AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

AMG 837

 Phase 3 drug, Uncategorized  Comments Off on AMG 837
Nov 172013
 

str1

AMG 837

865231-46-5 (AMG-837 free acid); 865231-45-4 (AMG-837 sodium salt)

(S)-3-(4-((4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)hex-4-ynoic acid

Description of AMG-837:  AMG-837 is a potent, orally bioavailable GPR40 agonist. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing ofAMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes.  (PLoS One. 2011;6(11):e27270).

 

Current developer: Amgen Inc

Hamilton JY, Sarlah D, Carreira EM * ETH Zürich, Switzerland
Iridium-Catalyzed Enantioselective Allylic Alkynylation.Angew. Chem. Int. Ed. 2013;
52: 7532-7535

A new versatile method for the iridium-catalyzed asymmetric substitution of racemic allylic alcohols is exemplified by the depicted synthesis of AMG 837, a GPR40 receptor agonist that is of interest for the treatment of type 2 diabetes.
The allylic alkynylation (27 examples) typically provides excellent branched-to-linear regioselectivity (rr > 50:1) and high enantioselectivity (≥99%). The scope of the allylic alkynylation was explored using 12 allylic alcohols and 15 potassium alkynyltrifluoroborates.

 

 

 

“Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide”
Yazaki, R.; Kumagai, N.; Shibasaki, M.
Org. Lett. 2011, 13, 952.   highlighted by Synfacts 2011, 6, 586.

 

PAPER

Scheme 18 Optimized preparation of biphenyl 54

 

Scheme 17 Original Suzuki reaction employed for the synthesis of biphenyl 54

Image result for AMG 837

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532014001202186

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TAK 733

 Phase 3 drug, Uncategorized  Comments Off on TAK 733
Nov 172013
 

(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Molecular Weight: 504.23
TAK-733 Formula: C17H15F2IN4O4
CAS Number: 1035555-63-5

Biological Activity of TAK-733:

TAK-733 is an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.

References:

BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors.
Dahlman et al. Cancer Discov. 2012 Jul 13. PMID: 22798288.Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer.
Dong et al. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9. PMID: 21310613.

 

Zhao Y * et al. Takeda California, San Diego, Millenium Pharmaceuticals Inc., Cambridge and IRIX Pharmaceuticals, Greenville, USA
Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor.Org. Process Res. Dev. 2012;
16: 1652-1659

MEK kinases regulate the pathway that mediates proliferative and anti-apoptotic signaling factors that promote tumor growth and metastasis. TAK-733 is an MEK kinase inhibitor that entered phase I clinical trials for the treatment of cancer. A noteworthy feature of this short synthesis (25% yield overall) is the one-pot, three-step synthesis of the fluoropyridone D, in which the fluorine atom is present at the outset.
The reaction of F with the nosylate G gave a mixture of N- and O-alkylation products (8:1) from which the desired N-alkylation product was isolated by crystallization. The mixture of N-methyl pyrrolidine (NMP) and methanol used in the final deprotection step, helped to ensure formation of the desired polymorph. The nine-step discovery synthesis (3% overall yield) is also presented.

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Zalicus starts Phase Ib clinical trial of neuropathic pain drug

 phase 2, Uncategorized  Comments Off on Zalicus starts Phase Ib clinical trial of neuropathic pain drug
Nov 142013
 

Zalicus

Biopharmaceutical firm Zalicus has started a Phase Ib clinical trial of Z944, a novel oral T-type calcium channel blocker, for the treatment of neuropathic pain.

The company expects to release the results from the laser-evoked potentials (LEP) study in the fourth quarter of 2013.

The study is designed to offer both objective and subjective data on a drug’s ability to modulate pain signalling.

http://www.drugdevelopment-technology.com/news/newszalicus-starts-phase-ib-clinical-trial-of-neuropathic-pain-drug

Z944 is a novel, oral, T-type calcium channel modulator that we are developing for pain.

Z944, an oral T-type Calcium Channel Modulator

Z944 is a novel, oral, state-dependent, selective T-type calcium channel modulator that has demonstrated efficacy in multiple preclinical inflammatory pain models and in a Phase 1b experimental model of pain. T-type calcium channels have been recognized as key targets for therapeutic intervention in a broad range of cell functions and have been implicated in pain signaling. Zalicus is planning to advance a modified release formulation of Z944 through further clinical development.

The wide distribution of T-type calcium channels found in brain, heart, endocrine cells and other tissues provides the possibility of developing therapeutics for multiple indications, including treatment of pain. Zalicus has utilized its expertise in this field to successfully discover high affinity, selective and orally available compounds, such as Z944, that show promise for further development.

 

T-type Calcium Channel Modulators

T-type, or transient-type (referring to the length of time activated), calcium channel modulators target low-voltage-activated, calcium channels. These channels have been recognized as critical components in numerous cell functions and have been implicated in the frequency and intensity of pain signals. Zalicus is investigating compounds to modulate T-type calcium channel signaling in the treatment of pain. Our orally-administered T-type calcium channel blockers have shown efficacy in animal models of acute, chronic and visceral pain, as well as other indications.

patent

WO2009146540

http://www.google.com/patents/WO2009146540A1

compd may be

N-[1-(N-tert-Butylcarbamoylmethyl)piperidin-4-ylmethyl]-3-chloro-5-fluorobenzamide

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Improving Drug Delivery Chemotherapy: Light activation improves penetration and efficacy of nanoparticles as carriers

 drugs, GENERIC  Comments Off on Improving Drug Delivery Chemotherapy: Light activation improves penetration and efficacy of nanoparticles as carriers
Nov 132013
 
A schematic showing how chemotherapy-carrying nanoparticles (left) penetrate deeper into tumor sites and decompress blood vessels after the tumors are irradiated with ultraviolet light (right).

Nanoparticles carrying a cancer drug are administered to mice and exposed to UV light, causing them to contract and release the drug into tumors.
Credit: Modified from Proc. Natl. Acad. Sci. US

http://cen.acs.org/articles/91/i45/Improving-Drug-Delivery.html

Nanoparticles are promising cargo ships for targeted drug delivery. But the materials have had limited success treating cancer, because they often can’t penetrate deep into tumors. The nanoparticles are stalled by the extracelluar matrix and compressed blood vessels.

http://cen.acs.org/articles/91/i45/Improving-Drug-Delivery.html

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TAMOXIFEN, can treat and prevent one type of breast cancer, without the side effects of chemotherapy.

 GENERIC, PROCESS, Uncategorized  Comments Off on TAMOXIFEN, can treat and prevent one type of breast cancer, without the side effects of chemotherapy.
Nov 082013
 

TAMOXIFEN

10540-29-1 CAS

READ ABOUT TITLE AT……….http://www.rsc.org/chemistryworld/sites/default/files/CIIE_Tamoxifen.mp3

 

Molecular Formula: C26H29NO•C6H8O7
CAS Number: 54965-24-1
Brands: Nolvadex, TAMOXIFEN CITRATE

 

Chemically, NOLVADEX (tamoxifen citrate) is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:

 

 

NOLVADEX (Tamoxifen Citrate) Structural Formula Illustration

 

Tamoxifen citrate has a molecular weight of 563.62, the pKa’ is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.

 

NDA021807 APPR2005-10-29 DARA BIOSCIENCES,

SOLTAMOX

US PATENT  6,127,425

US 6127425 APPROVED 1998-06-26 EXPIRY 2018-06-26

 

Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, and thus may be characterized as a mixed agonist/antagonist. Tamoxifen is the usual endocrine (anti-estrogen) therapy for hormone receptor-positive breast cancer in pre-menopausal women, and is also a standard in post-menopausal women although aromatase inhibitors are also frequently used in that setting.

Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Because of this competitive antagonism, tamoxifen acts like a key broken off in the lock that prevents any other key from being inserted, preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.

Tamoxifen was discovered by pharmaceutical company Imperial Chemical Industries (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name “tamoxifen.

 

Breast cancer

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women.Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

In 2006, the large STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer uterine cancers and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.

Nolvadex (tamoxifen) 20 mg tablets

In 2005, the ATAC trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received anastrozole (Arimidex) had significantly better results than the tamoxifen group in measures like disease free survival, but no overall mortality benefit. Data from the trial suggest that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to anastrozole.

 

 

Crystallographic structure of 4-hydroxy-tamoxifen (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (cyan ribbon)

Tamoxifen

lTamoxifen was first developed in 1962 as a morning-after birth control pill that was successful in experiments with laboratory rats.
lTamoxifen (brand name Nolvadex) is the best-known hormonal treatment and the most prescribed anti-cancer drug in the world.
lUsed for over 20 years to treat women with advanced breast cancer, tamoxifen also is commonly prescribed to prevent recurrences among women with early breast cancer.
lIs a SERMs.
Anti-estrogens work by binding to estrogen receptors, blocking estrogen from binding to these receptors, stopping cell proliferation
lBreast-cancer prevention occurred in 1998 when the National Cancer Institute (NCI) announced results of a six-year study showing that tamoxifen reduced the incidence of breast cancer by 45 percent among healthy but high-risk women.
l13,388 healthy women considered at high risk for breast cancer were recruited
l85 developed breast cancer compared to 154 of those on the placebo or dummy pill.
lpotentially life-threatening side effects. There were 33 cases of endometrial cancer in the tamoxifen group
lThere were 30 cases of blood clots in major veins (deep-vein thrombosis)
lBecause these problems developed exclusively among postmenopausal women
–60-year-old, an age at which 17 out of every 1,000 women can be expected to develop breast cancer within five years
–ages of 35 and 59 were eligible to participate if their risks matched or exceeded those of a 60-year-old
lAlthough tamoxifen has been useful both in treating breast cancer patients and in decreasing the risk of getting breast cancer.
lSide effects arise from the fact that while tamoxifen acts as an antiestrogen that blocks the effects of estrogen on breast cells, it mimics the actions of estrogen in other tissues such as the uterus. Its estrogen-like effects on the uterus stimulate proliferation of the uterine endometrium and increase the risk of uterine cancer.

Adequate patent protection is required to develop an innovation in a timely manner. In 1962, ICI Pharmaceuticals Division filed a broad patent in the United Kingdom (UK) (Application number GB19620034989 19620913). The application stated, “The alkene derivatives of the invention are useful for the modification of the endocrine status in man and animals and they may be useful for the control of hormone-dependent tumours or for the management of the sexual cycle and aberrations thereof. They also have useful hypocholesterolaemic activity”.

This was published in 1965 as UK Patent GB1013907, which described the innovation that different geometric isomers of substituted triphenylethylenes had either oestrogenic or anti-oestrogenic properties. Indeed, this observation was significant, because when scientists at Merrell subsequently described the biological activity of the separated isomers of their drug clomiphene, they inadvertently reversed the naming. This was subsequently rectified.

Although tamoxifen was approved for the treatment of advanced breast cancer in post-menopausal women in 1977 in the United States (the year before ICI Pharmaceuticals Division received the Queen’s Award for Technological Achievement in the UK), the patent situation was unclear. ICI Pharmaceuticals Division was repeatedly denied patent protection in the US until the 1980s because of the perceived primacy of the earlier Merrell patents and because no advance (that is, a safer, more specific drug) was recognized by the patent office in the United States. In other words, the clinical development advanced steadily for more than a decade in the United States without the assurance of exclusivity. This situation also illustrates how unlikely the usefulness of tamoxifen was considered to be by the medical advisors to the pharmaceutical industry in general. Remarkably, when tamoxifen was hailed as the adjuvant endocrine treatment of choice for breast cancer by the National Cancer Institute in 1984, the patent application, initially denied in 1984, was awarded through the court of appeals in 1985. This was granted with precedence to the patent dating back to 1965! So, at a time when world-wide patent protection was being lost, the patent protecting tamoxifen started a 17 year life in the United States. The unique and unusual legal situation did not go uncontested by generic companies, but AstraZeneca (as the ICI Pharmaceuticals Division is now called) rightly retained patent protection for their pioneering product, most notably, from the Smalkin Decision in Baltimore, 1996. (Zeneca, Ltd. vs. Novopharm, Ltd. Civil Action No S95-163 United States District Court, D. Maryland, Northern Division, March 14, 1996.)

 

Title: Tamoxifen
CAS Registry Number: 10540-29-1
CAS Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
Additional Names: 1-p-b-dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene
Molecular Formula: C26H29NO
Molecular Weight: 371.51
Percent Composition: C 84.06%, H 7.87%, N 3.77%, O 4.31%
Literature References: Nonsteroidal estrogen antagonist.
Prepn: BE 637389 (1964 to ICI). Identification and separation of isomers: G. R. Bedford, D. N. Richardson, Nature 212, 733 (1966); BE 678807; M. J. K. Harper et al., US 4536516 (1966, 1985 both to ICI). Stereospecific synthesis: R. B. Miller, M. I. Al-Hassan, J. Org. Chem. 50, 2121 (1985). Review of chemistry and pharmacology: B. J. A. Furr, V. C. Jordan, Pharmacol. Ther. 25, 127-205 (1984). Reviews of clinical experience in treatment and prevention of breast cancer: I. A. Jaiyesimi et al., J. Clin. Oncol. 13, 513-529 (1995); C. K. Osborne, N. Engl. J. Med. 339, 1609-1618 (1998).
Properties: Crystals from petr ether, mp 96-98°.
Melting point: mp 96-98°
Derivative Type: Citrate
CAS Registry Number: 54965-24-1
Manufacturers’ Codes: ICI-46474
Trademarks: Kessar (Pharmacia); Nolvadex (AstraZeneca); Tamofène (Aventis); Zemide (Alpharma); Zitazonium (Servier)
Molecular Formula: C26H29NO.C6H8O7
Molecular Weight: 563.64
Percent Composition: C 68.19%, H 6.62%, N 2.49%, O 22.71%
Properties: Fine, white, odorless crystalline powder, mp 140-142°. Slightly sol in water; sol in ethanol, methanol, acetone. Hygroscopic at high relative humidities. Sensitive to uv light. LD50 in mice, rats (mg/kg): 200, 600 i.p.; 62.5, 62.5 i.v.; 3000-6000, 1200-2500 orally (Furr, Jordan).
Melting point: mp 140-142°
Toxicity data: LD50 in mice, rats (mg/kg): 200, 600 i.p.; 62.5, 62.5 i.v.; 3000-6000, 1200-2500 orally (Furr, Jordan)
Derivative Type: (E)-Form
CAS Registry Number: 13002-65-8
Properties: mp 72-74° from methanol.
Melting point: mp 72-74° from methanol
Derivative Type: (E)-Form citrate
Manufacturers’ Codes: ICI-47699
Properties: mp 126-128°.
Melting point: mp 126-128°
CAUTION: Tamoxifen is listed as a known human carcinogen: Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-239.
Therap-Cat: Antineoplastic (hormonal).
Keywords: Antineoplastic (Hormonal); Antiestrogens; Selective Estrogen Receptor Modulator (SERM).
Synthesis of the E and Z isomers of the antiestrogen Tamoxifen. 
David W.Robertson and John A. Katzenellenbogen. 
Journal of Organic Chemistry 1982 , 47, Pages 2387-2393. 
An early synthesis of Tamoxifen : Production of non stereo specific products. 


 

 For easy of understanding the complete synthesis has been broken down into a number of steps.Step 1. 
 
Step 1.
 
This step shows use of a simple friedel-craft acylation involving Anisole(A) and Phenylacetic acid (B). The acylating agent in this process was a mixture of PCl5 / SnCl4. The ketone C was formed in a 78% yield.


 

Step 2.

 

 

 

Step 2.
 

Alkylation was promoted by treating the ketone C with Sodium hydride (NaH). This removed the acidic protons (located on the position alpha to the carbonyl group) to produce the enolate ion. This could be isolated as the sodium enolate of the ketone treatment of this with ethyl iodide resulted in the formation of compound (D) in a 94% yield. The Ethyl iodide was chosen as the acylating agent probably as it contains the iodide ion , which is an excellent leaving group. It can therefore facilitate an SN2 substitution reaction with relative easy.
 

 


 

Step 3.

 

 

 

Step 3.
  The phenol was deprotected using Lithium ethanthiolate in DMF ( Dimethyl This facilitated the removal of the methyl group and replaced it with a H to form a hydroxl group. Thus forming compound (E) in a 96% yield.

 

This is a key step as it has left a chink in the armour of the molecule. This can then be used to build up a characteristic part of the Tamoxifen molecule. (eg the (diemthylamino)ethyl group can be added easily from here)
 

 


Step 4.

 

 

 

 

Step 4.
 

Then product E can be alkylated by treatment with 2-(dimethylamino) ethy chloride. The most facile site of alklation is the OH group on the phenyl ring. This can be interpreted roughly by using HSAB theory. e.g Hard and Soft acid/base theory. The carbon adjacent to the chloride ion of the reactant 2-(dimethylamino)ethyl chloride is made slightly harder due to the process of symbiosis. This can rationalise the formation between the hard oxygen atom to the normally soft carbon atom. In this case the carbon atom has become slightly harder due to the presence of the hard chorine atom. Hence the interaction is favourable by HSAB theory. The above reaction gives product F via a SN2 substitution reaction in 70% yield.
 

 


Step 5.

 

 

Step5.
 

F on treatment with PhMgBr forms the tertiary alcohol (G).
 

Formation of the Grignard reagent can be achieved via reaction of PhBr + Mg —–> PhMgBr. The Grignard reagent has effectively formed a carbanion species eg C delta negative (-ve). This is due to the presence of the C-Mg bond. the fact that Magnesium is a more electropositive element thus making the Carbon atom the more electronegative element and hence acquiring a negative charge. As a result of the negative nature of the carbon atom it can now attack the delta positive (+ve) Carbon atom of the carbonyl group.
 

 


step 6.

 

 

 

 

Step 6.
The dehydration of F was initiated by treatment of methanoic hydrogen chloride. this gives the required structure of Tamoxifen. However it gives a racemic mixture of both cis and trans isomers.
 

The ratio of the Cis / Trans isomers was (1.3 / 1). These isomers of Tamoxifen can be separated by Silica gel thin layer chromatography with benzene / triethylamine (9:1) as the developing solvent. Analysis of this technique revealed that the Z (Trans) isomer was more mobile than the E (Cis) isomer.

Synthetic Route 2: A Stereospecific Approach.


 

Stereospecific Synthesis of (Z) – Tamoxifen via carbometalation of Alkynylsilanes.

Studied for historical reasons rather than synthetic brilliance. This synthesis was the first stereo specific synthesis of (Z) Trans Tamoxifen. Comparison between this synthesis and the previous route I believe can illustrate the development of synthetic approaches to large molecules. In particular the quest for stereo specific reactions. So starting from an alkynylsilane (A) and through a series of reactions we can generate only the (Z) – Trans isomer of Tamoxifen.


Again for ease of understanding the complete synthesis has been broken down into a number of steps.

Step1.

 

Step1.

 

 

This step contains the vital stereo specific step. Namely the carbometalation of the alkynylsilane.It is this step which establishes the stereochemistry about the double bond. The phenyl (trimethyl silyl) – acetylene was carbometalated with diethylaluminium chloride – titanocene dichloride reactant to produce an organometallic intermediate. This organometallic intermediate was then cleaved with N bromosucciniamide to produce the alkene (B) in 85% yield.

The stereochemistry was assigned as E (Cis) mechanistic evidence suggests that this is linked to some steric reasons.

(Earlier work dedicated to this reaction see : Miller, R.B. Al-Hassan.M.I J.Org.Chem. 1984, 49, 725)


Step2.

Step 2.

The second step shows the stereo specific replacement of the Br group by a phenyl group. This was achieved by use of Palladium – catalysed coupling of compound (B) with phenyl zinc chloride to form (C) the vinylsilane in a 95% yield.

Step3.

 

Step3.

This step during the synthesis was reported to be tricky and several approaches were attempted before a successful technique was discovered.

 

The objective of this step was to replace the trimethyl Silyl group by a suitable halogen atom (e.g. Bromine or Iodine)

However a facile reaction was reported when (C) was treated with bromine – sodium methoxide at -78�C to produce the vinyl bromide (D) in a yield of 85%

 

Step 4.

 

Step 4.

The vinyl bromide (D) coupled well with a Zinc organometallic species to produce (E) the ethyl triaryl olefin in a yield of 84%.


Step 5.

 

Step 5.

The formation of (F) Tamoxifen was achieved by demethylation with sodium ethylthoilate in refluxing dimethyl formamide. then reaction of the phenoxide ion with 2-( dimethylamino)ethyl chloride via a SN2 substitution.

Purification of the crude product was achieved via it’s hydrochloride salt ( via a reaction with HCl (g)) then F was regenerated by treatment with dilute base this produced the stereospecific (Z)- Trans isomer in an overall yield of 60%.

a synthesis

Palladium-Catalyzed Fluoride-Free Cross-Coupling of Intramolecularly ActivatedAlkenylsilanes and Alkenylgermanes: Synthesis of Tamoxifen as a Synthetic Application (pages 642–650)Kenji Matsumoto and Mitsuru ShindoArticle first published online: 23 FEB 2012 | DOI: 10.1002/adsc.201100627

Thumbnail image of graphical abstract

 

 

http://pubs.rsc.org/en/content/articlelanding/2011/cs/c0cs00129e#!divAbstract

 

 

 

 

EP 0883587 A1  WO1997026234A1)

 

Preparation of Z isomer of Tamoxifen

A solution of bromobenzene (3.92g, 25mmol) in ether (5ml) containing a crystal of iodine was added dropwise to a suspension of magnesium turnings (0.63g, 26mmol) in ether (5ml) at reflux, under nitrogen. After the addition was complete, the reaction mixture was cooled to room temperature and a solution of l- [ 4- ( 2- chloroethoxy)phenyl]-2-phenyl-l-butanone (3.75g, 12.4mmol) in ether (15ml) was added over 1 hour. The resulting mixture was refluxed for 16 hours, then poured into dilute hydrochloric acid (50ml) and extracted with ether (3x40ml) . The combined ether layers were concentrated, the residual oil was dissolved in ethanol (10ml) and refluxed with concentrated hydrochloric acid (5ml) for 4 hours. The organic phase was separated, dried (Na2S04) and evaporated to dryness to give a yellow oil. Η NMR (see Figures 1 to 4 and discussion below) showed this to be a 2:1 mixture of the Z and E isomers. The oil was then dissolved in warm methanol (about 40°C) and allowed to cool to room temperature. The colourless crystals formed proved to be pure Z isomer of 2-chloroethoxy tamoxifen (4.12g, 11.4mmol, 92% yield) . M.p. 107-109°C, m/z 362/364 (chlorine atom present), <SH 0.92 (3H, t, J = 7.33 Hz, CH3) , 2.46 (2H, q, J = 7.33 Hz, CH2CH3) , 3.72 (2H, t, J = 5.86 Hz, 0CH2CH2C1) , 4.09 (2H, t, J = 5.86 Hz, 0CH2CH2C1) , 6.55 (2H, d, J = 8.79 Hz, aromatic protons ortho to 0CH2CH2C1) , 6.79 (2H, d, J = 8.79 Hz, aromatic protons meta to 0CH2CH2C1) , 7.10-7.38 (10H, m, the two remaining C6H5 ,s) (see Figure 5) . The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z isomer of tamoxifen.

Analysis of Η NMR data

Figures 1 to 4 represent a mixture of the E- and Z- forms of compound XI described above.

The expansion of the region ό* 0.80 to 1.05 shows two overlapping triplets corresponding to the CH3 groups in the

Z- and E- derivatives respectively. The critical point is the ratio of the heights of the peaks at 0.92 (for the Z) and 0.94 (for the E) , which is approximately 2:1. The expansion of the 4.00 to 4.35 region reveals similar information where ratios are 10:6.4 and 5.56:3.43.

Similarly expansion of the region 3.6 to 3.9 shows the ratio to be 2.46:1. All of these measurements suggest an approximate 2:1 ratio.

Referring to Figure 5, this shows almost pure Z- isomer. It should be noted that there is 660 mg of this from an original mixture of a 2:1 ratio mixture of 780 mg which would contain only 520 mg of the Z-isomer.

 

 

 

Z isomer of tamoxifen and 4-hydroxytamoxi en include stereoselective syntheses (involving expensive catalysts) as described in J. Chem. Soc, Perkin Trans I 1987, 1101 and J. Org. Chem. 1990, 55, 6184 or chromatographic separation of an E/Z mixture of isomers as described in J. Chem. Res., 1985 (S) 116, (M) 1342, 1986 (S) 58, (M) 771.

(Z)-tamoxifen (1) as a white solid, mp: 95.8-96.3 ºC. 1H-NMR (500 MHz, CDCl3d 0.92 (3H, t, J 7.3 Hz), 2.29 (6H, s), 2.45 (2H, q, J 7.3 Hz), 2.65 (2H, t, J 5.8 Hz), 3.93 (2H, t, J 5.8 Hz), 6.68 (2H, d, J 9.5 Hz), 6.78 (2H, d, J 9.5 Hz), 7.08-7.28 (10H, m).13C-NMR (125 MHz, CDCl3d 13.6 (CH3), 29.0 (CH2), 45.8 (CH3), 58.2 (CH2), 65.5 (CH2), 113.4 (C), 126.0 (C), 126.5 (CH), 127.8 (CH), 128.1 (C), 129.7 (C), 131.8 (CH), 135.6 (CH), 138.2 (CH), 141.3 (CH), 142.4 (CH), 143.8 (C), 156.7 (C). IR (KBr film) nmax/cm-1: 3055, 2979, 2925, 2813, 2769, 1606, 1509, 1240, 1035, 707. GCMS (EI) m/z 371(5%), 58(100%).

 

(Z)-tamoxifen (1) and (E)-tamoxifen (2) in 52% yield. 1H-NMR (300 MHz, CDCl3d 0.91 (Z isomer. 3H, t, J 7.3 Hz), 0.94 (E isomer. 3H, t, J 7.3 Hz), 2.28 (Z isomer. 6H, s), 2.34 (E isomer. 6H, s), 2.42-2.52 (Z and Eisomers. 4H, m), 2.63 (Z isomer. 2H, t, J 5.9 Hz), 2.74 (E isomer. 2H, t, J 5.9 Hz), 3.94 (Z isomer. 2H, t, J 5.9 Hz), 4.07 (E isomer. 2H, t, J 5.9 Hz), 6.68 (Z isomer. 2H, d, J 9.7 Hz), 6.76 (E isomer. 2H, d, J 9.3 Hz), 6.86-7.36 (Z and E isomers. 10H, m). IR (KBr film) nmax/cm-1: 3081, 3056, 2974, 2826, 2770, 1611, 1509, 1238, 1044. GCMS (EI) m/z: Z isomer, 371(4%), 72 (24%), 58(100%); E isomer, 371(3%), 72 (24%), 58(100%). (the diastereoisomeric ratio was determined by capillary GC analysis and the configuration of the major diastereoisomer established by comparison of the NMR data of the synthetic mixture with an authentic sample of (Z)-tamoxifen (1).

 

 

nmr

 

 

ir

FTIR

shows the typical spectra’s of pure tamoxifen citrate, PCL, a physical mixture of tamoxifen citrate and PCL and drug-loaded implants. The spectrum of tamoxifen citrate shows characteristic absorption bands at 3027 cm−1 (=C-H stretching), 1507 and 1477 (C=C ring stretching) and 3180 cm -1 (-NH2). PCL displays a characteristic absorption band at strong bands such as the carbonyl stretching mode around 1727 cm−1 (C=O), asymmetric stretching 2949 cm−1 (CH 2 ) symmetric stretching 2865 cm−1 (CH 2 ). No changes in the spectrum of the physical mixture and drug-loaded microspheres were evident by FTIR spectroscopy. The strong bands such as the carbonyl peak were clear at all points.

Figure 2: Transmission FTIR spectra of (a) tamoxifen-loaded implant, (b) physical mixture of drug+PCL, (c) pure PCL, (d) pure tamoxifen citrate

enlarged view

Figure 2: Transmission FTIR spectra of (a) tamoxifen-loaded implant, (b) physical mixture of drug+PCL, (c) pure PCL, (d) pure tamoxifen citrate

FTIR spectra of A) tamoxifen citrate; B) PLGA; C) mixture of drug and excipients; D) freshly prepared nanoparticles in the formulation (BS-3HS).

 

FTIR spectra of A) tamoxifen citrate; B) PLGA; C) mixture of drug and excipients; D) freshly prepared nanoparticles in the formulation (BS-3HS).

Mentions: The pure drug tamoxifen citrate, PLGA-85:15, PVA, a mixture of PLGA and PVA, and a mixture of tamoxifen citrate, PLGA, and PVA; and a freshly prepared formulation were mixed separately with IR grade KBr in the ratio of 1:100 and corresponding pellets were prepared by applying 5.5 metric ton pressure with a hydraulic press. The pellets were scanned in an inert atmosphere over a wave number range of 4000–400 cm−1 in Magna IR 750 series II, FTIR instrument (Nicolet, Madison, WI, USA).

 

dsc

Figure 3: DSC thermograms of pure tamoxifen (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant. The experiment was carried with crimped aluminum pans and a heating rate of 10ºC/min

 

DSC thermograms of pure tamoxifen (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant. The experiment was carried with crimped aluminum pans and a heating rate of 10ºC/min

 

 

xrd

Figure 4: X-ray diffraction studies of pure drug (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant

X-ray diffraction studies of pure drug (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant

 

synthesis

J.Chem. Research,1985(S) 116, (M) 1342 and 1986 (S) 58, (M) 0771.

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Nov 022013
 

 

 

TEVETEN® (eprosartan mesylate) is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, TEVETEN® is chemically described as the monomethanesulfonate of (E)-2-butyl-1 -(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5 -acrylic acid.

Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is:

Teveten (Eprosartan Mesylate) Structural Formula Illustration

EPROSARTAN MESYLATE

tevetenEprosartan mesilate, SK&F-108566-J(?, SK&F-108566, Teveten SB, Navixen, Regulaten, Tevetenz, Teveten

US 5656650 exp Aug 12, 2014

CAS EPROSARTAN

144143-96-4 

133040-01-4 

Chemical Name: Eprosartan mesylate
Synonyms: EPROSARTAN MESYLATE;Eprosartan Methanesulfonate;4-[[2-butyl-5-(2-carboxy-3-thiophen-2-yl-prop-1-enyl)-imidazol-1-yl]methyl]benzoic acid mesylate;4-({2-butyl-5-[(1E)-2-carboxy-2-(thiophen-2-ylMethyl)eth-1-en-1-yl]-1H-iMidazol-1-yl}Methyl)benzoic acid;(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid Methanesulfonate;(αE)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid MonoMethanesulfonate
CBNumber: CB4842192
Molecular Formula: C24H28N2O7S2
Formula Weight: 520.61832

 

Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten byAbbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in India and by Abbott Laboratorieselsewhere. It is sometimes paired with hydrochlorothiazide, marketed in the US as Teveten HCT and elsewhere as TevetenPlus.

The drug acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding ofangiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympatheticnorepinephrine production, further reducing blood pressure.

As with other angiotensin II receptor antagonists, eprosartan is generally better tolerated than enalapril (an ACE inhibitor), especially among the elderly.[1]

Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding of angiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympathetic norepinephrine production, further reducing blood pressure.

  1.  Ruilope L, Jäger B, Prichard B (2001). “Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial”. Blood Press. 10 (4): 223–9. doi:10.1080/08037050152669747PMID 11800061.

PAT            APR                EXP

Canada 2250395 2005-09-06 2017-03-26
Canada 2115170 2004-05-25 2012-08-12
United States 5656650 1994-08-12 2014-08-12
United States 5185351 1993-02-09 2010-02-09
Canada 2115170 2004-05-25 2012-08-12
United States 5656650 1994-08-12 2014-08-12
Canada 2250395 2005-09-06 2017-03-26

J Med Chem1991,34,(4):1514-7

J Med Chem1993,36,(13):1880-92

Synth Commun1993,23,(22):3231-48

AU 9056901, EP 403159, JP 91115278, US 5185351.

Drugs Fut1997,22,(10):1079

 

Eprosartan mesylate was developed successfully by SmithKline Beecham Corporation in 1997, and marketed in Germany in 1998 under the trade-name Teveten and in the United States later in 1999. Eprosartan mesylate, as an angiotensin II receptor blocker, is an antihypertensive drug of the latest generation. Eprosartan mesylate is potent to lower systolic and diastolic pressures in mild, moderate and severe hypertensive patients, and is safe and tolerable. Eprosartan mesylate is rapidly absorbed when administrated orally, with a bioavailability of 13% and a protein binding rate of 98%. The blood peak concentration and AUC (Area Under Curve) can be elevated by about 50% in patients with liver and kidney dysfunction, or fullness after administration, and can be elevated by 2 to 3 folds in elderly patients. Eprosartan mesylate has a structure shown as follows:

 

Figure US20110046391A1-20110224-C00001

 

U.S. Pat. No. 5,185,351 discloses a method for preparing eprosartan mesylate using Eprosartan and methanesulfonic acid in isopropanol (U.S. Pat. No. 5,185,351, Example 41 (ii)). However, it is found when following this method for preparing eprosartan mesylate in industry, an esterification reaction can occur between eprosartan and isopropanol and the following two impurities can be generated:

 

Figure US20110046391A1-20110224-C00002

 

In addition to the above two esterification impurities, the salifying method provided by the above patent is prone to produce isopropyl mesylate. Considering currently known potential risk of gene toxicity of methylsulfonic acid ester on human as well as the stringent requirements of methylsulfonic acid ester from the Europe and the America authorities, it is important to produce eprosartan mesylate in a non-alcohol solvent during the process of producing eprosartan mesylate, since it avoids the formation of methylsulfonic acid ester and the residue thereof in the final product. Since the dosage of eprosartan mesylate is high, it is particularly important to strictly control methylsulfonic acid ester in eprosartan mesylate.

In addition, for the above salifying method, solid eprosartan is suspended in propanol at a low temperature, then methanesulfonic acid is added, about ten seconds later a great deal of eprosartan mesylate precipitate is obtained. Therefore, solid eprosartan may be embedded by the precipitated eprosartan mesylate. Since isopropyl alcohol has a high viscosity at low temperature, a heavy filtering operation burden is needed to obtain solid from isopropanol, and the obtained solid contains quite an amount of isopropanol.

 

 

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

…………………………………………………………………………………………………….

WO 1998035962 A1

 

 

…………………………………………………………………………………………..

 

 

Eprosartan mesylate.png

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Pfizer 2013 and beyond

 companies  Comments Off on Pfizer 2013 and beyond
Oct 252013
 

Pfizer

Pfizer gets a lot of coverage in the financial papers–even if some of it turns out to be misguided.

For example, Pfizer got the media coverage all drug companies desire on May 4 from Seeking Alpha, http://seekingalpha.com/article/560531-pfizer-alzheimers-drugs-will-carry-stock-to-new-highs-in-2013

a stock market blog that provides free stock market analysis. A piece entitled “Pfizer: Alzheimer’s Drugs Will Carry Stock To New Highs In 2013” had a subheading “strong pipeline.”

Turns out that was too optimistic, as Pfizer’s Alzheimer’s drug–along with Johnson and Johnson’s–both failed to produce. But many stock analysts still hold hope that Pfizer has a new ‘cash cow’ coming down the pipeline.

Daily Finance http://www.dailyfinance.com/2012/09/07/a-peek-at-pfizers-pipeline/

notes that Pfizer currently has 87 drugs in its pipeline. While its true that most are in the early stages, 11 are ready to be reviewed by the FDA.

That number puts it ahead of most of its rivals, with Eli Lilly, a close second, having 63 drugs in Phases 1-3, plus one currently being reviewed. Bristol-Myers Squibb has 46 drugs in development, 7 under review, Merck has 35 drugs in Phase 2 or 3 with two under review, and Johnson and Johnson has 18 drugs that are already in Phase 3 clinical trials or up for FDA approval.

But, of course, as the journal points out, “Quality trumps quantity. . . . One or two blockbusters can be better than several lower-revenue drugs.”

So what does Pfizer have up its sleeve that might begin to fill the very big shoes of Lipitor?

Well, the company has diversified the therapeutic areas under research, with 26% of R&D efforts going toward oncology treatments, 20% to neuroscience and pain, 17% to cardiovascular and metabolic diseases, 14% to inflammation and immunology, 5% to vaccines, and 18% toward ‘other.’

Pfizer has several medicines for diabetes alone coming up, in Phase I and Phase II trials, almost all meant to treat type 2 diabetes.

But, notes Seeking Alpha,http://seekingalpha.com/article/560531-pfizer-alzheimer-s-drugs-will-carry-stock-to-new-highs-in-2013

its blockbuster potential in this area is limited by the existing treatments of Merck and Sanofi. 10% of Sanofi’s total sales come from Lantus,

Lantus

a diabetes drug useful for both types 1 and 2, and Merck made $1.3 billion off its Januvia

januvia

franchise in the first quarter of this year alone.

So hopes are pinned on Pfizer’s tofacitinib, currently under FDA review, as the treatment with the potential to earn $1 billion or more in sales, easing the gaping wound left by Lipitor. Tofacitinib prompts such high hopes because it might possibly treat rheumatoid arthritis, psoriasis, and irritable bowel syndrome. Some analysts have pinned this as the cash cow Pfizer so badly needs to replace treatments lost to the patent cliff.

Tofacitinib

http://seekingalpha.com/article/812981-pfizers-success-with-its-jak-inhibitor

If it gets approved, Tofacitinib would be first treatment for rheumatoid arthritis (RA) in a new class of medicines (known as Jenus kinase, or JAK, inhibitors), and the first JAK inhibitor approved for rheumatoid arthritis.

Tofacitinib showed statistically significant improvement compared to placebo in decreasing the symptoms of RA (as measured by 20% improvement in the American College of Rheumatology scale), in improving physical function (as measured by mean change in Health Assessment Questionnaire-Disability Index), and in leading to remission (as measured by Disease Activity Score 28 ESR).

Joel Kremer, MD, chief of medicine at Albany Medical College in N.Y., after analyzing the data, commented, “Tofacitinib appears to reduce the signs and symptoms of rheumatoid arthritis very quickly. We hope that after carefully considering the benefit/risk equation, this compound will provide an additional valuable treatment option for patients who have experienced inadequate response to prior treatments.”

Pfizer also believes its blood thinner Eliquis, which it is developing with Bristol-Myers Squibb (see below) could be a big money-maker.

apixaban, eliquis

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Alzheimer’s Image Problem Solved

 Uncategorized  Comments Off on Alzheimer’s Image Problem Solved
Oct 252013
 

Copper-based radiopharmaceuticals for diagnostic imaging can target the amyloid-β plaques implicated in Alzheimer’s disease

Read more

http://www.chemistryviews.org/details/news/5384281/Alzheimers_Image_Problem_Solved.html

Alzheimer’s Image Problem Solved

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ViiV Healthcare files new drug application for three-drug HIV pill with US FDA

 NDA  Comments Off on ViiV Healthcare files new drug application for three-drug HIV pill with US FDA
Oct 242013
 

ViiV Healthcare, a joint venture involving GlaxoSmithKline (GSK), Pfizer and Shionogi, has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for its investigational single-tablet regimen (STR) combining dolutegravir, abacavir and lamivudine for treatment of HIV-1 patients.

click hereViiV Healthcare files new drug application for three-drug HIV pill with US FDA

 

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Ranbaxy obtains approval to market malaria drug in India

 INDIA  Comments Off on Ranbaxy obtains approval to market malaria drug in India
Oct 232013
 

Ranbaxy Laboratories has secured approval from India’s Central Drugs Standard Control Organisation (CDSCO) to produce and market its Synriam drug in the country to treat malaria caused by the Plasmodium vivax parasite in adults.

Ranbaxy obtains approval to market malaria drug in India  CLICK HERE

http://www.pharmaceutical-technology.com/news/newsranbaxy-obtains-approval-market-malaria-drug-india?WT.mc_id=DN_News

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