa J (1999) Therapy of human African trypanosomiasis: current situation. Mem Inst Oswaldo Cruz 94: 221–224
• Barrett MP, Boykin DW, Brun R, Tidwell RR (2007) Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br J Pharmacol 152: 1155–1171.

1. 1986. Epidemiology and control of African trypanosomiasis. Report of a WHO expert committee. World Health Organization. Geneva, Switzerland. Technical Report Series, No. 739. 126 pp.
2. Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis. Robert T Jacobs, Jacob J Plattner, Bakela Nare, Stephen A Wring, Daitao Chen, Yvonne Freund, Eric G Gaukel, Matthew D Orr, Joe B Perales, Matthew Jenks, Robert A Noe, Jessica M Sligar, Yong-Kang Zhang, Cyrus J Bacchi, Nigel Yarlett, and Robert Don. Future Medicinal Chemistry. August 2011. Vol. 3, No. 10. Pages 1259-1278.

http://www.swisstph.ch/fileadmin/user_upload/Pdfs/Events/2010_09_Jacobs.pdf  ……….POWERPOINT

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This blog New Drug Approvals will touch 10 lakh views soon……..as on 7 NOV 2015

http://newdrugapprovals.org/

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CEP-18770, Delanzomib

cas 847499-27-8

Chemical Formula: C21H28BN3O5

Exact Mass: 413.21220, UNII-6IF28942WO;

CT-47098
NPH 007098
NPH007098

[(1R)-1-[[(2S,3R)-3-Hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid

[(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid,

Boronic acid, ((1R)-1-(((2S,3R)-3-hydroxy-1-oxo-2-(((6-phenyl-2-pyridinyl)carbonyl)amino)butyl)amino)-3-methylbutyl)-

Cephalon, Inc.

CEP-18770 is a reversible P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Displays anti-multimyeloma (MM) effect.

HPLC………http://www.apexbt.com/downloader/document/A4009/HPLC.pdf

NMR………http://www.apexbt.com/downloader/document/A4009/NMR.pdf

CLICK ON IMAGE FOR CLEAR VIEW

Delanzomib, also known as CEP-18770,  is An orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Proteasome inhibitor CEP 18770 represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB

New series of dipeptidyl boronate inhibitors of 20S proteasome were identified to be highly potent drug-like candidates with IC₅₀ values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market

ref

The potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[ [ (2S,3R)- 3-hydroxy-2-[ (6-phenylpyridine- 2-carbonyl) amino]-1 -oxobutyl] amino]- 3-methylbutyl] boronic acid (CEP-18770, has been reported

ref .

Dorsey BD, Iqbal M, Chatterjee S, Menta E, Bernardini R, Bernareggi A, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem. 2008;51:1068–1072. [PubMed]

Further, the anti-multiple myeloma protea-some inhibitor CEP-18770 enhanced the anti-myeloma activity of bortezomib and melphalan. The combination of anti-multiple myeloma proteasome inhibitor CEP-18770 intravenously and bortezomib exhibited complete regression of bortezomib-sensitive tumours. Moreover, this combination markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone

PAPER

Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

http://pubs.acs.org/doi/abs/10.1021/jm7010589

The ubiquitin−proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

Patent

http://www.google.com/patents/WO2010056733A1?cl=en

Preferred among these compounds is [(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid, also known as CEP- 18770, which has the following structure:

PATENT

http://www.google.co.in/patents/WO2005021558A2

NOT SAME BUT SIMILAR

Example E.4 Boronic acid, [(lR)-l-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-l- oxobutyI]amino]-3-methyIbutyl].

[00275] A mixture of 4-(pyridin-3-yl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-

[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]- of Example D.8.3 (155 mg, 0.283 mmol), 2-methylpropylboronic acid (81 mg, 0.793 mmol) and 2N aqueous hydrochloric acid (0.3 ml) in a heterogeneous mixture of methanol (3 ml) and hexane (3 ml) was stirred at room temperature for 24 hours. The hexane layer was removed and the methanolic layer was washed with fresh hexane (about 5 ml). Ethyl acetate (10 ml) was added to the methanol layer which was then concentrated. The residue was taken up with ethyl acetate and the mixture was concentrated. This step was repeated (2-3 times) until an amorphous white solid was obtained. The solid was then triturated with diethyl ether (5 ml) and the surnatant was removed by decantation. This step was repeated. The residue (126 mg) was combined with the product of a similar preparation (140 mg) and dissolved in ethyl acetate (about 40 ml) and a small amount of methanol (2-3 ml). The solution was washed with a mixture of NaCl saturated solution (7 ml) and 10% NaHCO₃ (2 ml). The layers were separated and the aqueous phase was further washed with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was taken up with ethyl acetate (about 20 ml) and the minimum amount of methanol, and then concentrated to small volume (about 5 ml). The resulting white was collected by filtration and dried under vacuum at 50°C (160 mg, 65% overall yield).

1H NMR (MeOH-d4): 8.90 (IH, s); 8.49 (IH, d, J=4.0); 8.20 (IH, d, J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58 (IH, t br., J=6.0); 4.80 (IH, d, J=3.9); 4.40-4.29 (IH, m); 2.78 (IH, t, J=7.5); 1.73-1.61 (IH, m); 1.38 (2H, t, J=6.9); 1.31 (3H, d, J=6.3); 0.94 (6H, d, J=6.31). [00276] Further compounds prepared according to the above procedure for

Example E.4 are reported in Table E-4. Table E-4

E.4.3 IS THE COMPD

1. Fuchs, Ota. Proteasome inhibition as a therapeutic strategy in patients with multiple myeloma. Multiple Myeloma (2009), 101-125. CODEN: 69MVM2 AN 2010:737549

2. Genin, E.; Reboud-Ravaux, M.; Vidal, J. Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10(3), 232-256. CODEN: CTMCCL ISSN:1568-0266. CAN 152:516315 AN 2010:423458

3. Sanchez, Eric; Li, Mingjie; Steinberg, Jeffrey A.; Wang, Cathy; Shen, Jing; Bonavida, Benjamin; Li, Zhi-Wei; Chen, Haiming; Berenson, James R. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. British Journal of Haematology (2010), 148(4), 569-581. CODEN: BJHEAL ISSN:0007-1048. AN 2010:353952

4. Dick, Lawrence R.; Fleming, Paul E. \Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discovery Today (2010), 15(5/6), 243-249. CODEN: DDTOFS ISSN:1359-6446. AN 2010:318415

5. Ruggeri, Bruce; Miknyoczki, Sheila; Dorsey, Bruce; Hui, Ai-Min. The development and pharmacology of proteasome inhibitors for the management and treatment of cancer. Advances in Pharmacology (San Diego, CA, United States) (2009), 57(Contemporary Aspects of Biomedical Research: Drug Discovery), 91-135. CODEN: ADPHEL ISSN:1054-3589. AN 2010:62762

6. Chen-Kiang, Selina; Di Liberto, Maurizio; Huang, Xiangao. Targeting CDK4 and CDK6 kinases or genes thereof in cancer therapy for sensitizing drug-resistant tumors. PCT Int. Appl. (2009), 149pp. CODEN: PIXXD2 WO 2009061345 A2 20090514 CAN 150:531264 AN 2009:586623

7. Rickles, Richard; Lee, Margaret S. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents. PCT Int. Appl. (2009), 70 pp. CODEN: PIXXD2 WO 2009011893 A2 20090122 CAN 150:160095 AN 2009:86451

8. Rickles, Richard; Pierce, Laura; Lee, Margaret S. Combinations for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 79pp. CODEN: PIXXD2 WO 2009011897 A1 20090122 CAN 150:160094 AN 2009:83374

9. Hoveyda, Hamid; Fraser, Graeme L.; Benakli, Kamel; Beauchemin, Sophie; Brassard, Martin; Drutz, David; Marsault, Eric; Ouellet, Luc; Peterson, Mark L.; Wang, Zhigang. Preparation and methods of using macrocyclic modulators of the ghrelin receptor. U.S. Pat. Appl. Publ. (2008), 178pp. CODEN: USXXCO US 2008194672 A1 20080814 CAN 149:288945 AN 2008:975261

10. Piva, Roberto; Ruggeri, Bruce; Williams, Michael; Costa, Giulia; Tamagno, Ilaria; Ferrero, Dario; Giai, Valentina; Coscia, Marta; Peola, Silvia; Massaia, Massimo; Pezzoni, Gabriella; Allievi, Cecilia; Pescalli, Nicoletta; Cassin, Mara; di Giovine, Stefano; Nicoli, Paola; de Feudis, Paola; Strepponi, Ivan; Roato, Ilaria; Ferracini, Riccardo; Bussolati, Benedetta; Camussi, Giovanni; Jones-Bolin, Susan; Hunter, Kathryn; Zhao, Hugh; Neri, Antonino; Palumbo, Antonio; Berkers, Celia; Ovaa, Huib; Bernareggi, Alberto; Inghirami, Giorgio. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood (2008), 111(5), 2765-2775. CODEN: BLOOAW ISSN:0006-4971. CAN 149:486154 AN 2008:292777

11. Dorsey, Bruce D.; Iqbal, Mohamed; Chatterjee, Sankar; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Cassara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergio; Oliva, Ambrogio; Pezzoni, Gabriella; Allievi, Cecilia; Strepponi, Ivan; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry (2008), 51(4), 1068-1072. CODEN: JMCMAR ISSN:0022-2623. CAN 148:345774 AN 2008:146611

12. Dorsey, Bruce D.; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Casara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergi; Oliva, Ambrogio; Iqbal, Mohamed; Chatterjee, Sankar; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. CEP-18770: Discovery of a Potent, Selective and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena, Italy, October 7-9 (2007), COMC-027. CODEN: 69KAR2 AN 2007:1171000

13. Marblestone Jeffrey G Ubiquitin Drug Discovery & Diagnostics 2009 – First Annual Conference. IDrugs : the investigational drugs journal (2009), 12(12), 750-3.

/////CEP-18770, delanzomib

B(C(CC(C)C)NC(=O)C(C(C)O)NC(=O)C1=CC=CC(=N1)C2=CC=CC=C2)(O)O

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders

Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure

Dr. D. Srinivasa Reddy of NCL winner Shanti Swarup Bhatnagar Award 2015

see

http://oneorganichemistoneday.blogspot.in/2015/02/dr-d-srinivasa-reddy.html

Dr. Srinivasa Reddy of CSIR-NCL bags the

prestigious Shanti Swarup Bhatnagar Prize

sept 2015…………..http://www.biospectrumindia.com/biospecindia/news/222486/

dr-srinivasa-reddy-csir-ncl-bags-prestigious-shanti-swarup-bhatnagar-prize

The award comprises a citation, a plaque, a cash prize of Rs 5 lakh

The Shanti Swarup Bhatnagar Prize for the year 2015 in chemical sciences has been awarded to Dr. D. Srinivasa Reddy of CSIR-National Chemical Laboratory (CSIR-NCL), Pune for his outstanding contributions to the area of total synthesis of natural products and medicinal chemistry.

This is a most prestigious award given to the scientists under 45 years of age and who have demonstrated exceptional potential in Science and Technology. The award derives its value from its rich legacy of those who won this award before and added enormous value to Indian Science.

Dr. Reddy will be bestowed with the award at a formal function, which shall be presided over by the honourable Prime Minister. The award, named after the founder director general of Council of Scientific & Industrial Research (CSIR), Dr. Shanti Swarup Bhatnagar, comprises a citation, a plaque, a cash prize of Rs 5 lakh.

Dr. Reddy’s research group current interests are in the field of total synthesis and drug discovery by applying medicinal chemistry. He has also been involved in the synthesis of the agrochemicals like small molecules for crop protection. The total synthesis of more than twenty natural products has been achieved in his lab including a sex pheromone that attracts the mealy bugs and has potential use in the crop protection. On the medicinal chemistry front significant progress has been made by his group using a new concept called “Silicon-switch approach” towards central nervous system drugs. Identification of New Chemical Entities for the potential treatment of diabetes and infectious diseases is being done in collaboration with industry partners.

His efforts are evidenced by 65 publications and 30 patents. He has recently received the NASI-Reliance industries platinum jubilee award-2015 for application oriented innovations and the CRSI bronze medal. In addition, he is also the recipient of Central Drug Research Institute award for excellence in the drug research in chemical sciences and scientist of the year award by the NCL Research Foundation in the year 2013. Dr. Reddy had worked with pharmaceutical companies for seven years before joining CSIR-NCL in 2010.

AN INTRODUCTION

MYSELF WITH HIM

DEC2014 NCL PUNE INDIA

DR ANTHONY WITH DR REDDY

////////

IVACAFTOR

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201501048/abstract

SUPPORTING INFO……….http://onlinelibrary.wiley.com/store/10.1002/ejoc.201501048/asset/supinfo/ejoc_201501048_sm_miscellaneous_information.pdf?v=1&s=2b5b6ac6456ec88f478c07a692e49254e7239f80

REFERENCES

N. Vasudevan, Gorakhnath R. Jachak And D. Srinivasa Reddy, Breaking and Making of Rings: A Method for the Preparation of 4-Quinolone-3-carb­oxylic Acid Amides and the Expensive Drug Ivacaftor, Eur. J. Org. Chem., , 0000 (2015), DOI:10.1002/ejoc.201501048.

http://academic.ncl.res.in/publications/index/select-faculty/2015/ocd

READ ABOUT DR SRINIVASA REDDY at…………

ONE ORGANIC CHEMIST ONE DAY BLOG……..LINK

DEC2014 NCL PUNE INDIA

DR ANTHONY MELVIN WITH DR SRINIVASA REDDY

GKM 001……Several probables

Watch out on this post as I get to correct structure………..

Advinus Therapeutics Private L,

A glucokinase activator for treatment of type II diabetes

Advinus chief executive officer/MD Dr. Rashmi Barbhaiya.

PATENT

https://www.google.co.in/patents/WO2009047798A2?cl=en

Example Cl : (-)-{5-ChIoro-2-[2-(4-cyclopropanesulfonylphenyI)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid, ethyl ester

Step I: Preparation of (-)-(4-Cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Cl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate was added (S)-(-)-l-phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (-)-(4- cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = – 107.1 ° (c = 2%Chloroform) Enantiomeric purity > 99. % (chiral HPLC)

Step II: (-)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetyIamino]thiazol-4-yl}-acetic acid ethyl ester : To a solution of (-)-4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Cl-I) in DCM, was added DMF and cooled to 0 °C, followed by the addition of oxalyl chloride under stirring. Stirring was continued for 1 hour at the same temperature. The resulting mixture was further cooled to -35 °C, and to that, a solution of excess (2- amino-5-chlorothiazol-4-yl)acetic acid ethyl ester in DCM was added drop wise. After completion of reaction, the reaction mixture was poured into IN aqueous HCl under stirring, organic layer was washed with IN HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC to get the title compound. [α]²³ ₅89 = – ve (c = 2%Chloroform)

¹H NMR(400 MHz, CDCl₃): δ 1.06-1.08 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.33-1.38 (m, 2H), 2.42-2.50 (m, IH), 3.73 (d, J=2 Hz, 2H), 4.22 (q, J=7.2 Hz ,2H), 5.75 (s, IH), 6.76- 6.77 (m, IH), 6.83-6.86 (m, IH), 6.90-6.98 (m, IH), 7.73 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.96 (bs, IH). MS (EI) m/z: 571.1 and 573.1 (M+ 1; for ³⁵Cl and ³⁷Cl respectively).

Examples C2 and C3 were prepared in analogues manner of example (Cl) from the appropriate chiral intermediate:

Example Dl : (+)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}acetic acid, ethyl ester

Preparation of (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Dl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate, was added (R) (+)-l- phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = +93.07° (c = 2%Chloroform) Enantiomeric purity > 99. % (by chiral HPLC)

(+)-(4-CyclopropanesuIfonylphenyI)-(2,4-difluorophenoxy)acetic acid ethyl ester (Dl)

The example Dl was prepared using (+)-4-cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Dl-I), and following the same reaction condition for amide coupling as described in example Cl, [ot]²³ ₅89 = + ve (c = 2%Chloroform)

PATENT

https://www.google.co.in/patents/WO2008104994A2?cl=en

Synthesis Type-P

Example Pl : {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino]-thiazol-4-yI}-acetic acid

To a solution of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl- phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (0.03 g, 0.05 mmol) in THF: Ethanol: water ( ImI + 0.3ml + 0.3 ml) was added lithium hydroxide (0.0046 g, 0.11 mmol). The resulting mixture was stirred for 5 hours at room temperature followed by removal of solvent under reduced pressure. The residue was suspended in water (15 ml), extracted with ethyl acetate to remove impurities. The aqueous layer was acidified with IN HCl (0.5 ml) and extracted with ethyl acetate (2×10 ml), This ethyl acetate layer was washed with water (15 ml), brine (20 ml), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to give solid product {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4- methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl} -acetic acid (9 mg). ¹H NMR (400 MHz, CDCl₃): δ 1.85 (s, 3H) , 3.07 (s, 3H) , 3.72 ( s, 2H), 6.64-6.69 ( m, 2H ) , 6.89-6.91 (m, IH ), 7.84 ( d, J – 8.4 Hz, 2H), 8.00 ( d, J = 8.8 Hz, 2H). MS (EI) mlz: 530.70 (M + 1), mp: 109-111 ⁰C.

Preparation of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino)-thiazol-4-yl}-acetic acid methyl ester used in Example Pl:

To a mixture of 2-(2, 4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.110 g, 0.22 mmol), (2-Amino-5-chloro-thiazol-4-yl)-acetic acid methyl ester (0.071 g, 0.32 mmol), HOBt (0.052g, 0.38 mmol), and EDCI (0.074 g, 0.38 mmol) in methylene dichloride (10 ml) was added N-methylmorpholine (0.039 g, 0.38 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2x 20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile. To give desired compound (0.30 g). ¹H NMR (400 MHz, CDCl₃): δ 1.45 (t, J = 7.2 Hz, 3H), 1.93 (s, 3H), 3.14 (s, 3H), 3.77 (d, J = 2.8 Hz, IH), 4.26 (q, J = 7.2 Hz, IH), 6.69-6.77(m, 2H), 6.96-7.02 (m, IH), 7.89 (d, J = 8.4 Hz, 2H), 8.07 (d, J= 8.4Hz, IH).; MS (EI) m/z: 559 .00 (M + 1).

CLIPPINGS

Advinus’ GK-activator Achieves Early POC for Diabetes

November 29 2011

Partnership Dialog Actively Underway

Advinus Therapeutics, a research-based pharmaceutical company founded by globally experienced industry executives and promoted by the TATA Group, announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

The clinical trials on GKM-001 validate the company’s pre-clinical hypothesis that a liver selective Glucokinase activator would not cause hypoglycemia (very low blood sugar), while showing robust efficacy.

“GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action. GKM-001 has a prolonged pharmacological effect and a half-life that should support a once a day dosing as both mono and combination therapy.” said Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics. He added that Advinus is actively exploring partnership options to expedite further development and global marketing of GKM-001.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well. The resulting increase in insulin secretion creates a potential for hypoglycemia-a risk GKM-001 is designed to avoid. Advinus has the composition of matter patent on GKM-001 for all major markets globally. Both the Single Ascending Dose data, in healthy and type II diabetics, and the Multiple Ascending Dose Study in Type II diabetics has shown that the molecule shows effective glucose lowering in a dose dependent manner and has excellent safety and tolerability profile over a 40-fold dose range. The pharmacokinetic properties of the molecule support once a day dosing. GKM-001 has the potential to be “First-in-Class” drug to address this large, growing and yet poorly addressed market.

Advinus also has identified a clinical candidate as a back-up to GKM-001, which is structurally different. In its portfolio, the company has a growing pipeline for COPD, sickle cell disease, inflammatory bowel disease, type 2 diabetes, acute and chronic pain and rheumatoid arthritis in various stages of late discovery and pre-clinical development.

About the Diabetes Market:

The present 300 million diabetics population is estimated to jump to 450 million by 2030 worldwide. A large proportion of these patients are poorly controlled despite multiple therapies. Total sales of diabetic prescription products were $32 billion in 2010.

Advinus Therapeutics team discovers novel molecule for treatment of diabetes

• The first glucokinase modulator discovered and developed in India 
• A new concept for the management of diabetes for patients, globally 
• 100 per cent ‘made in India’ molecule for the treatment of diabetes 
• IND approved by DGCI, Phase I clinical trial shows excellent safety and tolerance profiles with efficacy

Bangalore: Advinus Therapeutics (Advinus), the research-based pharmaceutical company founded by leading global pharmaceutical executives and promoted by the Tata group, today, announced the discovery of a novel molecule for the treatment of type II diabetes — GKM-001.The molecule is an activator of glucokinase; an enzyme that regulates glucose balance and insulin secretion in the body.

GKM-001 is a completely indigenously developed molecule and the initial clinical trials have shown excellent results for both safety and efficacy.

“Considering past failures of other companies on this target, our discovery programme primarily focused on identifying a molecule that would be efficacious without causing hypoglycaemia; a side effect associated with most compounds developed for this target.

“Recently completed Phase I data indicate that Advinus’ GKM–001 is a liver selective molecule that has overcome the biggest clinical challenge of hypoglycaemia. GKM-001 is differentiated from most other GK molecules in development due to this novel mechanism of action,” said Dr Rashmi Barbhaiya, MD and CEO, Advinus Therapeutics.

He further added, “We are very proud that GKM-001 is 100 per cent Indian. Advinus’s discovery team in Pune discovered the molecule and entire preclinical development was carried out at our centre in Bangalore. The Investigational New Drug (IND) application was filed with the DGCI for approval to initiate clinical trials in India within 34 months of initiation of the discovery programme. Subsequent to the approval of the IND, we have completed the Phase I Single Ascending Dose study in India within two months.”

GKM-001 is a novel molecule for the treatment of type II diabetes. It is the first glucokinase modulator discovered and developed in India and has potential to be both first or best in class. The success in discovering GKM-001 is attributed to the science-driven efforts in Advinus laboratories and ‘breaking the conventional mold’ for selection of a drug candidate. Advinus has ‘composition of matter’ patent on the molecule for all major markets globally. Glucokinase as a class of target is considered to be novel as currently there is no product in the market or in late clinical trials. The strategy for early clinical development revolved around assessing safety (particularly hypoglycaemia) and early assessment of therapeutic activity (glucose lowering and other biomarkers) in type II diabetics. The Phase I data, in both healthy and type II diabetics, shows excellent safety and tolerability over a 40-fold dose range and desirable pharmacokinetic properties consistent with ‘once a day’ dosing. The next wave of clinical studies planned continues on this strategy of early testing in type II diabetics.

Right behind the lead candidate GKM-001, Advinus has a rich pipeline of back up compounds on the same target. These include several structurally different compounds with diverse potency, unique pharmacology and tissue selectivity. Having discovered the molecule with early indication of wide safety margins, desired efficacy and pharmacokinetic profiles, the company now seeks to out-licence GKM-001 and its discovery portfolio.

patent

wo 2008104994

wo 2008 149382

///////GKM 001, pipeline, Diabetes, Advinus, type II diabetes, glucokinase modulator, Rashmi Barbhaiya

GENERAL STRUCTURE

ZYDPLA 1……….Probable Representative structure only, I will modify it as per available info

Cadila Healthcare Limited

ZYDPLA1 is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre, the NCE research wing of Zydus. ZYDPLA1 is a novel compound in the Gliptin class of antidiabetic agents. It works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1.

By increasing the GLP-1 levels, ZYDPLA1 glucose-dependently increases insulin secretion and lowers glucagon secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

Zydus announces data presentations on ZYDPLA1 “A once-weekly small molecule DPP-IV inhibitor for treating diabetes”, at the ENDO conference in Chicago, Illinois, USA. Ahmedabad, India June 9, 2014 The Zydus group will be presenting data on its molecule ZYDPLA1 a novel compound in the Gliptin class of anti-diabetic agents during the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 to be held from June 21-24, 2014 in Chicago, Illinois.

ZYDPLA1, currently in Phase I clinical evaluation in USA, is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre. ZYDPLA1 works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1. By increasing the GLP- 1 levels, ZYDPLA1 glucose-dependently increases insulin secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

The Chairman & Managing Director of Zydus, Mr. Pankaj R. Patel said, “Currently, all available DPP-4 inhibitors are dosed once-daily. ZYDPLA1 with a once-a-week dosing regimen would provide diabetic patients with a more convenient treatment alternative. ZYDPLA1 will offer sustained action, which will result in an improved efficacy profile.”

The abstract of Poster Number: LB-PP02-4 can also be viewed on the ENDO web program at https://endo.confex.com/endo/2014endo/webprogram/authora.html. The Poster Preview is scheduled on Sunday, June 22, 2014 at McCormick Place West.

The number of diabetics in the world is estimated to be over 360 million. In 2025 nearly half of the world’s diabetic population will be from India, China, Brazil, Russia and Turkey. The sales of the DPP IV inhibitors is expected to peak at almost $14 billion by 2022. Research in the field of anti-diabetic therapy seeks to address the problems of hypoglycemia, GI side effects, lactic acidosis, weight gain, CV risks, edema, potential immunogenicity etc., which pose a major challenge in the treatment of diabetes.

About Zydus

Headquartered in Ahmedabad, India, Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 16,000 people worldwide including over 1100 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global researchbased pharmaceutical company by 2020. The group has a strong research pipeline of NCEs, biologics and vaccines which are in various stages of clinical trials including late stage.

About Zydus Research Centre

The Zydus Research Centre has over 20 discovery programmes in the areas of cardio-metabolic disorders, pain, inflammation and oncology. Zydus has in-house capabilities to conduct discovery research from concept to IND-enabling pre-clinical development and human proof-of-concept clinical trials. The Zydus Research group had identified and developed Lipaglyn™ (Saroglitazar) which has now become India’s first NCE to reach the market. Lipaglyn™ is a breakthrough therapy in the treatment of diabetic dyslipidemia and Hypertriglyceridemia. The company recently announced the commencement of Phase III trials of LipaglynTM (Saroglitazar) in patients suffering from Lipodystrophy.

PATENT

http://www.google.com/patents/WO2011013141A2?cl=en

Rajendra Kharul, Mukul R. Jain, Pankaj R. Patel

Substituted benzamide derivatives as glucokinase (gk) activators

Scheme 2:

Scheme 3:

Scheme 4A:

Scheme 4B.

] Scheme 5 A:

Scheme 5B:

Scheme 6:

http://zyduscadila.com/wp-content/uploads/2015/09/ZYDPLA1-a-Novel-LongActing-DPP-4-Inhibitor.pdf

http://zyduscadila.com/wp-content/uploads/2015/05/PressNote23-10-13.pdf

http://zyduscadila.com/wp-content/uploads/2015/07/annual_report_14-15.pdf

////////

DC_AC50

3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

licensed DC_AC50 to Suring Therapeutics, in Suzhou, China

INNOVATORS  Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

• Jing Wang,
• Cheng Luo,
• Changliang Shan,
• Qiancheng You,
• Junyan Lu,
• Shannon Elf,
• Yu Zhou,
• Yi Wen,
• Jan L. Vinkenborg,
• Jun Fan,
• Heebum Kang,
• Ruiting Lin,
• Dali Han,
• Yuxin Xie,
• Jason Karpus,
• Shijie Chen,
• Shisheng Ouyang,
• Chihao Luan,
• Naixia Zhang,
• Hong Ding,
• Maarten Merkx,
• Hong Liu,
• Jing Chen,
• Hualiang Jiang
• & Chuan He

Nature Chemistry, (2015)

doi:10.1038/nchem.2381

PATENT

http://www.google.com/patents/WO2014116859A1?cl=en

COMPD IS LC-1 COMPD 50

Scheme 1 (Compounds LCI -LCI 9):

Experimental procedure for Scheme 1 :

Step a: To 1 equivalent of sodium metal in anhydrous diethyl ether is added 1-2 equivalents of ethyl formate and 1-2 equivalents of cyclopentanone. The resulting mixture is stirred overnight. The mother liquor is filtered by suction filtration to obtain crude intermediate 2.

Step b: To a solution of intermediate 2 in an organic solvent, is added 0.1 to 1 equivalent of glacial acetic acid. The reaction is stirred at 50-100 °C, then 2′ and 0.1 to 1 equivalent of glacial acetic acid are added. The resulting reaction mixture is refluxed for 1-5 hours, filtered and recrystallized to produce product 3; the said organic solvent may optionally be tetrahydrofuran, ether, dimethylformamide, ethyleneglycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. Step c: To a solution of compound 3 in an organic solvent, is added 1 equivalent of methyl bromoacetate and an appropriate amount of base. The reaction mixture is stirted at room temperature to produce intermediate 4. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

Step d: The base described in Step c is added to a solution of compound 4 in an organic solvent. The reaction mixture is stirred and heated to produce intermediate 5. Step e: An appropriate amount of di-tert-butyl dicarbonate and alkali are added to a solution of compound 5 in an organic solvent. The reaction is stirred to produce intermediate 6.

Step f: An appropriate amount of base is added to a solution of compound 6 in an organic solvent, which is then hydro lyzed to produce intermediate 7.

Step g: 3′ and a stoichiometric amount of condensing agent are added to a solution of compound 7 in an organic solvent. The reaction mixture is stirred until 3′ reacts completely to produce the final product. The said organic so ί vers t may optional iy be tetrahydrofuran, aether, dimethyl formamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said condensing agent may optionally be DCC, EDO, HOBt, and GDI. Step h: To a solution of compound 7 in an organic solvent is added aqueous hydrochloric acid or trifluoroacetic acid. The reaction mixture is stirred vigorously to yield the BOC- deprotected final product.

Scheme 2 (Compounds LCI -LCI 9)

LCI ~LC39

Experimental procedure for Scheme 2(Compounds LC1-LC19):

Step a: Dissolve 1 equivalent of sodium in anhydrous ether, which shall be added slowly under an ice bath and rapid stirring condition. Add 1 equivalent of ethyl formate and 1 equivalent of cyclopentanone in a constant pressure dropping funnel, add 0.5 ml ethanol as an initiator, after 1 hour of stirring in ice bath, and stir overnight at room temperature until the reaction of sodium is finished. Perform suction filtration, wash with absolute ether to produce crude product for the following steps of reaction.

Step b: Dissolve the product in above steps directly in ethanol and control its amount, add an appropriate amount of glacial acetic acid, and stir and reflux under 70°C. Add cyano- sulfamide into the reaction solution, and add an appropriate amount of glacial acetic acid, react and reflux for about 3 hours. Recrystallize with ethanol to produce crude product.

Step c: Add 1 equivalent of the appropriate aniline or phenol and 2 equivalents of potassium carbonate solid in a round-bottomed flask that is placed in ice bath, add anhydrous THF to fully dissolve the solid, add 1.5 equivalents of bromoacetyl bromide into a constant pressure dropping funnel and dilute with THF, which is slowly dropped into the former said round- bottomed flask that is moved to room temperature in 10 min late and react for 1 hour; extract and dry with anhydrous sodium sulfate, filtrate by suction, and perform rotary evaporation to remove the solvent, and the crude product is obtained, which is to be used directly in the next step of reaction.

Step d: Dissolve the product from Step 2 into DMF under normal temperature by mixing, add 3 equivalents of 10% KOH solution, which is then transferred to an oil bath of 70°C and react, and add I equivalent of the product from step 3. Stir for about 3 hours and then extract directly with ethyl acetate, and recrystallize the crude product with ethanol to produce pure end product.

Steps a and b: Intermediate 3 is prepared in accordance with the method outlined in Scheme 1. Step c: 3′ and bromoacetyl bromide are condensed in the presence of a suitable base to produce intermediate 9. The said base may optionally be potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

Step d: An appropriate amount of base is added to a solution of compound 3 in an organic solvent, and the reaction mixture is heated to 40-100 °C. Intermediate 9 is added, and the heated solution is stirred for 1-10 hours to yield the final product. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

1H NMR (CDCI3, 400 MHz) δ 9.15 (s, 1H), 7.61 (s, 1H), 7.13(m, 1H), 6.60 (m, 1H), 6.27 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.39 (m, 2H); ESI-MS (EI) m/z 422 (M⁺)

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List of compounds as DPP-IV inhibitors

Watch out on this post as I get to correct structure………..

2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

One Example of 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

CAS  1601479-87-1

(2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]tetrahydro-2H-pyran-3-amine

MW 399.45, C18 H23 F2 N3 O3 S

INTRODUCTION

Dipeptidyl peptidase IV , CD26; DPP-IV; DP-IV inhibitors acting as glucose lowering agents reported to be useful for the treatment of type 2 diabetes.  compound inhibited human DPP-IV enzyme activity (IC50 < 10 nM) in fluorescence based assays.

It lowered glucose levels (with -49.10% glucose change) when administered to C57BL/6J mice at 0.3 mg/kg p.o. in oral glucose tolerance test (OGTT).

Compound displayed the following pharmacokinetic parameters in Wistar rats at 2 mg/kg p.o.: Cmax = 459.04 ng/ml, t1/2 = 59.48 h and AUC = 4751.59 h·ng/ml.

Dipeptidyl peptidase 4 (DPP-IV) inhibitor that inhibited human DPP-IV enzyme activity with an IC50 of < 10 nM in a fluorescence based assay.

Watch out on this post as I get to correct structure………..

PATENT

http://www.google.com/patents/WO2014061031A1?cl=en

Compound 8: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

1H NMR: (CD₃OD, 400 MHz): 7.32-7.28 (m, IH), 7.26-7.23 (m, 2H), 4.77 (d, IH, J= 10Hz), 4.32(dd, IH, J,= 2.0Hz, J₂= 10.8Hz), 4.19 (s, 4H), 3.89-3.83 (m, 4H), 3.70- 3.65 (m, IH), 3.61 (t, IH, J= 11.6Hz), 3.53-3.46 (m, IH), 3.04 (s, 3H), 2.65-2.62 (dd, IH, Ji= 1.2Hz, J₂= 12Hz), 1.84 (q, IH, J = 12 Hz); ESI-MS: (+ve mode) 400.0 (M+H)⁺ (100 %); HPLC: 99.4 %.

Compound 4: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(hexahydropyrrolo[3, 4-c Jpyrrol- 2(lH)-yl)tetrahydro-2H-pyran-3-amine

1H NMR: (CD₃OD, 400 MHz):

.23-7.20 (m, 2H), 4.64 (d, IH, J= 10.4 Hz), 4.38-4.35 (dd, IH, J,= 2.4Hz, J₂= 10.4Hz), 3.69 (t, IH, J= 11Hz), 3.57-3.53 (m, 4H), 3.34-3.30 (m, 8H), 2.68-2.65 (m, IH), 2.04 (q, IH, J = 1 1.6 Hz); ESI-MS: (+ve mode) 323.9 (M+H)⁺ (100 %), 345.9 (M+Na)⁺ (20%); HPLC: 98.6 %

PATENT

IN 2012MU03030

“NOVEL DPP-IV INHIBITORS”

3030/MUM/2012

Abstract:
The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of diabetes mellitus (DM), obesity and other metabolic disorders. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.

Pankaj R. Patel (right), Chairman and Managing Director,

////////////2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds, DPP-IV inhibitors

EV-077

SER  150 (formerly EV-077)

Also known as: formerly EV-077-3201

EV-077-3201-2TBS

CAS 1384128-29-3

Evolva INNOVATOR

Evolva Sa

Oral thromboxane receptor antagonist and thromboxane synthase inhibitor

EV-077 is a small compound being developed for the treatment of complications of diabetes. In Phase 2. Outlicensed to Serodus in 2013.

In 2013, Serodus licensed the product candidate for the treatment of diabetic nephropathy and it is conducting phase II clinical trials on this research.

EV-077 is an oral, small molecule compound, belonging to a new structural class. Preclinical and early clinical studies indicate EV-077 has potential in reducing vascular inflammation by inhibiting the activity of prostanoids and isoprostanes – in particular in diabetes. Towards the end of 2011, the Russian Patent Office granted patent protection for EV-077 in the treatment of complications of diabetes for a term extending to 2026. Evolva has outlicenced EV-077 to Serodus in 2013. Serodus aims to bring EV-077 further through clinical development and at a future time point decide whether Serodus or a partner will conduct the final clinical trials.

EV-077 is in development as a potential pharmaceutical for the treatment of  diabetic nephropathy and other diabetic complications. It is in Phase II clinical studies.

In 2013, Evolva out-licensed EV-077 to Serodus (Oslo, Norway). Serodus aims to bring EV-077 through Phase II and then decide whether or not to partner for the final clinical trials and commercialisation. Evolva is entitled to clinical and regulatory milestones as well as a single-digit royalty on sales. If Serodus sublicenses EV-077 then Evolva will receive up to 30% of Serodus’ total licensing income.

As of Q2 2015 Serodus continues active development of EV-077.

– See more at: http://www.evolva.com/ev-077/#sthash.4mgJ3E0f.dpuf

Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A2 (TXA2) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA2 stable analogue (7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP 20 μM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings.

WO 2014011273

http://www.google.com/patents/WO2014011273A2?cl=en