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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, 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...... , 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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Alexion obtains FDA breakthrough therapy status for cPMP to treat MoCD type A disorder

cyclic pyranopterin monophosphate (cPMP, ALXN1101)

Alexion Pharma International Sàrl has received a breakthrough therapy designation from the US Food and Drug Administration (FDA) for its cyclic pyranopterin monophosphate (cPMP, ALXN1101), an enzyme co-factor replacement therapy to treat patients with molybdenum cofactor deficiency (MoCD) type A.

Alexion obtains FDA breakthrough therapy status for cPMP to treat MoCD type A disorder

read all at

Cyclic pyranopterin monophosphate (cPMP) is an experimental treatment formolybdenum cofactor deficiency type A, which was developed by José Santamaría-Araujo and Schwarz at the German universities TU Braunschweig and the University of Cologne.[1][2]

cPMP is a precursor to molybdenum cofactor, which is required for the enyzme activity ofsulfite oxidasexanthine dehydrogenase/oxidase and aldehyde oxidase.[3]

  1. Günter Schwarz, José Angel Santamaria-Araujo, Stefan Wolf, Heon-Jin Lee, Ibrahim M. Adham, Hermann-Josef Gröne, Herbert Schwegler, Jörn Oliver Sass, Tanja Otte, Petra Hänzelmann, Ralf R. Mendel, Wolfgang Engel and Jochen Reiss (2004). “Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coliHuman Molecular Genetics 13 (12): 1249–1255. doi:10.1093/hmg/ddh136.PMID 15115759.
  2. Doctors risk untried drug to stop baby’s brain dissolving, TimesOnline, November 5, 2009
  3. José Angel Santamaria-Araujo, Berthold Fischer, Tanja Otte, Manfred Nimtz, Ralf R. Mendel, Victor Wray and Günter Schwarz (2004). “The Tetrahydropyranopterin Structure of the Sulfur-free and Metal-free Molybdenum Cofactor Precursor”The Journal of Biological Chemistry 279 (16): 15994–15999.doi:10.1074/jbc.M311815200PMID 14761975.

Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclicpyranopterin monophosphate; cPMP), MPT, and adenylated MPT. Mutations in the Moco biosynthetase genes result in the loss of production of the molybdenum dependent enzymes sulfite-oxidase, xanthine oxidoreductase, and aldehyde oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity. Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, unbeatable seizures, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.

It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis {see U.S. Patent No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the availability of the therapeutic active agent.

WO 2012112922 A1

In this synthesis, the deprotection may involve, for example, either sequential or one-pot deprotection of certain amino and hydroxyl protecting groups on a compound of formula (VII) to furnish the compound of formula (I). Suitable reagents and conditions for the deprotection of a compound of formula (VII) can be readily determined by those of ordinary skill in the art. For example, compound (I) may be formed upon treatment of a compound of formula (VII) under conditions so that hydroxyl protecting groups, such as acetate, isopropylidine, and benzylidine protecting groups, are removed from the formula (VII) structure. The acetate group can be cleaved, for example, under Zemplen conditions using catalytic NaOMe as a base in methanol. The benzylidene and isopropylidene groups can be cleaved by hydrogenation or using acidic hydrolysis as reported by R.M. Harm et ah, J. Am. Chem. Soc, 72, 561 (1950). In yet another example, the deprotection can be performed so that amino protecting groups, such as 9- fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) protecting groups are cleaved from the compound of formula (VII). 9-fluorenylmethyl carbamate (Fmoc) can be removed under mild conditions with an amine base (e.g. , piperidine) to afford the free amine and dibenzofulvene, as described by E. Atherton et al, “The

Fluorenylmethoxycarbonyl Amino Protecting Group,” in The Peptides, S. Udenfriend and J. Meienhofer, Academic Press, New York, 1987, p. 1. t-butyl carbamate (Boc) can be removed, as reported by G.L. Stahl et al., J. Org. Chem., 43, 2285 (1978), under acidic conditions (e.g., 3 M HC1 in EtOAc). Hydrogenation can be used to cleave the carboxybenzyl carbamate (cbz) protecting group as described by J. Meienhofer et al., Tetrahedron Lett., 29, 2983 (1988).

To prevent oxidation of formula (I) during the reaction, the deprotection may be performed under anaerobic conditions. The deprotection may also be performed at ambient temperature or at temperatures of from about 20 – 60 °C (e.g. , 25, 30, 35, 40, 45, 50, or 55 °C).

The compound of formula (I) may be isolated in the form of a pharmaceutically acceptable salt. For example, the compound of formula (I) may be crystallized in the presence of HC1 to form the HC1 salt form of the compound. In some embodiments, the compound of formula (I) may be crystallized as the HBr salt form of the compound. The compound of formula (I) may also be isolated, e.g., by precipitation as a sodium salt by treating with NaOH. The compound of formula (I) is labile under certain reaction and storage conditions. In some embodiments, the final solution comprising the compound of formula (I) may be acidified by methods known in the art. For example, the compound of formula (I), if stored in solution, can be stored in an acidic solution.

In some embodiments, the compound of formula (I) may be prepared, for example, by: reacting a compound of formula (II- A):


Figure imgf000073_0001

with a compound of formula (III- A):

Figure imgf000074_0001

in the presence of a hydrazine to produce a compound of formula (IV- A):


Figure imgf000074_0002

selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-A):


Figure imgf000074_0003


Rj is a protecting group, as defined above;

phosphorylating the compound of formula (V-A) to prepare a compound of formula (VI- A):


Figure imgf000074_0004

oxidizing the compound of formula (VI-A) to prepare a compound of formula (VII- A):

Figure imgf000075_0001

; and deprotecting the compound of formula (VII-A) to prepare the compound of formula (I). For example, a compound of formula (I) can be prepared as shown in Scheme 3.

Scheme 3.


Figure imgf000075_0002

5 R = Fraoc


Figure imgf000075_0003

In another embodiment, the compound of formula (I) is prepared by:

reacting a compound of formula (II- A):

Figure imgf000076_0001

with a compound of formula (III- A):


Figure imgf000076_0002

in the presence of a hydrazine to produce a compound of formula (IV-A):


Figure imgf000076_0003

selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-B):


Figure imgf000076_0004


each Ri is independently a protecting group, as defined above;

phosphorylating the compound of formula (V-B) to prepare a compound of formula (VI-B):

Figure imgf000077_0001

oxidizing the compound of formula (VI-B) to prepare a compound of formula (VII-B):


Figure imgf000077_0002

; and deprotecting the compound of formula (VII-B) to prepare the compound of formula (I), example, a compound of formula (I) can be prepared as shown in Scheme 4.

Scheme 4.


Figure imgf000078_0001

Alternatively, a compound of formula (I) can be formed as shown in Scheme 5. A diaminopyrimidinone compound of formula (II) can be coupled with a phosphorylated hexose sugar of formula (VIII), to give a compound of formula (IX). The piperizine ring nitrogen atoms can be protected to give a compound of formula (X) which can be oxidized to give a diol of formula (XI). The diol of formula (XI) can then be deprotected using appropriate conditions and converted to the compound of formula (I).

Scheme 5


Figure imgf000079_0001

In this embodiment, the phosphate may be introduced at the beginning of the synthesis to avoid undesirable equilibrium between the pyrano and furano isomers during subsequent steps of the synthesis. For example, a compound of formula (I) can be prepared as shown in Scheme 6.

Scheme 6.


Figure imgf000079_0002

A compound of formula (I) can also be formed as shown in Scheme 7. A diaminopyrimidinone compound of formula (II) can be coupled to a compound of formula (III) to afford the piperizine derivative of formula (IV). The piperizine ring nitrogen atoms of the compound of formula (IV) can be protected under standard conditions to give a derivative of formula (V). The formula (V) structure can be oxidized to afford compounds of formula (XII). Phosphorylation of a compound of formula (XII) gives a compound of formula (VII). Global deprotection of the compound of formula (VII) can afford the compound of formula (I).

Scheme 7

Piperizine ring protection



Figure imgf000080_0001


For example, a compound of formula (I) can be prepared as shown in Scheme 8.

Scheme 8.


Figure imgf000081_0001


Founder of leading Indian pharmaceutical company, Sun Pharmaceuticals has been named India’s third richest man


This is the first time Mr Dilip Shanghvi, founder of Sun Pharmaceutical has been named in the top three with a 66 percent surge in his wealth –

25 oct 2013

Singapore: For the first time, founder of leading Indian drugmaker Sun Pharmaceuticals, Mr Dilip Shanghvi has been named in the top three of India’s richest men. Mr Shanghvi has made an appearance in the list prepared by China based ‘Hurun India Rich List’ as the third richest Indian man with a 66 percent surge in his wealth. Energy tycoon and Reliance Industries chairman Mr Mukesh Ambani has topped the list as India’s richest man with personal assets of $18.9 billion, news reports mentioned. The report pointed out that Mr Ambani has retained the top position for the second year even after a wealth decrease of two percent. London-based steel baron Mr Lakshmi Narayan Mittal has been named the second richest, with assets of $15.9 billion. – See more at:

Read more at:

Potential of US pipeline continues to be under appreciated

SUNP’s US pipeline is shaping up well, with an interesting mix of complex products, branded generics and me-too products. Motilal Oswal believe that SUNP’s strong pipeline in the US is well placed to deliver revenue CAGR of 25% to USD1.8b. While a meaningful contribution to this growth is being led by Doxil and recently acquired URL Pharma, we estimate that SUNP’s own pipeline is set to witness revenue CAGR of 40% to USD6 20m. They build flat sales growth for Taro as they expect incremental competition to impact the market share for key Taro products. If competition is delayed, their estimates may have room for positive surprise.

Even after a 50-plus per cent return in one year, Sun Pharma’s stock continues to hold promise. While domestic revenues are growing well, US sales growth has been phenomenal, driven by a strong product pipeline and the acquisitions of Taro, DUSA, URL generics and Caraco.

  1. [PDF]

    NCE & NDDS Development Pipeline – Sun Pharma

    NCE & NDDS Development Pipeline / 2. Disclaimer. Except for the historical information contained herein, statements in this presentation and the subsequent 

  2. [PDF]

    Pipeline of Potential Ocular Therapies to Help Millions  – Sun Pharma…Press%20Release%20SunPh

    Oct 1, 2013 – 1. For Immediate Release. Sun Pharma and Intrexon Form Joint Venture to Develop. New Class of Therapeutics for Ocular Diseases. Pipeline 


    Sun Pharma Advanced Research (SPARC, US$345
    mn market cap), a proprietary product research
    company, detailed its NDDS and NCE product pipelines
    in its latest filing with the SEBI, pursuant to its proposed
    rights issue. Overall, there has been modest
    clinical/regulatory progression in the NDDS pipeline
    since the last disclosure six-seven months back. See
    Exhibits 1 and 4 inside.
    Key highlights: Big picture – New Drug Delivery
    System (NDDS) – Overall SPARC is developing a
    diverse collection of seven technology platforms for oral,
    injectable and topical delivery systems (including nano
    particulate, bio-degradable depot, DPI, SMM, GFR).
    SPARC has 19 NDDS products under development.
    New Chemical Entity (NCE) – The company has a
    pipeline of five compounds that are pro-drugs of existing
    molecules (such as baclofen, gabapentin etc). The NCE
    pipeline appears to be in its early stages, with market
    launch a few years away.
    Update on key products (NDDS) – Three lead drugs:
    1) levetiracetam XR 1000/1500 mg (505(b)(2) filing with
    USFDA is now targeted for F1Q13), 2) baclofen GRS
    (Special Protocol Assessment, SPA, agreement has
    been received from FDA and patient enrollment for
    Phase 3 studies is targeted in F4Q12) and 3) BAK-free
    latanoprost (Phase III patient enrollment over in US).
    These timelines imply that the first product launch in the
    US is likely in 2H13. SPARC continues to validate its
    underlying technology platforms by launching drugs in
    the domestic market (six proprietary launches, seven
    generic launches so far).
    Other milestones for CY12: IND filing with USFDA for
    two drugs – Octreotide Depot Inj (1 month) and Dry
    Powder Inhaler (Salmeterol and Fluticasone
    combination); paclitaxel (with carboplatin) Phase I
    results in US and clinical progress of second WRAP
    based drug, cardiovascular agent (and its combination)









    SUN L731

    SUN K706





    MAY 2013
    mn market cap), a proprietary product research
    company, detailed its NDDS and NCE product pipelines
    in its latest filing with the SEBI, pursuant to its proposed
    rights issue. Overall, there has been modest
    clinical/regulatory progression in the NDDS pipeline
    since the last disclosure six-seven months back. See
    Exhibits 1 and 4 inside.
    Key highlights: Big picture – New Drug Delivery
    System (NDDS) – Overall SPARC is developing a
    diverse collection of seven technology platforms for oral,
    injectable and topical delivery systems (including nano
    particulate, bio-degradable depot, DPI, SMM, GFR).
    SPARC has 19 NDDS products under development.
    New Chemical Entity (NCE) – The company has a
    pipeline of five compounds that are pro-drugs of existing
    molecules (such as baclofen, gabapentin etc). The NCE
    pipeline appears to be in its early stages, with market
    launch a few years away.
    Update on key products (NDDS) – Three lead drugs:
    1) levetiracetam XR 1000/1500 mg (505(b)(2) filing with
    USFDA is now targeted for F1Q13), 2) baclofen GRS
    (Special Protocol Assessment, SPA, agreement has
    been received from FDA and patient enrollment for
    Phase 3 studies is targeted in F4Q12) and 3) BAK-free
    latanoprost (Phase III patient enrollment over in US).
    These timelines imply that the first product launch in the
    US is likely in 2H13. SPARC continues to validate its
    underlying technology platforms by launching drugs in
    the domestic market (six proprietary launches, seven
    generic launches so far).
    Other milestones for CY12: IND filing with USFDA for
    two drugs – Octreotide Depot Inj (1 month) and Dry
    Powder Inhaler (Salmeterol and Fluticasone
    combination); paclitaxel (with carboplatin) Phase I
    results in US and clinical progress of second WRAP
    based drug, cardiovascular agent (and its combination)




Candesartan cilexetil Candesartan cilexetil, Candesartan hexetil, H212/91, TCV-116, Kenzen, Blopress 16 mg Plus, Parapres, Ratacand, Blopress, Amias, Atacand


ATACAND (candesartan cilexetil), a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Its empirical formula is C33H34N6O6, and its structural formula is:

ATACAND®(candesartan cilexetil) Structural Formula Illustration

Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. ATACAND is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil and the following inactive ingredients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.

Drug Patent Expiration and Exclusivity

Active Ingredient Form Dosage Drug Type Application Product


There are 6 patent(s) protecting ASTRAZENECA’s ATACAND. The last patent 5534534*PED expires on 2014-01-09.View patent at USPTO

Patent US US Expiration
5534534*PED 2014-1-9
5534534 Pharmaceutical compositions for oral use and method of preparing them

A pharmaceutical composition for oral use comprising an effective amount of a compound of the formula (I) having antagonistic action to angiotensin II ##STR1## (wherein the ring W is an optionally substituted N-containing heterocyclic residue; R.sup.3 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2) and an oily substance having a lower melting point, and a method for preparing a pharmaceutical composition for oral use comprising an effective amount of a compound of the formula (I) and an oily substance having a lower melting point, which comprises admixing the compound of the formula (I) with an oily substance having a lower melting point and then subjecting the mixture to molding.
5196444*PED 2012-12-4(expired)
5196444 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-c arboxylate and compositions and methods of pharmaceutical use thereof

1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof has potent angiotensin II antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
7538133*PED 2011-10-18(expired)
5705517*PED 2011-10-18(expired)


Exclusivity is marketing rights granted by the FDA to the ASTRAZENECA.

Approval History
Date Supplement No. Action Documents
2013-04-26 038 Labeling Revision
2012-04-27 035 Labeling Revision
2012-04-13 032 Labeling Revision
1998-06-04 000 Approval
2011-06-24 033 Labeling Revision
2009-10-22 031 Patient Population Altered
2006-08-17 026 Labeling Revision
2005-05-18 022 New or Modified Indication
2005-02-22 024 New or Modified Indication
2004-12-16 023 Labeling Revision
2000-06-14 008 Labeling Revision
2002-09-13 015 Comparative Efficacy Claim
2003-01-22 017 Labeling Revision
2003-04-23 019 Labeling Revision
2013-02-21 037 Manufacturing Change or Addition
1999-08-11 005 Package Change
2000-12-27 009 Manufacturing Change or Addition
2001-05-24 012 Manufacturing Change or Addition
2001-11-28 016 Labeling Revision
1999-07-28 004 Control Supplement
2001-04-02 011 Manufacturing Change or Addition
2001-10-04 014 Control Supplement
1998-11-16 002 Manufacturing Change or Addition
1999-12-08 006 Package Change
2001-06-07 010 Manufacturing Change or Addition
2001-03-29 013 Package Change
1998-12-07 001 Manufacturing Change or Addition

Candesartan is marketed as the cyclohexyl 1-hydroxyethyl carbonate (cilexetil) ester, known ascandesartan cilexetil. Candesartan cilexetil is metabolised completely by esterases in theintestinal wall during absorption to the active candesartan moieity. The use of a prodrug form increases the bioavailability of candesartan. Despite this, absolute bioavailability is relatively poor at 15% (candesartan cilexetil tablets) to 40% (candesartan cilexetil solution). Its IC50 is 15 µg/kg. U.S. Patent Nos. 5,196,444 and 5,578,733 describe the removal of a trityl protecting group of the N-protected tetrazolyl compounds using methanol in the presence of a mineral acid, such as hydrochloric acid, which requires complex extractions or chromatographic purification to produce pure candesartan cilexetil. U.S. Patent No. 7,345,072 describes the deprotection of tetrazolyl compounds, including candesartan cilexetil, in the presence of an anhydrous mineral acid or aqueous mineral acid at a concentration higher than 20% w/w. The strong acidic conditions produce more decomposition products and thereby reduces the overall purity of the final product. WO 05/021535 discloses the preparation of candesartan cilexetil by the deprotection of trityl moiety at a reflux temperature in the presence of anhydrous Ci to C5 alcohol under neutral or slightly basic conditions involving longer reaction time (for e.g. stirring for several hours, such as 18-24 hours); this is followed by removal of the triphenylmethylether moiety precipitated as a solid, and thereby increases the number of reaction steps. WO 05/037821 describes the deprotection of the trityl candesartan cilexetil by the use of methane sulphonic acid, p-toluene sulphonic acid, formic and trifluoroacetic acid in solvent mixture or by refluxing candesartan cilexetil in mixture of toluene, water, and methanol. The initial product obtained by these procedures is mostly a viscous oil or a semi solid, which is difficult to handle. WO 07/074399 and WO 07/042161 disclose the preparation of candesartancilexetil from trityl candesartan cilexetil involving Lewis acids such as boron trifluoride, zinc chloride, aluminium trihalide, or titanium tetrachloride which are costly and thus are not commercially viable.


Candesartan is synthesised as follows: Candesartan synth.png kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.; Nishikawa, K.; Naka, T. (1993). “Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids”. Journal of Medicinal Chemistry 36 (15): 2182–2195. doi:10.1021/jm00067a016PMID 8340921. Candesartan, a blocking agent against angiotensin II receptor, has been used for years for treating high blood pressure and heart failure. Candesartan cilexetil, a prodrug of candesartan is commercially available from AstraZeneca and Takeda Pharmaceuticals Ltd. European Patent No. 0459136B1 of Takeda Chemical Industries discloses that methods for preparing candesartan cilexetil schematically represented by the following Reaction Scheme 1: Reaction Scheme 1

Figure imgf000002_0001

The method has technical problems as follows: a) the starting material is obtained by a minor reaction, b) its yield is relatively low and its industrial applicability is poor (due to N2 gas formation) because the Curtius rearrangement reaction is involved, and c) materials industrially hard to handle such as SOCI2 or NaH are used. In addition, methods for preparing an intermediate of candesartan cilexetil are disclosed in Organic Process Research & Development 11:490-493(2007), as represented by the following Reaction Scheme 2: Reaction Scheme 2

Figure imgf000003_0001

3:1 s

Figure imgf000003_0002

However, the preparation process has also shortcomings of a) undesired byproducts formed by nitrogenation at ortho- or para-position, b) safety problems from strong acids (sulfuric acid and nitric acid) used twice when introducing and rearranging nitrogen groups, and c) utilization of high-flammable Raney Ni.

cut paste
Novel and Practical Synthesis of Candesartan Cilexetil

Yongjun Mao, Ruisheng Xiong, Zheng Liu, Haihong Li, Jingkang Shen, and Jingshan Shen* *Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, China


A novel and convergent synthetic route of candesartan cilexetil (API of Atacand), an effective angiotensin II receptor blocker, is described. Cleavage of the N-Boc and N-trityl protective group are implemented simultaneously and formation of the benzimidazole ring is conducted at the last step of this route, which gives candesartan cilexetil in 55% yield over six steps with 99.1% purity (HPLC). Full Text HTMLPDF (567KB)PDF with Links (932KB) This compound can be obtained by two related ways: 1) The partial esterification of 3-nitrophthalic acid (I) with ethanol and H2SO4 gives 3-nitrophthalic acid 1-monoethyl ester (II), which is treated with SOCl2 in refluxing benzene to yield the corresponding acyl chloride (III). The reaction of (III) first with sodium azide in DMF and then with refluxing tert-butanol affords 2-(tert-butoxycarbonylamino)-3-nitrobenzoic acid ethyl ester (IV), which is condensed with 4-(2-cyanophenyl)benzyl bromide (V) by means of NaH in THF giving 2-(2′-cyanobiphenyl-4-ylmethylamino)-3-nitrobenzoic acid ethyl ester (VI). The reduction of (VI) with SnCl2.2H2O in ethanol yields the corresponding 3-amino derivative (VII), which is cyclocondensed with ethyl orthocarbonate and acetic acid affording 1-(2′-cyanobiphenyl-4-ylmethyl)-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (VIII). The reaction of (VIII) with trimethyltin azide in refluxing toluene gives the 2′-(1H-tetrazol-5-yl) derivative (IX), which is saponified with NaOH in ethanol to the corresponding free acid (X). Protection of (X) with trityl chloride and triethylamine in dichloromethane gives the protected compound (XI), which is finally esterified with cyclohexyl 1-iodoethyl carbonate (XII) by means of K2CO3 in DMF. 2) Compound (VIII) can also be obtained by reaction of 2-chloro-1-(2′-cyanobiphenyl-4-ylmethyl)benzimidazole-7-carboxylic acid ethyl ester (XIII) with sodium ethoxide in refluxing ethanol.

Benzimidazole derivs., their production and use
Naka, T.; Nishikawa, K.; Kato, T. (Takeda Chemical Industries, Ltd.)
EP 0459136; EP 0720982; JP 1992364171; JP 1996099960; US 5196444; US 5328919; US 5401764; US 5703110; US 5705517; US 5962491; US 6004989

more info Candesartan cilexetil of Formula I, disclosed in U.S. Patent No. 5,196,444 as crystalline form, i.e., Form-I (C-type crystals), is chemically described as 1- cyclohexyloxycarbonyloxyethyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5- yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate.

Figure imgf000002_0001

H Formula I It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure. Candesartan cilexetil is poorly soluble in water, which is attributed to its hydrophobic nature. Solubility plays an important role in achieving the desired concentration of a drug in systemic circulation for accomplishing the pharmacological response. Various techniques are known in literature to increase the solubility of poorly-soluble drugs, including decreasing the particle size, complexation, changing the surface characteristics of the particles, and incorporation of drug particles into colloidal systems like nanoparticles and liposomes. Among these, the most commonly used technique to increase the solubility is particle size reduction. Sometimes the rate of dissolution of a poorly-soluble drug is the rate limiting factor in its rate of absorption by the body. These drugs may be more readily bioavailable if administered in a finely divided state. Particle size reduction increases the surface area causing an increase in the dissolution rate of the compound, and hence, its bioavailability. There are certain techniques reported in literature to reduce the particle size of such poorly-soluble drugs. PCT Publication No. WO 2006/122254 discloses stable candesartan cilexetil of fine particle size, wherein the stable micronized candesartan cilexetil is prepared by slurrying a sample of candesartan cilexetil of fine particle size in a suitable solvent for a suitable amount of time. In this application, candesartan cilexetil of fine particle size is obtained directly from the synthesis of candesartan cilexetil or by comminuting candesartan cilexetil using milling. PCT Publication No. WO 2005/123720 describes fine particles of candesartan cilexetil having improved pharmacokinetic profile and a process for their production, wherein fine particle size is obtained by a) dissolving candesartan cilexetil in an organic solvent; b) cooling the solution obtained in step a) under stirring to crystallize candesartan cilexetil from the solution; and c) isolating candesartan cilexetil having a particle size of with d90 not more than about 25 μ. U.S. Patent Application No. 2006/0165806 describes compositions comprising a candesartan, such as candesartan cilexitil. The candesartan particles of the composition have an effective average particle size of less than about 2000 nm. U.S. Patent Application No. 2008/0038359 describes a nanoparticle pharmaceutical formulation comprising a poorly soluble drug substance having an average particle size of less than about 1000 nm, a solid or semisolid dispersion vehicle, and optionally a non-surface modifying excipient. U.S. Patent No. 7,828,996 discloses the methods for forming nanoparticles of a material of narrow polydispersity with ultrasonic waves using a partially submersed sonicator that does not touch any part of the apparatus and the point of addition of organic solvent is in the wave funnel produced by sonication and within the selected distance from the wave-source depending on the desired particle size. U.S. Patent No. 7,780,989 discloses the preparation of a dispersion of nanocrystalline particles in an aqueous medium using ultrasound. U.S. Patent No. 5,314,506 describes a crystallization process in which a jet of a solution containing a substance is impinged with a second jet containing an anti-solvent for the substance. The rapid mixing produced by the impinging jets results in a reduction of the crystals so formed compared to conventional slow crystallization processes. The smallest crystals disclosed are about 3 μ and the majority are in the range of from about 3 μ to about 20 μ. PCT Publication No. WO 00/44468 describes a modification to the apparatus described in U.S. Patent No. 5,314,506, wherein ultrasound energy is applied at the point of impingement of the two jets to further enhance localized mixing and is stated to give direct formation of small crystals with a diameter of less than 1 μ. Generally, the crystalline particles described have an average size of 0.5 μ. Conventional particle size reduction methods such as high energy milling may result in loss of yield, noise and dusting, as well as unwanted exposure to highly potent pharmaceutical compounds. Also, in the case of crystalline compounds, stress generated on crystal surfaces during milling can adversely affect labile compounds. Therefore, there is a need for a process for particle size reduction of candesartan cilexetil, which is industrially advantageous, easy to handle and is cost effective.

  • Candesartan is a potent, selective AT1 subtype angiotensin II receptor antagonist and used for treatment of hypertension. Due to poor absorption of Candesartan in body, the prodrug candesartan cilexetilwas developed. The candesartan cilexetil is rapidly and completely hydrolyzed to candesartan in gastrointestinal tract.
  • [0004]
    U.S. Pat. No. 5,196,444 discloses Candesartan cilexetil and a process for its preparation by the reaction of 2-ethoxy-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid with trityl chloride in presence of triethyl amine in methylene chloride and purification by column chromatography gives 2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl] benzimidazole -7-carboxylic acid, which upon condensation with cyclohexyl 1-iodoethyl carbonate in presence of potassium carbonate in DMF followed by purification with column chromatography gives a colorless powder which is recrystallized in ethanol yields ‘C’ type crystals of Candesartancilexitil.
  • [0005]
    U.S. Pat. Application No. 2005/131027 discloses a process for preparation of candesartan cilexetil by reaction of trityl candesartanwith cilexetil halide and at least one base in a low boiling solvent in presence of phase transfer catalyst to give Trityl candesartan cilexetil, which upon deprotection with at least one organic acid in at least one organic solvent. U.S. Pat. Application 2005/131027 further discloses the deprotection of Trityl candesartan cilexetil in methanol without an acid.
  • [0006]
    The PCT publication WO 2005/021535 discloses the deprotection of Trityl candesartan cilexetil with neutral or slightly basic medium in alcohol.
  • [0007]
    Chem.Pharm.Bull. 47(2), 182-186 (1999) discloses two novel crystalline forms of Candesartan cilexetil, form-I and form-II.
  • [0008]
    PCT publication WO 04/085426 discloses Candesartan cilexetil 1,4-Dioxane solvate and two more crystalline forms, designated as form-III and form-IV. The disclosed process for preparation of form-III involves crystallization of Candesartan cilexetil in toluene and for form-IV involves crystallization in a mixture of methyl tert-butyl ether and methanol.
  • [0009]
    PCT publication WO 2005/077941 discloses several crystalline forms, solvates of Candesartan cilexetil along with a process for preparation of form-I (type-C).
  • [0010]
    The prior art disclosed methods for preparation of Candesartan cilexetilinvolves purification of Trityl candesartan and Candesartan cilexetil by column chromatography or involves the use of strong acids like IN HCl or the use of organic acids or without an acid in methanol for detrytilation of Trityl candesartan cilexetil.
  • [0011]
    There is a requirement of a process for preparation of Candesartancilexetil which yields a pure Candesartan cilexetil without involving the purification by column chromatography and the usage of strong acids for deprotection.

Candesartan cilexetil of formula (I) shown beiow is chemicaily described as (+/-)-1- [[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1 -[[2′-(1 H-tetrazol-5-yl)-1 , 1 ‘-biphenyl- 4-yl]methyl]-1 H-benzimidazoie-7-carboxylate. An alternative designation is (+-)-1- hydroxyethyf 2~Ethoxy-1 -{p-(o-1 H-tetrazo!-5-yIphenyi)benzyJ)-7-benzϊmidazoie~ carboxyiic acid cyclohexyl carbonate (ester), with candesartan being the underlying carboxylic acid, i.e. 2-Ethoxy-1 -(p-(o-1 H-tetrazol-5-ylphenyl)benzy!)-7-benz- imidazolecarboxylic acid.

Figure imgf000002_0001

Because of its ability to inhibit the angiotensin-converting enzyme it is widely used for the treatment of hypertension and related diseases and conditions. As an angiotensin Ii receptor antagonist, candesartan ciiexetil avoids the side-effects of calcium antagonists, and shows high stability and obvious curative effects. Currently candesartan ciiexetil is soid as racemic mixture, it is produced according to published patents, e.g. EP 0 720 982 B1 and EP 0 459 136. in Chem. Pharm. Bull. 47(2), 182-186 (1999) two crystalline forms (Form I and II), together with an amorphous form, are disclosed and characterized by their DSC thermograms, X-ray diffraction patterns and IR spectra. US 5,196,444 disclosed the C-type crystal (Form I) of candesartan cilexetif, and processes for producing it under acidic conditions. WO 04/085426 discloses the dioxane solvate of candesartan ciiexetil, together with two additional crystalline forms. WO 2005/077941 discloses hydrates and solvates of candesartan ciiexetil, together with processes for their preparation. WO 2006/048237 also describes the preparation of new polymorphic forms ofcandesartan ciiexetil, together with processes for their preparation, including the preparation of amorphous candesartan ciiexetil by precipitating it with a liquid cyclic hydrocarbon from a solution of candesartan ciiexetil in a chlorinated solvent. in WO 2005/123721 processes for the preparation of amorphous candesartanciiexetil are provided, comprised of spray-drying and precipitation. HPLC CUT PASTE , READER TO PICK ONLY REQUIRED INFO Candesartan cilexetil (60 g) is dissolved in isopropanol (900 m!_) at 60-65 0C. Solution is hot filtered into reactor and quickly cooled to 35 0C. At this temperature nucleation is provoked with 300 mg of candesartan cilexetil form I and stirring is enforced. Suspension is cooled to 3O0C in 1 hour and rigorous stirring is continued at this temperature for additional 5 hours. Then stirring power is reduced and the suspension is cooled to 2O0C in 8 hours. The product is filtered, washed with isopropanoi and dried for 2 hours at 38°C. Yield: 48.7 g of candesartan cilexetil form I. Area % HPLC: candesartan cilexetil: 99.73%, alky ester of candesartan cilexetil 0.08%, candesartan cilexetii pyran below 0.05%, tritylcandesartan cϋexetil 0.09% Average particle size: 19 /vm, no agglomerates present (see Figure 2) B) Detection of impurities in candesartan cilexetil Example 6 Detection of candesartan cϊlexetil pyran in candesartan cilexetii by HPLC HPLC (external standard method) was performed using the following specifications : Column: Zorbax Eclipse XDB-C18, 50 mm x 4.6 mm i.d.τ 1.8 μm particles Eluent A: 0.01 M NaH2PO4, pH 2.5 Eluent B: acetonitriie Gradient of Eluent:

Figure imgf000016_0001

Flow rate: about 1.2 ml/min Diluent: acetonitriie : water = 70 : 30 (V/V). Detection: UV, wavelength 225 nm injection volume: 5 μl Column temperature : 500C Autosampler temperature: 7°C Example 7 Detection of cilexetil pyran in 1 -chloroethyl cyclohexylcarbonate by GC GC/FID (area percent method) was performed using the following specifications: Column: capillary (fused-silica) AT-WAX or adequate Length: 30 m ID: 0.32 mm Film thickness: 0.25 μm Carrier gas: helium Carrier gas flow rate: 2.0 ml/mi n Split ratio: 10 : 1 Air flow rate: 400 ml/min Hydrogen flow rate: 40 ml/min Make up gas flow ISb rate: 25 ml/min Column temperature 100°C (0 min) → 10°C/min → 2000C (10 min or prolonged if necessary) Injector temperature: 21 O0C Detector temperature: 250OC Injection volume : 1 μl Diluent: Acetonithle: chromatography grade. Chromatographic system suitability Signal/noise of 1 -chloroethyl cyclohexyl carbonate: not less than 10



Seki M * Mitsubishi Tanabe Pharma Corporation, Osaka, Japan An Efficient C–H Arylation of a 5-Phenyl-1H-tetrazole Derivative: A Practical Synthesis of an Angiotensin II Receptor Blocker. Synthesis 2012; 44: 3231-3237


Candesartan cilexetil (Atacand®) is an angiotensin II receptor antagonist that is prescribed for the treatment of hypertension. It is a prodrug that is hydrolyzed to candesartan in the gut. The synthesis depicted, features an efficient protocol for ruthenium-catalyzed C–H arylation of the tetrazole A. Comment A significant challenge in this small-scale synthesis was the final removal of the benzyl protecting group from the tetrazole unit using transfer hydrogenation. Best results were obtained using a ‘thickshell’ Pd/C catalyst from Evonik

FDA In India: Going Global, Coming Home, Altaf Ahmed Lal, Ph.D. is the Director of FDA’s office in India.


Altaf Ahmed Lal, Ph.D. is the Director of FDA’s office in India.

By: Altaf Ahmed Lal, Ph.D. 

What is it like to be starting my new position as director of FDA’s office in India?

It’s like coming home.

My new tenure at FDA began in June, but as a former health attaché in the U.S. Embassy, I played an enthusiastic role in helping to establish FDA in my native country.  I was born in Kashmir, India, and though I left the country in 1980 to explore new professional opportunities in the United States, I have since been drawn back again and again.


FDA approves second brain imaging drug Vizamyl (flutemetamol F 18 injection)to help evaluate patients for Alzheimer’s disease, dementia

  is the structure on right

Vizamyl (flutemetamol F 18 injection) get structure


Chemical name: 2-{3-[18F]fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol    diagnostic aid
Cas Number 765922-62-1
INN  name flutemetamol
Molecular Formula:

GE Healthcare


For Immediate Release: Oct. 25, 2013

The U.S. Food and Drug Administration today approved Vizamyl (flutemetamol F 18 injection), a radioactive diagnostic drug for use with positron emission tomography (PET) imaging of the brain in adults being evaluated for Alzheimer’s disease (AD) and dementia.

Dementia is associated with diminishing brain functions such as memory, judgment, language and complex motor skills. The dementia caused by AD is associated with the accumulation in the brain of an abnormal protein called beta amyloid and damage or death of brain cells. However, beta amyloid can also be found in the brain of patients with other dementias and in elderly people without neurologic disease.

Vizamyl works by attaching to beta amyloid and producing a PET image of the brain that is used to evaluate the presence of beta amyloid. A negative Vizamyl scan means that there is little or no beta amyloid accumulation in the brain and the cause of the dementia is probably not due to AD. A positive scan means that there is probably a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of AD or other dementia. Vizamyl does not replace other diagnostic tests used in the evaluation of AD and dementia.

About GE Healthcare

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Flutemetamol [ 18 F] Injection is a diagnostic positron emission tomography (PET) agent for the imaging of β-amyloid plaques in the brain. The synthesis of the agent can be performed using automated synthesis platforms with or without using specially-tailored cassettes. For example, the synthesis can be performed using either the TRACERlab FX F-N platform or the FASTlab™ platform, commercially available from GE Healthcare a division of General Electric Company in conjunction with auxiliary preparative high pressure liquid

chromatography equipment. After synthesis, the bulk agent is transferred to high pressure liquid chromatography (HPLC) equipment to separate the physico-chemically similar compounds [ 18 F] flutemetamol from its deprotected precursor, AHl 11832 (6-hydroxy-2-(4′-(N- methyl)amino-3′-nitro)phenylbenzothiazole) and hence obtain purified [ 18 F] flutemetamol.

However there still exists a need in the art for alternative purification methods for the preparation of [ 18 F] flutemetamol. The invention as described below answers such a need. Specifically, Applicants have now found a process that eliminates the use of preparative HPLC equipment. SUMMARY OF THE INVENTION

As [ 18 F]flutemetamol and its deprotected precursor, AH111832 (6-hydroxy-2-(4′-(N- methyl)amino-3′-nitro)phenylbenzothiazole) are physico-chemically very similar, preparative HPLC is required to separate them. However, Applicants have now found that it is possible to replace the preparative HPLC equipment in previous purification processes with low cost, single-use solid phase extraction (SPE) cartridges for purification of [ 18 F]flutemetamol.

Accordingly, the present invention provides a purification process comprising the following steps:

(a) passing a diluted crude product reaction mixture comprising flutemetamol through a first reverse phase SPE cartridge;

(b) washing said first reverse phase SPE cartridge with a water/acetonitrile,

tetrahydrofuran(THF)/water, methanol(MeOH)/water or isopropanol/water mixture; preferably, a water/acetonitrile mixture;

(c) rinsing said first reverse phase SPE cartridge with water once step (b) is completed; (d) eluting said first reverse phase SPE cartridge with acetonitrile or tetrahydrofuran; preferably, acetonitrile;

(e) directly passing the mixture from said eluting step (d) through a normal phase SPE cartridge to give an acetonitrile or tetrahydrofuran solution; preferably, an acetonitrile solution, comprising purified flutemetamol; (f) diluting said acetonitrile or tetrahydrofuran solution; preferably, an acetonitrile solution, comprising purified flutemetamol, with water to form a diluted water/acetonitrile or a diluted water/tetrahydrofuran solution; preferably, a diluted water/acetonitrile solution, comprising purified flutemetamol, wherein said water/acetonitrile solution contains about 40- 70% (v/v) water; preferably at least about 40% (v/v) water; more preferably at least about 50% (v/v) water;

(g) passing the diluted water/acetonitrile or diluted water/tetrahydrofuran solution; preferably, diluted water/acetonitrile solution, comprising purified flutemetamol of step (f) through a second reverse phase SPE cartridge and trapping the flutemetamol on said cartridge second reverse phase SPE cartridge;

(h) rinsing said second reverse phase SPE cartridge with water; and

(i) eluting the trapped purified flutemetamol from second reverse phase SPE cartridge with an injectable organic solvent; preferably, ethanol or DMSO; preferably with ethanol.

According to the invention, the purified flutemetamol can be collected after step (i).

The present invention also provides a purification process of the present invention, wherein the process is automated.


yr 2011 clip

Alzheimer’s disease (AD) is defined histologically by the presence of extracellular β-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using [18F]fluorodeoxyglucose (FDG). These techniques, however, are not specific for AD. Based on the chemistry of histologic staining dyes, several Aβ-specific positron-emitting radiotracers have been developed to image neuropathology of AD. Among these, [11C]PiB is the most studied Aβ-binding PET radiopharmaceutical in the world. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between Aβ-containing amyloid plaques and in vivo [11C]PiB retention measured by PET imaging. Because 11C is not ideal for commercialization, several 18F-labeled tracers have been developed. At this time, [18F]3′-F-PiB (Flutemetamol), 18F-AV-45 (Florbetapir), and 18F-AV-1 (Florbetaben) are undergoing extensive phase II and III clinical trials. This article provides a brief review of the amyloid biology and chemistry of Aβ-specific 11C and 18F-PET radiopharmaceuticals. Clinical trials have clearly documented that PET radiopharmaceuticals capable of assessing Aβ content in vivo in the brains of AD subjects and subjects with mild cognitive impairment will be important as diagnostic agents to detect in vivo amyloid brain pathology. In addition, PET amyloid imaging will also help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of antiamyloid therapeutics currently under development in clinical trials.

Abbot’s device for leaky heart valves gains FDA approval

October 26, 2013 | By Anabela Farrica

The U.S. Food and Drug Administration has approved Abbot’s MitraClip, a device intended for patients with mitral valve regurgitation and for whom open-heart surgery for valve repair is deemed inadequate. Patients who find themselves in a too fragile state to endure such complex surgeries are generally treated with the available medicines and experience high rates of heart failure and rehospitalization.

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Veterinary-Dirlotapide, drug used to treat obesity in dogs


Chemical Formula


Molecular Weight


Therapeutic Category, dog

Antiobesity agent

Chemical Names

N-{(1S)-2-[Benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)biphenyl-2-carboxamido]-1H-indol-2-carboxamide (WHO)

1H-Indole-2-carboxamide, 1-methyl-N-[(1S)-2-[methyl(phenylmethyl)amino]-2-oxo-1-phenylethyl]-5-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]- (USAN)

1-Methyl-5-[(4′-trifluormethylbiphenyl-2-carbonyl)amino]-1H-indol-2-carbonsäure-[(S)-(benzylmethylcarbamoyl)phenylmethyl]amid (IUPAC)

5-[4′-(Trifluoromethylbiphenyl-2-carbonyl)amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide

CAS number 481658-94-0 
ATCvet code QA08AB91

Dirlotapide is a drug used to treat obesity in dogs. It is manufactured by Pfizer and marketed as Slentrol.

It works as a selective microsomal triglyceride transfer protein (MTTP) inhibitor. This blocks the assembly and release of lipoproteins into the bloodstream, thereby reducing fat absorption. It also elicits a satiety signal from lipid-filled cells lining the intestine.

It is supplied as an oral solution. It is not intended for use in humans, cats, or parrots.

On January 5 2007, the U.S. Food and Drug Administration (FDA) approved Slentrol, the first time the FDA has approved a drug for obese dogs.[1]

Dirlotapide is used to manage obesity in dogs and helps by reducing appetite. It should be used as part of an overall weight control program that also includes proper diet and exercise, under the supervision of a veterinarian. Side effects may include vomiting, diarrhea, lethargy, drooling, or uncoordination. Allergic reaction to the medication may include, facial swelling, hives, scratching, sudden onset of diarrhea, vomiting, shock, seizures, pale gums, cold limbs, or coma. Contact your veterinarian if you observe any of these signs. The dose of dirlotapide will need to be recalculated each month, based on your dog’s weight.

Canine patient information sheet

  1.  “FDA approves 1st drug for obese dogs”. Yahoo. Archived from the original on January 8, 2007. Retrieved 2007-01-06.

Generic Names

  • Dirlotapide (OS: USAN)
  • CP-742033 (IS)

Brand Names

  • Slentrol (veterinary use)
    Pfizer, Poland; Pfizer Animal Health, Belgium; Pfizer Animal Health, Switzerland; Pfizer Animal Health, United Kingdom; Pfizer Animal Health, United States; Pfizer GmbH Tiergesundheit, Germany; Pfizer Limited, Austria; Pfizer Santé Animale, France



Emedastine difumarate (Emadine) is a second generation antihistamine used in eye drops to treat allergic conjunctivitis. Its mechanism of action is a H1 receptor antagonist.


Drug Patent Expiration and Exclusivity

Active Ingredient Form Dosage Drug Type Application Product


There are 1 patent(s) protecting ALCON’s EMADINE.
The last patent expires on 2013-12-08.

Patent Expiration
US5441958 Ophthalmic compositions comprising emedastine and methods for their use

Topical ophthalmic compositions comprising 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole and its ophthalmically acceptable acid addition salts have been found to be useful in treating allergic conjunctivitis and related ailments.


Exclusivity is marketing rights granted by the FDA to the ALCON.

EMADINE ® (emedastine difumarate ophthalmic solution) 0.05% is a sterile ophthalmic solution containing emedastine, a relatively selective, H1-receptorantagonist for topical administration to the eyes. Emedastine difumarate is a white, crystalline, water-soluble fine powder with a molecular weight of 534.57. The chemical structure is presented below:

Structural Formula:

EMADINE ® (emedastine difumarate) structural formula illustration

Chemical Name:

lH-Benzimidazole, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl), (E)-2-butenedioate (1:2)

Each mL of EMADINE containsActive: 0.884 mg emedastine difumarate equivalent to 0.5 mg emedastine. Preservative: benzalkonium chloride0.01%. Inactives: tromethamine; sodium chloride; hydroxypropyl methylcellulose; hydrochloric acid/sodium hydroxide (adjust pH); and purified water. It has a pH of approximately 7.4 and an osmolality of approximately 300 mOsm/kg.

 l-(2- ethoxyethyl)-2-(4-methyl-l-homopiperazinyl)-benzimidazole, otherwise known asemedastine, and its ophthalmically acceptable acid addition salts and methods for their use.

Allergic conjunctivitis is frequently characterized by ocular pruritus

(itching), erythema (inflammatory redness), edema and tearing. This condition is one of the most frequently treated by ophthalmologists, optometrists and allergists. To date, treatment has been primarily through the use of topically applied histamine t antagonists in combination with α-agonists. See, for example, the following articles:

1. Miller, J. and E.H. Wolf, “Antazoline phosphate and naphazoline hydrochloride, singly and in combination for the treatment of allergic conjunctivitis – a controlled, double-blind clinical trial.” Ann. Allergy, 35:81-86 (1975). 2. Vandewalker, M.L. et al., “Efficacy of Vasocon-A and its components with conjunctival provocation testing (CPT).” j± Allergy Clin. Immunol., 83:302 (1989). 3. Abelson, M.B. et al., “Effects of topically applied ocular decongestant and antihistamine.” Am. I. Ophthalmol., 90:254- 257 (1980).

Recent studies indicate that the antihistamine levocabastine exhibits clinical activity in patients with allergic conjunctivitis without the addition of a vasoconstrictor. See, Dechant, K.L. and K.L. Goa, “Levocabastine. A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis/’ Drugs, 41:202-224 (1991). In addition, it has recently been demonstrated that Hα antagonists are effective in relieving conjunctival injection (hyperemia) and erythema, as well as pruritus. See, Berdy, G.J. et al., “Allergic conjunctivitis: A survey of new antihistamines.” T. Ocular Pharmacol.. 7:313-324 (1991).

Although there are many different antihistamines available for systemic treatment of allergies and related ailments, many such antihistamines are not suitable for topical ophthalmic use because of limited ocular bioavailability. For example, terfenadine (Seldane®, made by Marion Merrell Dow), astemizole (Hismanal®, made by Janssen Pharmaceutica) and loratadine (Claritin®, made by Schering) all have good systemic activity; however, terfenadine has little or no local ocular activity, and astemizole and loratadine each have greatly reduced local ocular activity (as compared to its systemic activity).

Data on Bristol-Myers Squibb’s Anti IL-6 Antibody, Clazakizumab, Developed by Alder Biopharmaceuticals, to Be Presented at the American College of Rheumatology (ACR) 2013 Annual Meeting

This week, Bristol-Myers Squibb Company announced new data on the investigational anti-IL-6 antibody clazakizumab in adult patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate will be highlighted at the 2013 annual meeting of the American College of Rheumatology (ACR), taking place from October 25-30 in San Diego, Calif.

This asset was developed by Alder Biopharmaceuticals, and partnered with Bristol-Myers Squibb in 2009 in a deal worth $85 million up front and an additional $764 million in potential milestone payments. The therapeutic was developed using Alder’s yeast-based production technology, Mab Xpress, which enables the production of high quantities of antibodies.

Alder’s technology allows this class of therapeutics to enter disease areas that have previously been inaccessible for antibodies, such as migraine and cardiovascular disease.  Alder is advancing an antibody therapeutic developed using this technology, ALD403, which targets the calcitonin gene-related peptide (CGRP) and holds promise for treating…

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With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.

By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),

Skeletal formula of riociguat

which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.

Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.

Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”


Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials

Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million

Drag and drop me


phase 1

Project Indication
CDK-Inhibitor (BAY 1000394) Cancer
Mesothelin-ADC (BAY 94-9343) Cancer
PSMA Bi TE Antibody (BAY 2010112) Cancer
PI3K-Inhibitor (BAY 1082439) Cancer
FGFR2 Antibody (BAY 1179470) Cancer
HIF-PH (BAY 85-3934) Anemia
Partial Adenosine A1 Agonist(BAY 1067197) Heart Failure
Vasopressin Receptor Antagonist(BAY 86-8050) Heart Failure
sGC Stimulator (BAY 1021189) Heart Failure
S-PRAnt (BAY 1002670) Symptomatic uterine fibroids
BAY 1026153 Endometriosis


Project Indication
PI3K-Inhibitor (BAY 80-6946) Cancer
Regorafenib Cancer
Refametinib (MEK-Inhibitor) Cancer
Radium-223-Dichloride Cancer
Sorafenib Additional Indications
MR-Antagonist (BAY 94-8862) Congestive Heart Failure (CHF)
MR-Antagonist (BAY 94-8862) Diabetic Nephopathy
Riociguat (sGC Stimulator) Pulmonary Hypertension
Neutrophil Elastase Inhibitor(BAY 85-8501) Bronchiectasis

phase 3

Project Indication
Sorafenib Breast Cancer
Sorafenib Adjuvant HCC
Sorafenib Adjuvant RCC
Regorafenib HCC 2nd line
Rivaroxaban Major Adverse Cardiac Events
Rivaroxaban CHF and CAD
peg rFVIII(BAY 94-9027) Hemophilia
Aflibercept Myopic choroidal neovascularization (mCNV)
Aflibercept Diabetic Macular Edema (DME)
LCS 16 Contraception
Vaginorm Vulvovaginal atrophy (VVA)
Sodium Deoxycholate Submental fat removal
Cipro DPI Lung infection
Tedizolid Skin and Lung Infections
Amikacin Inhale Gram-negative pneumonia

Information for Download from bayer

Sorafenib tosylate



Bayer Accelerates Clinical Development of Promising New Drug Candidates

Five new molecular entities projected to enter Phase III by 2015 / Addressing unmet medical needs in the areas of oncology, cardiology, and women’s health / Initiation of further studies with recently launched products planned to add new treatment options

Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.

“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”

Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”

Cl 223Ra Cl


The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.

Finerenone (BAY 94-8862)

The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

Molidustat (BAY 85-3934)

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.


Regorafenib, stivarga

Bayer’s Eylea (aflibercept),

Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.

In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.

Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.

In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.

In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.

About Bayer HealthCare 
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at

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