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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Register Today for the ACS Symposium in India on Recent Advances in Drug Development, 11-12 November 2016 in Hyderabad, India


acs

cas

Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India

Recent Advances in Drug Development

Register Today for the ACS Symposium in India on Recent Advances in Drug Development

To view this email as a web page, go here.

Register now for the inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India. Be sure to secure your seat today as rates will increase on 27 October!

http://acssymposium.org.in/
The theme of the Symposium is Recent Advances in Drug Development. The event will feature lectures by the world’s leading researchers and experts in the pharma industry, including:

  • Dr. Peter Senter of Seattle Genetics
  • Dr. Jagath Reddy Junutula of Cellerant Therapeutics, Inc.
  • Dr. Ming-Wei Wang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences

This is an exclusive event being organized in partnership with Dr. Reddy’s Laboratories for pharma professionals throughout India. Space is limited so register today!

Please visit our website to learn more about the speakers and the program.

Register today to ensure your access to the ACS Industry Symposium. We look forward to seeing you in Hyderabad in November.

CAS
2540 Olentangy River Rd Columbus, OH 43202 US

cas

http://acssymposium.org.in/

CAS
2540 Olentangy River Rd Columbus, OH 43202 US

cas

http://acssymposium.org.in/

 

 

Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India
Recent Advances in Drug Development

/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas

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Afatinib dimaleate, Dr Reddy’s, New patent, WO 2016027243


 

 

 

Afatinib dimaleate, Dr Reddy’s, New patent,  WO-2016027243, 

WO 2016027243

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Hyderabad, Telangana, India – 500034. Hyderabad 500034 (IN)

RAMAKRISHNAN, Srividya; (IN).
PEDDY, Vishweshwar; (IN).
MAHAPATRA, Sudarshan; (IN).
KANNIAH, Sundara Lakshmi; (IN).
CHENNURU, Ramanaiah; (IN).
JOSE, Jithin; (IN).
DHAGE, Yogesh Mohanrao; (IN).
PEDDIREDDY, Subba Reddy; (IN).
YARRAGUNTLA, Sesha Reddy; (IN).
RAGHUVEER, Sherial; (IN).
KOLLA, Srinivasa Rao; (IN).
ANIL KSHIRSAGAR, Shivani; (IN).
JAFAR SHAIKH, Latif; (IN).
BANDARU, Srinivasulu; (IN)

The drug compound having the adopted name afatinib dimaleate, has a chemical name N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1 :2), and is represented by structure of formula I

Formula I

Afatinib dimaleate is an anticancer protein kinase inhibitor indicated for treatment of non-small-cell lung cancer. Process for preparation of afatinib, afatinib dimaleate and intermediates useful in preparation of afatinib dimaleate are described in US Patent Nos. 7,019,012; 8,426,586 and 7,960,546.

US Patent No. 8,426,586 discloses crystalline Form A of afatinib dimaleate salt and processes for preparation thereof. US Patent Application Publication No. 20140051713 discloses crystalline Form B of afatinib dimaleate salt and processes for preparation thereof. PCT Application Publication No. 2013052157 discloses crystalline Form C, Form D and Form E of afatinib dimaleate salt and processes for preparation thereof. The PCT publication also discloses crystalline Form A, B, C and Form D of afatinib base.

Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Afatinib di-maleate.

SUMMARY

The present application provides novel solid state forms of Afatinib di-maleate, processes for preparing them, and pharmaceutical compositions containing them.

The present application also encompasses the use of novel solid state forms of Afatinib di-maleate provided herein, for the preparation of other afatinib salts, other solid state forms of afatinib dimaleate, and formulations thereof.

The present application also encompasses the use of any one of the novel solid state forms of Afatinib di-maleate disclosed herein for the preparation of a medicament, preferably for the treatment of cancer, particularly for the treatment of cancers mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases. The present invention further provides a pharmaceutical composition comprising any one of the Afatinib di-maleate crystalline forms of the present invention and at least one pharmaceutically acceptable excipient.

The present application also provides a method of treating cancer, comprising administering a therapeutically effective amount of at least one of the Afatinib di-

maleate novel solid state forms of the present application, or at least one of the above pharmaceutical compositions to a person suffering from cancer, particularly a person suffering from a cancer mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including but not limited to NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases.

Example 1 : Preparation of amorphous form of afatinib dimaleate.

2.0 g of afatinib dimaleate was dissolved in 80 mL of a mixture of methanol and acetone (3:1 ) at 26°C and stirred for 15 min. The solution was filtered to remove the undissolved particles and the filtrate was distilled under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 45°C to get 1 .29 g of amorphous afatinib dimaleate. PXRD pattern: Fig. 1 .

///////Afatinib dimaleate, Dr Reddy’s, New patent,  WO-2016027243, WO 2016027243

DRL 17822 from Reddy US Therapeutics/Dr Reddy’s


Figure imgf000125_0002

 

Figure imgf000076_0001Figure imgf000226_0001

CAS  920493-71-6 and  CAS 898911-09-6

 

reddys1

SCHEMBL14602922.pngSCHEMBL14602922.png

DRL 17822

MW 603.6045, MFC30 H31 F6 N7

Molecular Formula: C30H31F6N7
Molecular Weight: 603.604459 g/mol

Cas 898911-09-6, 1454689-50-9

3-([[3,5-Bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino]methyl)-N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amine

3-​Quinolinemethanamine​, 2-​[bis(cyclopropylmeth​yl)​amino]​-​N-​[[3,​5-​bis(trifluoromethyl)​phenyl]​methyl]​-​8-​methyl-​N-​(2-​methyl-​2H-​tetrazol-​5-​yl)​-

3-(((3,5-bis(trifluoromethyl)benzyl)(2- methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8- methylquinolin-2-amine

(3-{ [3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoIe-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

Reddy US Therapeutics   (Innovator)

Dr. Reddy’s Laboratories Ltd.

r1

 

Treatment of Atherosclerosis Therapy Lipoprotein Disorders,

CETP inhibitor (dyslipidemia/atherosclerosis/cardiovascular diseases), Dr Reddy’s

Selective inhibitor of cholesteryl ester transfer protein (CETP)

  • 30 Jun 2012Dr Reddy’s Laboratories completes a phase II trial in Hypercholesterolaemia in Italy, Poland and Ukraine (NCT01388816)
  • 09 Mar 2012Dr Reddy’s Laboratories completes enrolment in its phase II trial for Hypercholesterolaemia in Italy, Poland, and Ukraine (NCT01388816)
  • 02 Sep 2011Phase-II clinical trials in Hypercholesterolaemia in Ukraine (PO)

CLINICAL TRIALS…..Type II Hyperlipidemia PHASE 2…………https://clinicaltrials.gov/ct2/show/NCT01388816

Cardiovascular disease is a leading cause of death worldwide. Among cardiovascular disorders, coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events.

LDL-C lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. However even with stain use, residual CHD risk from dyslipidemia remains. Epidemiologic and observational studies have shown that HDL-C is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk.

Presently only niacin is approved by the FDA for HDL-C elevation and can raise HDL-C levels by 20-30%. However its use can be limited by a high incidence of flushing and, less commonly, by elevation of blood glucose and potential hepatic toxicity.

Cholesteryl ester transfer protein (CETP) inhibitors are being explored for their ability to elevate HDL-C. A small molecule CETP inhibitor, torcetrapib, has been demonstrated to elevate HDL-C by 60-100%. However, a large clinical trial (ILLUMINATE) where it increased HDL-C by a mean of 72% compared to baseline was halted as it failed to show benefit. Post-hoc analysis of this study implicated an off-target increase in blood pressure as potentially counteracting any anti-atherosclerotic benefits. Post-hoc subgroup analysis showed that patients in the highest HDL-C quartile had a 57% reduction in the risk of cardiovascular events.

Increased blood pressure appears to be specifically related to torcetrapib as two other small molecule CETP inhibitors, anacetrapib and dalcetrapib, have not shown this in clinical trials and have been well tolerated. DRL-17822 has also not shown elevation of blood pressure in either animals or in normal volunteers.

This study will investigate the efficacy and tolerability of DRL-17822 as dyslipidemia monotherapy in patients with Type II hyperlipidemia.

 

Hyperlipidemia or an elevation in serum lipids is associated with an increase incidence of cardiovascular disease and atherosclerosis. Primary hyperlipidemia is a term used to describe a defect in lipoprotein metabolism. The lipoproteins commonly affected are low density lipoprotein (LDL) cholesterol, which transports mainly cholesterol, and very low density lipoprotein-cholesterol (VLDL-cholesterol), which transports mainly triglycerides (TG). Most subjects with hyperlipidemia have a defect in LDL metabolism, characterized by raised cholesterol, LDL-C levels, with or without raised triglyceride levels; such subjects are termed hypercholesterolemic (Fredrickson Type II). Familial hypercholesterolemia (FH) is caused by any one of a number of genetically-determined defects in the LDL receptor, which is important for the entry of cholesterol into cells. The condition is characterized by a reduced number of functional LDL receptors, and is therefore associated with raised serum LDL-C levels due to an increase in LDL.

It is reasonably known in the art that the likelihood of cardiovascular disease can be decreased, if the serum lipids, and in particular LDL-C, can be reduced. It is further known that the progression of atherosclerosis can be retarded or the regression of atherosclerosis can be induced if serum lipids can be lowered. In such cases, individuals diagnosed with hyperlipidemia or hypercholesteremia should consider lipid-lowering therapy to retard the progression or induce the regression of atherosclerosis for purposes of reducing their risk of cardiovascular disease, and in particular coronary artery disease.

Cholesteryl ester-transfer protein (CETP) is an important player in metabolism of lipoproteins, such as, for example, a high density lipoprotein (HDL). CETP is a 70 kDa plasma glycoprotein that is physically associated with HDL particles. It facilitates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. This transfer is accompanied by transfer of triglycerides in the opposite direction. Thus, a decrease in CETP activity can result in an increase in the level of HDL cholesterol and a decrease in the level of very low density lipoprotein (VLDL) and low density lipoprotein (LDL). CETP can therefore simultaneously affect the concentrations of pro-atherogenic (for example, LDL) and anti-atherogenic (for example, HDL) lipoproteins.

Several CETP inhibitors are currently in various clinical phases of development for treating various aforementioned disorders. In spite of having various advantages, CETP inhibitors are proven to be difficult to formulate for oral administration. CETP inhibitors are of a highly lipophilic nature and have extremely low solubility in water. Due to their poor solubility, bioavailability of conventional oral compositions is very poor. The lipophilic nature of CETP inhibitors not only leads to low solubility but also tends to poor wettability, further reducing their tendency to be absorbed from the gastrointestinal tract. In addition to the low solubility, CETP inhibitors also tend to have significant, “food effect”, where a significant difference in rate and amount of drug absorption is observed when the drug is administered with or without a meal. This “food effect”, often complicates the dosing regimen and may require high dosing to achieve the desired therapeutic effect, resulting in potentially unwanted side effects.

Several attempts have been made to improve the solubility of CETP inhibitors, but have generally ended up with limited success. At the outset, most methods aimed at enhancing aqueous concentration and bioavailability of low-solubility drugs only offer moderate improvements. References describing improving the dissolution of poorly soluble drugs include: U.S. Patent Nos. 5,456,923, 5,993,858, 6,057,289, 6,096,338, 6,267,985, 6,280,770, 6,436,430, 6,451,339, 6,531,139, 6,555,558, 6,638,522, 6,962,931 and 7,374,779.

PATENT

WO 2014128564

https://www.google.co.in/patents/WO2014128564A2?cl=en

 

WO-2014076568

http://www.google.com/patents/WO2014076568A2?cl=en

EXAMPLES

In the following Examples 1-17, various compositions in accordance with the present application were prepared comprising 3-(((3,5-bis(trifluoromethyl)benzyl)(2- methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8- methylquinolin-2-amine as the CETP inhibitor.:

EXAMPLE 1 :

Figure imgf000066_0001

1. 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)- N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amineand hydroxypropyl methyl cellulose acetate succinate were mixed together in given solvent mixture to form clear solution.

2. To the solution of step I, Polyoxyl 35 castor oil and talc were added to form a homogenous suspension.

3. The suspension of step 2 was sprayed over inert sugar spheres and dried.

4. The drug layered spheres of step 3 were coated with dispersion made from given seal layer ingredients.

5. The coated spheres of step 4 were formulated further as capsule dosage form.

 

PATENT

WO 2013046045

https://www.google.co.in/patents/WO2013046045A1?cl=en

PATENT

WO 2013024358

 

PATENT

WO 2007075194

https://www.google.co.in/patents/WO2007075194A1?cl=en

Syntheis construction

Figure imgf000073_0001Figure imgf000073_0002Figure imgf000074_0001

Figure imgf000075_0001Figure imgf000075_0002

reddys1

Example 1

Synthesis of (3-{[3,5-bis trifluoromethyl-benzyl )-(2-cyclopropyImethyI-2H- tetrazole -5-yl)-amino]-methyl-}-8-methyI-quinolme-2-yl)-bis- cyclopropylmethyl-amine Step (i): Synthesis of 2~chloro-8-methyl-quinoline-3-carbaldehyde

Figure imgf000073_0001

DMF (1.22 g, 16.7 mmol) was taken in a flask equipped with a drying tube and POCl3 (7.32 g, 46.7 mmol) was added dropwise with stirring at 0° C. To this solution, TV-o-Tolyl acetamide (1.00 g, 6.7 mmol) was added and the solution was refluxed for 6 h at 90° C. The excess POCl3 was distilled off, water was added to the residue and this was stirred at room temperature for 10 min. The solid was filtered and dried under vacuum..This crude compound was purified over silica gel (100-200 mesh) using 6% ethyl acetate and petroleum ether to give the product as a yellowish solid (yield: 78%). 1H NMR (CDCl3, 200 MHz): δ 10.5 (s, IH)5 8.71 (s, IH), 7.83- 7.79 (m, IH), 7.74- 7.70 (m, IH), 7.56-7.49 (m, IH), 2.79 (s, 3H); m/z (EI-MS): 206 (M+, 100%). Step (ϋ): Synthesis of 2-(bis(cyclopropylmethyl)amino)-8-methylquinoline-3- carbaldehyde:

Figure imgf000073_0002

2-Chloro-8-methyl-quinoline-3-carbaldehyde (.115 g, 0.559 mmol), and potassium carbonate (0.231 g, 1.67 mmol) were put in a 25 mL two necked RB flask. To this, 3 mL of DMF was added followed by dropwise addition of bis- cyclopropylmethyl amine (0.083 g, 0.67 mmol). The reaction mixture was refluxed for 2 h and was cooled to RT. It was then poured on crushed ice (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine and dried over sodium sulphate. The solvent was evaporated under vacuum to give a yellow colored oil (0.081 g, 50%).

1H NMR (CDCl3, 400 MHz): δ 10.5 (s, IH), 8.71 (s, IH), 7.83- 7.79 (m, IH),

7.74-7.70 (m, IH), 7.56-7.49 (m, IH), 3.55-3.47 (m, 4H), 2.79 (s, 3H), 1.73-1.72

(m, 2H), 1.70-1.46 (m, 4H), 1.20-1.11 (m, 4H); m/z (ES-MS ): 295 (M+H-I5

100%); IR (neat, cm“1): 3385, 2948, 1691.

Step (iii): Synthesis of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N- bis(cyclopropylmethyl)-8-methylquinolin-2-amine

Figure imgf000074_0001

2-(Bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde (0.081 g, 0.39 mmol), 3,5-bis-trifluoromethylbenzylamine (0.096 g, 0.39 mmol) and acetic acid (0.047 g, 0.78 mmol) were put in a 25 mL RB flask. To this, 2 rnL of methanol was added and stirred at RT for 15 min. Sodium cyanoborohydri.de (0.075 g, 0.77 mmol) was added portionwise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated NaHCO3 solution, brine and dried over sodium sulphate. The solvent was evaporated and the crude residue was purified by column chromatography over silica gel (100-200 mesh) eluting with 4% ethyl acetate in petroleum ether to give the title amine (0.142 g, yield: 99%). 1R NMR (CDCl3, 400 MHz): δ 7.89-7.86 (m, IH), 7.80 (m, IH), 7.75-7.74 (m, IH), 7.60-7.40 (m, 3H), 7.30-7.26 (m,lH), 4.12 (s, 2H), 3.88 (s, 2H), 3.24-3.22 (m, 4H), 2.72 (s, 3H), 0.99-0.92 (m, 2H), 0.44-0.35 (m, 4H), 0.11-0.05 (m, 4H); m/z (EI-MS ): 522 (M++l, 100%); IR (neat, cm“1): 3357, 2929, 2851.

Step (iv): Synthesis of N-(3,5-bis(trifluoromethyl)benzyl)-N-((2- (bis(cyclopropylmethyl)amino)-8-methylqumolin-3-yl)methyl)cyanamide

Figure imgf000075_0001

To a solution of 3-((3,5~bis(trifluoromethyl)benzylamino)methyl)-N,N- bis(cyclopropylmethyl)-8-methylquinolin-2-amine (0.176 g , 0.33 mmol ), obtained in step (iii) , in MeOH (4 mL) under N2 atmosphere was added sodium bicarbonate (0.056 g, 0.67 mmol ) followed by the addition of cyanogen bromide (0.063 g, 0.60 mmol). The reaction mixture was stirred at RT for 2 h. The solvent was removed under vacuum to give the crude residue which was dissolved in water, extracted with ethyl acetate and dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo to afford N-(3,5-bis(trifluoromethyl)benzyl)- N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 64%).

1H NMR (CDCl3, 400 MHz ): δ 8.07 (s, IH) , 7.82 (s, IH), 7.70 (s, 2H), 7.56-7.55 (m, IH), 7.50-7.49 (m, IH), 4.49 (s, 2H), 4.23 (s, 2H), 3.17 -3.15 (m, 4H), 2.71 (s, 3H), 0.097-0.085 (m, 2H), 0.405-0.401 (m, 4H), 0.385-0.381 (m, 4H); m/z (ES- MS): 547 (M++l, 100%); IR(KBr ,Cm“1 ) : 2273, 1280.

Step (v): Synthesis of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

Figure imgf000075_0002

7V-(3,5-Bis(tiifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)- 8-methylqumolin-3-yl)methyl)cyanamide (0.118 g, 0.216 mmol), sodium azide (0.70 g 1.08 mmol) and ammonium chloride (.058 g, 1.08 mmol) were put in a RB flask under N2atmosphere. To this reaction mixture, DMF (2 mL) was added and was refluxed for 1 h. The reaction mixture was cooled to RT and ice was added to this and extracted with ethylacetate (3×10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine as a yellow solid (0.125 g, 99%).

1H NMR (CDCl3, 400 MHz ): δ 7.99 (s, IH) , 7.79 -7.74 (m, 4H ), 7.41-7.40 (m,

IH ), 7.33-7.31 (m, IH), 4.99 (s, 2H), 4.80 (s, 2H), 3.68 (s, 4H), 2.16 (s, IH) 1.56-

1.06 (m, HH); m/z (ES-MS): 578 (M++l, 100%); IR (KBr , cm“1) 3680 , 2922 ,

1660 , 1616.

METHYLATION SHOULD GIVE THE PRODUCT

Scheme 1

Figure imgf000046_0001
Figure imgf000046_0002

PATENT

WO 2006073973

http://www.google.co.in/patents/WO2006073973A2?cl=en

Example 47

Synthesis of [2-(bis-cycIopropylmethyI-amino)-8-methyl-quinolin-3-ylmethyI]-(3,5- bis-trifluoromethyl-benzyl)-carbamic acid methyl ester

Step (i): Synthesis of bis-cyclopropylmethyl-amine

(i) a. Synthesis of cyclopropanecarboxylic acid cyclopropylmethyl-amide:

Figure imgf000212_0002

Cyclopropyl carboxylic acid (1.0 g, 11.63 mmol) was added to a 50 mL two neck round bottom flask, along with DCM (25 mL). This mixture was cooled to 0° C, EDCI (4.15 g, 13.95 mmol) was added portionwise to the mixture with stirring under nitrogen atmosphere, and the temperature was maintained for 0.5 h. After this time, hydroxybenzotriazole (1.88 g, 13.95 mmol) was added to the 0° C mixture which was stirred for 10 min, then triethylamine (1.7 g, 11.63 mmol) was added, and stirring of the mixture was continued at the same temperature for another 0.5 h. Then, cyclopropylmethylamine (0.825 g, 11.63 mmol) was added, and the reaction was allowed to reach RT, and stirring was continued overnight. The solvent was then removed in vacuo, and the crude residue was purified by passing through a column over 60-120 silica gel, eluting with dichloromethane, to afford the title compound (1.6 g), yield: 87%. 1H NMR (CDCl3, 200 MHz): d 5.75 (br s, NH, D2O exchangeable), 3.17-3.16 (m, 2H), 1.00-0.80 (m, 4H), 0.77-0.67 (m, 2H), 0.56-0.43 (m, 2H), 0.24-0.16 (m, 2H) m/z (CI-MS): 139 (M+, 100%) (i) b. Synthesis of bis-cyclopropylmethyl-amine

Figure imgf000213_0001

To a suspension of lithium aluminum hydride (1.3 g, 9.35mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g), yield: 69%.

1H NMR (CDCl3, 200 MHz): d 5.75 (br s, NH, D2O exchangeable), 3.16-3.09 (m, 2H), 2.50-2.4 (m, 2H), 0.56-0.43 (m, 4H), 0.24-0.21 (m, 3H), 0.21-0.13 (m, 3H) m/z (ES-MS): 139 (M^+14, 100%)

Step (ii): Synthesis of [2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]- (S^-bis-trifluoromethyl-benzy^-carbamicacid methyl ester

Figure imgf000214_0001

The title compound was synthesized by using the same procedure as in Example 35, except using o-tolyl acetanilide in step (i) instead of acetanilide and bis- cyclopropylmethyl amine in step (iii), which yielded the desired product as a light yellow, viscous liquid (0.05 g), yield:40%, of purity 98.8% (HPLC: Symmetry Shield RP8, [0.01M KH2PO4: CH3CN], 217 nM, Rt12.719 min).

1H NMR (CDCl3, 400 MHz): d 7.7 (s, IH), 7.68-7.44 (m, 3H), 7.27-7.24 (m, 2H), 4.78- 4.65 (m, 2H), 4.47-4.4 (m, 2H), 3.8 (s, 3H), 3.16-3.14 (d, J=7Hz, 2H), 2.7 (s, 3H), 1.55 (s, 3H), 1.01-0.9(m, IH), 0.38-0.34 (m, 4H), 0.07-0.05 (m, 4H); m/z (CI-MS): 579 (M+, 100%)

Example 57

Synthesis of (3-{ [3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoIe-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

Figure imgf000226_0001

The title compound was prepared as an oil by following the same synthetic procedures as in Example 52, except using {3-[(3,5-bis-trifluoromethyl-benzylamino)- methyl]-8-methyl-quinolin-2-yl}-bis-cyclopropylmethyl-amine in step (i) instead of {3- [(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-2-yl}-cyclopentylmethyl-ethyl- amine (0.07 g), yield: 52%.

Purity: 95.53% (HPLC: Symmetry Shield RP8, [0.01M KH2PO4: CH3CN], 217 nM, Rt 9.538 min).

IR (neat, cm4) 3079, 2925, 1582;

1H NMR (CDCl3, 400 MHz): d 7.82 (s, IH), 7.69-7.67 (m, 2H), 7.44-7.41 (m, IH), 7.23- 7.2 (m, 3H), 4.91 (s, 2H), 4.65 (s, 2H), 4.21 (s, 3H), 3.29 -3.19 (m, 4H)5 2.71 (s, 3H), 1.01-1.00 (m, 2H), 0.99-0.83 (m, 2H), 0.39-0.34 (m, 3H), 0.08-0.07 (m, 3H). m/z (ES-MS): 604 (M++!, 100%)

 

Dr. Reddy’s announces start of Phase II study with the CETP inhibitor, DRL-17822 in dyslipidemia patients

Hyderabad, India, September 02, 2011: Dr Reddy’s Laboratories (NYSE: RDY) announced the initiation of dosing with DRL-17822 in patients with diagnosis of type II dyslipidaemia. DRL-17822, is a selective, orally bioavailable inhibitor of cholesteryl ester transfer protein (CETP), for the treatment and/or prevention of dyslipidaemia, atherosclerosis and associated cardiovascular disease.

The current study is being conducted under a CTA in a number of countries in Europe. The objective of the study is to evaluate the efficacy and safety of DRL-17822 in patients with Type-II dyslipidemia. This is a randomized, double blind, placebo controlled, parallel group study in 160 subjects. The primary outcome measure is to assess the elevation in HDL cholesterol and reduction in LDL cholesterol from baseline to end of treatment compared to placebo. Three doses (50, 150 & 300 mg) of DRL-17822 given once daily for 4 weeks will be evaluated during this study.

Three human Phase I studies with DRL-17822 had already been conducted in Europe, where DRL-17822 was shown to be safe and well tolerated. In these studies, the proof of mechanism had been demonstrated by dose-dependent inhibition of plasma CETP activity as well as by significant increase in HDL cholesterol & decrease in LDL cholesterol levels.

Cardiovascular disease is a leading cause of death among men and women worldwide. Among cardiovascular disorders, coronary heart disease (CHD), caused by atherosclerosis is the most common cause of morbidity and mortality. Stabilization and/or regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. Low-density lipoprotein cholesterol lowering agents, primarily the statins, are the current mainstay in the pharmacological management of dyslipidaemia. However, significant residual cardiovascular risk remains despite use of statins.

Epidemiological and observational studies demonstrate that reduced high density lipoprotein cholesterol levels are a strong, independent predictor of CHD, suggesting that raising HDL cholesterol levels might afford clinical benefit in the reduction of cardiovascular risk. One approach to raise HDL level has been inhibition of CETP activity. Currently it is believed that, raising HDL cholesterol and lowering LDL cholesterol through CETP inhibition would lead to a significant benefit in terms of CHD risk reduction.

Dr. K. Anji Reddy, Founder Chairman, Dr. Reddy’s Laboratories added, “We are committed to delivering products of differentiated value in this area of high global clinical unmet need. We are excited to continue to advance our CETP program and look forward to the data from our Phase II study. This class of therapy could transform the treatment of CHD and DRL 17822 is in a position to be one of the front-running products in the class”.

Disclaimer
This press release includes forward-looking statements, as defined in the U.S. Private Securities Litigation Reform Act of 1995. We have based these forward-looking statements on our current expectations and projections about future events. Such statements involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. Such factors include, but are not limited to, changes in local and global economic conditions, our ability to successfully implement our strategy, the market acceptance of and demand for our products, our growth and expansion, technological change and our exposure to market risks. By their nature, these expectations and projections are only estimates and could be materially different from actual results in the future.

About Dr. Reddy’s
Dr. Reddy’s Laboratories Ltd. (NYSE: RDY) is an integrated global pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses – Pharmaceutical Services and Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars, differentiated formulations and NCEs. Therapeutic focus is on gastro-intestinal, cardiovascular, diabetology, oncology, pain management, anti-infective and pediatrics. Major markets include India, USA, Russia and CIS, Germany, UK, Venezuela, S. Africa, Romania, and New Zealand. For more information, log on to: www.drreddys.com

For more information please contact:

Investors and Financial Analysts:
Kedar Upadhye at kedaru@drreddys.com / +91-40-66834297
Raghavender R at raghavenderr@drreddys.com / +91-40-49002135
Milan Kalawadia (USA) at mkalawadia@drreddys.com / +1 908-203-4931

Media:
S Rajan at rajans@drreddys.com / +91-40- 49002445

WO2005011634A1 * Jul 21, 2004 Feb 10, 2005 William John Curatolo Dosage forms providing controlled release of cholesteryl ester transfer protein inhibitors and immediate release of hmg-coa reductase inhibitors
WO2006073973A2 * Dec 28, 2005 Jul 13, 2006 Reddy Us Therapeutics Inc Novel benzylamine derivatives as cetp inhibitors
WO2006129167A1 * May 22, 2006 Dec 7, 2006 Pfizer Prod Inc PHARMACEUTICAL COMPOSITIONS OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS AND HMG-CoA REDUCTASE INHIBITORS
WO2007128568A1 * May 8, 2007 Nov 15, 2007 Novartis Ag Bicyclic derivatives as cetp inhibitors
EP0298666A2 * Jul 1, 1988 Jan 11, 1989 American Home Products Corporation Spray dried ibuprofen compositions
EP1741424A2 * Jul 27, 1998 Jan 10, 2007 Pfizer Products Inc. Solid pharmaceutical dispersions with enhanced bioavailabilty
US5456923 Dec 23, 1993 Oct 10, 1995 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
US5474989 Mar 1, 1994 Dec 12, 1995 Kurita Water Industries, Ltd. Drug composition
US5985326 May 30, 1996 Nov 16, 1999 Icos Corporation Method of producing a solid dispersion of a poorly water soluble drug
US6350786 Sep 7, 1999 Feb 26, 2002 Hoffmann-La Roche Inc. Stable complexes of poorly soluble compounds in ionic polymers
US6548555 Jan 31, 2000 Apr 15, 2003 Pfizer Inc Basic drug compositions with enhanced bioavailability
US6638522 Dec 10, 1999 Oct 28, 2003 Pharmasolutions, Inc. Microemulsion concentrate composition of cyclosporin
US6730679 Mar 20, 1997 May 4, 2004 Smithkline Beecham Corporation Pharmaceutical formulations
US7008640 Jul 16, 2001 Mar 7, 2006 Yamanouchi Pharmaceutical Co., Ltd. Pharmaceutical composition for oral use with improved absorption
US7034013 Mar 19, 2002 Apr 25, 2006 Cydex, Inc. Formulations containing propofol and a sulfoalkyl ether cyclodextrin
US7037528 Jun 5, 2001 May 2, 2006 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US7078057 Dec 19, 2000 Jul 18, 2006 Kerkhof Nicholas J Process for producing nanometer particles by fluid bed spray-drying
US7081255 Aug 14, 2002 Jul 25, 2006 Janssen Pharmaceutica, N.V. Antifungal compositions with improved bioavailability
US8030359 Feb 9, 2007 Oct 4, 2011 Merck Sharp & Dohme Corp. Polymer formulations of CETP inhibitors
US20060178514 Dec 28, 2005 Aug 10, 2006 Anima Baruah Novel benzylamine derivatives as CETP inhibitors
Reference
1 * EINFAL T ET AL: “Methods of amorphization and investigation of the amorphous state“, ACTA PHARMACEUTICA 20130901 CROATIAN PHARMACEUTICAL SOCIETY DEU, vol. 63, no. 3, 1 September 2013 (2013-09-01), pages 305-334, XP002721717, ISSN: 1330-0075
2 * KAI TOSHIYA ET AL: “Oral absorption improvement of poorly soluble drug using solid dispersion technique“, CHEMICAL AND PHARMACEUTICAL BULLETIN (TOKYO), vol. 44, no. 3, 1996, pages 568-571, XP002721716, ISSN: 0009-2363
3 * KIM TAE-WAN ET AL: “Characterization of dual layered pellets for sustained release of poorly water-soluble drug“, CHEMICAL & PHARMACEUTICAL BULLETIN (TOKYO), vol. 55, no. 7, July 2007 (2007-07), pages 975-979, XP002721715, ISSN: 0009-2363
4 * KIM TAE-WAN ET AL: “Modified release of coated sugar spheres using drug-containing polymeric dispersions.“, ARCHIVES OF PHARMACAL RESEARCH JAN 2007, vol. 30, no. 1, January 2007 (2007-01), pages 124-130, XP002721714, ISSN: 0253-6269
Citing Patent Filing date Publication date Applicant Title
WO2014128564A2 * Feb 21, 2014 Aug 28, 2014 Dr. Reddy’s Laboratories Ltd. Pharmaceutical compositions of cetp inhibitors
Patent Submitted Granted
Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors [US2007015758] 2007-01-18
Novel benzylamine derivatives as CETP inhibitors [US2006178514] 2006-08-10
Publication Number Publication Date IPCR Assignee/Applicant Structure hits Tools
1.

EP-2919765-A2

2015-09-23
PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS
EN
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
2.

US-20150216866-A1

2015-08-06
SUBSTITUTED BENZYLAMINO QUINOLINES AS CHOLESTEROL ESTER-TRANSFER PROTEIN INHIBITORS
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
3.

US-9040558-B2

2015-05-26
Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
4.

WO-2014128564-A2

2014-08-28
PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS
EN
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
5.

WO-2014076568-A2

2014-05-22
PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS
EN
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
6.

US-20140134235-A1

2014-05-15
NOVEL BENZYLAMINE DERIVATIVES AND THEIR UTILITY AS CHOLESTEROL ESTER-TRANSFER PROTEIN INHIBITORS
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1
7.

US-20070015758-A1

2007-01-18
Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors
CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1

 

 

SEE

http://circ.ahajournals.org/cgi/content/meeting_abstract/122/21_MeetingAbstracts/A13981

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CC1=CC=CC2=CC(=C(N=C12)N(CC3CC3)CC4CC4)CN(CC5=CC(=CC(=C5)C(F)(F)F)C(F)(F)F)C6=NN(N=N6)C

Dr. Reddy’s avoids pitfalls of Ranbaxy, Wockhardt by cutting workers out of production Read more: Dr. Reddy’s avoids pitfalls of Ranbaxy, Wockhardt by cutting workers out of production


FDA pressure pushes Indian drugmakers to move away from relying predominantly on low-wage workers

The execs at Dr. Reddy’s Laboratories have taken notice as some of its competitors in India have run afoul of the FDA over loose manufacturing standards. The actions have meant banned plants and plummeting revenues for Ranbaxy Laboratories and Wockhardt. To avoid that fate, Dr. Reddy’s and some other Indian drugmakers have decided it is worth investing hundreds of millions of dollars for new plants and equipment in a country that has traditionally relied on cheap human labor.

Anji Reddy founded Dr Reddy’s in 1984 with Rs.25 lakh in initial capital. Photo: Mint

Dr. Reddy’s launches Zenatane (Isotretinoin Capsules USP) in US


Isotretinoin

1 APRIL, 2013

India-based Dr. Reddy’s Laboratories has announced the launch of Zenatane (Isotretinoin Capsules USP) in 20mg and 40mg strengths in the US.

The launch follows the FDA approval of the company’s ANDA for Zenatane 10mg, 20mg and 40mg.

Zenatane (Isotretinoin Capsules USP) is a generic version, therapeutically equivalent to Accutane (Isotretinoin Capsules USP).

Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne.

The company is making the product available in 10mg, 20mg, and 40mg strengths in boxes of 30 as unit dose blisters.

Isotretinoin, first marketed as Accutane byHoffmann-La Roche, is a medication used mostly for cystic acne. It is also achemotherapy treatment used in brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.

 File:Isotretinoína3D.png

Isotretinoin’s best-known and most dangerous side effect is birth defects due to in utero exposure. This is because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. In the United States a special procedure is required to obtain the pharmaceutical (see below).

In 2009, Roche decided to pull Accutane off the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Among others, actor James Marshall sued Roche over Accutane-related disease that resulted in removal of his colon.

The most common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Isotroin(Cipla) or Sotret (Ranbaxy).

FOUNDER

LATE DR ANJI REDDY

Generic – Dr. Reddy’s Announces the Launch of Zoledronic Acid Injection equivalent of Navartis AG Zometa®


Zoledronic acid

Mar 5, 2013 –

Dr. Reddy’s Laboratories  announced today that it has launched Zoledronic Acid Injection (4 mg/5 mL), a bioequivalent generic version of Zometa® (zoledronic acid) 4 mg/5 mL Injection in the US market on March 4, 2013, following the approval by the United States Food & Drug Administration (USFDA) of Dr. Reddy’s ANDA for Zoledronic Acid Injection (4 mg/5 mL).

Dr. Reddy’s Zoledronic Acid Injection 4 mg/5mL is available in a single use vial of concentrate.

Zoledronic acid (INN) or zoledronate (marketed by Novartis under the trade names Zometa, Zomera, Aclasta and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.

Reclast is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the U.S. Food and Drug Administration (FDA) also approved Reclast for the treatment of postmenopausal osteoporosis.

About Dr. Reddy’s Laboratories Ltd.

Dr. Reddy’s Laboratories Ltd. (NYSE: RDY) is an integrated global pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses – Pharmaceutical Services and Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars, differentiated formulations and NCEs. Therapeutic focus is on gastro-intestinal, cardiovascular, diabetology, oncology, pain management, anti-infective and pediatrics. Major markets include India, USA, Russia and CIS, Germany, UK, Venezuela, S. Africa, Romania, and New Zealand. For more information, log on to: http://www.drreddys.com

Zometa® is a registered trademark of Novartis AG

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