The revised General Ph. Eur. Chapter on Raman Spectroscopy (2.2.48) comes into operation on April 1, 2016. The Chapter now includes hand-held devices and adaption to PAT purposes. Find out more about the revised  Ph. Eur. Raman Spectroscopy chapter.

http://www.gmp-compliance.org/enews_05181_Revised-Ph.-Eur.-Chapter-on-Raman-Spectroscopy-introducing-PAT_15153,15386,Z-PDM_n.html

The revision of the General Ph. Eur. Chapter on Raman Spectroscopy (2.2.48) comes into operation on April 1, 2016.

The revised Chapter has been published in Ph. Eur. Supplement 8.7. It has been completely rewritten to include now available handheld devices and adaption to Process Analytical Technology (PAT). Raman Spectroscopy has received more and more attention in pharmaceutical industry. Hand-held instruments are suitable for rapid identification purposes for example in the incoming goods control of raw and packaging materials.

Hand-held instruments require different tolerances for wavenumber scale verification than benchtop models. Therefore, an inter-laboratory study was organized and the results have been published in a corresponding paper titled “Rationale for the update of the European Pharmacopoeia general chapter 2.2.48. Raman Spectroscopy” in Pharmeuropa Bio & Scientific Notes 2015.

In addition, the chapter has been revised to focus more on the potential use of Raman Spectroscopy in a PAT environment. Raman Spectrometry is increasingly used for PAT and chemical imaging applications. Therefore, a chapter on Chemical Imaging is also under elaboration. The draft chapter on Chemical Imaging will be published for public consultation in Pharmeuropa 28.2 (April 2016).

For more information please visit the Newsroom on the EDQM website

///////////////Raman Spectroscopy,  PAT

Ilaprazole

cas 172152-36-2;

Iy 81149; IY-81149; 2-{[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl}-6-(1h-pyrrol-1-yl)-1h-benzimidazole; Aldenon;

MW 366.437, MF C19 H18 N4 O2 S

2-[(4-methoxy-3-methylpyridin-2-yl)methylsulfinyl]-6-pyrrol-1-yl-1H-benzimidazole

Ilaprazole is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and duodenal ulcer.

Ilaprazole is chemically known as 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-(lH-pyrrol-l-yl)-lH-benzimidazole

Il-Yang  Il Yang Pharmaceutical Company, Ltd.………. Innovator

launched in 2008 by Livzon in China

Ilaprazole (trade name Noltec) is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease (PUD),gastroesophageal reflux disease (GORD/GERD) and duodenal ulcer. It is available in strengths of 5, 10, and 20 mg.

Clinical studies show that ilaprazole is at least as potent a PPI as omeprazole when taken in equivalent doses. Studies also showed that ilaprazole significantly prevented the development of reflux oesophagitis.

Ilaprazole is developed by Il-Yang Pharmaceutical (Korea), and is still under clinical trials with US FDA. It has launched in Korea and China for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux disease and erosive esophagitis.^[1]

Ilaprazole is a substituted benzimidazole proton pump inhibitor first launched in 2008 by Livzon in China for the oral treatment of peptic ulcers. The compound was also being evaluated in early clinical trials at Il-Yang for the treatment of gastroesophageal reflux disease (GERD), but no recent development has been reported. In 2009, development of the compound was discontinued by Takeda Pharmaceuticals North America for the treatment of esophagitis due to a phase II study which did not meet its predefined endpoint.

The drug has been shown to significantly inhibit acute gastric erosion induced by indomethacin, ethanol or stress, acute mepirizole induced duodenal ulcers, and to accelerate the healing of acetic acid induced chronic ulcers through a H+/K+-ATPase inhibition mechanism.

In September 2005, TAP (a joint venture established between Abbott and Takeda which was dissolved in 2008) and Il-Yang signed a license agreement, granting the latter development and distribution rights to the drug candidate worldwide outside of Korea and China.

Il-Yang Pharm. Co., Ltd., Korea has developed a Novel PPI, i.e. racemic 5-(1H-pyrrol-1-yl)- 2[[(3-methyl-4-methoxy-2-Pyridyl)-methyl]sulfinyl]-benzimidaziole[1,2], which shows superior anti-ulcer effects as compared to Omeprazole in the treatment of GORD(gastro-oesophageal reflux diseases), gastric ulcer and duodenal ulcer (KR 179,401 and US 5,703,097). Gastric and duodenal ulcers are a gastrointestinal disease caused by various factors such as mental stress, dietary habit, intake of irritable food, and the like. The direct cause of peptic ulcers is damage to the gastric membrane due to excessive secretion of gastric acid.

Since their introduction in the late 1980s, proton pump inhibitors have improved the treatment of various acid-related gastrointestinal (GI) disorders, including gastroesophageal reflux disease (GERD), peptic ulcer disease, Zollinger-Ellison Syndrome (ZES), ulcers, and nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. GERD encompasses three disease categories: non-erosive reflux disease (NERD), erosive esophagitis, and Barrett’s esophagus. ZES is caused by a gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity. Proton pump inhibitors have also be used to treat ulcers such as duodenal, gastric, and NSAID-associated gastric/duodenal ulcers.

As antisecretory drugs, proton pump inhibitors are currently the recommended first line therapy, being viewed as more effective than other treatments. In general, proton pump inhibitors offer superior gastric acid suppression over histamine H2-receptor blockers. The use of proton pump inhibitors by patients who suffer from gastric acid-related disorders is generally believed to have led to an increase in their quality of life, productivity, and overall well being.

Proton pump inhibitors are also used to treat extra-esophageal manifestations of GERD (asthma, hoarseness, chronic cough, non-cardiac chest pain), and with antibiotics for Helicobacter pylori eradication. The goals of GERD management are threefold: prompt and sustained symptom control, healing of the injured esophageal mucosa and prevention of GERD-related complications (including stricture Formation, Barrett’s esophagus, and/or adenocarcinoma). Pharmacological therapy with proton pump inhibitors Forms the basis of both acute and long-term management of GERD. Proton pump inhibitors provide effective relief of symptoms and healing of the esophagitis, as well as sustaining long-term remission.

Although therapeutic efficacy is the primary concern for a therapeutic agent, the solid-state form, as well as the salt form, and the properties unique to the particular form of a drug candidate are often equally important to its development. Each solid state form (crystalline or amorphous) of a drug candidate can have different physical and chemical properties, for example, solubility, stability, or the ability to be reproduced. These properties can impact the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate form for further drug development can reduce the term and the cost of that development.

Ilaprazole, 2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl]sulfinyl]-5-(1H-pyrrol-1-yl) 1H-Benzimidazole, is a substituted benzimidazole that acts as a proton pump inhibitor. Ilaprazole selectively and irreversibly inhibits gastric acid secretion through inhibition of the hydrogen-potassium adenosine triphosphatase (H+K+-ATPase) (proton pump) mechanism. Inhibition of the proton pump occurs by formation of disulfide covalent bonds with accessible cysteines on the enzyme. Ilaprazole has a prolonged duration of action that persists after their elimination from plasma. See, for example, U.S. Pat. Nos. 5,703,097 and 6,280,773, which are incorporated herein by reference.

Ilaprazole has the empirical formula C₁₉H₁₈N₄O₂S having a molecular weight of 366.44 daltons. Ilaprazole is a chiral molecule and has the following structural Formula (I):

Ilaprazole, like all proton pump inhibitors, possesses the unique feature of a chiral sulfur atom, S*. This can be depicted as follows with the lone pair of electrons on the chiral sulfur atom occupying one position in each stereoisomer, as shown below:

The absolute structure and absolute confirmation of (−)-S-ilaprazole was made through single crystal structure determination and is shown below. See Example 7 of co-pending U.S. application Ser. No. 11/966,808 of Brackett et al. entitled, “Solid State Forms of Enantiopure Ilaprazole” filed Dec. 28, 2007, herein incorporated by reference in its entirety.

Thus, its complimentary enantiomer is (+)-R-ilaprazole, as shown below.

SYN 1

EP 0696281; JP 1997503000; US 5703097; WO 9523140

The condensation of 2-(chloromethyl)-4-methoxy-3-methylpyridine (I) with 5-(1-pyrrolidinyl)benzimidazole-2-thiol (II) by means of NaOH in hot methanol gives 2-(4-methoxy-3-methyl-2-pyridylmethylsulfanyl)-5-(1-pyrrolidinyl)benzimidazole (III), which is finally oxidized with m-chloroperbenzoic acid (MCPBA) in chloroform.

SYN 2

J Med Chem 1992,35(6),1049

http://pubs.acs.org/doi/pdf/10.1021/jm00084a010

3-Methoxy-2-methylpyridine (VII), prepared by methylation of 2-methyl-3-pyridinol (VI), was converted to the N-oxide (VIII) employing peracetic acid. Nitration of the pyridine N-oxide (VIII) with concentrated nitric acid gave the 4-nitro derivative (IX). Subsequent displacement of the nitro group of (IX) by sodium methoxide led to the dimethoxypyridine N-oxide (X). Rearrangement of the N-oxide group of (X) in hot acetic anhydride produced the acetoxymethyl pyridine (XI). After basic hydrolysis of the acetate ester (XI), the resultant hydroxymethyl pyridine (XII) was chlorinated by SOCl2, yielding chloride (XIII). Condensation between mercapto benzimidazole (V) and the chloromethyl pyridine (XIII) in ethanolic NaOH led to the sulfide adduct (XIV). This was finally oxidized to the desired sulfoxide by using meta-chloroperbenzoic acid in CH2Cl2. The oxidation of sulfide (XIV) has also been performed employing sodium perborate, sodium percarbonate in the presence of ammonium molybdate, or tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate.

The synthesis of IY-81149 can be obtained according to Scheme 22875502a. The oxidation of 2,3-lutidine (I) with hydrogen peroxide in acetic acid affords 2,3-dimethylpyridine-N-oxide (II), which is treated with sulfuric acid and nitric acid to give the corresponding nitro compound (III). The treatment of (III) with NaOH in methanol gives 2,3-dimethyl-4-methoxypyridine-N-oxide (IV), which is reacted with acetic acid and acetic anhydride and oxidized in refluxing NaOH, yielding 3-methyl-4-methoxypyridine-2-methanol (V). The chlorination of (V) with thionylchloride in CH2Cl2 affords 3-methyl-4-methoxy-2-chloromethylpyridine (VI). The reaction of 2-mercapto-5-nitrobenzimidazole (VII) with iron and concentrated HCl in refluxing ethanol and water gives monoamine (VIII), which by condensation with 2,5-dimethoxytetrahydrofuran (IX) in acetic acid yields 2-mercapto-5-(1-pyrrolyl)benzimidazole (X). The condensation of (VI) with (X) by means of NaOH in methanol gives 2-[(4-methoxy-3-methyl-2-pyridinyl)methylsulfanyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (XI), which is finally treated with m-chloroperoxybenzoic acid (m-CPBA) in chloroform.

PATENT

http://www.google.com/patents/WO2013114232A1?cl=en

Ilaprazole is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and duodenal ulcer.

Ilaprazole is chemically known as 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-(lH-pyrrol-l-yl)-lH-benzimidazole havin following structure

There are very few patent documents related to crystallization of ilaprazole.

The example 2 of Indian Patent No. 183088 describes crystallization of ilaprazole from mixture of ethyl acetate and ether.

Indian patent application No. 3607/DELNP/2009 discloses various crystalline forms: A, B, E, F, I of ilaprazole and process for their preparation. The crystalline form B of ilaprazole is obtained by crystallization from acetone/triethylamine in a refrigerator for 11 days. The form B is characterized by peaks at 12.6 and 18.1 degree 2Θ in X-ray powder differactogram.

Another Indian patent application No. 3634/DELNP/2009 discloses various solvates of ilaprazole, these are crystalline form C (1,4-dioxane hemisolvate), D (tetrahydrofuran hemisolvate), G (methanol solvate), K (hydrate) of ilaprzole and process for their preparation.

International Patent Publication No. WO 2011/071314 discloses process for the preparation of Form A and Form B. The process for the preparation of Form A involves conversion of ilaprazole to its inorganic salt followed by neutralization with suitable acid in a solvent. The process for preparation of Form B requires use of multiple solvents for the crystallization.

The earlier processes crystallization of ilaprazole has following disadvantages:

i) process is laborious due to concentration of solvent carried out several times;

ii) difficult to obtain the pharmaceutically acceptable purity; and

iii) time consuming.

The physical or chemical properties of a drug can vary depending on the crystalline form of the drug, and such physical and chemical properties can greatly influence a suitable dosage form of the drug, the optimization of a process for preparing the drug, and the in vivo absorption of the drug. The discovery of the most appropriate crystalline form of a drug in a procedure for developing the drug enables the development time and cost to be reduced.

Patent

http://www.google.co.in/patents/US8592599

FIG. 22 is the proton NMR spectrum of racemic ilaprazole, Form F.

FIG. 23 is the solid state ¹³C CP/MAS ssNMR spectrum of racemic ilaprazole, Form F.

FIG. 24 is the IR spectrum of racemic ilaprazole, Form F.

FIG. 25 is the RAMAN spectrum of racemic ilaprazole, Form F.

References

PatentSubmittedGranted

Solid dosage form comprising proton pump inhibitor and suspension made thereof [US2006134210]2006-06-22

Optimally stabilized microgranule comprising 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole derivative [US6280773]2001-08-28

Method and system for dosing a pharmaceutical sample in a packaging machine [US7536843]2007-07-262009-05-26

Parenteral Formulation Comprising Proton Pump Inhibitor Sterilized in its Final Container by Ionizing Radiation [US2009111856]2009-04-30

SOLID STATE FORMS OF ENANTIOPURE ILAPRAZOLE [US2008200515]2008-08-21

Injection [US2009036406]2009-02-05

Pharmaceutical compositions of ilaparazole [US2008050444]2008-02-28

Substituted sulfoxide compounds, methods for preparing the same and use thereof [US2006217423]2006-09-28

CRYSTALLINE FORMS OF SOLVATED ILAPRAZOLE [US7989632]2008-08-212011-08-02

SOLID STATE FORMS OF RACEMIC ILAPRAZOLE [US7999110]2008-08-212011-08-16

Ilaprazole

Systematic (IUPAC) name
2-[(RS)-[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole
Clinical data
Trade names	Noltec
Routes of administration	Oral
Identifiers
CAS Number	172152-36-2
ATC code	None
PubChem	CID 214351
ChemSpider	185839
UNII	776Q6XX45J
ChEMBL	CHEMBL2106370
Chemical data
Formula	C19H18N4O2S
Molar mass	366.436820 g/mol

/////////IY-81149, ILAPRAZOLE

CC1=C(C=CN=C1CS(=O)C2=NC3=C(N2)C=C(C=C3)N4C=CC=C4)OC

.

Vasicine (peganine) is a quinazoline alkaloid. It is the active compound of Justicia adhatoda, after which the chemical is named.

Vasicine has been compared to theophylline both in vitro and in vivo.^[1] It has also been studied in combination with the related alkaloid vasicinone. Both the alkaloids in combination (1:1) showed pronounced bronchodilatory activity in vivo and in vitro.^[2] Both alkaloids are also respiratory stimulants.^[2] Vasicine has a cardiac–depressant effect, while vasicinone is a weak cardiac stimulant; the effect can be normalized by combining the alkaloids.^[2][3] Vasicine is reported to have a uterine stimulant effect.^[3]

Vasicine

Synonym Peganine

Biological Sources It is obtained from the leaves of Adhatoda vasica (L.) Nees (Acanthaceae) (Malabar Nut, Adotodai, Paveltia); and the seeds of Peganum harmala L. (Rutaceae) (Harmel, Syrian Rue, African Rue).

Chemical Structure

1, 2, 3, 9-Tetrahydropyrrolo [2, 1-b] quinazoline-3-ol; (C₁₁H₁₂N₂O).

Isolation It is isolated from the leaves of Adhatoda vasica* and also from the seeds of Peganum harmala** by adopting the standard methods of isolation described earlier in this chapter.

Characteristic Features

dl-Form: 1. It is obtained as needles from ethanol having mp 210°C.

2. It sublimes on being subjected to high vacuum.
3. It is soluble in acetone, alcohol, chloroform; and slightly soluble in water, ether and

benzene.

l-Form: 1. It is obtained as needles from ethanol with mp 212°C.

2. Its specific rotation [α ]_D¹⁴-254⁰(C = 2.4 in CHCl₃); [α ]_D¹⁴–14  62° (C = 2.4 in ethanol).

Note: In dilute HCl it is obtained as its dextrorotatory form.

Identification Tests

1. Hydrochloride dihydrate derivative is obtained as needles having mp 208°C (dry).
2. Hydroiodide dihydrate derivative is formed as needles with mp 195°C (dry).
3. Methiodide derivative is obtained as needles from methanol having mp 187°C.
4. Acetyl vasicine derivative (C₁₁H₁₁N₂O COCH₃) is formed as crystals having mp 123°C and bp0.01 230-240°C.

Uses

1. It is mostly used as an expectorant and bronchodilator.
2. It also shows oxytocic properties very similar to those exhibited by oxytocin and methyl ergometrine.
3. Vasicine also shows abortifacient action which is due to the release of prostaglandins.

Biosynthesis of Vasicine Various studies in Peganum harmala have evidently revealed vasicine (peganine) to be derived from the anthranilic acid, while the remaining portion of the structure comprising of a pyrrolidine ring provided by ornithine. The probable mechanism of vasicine skeleton may be explained by virtue of the nucleophilic attack from the N-atom present in anthranilate upon the pyrrolidinium cation, ultimately followed by amide formation. However, interestingly this pathway is not being adopted in Justicia adhatoda.

Vasaka

http://www.himalayawellness.com/products/pharmaceuticals/vasaka.htm

Effective respiratory care

Vasaka (Malabar Nut Tree/Adhatoda zeylanica) is well known in Ayurveda for its beneficial effects in respiratory ailments, particularly as an expectorant in bronchitis. The leaves, flowers, fruits and roots are used extensively for treating cold, cough, whooping-cough, chronic bronchitis and asthma.

Vasaka grows throughout India, up to an altitude of 1,300 meters.

Active constituents:

Vasaka contains the pyrroquinazoline alkaloids, including vasicine, vasicol and vasinone along with other minor constituents. Vasicine and vasinone are the major bioactive constituents of Vasaka which have bronchodilatory and antitussive properties.

The alkaloids present in the plant show significant protection against allergen-induced bronchial obstruction.

Herb Functions:

Respiratory care: Vasaka exhibits anti-inflammatory, antitussive and bronchodilatory action which eases congestion and coughing by helping loosen and thin mucus in airways. Vasaka relieves dyspnea by dilating the airways and improves overall lung functions. The herb is an excellent supportive therapy for symptomatic relief in tuberculosis and pulmonary infections.

Indications

• Productive cough
• Bronchitis
• Bronchial asthma

Contraindications:

None

Recommended dose:

One capsule, twice a day or as directed by your physician

Composition:

Each capsule contains 250mg extract of Vasaka

Note: Since Himalaya’s Pure Herbs are in capsule form, some children below 14 years may find it difficult to swallow them. For this reason, Pure Herbs are recommended for children ages 14 and above.

The information on this page is not intended to be a substitute for professional medical advice. Do not use this information to diagnose or treat your problem without consulting your doctor.

http://kumarncsirihbt.weebly.com/publications.html

Adhatoda Vasica (Justicia Adhatoda) – Malabar Nut, Vasa, Vasaka …

Presentation “Herbal drugs for health Herbal drugs for health …

References

Vasicine

Names
IUPAC name 1,2,3,9-Tetrahydropyrrolo[2,1-b]quinazolin-3-ol
Other names Peganine
Identifiers
CAS Number	6159-56-4
Jmol interactive 3D	Image
PubChem	72610
SMILES[show]
Properties
Chemical formula	C11H12N2O
Molar mass	188.23 g·mol−1
Melting point	210 °C (410 °F; 483 K)
Solubility in acetone, alcohol, chloroform	Soluble

//////

ENJOY SOME ANIMATIONS

Nizatidine is a histamine H₂ receptor antagonist that inhibits stomach acid production, and is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease. It was developed by Eli Lilly and is marketed under the brand names Tazac and Axid.

Clinical use

Nizatidine is used to treat duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD/GORD), and to prevent stress ulcers.^[1]

Adverse effects

Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache, and muscle aches.^[1]

History and development

Nizatidine was developed by Eli Lilly, and was first marketed in 1987. It is considered to be equipotent with ranitidine and differs by the substitution of a thiazole ring in place of the furan ring in ranitidine. In September 2000, Eli Lilly announced they would sell the sales and marketing rights for Axid to Reliant Pharmaceuticals.^[2] Subsequently, Reliant developed the oral solution of Axid, marketing this in 2004, after gaining approval from the U.S. Food and Drug Administration (FDA).^[3] However, a year later, they sold rights of the Axid Oral Solution (including the issued patent^[4] protecting the product) to Braintree Laboratories.^[5]
Nizatidine proved to be the last new histamine H₂ receptor antagonist introduced prior to the advent of proton pump inhibitors.’

Nizatidine, the systematic chemical name of which is N-[2-[[[2-[ imemylammo)memyl]-4-tl iazolyl]memyl]mio]e yl]–N’- methyl-2-nitro-l,l-ethenecliamine, which has the formula (I).This compound is a histamine H₂-receptor antagonist which is useful as anti- ulcer agents capable of inmbiting gastric acid secretion in mammals.

United States Patent No. 4,375,547; 4587344, 4777260; 4,904,792 and 5334725 discloses Nizatidine and other related products. The synthesis of nizatidine disclosed in US patent No. 4,904,792 involves a multi-step process. The first step of the process comprises reacting dimethylaminotmoacetamide hydrochloride with ethyl bromopyruvate to obtain 2-(dinιethylaminon ethyl)-4-thiazolecarboxylate. Reduction of this 4- tbiazolecarboxylate derivative with lithium triethylborohydride gives 2-
(<-Umethylaminoπιethyl)-4-tI-ύazolenιethanol, which is then converted into 4- (2-ammoetϊhyl)ti omethyl-2-d by reacting with
2-aminoethanethiol hydrochloride (cysteamine hydrochloride). This 2- ό-imetihylan-ιinoπιethylthiazol derivative is then converted into Nizatidine by reacting _.with N-met-hyl-l-methyltHo-2-mt-coet-hyleneamine in the presence of an acid United States Patent No. 4,382,090 describes a method to prepare 4-
(2-aminoethyl)tMome1_hyl-2-din ethylaminon etihyltl iazol by fusing 4- cmoronιe yl-2-d- nethylaminonιet-hylthiazole with cysteamine hydrochloride at above 100 °C.
United States Patent No. 4,468,517 described a method to prepare 4- cldoronιethyl-2-<-ιimethylaminon et-hylt-lιiazole. The method described in this patent involved reaction of dimet-hylaminotmoacetamide hydrochloride with 1,3-dichloroacetone in haloalkane (1,2-dichloroethane) as a solvent to obta 4-cHoromethyl^-hydroxy-2-dimet^ This 2-thiazoline derivative is then dehydrated with a dehydrating agent like PC1₃, PBr₃, SOCl₂, POCl₃ etc., to get 4-chloromethyl-2- din etihyl-in monietihylthiazole.
European Patent Application EP 0,515,121 and EP 0,960,880 describe the process for the preparation of 2-(dim.et-hylarninomethyl)-4- thiazolemethanol. The process consists of reacting (-Umethylaminothioacetamide hydrochloride with 1,3-dichloroacetone in toluene to get 4-chlorometiιyl-4-hyαioxy-2-d-methylaminomethyl-2- thiazoline, which is then reacted with alkali metal base in an inert solvent such as toluene to get 2-(dimethylam-m.omethyl)-4-thiazolemethanol.
The methods described in United States Patent No. 4,468,517 for the synthesis of 4-chloromethyl-4-hy( oxy-2-dimethyl-ui-momethyl-2- thiazoline, requires complete evaporation of the solvent 1,2-dichloroethane to get the crude product; it is then washed with ethyl acetate to obtain a pure product. Evaporation of the solvent to complete dryness is an inconvenient and inappropriate operation in large-scale manufacturing. Such evapprations in large-scale operations would produce the solids as lumps; further washing such lumps with solvents would be ineffective due to improper -mixing of -the solid -with solvent. The method described in EP 0,515,121 and EP 0,960,880 for the synthesis of 4-cHorometlιyl-4-hyc oxy*-2-α_im requires isolation of the product from the reaction mixture by precipitation of the product from the mother liquor by the addition of petroleum ether. The crude product obtained by the precipitation is then subjected to an additional purification step by crystallisation from toluene.
A number of procedures are described for the preparation of dimethylammotmoacetamide. Examples are Japanese Patent No. JP 62,273,948, JP 62,273,949, JP 02,264,755 and Org. Prep. Proced. Int., 1992, 24, P.66-7. All the procedures described in the literature- or the preparation of dirnethylaminotitioacetamide from dimethylam oacetomtrile involve the use of hydrogen sulfide under pressure in the presence of promoters or catalysts. The disadvantage with the use of hydrogen sulfide is the difficulty it poses in handling commercial quantities, as it is a very toxic gas. The object of the present invention is to provide an improved manufactxiring process for 4-chloromethyl-4-hydr xy-2- di–netihylam omethyl-2-tibiazoline..

.

SYN2

The cyclization of dimethylaminothioacetamide (I) with ethyl bromopyruvate (II) in refluxing ethanol gives ethyl 2-(dimethylaminomethyl)-4-thiazolecarboxylate (III), which is reduced with lithium triethyl borohydride in THF yielding 2-(dimethylaminomethyl)-4-thiazolemethanol (IV). The condensation of (IV) with 2-aminoethanethiol (V) by means of 48% HBr affords 2-(dimethylaminomethyl)-4-(2-aminoethylthiomethyl)thiazole (VI), which is finally condensed with 1-(methylthio)-2-nitro-N-methylethyleneamine (VII) in water.

PATENT

http://www.google.com/patents/WO2004069817A1?cl=en

Example No: 1 Preparation of dirnethylaniinothioacetaniide hydrochloride Into water (3000 ml), phosphorus pentasulfi.de (1302 g; 2.93 mol) and dimethylam oacetonitrile (1000 g; 11.88 mol) are added one after another at 10°C. The mixture is then slowly warmed to 70°C and maintained for 3 hrs to complete the reaction. The reaction mixture is then cooled to 20°C and sodiu hydroxide (53% w/w, 2200 g, 29.15 mol) is added into it below 20°C. The reaction mixture is then warmed to 50°C and extracted with toluene (2 x 2000 l). Isopropanolic hydrochloric acid (12% w/w; 3700 ml) is added into the extract at 25 to 30°C to adjust the pH to 2 and the mass stirred for 1 h to precipitate the product. The slurry is filtered, washed with isopropyl alcohol (1000 ml) and dried to get (1360 g) dimethyl ammotMoacetamide hydrochloride. Yield = 74.0%, HPLC purity = 97.6% Example No: 2
Preparation of 4-chloromethyl-4-hydr oxy-2-dimethylaminomethyl-2- thiazoline
Dimethylam othioacetamide hydrochloride (1000 g; 6.472 mol) is suspended in diisopropyletiier (4000 ml). Added into this suspension is sodium bicarbonate (1200 g; 14.28 mol) and sodium sulphate (1000 g). The slurry is heated to 55-60° C and stirred for 1 hr. Into this suspension is added 1,3 dichloroacetone (1000 g; 7.87 mol) dissolved in diisopropylether (1000 ml). The reaction is continued at 50-55° C for 2 h. The progress of the reaction is monitored by a qualitative HPLC analysis. Upon completion of the reaction, the reaction mixture is^* filtered hot at 50-55° C to remove insoluble inorganic salts. The mother liquor is cooled slowly to 0-5° C to crystallize out the product. The product is then filtered and washed with precooled diisopropylether (250 ml). The product is dried at 50° C under reduced pressure to obtain 1120 g. Yield = 83%; HPLC purity = 98.2%. The following example illustrates the process to convert this pure 4- cHoromethyl-4-hyσ-roxy-2-ά-imet^^ Nizatidine. Example No 3: Preparation of N- [2- [ [ [2- [(Dimethylaι-nino)methyl] -4- thiazolyl] methyl] thio] ethyl] -N’-methyl-2-nitro-l,l-ethenediamine. A. Preparation of 4-chloromethyl-2-ααmethylam onιethylthiazole Hydrochloride.
Thionyl chloride (430 ml; 5.9 mol) is added into chloroform (1000 ml) and cooled to 20° C. Into this solution is added 4-chloromethyl-4- hyά^oxy-2-dinιethylam ome yl-2-thiazoline (1000 g; 4.79 mol), dissolved in chloroform (4000 ml). The reaction mixture is further gradually heated to 60-65° C and maintained at this temperature till qualitative HPLC analysis shows the completion of the reaction. The reaction mixture is then cooled slowly to 30° C to get the product crystallized out. The product is filtered, washed and dried under reduced pressure to obtain 900 g of pure product. Yield = 83.3 %. B. Preparation of 4-(2-am oethyl)thiomethyl-2- ά-imethylam omethylthiazole.
2-A-minoethanetl iol hydrochloride (cysteamine hydrochloride, 520 g; 4.5 mol) is suspended in water (500 ml). This suspension is cooled to 5° C and sodium hydroxide solution (45 % w/w, 870 ml; 14.7 mol) is added into it at 5-10° C. Into this suspension, hydroxylamine sulphate (100 g; 0.6 mol) is added and stirred. A solution of 4-chloromethyl-2- di-n ethyl- inomethylthiazole hydrochloride (1000 g; 4.43 mol) dissolved in water (1250 ml) is prepared separately. This solution is added into the said suspension below 10° C and the reaction continued at 10° C for another 1 h. The completion of the reaction is determined by qualitative HPLC. The reaction mixture is then diluted with water (2000 ml), heated to 40-45° C and extracted with toluene (2 x 2000 ml). The toluene extract is treated with activated carbon at 40-45° C for 30 min. Activated carbon is removed by filtration through hyflo bed and evaporated toluene from the filtrate under reduced pressure at 60° C to obtain 910 g of the product. Yield = 88 %. C. Preparation of N-(2-(((2-(Dimethylamino)methyl)-4- tltiazolyl)m.ethyl)tltio)elhyl)-N’-methyl-2-nitro-l ,1 -etheneά-iamine (Nizatidine).
N-methyl-l-methyltHo-2-mtroethyleneamine (NMSM, 610 g; 4.12 mol) is mixed with water (1500 ml), and the mixture is cool to 20-25° C. 4- (2-Am-hoethyl)d omethyl-2-<^ (1000 g; 4.32 mol) dissolved in water (1500 ml) is added into this suspension at 20-25° C. The reaction mixture is warmed to 30-35° C and continued the reaction for 8 h. The progress of the reaction is monitored by qualitative HPLC analysis. The reaction mixture is extracted with toluene (2 x 1000 ml), and the aqueous layer is treated with activated carbon (50 g) at 55-60° C for 30 min. Activated carbon is removed by filtration through hyflo bed and the aqueous filtrate is extracted with chloroform (4 x 1000 ml)rThe cHorόform extract is concentrated under reduced pressure at less than 50° C; ethyl acetate (3000 ml) is added into the concentrate and reconcentrated. Acetone (300 ml), ethyl acetate (300 ml) is added into the concentrate and cooled to 0-5° C to crystallize the product. The product is filtered, washed with precooled ethyl acetate (250 ml), and dried to obtain pure Nizatidine 1160 g. Yield = 81.0%; HPLC purity -= 99.3%.

References

Nizatidine

Systematic (IUPAC) name
(E)-1-N‘-[2-[[2-[(dimethylamino)methyl]-1,3-thiazol-4-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine
Clinical data
Trade names	Axid
AHFS/Drugs.com	monograph
MedlinePlus	a694030
Licence data	US FDA:link
Pregnancy category	AU: B3
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only and OTC[1]
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	>70%
Protein binding	35%
Metabolism	Hepatic
Biological half-life	1–2 hours
Excretion	Renal
Identifiers
CAS Number	76963-41-2
ATC code	A02BA04
PubChem	CID 3033637
IUPHAR/BPS	7248
DrugBank	DB00585
ChemSpider	2298266
UNII	P41PML4GHR
KEGG	D00440
ChEBI	CHEBI:7601
ChEMBL	CHEMBL653
Chemical data
Formula	C12H21N5O2S2
Molar mass	331.46 g/mol

MIANSERIN

Mianserin (brand names: Depnon (IN), Lantanon (ZA), Lerivon (AR, BE, CZ, PL, RU, SK), Lumin (AU), Norval (UK), Tolvon (AU, HK^†, IE^†,NZ, SG^†), Tolmin (DK); where † indicates discontinued products) is a psychoactive drug of the tetracyclic antidepressant (TeCA) therapeutic family. It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and has antidepressant,anxiolytic (anti-anxiety), hypnotic (sedating), antiemetic (nausea and vomiting-attenuating), orexigenic (appetite-stimulating), andantihistamine effects.

It is not approved for use in the US, but its analogue, mirtazapine, is. Mianserin was the first antidepressant to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose.^[3]

Medical uses

When used for the treatment of depression, its efficacy appears comparable to that of amitriptyline, citalopram, clomipramine,dothiepin, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, moclobemide, nortriptyline, paroxetine, and trazodone.^[1][4]Mianserin received TGA approval in May 1996.^[5]

Similarly to its analogue, mirtazapine, mianserin has been tried as an augmentation strategy in treatment-resistant depression with some success.^[6] Mianserin has been tried, similarly to mirtazapine, as an adjunct in schizophrenia and has been found to reduce negative and cognitive symptoms.^[7][8][9]

Mianserin has demonstrated efficacy as a monotherapy for the treatment of Parkinson’s disease psychosis in an open-label clinical trial.^[10]

Interactions

CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors (SSRIs), quinidine, ritonavir, etc. would likely raise plasma levels of mianserin and hence could lead to mianserin toxicity. Conversely, CYP2D6 inducers would likely lead to reduced mianserin plasma concentrations and hence potentially diminish the therapeutic effects of mianserin.^[1]

Withdrawal

Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks,^[14] decreased appetite or anorexia,insomnia, diarrhea, nausea and vomiting, and flu-like symptoms, such as allergies or pruritus, among others.

Pharmacology

Mianserin is an antagonist/inverse agonist of the H₁, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃, 5-HT₆, 5-HT₇, α₁-adrenergic, and α₂-adrenergic receptors, and also inhibits thereuptake of norepinephrine.^[16][17] As a high affinity H₁ receptor inverse agonist, mianserin has strong antihistamine effects (sedation, weight gain, etc.). Contrarily, it has negligible affinity for the mACh receptors, and thus lacks anticholinergic properties. It was recently found to be a weak (K_i = 1.7 μM, EC₅₀ = 0.53 μM) κ-opioid receptor partial agonist.^[18]

In addition, mianserin also appears to be a potent antagonist of the neuronal octopamine receptor.^[19] What implications this may have on mood are currently unknown, however octopamine has been implicated in the regulation of sleep, appetite and insulin production and therefore may theoretically contribute to the overall side effect profile of mianserin.^[20][21]

Blockade of the H₁ and α1-adrenergic receptors has sedative effects,^[2] and also antagonism of the 5-HT_2A and α₁-adrenergic receptors inhibits activation of intracellularphospholipase C (PLC), which seems to be a common target for several different classes of antidepressants.^[22] By antagonizing the somatodendritic and presynaptic α₂-adrenergic receptors which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, andacetylcholine in various areas of the brain and body.

Enantioselectivity

(S)-(+)-Mianserin is approximately 200–300 times more active than its enantiomer (R)-(−)-mianserin.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-11-164

(14bS)-(+)-1,2,3,4,10,14b-Hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine (1)

(S)-(+)-1 in the form of solidifying oil; during purification step a small degree of product decomposition was observed; []D 23 = +469.2 (c 1, CHCl3); []D 23 = +436.5 (c 1, EtOH) {[9] []D 23 = +450 (c 0.26, EtOH)}; []D 23 = +428.0 (c 0.5, MeOH) {[5] []D 25 = +469.0 (c 1, MeOH)}.

Enantiomeric purity was determined by HPLC analysis (Chiracel OD-H, hexane:2- propanol = 80:20, 1ml/min, S isomer 5.6min).

IR (CCl4): 3064, 3022, 2939, 2794, 1492, 1446, 1251, 1132 cm–1 ;

1H NMR (500 MHz, CDCl3): δ 2.37-2.42 (m, 4 H), 2.46 (t, J = 10.5 Hz, 1 H), 2.92 (dt, J1 = 2.0 Hz, J2 = 11.0 Hz, 1 H), 3.02 (dd, J1 = 1.5 Hz, J2 = 11.0 Hz, 1 H), 3.25-3.28 (m, 1 H), 3.30 (d, J = 13.0 Hz, 1 H, methylene bridge), 3.42 (td, J1 = 3.0 Hz, J2 = 11.0 Hz, 1 H), 4.14 (dd, J1 = 2.0 Hz, J2 = 10.0 Hz, 1 H,methine), 4.81 (d, J = 13.0 Hz, 1 H, methylene bridge), 6.87 (td, J1 = 1.0 Hz, J2 = 7.5 Hz, 1 H, Ar), 7.00-7.02 (m, 2 H, Ar), 7.05-7.13 (m, 4 H, Ar), 7.16 (td, J1 = 1.5 Hz, J2 = 7.5 Hz, 1 H, Ar);

13C NMR (125 MHz, CDCl3): δ 38.8, 45.6, 51.0, 55.4, 64.6, 66.2, 119.0, 122.3, 126.5, 126.6, 127.0, 127.3, 128.1, 129.5, 137.1, 139.3, 139.8, 148.4.

HRMS (ESI): m/z calcd for C18H21N2 [M+H]+ : 265.1705; found: 265.1712.

(±)-1,2,3,4,10,14b-Hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine (1)

The racemate was prepared in the same manner as pure enantiomer; mp = 109.5- 110.5 °C ([10] mp = 111–113 °C). The HPLC analysis (Chiracel OD-H, hexane/2- propanol = 80:20, 1mL/min, R isomer 5.0 min and S isomer 5.6 min)

SYN 1

The title compound has been synthesized by several procedures. Acylation of 2-benzylaniline (I) by chloroacetyl chloride (II) gave chloroacetamide (III). Subsequent cyclization of amide (III) under Vilsmeier conditions furnished the dibenzoazepine (IV). Nucleophilic substitution of the chlorine atom of (IV) by methylamine led to amine (V). The imine function of (V) was reduced with either LiAlH4 or NaBH4 to the diamine (VI), which was further converted into the fused diketopiperazine (VII) upon heating with diethyl oxalate. The amide groups of (VII) were then reduced by means of borane in THF, yielding the target tetracyclic diamine, which was finally isolated as the corresponding hydrochloride salt……US 3534041

SYN 2

In a further procedure, styrene oxide (XV) was condensed with 2-(benzylamino)ethanol (XXVIII) to give amino diol (XXIX). After chlorination of (XXIX) using SOCl2 and DMAP, dichloro derivative (XXX) was condensed with 2-aminobenzyl alcohol (X) yielding piperazine (XXXI). Cyclization of (XXXI) in hot sulfuric acid afforded the tetracyclic compound (XXXII). The N-benzyl group of (XXXII) was then removed by treatment with butyl chloroformate producing carbamate (XXXIII), which was further hydrolyzed and decarboxylated to (XXXIV) under basic conditions. Finally, methylation of the secondary amine (XXXIV) was performed by reductive alkylation with formaldehyde either in the presence of formic acid under Leuckart-Wallach conditions or by catalytic hydrogenation

DE 4305659; EP 0612745

SYN 3

In a different method, reaction of styrene oxide (XV) with methylamine provided amino alcohol (XVI), which was further condensed with ethylene oxide (XVII) to afford amino diol (XVIII). Alternatively, diol (XVIII) was prepared by a more direct procedure by condensation of epoxide (XV) with 2-(methylamino)ethanol (XIX). Chlorination of (XVIII) employing SOCl2 yielded the dichloro derivative (XX), which was subsequently condensed with 2-aminobenzyl alcohol (X) leading to piperazine (XXI). Cyclization of (XXI) to the title compound was accomplished by treatment with hot polyphosphoric acid. Optionally, alcohol (XXI) was converted to chloride (XXII), which was then cyclized in the presence of AlCl3. In a related method, alcohol (XXI) was esterified with AcOH, and the resultant acetate ester (XXIII) was then cyclized in the presence of polyphosphoric acid……US 4217452

The key intermediate (XXI) was also prepared by several related procedures. Chlorination of aminoalcohol (XVI) gave chloro amine (XXIV), which was condensed with 2-aminobenzyl alcohol (X) to afford diamine (XXV). Then, alkylation of diamine (XXV) with dibromoethane (XIII) in hot pyridine gave rise to the target piperazine (XXI). Alternatively, diamine (XXV) was condensed with ethyl chloroacetate or with diethyl oxalate to produce the mono- or dioxopiperazines (XXVII) and (XXVI), respectively, which were then reduced to (XXI) by means of LiAlH4. Cyclization of alcohol (XXI) to the title compound was achieved by treatment with concentrated sulfuric acid

SYN5

FR 2647114

Treatment of alpha-chlorophenylacetyl chloride (VIII) with methylamine provided the corresponding chloro amide (IX), which was subsequently condensed with 2-aminobenzyl alcohol (X) to afford amino alcohol (XI). Cyclization of (XI) in the presence of AlCl3 led to the dibenzoazepine (XII). This was converted to the tetracyclic compound (XIV) by reaction with dibromoethane (XIII) in the presence of Na2CO3. Reduction of the amide carbonyl group of (XIV) by means of LiAlH4 furnished the title compound. In a related strategy, amide (XII) was initially reduced to diamine (VI) by using LiAlH4. Subsequent condensation of (VI) with dibromoethane (XIII) led to the target tetracyclic derivative

OTHER……….

References

Further reading

External links

• Treatments for Depression – Mianserin

Mianserin

Systematic (IUPAC) name
(±)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine
Clinical data
Trade names	Bolvidon (discontinued), Tolvon
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B2
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	20–30%[1]
Protein binding	95%[1]
Metabolism	Hepatic (mediated byCYP2D6; most metabolism occurs via aromatic hydroxylation, N-oxidation and N-demethylation)[1]
Biological half-life	21–61 hours[2]
Excretion	Renal (4–7%) Faecal (14–28%)[1]
Identifiers
CAS Number	24219-97-4
ATC code	N06AX03
PubChem	CID 4184
IUPHAR/BPS	135
DrugBank	DB06148
ChemSpider	4040
UNII	250PJI13LM
KEGG	D08216
ChEBI	CHEBI:51137
ChEMBL	CHEMBL6437
Chemical data
Formula	C18H20N2
Molar mass	264.365

///////////MIANSERIN

c42c(N3C(c1ccccc1C2)CN(C)CC3)cccc4

Meloxicam ;

351.40, C₁₄H₁₃N₃O₄S_{2, MP 255 °C}

(8E)-8-[hydroxy-[(5-methyl-1,3-thiazol-2-yl)amino]methylidene]-9-methyl-10,10-dioxo-10$l^{6}-thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one;

4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide;

CAS 133687-22-6; Mobec;Mobic (TN);

2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-(5-methylthiazolyl)-, 1,1-dioxide;

The IUPAC name of Meloxicam is (3E)-3-[hydroxy-[(5-methyl-1,3-thiazol-2-yl)amino]methylidene]-2-methyl-1,1-dioxo-1λ6,2-benzothiazin-4-one. With the CAS registry number 71125-38-7, it is also named as 2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-(5-methylthiazolyl)-, 1,1-dioxide.

Uses of Meloxicam: this chemical is a nonsteroidal anti-inflammatory drug with analgesic and fever reducer effects. And it inhibits cyclooxygenase that can be used as an anti-inflammatory. Additionally, it can be used for the treatment of rheumatoid arthritis and osteoarthritis.

In Europe, where the product has been available since the early 1990s, it is also prescribed and licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs and cats. For many years, both injectable and oral (liquid and tablet) formulations of meloxicam have been licensed for use in dogs, and injectable ones for use in cats. In June 2007, a new oral version of Metacam was licensed in Europe for the long-term relief of pain in cats. As of June 2008, Meloxicam is registered for long term use in cats in Australia, New Zealand, and throughout Europe. ‘Metacam oral suspension 1.5 is not approved or recommended (according to the manufacture insert) for use in cats in the U.S.

1H NMR DMSOD6

13C NMR DMSOD6

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and fever reducer effects. It is a derivative of oxicam, closely related to piroxicam, and falls in the enolic acid group of NSAIDs.^[2] It was developed by Boehringer-Ingelheim. Meloxicam starts to relieve pain about 30–60 minutes after administration.^[3]

Mechanism of action

Meloxicam blocks cyclooxygenase (COX), the enzyme responsible for converting arachidonic acid into prostaglandin H₂—the first step in the synthesis of prostaglandins, which are mediators of inflammation. Meloxicam has been shown, especially at its low therapeutic doses, selectively to inhibit COX-2 over COX-1.^[1]

Meloxicam concentrations in synovial fluid range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown,^[2] but it may account for the fact that it performs exceptionally well in treatment of arthritis in animal models.^[4]

Side effects

Meloxicam use can result in gastrointestinal toxicity and bleeding, headaches, rash, and very dark or black stool (a sign of intestinal bleeding). Like other NSAIDs, its use is associated with an increased risk of cardiovascular events such as heart attack and stroke.^[5]It has fewer gastrointestinal side effects than diclofenac,^[6] piroxicam,^[7] naproxen,^[8] and perhaps all other NSAIDs which are not COX-2 selective.^[6] Although meloxicam does inhibit thromboxane A, it does not appear to do so at levels that would interfere withplatelet function.

A pooled analysis of randomized, controlled studies of meloxicam therapy of up to 60 days duration found that meloxicam was associated with a statistically significantly lower number of thromboembolic complications than the NSAID diclofenac (0.2% versus 0.8% respectively) but a similar incidence of thromboembolic events to naproxen and piroxicam.^[9]

Potential serious cardiovascular side effects

Persons with hypertension, high cholesterol, or diabetes are at risk for cardiovascular side effects. Persons with family history of heart disease, heart attack or stroke must tell their treating physician as the potential for serious cardiovascular side effects is significant.^[10][11]

Veterinary use

Meloxicam is also used in the veterinary field, most commonly in dogs and cats, but also sees off-label use in other animals such as cattle and exotics.^[12][13] The U.S. Food and Drug Administration sent a Notice of Violation to the manufacturer for its promotional materials which included promotion of the drug for off-label use.^[14] In the U.S. the drug is indicated for management of pain and inflammation associated with osteoarthritis in dogs only. In Europe, where the product has been available since the early 1990s,^{[citation needed]} it is also prescribed and licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs. Side effects in animals are similar to those found in humans; the principal side effect is gastrointestinal irritation (vomiting, diarrhea and ulceration). Rarer but important side effects include liver and kidney toxicity.

Since 2003, the oral (liquid) formulations of meloxicam have been licensed in the U.S for use in dogs only,^[15] with the January 2005 product insert specifically warning in bold-face type: “Do not use in cats.”^[16] An injectable formulation for use in dogs was approved by the FDA in November 2003,^[17] with a formulation for cats, for surgical use only, approved in October 2004.^[18]

In the U.S., per the manufacturer’s clinical instructions as of July 2010, injectable meloxicam is indicated in operative use with felines as a single, one-time dose only, with specific and repeated warnings not to administer a second dose.^[19] In June 2007, a new oral version of meloxicam was licensed in Europe for the long-term relief of pain in cats. As of June 2008, meloxicam is registered for long term use in cats in Australia, New Zealand, and throughout Europe. A peer-reviewed journal article cites feline overdose of NSAIDs, including meloxicam, as being a cause of severe kidney damage in cats.^[20]

The pharmacokinetics of meloxicam have been investigated in koalas (Phascolarctos cinereus).^[21]

Meloxicam has been investigated as an alternative to Diclofenac by the RSPB to prevent deaths of vultures.

Preparation of Meloxicam: this chemical can be prepared by Methyl 4-hydroxy-2-methyl-(2H)-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-Amino-5-methylthiazole. The yield is 74 %.

References

External links

• Manufacturer’s Official Product Website for the Veterinary formulations
• Manufacturer’s United States Division website for the Veterinary formulations
• FDA Metacam
• Meloxicam Side Effects

Meloxicam

Systematic (IUPAC) name
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Clinical data
Trade names	Mobic
AHFS/Drugs.com	monograph
MedlinePlus	a601242
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	89%[1]
Protein binding	99.4%[1]
Metabolism	Hepatic (CYP2C9 and 3A4-mediated)[1]
Biological half-life	20 hours[1]
Excretion	Urine and faeces equally[1]
Identifiers
CAS Number	71125-38-7
ATC code	M01AC06
PubChem	CID 5281106
IUPHAR/BPS	7220
DrugBank	DB00814
ChemSpider	10442740
UNII	VG2QF83CGL
KEGG	D00969
ChEBI	CHEBI:6741
ChEMBL	CHEMBL599
PDB ligand ID	MXM (PDBe, RCSB PDB)
Chemical data
Formula	C14H13N3O4S2
Molar mass	351.403 g/mol

/////

Cc1cnc(s1)NC(=O)C\3=C(/O)c2ccccc2S(=O)(=O)N/3C

Benfotiamine

S-[(Z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-phosphonooxypent-2-en-3-yl] benzenecarbothioate

Benphothiamine; Betivina; Biotamin; Neurostop; Nitanevril;22457-89-2

C₁₉H₂₃N₄O₆PS MF

466.447882 g/mol MW

Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine (vitamin B1).

It has been licensed for use in Germany since 1993 under the trade name Milgamma. (Combinations with pyridoxine or cyanocobalamin are also sold under this name.) It is prescribed there for treating sciatica and other painful nerve conditions.^[1]

It is marketed as a medicine and/or dietary supplement, depending on the respective Regulatory Authority.^{[citation needed]}

Uses

Benfotiamine is primarily marketed as an antioxidant dietary supplement. In a clinical study with six patients, benfotiamine lowered AGE by 40%.^[2]

Benfotiamine may be useful for the treatment of diabetic retinopathy, neuropathy, and nephropathy however “Most of the effects attributed to benfotiamine are extrapolated from in vitro and animal studies. Unfortunately apparent evidences from human studies are scarce and especially endpoint studies are missing. Therefore additional clinical studies are mandatory to explore the therapeutic potential of benfotiamine in both diabetic and non-diabetic pathological conditions”.^[3] It is thought that treatment with benfotiamine leads to increased intracellular thiamine diphosphate levels,^[3] a cofactor of transketolase. This enzyme directs advanced glycation and lipoxidation end products (AGE’s, ALE’s) substrates to the pentose phosphate pathway, thus reducing tissue AGEs.^{[4][5][6][7][8]}

Pharmacology

After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine.^[9] Benfotiamine should not be confused with allithiamine, a naturally occurring thiamine disulfide derivative with a distinct pharmacological profile.^[10]

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=48F4CE7167F2EB243FBAF807987983D5.wapp1nB?docId=WO2014059702&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

​ The Benfotiamine, disclosed in US pat. no. 19623064000 US english names: S-benzoylthiamine O-monophosphate common name: Benfotiamine, chemical name: S − 2-[ [ (2-methyl-4-amino-5-pyrimidinyl) methyl ]-propionylamino ]-5-phosphonato-2-pentene-3-thiol benzoate, formula C 19 H 23 N 406 PS molecular weight 466.45 the following structural formula:

​ Chemical composition of the same species, in various physico-chemical conditions, crystallization into two or more different structure of the crystalline phenomenon, also referred to as polymorphs or homogeneous an image drug polymorph is a common phenomenon of drug discovery, drug quality is an important factor. Various polymorphs have different physical properties such as appearance, melting point, hardness, dissolution rate, chemical stability, mechanical stability, etc. differences, these differences in the physical properties of the sometimes affect the stability of the drug, bioavailability, even the drug availability. Thus, in drug development, it should be fully considered drug poly-type problems, the type of study and control in drug development of significant research content.

​ The benfotiamine, vitamin B 1 lipid-soluble derivatives, improved water-soluble vitamins B1 low bioavailability of disadvantages, increased blood and tissues. Thiamine concentration, thereby enhancing efficacy. The primary application to the following aspects (1) for thiamine deficiency disease prevention and treatment; (2) vitamin B 1 demand increases, from the food uptake is not sufficient make-up, fatigue, hyperthyroidism, gestation, lactation, vigorous manual labor, etc.); (3) for the treatment of non-l 酒性 lopinavir, grams of brain disease; (4) for the treatment of foot disease; (5) for the disease, the speculative and thiamine deficiency and metabolic disorders associated with treatment, such as: neuropathic pain; muscle pain, joint pain ​; Peripheral-inflammatory, peripheral nerve

​ The paralysis; myocardial metabolism disorders, constipation, gastrointestinal motility dysfunction. The benfotiamine as vitamin B 1 supplemental agents have been in the united states, japan, europe, etc worldwide market. Recent studies have shown that, benfotiamine in diabetic peripheral neuropathy and retinopathy of significant therapeutic effect. In addition, our studies, benfotiamine may also be applied to the prevention and treatment of alzheimer’s disease, and aging.

​ Alzheimer’s disease (Altheimer’s disease, AD) is a cognitive, behavioral disorders is the primary clinical manifestations progressive neurodegenerative diseases, an age-related disorders, with age, their prevalence is a significant rise. 我国 the number of people in excess of 600 million AD patients, it is contemplated that in 2050 worldwide by the year AD patient may exceed 3000 million people as the medical scientific development, severe affect human health, mortality is a leading significant diseases such as cancer, stroke, cardiovascular disease, exhibit a decrease in mortality year by year, and AD mortality the rendering large increase in ​ . In addition, alzheimer’s disease course long, the disabling rate is high, thus, alzheimer’s disease will be the 21 st century threaten both human diseases the most serious. It is estimated that worldwide by the year AD 2010 for medical costs up to 6040 of millions of dollars, the same global of the gross national product of 1%

​ China and the USA, the world there have been the following two classes of drugs approved for AD treatment: cholinesterase inhibitors and N-methyl D-aspartate (NMDA) receptor antagonist are both improved AD patient symptoms, slow disease progression does not prevent or reverse the progression of a disease. The benfotiamine by inhibiting the sugar synthase kinase -3 (Glycogen synthase kinase -3, GSK -3) activity, decrease in brain beta-amyloid protein (beta-amyloid, alpha beta) the deposition and tau protein phosphorylation, reduce alzheimer’s disease, pathological damage.

​ Presently available, benfotiamine primarily in the form of tablets and powders is administered in the form of, all formulations are not related to the benfotiamine feedstock form has not yet been the benfotiamine crystalline be systematically studied, the present US pat. no. first for benfotiamine of systematic study of various forms, illustrating different form benfotiamine characteristics and their feasibility. As a pharmaceutical agent

PATENT

http://www.google.com/patents/CN103772432A?cl=en

Example 1:

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 8 hours, was added water quenching 3000kg off after the reaction, the temperature was raised to 80-90 ° C hydrolysis of 10 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine mixture of methyl tert-butyl ether = WPA / 1/1; aqueous phase 5000kg methanol to precipitate a solid, centrifuged to obtain a monoester 1200kg vitamin BI phosphoric acid crude; the 1200kg Vitamin `prime BI phosphate monoester crude in 6000kg water mixed beating, down to O ~ 5 ° C, dropping liquid in this temperature range adjusting the PH value of the base system to 12.0 ~ 14.0; PH after adjustment to ensure that the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered and the filtrate adjust PH from 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1200kg, namely benfotiamine. Yield: 77.38%, Purity: 98.70% ο

  Example 2:

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 80 ~ 100 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 6 hours, was added water quenching 5000kg off after the reaction was heated to reflux for 5 hours hydrolysis; cooled to room temperature, the autoclave was added to the mixture was extracted twice 4000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase 6000kg ethanol precipitation The solid obtained by centrifugation vitamin BI phosphate monoester 1200kg crude; after 1200kg vitamin BI crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjust PH value system in this temperature range to 10.0 ~ 12.0; PH adjusting finished, to ensure the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered, the solid was filtered, the filtrate was adjusted to 3.5 ~ PH value 4.0 precipitated solid was isolated and dried to give a white solid 1250kg, namely benfotiamine. Yield: 80.61%, Purity: 98.50% ο

  Example 3:

After the reactor was added 3000kg polyphosphoric acid, heated to 90 ~ 110 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after the insulation in this temperature range for 5 hours, 5000kg of water quenching off after the reaction, the temperature was raised to 90-100 ° C hydrolysis 5 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine methyl tert-butyl ether mixture was extracted twice = / 1/1; aqueous phase Join 7000kg acetone precipitate a solid, mono- 1230kg centrifuged to obtain crude vitamin BI phosphoric acid; vitamin BI after 1200kg crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjusted within this temperature range System PH value to 11.0 ~ 13.0; PH after adjustment to ensure that the temperature of the reactor was added dropwise within 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to 3.5 PH value to 4.0 precipitated solid was isolated and dried to give a white solid 1240kg, namely benfotiamine. Yield: 79.96%, Purity: 98.50% ο

Example 4

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 4 hours, water quenching 8000kg off after the reaction, the temperature was raised to 90 – 110 ° C hydrolysis seven hours; cooled to room temperature, was added to the kettle 4000kg trioctylamine / methyl tert-butyl ether mixture was extracted phosphoric = 1/1; aqueous phase 6000kg methanol precipitated solid was centrifuged to give 1200kg vitamin BI phosphate monoester crude; the 1200kg vitamin BI phosphate monoester crude 6000kg water were mixed after beaten, cooled to O ~ 5 ° C, caustic soda was added dropwise at this temperature adjustment range of the system PH value to 9.0 ~ 11.0; PH adjustment finished, the reactor temperature to ensure solution of 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to PH value

3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1260kg, namely benfotiamine. Yield: 81.24%, Purity: 98.70% ο

  Example 5

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 110 ~ 130 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 3 hours, water quenching 10000kg off after the reaction, the temperature was raised to 110 – 120 ° C under reflux for 3 hours hydrolysis; cooled to room temperature, the mixture was extracted phosphoric acid was added to the kettle 3000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase `6000kg ethanol was added to precipitate a solid, obtained by centrifugation 1200kg vitamin BI phosphate monoester crude; after 1200kg vitamin BI phosphate monoester crude mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda in this temperature range adjusting the PH value of the system to the 8.0 ~ 10.0; PH adjusting finished, 1200kg of benzoyl chloride was added dropwise to ensure the kettle temperature within 10 ~ 25 ° C, after the addition is complete heat the reaction to completion; filtered, the filtrate was adjusted to PH value 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1230kg, namely benfotiamine. Yield: 79.31%, purity: 98.60% ο

PATENT

http://www.google.com/patents/CN102911208A?cl=en

Example I: Phosphorus oxychloride 15. 33g (O. Imol) was added to the water 10. 8mL, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 26. 53g (O. lmol), warmed to 50 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 91.36%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, the 0_5 ° C under stirring, monitoring the reaction solution and pH changes, the pH value is stable, does not change when the reaction liquid PH, stirring was continued for I hour the reaction, the solution was adjusted to pH 3. 5-4. 0, suction filtration to give 33. 58g benfotiamine white solid. Yield 71.9%.

  MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, J = I. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

  Example 2: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 21. 23g (O. OSmol), warmed to 60 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 92.37%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, suction filtration to give 27. 69g benfotiamine white solid. Yield 74.2%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3):.. 2.18 (s, 3H), 2 56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H ), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

  Example 3: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 3. 6mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 15. 92g (O. 06mol), warmed to 70 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 93.23%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 23. 71g. Yield 84.7%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 4: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 10. 62g (O. 04mol), warmed to 80 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 95.26%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 15. 22g. Yield 85.2%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

PATENT

http://www.google.com/patents/CN103724374A?cl=en

Synthesis  I) thiamine monophosphate hydrochloride

  In the reaction flask was added phosphate, thiamine hydrochloride, phosphorous pentoxide was added and stirred to dissolve, controlling the reaction temperature to complete the reaction thiamine hydrochloride, was added and stirring was continued after dropwise addition of concentrated hydrochloric acid hydrolysis of purified water was added dropwise acetone crystallization dropwise at raising grain, filtration, washed with acetone crystal, vacuum drying intermediates thiamine monophosphate hydrochloride;

  2) Synthesis of crude benfotiamine

In the reaction flask thiamine monophosphate hydrochloride, dissolved in purified water, sodium hydroxide was added dropwise to adjust the pH to alkaline and steady, benzoyl chloride, sodium hydroxide was added dropwise while controlling alkaline pH, to control the temperature of the reaction pH remained stable, the end of the reaction, concentrated hydrochloric acid was added and extracted twice with ethyl acetate, the aqueous phase of sodium hydroxide was added dropwise until the pH is acidic, crystal seeding planting, filtration, purified water and acetone crystal, vacuum drying crude benfotiamine;

See also

• Vitamin B₁ analogue

References

• 1 “BBC news story: Back pain drug ‘may aid diabetics'”. BBC News. 18 February 2003.
• 2
• J Lin, A Alt, J Liersch, RG Bretzel, M Brownlee (May 2000). “Benfotiamine Inhibits Intracellular Formation of Advanced Glycation End Products in vivo” (PDF). Diabetes. 49 (Suppl1) (A143): 583.
• 3
• Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (2010). “The multifaceted therapeutic potential of benfotiamine”. Pharmacol Res 61 (6): 482–8. doi:10.1016/j.phrs.2010.02.008. PMID 20188835.
• 4
• Since AGEs are the actual agents productive of diabetic complications, in theory, if diabetic patients could block the action of AGEs completely by benfotiamine, strict blood sugar control, with its disruption of lifestyle and risks to health and life by severe hypoglycemic episodes, could be avoided, with revolutionary implications for the treatment of diabetes. Hammes, HP; Du, X; Edelstein, D; Taguchi, T; Matsumura, T; Ju, Q; Lin, J; Bierhaus, A; Nawroth, P; Hannak, D; Neumaier, M; Bergfeld, R; Giardino, I; Brownlee, M (2003). “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy”. Nat Med 9 (3): 294–299. doi:10.1038/nm834.
• 5
• Stirban A, Negrean M, Stratmann B; et al. (2007). “Adiponectin decreases postprandially following a heat-processed meal in individuals with type 2 diabetes: an effect prevented by benfotiamine and cooking method”. Diabetes Care 30 (10): 2514–6. doi:10.2337/dc07-0302. PMID 17630265.
• 6
• Stracke H, Hammes HP, Werkmann D; et al. (2001). “Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats”. Exp. Clin. Endocrinol. Diabetes 109 (6): 330–6. doi:10.1055/s-2001-17399. PMID 11571671.
• 7
• Stirban A, Negrean M, Stratmann B; et al. (2006). “Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes”. Diabetes Care 29 (9): 2064–71. doi:10.2337/dc06-0531. PMID 16936154.
• 8
• Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ (2003). “Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine”. Diabetes 52 (8): 2110–20. doi:10.2337/diabetes.52.8.2110. PMID 12882930.
• 9
• Yamazaki, M (1968). “Studies on the absorption of S-benzoylthiamine O-monophosphate : (I) Metabolism in tissue homogenates”. Vitamins 38 (1): 12–20.
• 10

Volvert, M.L.; Seyen, S.; Piette, M.; Evrard, B.; Gangolf, M.; Plumier, J.C.; Bettendorff, L. (2008). “Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives”. BMC Pharmacology 8 (1): 10. doi:10.1186/1471-2210-8-10. PMC 2435522. PMID 18549472.

External links

• BBC news story (2003): Back pain drug ‘may aid diabetics’

Benfotiamine

Systematic (IUPAC) name
S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate
Clinical data
Trade names	Milgamma
AHFS/Drugs.com	International Drug Names
Legal status	OTC
Routes of administration	Oral
Identifiers
CAS Number	22457-89-2
ATC code	A11DA03
PubChem	CID 3032771
ChemSpider	2297665
UNII	Y92OUS2H9B
ChEBI	CHEBI:41039
ChEMBL	CHEMBL1491875
Synonyms	S-Benzoylthiamine O-monophosphate
Chemical data
Formula	C19H23N4O6PS
Molar mass	466.448 g/mol

///////

O=P(O)(O)OCCC(/SC(=O)c1ccccc1)=C(/N(C=O)Cc2cnc(nc2N)C)C

PERAMPANEL

Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

(US20160039759) PROCESS FOR THE PREPARATION OF PERAMPANEL

CADILA HEALTHCARE LIMITED

Sanjay Jagdish DESAI
Jayprakash Ajitsingh Parihar
Kuldeep Natwarlal Jain
Sachin Ashokrao Patil

Perampanel, a non-competitive AMPA receptor antagonist, is the active ingredient of FYCOMPA® tablets (U.S) which is approved as an adjunctive therapy for the treatment of partial on-set seizures with or without secondarily generalized seizures in patients with aged 12 years and older. Chemically, Perampanel is 5′-(2-cyanophenyl)-1′-phenyl-2,3′-bipyridinyl-6′(1′H)-one, with an empirical formula C23H15N30 and molecular weight 349.384 g/mol which is represented by Formula (I).

U.S. Pat. No. 6,949,571 B2 discloses perampanel and its various processes for preparation thereof.

U.S. Pat. No. 7,759,367 B2 discloses the pharmaceutical composition of perampanel and an immunoregulatory agent and their uses.

U.S. Pat. No. 8,304,548 B2 discloses the reaction of 5′-bromo-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one with 2-(1,3,2-dioxaborinan-yl)benzonitrile in the presence of palladium compound, a copper compound, a phosphorus compound and a base to form perampanel of Formula (I). Also discloses the crystalline hydrate, anhydrous crystal Form I, anhydrous crystal Form III, & anhydrous crystal Form V of perampanel of Formula (I).

U.S. Pat. No. 7,803,818 B2 discloses an amorphous form of perampanel. U.S. Pat. No. 7,718,807 B2 discloses salts of perampanel. International (PCT) publication No. WO 2013/102897 A1 discloses anhydrous crystalline Form III, V & VII of perampanel.

U.S. PG-Pub. No. 2013/109862 A1 discloses the method for preparing 2-alkoxy-5-(pyridin-2-yl)pyridine, which is an intermediate for preparing perampanel key starting material 5-(2′-pyridyl)-2-pyridone.

U.S. Pat. No. 7,524,967 B2 discloses the preparation of 5-(2′-pyridyl)-2-pyridone, an intermediate in the preparation perampanel.

International (PCT) publication No. WO 2014/023576 A1 discloses the preparation of cyanophenyl boronic acid, an intermediate in the preparation perampanel.

The prior-art processes suffer with problems of poor yield and requirement of chromatographic purification or series of crystallizations which further reduces the overall yield of the final product, which is overcome by the process of the present invention.

Pankaj Patel, chairman, Zydus Cadila

EXAMPLES

The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-A: Preparation of 5-(2-pyridyl)-1,2-dihydropyridin-2-one In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 188.80 g 5-bromo-2-methoxypyridine in 190 mL tetrahydrofuran and 12.92 g pyridine-2-yl boronic acid were added and refluxed. The reaction mixture was cooled to 25-30° C. and aqueous solution of hydrochloric acid was added and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydroxide and extracted with tetrahydrofuran.

The organic layer was washed with saline water, dried over anhydrous magnesium sulfate, and then evaporated to obtain the titled compound.

Example-1

Preparation of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 201.5 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 208.3 g N-bromosuccinimide and 1300 mL N,N-dimethylforamide were stirred at 25-30° C. for 2-3 hours. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 min. The precipitate was filtered, washed with N,N-dimethylforamide and dried at 50° C. to obtain 230 g title compound.

Example-2

Preparation of 3-bromo-5-2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 18.75 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one in 300 mL methylene dichloride, 18.36 g 1-phenyl boronic acid, 3.47 g palladium triphenylphosphine and 10 mL triethyl amine were added and the reaction mixture was stirred for 1 hour at 25-35° C. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was crystallised from ethyl acetate to obtain the title compound.

Example-3

Preparation of Perampanel

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a suspension of 188 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one, 161.2 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 3.0 g tetrakis(triphenylphosphine)-palladium(0), 10 mL triethylamine (10 mL) in 300 mL methylene dichloride were stirred at 25-30° C. for 12 hours. To the reaction mixture was added 5 mL conc. aqueous ammonia, 10 mL water and 40 mL ethyl acetate. The separated organic layer was washed with water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under vacuum. Ethyl acetate was added to the residue and heated obtain clear solution. n-hexane was added to this solution and cooled to 25-30° C. The obtained solid was filtered and washed with ethyl acetate and dried to obtain perampanel.

Example-4

Preparation of 3-Bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 108.5 g N-bromosuccinimide and 500 mL N,N-dimethylforamide were stirred at 30-35° C. for 3 hours. 100 mL water was added to the reaction mixture at 5-15° C. and stirred at 30-35° C. for 1 hour. The solid obtained was filtered, washed with water and dried to obtain 129 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one.

Example-5

Preparation of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 72.8 g phenylboronic acid and 500 mL N,N-dimethylformamide were added at 30-35° C. and stirred. 11.9 g copper acetate and 15.7 g pyridine were added and air was purged into the reaction mixture and stirred for 16 hours at 30-35° C. After the completion of the reaction, the reaction mixture was poured into 1200 mL aqueous ammonia at 10-15° C. and stirred for 2 hours at 30-35° C. The obtained solid was filtered, washed with water and dried to obtain 120 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-6

Purification of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 500 mL isopropyl alcohol were stirred at 60-65° C. for 30 min. The reaction mixture was cooled to 20-25° C. and stirred for 30 min. The reaction mixture was filtered, washed with isopropanol and dried to obtain 96 g pure 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-7

Preparation of Perampanel

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 125 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile and 1500 mL N,N-dimethylformamide were added under inert atmosphere. 44 g potassium carbonate and 4.2 g palladium tetrakis were added and stirred at 115-125° C. for 3 hours. The solvent was removed under vacuum. Ethyl acetate was added to the residue and the organic layer was distilled off to obtain perampanel (78 g).

////////Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

Cipla, New Patent, WO 2016020664, Everolimus

CIPLA LIMITED [IN/IN]; Peninsula Business Park Ganpatrao Kadam Marg Lower Parel Mumbai 400 013 (IN).
KING, Lawrence [GB/GB]; (GB) (MW only)

RAO, Dharmaraj Ramachandra; (IN).
MALHOTRA, Geena; (IN).
PULLELA, Venkata Srinivas; (IN).
ACHARYA, Vinod Parameshwaran; (IN)

WO2016020664,  PROCESS FOR THE SYNTHESIS OF EVEROLIMUS AND INTERMEDIATES THEREOF

Everolimus (RAD-001) is the 40-O- 2-hydroxyethyl)-rapamycin of formula (I),

It is a derivative of sirolimus of formula III),

and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR). Everolimus is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. It is marketed by Novartis under the tradenames Zortress™ (USA) and Certican™ (Europe and other countries) in transplantation medicine, and Afinitor™ in oncology.

Trisubstituted silyloxyethyltrifluoromethane sulfonates (triflates) of the general formula (IV),

wherein R₂, R₃ are independently a straight or branched alkyl group, for example C^-Cw alkyl, and/or an aryl group, for example a phenyl group, are important intermediates useful in the synthesis of everolimus.

Everolimus and its process for manufacture using the intermediate 2-(t-butyldimethyl silyl) oxyethyl triflate of formula (IVA),

was first described in US Patent Number 5,665,772. The overall reaction is depicted in Scheme I.

Scheme

Everolimus (I)

For the synthesis, firstly sirolimus of formula (III) and 2-(t-butyldimethylsilyl)oxyethyl triflate of formula (IVA) are reacted in the presence of 2,6-Lutidine in toluene at around 60°C to obtain the corresponding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin of formula (I la), which is then deprotected in aqueous hydrochloric acid and converted into crude everolimus [40-O-(2-Hydroxy)ethyl rapamycin] of formula (I).

However, this process results in the formation of impure everolimus, which requires purification by column chromatography. The process results in very poor overall yield and purity and thereby the process is not suitable for the commercial scale production of everolimus.

Moenius et al. (I. Labelled Cpd. Radiopharm. 43, 1 13-120 (2000) have disclosed a process to prepare C-14 labelled everolimus using the diphenyltert-butylsilyloxy-protective group of formula (IV B),

as the alkylation agent. The overall yield reported was 25%.

International patent application, publication number WO 2012/103960 discloses the preparation of everolimus using the alkylating agent 2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl triflate of formula (IVC),

wherein the overall yield reported is 52.54%. The process involves a derivatization method based on the reaction of the triflate (IV) with a derivatization agent, which preferably is a secondary aromatic amine, typically N-methylaniline.

International patent application, publication number WO 2012/103959 also discloses the preparation of everolimus using the alkylating agent of formula (IVC). The process is based on a reaction of rapamycin with the compound of formula (IVC) in the presence of a base (such as an aliphatic tertiary amine) to form 40-O-2-(t-hexyldimethylsiloxy)ethylrapamycin, which is subsequently deprotected under acidic conditions to obtain everolimus.

European Patent Number 1518517B discloses a process for the preparation of everolimus which employs the triflate compound of formula (IVA), 2-(t-butyldimethyl silyl) oxyethyl triflate. The disclosed process for preparing the compound of formula (IVA) involves a flash chromatography purification step.

The compounds of formula (IV) are key intermediates in the synthesis of everolimus. However, they are highly reactive and also very unstable, and their use often results in decomposition during reaction with sirolimus. This is reflected by the fact that the yields of the reaction with sirolimus are very low and the compounds of formula (IV) are charged in high molar extent. Thus it is desirable to develop a process to stabilize compounds of formula (IV) without loss of reactivity.

Example 1 :

Step 1 : Preparation of protected everolimus (TBS-everoismus) of formula (Ma) using metal salt, wherein “Pg” is t-butyldimethylsilyl

t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in dichloromethane (DCM) (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). To this sirolimus solution, silver acetate (0.018g, 0.000109mol) was added and cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. The reaction was monitored by TLC. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and solvent was removed by vacuum distillation to obtain the title compound, which was directly used in the next step. HPLC product purity: 60%-85%.

Step 2: Preparation of everolimus of formula (I)

Protected everolimus of formula (I la) obtained in step 1 was dissolved in methanol (10 volumes) and chilled to 0-5° C. To this solution was added drop wise, a solution of 1 N HCI. The pH of the reaction was maintained between 1-3. The temperature of the reaction mixture was raised to 25° C and stirred for 1 hour. After completion of reaction, the reaction mixture was diluted with water (15 volumes) and extracted in ethyl acetate (2X20 volumes). The organic layers were combined and washed with brine, dried over sodium sulphate. The organic layer was distilled off under reduced pressure at 30-35° C, to obtain a crude everolimus (0.8 g). The crude everolimus was further purified by preparative HPLC to yield everolimus of purity >99%.

Example 2:

Step 1 : Preparation of TBS-everoiimus of formula (Ma) without using metal salt, wherein “Pg” is t-butyldimethylsilyl

t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in DCM (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). The solution was cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and

solvent was removed by vacuum distillation to obtain the title compound, which was directly used in next step. HPLC purity: 10%-20%.

Step 2: Preparation of everolimus of formula (I)

Protected everolimus of formula (I la) obtained in step 1 was dissolved in methanol (10 volumes) and chilled to 0-5° C. To this solution was added drop wise, a solution of 1 N HCI. The pH of the reaction was maintained between 1-3. The temperature of the reaction mixture was raised to 25° C and stirred for 1 hour. After completion of reaction, the reaction mixture was diluted with water (15 volumes) and extracted in ethyl acetate (2X20 volumes). The organic layers were combined and washed with brine, dried over sodium sulphate. The organic layer was distilled off under reduced pressure at 30-35° C, to obtain a crude everolimus which was further purified by preparative HPLC.

Example 3:

Preparation of crude Everolimus

Step 1 : Preparation of TBS-ethylene glycol of formula (Va)

Ethylene glycol (1.5L, 26.58 mol) and TBDMS-CI (485g, 3.21 mol) were mixed together with stirring and cooled to 0°C. Triethyl amine (679 ml, 4.83 mol) was then added at 0°C in 30-45 minutes. After addition, the reaction was stirred for 12 hours at 25-30°C for the desired conversion. After completion of reaction, the layers were separated and the organic layer (containing TBS-ethylene glycol) was washed with water (1 L.x2) and brine solution (1 L). The organic layer was then subjected to high vacuum distillation to afford 350g of pure product.

Step 2: Preparation of TBS-glycol-Triflate of formula (IVa)

The reaction was carried out under a nitrogen atmosphere. TBS- ethylene glycol prepared as per step 1 (85.10g, 0.48 mol) and 2, 6-Lutidine (84.28ml, 0.72 mol) were stirred in n-heptane (425ml) to give a clear solution which was then cooled to -15 to – 25°C. Trif!uoromethanesulfonic anhydride (Tf₂0) (99.74 ml, 0.590 mol) was added drop-wise over a period of 45 minutes to the n-heptane

solution (white precipitate starts to form immediately) while maintaining the reaction at -15 to -25°C. The reaction mixture was kept at temperature between -15 to -25°C for 2 hours. The precipitate generated was filtered off. The filtrate was then evaporated up to ~2 volumes with respect to TBS-ethyiene glycol (~200 ml).

Step 3: Preparation of TBS-evero!imus of formula (Ha)

30g of sirolimus (0,0328 mo!) and toluene (150m!) were stirred together and the temperature was slowly raised to 60-65°C. At this temperature, a first portion of TBS-g!yco!-triflate prepared as per step 2 (100ml) and 2,6-Lutidine (1 1.45ml, 0.086 moles) were added and stirred for 40 min. Further, a second portion of TBS- glycol-triflate (50mi) and 2, 6-Lutidine (19.45ml, 0.138 mol) were added and the reaction was stirred for another 40 min. This was followed by a third portion of TBS- glycol-triflate (50m!) and 2, 6-Lutidine (19.45ml, 0.138 mol), after which the reaction was stirred for further 90 minutes. The reaction was monitored through HPLC to check the conversion of Sirolimus to TBS-everolimus after each addition of TBS-glycol-trifiate. After completion of the reaction, the reaction mixture was diluted with n-heptane (150mi), cooled to room temperature and stirred for another 60 minutes. The precipitated solids were filtered off and the filtrate was washed with deionized water (450 ml x4) followed by brine solution (450ml). The filtrate was subsequently distilled off to afford TBS-everolimus (60-65g) with 60-70% conversion from sirolimus.

Step 4: Preparation of everolimus of formula (I)

TBS-everolimus (65g) obtained in step 3 was dissolved in 300 mi methanol and cooled to 0°C. 1 N HCI was then added to the methanol solution (pH adjusted to 2-3) and stirred for 2 h. After completion of reaction, toluene (360m!) and deionized wafer (360mi) were added to the reaction mixture and the aqueous layer was separated. The organic layer was washed with brine solution (360ml). The organic layer was concentrated to obtain crude everolimus (39g) with an assay content of 30-35%, HPLC purity of 60-65%.

The crude everolimus purified by chromatography to achieve purity more than 99 %.

////Cipla, New Patent, WO 2016020664, Everolimus, INDIA

Fosdagrocorat, PF-04171327,

CAS 1044535-58-1

(2R,4aS,10aR)-4a-Benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-N-(2-methyl-3-pyridinyl)-4b-(phenylmethyl)-7-(phosphonooxy)-7-(trifluoromethyl)-, (4bS,7R,8aR)-

(2R,4aS,10aR)-4a-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

MF C29H30F3N2O5P
Exact Mass: 574.1844

• PF 04171327
• PF-04171327
• UNII-HPI19004QS
• Selective Glucocorticoid Receptor Modulator

phase 2 .Rheumatoid Arthritis

Glucocorticoid receptor modulators

Pfizer

• 03 Sep 2015Phase II development of fosdagrocorat is ongoing
• 01 Jun 2014Pfizer completes a phase II trial in Rheumatoid arthritis in US, Bulgaria, Colombia, the Czech Republic, Germany, Hungary, India, South Korea, Malaysia, Mexico, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Spain and the Ukraine (NCT01393639)
• 30 Sep 2011Phase-II clinical trials in Rheumatoid arthritis in Bulgaria, Colombia, Germany, India, Malaysia, Mexico, Poland, Romania and South Africa (PO)

Fosdagrocorat, also known as PF-04171327, a dissociated agonist of the glucocorticoid receptor (DAGR), a selective high-affinity partial agonist of the GR with potent anti-inflammatory activity at exposures that provide less undesirable effects on bone and glucose metabolism compared with prednisone (pred).

Glucocorticoid receptor modulators are glucocorticoid receptor ligands that are used to treat a variety of conditions because of their powerful anti-inflammatory, antiproliferative and immunomodulatory activity. J. Miner, et al., Expert Opin. Investig. Drugs (2005) 14(12):1527-1545.
Examples of glucocorticoid receptor modulators include dexamethasone, prednisone, prednisolone, RU-486, and as described in WO 2000/66522 and WO 2004/005229.
Treatment with glucocorticoid receptor modulators is often associated with side effects, such as bone loss and osteoporosis.
Identifying a glucocorticoid receptor modulator that is efficacious, potent, and has mitigated side-effects fulfills a medical need.

SYNTHESIS COMING…………

PATENT

WO 2008093227/US 20100286214

https://www.google.com/patents/WO2008093227A1?cl=en

SCHEME A

The 1 (/?)-Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²‘⁷]trideca-2,4,6-trien-13-one of Formula A-8 was prepared using the protocol described in Scheme A, which is generally disclosed in WO 00/66522. Ph depicts Phenyl. Bn depicts Benzyl. Compound A-1 can be purchased (for example, VOUS and Riverside; CAS No. 4133-35-1 ). Compound A-2 can be prepared as described in Org. Syn. 1971 , 51 , 109-112.

SCHEME B

The (4βS,7R,8αR)-4β-benzyl-7-hydroxy-Λ/-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8α,9,10-octahydrophenanthrene-2-carboxamide was prepared as described in Scheme B.

SCHEME C

The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme C. Bn depicts benzyl.

SCHEME D

The (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme D. Bn depicts benzyl. Ph depicts phenyl.

SCHEME E

The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoy[)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme E. Bn depicts benzyl. Ph depicts phenyl.

Starting Material A-8 is 1(R)~Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²‘⁷]trideca-2,4,6-trien-13-one as depicted by the following formula:

Preparation 1 : (S)-4a-benzyl-7-bromo-2-ethoxy-3,4,4a,9-tetrahydrophenanthrene

Starting Material A-8 (450 g; 1.17 moles) was dissolved in ethanol (4.5 L) at ambient temperature. 21% sodium ethoxide in ethanol (44 mL; 0.12 moles) was added and the mixture was heated to reflux for three hours. Once the Starting Material A-8 was consumed, the reaction mixture was chilled to -25⁰C. Acetyl chloride (250 mL; 3.51 moles) was slowly added to the mixture while the temperature was maintained near -25°C. After the addition was complete, the mixture was warmed to O⁰C and held there until the intermediate enone was consumed. The mixture was slurry at this point. 21 % sodium ethoxide in ethanol (1.31 L; 3.51 moles) was added to the mixture while the temperature was maintained between -5°C and 5⁰C. If the mixture was not basic, more sodium ethoxide was added. The temperature of the mixture was increased to 25°C and then diluted with water (5.9 L). The mixture was filtered and the solid was washed with water (3 X). The title compound (440 g; 85 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.27 (t, 3H), 1.65 (dt, 1 H), 2.06 (d, 1 H), 2.21 (dd, 1 H)₁ 2.49 (m, 1 H), 2.65 (m, 2H), 2.89 (m, 2H), 3.85 (q, 2H), 5.45 (m, 2H), 6.44 (d, 2H), 6.98 (t, 2H), 7.06 (m, 2H), 7.25 (d, 1 H), 7.33 (dd, 1 H).

Preparation 2: (S)-4a-benzyl-7-bromo-2,2-(1,2-ethylenedioxy)-1,2,3,4,4a,9-hexahydrophenanthrene

The (S)-4α-benzyl-7-bromo-2-ethoxy-3,4,4α,9-tetrahydrophenanthrene (1270 g; 3.2 moles; 85 area %, which may be prepared as described in Preparation 1 ) was dissolved in toluene (6.45 L). The ethylene glycol (898 mL; 16.1 moles) and p-toluenesulfonic acid (6.1 g; 0.03 moles) were added and the reaction heated to reflux. Solvent (1 L) was distilled from the mixture and replaced with fresh toluene (1 L). This distillation process was repeated twice more. More p-toluenesulfonic acid (6.1 g) was added each time fresh toluene was added. During the reaction, two intermediates (detected by LC) were formed as the substrate was converted into product. The end point of the reaction was an equilibrium point between the two intermediates and the product. Once the endpoint was reached, the mixture was cooled to ambient temperature. The mixture was washed with 0.5 M NaOH (2 L). The phases separated quickly and both were dark with a small rag layer. The mixture was washed with water (2 L). The phases
separated very slowly. The mixture was dried by azeotropic distillation. Methanol (4 L) was added to the mixture and solvent (4 L) was distilled from the mixture. The methanol addition and solvent distillation were repeated twice more. Methanol was added to the mixture and precipitation occurred a few minutes later. More methanol (4 L) was added to the mixture and then brought to reflux. After 30 minutes, the mixture was cooled to 0⁰C. The mixture was filtered and the solid was washed with chilled methanol (2 X 2L). The solid was dried in a vacuum oven at 65°C. The title compound (882 g; 98 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.71 (m, 2H), 2.06 (m, 2H), 2.31 (dd, 1 H), 2.39 (m, 1 H), 2.68 (d, 1 H), 2.77 (m, 1 H), 2.86 (dd, 1 H), 3.36 (d, 1 H), 3.86 (m, 4H), 5.45 (m, 1 H), 6.50 (m, 2H), 7.00 (m, 4H), 7.37 (dd, 1 H), 7.44 (d, 1 H).

Preparation 3: (S)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate

The (S)-4α-benzyl-7-bromo-2,2-(1 ,2-ethylenedioxy)-1 ,2,3,4,4α,9-hexahydrophenanthrene (719 g; 1.75 moles, which may be prepared as described in Preparation 2) was dissolved in tetrahydrofuran (7.19 L) and chilled to -7O⁰C. The 1.6 M n-butyl lithium in hexane (2270 mL; 2.27 moles) was added at a rate such that the temperature was maintained below -6O⁰C. The mixture held an additional 15 minutes after the addition. Carbon dioxide (108 g; 2.45 moles) was added while the temperature was maintained below -60°C. The mixture held an additional 15 minutes after the addition. The mixture was warmed to ambient temperature. Solvent (7 L) was distilled from the mixture at atmospheric pressure. DMF (7 L) was added to the mixture. The mixture was cooled to ambient temperature. Methyl iodide (152 mL; 2.45 moles) was added and the mixture was held until the reaction was completed (~1 hour). The mixture was heated to 7O⁰C and solvent was distilled by gradually reducing the pressure to 70 mmHg. Once distillation had ceased, the mixture was cooled to room
temperature. Water (6.5 L) was slowly added to the mixture to precipitate the product. The mixture was filtered and the solid washed with water (3 X). The solid was dried on the filter. The crude product (736 g; 74 area %) was obtained as a beige solid. The product was purified by chromatography. 463 g of product was recovered from the chromatography. This material was separated from n-heptane (6130 mL). 394 g of the title compound was recovered. Another 70 g of title compound was recovered from the mother liquor by chromatography. ¹H NMR (DMSO) δ ppm: 1.74 (m, 2H), 2.10 (m, 2H)₁ 2.33 (dd, 1 H), 2.45 (m, 1 H), 2.72 (d, 1 H), 2.79 (m, 1 H), 2.94 (dd, 1 H), 3.40 (d, 1 H), 3.87 (m, 7H), 5.49 (m, 1 H), 6.47 (m, 2H), 6.93 (m, 2H), 7.01 (m, 1 H), 7.42 (d, 1 H), 7.64 (d, 1 H), 7.79 (dd, 1 H).

Preparation 4: (4βS,8α/?)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (S)-methyl 4β-benzyl-7,7-(1 ,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate (201 g; 0.515 moles, which may be prepared as described in Preparation 3) and 50 ml of ethylene glycol was dissolved in toluene (2.0 L) in an autoclave. To this was added 10 grams of a 5% Pd/C (dry catalyst). The autoclave was then sealed and purged with nitrogen (three cycles) followed by hydrogen (three cycles). The reaction was run for 18 hours with a pressure of 80 psig and temperature of 50 ⁰C. HPLC analysis for completion and selectivity (typical selectivity’s are: 95 to 5, Trans to Cis). The suspension was filtered through Celite® to remove the catalyst and the toluene solution is concentrated at 50 ⁰C, under vacuum, to
approximately 200 ml. While still at 50 ⁰C, 1 L of 1-butanol was added and the solution heated to 60 ⁰C, until clear. Upon cooling, the resulting solid title compound was isolated by vacuum filtration (196 grams; 97%; Trans to Cis 95.75 to 4.24). ¹H NMR (300 MHz, CDCI₃) δ ppm: 7.79 (bs, 1 H₁ Ar-H), 7.47 (d, J= 9 Hz, 1 H, Ar-H), 7.13-7.05 (cm, 3H, Ar-H), 6.56-6.53 (cm, 2H, Ar-H), 6.43 (d, J= 9 Hz, 1 H, Ar-H), 4.04-3.93 (cm, 4H, 2-CH₂), 3.89 (s, 3H, CH₃),3.08-3.03 (cm, 3H, CH₂, CH-H), 2.63 (d, J= 15 Hz, CH-H), 2.22-1.72 (cm, 8H, 4-CH₂), 1.57 (cm, 1 H, CH-H).; ¹³CNMR (CDCI₃, δ): 167.7, 149.2, 137.7, 136.4, 131.1 , 130.5, 127.8, 127.7, 127.4, 126.3, 125.5, 108.9, 64.6, 64.5, 52.1 , 40.5, 39.8, 38.3, 35.8, 31.6, 30.3, 27.9, 24.6.

Preparation 5: (4βS,8α/?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

ThΘ (4βS,8αR)-mΘthyl 4β-benzyl-7,7-(1 ,2-ethylenΘdioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (150 g, 382 mmol, which may be prepared as described in Preparation 4) was dissolved in dichloromethane (630 ml). Water (270 ml) was added with stirring followed by trifluoroacetic acid (73 ml. 1150 mmol) via drop funnel over 30 minutes, maintaining the internal temperature below 3O⁰C. After the addition was complete, the reaction was heated at 4O⁰C for 2 hours. In process check indicated incomplete reaction with around 9% (area percent) starting material. The layers were separated and fresh water (270 ml) and trifluoroacetic acid (31 ml) was added. The reaction mixture was heated at 4O⁰C for 1 hour. This process was continued until the starting material was consumed. The organic phase was washed with 5% aqueous sodium bicarbonate (300 ml), water (300 ml) and dried over MgSO₄ and concentrated to dryness to give 126.4 g of the title compound (representing a 95% yield). ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.4 Hz, 1 H), 7.11 (m, 3H), 6.6 (d, J= 5.70 Hz, 2H), 6.45 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 3.80 (m, 2H), 3.04-1.48 (m, 11 H).

Preparation 6: (4βS,7f?,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5_J6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,8αf?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8_I8α,9,10-octahydrophenanthrene-2-carboxylate (118g, 0.339 mole, which may be prepared as described in Preparation 5) dissolved in dichloromethane was chilled to -5O⁰C. The solution became turbid. 1.0 M Tetrabutylammonium fluoride a solution in THF (3.4 ml, 0.003 mol) was added with no appreciable temperature change. Trifluorotrimethylsilane (79 ml, 0.51 mol) was added over 20 minutes with a color change to bright orange to light red in color. The reaction mixture was held at -50 ⁰C for about 2 hours and then allowed to warm to 0 ⁰C.
Tetrabutylammonium fluoride (340 ml, 0.34 moles) was added very slowly at 0 ⁰C, to the reaction mixture over 45 minutes. An exotherm was observed with gas evolution. The reaction mixture was stirred 10 minutes and HPLC analysis indicated complete desilylialation. Water (1 L) was added to the reaction mixture and with vigorous stirring and allowed to warm to room temperature. The organic layer was washed with water (1 L). The organic layer was concentrated and chromatographed to produce 72 g, 51 % of the title compound, with an additional 32 g of impure product. ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.1 Hz, 1 H)₁ 7.09 (m, 3H), 6.5 (dd, J=1.2, 6.6 Hz, 2H), 6.38 (d, J=8.4 Hz, 1 H), 3.80 (s, 3H), 3.80 (m, 2H), 3.09-1.21 (m, 13H).

Preparation 7: (4βS,7/?,8α/?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β₎5,6,7₎8,8α,9,10-octahydrophenanthrene-2-carboxylate (5.0 g; 11.9 mmol, which may be prepared as in Preparation 6) and 5-methyltetrazole (3.6 g; 43.0 mmol) were mixed together in dichloromethane (50 mL) at ambient temperature. Dibenzylphosphoramidite (8.3 mL; 25.1 mmol) was added and the mixture was stirred until the reaction was completed (1 hour). The mixture was chilled to 0⁰C and 30% hydrogen peroxide (10 mL) was added. The reaction was stirred until the oxidation was completed (30 minutes). The aqueous phase was separated from the organic phase. The organic phase was washed with 10% sodium meta-bisulfite (50 ml_). The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 15% ethyl acetate in hexanes. The purified title compound (8.41 g; 94% yield) was obtained as a colorless oil that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.31 (t, 1 H), 1.63-1.92 (m, 3H), 2.05-2.35 (m, 3H), 2.63 (d, 1 H), 2.75-3.16 (m, 4H), 3.80 (s, 3H), 5.13 (m, 4H), 6.43 (d, 1 H), 6.49 (m, 2H), 7.04-7.17 (m, 3H), 7.33-7.42 (m, 12H), 7.71 (d, 1 H).

Preparation 8: dibenzyl (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-o yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yI phosphate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (7.9 g; 11.6 5 mmol, which may be prepared as in Preparation 7) and 3-amino-2-picoline (1.3 g; 12.2 mmol) were mixed together in tetrahydrofuran (80 ml_) and chilled to 0°C. The 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (24 ml_; 24.4 mmol) was added while maintaining the temperature below 10⁰C. The mixture was stirred for 30 minutes. Water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic extract was washed with water. The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 70% ethyl acetate in hexanes. The purified title compound (6.79 g; 68% yield) was obtained as a yellow gum that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.33 (t, 1 H), 1.66-1.93 (m, 3H), 2.08-2.34 (m, 3H), 2.41 (s, 3H), 2.68 (d, 1 H), 2.76-3.19 (m, 4H), 5.14 (m, 4H), 6.47 (d, 1 H), 6.56 (m, 2H), 7.07-7.19 (m, 3H), 7.20-7.53 (m, 12H), 7.71 (d, 1 H), 7.76 (s, 1 H), 8.32 (d, 1 H), 9.93 (s, 1 H).

Example 1 : (4βS,7/?,8αR)-4β-benzyl-7-hydroxy-W-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7ft,8αR)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 mL; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 mL) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 mL) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 mL). Solvent (230 mL) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1 H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1H), 7.44 (dd, 1H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-i ,2,3,4,4α,9,10,1 Oα-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS, 10αR)-4α-bθnzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 70⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1.33 (t, 1 H)₁ 1.69-1.98 (m, 3H), 2.07-2.29 (m, 3H)₁ 2.42 (s, 3H), 2.61-2.80 (m, 2H)₁ 2.93-3.19 (m, 3H)₁ 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

PATENT

WO 2008093236

http://www.google.co.in/patents/WO2008093236A1?cl=en

Example 1 : (4βS,7/?,8α/?)-4β-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7R,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6_J7,8,δα,9, 10- octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 ml_; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 ml_) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 ml_) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 ml_). Solvent (230 ml_) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1 H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1 H), 7.44 (dd, 1 H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10α/?)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 7O⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1 .33 (t, 1 H), 1 .69- 1.98 (m, 3H), 2.07-2.29 (m, 3H), 2.42 (s, 3H), 2.61 -2.80 (m, 2H), 2.93-3.19 (m, 3H), 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

REFERENCES

https://www.pfizer.com/sites/default/files/product-pipeline/July%2028%202015%20Pipeline%20Update.pdf

https://clinicaltrials.gov/ct2/show/NCT00938587

////////

Cc1c(cccn1)NC(=O)c2ccc3c(c2)CC[C@H]4[C@]3(CC[C@@](C4)(C(F)(F)F)OP(=O)(O)O)Cc5ccccc5

O=P(O)(O[C@@]1(C(F)(F)F)C[C@@]2([H])CCC3=C(C=CC(C(NC4=CC=CN=C4C)=O)=C3)[C@]2(CC5=CC=CC=C5)CC1)O

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

.

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

/////WO 2016020324, BASF AG, vismodegib , new patent

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Vismodegib

2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Vismodegib; 879085-55-9; GDC-0449; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge; HhAntag691; CUR-691
GDC-449
Hh-Antag691
HhAntag
R-3616
RG-3616

421.29706 g/mol

C₁₉H₁₄Cl₂N₂O₃S

LAUNCHED 2012

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

Hedgehog Antagonist GDC-0449 is an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

NMR from net

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.^[1] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011.^[2] The drug was developed by thebiotechnology/pharmaceutical company Genentech, which is headquartered at South San Francisco, California, USA.

Indication

Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.^{[3] [4]}

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.^[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.^[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.^[6]

PAPER

Bioorg Med Chem Lett 2009, 19(19): 5576

http://www.sciencedirect.com/science/article/pii/S0960894X10012709

CN 103910671

http://www.google.com/patents/CN103910671A?cl=en

In embryonic development, Hedgehog signaling in cell differentiation, tissue development and organogenesis play an important role. In the adult body, Hedgehog signaling pathway is mainly in slumber, but when abnormal tissue growth and self-healing, Hedgehog pathway may be activated. With the in-depth study of the tumor, the presence of numerous evidence of abnormal tumor occurrence and the close relationship between Hedgehog signaling pathway, such as sporadic basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, therefore Hedgehog signaling pathway targeted anti-cancer therapy inhibitors become hot.

 Vismodegib chemical name 2_ chlorine -N_ (4_ chlorine _3_ (_2_ pyridyl) phenyl) _4_ (methylsulfonyl) benzamide, is by Roche’s Genentech (Genentech) Hedgehog pathway inhibitors developed, and can be inhibited by binding seven transmembrane protein Smoothened (Smo), thereby preventing signal transduction. Vismodegib capsule in January 2012 I was approved and listed by the US Food and Drug Administration, under the trade name Erivedge, for the treatment of adults with the most common type of skin cancer – basal cell carcinoma. This medicine is not intended for surgery or radiotherapy of cancer and basal cell skin cancer locally advanced patients have been transferred. This was the first drug approved for the treatment of basal cell carcinoma.

W02006028958 Vismodegib disclose the following synthesis route:

 Route One Negishi coupling reactions

wherein, X1 is chloro, bromo or iodo; X2 is bromo, iodo or tosylate. The route to the 2-halo-pyridine as starting material an organic zinc compound, and then prepared by Negishi coupling reaction to give 2- (2-chloro-5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine in turn through a reduction reaction with acylation reaction, to give the final product Vismodegib. The key coupling step of the route using an organic zinc reagent required to react under strict anhydrous, anaerobic conditions.

 The second route Suzuki coupling reaction [0010]

 wherein, X2 is bromo, iodo or tosylate. The route from 3-halo-4-chloro-nitrobenzene as raw material, and 2-chloro-5-nitrophenyl boronic acid pinacol ester, and then reacted with a 2-halo-pyridine was prepared to give 2- (2-chloro 5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine then after reduction and acylation reaction, to give the final product Vismodegib. The key coupling step of the route using the Suzuki coupling reaction, organic boron reagent price to use expensive, high production costs.

 The route three Suzuki coupling reaction

wherein, X2 is bromo, iodo or tosylate. Similar to the second route, the route is still critical coupling step using a Suzuki coupling reaction, the same need to use expensive organic boron reagents, higher production costs.

 route four Stille coupling reaction

 The route to 2-p-toluenesulfonyl pyridine as starting material, is reacted with an organotin reagent, prepared to give pyridin-2-yl trimethyltin, then by Stille coupling reaction, was prepared to give 2- (2-chloro – 5- nitrophenyl) pyridine, followed by reduction reaction, acylation prepared to give Vismodegib. The key step of the route using the Stille coupling reaction, this step need to use expensive and toxic organotin reagents, and the need to carry out the reaction under strict anhydrous, anaerobic conditions.

A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising: a compound of formula III was prepared as a compound of Formula II;

Then, the compound of formula II with a compound of formula I, to give 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

Wherein, R1 is halogen or hydroxy, preferably chlorine, or a hydroxyl group.

2. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

3. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

Method 2 or claim 3,

Example 1: N–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

[0108] To a 100mL three-necked flask were added 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol potassium carbonate, 0.05mmol tri-butyl acetate button and 0.15mmol phosphorus tetrafluoroborate salt, 40ml of toluene, IS gas exchange three times, under argon at reflux for 2 days, then the reaction mixture was poured into 100mL of ethyl acetate, filtered, and the filtrate was washed with saturated brine, dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50), fractions were collected and the solvent was distilled off under reduced pressure to give a pale yellow solid, yield 60%.

 1HMffi (500Hz, DMS0_d6): 8.35 (m, 3H), 7.90 (d, 1Η), 7.62 (q, 1Η), 7.55 (m, 1Η), 7.48 (m, 1Η);

 MS: 251.1,253.1 ([Μ + Η] +).

2  Example: Ν–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

 To a 100mL three-necked flask 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol of potassium carbonate, 0.05mmol iodide and 0.1Ommoll, 10- Fei Luo Jie morpholine, 40ml of xylene, an argon gas exchange three times, under argon at reflux for 2 days, cooled to room temperature and then the reaction system was poured into 100mL methylene chloride, filtered and the filtrate washed with saturated brine, dried, filtered, The filtrate solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50) to give a pale yellow solid, yield 42%. .

3  Example: 2- (2-chloro-5-nitrophenyl) pyridine

 

After 3.0mmol N- oxo added to 100mL of Lord vial _2_ (2_ chloro _5_ nitrophenyl) pyrazole 唳, 15mmol phosphorus trichloride and 30ml of chloroform was heated at reflux for 12h, the reaction It was poured into 100mL of water and extracted with ethyl acetate (50ml X 2), and the combined organic phase was dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: petroleum ether / ethyl acetate = 20/1) , fractions were collected, the solvent was distilled off under reduced pressure to give a white solid, yield 95%.

 1Hnmr (SooHzJDCI3): 8.78 (d, 1H), 8.51 (d, 1H), 8.20 (m, 1H), 7.85 (m, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.40 (m, 1H);

MS: 235.1,237.1 ([M + H] +).

4 Example 2: Preparation 4_ chlorine _3_ (topiramate 唳 _2_ yl) aniline

 

 To a vial was added 100mL of Lord 20mmol2- (2- chloro-5-nitrophenyl) pyridine 唳, 50ml of acetic acid, heated to 80 ° C and stirred, and then slowly added IOOmmol iron, reaction 0.5h The reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X 3), the combined organic phases, the organic phase was washed with saturated sodium carbonate solution (50ml X 3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a pale yellow solid, yield 75%.

1HMflUSOOHz, DMS0_d6): 8.63 (m, 1H), 7.84 (m, 1H), 7.56 (d, 1H), 7.37 (m, 1H),

7.13 (d, 1H), 6.76 (d, 1H), 6.61 (q, 1H), 5.32 (s, 2H);

 MS: 205.1,207.1 ([M + H] +).

5 Example: 4-chloro-3- (pyridin 唳-2-yl) aniline

 

to 100mL of God-shaped flask 20mmol2_ (2_ chlorine _5_ nitrophenyl) pyridine Jie set, 50ml of methanol, Ig activated carbon, 2mmol FeOOH and 60mmol85% of hydrazine hydrate, heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution (20ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product was recrystallized from n-propanol to give a pale yellow solid, yield 96%.

6 Example 2: Preparation 4_-chloro-3- (2-yl) aniline

 

 20mmol N- oxo added to 100mL eggplant-shaped flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of acetic acid, heated to 80 ° C and stirred, and then iron powder was slowly added IOOmmol After 0.5h the reaction the reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X3), the combined organic phases were washed with saturated sodium carbonate solution (50ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propanol recrystallized to give a white solid, yield 70%.

Preparation 7.Α ~ chlorine -3_ (topiramate 唳 2-yl) aniline [0130] Example

 

 20mmol N- oxo added to 100mL eggplant type flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of methanol, Ig active carbon, 2mmol FeOOH 60mmol85% hydrazine hydrate and heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase (20mlX3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a white solid, yield 82%.

Vismodegib Preparation: 8 Example

 

In the Lord 50ml vial, the 1.50mmol2- chloro-4-methanesulfonyl-chloride in 15ml of dry tetrahydrofuran, cooled to ice bath O ~ 10 ° C, a solution of 4-chloro-3 – (pyridin-2-yl) aniline in anhydrous tetrahydrofuran (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction system was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

1HNMR (500Hz, DMS0_d6): 10.90 (s, 1H), 8.70 (d, 1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.92 (m, 2H), 7.74 (q, 1H ), 7.69 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 3.34 (s, 3H).

 MS: 421.1,423.1 ([M + H] +).

Vismodegib Preparation: 9  Example

 

 In 50ml vial of God, will 1.50mmol2_ chlorine _4_ methylsulfonyl benzoic acid, 1.47mmol4_ chlorine _3_ (batch 唳 2-yl) aniline and triethylamine were dissolved in 25ml 2.5mmol anhydrous tetrahydrofuran in an ice bath to cool to O ~ 10 ° C, was added in portions N, N ‘- dicyclohexyl carbodiimide (DCC) 1.50mmol, After the addition, the reaction at room temperature 6h, after the reaction, white solid was removed by filtration, the filtrate was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 84%.

Vismodegib Preparation: 10 [0141] Example

 

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

CN 103910672

http://www.google.com/patents/CN103910672A?cl=en

Vismodegib PreparatioN

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

WO2006028958

https://www.google.co.in/patents/WO2006028958A2?cl=en

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the following general procedures.

A: Suzuki Coupling Procedure

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene :ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 ⁰C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

B: Negishi Coupling Procedure

X = I or Br R = H, 3-Me, 4-Me₅ 5-Me, 6-Me

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged with the appropriate aryl halide (1.0 eq) and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 140 ⁰C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

R = I or pyridin-2-yl

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 °C. The solution was stirred at 70 ⁰C for 30-60 minutes. The reaction mixture was cooled to 23 ⁰C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 mL), washed with saturated aq. NaHCO₃ (2 x 15 rnL) and water (2 x 10 niL), dried (MgSO₄), and concentrated. The oily residue was used with out further purification.

D: Amide Bond Formation

R = I or pyridin-2-yI

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO₃, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

R = I or pyridin-2-yl

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 ⁰C for 2 hours, poured onto a 1 :1 mixture of saturated aq. NH₄Cl and water, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. F: addition of amines to 2-chloropyridine

NHRR’ = ethanolamine, analine, benzylamine, 2-methylpropylamine, N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 ⁰C for 20 min in a sealed tube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the product was extracted into ethyl acetate, dried (MgSO^, and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product.

G: Amide bond coupling with HATU

HATU, DIPEA, DMF NaOH or NaHCO₃

ethyl acetate extraction

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 – 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCθ₃, extracted into ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried (MgSO₄), concentrated and the crude mixture was purified by reverse phase HPLC. H: Preparation of sulfonamide benzoic acids

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% DEPEA/methanol (1 M) at 4 ⁰C. After 1 h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC.

I : Stannylation of 2-pyridyl triflates

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene (1 mL) was added to degassed solution of aryltriflate (1 eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 ⁰C, diluted with ethyl acetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSO₄) and concentrated. The crude material was used without further purification.

J: Stannylation of substituted pyridines

^ιM^mβ^co3 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 ⁰C. The solution was stirred at 0 ⁰C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stirred at 0 ⁰C for an additional hour, then cooled to -78 ⁰C. A solution of trialkyltin in hexane was added dropwise. The solution was stirred at -78 ⁰C for thirty minutes, warmed to 0 ⁰C, quenched with water, extracted twice with ether, dried (MgSO₄), and concentrated. K: Stille Coupling

Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 ⁰C for 15 minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC>₄), concentrated and purified by silica gel chromatography.

L: Synthesis of alky lethers

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 100⁰C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC^), concentrated and purified by silica gel chromatography.

M: Methyl Ester Saponification

The methyl ester (leq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCl to pH 2. The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the presence of a free acid functionality

The paramethylbenzoic acid (leq) was combined with Benzoyl Peroxide (O.leq) and N- Bromosuccinimde (0.9eq) in a solution of 5%AcOH in Benzene and heated in the microwave at 120°C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system.

O: Sodium Methanesulfinate displacement of Bromine

To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and heated to 120°C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60°C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone.

P: Amine displacement of Bromine

To the bromo starting material (leq) was added appropriate amine (3eq) in either DMSO or BuOH and stirred at room temperature until complete. For less nucleophilic amines or anilines, the reactions were forced to completion using microwave conditions ranging from 150°-170°C for 15 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product.

Q: Thiol displacement of halogen

The paramethylbromo benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (l,leq) in DMF (or CH₃CN) and stirred overnight at room temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

oxone 2:1 MeOHTH₂O

Derivatized thiol (leq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in MeOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone.

S: Thio lysis of epoxides at alumina surfaces

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (~70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield β -hydroxysulfide product.

T: Conversion of nitrile group to carboxylic acid

R

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H₂O was heated to 120 ° C for 2h. The reaction mixture was cooled to room temperature and acidified with HCl to pH 2. The resulting solid was filtered to afford the pure acid product.

U. Alkylation of phenols

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 5O⁰C for 1 to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSC>₄, and evaporated to a crude oil which was purified on reverse phase HPLC.

V. Amide bond formation with an acid chloride and an aniline

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase HPLC.

W. Amidine formation from an imidate

A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq.) at room temperature for 18 hours. The methanol was removed on a rotary evaporator and the residue purified by reverse phase HPLC.

Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4- methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide. MS (Ql) 421.0 (M)⁺. The product was then dissolved in 1 Ν HCI solution followed by freebasing with 0.5 Ν NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4- (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-

(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with

Et₂O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO₃ and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone :EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.

Patent

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

.

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

update……………

Vismodegib Synthesis

WO2009126863A2: also see Ref. 1. It all started from here.

Identification:

Experimental: ¹H NMR (400MHz, CDCl₃) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).

References

External links

• Erivedge® (vismodegib), a prescription oral medica on approved for advanced basal cell carcinoma treatment
• Efficacy and Safety of Vismodegib
• Food and Drug Administration (FDA) approved vismodegib

PatentSubmittedGranted

Pyridyl inhibitors of hedgehog signalling [US7888364]2006-03-232011-02-15

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2009281089]2009-11-12

ANTI-HEDGEHOG ANTIBODIES [US8030454]2010-01-072011-10-04

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2011092461]2011-04-21

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2012094980]2011-10-142012-04-19

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2013045240]2010-08-252013-02-21

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2014072630]2013-02-282014-03-13

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway [US8889678]2010-07-192014-11-18

COMBINATION THERAPY [US2012184529]2012-01-032012-07-19

METHOD OF INHIBITING DYRK1B [US2014371251]2014-06-182014-12-18

USE OF SUBSTITUTED HEXITOLS INCLUDING DIANHYDROGALACTITOL AND ANALOGS TO TREAT NEOPLASTIC DISEASE AND CANCER STEM AND CANCER STEM CELLS INCLUDING GLIOBLASTOMA MULTIFORME AND MEDULLOBLASTOMA [US2014377336]2013-01-222014-12-25

SHH Regulation and Methods Thereof [US2012082623]2011-09-302012-04-05

NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS [US2015025070]2012-07-132015-01-22

Compositions and Methods for Modulating Neuron Degeneration and Neuron Guidance [US2011065645]2010-09-102011-03-17

SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS [US2014200217]2014-01-242014-07-17

Vismodegib

Systematic (IUPAC) name
2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Clinical data
Trade names	Erivedge
AHFS/Drugs.com	monograph
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: X (High risk) US: D (Evidence of risk)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	31.8%
Protein binding	>99%
Metabolism	<2% metabolised byCYP2C9, CYP3A4, CYP3A5
Biological half-life	4 days (continuous use), 12 days (single dose)
Excretion	Faeces (82%), urine (4.4%)
Identifiers
CAS Number	879085-55-9
ATC code	L01XX43
PubChem	CID 24776445
IUPHAR/BPS	6975
DrugBank	DB08828
ChemSpider	23337846
UNII	25X868M3DS
ChEBI	CHEBI:66903
ChEMBL	CHEMBL473417
Synonyms	GDC-0449, RG-3616
Chemical data
Formula	C19H14Cl2N2O3S
Molar mass	421.30 g/mol

SEE…http://apisynthesisint.blogspot.in/2016/02/vismodegib.html

/////

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

Biocon’s Rosuvastatin Calcium tablets get EU approval to treat hyperlipidemia
Indian biopharmaceutical company Biocon has received approval from the European Commission for its Rosuvastatin Calcium tablets to treat hyperlipidemia or mixed dyslipidemia.

http://www.pharmaceutical-technology.com/news/newsbiocons-rosuvastatin-calcium-tablets-gets-eu-approval-to-treat-hyperlipidemia-4811839?WT.mc_id=DN_News

Indian biopharmaceutical company Biocon has received approval from the European Commission for its Rosuvastatin Calcium tablets to treat hyperlipidemia or mixed dyslipidemia.

Hyperlipidemia is a common genetic disorder that increases lipids and/or lipoproteins levels in the blood.

The first generic formulation approval will allow Biocon to sell Rosuvastatin Calcium 5mg, 10mg, 20mg and 40mg tablets in more than 15 European countries, starting in fiscal 2017.

The company plans to collaborate with regional partners to market the drug; a generic equivalent of Crestor tablets.

Biocon chairperson and managing director Kiran Mazumdar-Shaw said: “This is indeed a proud moment for Biocon’s Small Molecules business.

Biocon chairperson and managing director Kiran Mazumdar-Shaw

“This approval paves the way for Biocon to launch Rosuvastatin Calcium tablets in several European countries.”

The approval will allow the company to address the $1.2bn opportunity in the EU. It will also make it easier for the company to market its products in emerging markets, where regulatory clearances are primarily based on approvals given by regulators in the US / EU.

Biocon was the first generic company to receive a certificate of suitability (CEP) for Rosuvastatin Calcium API from the European Directorate for the Quality of Medicines (EDQM).

CEP certification indicates that an API is suitable for use in medicinal products in the EU.

Biocon CEO and joint managing director Dr Arun Chandavarkar said: “The European approval for Biocon’s generic version of Rosuvastatin Calcium underscores Biocon’s unique strengths in the chronic therapies space and our compliance with global standards that enable us to achieve the highest quality standards for all our products.

“It augurs well for this nascent business, which will be one of our growth drivers in the coming years.”

The company plans to boost its generic formulations business with a target of 20-25 filings over the next few years.

Additionally, Biocon is developing a new facility in Bengaluru, in the Indian state of Karnataka, where it will produce oral solid dosage formulations.

Biocon CEO and joint managing director Dr Arun Chandavarkar

/////////

OR

ONL 1204

CAS 1349038-53-4

(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[2-[(3R)-3-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-2-oxopiperidin-1-yl]acetyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]propanoic acid

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

ONL Therapeutics Inc.

Fas receptor (CD95)

Peptide, Retinal detachment, OPTHALMIC DRUGS

C71 H100 N18 O16, 1461.66

L-Histidyl-L-histidyl-L-isoleucyl-L-tyrosyl-L-leucylglycyl-L-alanyl-L-valyl-L-asparaginyl-L-tyrosyl-L-isoleucyl-L-tyrosinamide

RFVTGHFXGL YPA

ORPHAN DRUG DESIGNATION DATA

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

01/13/2016

Treatment of retinal detachment

ONL Therapeutics, Inc
1600 Huron Parkway
Second Floor
Ann Arbor, Michigan 48109…….http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=501215

ONL1204, ONL’s lead therapeutic candidate, is a first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, against the apoptosis (programmed cell death) that occurs in a range of retinal diseases and conditions. It is this death of these retinal cells that is the root cause of vision loss and the leading cause of blindness.

Researchers have shown that ONL1204 effectively inhibits the Fas pathway; one of the body’s primary mechanisms for inducing programmed cell death (apoptosis). Specifically, the compound’s activity inhibits the Fas receptor, blocks the activation of the Fas pathway, and prevents the apoptosis cascade which results in the death of key retinal cells, including photoreceptor.

While initial development efforts for ONL1204 are focused on retinal detachment, preclinicalin vivo data, along with a growing body of literature, support potential application in age-related macular degeneration (AMD) and other chronic retinal diseases. Combined, the estimated market for the initial indications that ONL plans to target is >$12 billion globally.

ONL Therapeutics, Inc., a biopharmaceutical company developing novel therapies for preserving sight in a range of retinal diseases, today announced that the United States Food and Drug Administration (FDA) has granted orphan drug designation to ONL1204 for the treatment of retinal detachment. ONL1204 is a novel, first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, from cell death that occurs in a range of retinal diseases and conditions. Death of these retinal cells is the root cause of vision loss and the leading cause of blindness. ONL expects to advance ONL1204 into clinical trials for retinal detachment patients in 2016.

Retinal detachment occurs when the retina is separated from the underlying layer of cells called the retinal pigment epithelium (RPE). The RPE provides nutritional support to the highly-active photoreceptors in the retina. When there is a detachment, the photoreceptors no longer receive these nutrients and undergo cell death processes that dramatically impact a patient’s vision. Retinal detachments occur in approximately 50,000 people each year in the United States and affect people of all ages, although risk increases as people reach fifty years of age.

Patients experiencing a retinal detachment are normally treated by surgical reattachment of the retina to reconnect the photoreceptors with the RPE and prevent additional loss of vision. However, these procedures do not address the photoreceptor death and vision loss, which can be significant, that occurs prior to surgery. ONL1204 will be delivered to patients upon diagnosis and is intended to block photoreceptor cells from dying until surgery can be completed.

“When retinal detachments involve the center of vision called the macula, more than a third of patients have final best corrected vision of 20/60 or worse after successful surgery,” said David Zacks, M.D., Ph.D., co-founder and chief science officer of ONL Therapeutics. “Those are truly poor outcomes from successful surgeries. We are very pleased the FDA has recognized this need and that ONL is the only company to have received an orphan designation for this disease. It reinforces our belief that ONL1204 can play a key role in preventing vision loss in these patients by protecting their photoreceptors.”

The FDA’s Orphan Drug Designation program provides certain incentives for companies developing therapeutics to treat rare diseases or conditions that affect less than 200,000 individuals in the US. A drug candidate and its developer must meet several key criteria in order to qualify for, and obtain, orphan drug status. Once a drug has received orphan drug designation, the developer qualifies for a range of benefits, including federal grants, tax credits, reduction in certain regulatory fees, and the potential for seven years of market exclusivity for the drug following FDA marketing approval.

About ONL Therapeutics

ONL Therapeutics (ONL) is a biopharmaceutical company committed to protecting and improving the vision of patients with retinal disease. By advancing a novel breakthrough technology designed to protect key retinal cells from Fas-mediated cell death, ONL is pioneering an entirely new approach to preserving sight. The death of key retinal cells is the root cause of vision loss and leading cause of blindness, and is implicated in a wide range of retinal diseases, including retinal detachment and both the wet and dry forms of age related macular degeneration (AMD).

read

FDA grants orphan status for ONL Therapeutics’ ONL1204 to treat retinal detachment
The US Food and Drug Administration (FDA) has granted orphan drug designation for ONL Therapeutics’ first-in-class small molecule peptide, ONL1204, for the treatment of retinal detachment.

SEE………http://www.allfordrugs.com/2016/02/17/onl-1204-a-small-molecule-peptide-for-treatment-of-retinal-detachment/

/////

Use smiles

N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)O)C(=O)NCC(=O)N[C@@H](Cc2cncn2)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H]6CCCN(CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc4ccc(O)cc4)C(=O)N5CCC[C@H]5C(=O)N[C@@H](C)C(=O)O)C6=O

OR

CC(C)CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)N2CCCC2C(=O)NC(C)C(=O)O)NC(=O)CN3CCCC(C3=O)NC(=O)C(CC4=CC=CC=C4)NC(=O)C(CC5=CN=CN5)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(C(C)C)NC(=O)C(CC6=CC=CC=C6)NC(=O)C(CCCN=C(N)N)N

OR

C[C@@H](CC)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](Cc3cncn3)N)Cc4cncn4)[C@@H](C)CC)C(C)C)C(=O)N[C@@H](Cc5ccc(O)cc5)C(N)=O

Selurampanel, BGG492, 

cas 912574-69-7

Chemical Formula: C16H19N5O4S
Exact Mass: 377.1158

UNII-7WG1MR7DAR;

N-(7-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methanesulfonamide

N-[7-Isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]methanesulfonamide

PHASE 2 , FOR EPILEPSY, TITINUS

NOVARTIS INNOVATOR

Selurampanel (INN, code name BGG492) is a drug closely related to the quinoxalinedione series which acts as a competitive antagonist of the AMPA and kainate receptors and, as of 2015, is being investigated in clinical trials by Novartis for the treatment ofepilepsy.^[1][2][3] It has also been studied in the acute treatment of migraine, and was found to produce some pain relief, but with a relatively high rate of side effects.^[4]

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006108591&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 44: N-[7-IsopropyI-6-(l-methyl-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yl]-methanesulfonamide
2-Amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

The 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester required for the coupling reaction described below was prepared according to the procedures described in WO 2004/033435 Al.

The l-methyl-5-tributylstannanyl-lH-pyrazole required for the coupling reaction was prepared according to the procedure described above.

2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and l-methyl-5-tributylstannanyl-lH-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100 ⁰C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H- pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 21 A [M+H]⁺, rt 5.20 min).

2-(4-Chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

4-Chlorophenyl-chloroformate (88 μL, 1.1 equiv) was added to a solution of 2-amino-4-isopropyl-5-(2~ methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (156 mg, 0.57 mmol) in dioxane (1.5 mL). The mixture was stirred for 2 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The obtained yellow solid was used in the next step without further purification, (rt 6.77 min)

N-[7-Isopropyl-6-(2-methyl-2H-pyrazol-3 -yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl] -methanesulfonamide

CH₃SO₂NHNH₂ (79.5 mg, 1.1 equiv) and J-Pr₂NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH / DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3 ~yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]⁺, rt 4.20 min).

References

Selurampanel

Systematic (IUPAC) name
N-[7-Isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide
Identifiers
CAS Number	912574-69-7
ATC code	None
PubChem	CID 45381907
ChemSpider	32698379
Chemical data
Formula	C16H19N5O4S
Molar mass	377.418 g/mol

see……..http://apisynthesisint.blogspot.in/2016/02/selurampanel-bgg-492.html

////Selurampanel, BGG492, 912574-69-7

CC(C)c1cc2c(cc1c3ccnn3C)c(=O)n(c(=O)[nH]2)NS(=O)(=O)C

CS(=O)(NN1C(NC2=C(C=C(C3=CC=NN3C)C(C(C)C)=C2)C1=O)=O)=O

Should Equipment Status Identification Labels be retained with the Batch Record?

Keeping equipment status identification labels with the batch record provides additional confirmation during the review process. But is it required?

http://www.gmp-compliance.org/enews_05182_Should-Equipment-Status-Identification-Labels-be-retained-with-the-Batch-Record_15218,15179,15156,15355,Z-QAMPP_n.html

Keeping equipment status identification labels with the batch record or other files is often done to provide additional confirmation during review of the record. It supports verification that certain equipment was cleaned before usage for manufacturing. But is it required?

The U.S. Food and Drug Administration FDA has answered this question in an Q&A Document. Assuming each major piece of equipment has a unique “Cleaning and Use Log” that is adequately retained, these “quick reference” equipment labels can be discarded according the agency. FDA sees “no value in the retention of such labels in addition to the required equipment log or batch record documentation. The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process. Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment. The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for non-dedicated equipment.”

However, as said before, it might be useful keeping these labels in a batch record. Many companies are doing so; not because it is a requirement but it is a helpful and reliable practice.

/////////

Lipaglyn (Saroglitazar) won a lot of support at the 75th Anniversary Conference of the American Diabetes Association. Lipaglyn is currently under Phase III clinical development for treatment of Non Alcoholic SteatoHepatitis (NASH), a serious liver disease and an unmet healthcare need, globally. There is currently no drug approved for treating NASH. Lipaglyn is already approved in India for the treatment of diabetic dyslipidemia

Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “These new robust scientific data on the safety and efficacy of Lipaglyn
(Saroglitazar) being presented at the 75^th Annual Scientific Sessions of the American Diabetes Association (ADA) reflect our continued commitment to millions of patients living with Diabetes, Dyslipidemia, Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH).”

Zydus Cadila, a leading global healthcare provider, today announced that new scientific and clinical data on Saroglitazar will be presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, USA from 5^thto 9^th June, 2015. Several analyses of real-world patient data of Saroglitazar will also be presented. The abstracts are available on theADA website.

Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd

Zydus is an innovation-led global healthcare provider that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 19,000 people worldwide including over 1200 scientists engaged in research and is dedicated to creating healthier communities globally.

With a strong research pipeline of NCEs, biologics and vaccines, the group became India’s first pharmaceutical company to launch its own indigenously researched therapy Lipaglyn which is also the world’s first approved therapy for diabetic dyslipidaemia. Exemptia, the world’s first biosimilar of Adalimumab is also a product of Zydus innovation. Zydus also collaborates with partners to support and make therapies affordable and accessible to communities across the world.

As a leading healthcare provider, it aims to become a global research-based pharmaceutical company by 2020.

Lipaglyn (Saroglitazar) sparkled bright at the first ever Indian Heart Journal Award Ceremony at the Cardiological Society of India’s Annual Conference, Chennai attended by a galaxy of leading cardiologists from across India.

Pankaj R. Patel (left), Chairman & Managing Director, Zybus Cadila,

Ganesh Nayak, Chief Operating Officer and Executive Director, Zydus Cadila

Zydus Cadila has announced a breakthrough in the anti-diabetic drug Lipaglyn. Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

The Zydus Group announced a breakthrough in its research efforts with Lipaglyn (Saroglilazar), a novel drug targeted at bridging an unmet healthcare need for treating Diabetic Dyslipidemia or Hypertriglyeeridemia in Type II diabetes, not controlled by statins alone. The drug has been approved for launch in India by the Drug Controller General of India (DCGI). With a novel action that offers lipid and glucose lowering effects in one molecule, Lipaglyn is the first Glitazar to be approved anywhere in the world.
“Lipaglyn provides patients suffering from diabetic dyslipidemia the option of a once-daily oral therapy that has a beneficial effect on both lipid parameters as well as glycemic control,” said Pankaj R. Fatel, Chairman and Managing Director, Zydus Cadila. “It has always been our dream to take a molecule right from the concept stage up to its launch. Today, we have realized this dream. It is an important breakthrough and I would like to dedicate this to all the Indian research scientists in the Held of drug discovery,” Patel added,
Diabetic Dyslipidemia is a condition where a person is diabetic and has elevated levels of the total cholesterol, the “bad” low-density lipoprotein (LDL) cholesterol and the triglycerides and a decrease in the “good” high-density lipoprotein (HDL) cholesterol concentration in the blood. Optimal LDL cholesterol levels ibr adults with diabetes are less than 100 mg/dh, optimal HDL cholesterol levels are equal to or greater than 40 mg/dL, and desirable triglycerides levels are less than 150 mg/dLT LipaglynrM, a non-thiazoKdinedione, is the first therapy to be approved for this condition,
World over, it is estimated that 30% of all deaths occur due lo cardiovascular diseases (CVD). In India, one out of every five persons is at serious risk of developing CVD, Research has shown that diabetes is one of the major risk factors of CVD. India has a population of nearly 65 million diabetics and 77 million prc-diabctics, 85 – 97% of the diabetes patients suffer from dyslipidemia or lipid abnormalities. Hence, addressing the problem of diabetes and dyslipidemia is crucial in tackling the health risk posed by CVD.
Discovered by the Zydus Research Centre, the dedicated NCE research arm of the Zydus group, LipaglynrM is a best-in-class innovation, designed to have a unique cellular mechanism of action following an extensive structure-activity relationship study initiated in the year 2000, Lipaglyn1M has a predominant affinity to PPAR alpha isoform and moderate affinity to PPAR gamma isoform of PPAR nuclear receptor subfamily. The molecule has shown beneficial effects on lipids and glyeemic control without side effects. This molecule underwent extensive pre-clinical characterisation and the I.ND was submitted in the year 2004,
As a part of the clinical development programme, extensive Phase-I, Phase-II and Phase-Ill clinical trials were conducted to evaluate the phamacokinetics, pharmacodynamics, efficacy and safety of Lipaglyn. The new drug application for Lipaglyn1 was based on a comprehensive clinical development programme spanning eight years.
Results from the first Phase III programme with Pioglitazone as a comparator drug in diabetes patients showed that the 4 mg dose of Lipaglyn led to a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and also showed a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbAlc) thereby confirming its beneficial effects of both lipid and glyeemic control in diabetic patients,
In the second Phase III study, Lipaglyn was studied in diabetic dyslipidemic patients insufficiently controlled with statin therapy. The results from this study confirmed that Lipaglyn had a pronounced beneficial effect on both the lipid and glyeemic parameters in these subjects.
In both the studies, Lipaglyn was well tolerated and had a better safety profile than the comparators. Importantly Lipaglyn1 M has a non-renal route of elimination, and did not show adverse events like edema, weight gain, myopathies or derangement of liver and/or kidney functions, thus making it sale and efficacious. LipaglynIM is recommended for once daily administration as 4 mg tablets.
Zydus will offer a dedicated LipaglynIM support programme to patients and earegivers, The programme shall provide important support and information regarding access, adherence, education and thereby help patients to start and appropriately manage their disease and therapy over time.

About Lipaglyn

Lipaglyn^[TM] (Saroglitazar) was launched in September 2013 in India, for treating Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Since then, more than 80,000 patients are availing this drug with a prescriber base over 3500 diabetologists, cardiologists and physicians. Lipaglyn^[TM] helps in a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and has also shown a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbA1c), thereby confirming its beneficial effects on both lipid and glycemic control in diabetic patients. Lipaglyn^[TM] is a prescription medicine, and can be taken only under the advice and guidance of a registered medical practitioner.

About Zydus

Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 16,500 people worldwide including over 1200 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global research based pharmaceutical company by 2020.

References

Zydus to present new scientific data on Lipaglyn in the US

New Delhi, Jun 8 (UNI) Healthcare services provider, Zydus Cadila today said the new scientific and clinical data on Lipaglyn (Saroglitazar) will be presented at the 75th annual scientific sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, US from 5th to 9th June,2015.
Read more at http://www.uniindia.com/news/business-economy/zydus-to-present-new-scientific-data-on-lipaglyn-in-the-us/84440.html

READ …..https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

SEE…..https://newdrugapprovals.org/2015/03/09/saroglitazar-magnesium-new-patent-wo-2015029066-cadila-healthcare-ltd/

http://lipaglyn.com/downloads/Lipaglyn_Product_Monograph.pdf

http://www.ijpcs.net/sites/default/files/IJPCS_3_1_02_0.pdf

http://zyduscadila.com/wp-content/uploads/2015/08/Saroglitazar-in-Diabetic-Dyslipidemia-1-Year-Data.pdf

http://onlinelibrary.wiley.com/doi/10.1002/prp2.136/pdf

//////

(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid

(αS)-α-Ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-1H-pyrrol-1-yl]ethoxy]benzenepropanoic Acid

alpha-ethoxy-4-(2-(2-methyl-5-(4-methylthio)phenyl))-1H-pyrrol-1-yl)ethoxy))benzenepropanoic acid

alpha-ethoxy-4-(2-(2-methyl-5-(4-methylthio)phenyl))-1H-pyrrol-1-yl)ethoxy))benzenepropanoic acid magnesium salt

(2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic acid

Benzenepropanoic acid, α-​ethoxy-​4-​[2-​[2-​methyl-​5-​[4-​(methylthio)​phenyl]​-​1H-​pyrrol-​1-​yl]​ethoxy]​-​, (αS)​-

ZYH1 compound

E0YMX3S4JD

Cas no 495399-09-2

Saroglitazar, Lipaglyn

Cadila Healthcare Ltd innovator

Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.

In September 2013, saroglitazar was launched in India for treating dyslipidemia and hypertriglyceridemia.

As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clinical trials).

Saroglitazar (INN, trade name Lipaglyn) is a drug for the treatment of type 2 diabetes mellitus and dyslipidemia. It is approved for use in India by the Drug Controller General of India.^[1] Saroglitazar is indicated for the treatment of diabetic dyslipidemia andhypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown favorable Anti-diabetic medication property by reducing the fasting plasma glucose and HBA_1c in diabetes patients. The recommended dose of saroglitazar is one tablet of 4 mg once a day.

In February 2013, Saroglitazar became the first glitazar that has been approved by any FDA for clinical use. Saroglitazar is marketed under the trade name Lipaglyn and developed by Zydus Cadila. Saroglitazar (2 and 4 mg q.d.) is currently approved in India by Drug Controller General of India (DCGI ) for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy. Lipaglyn provides the option of a once-daily oral therapy for the patients suffering from diabetic dyslipidemia.

Saroglitazar has another first attached to it. It is the first indigenously developed NCE by any Indian company; in this case Zydus Cadila.

Lipaglyn is indicated 4 mg (or 2 mg where such a need arise) oral dose once daily.

Saroglitazar Synthesis

http://ayurajan.blogspot.in/2016/01/saroglitazar.html
WO2003009841A1:

Identification:

Experimental: ¹H NMR: 1.14 (3H, t, J = 6.9Hz); 2.37 (3H, s); 2.48 (3H, s); 2.92-3.06 (2H, m); 3.32-3.42 (1H, m); 3.57-3.64 (1H, m); 3.9 (2H, t, J=6.36 Hz); 4.0 (1H, dd); 4.28(2H, t, J = 6.2 Hz); 5.9 (1H, d, J = 3.3 Hz); 6.08 (1H, d, J = 3.38 Hz); 6.6 (2H, d, J = 8.5Hz); 7.1(2H, d, J = 8.5Hz); 7.26 (2H, d, J = 8.4Hz); 7.3 (2H, d, J = 8.34Hz)

Details see below

Mechanism of action

Saroglitazar is novel first in class drug which acts as a dual PPAR agonist at the subtypes α (alpha) and γ (gamma) of theperoxisome proliferator-activated receptor (PPAR). Agonist action at PPARα lowers high blood triglycerides, and agonist action onPPARγ improves insulin resistance and consequently lowers blood sugar.^[2]

Efficacy

Being a dual PPAR agonist, Saroglitazar (Lipaglyn) helps in controlling blood glucose and Lipid parameters especially high triglycerides and high non HDL-Cholesterol.^[3] Lipaglyn effectively reduces triglycerides and non HDL-C and controlles high blood sugar, a typical situation in Insulin Resistance condition.^[4][5]

Safety

Saroglitazar has not demonstrated any of the adverse effects like weight gain and edema that are usually identified with similar molecules like the glitazone class of drugs.^[6] Because it is an insulin sensitizer, Saroglitazar (Lipaglyn) has less potential for hypoglycemia. No major serious adverse events have been reported; however, long-term cardiovascular safety has not been established.^[7]

PAPER

A new enantioselective synthesis of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid esters (EEHP and IEHP), useful pharmaceutical intermediates of PPAR agonists
Tetrahedron Lett 2014, 55(21): 3223

http://www.sciencedirect.com/science/article/pii/S0040403914006200

PATENT

WO 2003009841

http://www.google.co.in/patents/WO2003009841A1?cl=en

PATENT

US 20030236254

http://www.google.com/patents/US20030236254

PATENT

US 20140099333

http://www.google.com/patents/US20140099333

PATENT

WO2014174524

http://patentscope.wipo.int/search/en/WO2014174524

(I)

The compound as claimed in claim 1 wherein R is -SMe and M⁺ is Mg⁺².

The compound of claim 1 is Saroglitazar.

wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M⁺ represents suitable metal cations such as Na⁺, K⁺, Ca⁺², Mg⁺² and the like. ^r .

PATENT

WO2014181362

http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014181362&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

3-Aryl-2-hydroxy propanoic acid derivatives serve as a key intermediate for the synthesis of many pharmaceutically important compounds especially, peroxime proliferator activated receptor (PPAR) agonist.

Optically active 3-aryl-2-alkoxy propanoic acid and its esters, particularly, ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP) and isopropyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (IEHP) are versatile chiral pharmacophores present in many pharmaceutically important compounds, especially in peroxisome proliferator activated receptor (PPAR) agonists that have beneficial effects in treating Type 2 diabetes.

Several PPAR agonists, in particular PPAR α/γ dual agonists, commonly termed as glitazars (Ragaglitazar, Tesaglitazar, Navaglitazar etc.), as shown in the figure below were developed by many pharmaceutical companies that have a potential application in the treatment of Type 2 diabetes and dyslipidemia.

However, many of these drugs were discontinued due to their undesirable side effects, but some of them still have great potential [For example, Saraglitazar (LipaglynTM) developed by Zydus Cadila got approval in India for the treatment of diabetic dyslipidemia or hypertriglyceridemia]. Several PPAR α/γ agonists possessing chiral (S)-l moieties are shown below.

Tesaglitazar                                       Naveglitazar

In addition, these derivatives find an application in photosensitive materials, sweetening agents, treatment of certain eating disorders etc. Therefore, these compounds have attracted a great deal of attention of synthetic chemists and different methods of preparation of the compound of formula (S)-l have been extensively studied.

Generally, the reported protocols for the synthesis involve chiral pool approaches starting from L-tyrosine and its derivatives (Refer WO 02/24625, US 6559335B2, WO 2003/027084), asymmetric synthesis (Org. Lett. 2005, 7, 1947, US 2007/0149804) and resolution processes using chiral amines or enzymes (WO 2000/026200, WO 2001/11073, Org. Process Res. Dev. 2003, 7, 82, Org. Process Res. Dev. 2004, 8, 838, Tetrahedron Asymmetry 2009, 20, 2594).

Some of these methods have disadvantages such as expensive chiral starting materials and catalysts, low enantioselectivity and overall yields, problems associated with the O-alkylation step which often leads to the loss of optical purity, and many others.

The processes described in WO20026200 (Rao et. al.) uses benzyl bromide for benzylation, which is highly lachrymatory. Again, in the processes described, the debenzylation of the final intermediate was done by using Pd/C under pressure, which escalates the process economics.

WO2003024915 describes a process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives from 3-(4-hydroxyphenyl)-2-oxopropanoic acid.

WO 2003008362 describes 3-Aryl-2-hydroxy propanoic acid derivatives of formula I and the preparation thereof.

wherein Rland R2 may be same or different and represent hydrogen or (CI- C6) alkyl.

The process is depicted in Scheme 1 below.

Scheme 1

In another process variant as in Scheme 2, WO’362 discloses a process for the preparation of novel 3-aryl-2 -hydroxy propanol and their derivatives of the formula (I)

wherein OR and OR together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, which comprises: i) reducing the compound of formula (III) where R represents hydrogen or alkyl group, R3 represents benzyl to a compound of formula (IV) where R3 represents benzyl, ii) cyclizing the compound of formula (IV) to a compound of formula (V) where ORl and OR2 together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms and R3 represents benzyl and iii) debenzylating the compound of formula (V) in the presence of metal catalysts to yield pure compound of formula (I).

Scheme 2

Both the processes described in WO’362 result in poor overall yield and further fail to describe the preparation of compound of formula V using different alkylating agents. This document exemplifies the compound of formula V with similar ether groups as it fails to teach selective alkylation of formula IV.

WO2005019152 discloses an improved process for the preparation of compound of the general formula (la) and (lb).

Wherein, Rl represent H or (C1-C6) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like. R2 represents (Ci-Ce) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl and the like. R3 represents H, protecting groups such as benzyl, substituted benzyl, (C1-C3) alkyl and like.

The compound of general formula (la) is prepared according to the following schemes 3 and 4.

Scheme 3

Both the processes start with selective O-alkylation or O-aralkylation of L-Tyrosine of formula (2a) using a base, a chelating agent, an alkyl or aralkyl halide in the presence of solvents to obtain the compound of formula (3a), which is diazotized to obtain formula (4a) which upon dialkylation using an excess of alkylating agent and excess base, in presence of suitable solvent to obtain optically pure compound of formula (la). Alternatively, compound of formula (4a) may be selectively esterified to obtain compound of formula (5a), which is subsequently O-alkylated to obtain compound of formula (la) (Scheme 2).

However, the above processes have many disadvantages such as multistep synthesis including protection & deprotection and low overall yield. Further, low temperature diazotization on industrial scale is not viable. Moreover, the starting material is very expensive and hence escalates the process.

In the light of the foregoing, development of a new, alternate enantio-selective synthetic route to these important chiral intermediates, which are simple and can preserve the optical purity at the C-2 carbon of 3-Aryl-2-hydroxy propanoic acid derivatives, is highly desirable. There is a need for an efficient process for synthesis of 3-Aryl-2-hydroxy propanoic acid derivatives of formula (S)-l in high enantiopurity and good overall yield from commercially available starting material.

OR

Synthesis of saroglitazar

1. 2-Bromo-1-[4-(methylthio)phenyl]ethanone  is condensed with methyl acetoacetate  in the presence of NaOMe and Na2SO4 in toluene, to give alpha-keto methyl ester ,

2. This alpha-keto methyl ester ,is  hydrolyzed and decarboxylated by means of NaOH in MeOH/toluene at 50 °C giving diketone .

3. Diketone is subjected to Paal-Knorr reaction with ethanolamine  in the presence of pivallic acid in toluene at 110 °C to yield pyrrole primary alcohol derivative .

4. Sulfonylation of this pyrrole primary alcohol  with MsCl in the presence of Et3N,

5.  O-alkylation of mesylate with ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate  in the presence of K2CO3, optionally in the presence of 18-crown-6 in toluene/THF at 80 °C provides ether.

6. Finally, hydrolysis of ethyl ester using NaOH in H2O affords the target saroglitazar.

PATENT

WO2015033357

saroglitazar magnesium alongwith its intermediates may be prepared by the reaction scheme- 1, scheme-2 and scheme-3 as shown below, which is also the scope of the present invention.

Scheme-1

EXAMPLES

Example-l:

Preparation of methanesulfonic acid 2-r2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al)

In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, sodium methoxide (165 g) and toluene (1000.0 ml) were added under nitrogen environment and cooled to 8°C to 12°C. Methyl acetoacetate (331.55 g) was added dropwise and stirred for 1 hour. 2-bromo-l-(4-methyl sulfonyl phenyl) ethanone (500.0 g) compound (El) in toluene (1500.0 ml) and sodium sulfate

(75.0 g) mixture was stirred for 10 min and filtered at 25° to 35°C. The filtrate as obtained was added dropwise into the previous reaction mixture and stirred at 30°C to 35°C for 30 min. The organic layer was collected and washed with 10% sodium bicarbonate solution. The separated organic layer was collected and washed with water. 2-[2-(4-Methyl sulfanyl-phenyl)-2-oxo-ethyl]-3-oxo-butynic acid methyl ester as obtained in toluene layer is diluted with methanol (2500 ml) and sodium hydroxide solution (89.75 g) in water (2500 ml) was added and heated to 50° to 55°C for 1 hour. The layers were separated and the toluene layer was collected and heated to 45° to 55°C and charcoalized. The reaction mixture was filtered and pivalic acid (57.3 g) and ethanol amine (143.9 g) were added and heated to 105° to 1 15°C for removing water azeotropically. The toluene layer was separated and triethyl amine (271.85 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C. Methane sulphonyl chloride (282.5 g) was added dropwise, and stirred for 2 hours and heated to 35° to 45°C. The reaction mixture was filtered and washed with toluene. Toluene was distilled out completely under the vacuum to obtain the residue. The residue was dissolved in toluene (1500 mL) and used for further process.

ExampIe-2:

Preparation of methanesulfonic acid 2-f2-methyl-5-(4-methylsulfanyl-pheny0-pyrrol- 1-viyethyl ester (Al)

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 4-(methylthio)benzaldehyde (10 g), methyl vinyl ketone (3.63 g), triethylamine (9.95 g) and 3-methyl-5-(2-hydroxyethyl)-4-methyI thiazolium iodide (stetter

catalyst) (2.8 g) were heated to 70°C to 80°C and maintained overnight. The reaction mixture was cooled to room temperature and ethanol (100 mL) was added. The reaction mixture was stirred for 30 min and filtered. The product was washed with ethanol and dried to obtain 1 ,4-diketo compound (CI).

1 ,4-diketo compound (CI) obtained above and toluene (50 mL) were heated to 45° to 55°C and charcoalized. The reaction mixture was filtered and pivalic acid (5.7 g) and ethanol amine (14.4 g) were added and heated to 105° to 1 15°C and cooled to 25°C. Triethyl amine (27.2 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C. Methane sulphonyl chloride (28.3 g) was added dropwise, and stirred for 2 hours and heated to 35° to 45°C. The reaction mixture was filtered and washed with toluene. Toluene was distilled out completely under the vacuum, methanol (2500 ml) was added and heated to 55° to 65 °C and charcoalized for 30 min. The reaction mixture was filtered and washed with methanol. The reaction mixture was cooled to 25° to 35°C and stirred for 30 min. Reaction mass was further cooled to -5° to 5°C and filtered. The wet-cake was washed with methanol and dried to obtain compound (Al). The compound (Al) was characterized as crystalline solid by x-ray powder diffraction (FIG.2).

Example-3:

Purification of methanesulfonic acid 2-r2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al)

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 70 g methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l -yl]-ethyl ester (Al) and 420 mL ethyl acetate were added at 25°C. The reaction mixture was stirred for 30 min to obtain clear solution. 3.5 g charcoal was added and stirred for 30 min. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and 315 mL methanol was added. The reaction mixture was stirred for 2 hours at 25°C and cooled to 0°C. The product precipitated was filtered and washed with methanol to obtain crystalline

compound (Al). The compound (Al) was characterized as crystalline solid by x-ray powder diffraction (FIG.3).

Example-4:

Preparation of saroglitazar magnesium (T)

In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (A) (100.0 g) and toluene (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. Toluene solution of methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol- 1 -yl]-ethyl ester (Al) (150.24 g) obtained in example- 1, 18-Crown-6 (5.0 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour, The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with toluene (200.0 ml) and stirred for 15 min. The organic, layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with HP-120 (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was added sodium hydroxide 20.14 g solution in water (200.0 ml) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for 1 hour. The aqueous layer was extracted with methylene dichloride (2000 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove toluene completely. The residue was diluted with toluene (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.l).

The reaction of methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (A) may also be performed in similar manner as above in absence of phase transfer catalyst 18-Crown-6.

ExampIe-5:

Preparation of saroglitazar (S)-(-)-phenyl ethylamine salt:

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, residue-A obtained in example- 1 and ethanol (400 mL) were stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with isopropyl acetate (400 mL). The separated aqueous layer was diluted with isopropyl acetate (500 mL) and acidified with cone. HCI at adjust the pH 2-3. The separated aqueous layer was washed with isopropyl acetate. The combined organic layer was treated with (S)-(-)-phenyl ethylamine (55.94 g) and stirred for 2 hours at 25°C and 30 min at 45°C. The reaction mixture was cooled to 0°C and stirred for 2 hours, filtered and washed with isopropyl acetate. The wet-cake was dried to obtain saroglitazar phenyl ethylamine salt.

ExampIe-6:

Preparation of saroglitazar magnesium from saroglitazar (SH-)-phenyl ethylamine salt:

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, saroglitazar phenyl ethylamine wet-cake obtained in example-7 and isopropyl acetate (800 mL) were added at 25°C. The reaction mixture was diluted with water (400.0 ml) and acidified with cone. HCI at adjust the pH 2-3. The separated aqueous layer was washed with isopropyl acetate. The combined organic layer was treated with sodium hydroxide solution (20.14 g) in water (200 mL) and stirred for 30 min. The separated aqueous layer was treated with magnesium acetate tetrahydrate (2.29 g) in water (5 mL) solution and stirred for 60 min. The reaction mixture was extracted with methylene dichloride (800 mL). The methylene dichloride was complete removed by distillation under vacuum below 40°C to obtain the residue. The residue was diluted with methylene dichloride (50 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.l).

PATENT

WO 2015029066

Dwivedi, Shri Prakash Dhar; Singh, Ramesh Chandra; Patel, Vikas; Desai, Amar Rajendra

Cadila Healthcare Ltd

Polymorphic form of pyrrole derivative and intermediate thereof

Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)pKenyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound of Formula (I), having below chemical structure.

The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivs. thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of prepn. thereof. The present invention also provides pharmaceutical compn. comprising an amorphous form saroglitazar magnesium.

Amorphous forms of saroglitazar free acid and its salt form are claimed. Also claims the process for the synthesis the same compound. Useful for treating obesity, hyperlipidemia and hypercholesteremia. Picks up from WO2015011730, claiming the stable composition comprising saroglitazar magnesium or its derivatives. Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.

In September 2013, saroglitazar was launched for treating dyslipidemia and hypertriglyceridemia.

As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clainical trials).

Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl- 5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)ph’enyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound o f saroglitazar,

the process comprising: 5WO 2015/029066 PCT/IN2014/000551 (a) dissolving saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution, (b) adding the solution in one or more o f anti-solvent at temperature from about -80°C to about 150°C to obtain saroglitazar magnesium o f Formula (I); and (c) obtaining the amorphous saroglitazar magnesium by removal of anti-solvent.

Example-1: Preparation of saroglitazar magnesium (Ί) In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)- propionic acid ethyl ester (A) (100.0 g) and cyclohexane (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. methanesulfonic acid 2-[2-methyl-5-(4-methyIsulfanyl-phenyl)-pyrroll-yl]-ethyl ester (A l) (150.24 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour. The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with cyclohexane (200.0 ml) and stirred for 15 min. The organic layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was distilled to remove cyclohexane and the residue was collected (residue-A). The residue-A as obtained was treated with ethanol (400.0 ml) and stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for I hour. The aqueous layer was extracted with methylene dichloride (200 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove methylene dichloride completely. The residue was diluted with methylene dichloride (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.I).

PATENT

 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015011730

The present invention relates to the stable pharmaceutical composition of a suitable hypolipidemic agent. Preferably, the present invention discloses novel formulations of the compound of formula (I), or pharmaceutically acceptable salts of compounds of formula (I). More particularly the present invention relates to the stable pharmaceutical composition of compounds of formula (I) comprising compounds of formula (I) or its pharmaceutically acceptable salts, wherein the pH of the formulation is maintained above 7. formula (I)

REFERENCES

Indian Pat. Appl. (2015), IN 2013MU02905

WO 2015033357

WO 2015150565

WO 2015001573

IN 2013MU02828

WO 2015029066

IN 2013MU01910

Zydus Cadila chairman and MD Pankaj R. Patel (centre) and deputy managing director Sharvil P. Patel (left) in Mumbai on Wednesday. (PTI)JUNE 5, 2013

Cadila banks on diabetes drug
Calcutta Telegraph
It generally takes around 10-15 years for a drug to be developed from the time of its discovery In the case of Lipaglyn, the molecule was identified in 2001, and Phase III clinical trials was completed around four years ago. While Zydus has not yet …http://www.telegraphindia.com/1130606/jsp/business/story_16976915.jsp

Mumbai, June 5: Cadila Healthcare will launch a homegrown drug against diabetes by the third quarter of this year.

The Drug Controller General of India has approved its drug — Lipaglyn — to treat “diabetic dyslipidemia”.

Diabetic dyslipidemia is a condition where a person is diabetic and has elevated levels of total cholesterol. Over 80 per cent of diabetic patients are dyslipidemic.

http://www.telegraphindia.com/1130606/jsp/business/story_16976915.jsp

Zydus Cadila  said it is looking for partnership to market its new chemical entity (NCE) Lipaglyn, to be used for treating a type of diabetes in developed and developing markets. “Lipaglyn is the first glitazar to be approved in the world and the first NCE discovered and developed indigenously by an Indian pharma company.

The new drug is expected to be launched in Q3 of this fiscal in the country,” Zydus Cadila Chairman and Manging Director Pankaj Patel told reporters.

The company has spent USD 250 million in developing Lipaglyn and aims to spend another USD 150-200 million to launch the drug in overseas markets in next 3-5 years period, Patel said, adding that the company is looking for marketing partnerships.

“We expect this to be a blockbuster drug, which means over USD 1 billion sales a year, when the drug is sold globally, he said. The market for this drug is estimated at Rs 100 crore in the local market over the next three years and having market potential size of over USD 30 billion in the world market, he said.

Zydus Cadila took about eight years to develop the molecule and conducted clinical trials on more than 1,000 patients in India, Patel said, adding that the company is yet to finalise the price, but believes that it will be reasonably priced in the local market.

The company said that the Indian drug regulator Drug Controller General of India (DCGI) has approved Lipaglyn to be used for treating ‘diabetic dyslipidemia’.

Saroglitazar

Systematic (IUPAC) name
(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid
Clinical data
Trade names	Lipaglyn
Pregnancy category	C
Legal status	Approved in India
Routes of administration	Oral
Identifiers
CAS Number	495399-09-2
ATC code	None
PubChem	CID 60151560
ChemSpider	32079086
Chemical data
Formula	C25H29NO4S
Molar mass	439.56 g/mol

by WORLD DRUG TRACKER
DR ANTHONY

do not miss out on updates

see my update at https://newdrugapprovals.org/2015/03/09/saroglitazar-magnesium-new-patent-wo-2015029066-cadila-healthcare-ltd/ 9 may 2015

SEE.https://newdrugapprovals.org/2016/02/18/zydus-cadilas-lipaglyn-saroglitazar-won-a-lot-of-support-at-the-75th-anniversary-conference-of-the-american-diabetes-association/

Lipaglyn (Saroglitazar) won a lot of support at the 75th Anniversary Conference of the American Diabetes Association. Lipaglyn is currently under Phase III clinical development for treatment of Non Alcoholic SteatoHepatitis (NASH), a serious liver disease and an unmet healthcare need, globally. There is currently no drug approved for treating NASH. Lipaglyn is already approved in India for the treatment of diabetic dyslipidemia

Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “These new robust scientific data on the safety and efficacy of Lipaglyn
(Saroglitazar) being presented at the 75^th Annual Scientific Sessions of the American Diabetes Association (ADA) reflect our continued commitment to millions of patients living with Diabetes, Dyslipidemia, Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH).”

Zydus Cadila, a leading global healthcare provider, today announced that new scientific and clinical data on Saroglitazar will be presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, USA from 5^thto 9^th June, 2015. Several analyses of real-world patient data of Saroglitazar will also be presented. The abstracts are available on theADA website.

Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd

Zydus is an innovation-led global healthcare provider that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 19,000 people worldwide including over 1200 scientists engaged in research and is dedicated to creating healthier communities globally.

With a strong research pipeline of NCEs, biologics and vaccines, the group became India’s first pharmaceutical company to launch its own indigenously researched therapy Lipaglyn which is also the world’s first approved therapy for diabetic dyslipidaemia. Exemptia, the world’s first biosimilar of Adalimumab is also a product of Zydus innovation. Zydus also collaborates with partners to support and make therapies affordable and accessible to communities across the world.

As a leading healthcare provider, it aims to become a global research-based pharmaceutical company by 2020.

Lipaglyn (Saroglitazar) sparkled bright at the first ever Indian Heart Journal Award Ceremony at the Cardiological Society of India’s Annual Conference, Chennai attended by a galaxy of leading cardiologists from across India.

Pankaj R. Patel (left), Chairman & Managing Director, Zybus Cadila,

Ganesh Nayak, Chief Operating Officer and Executive Director, Zydus Cadila

Zydus Cadila has announced a breakthrough in the anti-diabetic drug Lipaglyn. Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

The Zydus Group announced a breakthrough in its research efforts with Lipaglyn (Saroglilazar), a novel drug targeted at bridging an unmet healthcare need for treating Diabetic Dyslipidemia or Hypertriglyeeridemia in Type II diabetes, not controlled by statins alone. The drug has been approved for launch in India by the Drug Controller General of India (DCGI). With a novel action that offers lipid and glucose lowering effects in one molecule, Lipaglyn is the first Glitazar to be approved anywhere in the world.
“Lipaglyn provides patients suffering from diabetic dyslipidemia the option of a once-daily oral therapy that has a beneficial effect on both lipid parameters as well as glycemic control,” said Pankaj R. Fatel, Chairman and Managing Director, Zydus Cadila. “It has always been our dream to take a molecule right from the concept stage up to its launch. Today, we have realized this dream. It is an important breakthrough and I would like to dedicate this to all the Indian research scientists in the Held of drug discovery,” Patel added,
Diabetic Dyslipidemia is a condition where a person is diabetic and has elevated levels of the total cholesterol, the “bad” low-density lipoprotein (LDL) cholesterol and the triglycerides and a decrease in the “good” high-density lipoprotein (HDL) cholesterol concentration in the blood. Optimal LDL cholesterol levels ibr adults with diabetes are less than 100 mg/dh, optimal HDL cholesterol levels are equal to or greater than 40 mg/dL, and desirable triglycerides levels are less than 150 mg/dLT LipaglynrM, a non-thiazoKdinedione, is the first therapy to be approved for this condition,
World over, it is estimated that 30% of all deaths occur due lo cardiovascular diseases (CVD). In India, one out of every five persons is at serious risk of developing CVD, Research has shown that diabetes is one of the major risk factors of CVD. India has a population of nearly 65 million diabetics and 77 million prc-diabctics, 85 – 97% of the diabetes patients suffer from dyslipidemia or lipid abnormalities. Hence, addressing the problem of diabetes and dyslipidemia is crucial in tackling the health risk posed by CVD.
Discovered by the Zydus Research Centre, the dedicated NCE research arm of the Zydus group, LipaglynrM is a best-in-class innovation, designed to have a unique cellular mechanism of action following an extensive structure-activity relationship study initiated in the year 2000, Lipaglyn1M has a predominant affinity to PPAR alpha isoform and moderate affinity to PPAR gamma isoform of PPAR nuclear receptor subfamily. The molecule has shown beneficial effects on lipids and glyeemic control without side effects. This molecule underwent extensive pre-clinical characterisation and the I.ND was submitted in the year 2004,
As a part of the clinical development programme, extensive Phase-I, Phase-II and Phase-Ill clinical trials were conducted to evaluate the phamacokinetics, pharmacodynamics, efficacy and safety of Lipaglyn. The new drug application for Lipaglyn1 was based on a comprehensive clinical development programme spanning eight years.
Results from the first Phase III programme with Pioglitazone as a comparator drug in diabetes patients showed that the 4 mg dose of Lipaglyn led to a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and also showed a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbAlc) thereby confirming its beneficial effects of both lipid and glyeemic control in diabetic patients,
In the second Phase III study, Lipaglyn was studied in diabetic dyslipidemic patients insufficiently controlled with statin therapy. The results from this study confirmed that Lipaglyn had a pronounced beneficial effect on both the lipid and glyeemic parameters in these subjects.
In both the studies, Lipaglyn was well tolerated and had a better safety profile than the comparators. Importantly Lipaglyn1 M has a non-renal route of elimination, and did not show adverse events like edema, weight gain, myopathies or derangement of liver and/or kidney functions, thus making it sale and efficacious. LipaglynIM is recommended for once daily administration as 4 mg tablets.
Zydus will offer a dedicated LipaglynIM support programme to patients and earegivers, The programme shall provide important support and information regarding access, adherence, education and thereby help patients to start and appropriately manage their disease and therapy over time.

About Lipaglyn

Lipaglyn^[TM] (Saroglitazar) was launched in September 2013 in India, for treating Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Since then, more than 80,000 patients are availing this drug with a prescriber base over 3500 diabetologists, cardiologists and physicians. Lipaglyn^[TM] helps in a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and has also shown a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbA1c), thereby confirming its beneficial effects on both lipid and glycemic control in diabetic patients. Lipaglyn^[TM] is a prescription medicine, and can be taken only under the advice and guidance of a registered medical practitioner.

About Zydus

Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 16,500 people worldwide including over 1200 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global research based pharmaceutical company by 2020.

References

Zydus to present new scientific data on Lipaglyn in the US

New Delhi, Jun 8 (UNI) Healthcare services provider, Zydus Cadila today said the new scientific and clinical data on Lipaglyn (Saroglitazar) will be presented at the 75th annual scientific sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, US from 5th to 9th June,2015.
Read more at http://www.uniindia.com/news/business-economy/zydus-to-present-new-scientific-data-on-lipaglyn-in-the-us/84440.html

READ …..https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

SEE…..https://newdrugapprovals.org/2015/03/09/saroglitazar-magnesium-new-patent-wo-2015029066-cadila-healthcare-ltd/

http://lipaglyn.com/downloads/Lipaglyn_Product_Monograph.pdf

http://www.ijpcs.net/sites/default/files/IJPCS_3_1_02_0.pdf

http://zyduscadila.com/wp-content/uploads/2015/08/Saroglitazar-in-Diabetic-Dyslipidemia-1-Year-Data.pdf

http://onlinelibrary.wiley.com/doi/10.1002/prp2.136/pdf

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CCO[C@@H](Cc1ccc(cc1)OCCn2c(ccc2c3ccc(cc3)SC)C)C(=O)O

CCOC(CC1=CC=C(C=C1)OCCN2C(=CC=C2C3=CC=C(C=C3)SC)C)C(=O)O

Saperconazole

Properties: Crystals from acetonitrile, mp 189.5°. Poorly sol in water.

Melting point: mp 189.5°

Therap-Cat: Antifungal.

Janssen Pharmacuetica N.V.

PHASE 2

The development of effϊcaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and US-4,764,604.

Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared. The present invention is concemced with the stereoisomeric forms of itraconazole (X = CI) and saperconazole (X = F), which may be represented by the formula

cis-©,and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and ‘cis’ means that the (lH-l,2,4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3-dioxolane ring.

The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C. A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical

20 rotation [α]_jj in 1% methanol (itraconazole; table I) (saperconazole; table H).

Table I

itraconazole

Table π

saperconazole