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Anakinra licensed in UK to treat CAPS in infants and adults

December 11, 2013 3:30 am / Leave a comment

The Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK has granted a licence to an interleukin-1 (IL-1) inhibitor Anakinra (Kineret) for the treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children as young as eight months.

Anakinra (brand name Kineret) is a drug used to treat rheumatoid arthritis.^[1] It is aninterleukin-1 (IL-1) receptor antagonist.

Anakinra is an interleukin-1 (IL-1) receptor antagonist.Anakinra blocks the biologic activity of naturally occurring IL-1, including inflammation and cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in many tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunologic reactions. IL-1 additionally stimulates bone resorption and induces tissue damage like cartilage degradation as a result of loss ofproteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist is not found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients.

Anakinra is not considered a ‘Disease-modifying antirheumatic drug‘ (DMARD) but rather a ‘Biological Response Modifier’ (BRM) because its able to selectively target the pathologic element of the disease.

Baxter seeks FDA approval of Rixubis in paediatric hemophilia B patients

December 11, 2013 3:25 am / Leave a comment

Baxter International has filed an application to the US Food and Drug Administration (FDA) for a paediatric indication for Rixubis, Coagulation Factor IX (Recombinant), for the treatment of hemophilia B.

http://www.pharmaceutical-technology.com/news/newsbaxter-seeks-fda-approval-of-rixubis-in-pediatric-hemophilia-b-patients-4143322?WT.mc_id=DN_News

old article

Rixubis [Coagulation Factor IX (Recombinant)]

June 27, 2013 — The U.S. Food and Drug Administration yesterday approved Rixubis [Coagulation Factor IX (Recombinant)] for use in people with hemophilia B who are 16 years of age and older. Rixubis is indicated for the control and prevention of bleeding episodes, perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management, and routine use to prevent or reduce the frequency of bleeding episodes (prophylaxis).

read all at

http://www.drugs.com/newdrugs/fda-approves-rixubis-first-recombinant-coagulation-factor-ix-preventing-bleeding-episodes-3830.html

All About Drugs

December 11, 2013 1:01 am / Leave a comment

All About Drugs

Rilpivirine

December 10, 2013 7:18 am / 2 Comments on Rilpivirine

Rilpivirine

500287-72-9 cas no

4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile

Rilpivirine (TMC278, trade name Edurant) is a pharmaceutical drug, developed byTibotec, for the treatment of HIV infection.^[1]^[2] It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reducedside-effect profile compared with older NNRTIs, such as efavirenz.^[3]^[4]

Rilpivirine entered phase III clinical trials in April 2008,^[5]^[6] and was approved for use in the United States in May 2011.^[7] A fixed-dose drug combining rilpivirine with emtricitabine andtenofovir, was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera.^[8]

Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine(DAPY). Rilpivirine in combination with emtricitabine and tenofovir has been shown to have higher rates of virologic failure than Atripla in patients with baseline HIV viral loads greater than 100,000 copies.

Rilpivirine bound to proteins in the PDB

“TMC278 – A new NNRTI”. Tibotec. Retrieved 2010-03-07.
Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”.Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B (2006). “Short-term antiviral activity of TMC278–a novel NNRTI–in treatment-naive HIV-1-infected subjects”. AIDS 20 (13): 1721–6.doi:10.1097/01.aids.0000242818.65215.bd. PMID 16931936.
Pozniak A, Morales-Ramirez J, Mohap L et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. Oral abstract 144LB.
ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine
ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
“FDA approves new HIV treatment”. FDA. Retrieved 2011-05-20.
“Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination”. FDA. August 10, 2011.

FORMULATION

EDURANT (rilpivirine, Janssen Therapeutics) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C₂₂H₁₈N₆ • HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

EDURANT (rilpivirine) Structural Formula Illustration

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

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papers

Sun, et al.: J. Med. Chem., 41, 4648 (1998),

Kashiwada, et al.: Bioorg. Med. Chem. Lett., 11, 183 (2001)

Journal of Medicinal Chemistry, 2005 , vol. 48, 6 , pg. 2072 – 2079

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patents

WO201356003, WO200635067,

WO2013038425

The following PCT Publications describe the synthesis of Rilpivirine:

WO03016306, WO2005021001, WO2006024667, WO2006024668, W02994916581, WO2009007441, WO2006125809, and WO2005123662. [0006] Crystalline Rilpivirine base Forms I and II are described in the US Patent

Publication: US2010189796. Crystalline Rilpivirine HC1, Forms A, B, C, and D, are described in the US Patent Publications: US2009/012108, and US2011/0008434. Rilpivirine fumarate and a synthesis thereof are disclosed in WO2006024667.

country……………….patent……………approved……………expiry

United States	6838464	2011-05-20	2021-02-26
United States	7067522	2011-05-20	2019-12-20
United States	7125879	2011-05-20	2014-04-14
United States	7638522	2011-05-20	2014-04-14
United States	8080551	2011-05-20	2023-04-11
United States	8101629	2011-05-20	2022-08-09

Rilpivirine and its hydrochloride salt were disclosed in U.S. patent no. 7,125,879.Process for the preparation of rilpivirine was disclosed in U.S. patent no. 7,399,856 (‘856 patent). According to the ‘856 patent, rilpivirine can be prepared by reacting the (E)-3-(4-amino-3,5-dimethylphenyI)acrylonitrile hydrochloride of formula II with 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a in the presence of potassium carbonate and acetonitrile under reflux for 69 hours. The synthetic procedure is illustrated in scheme I, below:

Scheme 1 Process for the preparation of rilpivirine was disclosed in U.S. patent no.

7,705,148 (Ί48 patent). According to the Ί48 patent, rilpivirine can be prepared by reacting the 4-[[4-[[4-bromo-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile with acrylonitrile in the presence of palladium acetate, Ν,Ν-diethylethanamine and tris(2-methylphenyl)phosphine in acetonitrile. According to the Ί48 patent, rilpivirine can be prepared by reacting the compound of formula IV with 4-(4-chloropyrimidin-2-ylamino)benzonitrile formula Ill-a in the presence of hydrochloric acid and n-propanol to obtain a compound of formula Vll, and then the compound was treated with acetonitrile and potassium carbonate under reflux for 69 hours. The synthetic procedure is illustrated in scheme II, below:

Rilpivirine

Scheme II

U.S. patent no. 7,563,922 disclosed a process for the preparation of (E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride. According to the patent, (E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride can be prepared by reacting the 4- iodo-2,6-dimethyl-benzenamine in Ν,Ν-dimethylacetamide with acrylonitrile in the presence of sodium acetate and toluene, and then the solid thus obtained was reacted with hydrochloric acid in 2-propanol in the presence of ethanol and diisopropyl ether.

U.S. patent no. 7,956,063 described a polymorphic Form A, Form B, Form C and Form D of rilpivirine hydrochloride.

An unpublished application, IN 1415/CHE/201 1 assigned to Hetero Research

Foundation discloses a process for the preparation of rilpivirine. According to the application, rilpivirine can be prepared by reacting the 4-(4-chloropyrimidin-2- ylamino)benzonitrile with (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride in the presence of p-toluene sulfonic acid monohydrate and 1 ,4-dioxane. It has been found that the rilpivirine produced according to the prior art procedures results in low yields.

The synthesis is as follows:

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more info………………………..

Rilpivirine, which is chemically known as 4-{[4-({4-[(lE)-2-cyanoethenyl]-2,6- dimethylphenyl} amino) pyrimidin-2-yl]amino}benzonitrile, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and exhibits human immunodeficiency virus (HIV) replication inhibiting properties. Rilpivirine is used as its hydrochloride salt in the anti-HIV formulations.

Conventionally, various processes followed for the synthesis of Rilpivirine hydrochloride (I), generally involve preparation of the key intermediate, (E)-4-(2- cyanoemenyl)-2,6-dimethylphenylamine hydrochloride of formula (II).

(E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II)

WO 03/016306 first disclosed the synthesis of Rilpivirine involving different routes for synthesis of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine. The first route involved protection of the amino group of 4-bromo-2,6-dimemylphenylarnine by converting to Ν,Ν-dimethylmethanimidamide, followed by formylation involving n- butyl lithium and dimethylformamide. The resulting formyl derivative was treated with diethyl(cyanomethyl) phosphonate to give the cyanoethenyl compound which was deprotected using zinc chloride to yield the cyanoethenylphenylamine intermediate having an undisclosed E/Z ratio. This route involved an elaborate sequence of synthesis comprising protection of amine by its conversion into imide, use of a highly moisture sensitive and pyrophoric base such as butyl lithium and a low yielding formylation reaction. All these factors made the process highly unviable on industrial scale.

The second route disclosed in WO 03/016306 employed 4-iodo-2,6- dimethylphenylamine as a starting material for synthesis of cyanoemenylphenylamine intermediate, which involved reaction of the dimethylphenylamine derivative with acrylonitrile for atleast 12 hours at 130 C in presence of sodium acetate and a heterogeneous catalyst such as palladium on carbon. Isolation of the desired compound involved solvent treatment with multiple solvents followed by evaporation. This route also does not give any details of the E/Z ratio of the unsaturated intermediate product. Although this route avoids use of phosphine ligands but lengthy reaction time and problem of availability of pure halo-phenylamine derivatives coupled with moderate yields hampers the commercial usefulness of this route.

The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6- dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2- methylphenyl)phosphine and N,N-diethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2-cyanoethenyi)-2,6- dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio. Although the E/Z isomer ratio for the cyanoethenyl derivative obtained from these routes is not specifically disclosed in the patent, however, reproducibility of the abovementioned reactions were found to provide an E/Z ratio between 70/30 and 80/20. Various other methods have also been reported in the literature for introduction of the ‘ cyanoethenyl group in Rilpivirine. The Journal of Medicinal Chemistry (2005), 48, 2072-79 discloses Wittig or Wadsworth-Emmons reaction of the corresponding aldehyde with cyanomethyl triphenylphosphonium chloride to provide a product having an E/Z isomer ratio of 80/20. An alternate method of Heck reaction comprising reaction of aryl bromide with acrylonitrile in presence of tri-o- tolylphosphine and palladium acetate gave the same compound with a higher E/Z isomer ratio of 90/10. The method required further purification in view of the presence of a significant proportion of the Z isomer in the unsaturated intermediate. A similar method was disclosed in Organic Process Research and Development (2008), 12, 530-536. However, the E/Z ratio of 4-(2-cyanoethenyl)-2,6- dimethylphenylamine was found to be 80/20, which was found to improve to 98/2 (E/Z) after the compound was converted to its hydrochloride salt utilizing ethanol and isopropanol mixture.

It would be evident from the foregoing that prior art methods are associated with the following drawbacks:

a) High proportion of Z isomer, which requires elaborate purification by utilizing column chromatographic techniques, crystallization, or successive treatment with multiple solvents, which decreases the overall yield,

b) Introduction of cyanoethenyl group to the formylated benzenamine derivatives involves a moisture sensitive reagent like n-butyl lithium, which is not preferred on industrial scale. Further, the method utilizes cyanomethyl phosphonate esters and is silent about the proportion of the Z isomer and the higher percentage of impurities which requires elaborate purification and ultimately lowers the yield,

c) Prior art routes involve use of phosphine ligands which are expensive, environmentally toxic for large scale operations,

d) Prior art methods utilize phase transfer catalysts such as tetrabutyl ammonium bromide in stoichiometric amounts and the reactions are carried out at very high temperatures of upto 140-150°C.

Thus, there is a need to develop an improved, convenient and cost effective process for preparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) having Z-isomer less than 0.5%, without involving any purification and does not involve use of phosphine reagent and which subsequently provides Rilpivirine hydrochloride (I) conforming to regulatory specifications.

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http://www.google.com/patents/EP2643294A2?cl=en

The present inventors have developed a process for stereoselective synthesis of the key Rilpivirine intermediate, (E)-4-(2-cyanoethenyl)-2,6-dimemylphenylarnine hydrochloride (II), comprising diazotization of 2,6-dimethyl-4-amino-l- carboxybenzyl phenylamine followed by treatment with alkali tetrafluoroborate to provide the tetrafluoroborate salt of the diazonium ion which is followed by reaction with acrylonitrile in presence of palladium (II) acetate and subsequent deprotection of the amino group with an acid followed by treatment with hydrochloric acid to give the desired E isomer of compound (II) having Z isomer content less than 0.5% and with a yield of 75-80%. The compound (II) was subsequently converted to Rilpivirine hydrochloride of formula (I) with Z isomer content less than 0.1%.

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Chemical structures of selected NNRTIs

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http://pubs.acs.org/doi/full/10.1021/jm040840e

J. Med. Chem., 2005, 48 (6), pp 1901–1909

DOI: 10.1021/jm040840e

R278474, rilpivirine is the E-isomer of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, which can be synthesized in six high-yield reaction steps.⁶⁰ The end product contains minimal amounts (less than 0.5%) of the Z-isomer.

R278474 is a slightly yellow crystalline powder with molecular mass of 366.4 Da and a melting point of 242 °C. It is practically insoluble in water (20 ng/mL at pH 7.0), moderately soluble in poly(ethylene glycol) (PEG 400, 40 mg/mL), and readily soluble in dimethyl sulfoxide (>50 mg/mL). The compound is ionizable in aqueous solution (pK_a = 5.6) and is very lipophilic (log P = 4.8 at pH 8.0). For comparison, the pK_a value for TMC120 is 5.8 and the corresponding log P value amounts to 5.3.

Under daylight and in weak acid solution a conversion of 8% of the E-isomer of R278474 into the Z-isomer has been observed.

Purslane – The Gourmet Weed

December 10, 2013 4:03 am / 4 Comments on Purslane – The Gourmet Weed

Health benefits of Purslane

This wonderful green leafy vegetable is very low in calories (just 16 kcal/100g) and fats; nonetheless, it is rich in dietary fiber, vitamins, and minerals.
Fresh leaves contain surprisingly more omega-3 fatty acids (α-linolenic acid) than any other leafy vegetable plant. 100 grams of fresh purslane leaves provide about 350 mg of α-linolenic acid. Research studies show that consumption of foods rich in ω-3 fatty acids may reduce the risk of coronary heart disease, stroke, and help prevent the development of ADHD, autism, and other developmental differences in children.
It is an excellent source of Vitamin A, (1320 IU/100 g, provides 44% of RDA) one of the highest among green leafy vegetables. Vitamin A is a known powerful natural antioxidant and is essential for vision. This vitamin is also required to maintain healthy mucus membranes and skin. Consumption of natural vegetables and fruits rich in vitamin A is known to help to protect from lung and oral cavity cancers.
Purslane is also a rich source of vitamin C, and some B-complex vitamins like riboflavin, niacin, pyridoxine and carotenoids, as well as dietary minerals, such as iron, magnesium, calcium, potassium, and manganese.
Furthermore, present in purslane are two types of betalain alkaloid pigments, the reddish beta-cyaninsand the yellow beta-xanthins. Both pigment types are potent anti-oxidants and have been found to have anti-mutagenic properties in laboratory studies. [Proc. West. Pharmacol. Soc. 45: 101-103 (2002)].

Portulaca oleracea (common purslane, also known as verdolaga, pigweed, little hogweed, or pursley, and moss rose) is an annual succulent in the family Portulacaceae, which may reach 40 cm in height.

Greek salad with Purslane

Approximately forty varieties currently are cultivated.^[1] It has an extensive Old World distribution extending from North Africa through the Middle East and the Indian Subcontinentto Malesia and Australasia. The species status in the New World is uncertain: in general, it is considered an exotic weed, however, there is evidence that the species was in Crawford Lake deposits (Ontario) in 1430-89 AD, suggesting that it reached North America in the pre-Columbian era.^[2] It is naturalised elsewhere and in some regions is considered an invasiveweed. It has smooth, reddish, mostly prostrate stems and alternate leaves clustered at stem joints and ends. The yellow flowers have five regular parts and are up to 6 mm wide. Depending upon rainfall, the flowers appear at anytime during the year. The flowers open singly at the center of the leaf cluster for only a few hours on sunny mornings. Seeds are formed in a tiny pod, which opens when the seeds are mature. Purslane has a taproot with fibrous secondary roots and is able to tolerate poor, compacted soils and drought.

A Purslane cultivar grown as a vegetable

Although purslane is considered a weed in the United States, it may be eaten as a leaf vegetable. It has a slightly sour and salty taste and is eaten throughout much of Europe, the middle east, Asia, and Mexico.^[1]^[3] The stems, leaves and flower buds are all edible. Purslane may be used fresh as a salad, stir-fried, or cooked as spinach is, and because of its mucilaginous quality it also is suitable for soups and stews. Australian Aborigines use the seeds to make seedcakes. Greeks, who call it andrakla (αντράκλα) or glystrida (γλυστρίδα), fry the leaves and the stems with feta cheese, tomato, onion, garlic, oregano, and olive oil, add it in salads, boil it or add to casseroled chicken. In Turkey, besides being used in salads and in baked pastries, it is cooked as a vegetable similar to spinach. InAlbania it is called burdullak, and also is used as a vegetable similar to spinach, mostly simmered and served in olive oil dressing, or mixed with other ingredients as a filling for dough layers of byrek. In the south of Portugal (Alentejo), “baldroegas” are used as a soup ingredient.

Purslane contains more omega-3 fatty acids (alpha-linolenic acid in particular^[4]) than any other leafy vegetable plant. Studies have found that Purslane has 0.01 mg/g ofeicosapentaenoic acid (EPA). This is an extraordinary amount of EPA for a land-based vegetable source. EPA is an Omega-3 fatty acid found mostly in fish, some algae, and flax seeds.^[5] It also contains vitamins (mainly vitamin A, vitamin C, Vitamin E (alpha-tocopherol)^[6] and some vitamin B and carotenoids), as well as dietary minerals, such asmagnesium, calcium, potassium, and iron. Also present are two types of betalain alkaloid pigments, the reddish betacyanins (visible in the coloration of the stems) and the yellow betaxanthins (noticeable in the flowers and in the slight yellowish cast of the leaves). Both of these pigment types are potent antioxidants and have been found to have antimutagenic properties in laboratory studies.^[7]

100 Grams of fresh purslane leaves (about 1 cup) contain 300 to 400 mg of alpha-linolenic acid.^[8] One cup of cooked leaves contains 90 mg of calcium, 561 mg of potassium, and more than 2,000 IUs of vitamin A. A half-cup of purslane leaves contains as much as 910 mg of oxalate, a compound implicated in the formation of kidney stones; however, many common vegetables, such as spinach, also can contain high concentrations of oxalates. Cooking purslane reduces overall soluble oxalate content by 27%, which is important considering its suggested nutritional benefits of being part of a healthy diet.^[9]

When stressed by low availability of water, purslane, which has evolved in hot and dry environments, switches to photosynthesis usingCrassulacean acid metabolism (the CAM pathway): At night its leaves trap carbon dioxide, which is converted into malic acid (the souring principle of apples), and, in the day, the malic acid is converted into glucose. When harvested in the early morning, the leaves have ten times the malic acid content as when harvested in the late afternoon, and thus have a significantly more tangy taste.

Portulaca oleracea showing blooms

Seed pods, closed and open, revealing the seeds

Known as Ma Chi Xian (pinyin: translates as “horse tooth amaranth”) in traditional Chinese medicine, its active constituents include: noradrenaline, calcium salts, dopamine,DOPA, malic acid, citric acid, glutamic acid, asparagic acid, nicotinic acid, alanine, glucose, fructose, and sucrose.^[10] Betacyanins isolated from Portulaca oleracea improved cognition deficits in aged mice.^[11] A rare subclass of Homoisoflavonoids, from the plant, showed in vitro cytotoxic activities towards four human cancer cell lines.^[12]Use is contraindicated during pregnancy and for those with cold and weak digestion.^[10]Purslane is a clinically effective treatment for oral lichen planus,^[13] and its leaves are used to treat insect or snake bites on the skin,^[14] boils, sores, pain from bee stings, bacillary dysentery, diarrhea, hemorrhoids, postpartum bleeding, and intestinal bleeding.^[10]

Portulaca oleracea efficiently removes bisphenol A, an endocrine-disrupting chemical, from a hydroponic solution. How this happens is unclear.^[15]

Purslane, also known as Khulpha, Khursa in Hindi or Ghol in Marathi, is a water-retaining plant that can reach a height of 6″ – 12”. It’s smooth, reddish, thick leaves are wedge shaped. The leaves are alternately clustered at stem joints and are greenish on top and purplish on the underside.

The very tiny yellow flowers are around 6 mm wide and depending upon rainfall, the flowers appear at anytime during the year. Purslane has a taproot with fibrous secondary roots and is able to tolerate poor, compacted soils and drought.

It’s smooth, reddish, thick leaves are wedge shaped. The leaves are alternately clustered at stem joints and are greenish on top and purplish on the underside.

All that purslane needs to grow is part to full sun and clear ground. They are not picky about soil type or nutrition. If you decide to plant purslane seeds, simply scatter the seeds over the area that you plan on growing the purslane. Do not cover the seeds with soil. Purslane seeds need light to germinate, so they must stay on the surface of the soil. If you are using Purslane cuttings, lay them on the ground where you plan on growing purslane. Water the stems and they should take root in the soil in a few days.

About a month after the seeds are planted, the first flowers will begin to appear. Once the flowers open, the seeds will begin to set within about a week to ten days. Since the Purslane is an invasive plant, it is difficult to get rid of. This is because the plant has stored enough energy for the seeds to continue to mature even after you pull the plant. Therefore, if you are trying to get rid of purslane, don’t try to compost it. If the compost pile is not hot enough to destroy the seeds, you will end up with more plants you don’t want.

Purslane is ready to harvest in about 2 months from the time the seeds are sown. Make sure to harvest it regularly and be aware that it can become invasive. Harvesting before it develops flowers will help cut down on its spreading. Generally, you can harvest two or three times before the plants are exhausted.

The erect, tangy and succulent stems are high in Vitamin C. The leaves contain the highest concentration of Omega-3 fatty acids found in land plants. This is 5 times more than Spinach and 10 times more than any Lettuce or Mustard. It also contains Vitamin A, Vitamin C, and some Vitamin B and carotenoids as well as dietary minerals such as Magnesium, Calcium, Potassium and Iron.

100 Grams of fresh purslane leaves contain 300 to 400 mg of essential fatty acids (EFAs). One cup of cooked leaves contains 90 mg of Calcium, 561 mg of Potassium, and more than 2,000 IUs of Vitamin A.

As a companion plant, Purslane provides ground cover to create a humid microclimate for nearby plants, stabilizing ground moisture. Its deep roots bring up moisture and nutrients that those plants can use, and some, including corn, will “follow” purslane roots down through harder soil that they cannot penetrate on their own.

Widely used in East Mediterranean countries, archaeobotanical finds are common at manyprehistoric sites. In historic contexts, seeds have been retrieved from a protogeometric layer in Kastanas, as well as from the Samian Heraion dating to seventh century B.C. In the fourth century B.C., Theophrastus names purslane, andrákhne (ἀνδράχνη), as one of the several summer pot herbs that must be sown in April (H.P 7.12).^[16] As portulaca it figures in the long list of comestibles enjoyed by the Milanese given by Bonvesin de la Riva in his “Marvels of Milan” (1288).^[17]

In antiquity, its healing properties were thought so reliable that Pliny advised wearing the plant as an amulet to expel all evil (Natural History 20.120).^[16]

A common plant in parts of India, purslane is known as Sanhti, Punarva, or Kulfa.

The name verdolaga, associated with the plant that grows in South America is a nickname for Football clubs with green-white schemes in their uniforms, such as Colombia‘s Atletico Nacional and Argentina‘s Ferrocarril Oeste.

Marlena Spieler (July 5, 2006). “Something Tasty? Just Look Down”. The New York Times.
Byrne, R. and McAndrews, J. H. (1975). “Pre-Columbian puslane (Portulaca oleracea L.) in the New World”. Nature 253(5494): 726–727. doi:10.1038/253726a0.
Pests in Landscapes and Gardens: Common Purslane. Pest Notes University of California Agriculture and Natural Resources Publication 7461. October 2003
Jump up^ David Beaulieu. “Edible Landscaping With Purslane”. About.com.
ARTEMIS P SIMOPOULOS Omega-3 Fatty Acids and Antioxidants in Edible Wild Plants. 2004. Biol Res 37: 263-277, 2004
Simopoulos AP, Norman HA, Gillaspy JE, Duke JA. Common purslane: a source of omega-3 fatty acids and antioxidants. J Am Coll Nutr. 1992;11(4):374-82.
Evaluation of the Antimutagenic Activity of Different Vegetable Extracts Using an In Vitro Screening Test
A. P. Simopoulos, H. A. Norman, J. E. Gillaspy, and J. A. Duke. Common purslane: a source of omega-3 fatty acids and antioxidants. Journal of the American College of Nutrition, Vol 11, Issue 4 374-382, Copyright © 1992
http://world-food.net/oxalate-content-of-raw-and-cooked-purslane/
Tierra, C.A., N.D., Michael (1988). Planetary Herbology. Lotus Press. p. 199.
Wang CQ. Yang GQ., “Betacyanins from Portulaca oleracea L. ameliorate cognition deficits and attenuate oxidative damage induced by D-galactose in the brains of senescent mice.,Phytomedicine. 17(7):527-32, 2010 Jun.
Yan J, Sun LR, Zhou ZY, Chen YC, Zhang WM, Dai HF, Tan JW “Homoisoflavonoids from the medicinal plant Portulaca oleracea.” Phytochemistry. 2012 Aug;80:37-41
Agha-Hosseini F, Borhan-Mojabi K, Monsef-Esfahani HR, Mirzaii-Dizgah I, Etemad-Moghadam S, Karagah A (Feb 2010). “Efficacy of purslane in the treatment of oral lichen planus”.Phytother Res. 24 (2): 240–4. doi:10.1002/ptr.2919.PMID 19585472.
Bensky, Dan, et al. Chinese Herbal Medicine, Materia Medica. China: Eastland Press Inc., 2004.
Watanabe I. Harada K. Matsui T. Miyasaka H. Okuhata H. Tanaka S. Nakayama H. Kato K. Bamba T. Hirata K.”Characterization of bisphenol A metabolites produced by Portulaca oleracea cv. by liquid chromatography coupled with tandem mass spectrometry.” , Biotechnology & Biochemistry. 76(5):1015-7, 2012.
Megaloudi Fragiska (2005). “Wild and Cultivated Vegetables, Herbs and Spices in Greek Antiquity”.Environmental Archaeology 10 (1): 73–82.Noted by John Dickie, Delizia! The Epic History of Italians and Their Food (New York, 2008), p. 37.
Noted by John Dickie, Delizia! The Epic History of Italians and Their Food (New York, 2008), p. 37.

“Portulaca oleracea”. FloraBase. Department of Environment and Conservation, Government of Western Australia.
Online Field guide to Common Saltmarsh Plants of Queensland
Portulaca oleracea in West African plants – A Photo Guide.
Purslane Recipes, Prairieland Community Supported Agriculture

more info………..

Purslane, raw
Nutritional value per 100 g (3.5 oz)
Energy	84 kJ (20 kcal)
Carbohydrates	3.39 g
Fat	0.36 g
Protein	2.03 g
Water	92.86 g
Vitamin A	1320 IU
Thiamine (vit. B₁)	0.047 mg (4%)
Riboflavin (vit. B₂)	0.112 mg (9%)
Niacin (vit. B₃)	0.48 mg (3%)
Vitamin B₆	0.073 mg (6%)
Folate (vit. B₉)	12 μg (3%)
Vitamin C	21 mg (25%)
Vitamin E	12.2 mg (81%)
Calcium	65 mg (7%)
Iron	1.99 mg (15%)
Magnesium	68 mg (19%)
Manganese	0.303 mg (14%)
Phosphorus	44 mg (6%)
Potassium	494 mg (11%)
Zinc	0.17 mg (2%)
Link to USDA Database entry Percentages are roughly approximated using US recommendations for adults. Source: USDA Nutrient Database

Preparation and serving methods

The stems and flower buds are also edible. Trim the tough stems near roots using a sharp knife. Cook under low temperature for a shorter period in order to preserve the majority of nutrients. Although antioxidant properties are significantly decreased on frying and boiling, its minerals, carotenes and flavonoids may remain intact with steam cooking.

India gift to the world

In fact, among the many names given to purslane around the world, there are some like the old Arabic baqla hamqa or the Spanish verdilacas or yerba orate that mean crazy plant. It is a reference not just to its appearance, but to the madly unrestrained way it grows, spreading rapidly in all directions at ground level in a mesh of stems, roots and leaves, which is one reason why for many gardeners purslane is one of the most annoying weeds.

Added to this is its remarkable resilience — it stores water it in its succulent stems and leaves, allowing it to tolerate hot, dry conditions, and can produce over 240,000 tiny seeds per plant, making it really hard to remove. It’s no surprise that purslane has spread remarkably widely, growing in different forms in most parts of the world and known by a wide variety of names such as portulaca or little door, from the way its seed pod opens, or the Hebrew regelah or foot, since that’s near where it grows, though the most unusual must be the term from Malawi that translates as ‘the buttocks of the chief’s wife”, an apparent reference to the fleshy rounded leaves of some forms.

Despite this wide range, most botanical studies give India as the origin for purslane, and some writers, like the American expert on wild food, Euell Gibbons, have even labelled it “India’s gift to the world.” But it is a gift that we have largely forgotten about, since few people here eat purslane these days, or even know that this weed is edible. It is rarely cultivated, but gathered from the wild and only rarely appears in places like Bhaji Gully because few know its value, other than old people or poor migrants from rural areas who have some memory of eating it.

One who did know the value of luni was Mahatma Gandhi, and while it’s a bit of a stretch to describe purslane as his favourite food, as some of its enthusiasts abroad have done, he did recommend it to several people and, in an article in his magazine Harijan, he wrote about “the nourishing properties of the innumerable leaves that are to be found hidden among the grasses that grow wild in India.” He had discovered these while living in Wardha and following a diet of uncooked food that required what he felt was an unreasonable amount of purchases from the local market. So he was delighted when an ashram resident “brought to me a leaf that was growing wild among the Ashram grasses. It was luni. I tried it, and it agreed with me.” It soon was a regular part of his diet.

Gandhi’s recommendations, of course, are no guide to taste, since he didn’t believe in enjoying food for its own sake. But luni has a pleasant lightly acid taste when raw, though with a slightly grassy, earthy undertone that does take some getting used to. It is probably never going to be one of those foods you have to try-before-you-die, but it is not bad at all to eat, either raw in a salad, or cooked. I find that the version we get here, which is rather less fleshy than purslane I’ve seen abroad, is worth stir-frying or adding to a dal, which brings out a nice, slightly peanutty taste. Another interesting way to cook it is in the Persian style, first sautéing it with onions and then cooking with eggs to make a firm omelette that has a nicely herbal taste when cut up and eaten cold.

The real reason for valuing purslane though is not taste, but health. It has always had a reputation for medicinal properties, with physicians over the centuries, from India to the Middle East to Europe, recommending it for everything from reducing fever, removing worms and soothing urinary infections. But modern science has made clear why it is of such value: apart from providing significant amounts of vitamins A, B and C. and decent amounts of protein, purslane probably contains more omega-3 fatty acids than any other commonly available vegetable source.

These fatty acids are essential for reducing cholesterol and heart diseases, but their most easily accessible source is oily fish, which makes it hard for vegetarians to get them. Some health conscious ones do force themselves to swallow fish oil capsules, or eat alsi (flax seeds) which are also a decent source of omega-3 acids. But purslane is probably a better source, and can be cooked and eaten as part of one’s meal. (The only caution is for people prone to kidney stones, since it also contains high levels of the oxalates which cause them). Luni may seem like a crazy thing to eat, but when people around the world are realising the value of this Indian plant, it is the way we are letting it become forgotten that may be what is really loony.

Loxiglumide

December 10, 2013 3:37 am / 1 Comment on Loxiglumide

Loxiglumide

Loxiglumide, CR-1505
molecular formula :C21H30Cl2N2O5
molecular weight 461.3793
CAS NO:107097-80-3

WO 1987003869

Rottapharm (Originator)

4-[(3,4-Dichlorobenzoyl)amino]-5-[(3-methoxypropyl)pentylamino]-5-oxopentanoic acid, (±)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylglutaramic acid

Cholecystokinin (CCK) belongs to the group of substances known as brain-gut peptides and function as a neuropeptide and as a gut hormone. (Noble et al., Pharmacol. Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994, 15(4):731-755). It is now evident that at least two different receptors, namely CCK1 (formerly CCKA or alimentary) and CCK2 (formerly CCKB or brain) receptors, mediate CCK biological actions. (Noble et al., Pharmacol. Rev., 1999, 51(4):745-781; Woodruff and Hughes, Ann. Rev. Pharmacol. 1991, 31:469-501). CCK1 receptors are found in peripheral tissues, including the GI tract.

CCK is secreted primarily in response to meals and plays a well-recognized role in regulating gallbladder contraction and pancreatic enzyme secretion. Over the last decade, considerable evidence has emerged to support the concept that CCK plays an equally important role in the regulation of motor and sensory functions at various levels of the human upper GI tract. Specifically, the native peptide delays gastric emptying, modulates gastric sensory function (especially in response to fat), increases the rate of meal-induced, transient lower esophageal sphincter relaxations (TLESRs) and affects small bowel and colonic transit.

The CCK1 antagonists loxiglumide and dexloxiglumide have demonstrated the ability to reverse the physiologic effects of CCK on gastric emptying and to decrease dyspeptic symptoms induced by air distension and fat infusion. By example,loxiglumide reduced both exogenous and endogenous CCK-induced delay in gastric emptying of liquids and solids in healthy subjects (Borovicka et al., Am J Physiol. 1996, 271:448-453; Schwizer et al., Gut. 1997, 41(4):500-504). Dexloxiglumide reversed the diminished tolerance to water volume that occurred from CCK release in response to duodenal lipid infusion; the effect was due to reduction of intragastric volume, primarily due to accelerated gastric emptying (Lal et al., Am J Physiol Gastrointest Liver Physiol. 2004, 287(1):72-79). When proximal gastric relaxation was produced in healthy subjects by duodenal infusion of lipid, a potent stimulus of CCK release, the relaxation was reversed by loxiglumide (Feinle et al., Gastroenterology 1996, 110(5):1379-1385). Also, loxiglumide modulated antro-pyloroduodenal dysmotility, which is postulated to play a role in generation of dyspeptic symptoms, after it was experimentally induced in healthy subjects by intraduodenal infusion of a mixed liquid meal (Katschinski et al., Eur J Clin Invest. 1996, 26(7):574-583). Loxiglumide was also able to reverse the lowering of intragastric pressure of healthy subjects after duodenal infusion of lipids induced sensations such as fullness and nausea (See Feinle et al., 1996).

In patients with nonulcer dyspepsia and delayed gastric emptying, loxiglumide was shown to accelerate gastric emptying by comparison to placebo (Chua AS, Bekkering M, et al., 1994). Loxiglumide significantly improved dyspeptic symptoms in patients with non-ulcer dyspepsia in an 8-week study (Chua et al., Ann N Y Acad. Sci. 1994, 713:298-299). In another study in patients with functional dyspepsia, aggravation of nausea, fullness, discomfort, bloating and pain was produced by duodenal infusion of lipid with or without balloon distension; dexloxiglumide significantly improved dyspepsia symptom scores compared to placebo (Feinle et al., Gut. 2001, 48(3): 347-355).

Pharmaceutical compositions comprising CCKB antagonists and a proton pump inhibitor to control gastric acid secretion in gastrointestinal disorders have been described in the literature. (See WO 04/098610, WO 04/101533, WO 04/098609, WO 03/041714, WO 01/90078, WO 01/85724, WO 01/85723, WO 01/85704, WO 01/85167, and WO 93/12817) CCK-B receptors mediate CCK biological actions in the brain and are one of several regulators of gastric acid secretion. It is the CCK1 receptors, however, that mediate the CCK biological actions in peripheral tissues including gastric emptying and esophageal sphincter effects.

In addition, combination therapy of a PPI and a second agent, e.g., loxiglumide, to improve impaired esophageal motility has been disclosed as a possible treatment to gastroesophageal reflux disease. (Tonini et al., Drugs 2004, 64(4): 347-361). International Application Nos. PCT/EP2004/050936 and PCT/EP2005/050336 also disclose pharmaceutical combinations of a proton pump inhibitor and a compound that modifies gastrointestinal motility. Both international applications disclose that dexloxiglumide may be useful for therapy of irritable bowel syndrome (IBS) or GERD and may be used to modify gastrointestinal motility.

D,l-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide.

N-(3,4-dichlorobenzoyl)-glutamic acid anhydride (I) is condensed with N-(3-methoxypropyl)-N-pentylamine (II) in water at 5 °C to produce Loxiglumide.

loxiglumide

Percent Composition: C 54.67%, H 6.55%, Cl 15.37%, N 6.07%, O 17.34%

Literature References: Cholecystokinin type-1 (CCK-1) antagonist. Prepn: F. Makovec et al., WO 8703869; eidem, US 4769389(1987, 1988 both to Rotta).

Pharmacology and receptor binding: I. Setnikar et al., Arzneim.-Forsch. 37, 703 (1987). Pharmacokinetics: idem et al., ibid. 38, 716 (1988). Effect on bilio-pancreatic secretion: W. E. Schmidt et al., Digestion 46, Suppl. 2, 232 (1990). Clinical evaluation in irritable bowel syndrome: P. A. Cann et al., Ann. N.Y. Acad. Sci. 713, 449 (1994); in nonulcer dyspepsia: A. S. B. Chua et al. ibid. 451; in pancreatitis: K. Shiratori et al., Pancreas 25, e1 (2002).

Properties: Crystals from acetone, mp 113-115°. pKa ~5. Soly in water: 0.01%.

Melting point: mp 113-115°

pKa: pKa ~5

………………………………………………………………….

Derivative Type: (R)-Form

CAS Registry Number: 119817-90-2

Additional Names: Dexloxiglumide

Manufacturers’ Codes: CR-2017

Literature References: HPLC determn in plasma: R. Brodie et al., J. Chromatogr. B 784, 91 (2003). In vitro biopharmaceutical properties: S. Tolle-Sander et al., J. Pharm. Sci. 92, 1968 (2003). Clinical pharmacokinetics: C. Webber et al., Xenobiotica 33, 625 (2003). Clinical evaluation in irritable bowel syndrome: F. Cremonini et al., Am. J. Gastroenterol. 100, 652 (2005).

Properties: Soly (mg/ml): 33 (pH 3.4), 533 (pH 7.5). pKa 4.48.

pKa: pKa 4.48

Therap-Cat: Gastroprokinetic.

Keywords: CCK Antagonist; Gastroprokinetic.

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FDA Advisory Committee Recommends Approval of Takeda’s Investigational Biologic Vedolizumab

December 10, 2013 3:27 am / Leave a comment

Deerfield, Ill., December 9, 2013 and Osaka, Japan, December 10, 2013 — Takeda Pharmaceutical Company Limited (“Takeda”) and its wholly-owned subsidiary, Takeda Pharmaceuticals U.S.A., Inc., today announced that a joint panel of members from the Gastrointestinal Drugs and Drug Safety and Risk Management Advisory Committees of the United States (U.S.) Food and Drug Administration (FDA) voted to recommend approval of Takeda’s vedolizumab for the treatment of adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). All 21 committee members voted that based on currently available efficacy and safety data, the benefits outweigh the potential risks of vedolizumab to support approval for UC. Specifically, 13 committee members supported approval for UC patients who have failed steroids or immunosuppressants or TNF-α antagonists, while eight committee members supported approval for UC patients who have failed immunosuppressants or TNF-α antagonists (the indicated population would not include patients that failed steroids only). Twenty of the 21 committee members voted to support approval for CD. Specifically, 14 committee members supported approval for CD patients who have failed steroids or immunosuppressants or TNF-α antagonists while six supported approval for CD patients who have failed immunosuppressants or TNF-α antagonists (the indicated population would not include patients that failed steroids only).

read at

http://www.drugs.com/nda/vedolizumab_131209.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+December+9%2C+2013

About Crohn’s disease and ulcerative colitis
Crohn’s disease (CD) and ulcerative colitis (UC) are the two most common forms of inflammatory bowel disease (IBD), which is marked by inflammation in the lining of the GI tract. CD can impact any part of the digestive tract, and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and/or fever. UC impacts the large intestine only, which includes the colon and the rectum. The most common symptoms of UC include abdominal discomfort and blood or pus in diarrhea. There is no known cause for CD or UC, although many researchers believe that the interaction of an outside agent, such as a virus or bacteria, with the body’s immune system may trigger them. No cure exists for CD or UC; the aim of IBD treatments is to induce and maintain remission, or achieve extended periods of time when patients do not experience symptoms.

About vedolizumab
Vedolizumab was developed for the treatment of CD and UC, as a gut-selective, humanized monoclonal antibody that specifically antagonizes the alpha4beta7 (α4β7) integrin, which is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in CD and UC. α4β7 binds with a specific adhesion molecule primarily expressed in the intestinal tract. Therefore, vedolizumab, by preventing this interaction, has a gut selective effect.

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, http://www.takeda.com.

Vedolizumab is a monoclonal antibody being developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn’s disease.It binds to integrin α₄β₇(LPAM-1, lymphocyte Peyer’s patch adhesion molecule 1).^[1]^[2]

The molecule was first identified by Dr. Andrew Lazarovits [1][2] as the murine MLN0002 homologue. His discovery of the mouse equivalent of this antibody—originally applied to anti-rejection strategies in kidney transplantation—was published in the journal Nature in 1996. The drug was then licensed to Millennium Pharmaceuticals of Boston for further development.

As of October 2009, vedolizumab is undergoing Phase III trials.^[3] Clinical trials indicate that Vedolizumab was found safe and highly effective for inducing and maintaining clinical remission in patients with moderate to severe ulcerative colitis [3]. Dr. Brian Faegan, head researcher, reported an absence of any instances of progressive multifocal leukoencephalopathy (PML), which is a particularly important finding [4]. It looks like it will be an effective abiologic agent without some of the toxicity issues previously seen with anti-TNF drugs .

It is widely believed now that “vedolizumab can be used either as a first-line treatment or in case of anti-TNF failure”

Statement On A Nonproprietary Name Adopted By The USAN Council – Vedolizumab, American Medical Association.
Soler, D; Chapman, T; Yang, LL; Wyant, T; Egan, R; Fedyk, ER (2009). “The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases”. The Journal of Pharmacology and Experimental Therapeutics 330 (3): 864–75. doi:10.1124/jpet.109.153973. PMID 19509315.
ClinicalTrials.gov NCT00790933 Study of Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn’s Disease (GEMINI II)

RIVASTIGMINE

December 9, 2013 8:02 am / 1 Comment on RIVASTIGMINE

RIVASTIGMINE

123441-03-2 cas no

129101-54-8 CAS NO

Rivastigmine, (sold under the trade name Exelon) is a parasympathomimetic orcholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s typeand dementia due to Parkinson’s disease. The drug can be administered orally or via atransdermal patch; the latter form reduces the prevalence of side effects, which typically include nausea and vomiting.The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of Jerusalem and sold to Novartis by Yissum for commercial development.(It is a semi-synthetic derivative of physostigmine) It has been available in capsule and liquid formulations since 1997. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated withParkinson’s disease; and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia

PATENT

US 4,948,807

Patent 5,602,176
Issued: February 11, 1997
Inventor(s): Enz; Albert
Assignee(s): Sandoz Ltd.Patent expiration dates:

February 11, 2014

R. Amstutz, A. Enz, M. Marzi, M. Boelsterli, M. Walsinshaw

Amstutz, R.; Enz, A.; Marzi, M.; Boelsterli, J.; Walkinshaw, M. (1990). “Cyclische Phenyl-carbamate des Miotin-Typs und ihre Wirkung auf die Acetylcholinesterase”. Helvetica Chimica Acta(in German) 73 (3): 739. doi:10.1002/hlca.19900730323.

Rivastigmine hydrogen tartrate is chemically known as (S)-N-Ethyl-N-methyl-3- [1-(dimethylamino) ethyl]-phenyl carbamate hydrogen- (2R, 3R)-tartrate (hereinafter referred to as “rivastigmine tartrate”) and has structural Formula I.
Rivastigmine hydrogen tartrate is administered for the inhibition of reversible cholinesterase and is marketed under the brand name EXELON^™ as capsules containing 0.5, 3, 4.5 and 6 mg rivastigmine base equivalent.
U.S. Patent No. 4,948,807 describes the compound N-ethyl, N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anticholinesterase activity in humans.
U.S. Patent No. 5,602,176 describes (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl carbamate in free base or acid addition salt form as useful for its anticholinesterase activity.
International Application Publication No. WO 2004/037771 A1 and European Patent 193926 describe a process for the preparation of (S)-3-[1-(dimethylamino)-ethyl]-phenyl-N-ethyl-N-methyl carbamate by the reaction of optically active m-hydroxyphenylethyl dimethylamine with a carbamoylhalide
International application No. WO 2005/058804A1 describes a process for the preparation of rivastigmine by streoselective reduction.

The synthesis of rivastigmine was reported in U.S. Pat. No. 5,602,176, GB2409453, and Yonwen, Jiang et. al. [Journal of East China Normal University (Natural Science), 2001, 1, 61-65], in which the method is disclosed as: preparing racemic rivastigmine by a series of reactions, then salifying the result with D-(+)-O, o′-bis-p-tolyl formacyl tartaric acid monohydrate (D-DTTA) to separate the racemic mixture, and recrystallizing at least three time to obtain (S)-rivastigmine with an optical purity of above 99%. The final yield is only 5.14%.

A method for resolution of a intermediate of rivastigmine is disclosed in WO200403771, in which S-(+)-camphor sulfonic acid is used to separate racemic intermediates of 3-(1-(S)—(N,N-dimethylamino) ethyl)phenol, and optically pure 3-(1-(S)—(N,N-dimethylamino) ethyl)phenol is obtained after three times recrystallization and then condensates with N-methyl-N-ethyl-amino formacyl chloride to obtain (S)-rivastigmine. The specific synthesis route is shown below:

A method for resolution of a intermediate of rivastigmine is also disclosed in WO2007014973, in which S-(+)-camphor sulfonic acid is used to separate racemic intermediates of 3-(1-(methylamino) ethyl)phenol, and the result condensates with N-methyl-N-ethyl-amino formacyl chloride to obtain N-methylethylcarbamino-3-[(S)-1-(methylamino)-ethyl]phenyl ester, and a methylation is then performed on the nitrogen atom followed by salifying with L-(+)-tartaric acid so that rivastigmine is obtained. The methylation needs a reduction system of sodium cyanoborohydride/formaldehyde, in which sodium cyanoborohydride is highly toxic, so that the method is not suitable for industrial production. The specific synthesis route is shown below:

The resolution methods mentioned above are time consuming with low yields, so that final yields are reduced and costs are increased, which are not beneficial for industrial production and the optical purity of rivastigmine cannot be guaranteed.

K. Han, C. Kim, J. Park*, M.-J. Kim*
Pohang University of Science and Technology, Korea
Chemoenzymatic Synthesis of Rivastigmine via Dynamic Kinetic Resolution as a Key Step
J. Org. Chem. 2010, 75: 3105-3108

Rivastigmine (Exelon®) is an acetylcholinesterase inhibitor that is prescribed for the treatment of mild to moderate dementia in patients with Alzheimer’s disease and Parkinson’s disease. The key step in the synthesis depicted is a dynamic kinetic resolution of the benzylic secondary alcohol B involving a lipase (Novozyme 435) coupled with a polymer-bound racemization catalyst (C).

The polymer-bound racemization catalyst C was prepared by heating a polymer-bound benzoyl chloride with [Ph4(η4-C4CO]Ru(CO)3 in toluene for one day. The catalyst can be recycled several times. The enzymatic resolution was performed on a 1 mmol scale. For an alternative chemoenzymatic synthesis of rivastigmine, see: J. Mangas-Sánchez et al. J. Org. Chem. 2009, 74, 5304.

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http://www.google.com/patents/EP1980552A2

EXAMPLES

EXAMPLE 1:

To a solution of 200 g of 3-hydroxyacetophenone of Formula IX in 400 ml of acetone, 244 g of potassium carbonate were charged and stirred for about 10 minutes. To the above reaction mixture 204 g of dimethyl sulphate was added for about 60 minutes followed by heating to about 45 °C and stirred for about 1 hour. After completion of the reaction, the reaction mixture was quenched by charging of 800 ml of water. Organic and aqueous layers were separated and 370 g of ammonium formate was added to the organic layer. The contents were then heated to about 180 °C and stirred for about 2 hours. The reaction mixture was then cooled to about 30° C and 600 ml of water was charged. The mixture was extracted with ethyl acetate (1×400 ml, 2×150 ml). The organic layers were combined and charged 600 ml of hydrogen chloride in isopropanol (18% w/w) followed by heating to about 75 °C and stirred for about 3 hours. The mixtures was distilled completely at about 65 °C under vacuum and again charge 100 ml ethyl acetate and distilled completely at about 65°C to afford residue.
600 ml of ethyl acetate was charged to the residue and stirred for 30 minutes. Filtered the solid and was washed with 200 ml of ethyl acetate. The wet solid was then charged into 600 ml of water and pH was adjusted to about 11 by addition of 68.8 ml of 40% aqueous sodium hydroxide. The reaction mixture was extracted with ethyl acetate (1×200 ml, 2×100 ml). Organic and aqueous layers were separated and the organic layer was distilled off completely at about 65 °C under vacuum to afford 128 g of the title compound.
HPLC purity: 99.1%

EXAMPLE 2:

To a solution of 40 g of 1- (3-methoxyphenyl) ethyl amine of Formula VI in 1400 ml of isopropyl alcohol, 41.2 g of L-(+)-mandelic acid was added and stirred for about 15 minutes. The mixture was heated to about 75°C and stirred for about 45 minutes followed by cooling to about 37°C and stirred for about 10 minutes. The separated solid was filtered and the solid was washed 80 ml of isopropyl alcohol. The solid obtained was suck dried for 3 hours to obtain the wet compound of the diasteromeric salt of Formula V.
The obtained diasteromeric salt of Formula V was charged into a clean and dry round bottom flask containing 480 ml of isopropyl alcohol followed by heating to reflux. The resultant solution was stirred at reflux for about 45 minutes followed by cooling to about 37° C and stirred for about 10 minutes. Solid was separated by filtration and the solid was washed with 20 ml of isopropyl alcohol. The solid obtained was dried at about 55 °C for about 2 hours to yield 29 g of the title compound.
Purity by chiral HPLC: 99.9%.

EXAMPLE 3:

To a solution of 200 g of S-(-)-1-(3-methoxyphenyl)ethyl amine L (+)-Mandalate (diasteromeric salt) of Formula V in 800 ml of water, charged 148 g of formaldehyde (40%), 182.1 g of formic acid (98%) and the contents were heated to about 100 °C. The resultant mixture was stirred at about 100 °C for about 5 hours. After the completion of the reaction, the mixture was cooled to about 30° C and washed with toluene (3x1000ml). Aqueous layer pH was adjusted to 10.5 using 160 ml of 40% aqueous sodium hydroxide solution and extracted with ethyl acetate (2×500 ml). The organic layers were combined and washed with water (2×400 ml). The organic layer was distilled completely at about 60 °C under vacuum to yield 108 g of the title compound.
Purity by HPLC: 98.15%.

EXAMPLE 4:

50 g of S-(-)-[1-(3-methoxyphenyl) ethyl] dimethyl amine of Formula IV and 283 g of 48% aqueous HBr solution were charged into a clean and round bottom flask followed by heating to about 110° C and stirred for about 6 hours. After completion of the reaction, the mixture was cooled to about 30°C and charged 250 ml of water and pH was adjusted to about 10.5 using 162 ml caustic lye and the reaction mixture was extracted with ethyl acetate ((1×150 ml, 2×50 ml)). The organic layer thus obtained was washed with water (2×50 ml) and treated with activated charcoal. The organic layer is filtered through celite and washed with 100 ml of ethyl acetate. The filtrate was distilled completely at below 60° C under vacuum. To the residue charged 200 ml of n-heptane at about 50°C and stirred for about 90 minutes at about 25°C. The separated solid was filtered and washed the solid with n-heptane 50 ml and suck dried. The solid obtained was dried at about 50°C for about 5 hours to yield 41.5 g of the title compound.
Purity by HPLC: 99.07%.

EXAMPLE 5:

6 kg of S-(-)-[1-(3-hydroxyphenyl) ethyl] dimethyl amine of Formula III and 12 L of Methyl Isobutyl Ketone(MIBK) were charged and stirred for about 10 minutes. To this reaction solution 3.44 kg of pyridine, 1.18 kg of tetrabutylammonium bromide were charged and stirred for about 15 minutes to form clear solution. 3.97 kg of N-ethyl, N-methyl carbomyl chloride was added to the reaction mixture for about 30 minutes. Heated the contents to about 30°C and stirred for about 15 hours. After completion of the reaction 48 lit of water was charged and pH was adjusted to about 1.5 using 3.72 lit of 36% aqueous hydrochloric acid. Stirred the contents for about 30 minutes at about 25°C and aqueous layer was separated. The aqueous layers were then washed with MIBK (2×12 lit) and separate the aqueous layer. Aqueous layer pH was adjusted to 12.5 using 6 lit of 40% aqueous sodium hydroxide solution and stirred for about 15 minutes. The aqueous layer was then extracted with MIBK (2×12 lit) and separated the organic layer. Washed the organic layer with water (2×12 lit) and separated the organic layer. The obtained organic layer was distilled off completely at about 60°C to afford residue.
To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5°C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution(caustic lye). The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2×12 lit). The organic layer was distilled completely at about 60°C to afford residue.
To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5°C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution. The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2x121it). The organic layer was distilled completely at about 60°C to afford the title compound
Purity by HPLC. 99.33%

EXAMPLE 6

3 kg of rivastigmine freebase of Formula II in 105 lit of acetone, 1.8 kg of L-(+)-Tartaric acid was charged and heated to about 60° C followed by stirring for about 30 minutes for complete dissolution. The resulting reaction solutions was passed through celite and wash the bed with 13.5 lit acetone to made particle free. The obtained clear solution was distilled off up to 50% of the initial volume and cooled to 30°C. 12 g of rivastigmine hydrogen tartrate was added and stirred for about 60 minutes. The reaction mixture was heated to reflux and stirred for about 60 minutes and cooled to about 30°C and stirred for about 60 minutes for solid separation. The separated solid was filtered and washed the solid with 3 lit of acetone. Solid obtained was dried at about 60° C for about 9 hours to afford 4.10 kg of the title compound.
Purity by HPLC: 97.37%.

………………………

Achiral bis-imine in combination with CoCl₂: A remarkable effect on enantioselectivity of lipase-mediated acetylation of racemic secondary alcohol

K. Arunkumar^1,2, M. Appi Reddy¹, T. Sravan Kumar¹, B. Vijaya Kumar¹, K. B. Chandrasekhar²,P. Rajender Kumar¹ and Manojit Pal³

¹Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
²Department of Chemistry, Jawaharlal Nehru Technological University of Anantapur, Anantapur 515002, Andhra Pradesh, India,
³Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India

Corresponding author email

Associate Editor: S. Flitsch

Beilstein J. Org. Chem. 2010, 6, 1174–1179.

SPECTRAL DATA FOR FREE BASE DEPICTED AS (S)-8

1H NMR (CDCl3, 300 MHz) δ 1.17-1.27 (m, 3H), 1.37 (d, 3H, J = 6.4 Hz, CH3), 2.21 (s, 6H), 3.04 (s, 3H, CH3), 3.25 (q, J1 = 7.2 Hz, J2 = 6.4 Hz), 3.43 (q, 1H, J1 = 7.2 Hz, J2 = 6.8 Hz), 3.48 (q, 1H, J1 = 6.8 Hz, J2 = 7.2 Hz), 7.01 (d, 1H, J = 8.0 Hz), 7 . 1 8 ( d , 1 H , J = 8 . 0 H z ) ,7.26 (s, 1H,), 7.33 (t, 1H, J = 8.0 Hz);

13C NMR (CDCl3, 100 MHz) δ 154.4 (1C, C=O), 151.4 (CH), 129.3
(CH), 124.7 (CH), 121.2 (CH), 120.8 (2C, CH), 77.1 (1C), 66.0 (1C, CH2), 43.9 (2C, N-Me),34.6 (1C, Mecarbamoyl), 20.3 (1C, CH3), 12.4 (1C, Mecarbamoyl); M/z 251.20 (M+ H) +;

IR (cm -1, KBr) 2975, 1723 (C=O); HRMS (ESI): calcd for C14H22N2O2 (M+ H)+251.1760, found 251.1767;

[α]20D = -33.90 (C=1, CHCl3).

……………………………

http://www.google.com/patents/US8324429

US8324429

SPECTRAL DATA FOR TARTRATE

Figure US08324429-20121204-C00001

Optical rotation [α]²⁰ _D=+6.0°, C=5, ethanol; mp 122.3-124.1

¹H NMR (CDCl₃) δ ppm: 1.24, 1.16 (2×t, 3H), 1.67 (d, 3H), 2.65 (s, 6H), 2.96, 3.05 (2×s, 3H), 3.37, 3.45 (2×q, 2H), 4.34 (q, 1H), 4.47 (s, 2H), 7.14 (t, 1H), 7.20 (s, 1H), 7.28 (d, 1H), 7.39 (t, 1H); MS (ESI) m/z: 251.2.

…………………………….

US8324429

FREE BASE

Optical rotation [α]²⁰ _D=−32.1°, C=5, ethanol.

¹H NMR (CDCl₃) δ ppm: 1.22 (m, 3H), 1.35 (q, 3H), 2.20 (s, 6H), 3.02 (d, 3H), 3.25 (m, 1H), 3.44 (s, 2H), 7.05 (m, 3H), 7.27 (m, 1H); MS (ESI) m/z: 251.2 (M⁺+1).

Figure US08324429-20121204-C00011

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

Farletuzumab

December 9, 2013 7:23 am / Leave a comment

Farletuzumab

Farletuzumab (MORAb-003) is a monoclonal antibody^[1] which is being investigated for the treatment of ovarian cancer.^[2]^[3]

This drug was developed by Morphotek, Inc.

It is targeted at FR-alpha which is overexpressed in some cancers such as ovarian cancer.

USAN FARLETUZUMAB
PRONUNCIATION far” le tooz’ oo mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL NAMES
1. Immunoglobulin G1, anti-(human receptor FR-α (folate receptor α)) (human-mouse monoclonal MORAb-003 heavy chain), disulfide with human-mouse monoclonal MORAb-003 κ-chain, dimer
2. Immunoglobulin G1, anti-(human folate receptor alpha (ovarian tumor-associated antigen Mov18)); humanized mouse monoclonal MORAb-003 γ1 heavy chain (222-217′)-disulfide with humanized mouse monoclonal MORAb-003 κ light chain (228-228”:231-231”)-bisdisulfide dimer
MOLECULAR FORMULA C6466H9928N1716O2020S42
MOLECULAR WEIGHT 145.4 kDa

MANUFACTURER Morphotek, Inc.
CODE DESIGNATION MORAb-003
CAS REGISTRY NUMBER 896723-44-7

Farletuzumab, a humanized monoclonal antibody that targets the folate receptor alpha (FRα), could potentially be used in the treatment of patients with relapsed ovarian cancer, according to the results of a recent open-label phase II trial.Armstrong and colleagues investigated the efficacy of farletuzumab as a single agent or in combination with standard chemotherapy in patients with relapsed ovarian cancer following first-line therapy.

Farletuzumab is a humanized IgG1 monoclonal antibody that targets
the human folate receptor FRα, which is overexpressed in most ovarian
epithelial cancers. It is being developed by Morphotek (now part of
Eisai) for the treatment of ovarian cancer, with regulatory submissions
in 2012.

The pivotal Phase III study in ovarian cancer began
in March 2009; Phase II studies in other indications have since begun.
The 900-patient Phase III study is evaluating two doses of
farletuzumab as an add-on to the standard treatment regimen of
carboplatin and a taxane; this study is completed in
September 2012. A 165-patient study in lung adenocarcinoma began in
December 2010. The initial Phase I study in 25 patients with epithelial
ovarian cancers showed farletuzumab to be well tolerated, with evidence
of efficacy in 36% of the patients (Konner et al. 2010).22

Phase II data from a 54-patient study were presented at the 2008 ASCO meeting, with at least some evidence of efficacy seen in 90% of the treated patients.
Farletuzumab represents one of a number of new treatment options
being developed for the treatment of ovarian cancer, with several other
modalities such as kinase inhibition or PARP inhibition also showing
promise. However, the available evidence suggests that farletuzumab
is likely to represent a significant enhancement in the subset of ovarian
cancer patients at which it has been targeted. If it becomes widely
accepted as a component of the platinum-based treatment regimen, then
it can be expected to be a significant commercial success.

Statement On A Nonproprietary Name Adopted By The Usan Council – Farletuzumab, American Medical Association.
ClinicalTrials.gov: Phase II Efficacy and Safety Study of MORAb-003 in Platinum-Resistant or Refractory Relapsed Ovarian Cancer
ClinicalTrials.gov: Phase III Efficacy and Safety of MORAb-003 in Subjects With Platinum-sensitive Ovarian Cancer in First Relapse

…………………

Monoclonal antibodies for tumors

Tumor (“-t(u[m])-“)

Human (“-tumu-“)	Adecatumumab Cixutumumab Conatumumab Daratumumab Drozitumab Duligotumab Dusigitumab Figitumumab Ganitumab Glembatumumab vedotin Intetumumab Iratumumab Lexatumumab Lucatumumab Mapatumumab Narnatumab Necitumumab Ofatumumab Olaratumab Panitumumab Patritumab Pritumumab Radretumab Rilotumumab Robatumumab Teprotumumab Tovetumab Vantictumab Votumumab Zalutumumab “-melu-” (melanoma): Flanvotumab

Mouse (“-tumo-“)	Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab CC49 Detumomab Ibritumomab tiuxetan Minretumomab Mitumomab Moxetumomab pasudotox Naptumomab estafenatox Nofetumomab merpentan Pemtumomab^† Pintumomab Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Tenatumomab Tositumomab 3F8 “-govo-” (ovarian tumor): Abagovomab · Igovomab · Oregovomab “-pro-” (prostate tumor): Capromab pendetide “-colo-” (colonic tumor): Edrecolomab · Nacolomab tafenatox

Chimeric (“-tuxi-“)	Amatuximab Bavituximab Brentuximab vedotin Cetuximab Ensituximab Futuximab Girentuximab Indatuximab ravtansine Margetuximab Rituximab Siltuximab Ublituximab “-mexi-” (melanoma): Ecromeximab

Humanized (“-tuzu-“)	Obinutuzumab Alemtuzumab Bevacizumab Bivatuzumab mertansine Cantuzumab mertansine Cantuzumab ravtansine Citatuzumab bogatox Clivatuzumab tetraxetan Dacetuzumab Dalotuzumab Elotuzumab^† Etaracizumab Farletuzumab Ficlatuzumab Gemtuzumab ozogamicin Imgatuzumab Inotuzumab ozogamicin Labetuzumab Lintuzumab Lorvotuzumab mertansine Matuzumab^§ Milatuzumab Nimotuzumab Ocaratuzumab Onartuzumab Oportuzumab monatox Parsatuzumab Pertuzumab Sibrotuzumab Simtuzumab Tacatuzumab tetraxetan Tigatuzumab Trastuzumab Tucotuzumab celmoleukin Veltuzumab Vorsetuzumab mafodotin

Rat/mouse hybrid (“-tumaxo-“)	Catumaxomab Ertumaxomab

Chimeric + humanized (“-tuxizu-“)	Ontuxizumab

Traxoprodil mesylate

December 9, 2013 1:04 am / Leave a comment

Traxoprodil mesylate

Traxoprodil mesylate
MF:C23-H35-N-O2.C-H4-O3-S
MW:453.6401
CAS:189894-57-3 mesylate

134234-12-1 (free base)

Traxoprodil mesylate, CP-101606-27,

(S, S) -1 – (4-Hydroxyphenyl) -2 – [4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol methanesulfonate trihydrate

Pfizer (Originator)

Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists

J Med Chem 1995, 38, 16, 3138, EP 1151995,EP 1149831,

US 5272160,WO 1997007098 , US 6645986

this exhibits activity as NMDA (N-methyl-D-aspartic acid) receptor antagonists and are useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscular spasms, multiinfarct dementia, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, urinary incontinence and degenerative CNS (central nervous system) disorders such as stroke, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

The free base, the anhydrous mesylate and methods of preparing them are referred to, generically, in United States Patent 5,185,343, which issued on February 9, 1993. They and their use in treating certain of the above disorders are referred to, specifically, in United States Patent 5,272,160, which issued on December 21 , 1993. Their use in treating the above disorders is referred to in lntemational Patent Application PCT/IB 95/00380, which designates the United States and was filed on May 18, 1995. Their use in combination with a compound capable of enhancing and thus restoring the balance of excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex to treat Parkinson’s disease is referred to in International Patent Application PCT/IB 95/00398, which designates the United States and was filed on May 26, 1995. The foregoing U.S. patents and patent applications are incoφorated herein by reference in their entireties.

NMDA is an excitatory amino acid. The excitatory amino acids are an important group of neurotransmitters that mediate excitatory neurotransmission in the central nervous system. Glutamic acid and aspartic acid are two endogenous ligands that activate excitatory amino acid (EAA) receptors. There are two types of EAA receptors, ionotropic and metabotropic, which differ in their mode of signal transduction. There are at least three distinct ionotropic EAA receptors characterized by the selective agonist that activates each type: the NMDA, the AMPA (2-amino-3-(5-methyl-3- hdyroxyisoxazol-4-yl)propanoic acid) and the kainic acid receptors. The ionotropic EAA receptors are linked to ion channels that are permeable to sodium and, in the case of NMDA receptors, calcium. Metabotropic receptors, linked to phosphoinositide hydrolysis by a membrane associated G-protein, are activated by quisqualic acid, ibotenic acid, and (1S, 3R)-1-aminocyclopentane 1 ,3-dicarboxyiic acid.

The NMDA receptor is a macromolecular complex consisting of a number of distinct binding sites that gate on ion channels permeable to sodium and calcium ions. Hansen and Krogsgaard-Larson, Med. Res. Rev.. .10, 55-94 (1990). There are binding sites for glutamic acid, glycine, and polyamines, and a site inside the ion channel where compounds such as phencyclidine (PCP) exert their antagonist effects.

Competitive NMDA antagonists are compounds that block the NMDA receptor by interacting with the glutamate binding site. The ability of a particular compound to competitively bind to the NMDA glutamate receptor may be determined using a radioligand binding assay, as described by Murphy e l., British J. Pharmacol.. 95, 932- 938 (1988). The antagonists may be distinguished from the agonists using a rat cortical wedge assay, as described by Harrison and Simmonds, British J. Pharmacol.. 84, 381- 391 (1984). Examples of competitive NMDA antagonists include D-2 amino 5- phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et a]. , J. Neur. Transm.. 85, 131-143 (1991).

4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the . corresponding D-tartaric acid salts Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid

EXAMPLE 1 Enantiomeric (1S,2S)- and (1R,2R)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanols

(+)-Tartaric acid (300 mg, 2 mmol) was dissolved in 30 mL warm methanol. Racemic 1S*,2S*-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (655 mg, 2 mmol) was added all at once. With stirring and gentle warming a colorless homogeneous solution was obtained. Upon standing at ambient temperature 24 hours, 319 mg (66%) of a fluffy white precipitate was obtained. This product was recrystallized from methanol to give 263 mg of the (+)-tartrate salt of levorotatory title product as a white solid; mp 206.5-207.5.degree. C.; [alpha].sub.D =-36.2.degree.. This salt (115 mg) was added to 50 mL of saturated NaHCO.sub.3. Ethyl acetate (5 mL) was added and the mixture was vigorously stirred 30 minutes. The aqueous phase was repeatedly extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over calcium sulfate, and concentrated. The tan residue was recrystallized from ethyl acetate-hexane to give 32 mg (39%) of white, levorotatory title product; mp 203-204 C.sub.20 H.sub.25 NO.sub.3 : C, 73.37; H, 7.70; N. 4.28. Found: C, 72.61; H, 7.45; N. 4.21.

The filtrate from the (+)-tartrate salt preparation above was treated with 100 mL saturated aqueous NaHCO.sub.3 and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over calcium sulfate and concentrated to give 380 mg of recovered starting material (partially resolved). This material was treated with (-)-tartaric acid (174 mg) in 30 mL of methanol as above. After standing for 24 hours, filtration gave 320 mg (66%) of product which was further recrystallized from methanol to produce 239 mg of the (-)-tartrate salt of dextrorotatory title product; mp 206.5-207.5.degree. C. [alpha].sub.D =+33.9.degree.. The latter was converted to dextrorotatory title product in the manner above in 49% yield; mp 204-205 Found: C, 72.94; H. 7.64; N, 4.24.

EXAMPLE 2 (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-yl)-1-propanol Methanesulfonate Trihydrate

STEP 1

A 50 gallon glass lined reactor was charged with 17.1 gallons of acetone, 8.65 kilograms (kg) (57.7 mol) of 4′-hydroxypropiophenone, 9.95 kg (72.0 mol) of potassium carbonate and 6.8 liters (l) (57.7 mol) of benzylbromide. The mixture was heated to reflux (56 hours. Analysis of thin layer chromatography (TLC) revealed that the reaction was essentially complete. The suspension was atmospherically concentrated to a volume of 10 gallons and 17.1 gallons of water were charged. The suspension was granulated at 25 product was filtered on a 30″ Lapp and washed with 4.6 gallons of water followed by a mixture of 6.9 gallons of hexane and 2.3 gallons of isopropanol. After vacuum drying at 45 (96.4%) of the above-depicted product.

A second run was carried out with 9.8 kg (65.25 mol) of 4′-hydroxypropiophenone using the procedure described above. After drying 15.1 kg (96.3%) of the above-depicted product was obtained.

STEP 2

Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 75 gallons of methylene chloride and 28.2 kg (117.5 mol) of the product from step 1. The solution was stirred five minutes and then 18.8 kg of bromine was charged. The reaction was stirred for 0.5 hours at 22 complete. To the solution was charged 37 gallons of water and the mixture was stirred for 15 minutes. The methylene chloride was separated and washed with 18.5 gallons of saturated aqueous sodium bicarbonate. The methylene chloride was separated, atmospherically concentrated to a volume of 40 gallons and 60 gallons of isopropanol was charged. The concentration was continued until a pot temperature of 80 40 gallons were obtained. The suspension was cooled to 20 granulated for 18 hours. The product was filtered on a 30″ Lapp and washed with 10 gallons of isopropanol. After vacuum drying at 45 yielded 29.1 kg (77.6%) of the above-depicted product.

STEP 3

Under a nitrogen atmosphere, a 20 gallon glass lined reactor was charged with 4.90 kg (15.3 mol) of the product from step 2, 7.0 gallons of ethyl acetate, 2.70 kg (15.3 mol) of 4-hydroxy-4-phenylpiperidine and 1.54 kg of triethylamine (15.3 mol). The solution was heated to reflux (77 C.) for 18 hours. The resulting suspension was cooled to 20 Analysis by TLC revealed that the reaction was essentially complete. The byproduct (triethylamine hydrobromide salt) was filtered on a 30″ Lapp and washed with 4 gallons of ethyl acetate. The filtrate was concentrated under vacuum to a volume of 17 liters. The concentrate was charged to 48 liters of hexane and the resulting suspension granulated for 2 hours at 20 gallons of hexane. After vacuum drying at 50 kg (77%) of the above-depicted product.

A second run was carried out with 3.6 kg (11.3 mol) of the product from step 2 using the procedure described above. After drying 4.1 kg (87%) of the above-depicted product was obtained.

STEP 4

Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 87.0 gallons of 2B ethanol and 1.7 kg (45.2 mol) of sodium borohydride. The resulting solution was stirred at 25 kg (22.6 mol) of the product from step 3 was charged. The suspension was stirred for 18 hours at 25-30 reaction was essentially complete to the desired threo diastereoisomer. To the suspension was charged 7.8 liters of water. The suspension was concentrated under vacuum to a volume of 40 gallons. After granulating for 1 hour, the product was filtered on a 30″ Lapp and washed with 2 gallons of 2B ethanol. The wet product, 9.4 gallons of 2B-ethanol and 8.7 gallons of water were charged to a 100 gallon glass lined reactor. The suspension was stirred at reflux (78 cooled to 25 water followed by 4 gallons of 2B ethanol. After air drying at 50 C., this yielded 8.2 kg (86.5%) of the above-depicted product. This material was recrystallized in the following manner.

A 100 gallon glass lined reactor was charged with 7.9 kg (18.9 mol) of the product from step 3, 20 gallons of 2B ethanol and 4 gallons of acetone. The suspension was heated to 70 solution was concentrated atmospherically to a volume of 15 gallons. The suspension was cooled to 25 product was filtered on a 30″ Lapp. The wet product and 11.7 gallons of 2B ethanol was charged to a 100 gallon glass lined reactor. The suspension was heated to reflux (78 cooled to 25 of 2B ethanol. After air drying at 50 (70.6%) of the above-depicted product.

STEP 5

Under a nitrogen atmosphere, a 50 gallon glass lined reactor was charged with 825 g of 10% palladium on carbon (50% water wet), 5.5 kg (13.2 mol) of the product from step 4 and 15.5 gallons of tetrahydrofuran (THF). The mixture was hydrogenated between 40-50 time, analysis by TLC revealed that the reduction was essentially complete. The reaction was filtered through a 14″ sparkler precoated with Celite and washed with 8 gallons of THF. The filtrate was transferred to a clean 100 gallon glass lined reactor, vacuum concentrated to a volume of 7 gallons and 21 gallons of ethyl acetate were charged. The suspension was atmospherically concentrated to a volume of 10 gallons and a pot temperature of 72 filtered on a 30″ Lapp and washed with 2 gallons of ethyl acetate. After air drying at 55 above-depicted product (i.e., the free base).

STEP 6

A 100 gallon glass lined reactor was charged with 20 gallons of methanol and 3.7 kg (11.4 mol) of the product from step 5 (i.e., the free base). The suspension was heated to 60 D-(-)-tartaric acid were charged. The resulting solution was heated to reflux (65 suspension was cooled to 35 with 1 gallon of methanol. The wet solids were charged to a 100 gallon glass lined reactor with 10 gallons of methanol. The suspension was stirred for 18 hours at 25 Lapp and washed with 2 gallons of methanol. After air drying at 50 C. this yielded 2.7 kg (101%) of the above-depicted product (i.e., the tartaric acid salt of the free base (R-(+)-enantiomer)). This material was purified in the following manner:

A 100 gallon glass lined reactor was charged with 10.6 gallons of methanol and 2.67 kg (5.6 mol) of the above tartaric acid salt. The suspension was heated to reflux (80 to 30 methanol. After air drying at 50 of the above-depicted product (i.e., the tartaric acid salt of the free base).

STEP 7

•Tar tar i c Rc i d

A 55 liter nalgene tub was charged with 30 liters of water and 1056 g (12.6 mol) of sodium bicarbonate at 20 charged 2.0 kg (4.2 mol) of the product from step 6 (i.e., the tartaric acid salt of the free base). The suspension was stirred for 4 hours during which a great deal foaming occurred. After the foaming ceased, the suspension was filtered on a 32 cm funnel and washed with 1 gallon of water. After air drying at 50 the above-depicted product (i.e., the free base).

STEP 8

A 22 liter flask was charged with 1277 g (3.9 mol) of product from step 7 and 14 liters of water. The suspension was warmed to 30 g (3.9 mol) of methane sulfonic acid were charged. The resulting solution was warmed to 60 washed with 2 liters of water. The speck-free filtrate was concentrated under vacuum to a volume of 6 liters. The suspension was cooled to 0-5 18″ filter funnel and washed with 635 ml of speck-free water. After air drying at 25 above-depicted product (i.e., the mesylate salt trihydrate).

Proton and Carbon Nuclear Magnetic Resonance (NMR) Spectra of the Mesylate Salt Trihydrate

The proton and carbon NMR spectra of the mesylate salt trihydrate are described below. Chemical shift assignments in CD₃OD (relative to tetramethylsilane (TMS) were made on the basis of ‘HJH Correlated Spectroscopy (COSY), ‘H-‘O Distortionless Enhancement by Polarization Transfer (DEPT), and ‘HJ’C Heteronuclear Chemical Shift Correlation (HETCOR) two-dimensional NMR experiments. The tentative proton and carbon peak assignments are given below and are consistent with the structure of the mesylate salt trihydrate. III

assignment, 13 C (δ, ppm),   Protons,  1 H (δ, ppm)
4'          159.2            0         --        
1"'         148.2            0         -- 
1'          132.6            0         -- 
2'          129.8            2         7.30 (m) 
3"'         129.5  m         2         7.38 (t) 
4"'         128.4            1         7.30 (m) 
2"'         125.6            2         7.56 (d) 
3'          116.5            2         6.84 (d) 
1           73.5             1         4.66 (d) 
4"          69.8             0         -- 
2           68.3             1         3.58 (m) 
6"(1)       48.8             2         3.32 (d),3.72(t) 
2"(1)       43.2             2         3.58 (m) 
4           39.5             3         2.70 (s) 
5"(2)       36.6             2         2.64 (t),1.98(d) 
3"(2)       36.5             2         2.42 (t),1.98(d) 
3           9.7              3         1.12(d)

(1) The 6″ and 2″ positions are not chemically equivalent; the assignments may be interchangeable. (2) The 5″ and 3″ positions are not chemically equivalent the assignments may be interchangeable. The proton splitting pattem at 1.96-2.06 ppm appears as two doublets when acquired on a high-field instrument (500 MHz), but only as a triplet when acquired with a lower field (300 MHz) instrument. This is believed to be due to a salt effect arising from the mesylate.

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