Licorice or Mulethi is a medicinal herb which is used in various Ayurvedic medicines. Its underground stems and roots are used for medicinal purpose. It has antioxidant, antimicrobial, anti-inflammatory and hepatoprotective properties.
Mulethi is useful in cough, sore throat, bronchitis, sexual weakness, skin problems, jaundice, hoarseness, vata dosha, ulcers etc. It has demulcent and expectorant properties.

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Liquorice, or licorice, (/ˈlɪk(ə)rɪʃ/ lik-(ə-)rish or /ˈlɪk(ə)rɪs/ lik-(ə-)ris)^[2] is the root of Glycyrrhiza glabra from which a sweet flavour can be extracted. The liquorice plant is a legume native to southern Europe, India, and parts of Asia. It is not botanically related to anise, star anise, or fennel, which are sources of similar flavouring compounds. The word liquorice / licorice is derived (via the Old French licoresse) from the Greek γλυκύρριζα (glukurrhiza), meaning “sweet root”,^[3] from γλυκύς (glukus), “sweet”^[4] + ῥίζα (rhiza), “root”,^[5][6] the name provided by Dioscorides.^[7] It has been traditionally known and used as medicine in Ayurveda for rejuvenation.^[8] It is called asadhimadhuram (அதிமதுரம்) in Tamil, irattimadhuram in Malayalam, yastimadhu (यस्टिमधु) in Sanskrit, mulethi (मुलेठी) in Hindi, andjethimadh (જેઠીમધ) in Gujarati language.^[9]

Licorice (Glycyrrhiza glabra), locally known as mulethi, has been revered for centuries as a medicinal herb in Ayurveda. Besides possessing numerous medicinal properties, it is also a popular flavoring herb as it is 50 times sweeter than sugar, due to the presence of a compound called glycyrrhizin.

Through research, the anti-oxidant, anti-inflammatory, anti-microbial, analgesic (pain-relieving) and expectorant properties of this is sweet, moist herb have been established worldwide. It is also diuretic, rejuvenating and mildly laxative in nature. These properties have helped Licorice find a place in both Eastern and Western medicine for treating an array of ailments, ranging from cold and cough to arthritis, respiratory, digestive and liver problems.

The Sanskrit name for licorice is Yashtimadhu, which literally means “sweet root”. It is sweet, cool and heavy to digest. The Rasa (taste) of this herb is madhura (sweet), which makes it beneficial for vata and pitta doshas, while it’s Virya (action) is sheetal (cooling), which generally increases kapha when consumed in large doses over long term.

The medicinal property of mulethi is mainly because of the presence of powerful phytochemicals namely flavonoids, chalcones, saponins and xenoestrogens. Glycyrrhizin (salts of glycyrrhizic acid) is a popular saponin found in roots of mulethi that is responsible for the characteristic sweet taste (50 times more sweet than sugar) flavor. Liquiritin, licoflavonol, liquiritigenin, etc are the common chalcones that provide the distinct yellowish color to mulethi; while, the aroma of its root is mainly because of anethole. Here are the ten health benefits of mulethi:

Information

Latin name: Glycyrrhiza glabra
Sanskrit: Madhuyashti
Hindi: Mulhatti, Jethimadh, Mithilakdi
English: Sweetwood, Liquorice, Licorice
Bengali: Jashtimadhu
Gujrati: Jethi Madh
Marathi: Jeshtamadhu
Kannada: Jeshthamadhu
Malayalam: Itarttimadhuram, Erattimadhuram
Tamil: Atimadhuram
Telugu: Atimadhuramu

Anti-microbial activity – Roots of mulethi are very effective in protecting against virus, bacteria and fungi due to the presence of Glycyrrhizin that blocks the microbial growth. The root extract possesses the power to control malaria (as per preliminary research), influenza and also helps in the treatment of herpes resulting in virus suppression and severity of sores.

Anti-inflammatory activity – Liquorice has powerful anti-inflammatory and anti-allergic activity and can be used to treat chronic inflammation like rheumatic problems & arthritis, skin diseases and autoimmune diseases. It is also used for preventing any inflammatory conditions related to eye and also to treat conjunctivitis with the help of glycyrrhizin activity that counteracts negative effects caused by cortisol.

Improves immunity – Root extracts of mulethi aids in increasing the production of lymphocytes and macrophage thereby improving your defense mechanism & preventing microbial attack. It also helps in minimizing immune related allergic reactions and autoimmune complications.

Memory improvement – Roots of licorice exert supportive effect on the adrenal gland and thus indirectly aid in stimulating the brain. It not only decreases the effects of amnesia & improves learning but its antioxidant property (mulethi contains flavonoids) renders a shielding effect on the brain cells.

Anti-ulcer activity – The potent antioxidant and anti-inflamatory properties of licorice makes it the best natural medicinal aid to treat ulcers of stomach, intestine and mouth. The compound carbenoxolone synthesized from glycyrrhizin plays key role in healing mouth and gastric ulcers along with reducing gastric secretions and promoting development of intestinal mucus lining.

Liver protection – Licorice is one of the most common traditional remedy used to treat jaundice. Its antioxidant property is the key for preventing your liver from the action of free radicals and toxic materials. This herb is also reported to exhibit protection against diclofenac induced toxicity and also, in inhibiting damage of liver.

Digestive aid – Roots of licorice are also used to deal with stomach and digestion problems with the help of glycyrrhizin and its compound, carbenoxolone. It is one of the ancient home remedies for relieving constipation, acidity, heartburn, stomach discomfort, inflammation of digestive system and gastro esophageal acid reflux. As a mild laxative, it plays an effective role in bowel movements and also for treatment of allergic cough in addition to maintaining normal pH levels.

Hormonal regulation – The phytoestrogenic compounds present in mulethi roots exert valuable action against women hormonal imbalance problems, menopause symptoms like hot flashes & exhaustion, mood swings, etc. It is also found to help in cortisol production and relieving premenstrual issues like nausea and menstrual cramps. Licorice powder acts as the traditional medicine for nursing mothers to regulate body hormones and aid in milk secretion.

Heart healthy effects – Research studies have proved that licorice roots help in controlling cholesterol levels by increasing the body’s flow of bile and also reducing high blood cholesterol levels. The anti-oxidant property of licorice acts in increasing the blood capillary health, reducing inflammation, prevents blood vessel damage and block development of arterial plaque.

Other effects – Licorice roots work wonders in treatment of depression, diabetes and respiratory tract infection like sore throat (hoarseness of voice), cold and cough, etc in addition to rendering effective skin benefits, oral hygiene and weight loss. It is found to act as a cancer cure remedy, a potent aphrodisiac and a powerful analgesic agent.

Description

It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 cm (3–6 in) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 in) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 cm (1 in) long, containing several seeds.^[10] The roots are stoloniferous.^[11]

Chemistry

The scent of liquorice root comes from a complex and variable combination of compounds, of which anethole is up to 3% of total volatiles. Much of the sweetness in liquorice comes from glycyrrhizin, which has a sweet taste, 30–50 times the sweetness of sugar. The sweetness is very different from sugar, being less instant, tart, and lasting longer.

The isoflavene glabrene and the isoflavane glabridin, found in the roots of liquorice, are phytoestrogens.^[12][13]

Cultivation and uses

Liquorice, which grows best in well-drained soils in deep valleys with full sun, is harvested in the autumn two to three years after planting.^[10] Countries producing liquorice include Iran, Afghanistan, the People’s Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan, and Turkey.^[14]

The world’s leading manufacturer of liquorice products is M&F Worldwide, which manufactures more than 70% of the worldwide liquorice flavours sold to end users.^[15]

Safe dosage

Licorice is available in various forms – root, powder and extracts. Licorice root can be chewed directly while licorice tea (prepared by boiling licorice root in water) is also extremely beneficial as a home remedy.

Daily intake of 5-6 grams of licorice powder is considered safe while 250-500 mg of concentrated extracts can be taken thrice a day. Unsupervised use in high doses is not recommended for long term. People with hypertension or heart disease, pregnant women and breastfeeding mothers should avoid using licorice without prior consulation with an Ayurveda doctor.

plant

Medicine

The compound glycyrrhizin (or glycyrrhizic acid), found in liquorice, has been proposed as being useful for liver protection in tuberculosis therapy, but evidence does not support this use, which may in fact be harmful.^[24] Glycyrrhizin has also demonstrated antiviral, antimicrobial, anti-inflammatory, hepatoprotective, and blood pressure-increasing effects in vitro and in vivo, as is supported by the finding that intravenous glycyrrhizin (as if it is given orally very little of the original drug makes it into circulation) slows the progression of viral and autoimmune hepatitis.^[25][26] Liquorice has also demonstrated promising activity in one clinical trial, when applied topically, against atopic dermatitis.^[27] Additionally, liquorice has also proven itself effective in treating hyperlipidaemia (a high amount of fats in the blood).^[28] Liquorice has also demonstrated efficacy in treating inflammation-induced skin hyperpigmentation.^[29][30] Liquorice may also be useful in preventing neurodegenerative disorders and dental caries.^[31][32][33]

The antiulcer, laxative, antidiabetic, anti-inflammatory, immunomodulatory, antitumour and expectorant properties of liquorice have been investigated.^[34]

Folk medicine

In traditional Chinese medicine, liquorice (मुलेठी, 甘草, شیرین بیان) is believed to “harmonize” the ingredients in a formula and to carry the formula to the 12 “regular meridians”.^[35]

References

38 Toxicology Center[2]

External links

Glycyrrhiza glabra (licorice), Kew plant profile

• Licorice, Medline, National Institutes of Health
• What’s That Stuff?: Licorice, Chemical & Engineering News

Zibotentan (INN) (earlier code name ZD4054) is an anti-cancer candidate.^[1] It is an endothelin receptor antagonist.^[2]

It failed a phase III clinical trial for prostate cancer^[3] but other trials are planned.^[4] Tolerability of zibotentan plus docetaxel has been evaluated.^[5]

SYN

https://www.google.com/patents/WO1996040681A1?cl=en

Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.

https://www.google.com/patents/WO1996040681A1?cl=en

Example 36

Hydrazine hydrate (1.2 ml) was added to a solution of N-(isobutoxycarbonyl)-2- (4-memoxycarbonylphenyl)-N-(3-metJ oxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.54 g) in methanol (15 ml) and the mixture was heated and stiπed under reflux for 24 hours then cooled. The solid was collected and dried under reduced pressure to give the free sulphonamido-acylhydrazide (0.857 g); 1H NMR (cVDMSO): 2.2 (s, 3H), 3.7 (s, 3H), 6.7 (br s, 2H), 7.3 (s, IH), 7.5 (m, 3H), 7.8 (d, 2H), 8.4 (d, IH), 8.75 (dd, IH), 9.8 (br s, IH). A solution of this acylhydrazide (207 mg) in triethylorthoformate (5 ml) was heated under reflux for 17 hours then cooled. The resultant solid was collected and purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-10% methanol/dichloromethane to give N-(3-methoxy-5-mef ylpyrazin-2-yl)-2-(4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3- sulphonamide (39 mg) as a solid; 1H NMR (DMSO-d_o): 2.2 (br s, 3H), 3.8 (s, 3H), 7.4 (br s, IH), 7.6-7.8 (m, 3H), 8.0 (m, 2H), 8.5 (dd, IH), 8.9 (dd, IH), 9.4 (s, IH); mass spectrum (+ve ESP): 425 (M+H)⁺.

………………………….

http://www.google.im/patents/EP1904490A1?cl=en

N-(3-methoxy-5-methylpyrazin-2-yl)-2- (4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide (hereafter “Compound (I)). More specifically the invention relates to the ethanolamine salt of Compound (I) (hereafter “Compound (I) ethanolamine salt), and to pharmaceutical compositions containing it. The invention further relates to the use of Compound (I) ethanolamine salt in the manufacture of medicament for use in treating cancer and to methods of treating cancer in a warm blooded animal such as man using this salt. The invention further relates to the use of Compound (I) ethanolamine salt in producing Compound (I) during manufacture.

Compound (I) is an endothelin antagonist. The endothelins are a family of endogenous 21 amino acid peptides comprising three isoforms, endothelin-1 (ET-I), endothelin-2 and endothelin-3. The endothelins are formed by cleavage of the Trp^2I-Val²² bond of their corresponding proendothelins by an endothelin converting enzyme. The endothelins are among the most potent vasoconstrictors known and have a characteristic long duration of action. They exhibit a wide range of other activities including cell proliferation and mitogenesis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents.

The endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including cancers.

Recently, endothelin A receptor antagonists have been identified as potentially of value in the treatment of cancer (Cancer Research, 56, 663-668, February 15^th, 1996 and Nature Medicine, Volume 1, Number 9, September 1999, 944-949).

Cancer affects an estimated 10 million people worldwide. This figure includes incidence, prevalence and mortality. More than 4.4 million cancer cases are reported from Asia, including 2.5 million cases from Eastern Asia, which has the highest rate of incidence in the world. By comparison, Europe has 2.8 million cases, North America 1.4 million cases, and Africa 627,000 cases. In the UK and US, for example, more than one in three people will develop cancer at some point in their life, Cancer mortality in the U.S. is estimated to account for about 600,000 a year, about one in every four deaths, second only to heart disease in percent of all deaths, and second to accidents as a cause of death of children 1-14 years of age. The estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually, exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.

Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases (excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects mainly older people, with 65% of cases occurring in those over 65. Since the average life expectancy in the UK has almost doubled since the mid nineteenth century, the population at risk of cancer has grown. Death rates from other causes of death, such as heart disease, have fallen in recent years while deaths from cancer have remained relatively stable. The result is that 1 in 3 people will be diagnosed with cancer during their lifetime and 1 in 4 people will die from cancer. In people under the age of 75, deaths from cancer outnumber deaths from diseases of the circulatory system, including ischaemic heart disease and stroke. In 2000, there were 151,200 deaths from cancer. Over one fifth (22 per cent) of these were from lung cancer, and a quarter (26 per cent) from cancers of the large bowel, breast and prostate.

Worldwide, the incidence and mortality rates of certain types of cancer (of stomach, breast, prostate, skin, and so on) have wide geographical differences which are attributed to racial, cultural, and especially environmental influences. There are over 200 different types of cancer but the four major types, lung, breast, prostate and colorectal, account for over half of all cases diagnosed in the UK and US. Prostate cancer is the fourth most common malignancy among men worldwide, with an estimated 400,000 new cases diagnosed annually, accounting for 3.9 percent of all new cancer cases. Current options for treating cancers include surgical resection, external beam radiation therapy and / or systemic chemotherapy. These are partially successful in some forms of cancer, but are not successful in others. There is a clear need for new therapeutic treatments. Compound (I) is exemplified and described in WO96/40681 as Example 36. WO96/40681 claims the endothelin receptors described therein for the treatment of cardiovascular diseases. The use of Compound (I) in the treatment of cancers and pain is described in WO04/018044. Compound (I) has the following structure:

Compound (I)

In WO04/018044 an endothelin human receptor binding assay is described. The pICjo (negative log of the concentration of compound required to displace 50% of the ligand) for Compound (I) at the ET_A receptor was 8.27 [8.23 – 8.32] (n=4). Compound (I) is thus an excellent endothelin antagonist.

WO96/40681 and WO04/018044 disclose, in general terms, certain pharmaceutically acceptable salts of the compounds disclosed therein. Specifically it is stated that suitable pharmaceutically-acceptable salts include, for example, salts with alkali metal (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine. In addition, it was stated that suitable pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid- addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.

Example 2 Formation of Compound (I) using ethanolamine

The above organic layer from Example 1 was adjusted to 42°C and isopropyl alcohol (114 ml), water (170ml) and ethanolamine (28.2 ml) were added and stirred at 42°C for 90 mins. The reaction mixture was allowed to cool to 2O⁰C and the lower aqueous phase separated and filtered through a 1 μm filter. The aqueous phase was then charged over 40min to a stirred solution of acetic acid (141 g) and water (33.5 g) at 50⁰C and then cooled to 2O⁰C over 60 mins. The product was isolated by filtration and washed with a mixture of isopropyl alcohol (48.5 ml) and water (48.5 ml) and then isopropyl alcohol (48.5 ml). The product was dried overnight in a vacuum oven at 55°C. Weight 43.08g, Strength = 100%, 86.7%yield. ¹H NMR (400 MHz₅ DMSOd₆) 9.87 (IH, s), 9.14 (IH, s), 8.81 (lH,d), 8.52 (IH, d), 7.98 (2H, d), 7.65 (2H, d), 7.62 (IH, dd), 7.41 (IH, bs), 3.80 (3H, s), 2.23 (3H, s). Mass Spectra MH+ 425.1036 (Ci₉Hi₇N₆O₄S calculated 425.1032).

Zibotentan
IUPAC name[hide] N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide
Other names[hide] ZD4054
Identifiers
CAS number	186497-07-4
PubChem	9910224
ChemSpider	8085875
UNII	8054MM4902
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C19H16N6O4S
Molar mass	424.43 g mol−1

References

External links

• Zibotentan

RAMELTEON

An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 2 and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound 13where dibenzoyl-l-tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound 1 is easily obtained from13 via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound 2.

A Novel and Practical Synthesis of Ramelteon

http://pubs.acs.org/doi/abs/10.1021/op500386g

Lesogaberan

Lesogaberan (AZD-3355) was^[1] an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD).^[2] As a GABA_B receptor agonist,^[3] it has the same mechanism of action as baclofen, but is anticipated to have fewer of the central nervous system side effects that limit the clinical use of baclofen for the treatment of GERD.^[4]

http://pubs.acs.org/doi/abs/10.1021/jm701425k

We have previously demonstrated that the prototypical GABA_B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA_B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA_B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA_B agonists devoid of classical GABA_B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.

(2R)-(3-Amino-2-fluoropropyl)phosphinic Acid ((R)-7)

References

Lesogaberan
IUPAC name[hide] ((R)-3-Amino-2-fluoropropyl)phosphinic acid
Other names[hide] AZD-3355
Identifiers
CAS number	344413-67-8 =
PubChem	9833984
ChemSpider	23254384
UNII	4D6Q6HGC7Z
ChEMBL	CHEMBL448343
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C3H9FNO2P
Molar mass	141.08 g mol−1

Sarpogrelate

135159-51-2,HYROCHLORIDE

125926-17-2 (free base)

5-HT 2a receptor antagonist

Useful for treating arterial occlusive disease and ischemic heart disease.

Sarpogrelate (Anplag, MCI-9042, LS-187,118) is a drug which acts as an antagonist at the 5HT_2A^[1][2] and 5-HT_2B^[3] receptors. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including diabetes mellitus,^[4][5] Buerger’s disease,^[6] Raynaud’s disease,^[7] coronary artery disease,^[8] angina pectoris,^[9] and atherosclerosis.^[10]

사르포그렐레이트염산염

Sarpogrelate Hydrochloride

C24H31NO6& : 465.97

1-[2-(Dimethylamino)-1-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl hydrogen butanedioate hydrochloride [135159-51-2]

第十六改正日本薬局方(JP16)名称データベース 検索結果

詳細については第十六改正日本薬局方でご確認ください。

[検索ページへ戻る]

検索キーワード:Sarpogrelate Hydrochloride
検索件数:1

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第十六改正日本薬局方　化学薬品等サルポグレラート塩酸塩 Sarpogrelate Hydrochloride 塩酸サルポグレラート C24H31NO6.HCl : 465.97 [135159-51-2] 本品は定量するとき，換算した脱水物に対し，サルポグレ ラート塩酸塩(C24H31NO6・HCl)98.5～101.0％を含む

 

 

Sarpogrelate hydrochloride tablets in 1993 Japan’s first listed under the tradename Anplag, is a 5-HT2 receptor blocker, can inhibit platelet aggregation, inhibition of vascular contraction, has antithrombotic effect and microcirculation. Ulcer indications for the improvement of their chronic arterial occlusive disease caused by pain, and cold ischemic various flu symptoms. -1_ {[2- (3-methoxyphenyl) phenoxy] methyl} succinic acid ethyl ester hydrochloride, the structural formula of sarpogrelate hydrochloride chemical name 2- (dimethylamino)

As follows:

 

  Journal of Medicinal Chemistry (J.Med.Chem, 1990,33: 1818-1823) published synthetic routes as follows:

 

  Sarpogrelate hydrochloride drug substance used in the preparation Sarpogrelate hydrochloride tablets needed to achieve acceptable purity, single hetero content must meet the corresponding requirements. US4485258 discloses a synthesis method of the first sarpogrelate hydrochloride, and recrystallized from acetone to obtain, but the experiments show that sarpogrelate hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent sarpogrelate. CN101239920A disclosed as acetonitrile, propionitrile, 1,4_ dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, , acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent sarpogrelate hydrochloride, the purity of the product can reach 98%. And C2-C10 alkanes, C3-C10 ketones, C2-C10 carboxylic acid esters, Cl-ClO halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature of the hydrochloric acid solubility is small should not alone sarpogrelate as a recrystallization solvent, sarpogrelate hydrochloride, and water as a recrystallization solvent or an organic solvent, an aqueous 5% or more can not be obtained a high purity product. Existing literature does not mention the issue of a single impurity content control.

The reaction of 2-hydroxy-3′-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3′-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3′-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.

……………………………..

http://www.google.com/patents/CN103242179A?cl=en

Specific embodiments

Example 1 Preparation of crude sarpogrelate hydrochloride [0019] Example

[0020] 1_ dimethylamino _3- [2- [2- (3_-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride A 250ml 13.7g plus a single-neck flask, then add water 25ml, and stirred to dissolve. With 20% aqueous sodium hydroxide to adjust PH value to 9_14, and extracted with 30ml of toluene, and the organic layer was concentrated to 50 ° C under reduced pressure until no liquid slipped 0 to give a brown oil. Of tetrahydrofuran was added 30g, and stirred to dissolve, butyryl anhydride 4.5g, was heated to reflux with stirring. After the reaction was refluxed for I~4 hours, the reaction was incubated at 40 ° C and concentrated to dryness under reduced pressure; the residue was added ethyl acetate 25g, After stirring to dissolve, the dropwise addition of saturated hydrogen chloride in ethyl acetate solution to adjust PH value to I below, was stirred 50~60min. Centrifugal filtration, was Sarpogrelate hydrochloride crude wet product. 45~55 ° C under reduced pressure (-0.08~-0.1MPa) the residue was dried to less than 0.5% of ethyl acetate to give the crude sarpogrelate hydrochloride 14.7g, yield 86%, HPLC purity 98.6%, largest single heteroatom content of 1.2 %.

Purification of the crude hydrochloride Sarpogrelate Example 2 [0021] Example

[0022] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9% and a maximum content of 0.04%, a single hybrid.

Example 3 Purification of the crude hydrochloride Sarpogrelate [0023] Example

[0024] The crude product was sarpogrelate hydrochloride 5g, join butanone 30ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give 4.55 sarpogrelate hydrochloride, yield 91%, HPLC purity 99.7%, largest single matter content of 0.05%.

Example 4 Purification of the crude hydrochloride Sarpogrelate [0025] Example

[0026] The crude product was sarpogrelate hydrochloride 5g, join butanone 40ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.5g, yield 90%, HPLC purity 99.8%, largest single matter content 0.05%.

Example 5 Purification of the crude hydrochloride Sarpogrelate [0027] Example

[0028] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooled slowly with stirring to room temperature, at -10 ° c~o ° c stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55~65 ° C and dried under reduced pressure to 24h, to give the hydrochloride sarpogrelate 4.62g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.

………………………………..

WO-2015008973 NEW PATENT

Method for preparing crystalline form II of sarpogrelate hydrochloride is claimed.  Represents first filing from Dae He Chemical on sarpogrelate, which was developed and launched by Mitsubishi Tanabe Pharma.

References

Sarpogrelate

Systematic (IUPAC) name
4-[2-(dimethylamino)-1-({2-[2-(3-methoxyphenyl)ethyl]phenoxy}methyl)ethoxy]-4-oxobutanoic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Identifiers
CAS number	125926-17-2
ATC code	None
PubChem	CID 5160
IUPHAR ligand	210
ChemSpider	4976
UNII	19P708E787
ChEMBL	CHEMBL52939
Synonyms	Sarpogrelate, (-)-4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid
Chemical data
Formula	C24H31NO6
Molecular mass	429.506 g/mol

EMA approves AstraZeneca’s lesinurad to treat gout patients
British-Swedish drugmaker AstraZeneca has received approval from European Medicines Agency (EMA) for its lesinurad 200mg tablets to treat gout patients. READ AT…..[LINK]

SYNTHESIS………..http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

“The company submitted a MAA based on data from the Clear1, Clear2 and Crystal pivotal Phase III combination therapy studies.”

AstraZeneca’s subsidiary Ardea Biosciences carried out Clear1, Clear2 and Crystal trials.

LESINURAD

SYNTHESIS………..http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

BioCryst’s BCX4161 receives FDA fast-track designation to treat HAE

BioCryst Pharmaceuticals has received fast-track designation from the US Food and Drug Administration (FDA) for its BCX4161, an orally administered and selective inhibitor of plasma kallikrein in advanced clinical development to treat hereditary angioedema (HAE).

READ HERE……[LINK]

“BCX4161 and our second-generation molecules have the potential to significantly improve HAE patient treatment and their quality of life.”

………………………………………….

PREVIOUS ARTICLE CUT PASTE

(RTTNews.com) – BioCryst Pharmaceuticals Inc. ( BCRX ) will be reporting results from OPuS-1, a phase IIa trial of orally-administered BCX4161 in patients with hereditary angioedema, on Tuesday, May 27, 2014 at 8:30 a.m. Eastern Time.

The OPuS-1 clinical trial is testing 400 mg of BCX4161 administered three times daily for 28 days in up to 25 hereditary angioedema patients who have a high frequency of attacks (≥ 1 per week), in a randomized, placebo-controlled, two-period cross-over design.
Read more: http://www.nasdaq.com/article/bcrx-to-watch-out-for-gtiv-adopts-poison-pill-teva-qgen-drtx-get-fda-nod-20140527-00005#ixzz335Khl0sk

BCX-4161 is a novel, selective inhibitor of plasma kallikrein in development for prevention of attacks in patients with hereditary angioedema (HAE). By inhibiting plasma kallikrein, BCX-4161 suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients.

……………………………….

old article

Carfilzomib

synthesis………http://newdrugapprovals.org/2014/08/05/amgens-multiple-myeloma-drug-shows-promise-in-phase-3-trial/

supplemental New Drug Application filed

Amgen and its subsidiary Onyx Pharmaceuticals have submitted filings for their multiple myeloma drug Kyprolis (carfilzomib) on both sides of the Atlantic.

The companies are seeking approval to market their drug for the treatment of patents with relapsed multiple myeloma who have received at least one prior therapy.

read all at…………http://www.pharmatimes.com/Article/15-01-28/Amgen_Onyx_file_multiple_myeloma_drug_in_US_EU.aspx

synthesis………http://newdrugapprovals.org/2014/08/05/amgens-multiple-myeloma-drug-shows-promise-in-phase-3-trial/

Systematic (IUPAC) name
(S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
Clinical data
Trade names	Kyprolis
Licence data	US FDA:link
Pregnancy category	US: D
Legal status	US: ℞-only
Routes	Intravenous
Identifiers
CAS number	868540-17-4
ATC code	L01XX45
PubChem	CID 11556711
ChemSpider	9731489
KEGG	D08880
ChEMBL	CHEMBL451887
Synonyms	PX-171-007
Chemical data
Formula	C40H57N5O7
Molecular mass	719.91 g mol

LUCITANIB

6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide

6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)- N-methyl- 1 -naphthamide

1058137-23-7 (E-3810 free base); 1058137-84-0  (E-3810 HCl salt)

A 4-(3-methoxypropoxy)-3-methylpyridinyl derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS.
For in advanced solid tumors.

Lucitanib (E-3810): Lucitanib, also known as E-3810,  is a novel dual inhibitor targeting human vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs) with antiangiogenic activity. VEGFR/FGFR dual kinase inhibitor E-3810 inhibits VEGFR-1, -2, -3 and FGFR-1, -2 kinases in the nM range, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. Both VEGFRs and FGFRs belong to the family of receptor tyrosine kinases that may be upregulated in various tumor cell type

Overview

http://www.clovisoncology.com/products-companion-diagnostics/lucitanib/

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR1-3), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR α-ß). We own exclusive development and commercial rights to lucitanib on a global basis, excluding China. Lucitanib rights to markets outside of the U.S. and Japan have been sublicensed to Les Laboratoires Servier (Servier). We are collaborating with Servier on the global clinical development of lucitanib.

A Phase I/IIa clinical trial of lucitanib was initiated in 2010 and has demonstrated multiple objective responses in FGFR1 gene-amplified breast cancer patients, and objective responses were also observed in patients with tumors often sensitive to VEGFR inhibitors, such as renal cell and thyroid cancer. FGFR amplification is common in a number of tumor types, including breast cancer and squamous non-small cell lung cancer, and we intend to study lucitanib in these cancers as well as other solid tumors exhibiting FGFR pathway activation. A broad Phase II development program has been initiated by us and Servier in multiple indications, including advanced breast cancer and squamous NSCLC. For more information or to participate in the trials, contact the Clovis Oncology Clinical Trial Navigation Service at 1-855-262-3040, or 303-625-5010, or clovistrials@emergingmed.com.

http://www.asianscientist.com/2013/09/pharma/servier-license-lucitanib-simm-china-2013/

WO 2008/112408 Al and US 2008/0227812 Al disclose angiogenesis inhibitors with quinoline structure, useful for the treatment of neoplasias. One of the disclosed products is 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide of formula (I), described in example 3 of the above mentioned patent applications.

According to said documents, compound (I) is prepared by removing the benzyloxycarbonyl protective group from the compound benzyl l-((6- methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropyl carbamate (II):

in acid medium or by hydrogenolysis, to give compound (I).

Compound (II) is obtained in a number of steps with different processes in which the benzyloxycarbonyl protected 1 -amino- 1-cyclopropylmethyl moiety is introduced by subjecting the acyl azide obtained from l-((6- methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropanecarboxylic acid of formula (III):

to Curtius rearrangement, in the presence of benzyl alcohol, or by alkylation of 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N- methyl-1-naphthamide of formula (IV):

with 1 -benzyloxy carbony lamino- 1 -methylsolfonyloxymethyl- cyclopropane of formula (V):

The above mentioned applications do not provide yields concerning both the preparation of compound (II) by the two above mentioned reactions, and the conversion of compound (II) to (I).

Compound (III) is prepared by a process in which the 1-carboxy-l- cyclopropylmethyl moiety is introduced in 4-hydroxy-3-methoxyacetophenone as in the form of the ethyl ester, followed by formation of the 4- hydroxyquinoline ring and, finally, by the introduction of the 1- naphthylcarboxyamido fragment.

It is well known that the reactions requiring the use of azides, such as the formation of acyl azides, or Curtius rearrangement of the latter, are potentially hazardous as they involve risk of explosions, therefore they are not suitable for use in preparations on large scale. The synthetic methods reported in WO 2008/1 12408 and US

2008/0227812 include, inter alia, a general synthetic scheme in which the cycloalkyl-alkyl portion of the products is introduced by reaction between a cycloalkyl-alkyl mesylate and an hydroxy or amino acetophenone, followed by nitration to give a nitroacetofenone, reduction of the nitro group to amino group, formation of the 4-hydroxyquinoline ring and further work up of the latter to the final products. The above mentioned applications do not provide examples of the use of this process for compound (I) or the other described products.

…………………………….

http://www.google.com/patents/WO2010105761A1?cl=en

LUCITANIB

Example 1: Preparation of l-[(4-acetyl-2-methoxyphenoxy)methyl]- N-benzyloxycarbonyl-1-aminocyclopropane

A 10 L reactor equipped with mechanical stirrer was loaded with triphenylphosphine (340.0 g, 1.296 mol) and THF (2 L) and the suspension was cooled with an ice bath. The stirred suspension was then slowly added with DIAD (264 g, 1.296 mol) over 30 minutes. After stirring for 30 min at 0⁰C, the stirred suspension was added dropwise with a solution of 4-hydroxy- 3-methoxyacetofenone (180 g, 1.08 mol) and DIPEA (210 g, 1.62 mol) in THF (1500 mL). The suspension was left under stirring for 45 min at 0⁰C, then added dropwise with a solution of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane (China Gateway) (240 g, 1.08 mol) in THF (1500 mL). After Ih, LC-MS analysis of a sample from the reaction mixture showed the complete disappearance of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane. The reaction mixture was evaporated and the crude product was recrystallized with EtOH 95% (4000 mL) to give l-[(4- acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl- 1 – aminocyclopropane (214 g, yield: 53.5%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.41-7.45 (m, 2 H), 7.26 (s, 5 H), 6.77 (d, 1 H), 5.43 (s, 1 H), 5.00 (s, 2 H), 4.04 (s, 2 H), 3.82 (s, 3 H), 2.49 (s, 3H), 0.92 (m, 4 H).

LC-MS: M+H⁺: 370.4

Example 2: Preparation of l-[(4-acetyl-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l-aminocycIopropane

A solution of HNO₃ (65%, 3 mL) in Ac₂O (2 mL) at 0°C was slowly added with a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in

Ac₂O (3 mL). After stirring at 0⁰C for 2 h, the reaction mixture was poured into 50 mL of ice/water and the precipitate was recovered by filtration. The resulting yellow solid was recrystallized with 95% EtOH (5 mL) to give l-[(4- acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane (0.69 g, yield: 56%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.52 (s, 1 H), 7.26 (s, 5 H), 6.67 (s, 1 H), 5.36 (s, IH), 5.02 (s, 2 H), 4.05 (s, 2 H), 3.86 (s, 3 H), 2.42 (s, 3 H), 0.94 (m, 4 H).

LC-MS: M+H⁺: 414.41

Example 3: Preparation of l-[(4-(3-dimethylaminopropenoyl)-2- methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane

A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N₅N- dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100⁰C for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried and evaporated to give l-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l -aminocyclopropane (1.9 g, yield: 95%) as a yellow solid. 1H-NMR (300 MHz, CDCl₃): δ: 7.50 (s, 1 H), 7.27 (s, 5 H), 6.75 (s, 1

H), 5.44 (s, 1 H), 5.23 (s, 1 H), 5.1 1 (br, 1 H), 5.01 (s, 2 H), 4.04 (s, 2 H), 3.83 (s, 3 H), 2.78-3.00 (m, 6 H), 0.94 (m, 4 H) LC-MS: M+H⁺: 470.49

Example 4: Preparation of l-[(4-hydroxy-6-methoxyquinolin-7- yloxy)methyl]-N-benzyloxycarbonyl-l-aminocyclopropane

A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron (1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80⁰C for 2 h. The reaction mixture was cooled at room temperature, diluted with AcOEt (150 mL), filtered and washed with 50 ml of AcOEt. The filtration liquors were combined, washed with water (2 x 100 mL) and an NaHCO₃ saturated solution (2 x 100 mL), dried and evaporated to give l-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N- benzyloxycarbonyl-1 -aminocyclopropane (1.2 g, yield: 95%) as a yellow solid.

¹H-NMR (300 MHz, MeOD): δ: 7.75 (d, 1 H), 7.51 (s, 1 H), 7.15 (m, 5 H), 6.80 (br, 1 H), 6.20 (d, 1 H), 4.97 (s,2 H), 4.05 (s, 2 H), 3.84 (s, 3 H), 0.87 (m, 4 H).

LC-MS: M+H⁺: 395.2

Example 5: Preparation of l-[(4-chloro-6-methoxyquinolin-7- yloxy)methyl]-N-benzyIoxycarbonyl-l-aminocyclopropane

a) By chlorination of the compound of Example 4

A 50 ml round-bottom flask fitted with magnetic stirrer, thermometer, condenser and kept under nitrogen atmosphere, was loaded at 20°/25°C with 3.90 g (9.89 mmol) of the compound of Example 4 and 25 ml of POCl₃. The resulting suspension became a solution after stirring for a few minutes. The solution was heated at 85°C inner T and after 30 minutes the reaction was monitored by TLC, showing the disappearance of the starting product. The solution was cooled and dropwise added, over about 30 minutes and keeping the temperature below 10⁰C, to a mixture of 250 ml of DCM and 250 ml of water, cooled at 0⁰C. After completion of the addition, stirring was maintained for 30 minutes at 0°-10°C. The phases were separated and the aqueous phase was washed with 150 ml of DCM; the phases were separated and the organic phases combined. The combined organic phase was added with 150 ml of water, stirred at 20°/25°C for 15 minutes and pH was adjusted to 7-8 with a sodium bicarbonate saturated solution. The phases were separated and the organic phase was washed with 150 ml of water; the phases were separated, the organic phase was dried with sodium sulfate, filtered and the solvent evaporated off by distillation under vacuum. Stripping with ethyl ether afforded 3.8 g of a brownish solid. The solid residue was dissolved in 20 ml of tert-butyl methyl ether, stirring at 20°/25°C for an hour; filtered and washed with ter /-butyl methyl ether, then dried to obtain l-[(4-chloro-6- methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl- l- aminocyclopropane (3.4 g; yield: 87%) having (¹H-NMR) titre of 95%.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.61 (d, 1 H), 7.91 (s, 1 H), 7.56 (s, 1 H), 7.44 (s, 1 H), 7.38 (s, 1 H), 7.29 (m, 5 H), 4.99 (s, 2 H), 4.23 (s, 2 H), 3.97 (s, 3 H), 0.87 (m, 4 H). b) by Mitsunobu reaction between 4-chloro-7-hydroxy-6- methoxyquinoline and 1 -benzyloxycarbonylamino- 1 – hydroxymethylcyclopropane 20 ml of DCM were added with 4-chloro-7-hydroxy-6- methoxyquinoline (300 mg, 1.43 mmol; from China Gateway),

1 -benzyloxycarbonylamino- 1 -hydroxymethylcyclopropane (412 mg,

1.87 mmol, 1.3 eq; from China Gateway) and triphenylphosphine (490 mg,

1.87 mmol, 1.3 eq). The resulting solution was dropwise added with a solution of DEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperature at 0⁰C for 2 hours. The mixture was then left at 10⁰C for 20 hours, then filtered to recover the unreacted 4-chloro-7-hydroxy-6- methoxyquinoline. The filtrate was evaporated under vacuum and the resulting residue was added with 20 ml of 95% EtOH and left under stirring for 30 min. The solid was collected by filtration, washed with 5 ml of 95% EtOH and dried under vacuum to give l-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-

N-benzyloxycarbonyl-1-aminocyclopropane (273 mg; yield: 46%).

LC-MS: M+H⁺: 413.1

Example 6: Preparation of benzyl l-[(6-methoxy-4-(5- (methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II)

A solution of 0.51 g (2.53 mmol) of 6-hydroxy-N-methyl- 1 – naphthamide prepared according to WO2008/112408, 2, 7 ml of 2,6-lutidine and 0.3 g (2.42 mmol) of DMAP, kept at 20°/25°C and under nitrogen atmosphere, was added with the compound of Example 5 (1.0 g, NMR titre 95%, 2.30 mmol). The suspension was heated to 140⁰C inner temperature for

6 hours; then cooled to 20°/25°C and added with 80 ml of water and kept under stirring a 20°/25°C for 1 hour; the suspension was filtered and washed with water, to afford 0.88 g (yield: 66%) of benzyl l-[(6-methoxy-4-(5-

(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: δ: 8.56 (d, 1 H), 8.50 (d, 1 H), 8.39 (d, 1 H), 8.04 (d, 1 H), 7.94 (s, 1 H), 7.87 (s, 1 H), 7.59 (m, 4 H), 7.41 (s, 1 H), 7.44 (s, 1 H), 7.30 (m, 5 H), 6.56 (d, 1 H), 5.01 (s, 2 H), 4.48 (s, 2 H), 4.23 (s, 2 H), 3.95 (s, 3 H), 0.87 (m, 4 H). LC-MS: M+H⁺: 578.3

Example 7: Preparation of 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide (I)

A mixture of the compound of Example 6 (0.24 g, 0.42 mmol) in 2 ml of a solution of 40% HBr in acetic acid was stirred at 30⁰C for 3h, then added with 10 ml of water and the reaction mixture was extracted with AcOEt (2 x 10 mL). The organic phases were removed. The aqueous solution was dropwise added with a solution of 50% NaOH to reach pH 10. The mixture was extracted with DCM (3 x 20 mL) and the combined organic phases were dried and evaporated to give a crude containing 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4- yloxy)-N-methyl-l-naphthamide (I) with purity higher than >94% by LC-MS analysis. This crude was further purified by chromatography on a silica gel column eluting with DCM/MeOH 10: 1), to afford 6-(7-((l- aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-l- naphthamide (I) having purity higher than 98% by LC-MS analysis (140 mg, yield: 76%).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.47 (d, 2 H), 7.87 (d, 1 H), 7.53 (m, 3 H), 7.51 (m, 1 H), 7.44 (d, 1 H), 7.38 (s, 1 H), 6.50 (d, 1 H), 6.16 (d, 1 H), 5.01 (s, 2 H), 4.05 (s, 2 H), 4.03 (s, 3 H), 3.12 (d, 3 H), 2.09 (m, 2 H), 0.80 (m, 4 H).

LC-MS: M+H⁺: 444.0

synthesis…….will be updated

1: Colzani M, Noberini R, Romanenghi M, Colella G, Pasi M, Fancelli D, Varasi M, Minucci S, Bonaldi T. Quantitative chemical proteomics identifies novel targets of the anti-cancer multi-kinase inhibitor E-3810. Mol Cell Proteomics. 2014 Jun;13(6):1495-509. doi: 10.1074/mcp.M113.034173. Epub 2014 Apr 2. PubMed PMID: 24696502; PubMed Central PMCID: PMC4047469.

2: Zangarini M, Ceriani L, Bello E, Damia G, Cereda R, Camboni MG, Zucchetti M. HPLC-MS/MS method for quantitative determination of the novel dual inhibitor of FGF and VEGF receptors E-3810 in tumor tissues from xenograft mice and human biopsies. J Mass Spectrom. 2014 Jan;49(1):19-26. doi: 10.1002/jms.3305. PubMed PMID: 24446259.

3: Bello E, Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro SA, Berndt A, Richter P, D’Incalci M, Cavalletti E, Giavazzi R, Camboni G, Damia G. The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced-stage triple-negative breast cancer xenografts. Mol Cancer Ther. 2013 Feb;12(2):131-40. doi: 10.1158/1535-7163.MCT-12-0275-T. Epub 2012 Dec 27. PubMed PMID: 23270924.

4: Damia G, Colella G, Camboni G, D’Incalci M. Is PDGFR an important target for E-3810? J Cell Mol Med. 2012 Nov;16(11):2838-9. doi: 10.1111/j.1582-4934.2012.01601.x. PubMed PMID: 22805298.

5: Sala F, Bagnati R, Livi V, Cereda R, D’Incalci M, Zucchetti M. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study. J Mass Spectrom. 2011 Oct;46(10):1039-45. doi: 10.1002/jms.1985. PubMed PMID: 22012670.

6: Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC, D’Incalci M, Cavalletti E, Giavazzi R, Damia G, Camboni G. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405. doi: 10.1158/0008-5472.CAN-10-2700. Epub 2011 Jan 6. PubMed PMID: 21212416.

7: Kawai T, Ikeda H, Harada Y, Saitou T. [Changes in the rat stomach after long-term administration of proton pump inhibitors (AG-1749 and E-3810)]. Nihon Rinsho. 1992 Jan;50(1):188-93. Japanese. PubMed PMID: 1311785.

Patent Reference:

EOS ETHICAL ONCOLOGY SCIENCE S.p.A. in abbreviated form EOS S.p.A.; SPINELLI, Silvano; LIVI, Valeria Patent: WO2010/105761 A1, 2010 ; Location in patent: Page/Page column 21 ;

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide H-NMR spectral analysis

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide C-NMR spectral analysis

Dronapushpi is Sanskrit name of plant Leucas cephalotes. It is a medicinal herb that grows as a weed in India and many South East Asian countries. The folk use of this herb is for treating scorpion stings, snake bite, cough, fever etc. The whole plant has fever educing and insecticidal properties. The leaves are applied externally on snake bites and scorpion stings. To know more about this medicinal herb,

‘Leucas aspera ‘

SYNONYMS

• Ksavapatra
• Chatrini
• Palepushpa
• Guma
• Nahula
• Adhicchatra
• Dvesyamesa
• Gotamah
• Putigandhika
• Kumbhayoni
• Kutumbaka
• Drona
• Swasanaka
• Palindi
• Chatrani
• Chatraka
• Koodinya
• Vrakshasaraka
• Dhirgapatra
• Supuspa
• Chitrapatrika

TYPES

According to Abhidhana ratnamala

• Two varieties
• Mahadrona
• Dronapushpa

According to Raja narahari

• Drona – Lucas aspera
• Mahadrona – L. Cephalotus
• Another species – L. indica

PART USED

• Panchanga

FORMULATION

• Plihari vati
• Gorocanadi vati
• Nimbadilepa
• Sahacharadi taila

DOSAGE

• Swarasa-5-10ml.
• Churna-1-3gm

PROPERTIES

Rasa: katu, lavana, Madhura.

Guna: Guru, Ruksha, Theekshna

Veerya: Ushna.

Vipaka: Madhura

Doshsgnhtha: Kapha, vata, shamaka.

CHEMICAL COMPOSITION

• Its Panchanga contains B-sisstesterol, flavinol, Glycoside.
• Flowers  contain an essential oil, A bitter principle seeds a contain a fixed oil , caryophyllene, oxide, 26.56% Gama- Fenchene 12.02%, Alpha- cordional 2.13% , 1-hepten 3-01, 6.53%, menthol 6.30%, deca hydro naphthalene 5.15%, and trans –caryophyllene 4.05%.

• Labdane, Noraladane, laballenic acid lauric acid, glutaric acid, Adipic acid , tridecanoic acid.

KARMA

• Bhedana
• Kaphagna
• Amapacaka
• Kamalahara
• Shothoghna
• Shvasagna
• Krimigana
• Swedajanana
• Vata prashamana
• Samsrana
• Vishamajvarahara

PRAYOGA

• Kaamala
• Shotha
• Shwasa
• Vishamajvara
• Kandu
• Udara shoola
• Pratisyaya
• Jvara
• Shira shoola

THERAPEUTIC USES

Vishamajvara- Fresh juice of dronapuspi and tulasi are useful.            [Sharangadhara Samhita madhyamakhanda]

 Kaamala: Anjana with the juice of dronapuspi useful. [Gadanigraha].                                            

Netrarogani: dronapuspi juice is mixed with rice water and used orally as well as topically.                                 [G.N]

Pittajavikara : Hima prepared by sariva, rasani, guduchi,  rakthachandana and dronapuspi.         [Siddhayogasangraha]

Paandu : Hima prepared by dronapuspi and padmaka, sariva drugs are useful.                 [Siddhayogasangraha]

PHARMACO THERAPEUTIC ACTION AND USES

Lecus cephalotes has been reported to exert hepatoprotective action in carbon tetra chloride induced hepatotoxicity in animals.

Juice of it has been reported to act as an antibilious in herbal therapy for jaundice

It has shown positive test in filariesis

The whole plant powder in the proportion of 70% in the herbal composition is patented to cure epileptic convulsions and cerebral function disorders.

It is also having the properties of antipyretic, stimulant , expectorant, aperients , diaphoretic, insecticidal, emmenagogue, and antioxidant, anti-inflammatory and anti diabetic.

They are useful in colic, dyspepsia arthralgia.

FOLKLORE USES

• Plant decoction is used in the treatment of malarial fever .
• The leaves juice is used topically in psoriasis, skin eruption , and scabies and internally for the treatment of urinary complaints.
• The flowers are administered in the form of syrup or with honey for cough and cold.
• The dried inflorescences are smoked and the smoke exhaled through the nose to treat nose bleeds.
• Dried leaves along with tobacco (1:3) are smoked to treat bleeding as well as itching piles and fresh leaves eaten as a potent herb.

CULTIVATION

Cultivated fields as a weed , especially after a period of rain . It is collected for use as a leafy vegetable in rural areas . it is cultivated itself for its medicinal uses . And really available in market.

RESEARCH STUDIES

ANTIBACTERIAL

Leucas cephalotes a common ethanomedicinal plant’s used by folklore of tirupathi andrapradesh for fever and urinary tract infection.  Organic extracts hexane and methanolic extracts showed prominent antibacterial activity .

IN VITRO ANTHELMINTIC ACTIVITY

It is mild stimulant diaphoretic and used for fever

The overall study showed that dronapushpi decoction was beneficial to naveen (new) amavata.

The claim of folk ore amavata probably more beneficial if used with suitable vedanasthapana (analgesic)  drugs

Traditional medicinal uses

Dronapushpi is a weed that grows on wastelands. Medicinally, it has antimicrobial, insecticidal, fever reducing, larvicidal and inflammation reducing properties. It is useful in skin diseases. In malarial fever, the leaves juice is given. In some part of country, the decoction of whole plant is used for curing fever. The juice removes toxins from body. The leaves juice is applied externally for skin diseases and swelling. In cod and cough, the leaves juice is recommended.

Scorpion sting

In scorpion sting the plant is used internally as well externally. The leaves juice (few drops) is mixed with honey and taken orally.

Topically, the leaves juice is applied on place of sting.

Snake bite

The folk remedy is to put few drops of whole plant in nostrils.

Skin diseases, removing blood toxins

Skin diseases mainly occur due to toxins in blood. Dronapushpi plant has ability to flush the toxins from body.

In skin diseases, whole plant of Dronapushpi is used. The plant is dried. Five grams of dried powder is taken with three grams Neem/Margosa leaves in 2 glass water. This is boiled till volume reduce to one fourth. Then it filtered and taken two times a day.

Abnormally heavy bleeding at menstruation

The leaves of plant are taken a handful. These are washed and then ground to make fine paste. This paste is mixed with lemon juice and sesame oil/til oil (edible). The preparation is eaten empty stomach every morning for a week.

Asthma, cold, cough

The leaves juice of plant is taken in dose of 1-3 teaspoons.

Excessive thirst

The flowers (2 tablespoon) are boiled in water (150 ml) till volume reduces to half. This is filtered and taken thrice a day.

Cough, leucorrhoea

The leaves of plant are cooked and eaten with rice.

Skin diseases (itching, patchy skin, psoriasis, scabies etc.)

The paste of leaves is applied externally at the affected body areas.

Cough, congestion, blockage of nose, headache due to cough, Sinusitis, Migraine, Phlegm

The juice of leaves is put in nostrils as drops. For this purpose, the leaves juice is extracted and mixed with two times water. Then the diluted juice is put in nostrils (4 dops) for 3-4 days.

The flowers are heated in til/sesame oil and applied on head.

Fever (acute, chronic), Allergy

The decoction of plant (2-3 grams in boiled in two glass water till water reduces to one fourth) is used

This medicinal herb should be used in recommended doses only. It is hot in potency and heats up body. Avoid its use in excess. The leaves juice can be diluted for putting in nose of oral use.

Figure 2. a. Fragment-based screening: Small and structurally diverse molecules (circles represent functional groups) are screened for a biological target, and they are combined and modified to generate drug-like compounds. b. Diversity-oriented synthesis: Large collections of structurally diverse and complex molecules are made using a short number of reactions. The resulting compounds are optimized to produce the drug-like compounds. | Credit: P. J. Hajduk,W. R. J. D. Galloway & D. R. Spring Nature, 2011, 470, 42–43. DOI: 10.1038/470042a

The discovery and development of new drugs is a long and expensive process, and despite of it, essential to face present and new diseases. For small molecules, which account for the majority of the marketed drugs, the discovery process generally involves finding a starting point termed hit or lead compound. These molecules have biological activity but need to be optimized to enhance their potency and selectivity (i.e. minimize the toxicity) and improve pharmacokinetic parameters making them suitable to go to the next stage, the pre-clinical tests……….http://mappingignorance.org/2014/07/04/lead-oriented-synthesis-new-concept-aid-drug-discovery-process/

Author

pablo ortiz

Pablo Ortiz graduated in Pharmacy from the University of the Basque Country (UPV/EHU) and received a MSc in Synthetic and Industrial Chemistry by the same university. He is currently a PhD student in Synthetic Organic Chemistry at the University of Groningen (The Netherlands). His research is focused on novel copper catalysed transformations.

• Website: https://www.linkedin.com/pub/pablo-ortiz/72/517/390

PhD at Rijksuniversiteit Groningen

Experience

PhD Student, Rijksuniversiteit Groningen

October 2013 – Present 

Asymmetric organometallic catalysis focused on tertiary alcohols and amines

Harutyunyan research group

Master Thesis Project

University of the Basque Country

February 2013 – September 2013 (8 months)Vitoria-Gasteiz Area, Spain

Estereoselective synthesis of quaternary alpha-aminophosphonic acid derivatives (organocatalysis)

Locum pharmacist

Community pharmacy

August 2012 – August 2012 (1 month)La Rioja, Spain

Pre-registration pharmacist

NHS Trust

January 2012 – June 2012 (6 months)Southport, England

In-patient and out-patient dispensing
Clinical pharmacy
Medicines information
Anticoagulant management
Aseptic preparation of medicines
Clinical audit of antimicrobial use

Publications

Tertiary α-diarylmethylamines derived from diarylketimines and organomagnesium reagents(Link)

Chem. Commun. 2015, 51, 703-706.

November 13, 2014

Organomagnesium reagents enable swift and versatile derivatisation of diarylimines to the corresponding α-substituted diarylmethylamines in excellent yields, through fast and clean reactions. Where it occurs, 1,2-reduction can be circumvented using readily accessible dialkylmagnesium reagents.

Asymmetric Synthesis of Functionalized Tetrasubstituted α-Aminophosphonates through Enantioselective Aza-Henry Reaction of Phosphorylated Ketimines(Link)

J. Org. Chem., 2015, 80, 156–164

November 2014

Bifunctional Cinchona alkaloid thioureas efficiently catalyze asymmetric nucleophilic addition of nitromethane to ketimines derived from α-aminophosphonic acids to afford tetrasubstituted α-amino-β-nitro-phosphonates.

Catalytic Asymmetric Alkylation of Aryl Heteroaryl Ketones(Link)

Eur. J. Org. Chem., 2015, 72–76.

November 2014

Tertiary diarylmethanols are highly bioactive structural motifs. A new strategy to access chiral tertiary diarylmethanols through copper-catalyzed direct alkylation of (di)(hetero)aryl ketones by using Grignard reagents was developed. The low reactivity and the similarity of the enantiotopic faces of bis-aromatic ketones were partially overcome, which resulted in moderate to good yields and…more

Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives from Trisubstituted α-Aminophosphonates(Link)

Eur. J. Org. Chem., 2013: 7095–7100

September 2013

Concerns on Tramadol Overprescription(Link)

Pharma Mirror

June 2012

Education

Universidad del País Vasco/Euskal Herriko Unibertsitatea

Master’s degree, Synthetic and Industrial Chemistry, 9.2

2012 – 2013

(Open)1 course

Universidad del País Vasco/Euskal Herriko Unibertsitatea

Bachelor’s degree, Pharmacy, Extraordinary Degree Award, 9.06

2007 – 2012

(Open)1 honor or award

(Open)2 courses

Courses

Universidad del País Vasco/Euskal Herriko Unibertsitatea

• How to write and publish a research article
• X Pharmaceutical Chemistry Sessions: New strategies for the design and synthesis of drugs

Universidad del País Vasco/Euskal Herriko Unibertsitatea

• II Organic Chemistry Synthesis and Catalysis Workshop: Methods and strategies in synthesis

 

GRONINGEN, NETHERLANDS

 

http://www.rug.nl/

Groningen City – Holland.

stadtmitte groningen niederlande stadtwanderung

Yet more good news for Shire has come with the US Food and Drug Administration approving its attention-deficit hyperactivity disorder blockbuster Vyvanse for binge-eating disorder, the first medicine approved by the agency to treat this condition.

The agency has expanded approval on Vyvanse (lisdexamfetamine dimesylate) for adults with BED based on two Phase III studies which showed that it was statistically superior to placebo in terms of number of binge days per week. BED affects around 2.8 million US adults and is more prevalent than anorexia nervosa and bulimia nervosa combined.

Read more at: http://www.pharmatimes.com/Article/15-01-30/FDA_okays_Shire_ADHD_drug_Vyvanse_for_binge_eating.aspx

Originally discovered and developed by New River Pharmaceuticals, the company entered into a collaborative agreement with Shire Pharmaceuticals in 2005 for global commercialization of the drug candidate. After Shire’s acquisition of New River Pharmaceuticals in April 2007, lisdexamfetamine entered the product portfolio of Shire.

In 2009, the compound was licensed to GlaxoSmithKline by Shire in the U.S. for comarketing for the treatment of attention deficit/hyperactivity disorder (ADHD). In 2010, this license agreement was terminated. The product was licensed to Shionogi by Shire in Japan for co-development, co-commercialization, and co-promotion for the treatment of attention deficit/hyperactivity disorder (ADHD).

Lisdexamfetamine (NRP-104), a conditionally bioreversible derivative of amphetamine, was launched in the U.S. in 2007 for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-12 years old. In 2008, the product was approved for use in adults, and in 2009 it was approved in Canada, followed by commercialization in 2010. In 2010, FDA approval was obtained for use in treatment of ADHD in adolescents aged 13 to 17 years and launch took place the same year. Approval for the treatment of adolescents was assigned in Canada in 2011.

In 2012, Shire filed a regulatory application in Europe via the decentralized procedure with the U.K. acting as the reference member state, for the treatment of ADHD in children and adolescent patients aged 6 to 17 years. This indication was approved in 2013. Also, in 2012 FDA approval was granted for the maintenance treatment for adults with ADHD. U.K., DK and SE are awaiting approval for the same indication in a decentralized procedure initiated in 2014 with the U.K. acting as the reference member state. In 2014, the company filed with priority review a supplemental New Drug Application (sNDA) in the U.S. for the treatment binge eating in adults.
cas 608137-33-3

(2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate

Binge eating,,,,,, express their stress as temper tantrums or by indulging in compulsive eating spree

In terms of clinical development, phase III clinical trials are ongoing at Shionogi in Japan for the treatment of ADHD.. The National Institute on Drug Abuse (NIDA) is evaluating the compound in early clinical studies for the treatment of methamphetamine dependence. Phase III trials were underway as an adjunctive treatment of major depressive disorder; however, they were discontinued due to lack of efficacy. A phase II clinical trial for the treatment of excessive daytime sleepiness (EDS) has been completed. Shire had been evaluating the compound in clinical studies for the treatment of chronic fatigue syndrome.

In 2013, Shire cancelled its phase III program evaluating the product for the negative symptoms of schizophrenia based on a review and prioritization of the company’s development portfolio.

http://www.google.co.in/patents/US7662787

RIVER PHARMA

Patent and Exclusivity Search Results from query on Appl No 021977 Product 003 in the OB_Rx list.

Patent Data

Exclusivity Data

EDIVOXETINE, LY 2216684

(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol

Edivoxetine (INN; LY-2216684) is a drug which acts as a selective norepinephrine reuptake inhibitor and is currently under development by Eli Lilly for attention-deficit hyperactivity disorder (ADHD) and as an antidepressant treatment.^[1][2] It was in phase IIIclinical trials, in 2012, for major depressive disorder, but failed to get approval.^[1][3]

Effectiveness

In a study published in 2010, edivoxetine failed to prove superiority over placebo, as measured by Hamilton Depression Rating Scale. However, effectiveness could be observed using the Self-Rated Quick Inventory of Depressive Symptomatology.^[4]

In a study published in 2011, using the Montgomery-Åsberg Depression Rating Scale and the Sheehan Disability Scale, edivoxetine showed superiority over placebo, with higher response and remission rates.^[5]

In December 2013, Eli Lilly announced that the clinical development of edivoxetine will be stopped due to lack of efficacy compared to SSRI alone in three separate clinical trials.^[6]

Side effects

Side effects significantly associated with edivoxetine are headache, nausea, constipation, dry mouth and insomnia.^[4]

The above mention studies report increases of the cardiac rhythm, and one also increases of diastolic and systolic blood pressures.^[4][5]

There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.

Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre,University College Cork, Cork, Ireland

E-mail: a.maguire@ucc.ie.

University College Cork

http://www.ucc.ie/en/support/senior-mgt/researchandinnovation/

http://chemweb.ucc.ie/people/amaguire.htm

References

1.  Jun Yan (March 2012). “Pipeline for new antidepressants flowing slowly”. Psychiatric News (American Psychiatric Association) 47 (5): 1b-29. Retrieved 2012-04-27.
2.  “Statement on a nonproprietary name adopted by the USAN council – Edivoxetine” (Press release). American Medical Association. 2012. Retrieved 2012-04-12.
3.  Chancellor D (November 2011). “The depression market”. Nature Reviews. Drug Discovery 10 (11): 809–10. doi:10.1038/nrd3585. PMID 22037032.
4.  Dubé S, Dellva MA, Jones M, Kielbasa W, Padich R, Saha A, Rao P (April 2010). “A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression”. Journal of Psychiatric Research 44 (6): 356–363. doi:10.1016/j.jpsychires.2009.09.013. PMID 19909980.
5.  Pangallo P, Dellva MA, D’Souza DN, Essink B, Russell J, Goldberger C (June 2011). “A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder”. Journal of Psychiatric Research 45 (6): 748–755. doi:10.1016/j.jpsychires.2011.03.014. PMID 21511276.
6.  https://investor.lilly.com/releasedetail.cfm?ReleaseID=811751

H-NMR spectral analysis

CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol H-NMR spectral analysis

C-NMR spectral analysis

CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol C-NMR spectral analysis

PALBOCICLIB

Mechanism of action: selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6
Indication: Estrogen receptor-positive (ER+), HER2-negative (HER2 -) breast cancer

FDA approves Ibrance for postmenopausal women with advanced breast cancer

February 3, 2015

syn……….http://newdrugapprovals.org/2014/01/05/palbociclib/

The U.S. Food and Drug Administration today granted accelerated approval to Ibrance (palbociclib) to treat advanced (metastatic) breast cancer.

Breast cancer in women is the second most common type of cancer in the United States. It forms in the breast tissue and in advanced cases, spreads to surrounding normal tissue. The National Cancer Institute estimates that 232,670 American women were diagnosed with breast cancer and 40,000 died from the disease in 2014.

Ibrance works by inhibiting molecules, known as cyclin-dependent kinases (CDKs) 4 and 6, involved in promoting the growth of cancer cells. Ibrance is intended for postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have not yet received an endocrine-based therapy. It is to be used in combination with letrozole, another FDA-approved product used to treat certain kinds of breast cancer in postmenopausal women.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to expediting marketing approval of cancer drugs through our accelerated approval regulations.”

syn……….http://newdrugapprovals.org/2014/01/05/palbociclib/

The FDA granted Ibrance breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received a priority review, which provides for an expedited review of drugs intended to provide a significant improvement in safety or effectiveness in the treatment of a serious condition or meet an unmet medical need. Ibrance is being approved more than two months ahead of the prescription drug user fee goal date of April 13, 2015, the date when the agency was scheduled to complete its review of the application.

Ibrance is being approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.

The drug’s efficacy was demonstrated in 165 postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous treatment for advanced disease. Clinical study participants were randomly assigned to receive Ibrance in combination with letrozole or letrozole alone. Participants treated with Ibrance plus letrozole lived about 20.2 months without their disease progressing (progression-free survival), compared to about 10.2 months seen in participants receiving only letrozole. Information on overall survival is not available at this time.

The most common side effects of the drug were a decrease in infection-fighting white blood cells called neutrophils (neutropenia), low levels of white blood cells (leukopenia), fatigue, low red blood cell counts (anemia), upper respiratory infection, nausea, inflammation of the lining of the mouth (stomatitis), hair loss (alopecia), diarrhea, low blood platelet counts (thrombocytopenia), decreased appetite, vomiting, lack of energy and strength (asthenia), damage to the peripheral nerves (peripheral neuropathy) and nosebleed (epistaxis). Healthcare professionals should inform patients of these risks.

It is recommended that treatment begin with a 125 milligram dose for 21 days, followed by seven days without treatment. Healthcare professionals are advised to monitor complete blood count prior to start of therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.

Ibrance is marketed by New York City-based Pfizer, Inc.

see synthesis……….http://newdrugapprovals.org/2014/01/05/palbociclib/

New York City-based Pfizer, Inc.

Pfizer World Headquarters building in New York City. Zoetis, based in Madison, N.J., traces its roots back to 1952 as a Pfizer unit and has made at least 10 …

Pfizer’s NYC headquarters