Lupin launches insulin glargine in India:

Indian pharma company, Lupin Limited announced a strategic distribution agreement with LG Life Sciences of South Korea to launch Insulin Glargine, a novel insulin analogue under the brand name Basugine™.

According to the agreement, Lupin would be responsible for marketing and sales of Basugine™ in India.

READ MORE

http://www.biosimilarnews.com/lupin-launches-insulin-glargine-in-india?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

Antimicrobials are medicines that kill or inactivate microbes, small disease-causing organisms. They include antibiotics, which are used against bacteria. After being exposed to an antimicrobial repeatedly, microbes can undergo changes that stop them being killed or inactivated by the treatments. This is known as antimicrobial resistance.

The European Medicines Agency is concerned about the development of antimicrobial resistance, particularly resistance to antibiotics. A well-known example of a bacterium that is resistant to a number of antibiotics is meticillin-resistant Staphylococcus aureus(MRSA), which has caused infections that are difficult to treat across the European Union (EU).

This problem is being made worse by the fact that few new antimicrobials have been authorised over the past few years. This may lead to infections becoming more difficult to treat in the future.

Antimicrobial resistance is a growing problem in humans and in animals. Resistance can also spread from animals to humans through the food chain or direct contact.

The role of the Agency

The Agency works in collaboration with its EU and international partners in a number of initiatives aiming to limit the development of resistance. It is also monitoring and evaluating the risks to human and animal health.

A major such initiative is the Transatlantic Task Force on Antimicrobial Resistance(TATFAR), which was established following the EU-United States summit in November 2009. The Task Force aims to increase levels of communication, coordination and co-operation between the EU and the United States on human and veterinary antimicrobials.

Human health

In human medicine, the availability of medicines to treat infections with resistant organisms has become a major problem in recent years.

In September 2009, the Agency published a joint report together with the European Centre for Disease Prevention and Control (ECDC) and the international network ReAct – Action on Antibiotic Resistance. This report highlights the gap between infections due to resistant bacteria and the development of new antibiotics.

The report states that at least 25,000 patients in the EU die each year from infections due to bacteria that are resistant to many medicines, and that infections due to these bacteria in the EU result in extra healthcare costs and productivity losses of at least €1.5 billion each year. Although it identified 15 antibiotics under development, most of these were early in development and were targeted against bacteria for which treatment options were already available.

• The bacterial challenge: time to react

Authorisation of new antibiotics

The Agency plays a key role in the authorisation of new antibiotics, because medicines with a significant therapeutic innovation or that are in the interest of public or animal health are authorised centrally in the EU, on the recommendation of the Agency.

In January 2012, the Agency updated its guidance to companies developing antibiotics, covering how they should carry out studies to test these medicines’ benefits and risks:

• Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections

This is accompanied by an addendum giving information on how to study medicines for specific indications. The final addendum was published in November 2013 following a public consultation:

• Addendum on the note for guidance on the evaluation of medicinal products indicated for treatment of bacterial infections

Animal health

The Agency is focused on promoting the prudent use of antimicrobials in animals, to limit the development of resistance. This goal is addressed in this document:

• Committee for Medicinal Products for Veterinary Use (CVMP) strategy on antimicrobials 2011-2015

In line with this strategy, the Agency published a revised version of its guideline onefficacy for public consultation in May 2013. This draft guideline provides detailed recommendations for the design and conduct of pre-clinical and clinical studies to support clinical efficacy for antimicrobial veterinary products:

• Draft guideline for the demonstration of efficacy for veterinary medicinal products containing antimicrobial substances

Since early 2010, the Agency has been leading a project collecting information on the sale of veterinary antimicrobials across the EU:

• European Surveillance of Veterinary Antimicrobial Consumption

The CVMP has also published a large number of documents on microbial resistance in animals and its risks for humans.

• Regulatory information on antimicrobial resistance
• Scientific guidance on antimicrobial resistance

Reports published by the Agency together with other European bodies, including ECDC, EFSA and the European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) have emphasised the need for the prudent use of antibiotics in animals and the role of basic hygiene, and called for strengthened surveillance of resistance, the development of new antimicrobials and new strategies to combat the spread of resistance:

• Joint scientific report of ECDC, EFSA and the European Medicines Agency on MRSA in livestock, companion animals and food
• Joint opinion on antimicrobial resistance focused on zoonotic infections

In 2013 and 2014, the Agency carried out a large body of work to provide advice to the European Commission on the use of antibiotics in animals and the impact on public health and animal health.

August 20, 2014: Glenmark Pharmaceuticals S.A. (GPSA), a wholly owned subsidiary of Glenmark Pharmaceuticals Limited India (GPL), announces the discovery and initiation of IND enabling studies of a novel clinical development candidate, GBR 1302, a HER2xCD3 bispecific antibody. GBR 1302 was discovered and developed by the Glenmark Biologics Research Centre located in La Chaux-de-Fonds, Switzerland. GBR 1302 is based on Glenmark’s innovative BEAT antibody technology platform which facilitates the efficient development and manufacture of antibodies with dual specificities, so-called bispecific antibodies. GBR 1302 is the first clinical development candidate based on the BEAT technology. Glenmark expects to obtain approval for the initiation of clinical studies during this financial year.

·GBR 1302 is the first bispecific antibody based on Glenmark’s proprietary BEAT platform

• GBR 1302 is Glenmark’s first clinical candidate targeting oncology indications

  Glenmark Pharmaceuticals announced the discovery and initiation of IND enabling studies of a novel clinical development candidate, GBR 1302, a HER2xCD3 bispecific antibody. GBR 1302 was discovered and developed by the Glenmark Biologics Research Centre located in La Chaux-de-Fonds, Switzerland. GBR 1302 is based on Glenmark’s innovative BEAT antibody technology platform which facilitates the efficiend development and manufacture of antibodies with dual specificities, so-called bispecific antibodies. GBR 1302 is the first clinical development candidate based on the BEAT technology.Glenmark expect to obtain approval for the initiation of clinical studies during this financial year.

  read at

http://www.sharekhan.com/stock-market/news/Glenmark-enters-Oncology-with-the-Discov/879A76C4-601D-40F7-B402-BCD9BACED8E3/MustKnowNews/161/News.htm

- See more at: http://worlddrugtracker.blogspot.in/#sthash.tJzVgHVT.dpuf

read synthesis at
http://newdrugapprovals.org/2013/12/14/the-us-food-and-drug-administration-fda-has-granted-a-six-month-priority-review-designation-to-genzymes-new-drug-application-nda-for-cerdelga-eliglustat/ – See more at: http://worlddrugtracker.blogspot.in/#sthash.tJzVgHVT.dpuf

Migalastat hydrochloride

CAS Number: 75172-81-5 hydrochloride

CAS BASE….108147-54-2

ABS ROT = (+)

IN Van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-

Molecular Structure:

Formula: C6H14ClNO4

Molecular Weight:199.63

Synonyms:  3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, (2R,3S,4R,5S)- (9CI);

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, [2R-(2a,3a,4a,5b)]-;

Migalastat hydrochloride;Galactostatin hydrochloride;

(2S,3R,4S,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride;

• 1-Deoxygalactonojirimycin
• 1-Deoxygalactostatin
• Amigal
• DDIG
• Migalastat
• UNII-C4XNY919FW

Melting Point:160 °C-162…….http://www.google.com/patents/DE3906463A1?cl=de

Boiling Point:382.7 °C at 760 mmHg

Flash Point:185.2 °C

Amicus Therapeutics, Inc. innovator

Aug 2014

http://www.xconomy.com/new-york/2014/08/20/with-persistence-and-phase-3-win-amicus-nears-first-drug-approval/?utm_source=rss&utm_medium=rss&utm_campaign=with-persistence-and-phase-3-win-amicus-nears-first-drug-approval

Amicus Therapeutics was on the ropes in late 2012 when its pill for a rare condition called Fabry Disease108147-54-2 failed a late-stage trial. It had already put seven years of work into the drug, and the setback added even more development time and uncertainty to the mix. But the Cranbury, NJ-based company kept plugging away, and now it looks like all the effort could lead to its first approved drug.

Amicus (NASDAQ: FOLD) is reporting today that the Fabry drug, migalastat, succeeded in the second of two late-stage trials. It hit two main goals that essentially measured its ability to slow the decline of Fabry patients’ kidney function comparably to enzyme-replacement therapy (ERT)—the standard of care for the often-fatal disorder.

Amicus believes the results, along with those from an earlier Phase 3 trial comparing migalastat to a placebo, are good enough to ask regulators in the U.S. and Europe for market approval.

“These are the good days to be a CEO,” says Amicus CEO John Crowley (pictured above). “It’s great when a plan comes together and data cooperates.”

Crowley says Amicus will seek approval of migalastat first in Europe and is already in talks with regulators there. In the next few months, Amicus will begin talking with the FDA about a path for approval in the U.S. as well.

End feb 2013

About Amicus Therapeutics

Amicus Therapeutics  is a biopharmaceutical company at the forefront of therapies for rare and orphan diseases. The Company is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases. Amicus’ late-stage programs for lysosomal storage disorders include migalastat HCl monotherapy in Phase 3 for Fabry disease; migalastat HCl co-administered with enzyme replacement therapy (ERT) in Phase 2 for Fabry disease; and AT2220 co-administered with ERT in Phase 2 for Pompe disease.

About Migalastat HCl

Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world.

As a monotherapy, migalastat HCl is designed to bind to and stabilize, or “chaperone” a patient’s own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.

For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development.

About Fabry Disease

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called “substrates” of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

1. Bichet, et al., A Phase 2a Study to Investigate the Effect of a Single Dose of Migalastat HCl, a Pharmacological Chaperone, on Agalsidase Activity in Subjects with Fabry Disease, LDN WORLD 2012

2. Benjamin, et al., Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726.

http://clinicaltrials.gov/show/NCT01458119

http://www.docstoc.com/docs/129812511/migalastat-hcl

Migalastat hydrochloride is a pharmacological chaperone in phase III development at Amicus Pharmaceuticals for the oral treatment of Fabry’s disease. Fabry’s disease occurs as the result of an inherited genetic mutation that results in the production of a misfolded alpha galactosidase A (alpha-GAL) enzyme, which is responsible for breaking down globotriaosylceramide (GL-3) in the lysosome. Migalastat acts by selectively binding to the misfolded alpha-GAL, increasing its stability and promoting proper folding, processing and trafficking of the enzyme from the endoplasmic reticulum to the lysosome.

In February 2004, migalastat hydrochloride was granted orphan drug designation by the FDA for the treatment of Fabry’s disease.

The EMEA assigned orphan drug designation for the compound in 2006 for the treatment of the same indication. In 2007, the compound was licensed to Shire Pharmaceuticals by Amicus Therapeutics worldwide, with the exception of the U.S., for the treatment of Fabry’s disease.

In 2009, this license agreement was terminated. In 2010, the compound was licensed by Amicus Therapeutics to GlaxoSmithKline on a worldwide basis to develop, manufacture and commercialize migalastat hydrochloride as a treatment for Fabry’s disease, but the license agreement terminated in 2013.

………………………..

http://www.google.co.in/patents/WO1999062517A1?cl=en

Example 1

A series of plant alkaloids (Scheme 1, ref. 9) were used for both in vitro inhibition and intracellular enhancement studies of α-Gal A activity. The results of inhibition experiments are shown in Fig. 1 A.

f^

Among the tested compounds, 1-deoxy-galactonojirimycin (DGJ, 5) known as a powerful competitive inhibitor for α-Gal A, showed the highest inhibitory activity with IC₅₀ at 4.7 nM. α-3,4-Di-epi-homonojirimycin (3) was an effective inhibitor with IC₅₀ at 2.9 μM. Other compounds showed moderate inhibitory activity with IC₅₀ ranging from 0.25 mM (6) to 2.6 mM (2). Surprisingly, these compounds also effectively enhanced α-Gal A activity in COS-1 cells transfected with a mutant α-Gal A gene (R301Q), identified from an atypical variant form of Fabry disease with a residual α- Gal A activity at 4% of normal. By culturing the transfected COS-1 cells with these compounds at concentrations cat 3 – 10-fold of IC₅₀ of the inhibitors, α-Gal A activity was enhanced 1.5 – 4-fold (Fig. 1C). The effectiveness of intracellular enhancement paralleled with in vitro inhibitory activity while the compounds were added to the culture medium at lOμM

concentration (Fig. IB).

………………………

WO 2008045015

or  http://www.google.com/patents/EP2027137A1?cl=en, http://www.google.com/patents/US7973157?cl=en

This invention relates to a process for purification of imino or amino sugars, such as D-1-deoxygalactonojirimycin hydrochloride (DGJ’HCl). This process can be used to produce multi-kilogram amounts of these nitrogen-containing sugars.

Sugars are useful in pharmacology since, in multiple biological processes, they have been found to play a major role in the selective inhibition of various enzymatic functions. One important type of sugars is the glycosidase inhibitors, which are useful in treatment of metabolic disorders. Galactosidases catalyze the hydrolysis of glycosidic linkages and are important in the metabolism of complex carbohydrates. Galactosidase inhibitors, such as D-I- deoxygalactonojirimycin (DGJ), can be used in the treatment of many diseases and conditions, including diabetes (e.g., U.S. Pat. 4,634,765), cancer (e.g., U.S. Pat. 5,250,545), herpes (e.g. , U.S. Pat. 4,957,926), HIV and Fabry Disease (Fan et al, Nat. Med. 1999 5:1, 112-5).

Commonly, sugars are purified through chromatographic separation. This can be done quickly and efficiently for laboratory scale synthesis, however, column chromatography and similar separation techniques become less useful as larger amounts of sugar are purified. The size of the column, amount of solvents and stationary phase (e.g. silica gel) required and time needed for separation each increase with the amount of product purified, making purification from multi-kilogram scale synthesis unrealistic using column chromatography.

Another common purification technique for sugars uses an ion- exchange resin. This technique can be tedious, requiring a tedious pre-treatment of the ion exchange resin. The available ion exchange resins are also not necessarily able to separate the sugars from salts (e.g., NaCl). Acidic resins tend to remove both metal ions found in the crude product and amino- or imino-sugars from the solution and are therefore not useful. Finding a resin that can selectively remove the metal cations and leave amino- or imino-sugars in solution is not trivial. In addition, after purification of a sugar using an ion exchange resin, an additional step of concentrating the diluted aqueous solution is required. This step can cause decomposition of the sugar, which produces contaminants, and reduces the yield.

U.S. Pats. 6,740,780, 6,683,185, 6,653,482, 6,653,480, 6,649,766, 6,605,724, 6,590,121, and 6,462,197 describe a process for the preparation of imino- sugars. These compounds are generally prepared from hydroxyl-protected oxime intermediates by formation of a lactam that is reduced to the hexitol. However, this process has disadvantages for the production on a multi-kg scale with regard to safety, upscaling, handling, and synthesis complexity. For example, several of the disclosed syntheses use flash chromatography for purification or ion-exchange resin treatment, a procedure that is not practicable on larger scale. One particularly useful imino sugar is DGJ. There are several DGJ preparations disclosed in publications, most of which are not suitable for an industrial laboratory on a preparative scale (e.g., >100 g). One such synthesis include a synthesis from D-galactose (Santoyo-Gonzalez, et al, Synlett 1999 593-595; Synthesis 1998 1787-1792), in which the use of chromatography is taught for the purification of the DGJ as well as for the purification of DGJ intermediates. The use of ion exchange resins for the purification of DGJ is also disclosed, but there is no indication of which, if any, resin would be a viable for the purification of DGJ on a preparative scale. The largest scale of DGJ prepared published is 13 g (see Fred-Robert Heiker, Alfred Matthias Schueller, Carbohydrate Research, 1986, 119-129). In this publication, DGJ was isolated by stirring with ion-exchange resin Lewatit MP 400 (OH^“) and crystallized with ethanol. However, this process cannot be readily scaled to multi- kilogram quantities.

Similarly, other industrial and pharmaceutically useful sugars are commonly purified using chromatography and ion exchange resins that cannot easily be scaled up to the purification of multi-kilogram quantities.

Therefore, there is a need for a process for purifying nitrogen- containing sugars, preferably hexose amino- or imino-sugars that is simple and cost effective for large-scale synthesis

FIG. 1. HPLC of purified DGJ after crystallization. The DGJ is over 99.5% pure.

FIG. 2A. ¹H NMR of DGJ (post HCl extraction and crystallization), from 0 – 15 ppm in DMSO.

FIG. 2B. ¹H NMR of DGJ (post HCl extraction and crystallization), from 0 – 5 ppm, in DMSO.

FIG. 3 A. ¹H NMR of purified DGJ (after recrystallization), from 0 – 15 ppm, in D₂O. Note OH moiety has exchanged with OD.

FIG. 3B. ¹H NMR of purified DGJ (after recrystallization), from 0 -

4 ppm, in D₂O. Note OH moiety has exchanged with OD.

FIG. 4. ¹³C NMR of purified DGJ, (after recrystallization), 45 – 76 ppm.

One amino-sugar of particular interest for purification by the method of the current invention is DGJ. DGJ, or D-l-deoxygalactonojirimycin, also described as (2R,3S,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine and 1- deoxy-galactostatin, is a noj irimycin (5-amino-5-deoxy-D-galactopyranose) derivative of the form:

……………………….

Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine

Tetrahedron Lett 1995, 36(5): 653

• Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine

  Original Research Article

• Pages 653-654
• Carl R. Johnson, Adam Golebiowski, Hari Sundram, Michael W. Miller, Renee L. Dwaihy

• Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and indolizidine 4.

Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and the structurally related indolizidine 4.

………………………

Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-galactitol) starting from 1-deoxynojirimycin

Carbohydr Res 1990, 203(2): 314

• Synthesis of d-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-d-galactitol) starting from 1-deoxynojirimycin

• Pages 314-318
• Fred-Robert Heiker, Alfred Matthias Schueller
• • First page PDF

………………………………..

Synthesis of (+)-1,5-dideoxy-1,5-imino-D-galactitol, a potent alpha-D-galactosidase inhibitor

Carbohydr Res 1987, 167: 305

• Synthesis of (+)-1,5-dideoxy-1,5-imino-d-galactitol, a potent α-d-galactosidase inhibitor

• Pages 305-311
• Ronald C. Bernotas, Michael A. Pezzone, Bruce Ganem
• • First page PDF

……………………………..

SEE

Monosaccharides containing nitrogen in the ring, XXXVII. Synthesis of 1,5-didexy-1,5-imino-D-galactitol

Chem Ber 1980, 113(8): 2601

…………………………

http://pubs.acs.org/doi/abs/10.1021/ol101556k

IN

van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction−transimination−sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.

http://pubs.acs.org/doi/suppl/10.1021/ol101556k/suppl_file/ol101556k_si_002.pdf

COMPD 18

D-galacto-1-deoxynojirimicin.HCl (18).

D-N-Boc-6-OBn-galacto-1-deoxynojirimicin (159 mg, 0.450 mmol) was dissolved in a mixture of MeOH

(10 mL) and 6 M HCl (2 mL). The flask was purged with argon, Pd/C-10% (20 mg) was added and a balloon

with hydrogen gas was placed on top of the reaction. The mixture was stirred overnight at room temperature.

Pd/C was removed by filtration and the filtrate evaporated to yield the crude product (90 mg, 100%) as a

white foam that needed no further purification.

[α]24D = + 53.0 (c = 1, H2O);

[lit4a [α]24D = +44.6 (c = 0.9, H2O); lit4b [α]20D = +46.1 (c = 0.9, H2O)].

HRMS calculated for [C6H13NO4 + H]+164.09173; Found 164.09160.

1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 2.7, 1.1 Hz, 1H), 4.11 (ddd, J = 11.4, 9.7, 5.4 Hz, 1H), 3.88 (ddd,

J = 20.9, 12.2, 6.8 Hz, 2H), 3.68 (dd, J = 9.7, 3.0 Hz, 1H), 3.55 (dd, J = 12.5, 5.4 Hz, 1H), 3.46 (ddd, J = 8.6,

4.8, 1.0 Hz, 1H), 2.97 – 2.86 (t, J = 12.0 Hz, 1H). [lit4c supporting information contains 1

H NMR-spectrumof an authentic sample].

13C NMR (101 MHz, D2O) δ 73.01, 66.97, 64.69, 60.16, 59.15, 46.15

4a) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Núñez, F.; Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240

– 2255.

4b) Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601 – 2608. c)

McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565 – 3568.

……………………………………….

(- ) FORM………… BE CAREFUL

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin

Org Lett 2010, 12(6): 1145

 http://pubs.acs.org/doi/abs/10.1021/ol100037c

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to α-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.

…………………………………………………..

Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block

Org Lett 2003, 5(14): 2527

 http://pubs.acs.org/doi/abs/10.1021/ol034886y

A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 1−3 was carried out via the use of 4in a highly stereocontrolled mode.

mp 135-135.5 °C [lit.3mp 137-139 °C];

[α]D25 +27.8° (c 0.67, H2O)

[lit.3[α]D23 +28° (c 0.5, H2O)];

1H NMR (300 MHz, D2O) δ 2.59–2.65 (m, 1H), 2.81–2.87 (m, 1H),

3.02–3.08 (m, 1H), 3.46–3.48 (m, 2H), 3.59–3.66 (m, 3H); 13C NMR (75 MHz, D2O) δ 44.7, 57.1,

58.4, 70.9, 71.4, 73.3 [lit4 13C NMR (125 MHz, D2O) δ 44.5, 56.8, 58.3, 70.1, 70.7, 72.3];

HRMScalcd for C6H13NO4 (M+) 163.0855, Found 163.0843. Anal. calcd for C6H13NO4: C, 44.16; N,

8.58; H, 8.03. Found: C, 44.31; N, 8.55; H, 7.71.

3. Schaller, C.; Vogel, P.; Jager, V. Carbohydrate Res. 1998, 314, 25-35.

4. Lee, B. W.; Jeong, Ill-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305-1309.

…………………………………………..

Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: Five- versus six-membered ring formation

J Org Chem 2013, 78(19): 9791

http://pubs.acs.org/doi/abs/10.1021/jo401512h

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

……………………………………………

Ruiz, Maria; Journal of Organic Chemistry 2008, 73(6), 2240-2255 

http://pubs.acs.org/doi/abs/10.1021/jo702601z

ROT  +44.6 °  Conc: 0.9 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the γ-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, hightrans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-l-altronojirimycin, 1-deoxy-d-gulonojirimycin, 1-deoxy-d-galactonojirimycin, 1-deoxy-l-idonojirimycin and 1-deoxy-d-talonojirimycin.

…………………..

http://pubs.acs.org/doi/abs/10.1021/jo00002a057

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Hinsken, Werner; DE 3906463 A1 1990

http://www.google.com/patents/DE3906463A1?cl=de

Example 1 Preparation of 1,5-dideoxy-1,5-imino-D-glucitol hydrobromide

A suspension of 1,5-dideoxy-1,5-imino-D-glucitol (500 g) in isopropanol (2 l) with 48% hydrochloric acid, bromine (620 g). The suspension is stirred for 2 hours at 40 ° C, cooled to 0 ° C and the product isolated by filtration.

Yield: 700 g (93% of theory),
mp: 184 ° C.

Example 2 Preparation of 1,5-dideoxy-1,5-imino-D-mannitol hydrobromide

The prepared analogously to Example 1 from 1,5-dideoxy 1,5-imino-D-mannitol and 48% hydrobromic acid.

Yield: 89% of theory;

C₆H₁₄NO₄Br (244.1)
Ber .: C 29.5%; H 5.8%; N 5.7%; Br 32.7%;
vascular .: C 29.8%; H 5.8%; N 5.8%; Br 32.3%.

Example 3 Preparation of 1,5-dideoxy-1,5-imino-D-Galactitol- hydrochloride

The preparation was carried out analogously to Example 1 from 1,5-dideoxy-1,5-imino-D-galactitol and corresponding mole ratios of 37% hydrochloric acid.
yield: 91% of theory
, mp: 160-162 ° C.

1-Deoxygalactonojirimycin:

(a) Liguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron2000, 56, 5819−5833.

(b) Mehta, G.; Mohal, N. Tetrahedron Lett. 2000, 41, 5741−5745.

(c) Asano, K.; Hakogi, T.; Iwama, S.; Katsumura, S. Chem. Commun. 1999, 41−42.

(d) Johnson, C. R.; Golebiowsky, A.; Sundram, H.; Miller, M. W.; Dwaihy, R. L. TetraherdonLett. 1995, 36, 653−654.

(e) Uriel, C.; Santoyo-Gonzalez, F. Synlett 1999, 593−595.

(f) Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J. M. Tetrahedron Lett. 1999, 40, 2021−2024.

(g) Shilvock, J. P.; Fleet, G. W. J. Synlett 1998, 554−556.

(h) Chida, N.; Tanikawa, T.; Tobe, T.; Ogawa, S. J. Chem. Soc., Chem. Commun. 1994, 1247−1248.

(i) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 815−819.

(j) Kajimoto, T.; Chen, L.; Liu, K. K. C.; Wong, C. H. J. Am. Chem. Soc. 1991, 113, 6678−6680.

(k) Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167, 305−311. 1-Deoxyidonojirimycin:

(l) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387−2391.

(m) Schaller, C.; Vogel, P.; Jager, V. Carbohydr. Res. 1998, 314, 25−35.

(n) Fowler, P. A.; Haines, A. H.; Taylor, R. J. K.; Chrystal, E. J. T.; Gravestock, M. B. Carbohydr. Res. 1993,246 377−381.

(o) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C. H.J. Org. Chem. 1991, 56, 6280−6289. 1-Deoxygulonojirimycin:  ref 5l.

(p) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401−404.

(q) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahedron:  Asymmetry 2002, 13, 795−799. (r) Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron:  Asymmetry 1999, 10, 3649−3657.

Etirinotecan pegol (NKTR-102)

848779-32-8

PEG-irinotecan

Molecular Formula: C₁₆₁H₁₉₂N₂₀O₄₀ Molecular Weight: 3047.35718

Nektar Therapeutics innovator

http://www.acsmedchem.org/mediabstractf2013.pdf

CAS: 1193151-09-5

Synonym: NKTR102; NKTR 102; NKTR-102; pegylated irinotecan NKTR 102; Etirinotecan pegol.

IUPAC/Chemical name: (1). Tetrakis{(4S)-9-[([1,4'-bipiperidinyl]-1′-carbonyl)oxy]-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl} N,N’,N”,N”’- {methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(1-oxoethylene)]}tetraglycinate tetrahydrochloride

(2). Poly(oxy-1,2-ethanediyl), α-hydro-ω-[2-[[2-[[(4S)-9-[([1,4'-bipiperidin]-1′-ylcarbonyl)oxy]- 4,11-diethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2- b]quinolin-4-yl]oxy]-2-oxoethyl]amino]-2-oxoethoxy]-, ether with 2,2-bis(hydroxymethyl)- 1,3-propanediol, hydrochloride (4:1:4)

Etirinotecan pegol tetratriflutate [USAN]

RN: 1193151-12-0

Tetrakis((4S)-9-(((1,4′-bipiperidinyl)-1′-carbonyl)oxy)-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano(3′,4′:6,7)indolizino(1,2-b)quinolin-4-yl) N,N’,N”,N”’- (methanetetrayltetrakis(methylenepoly(oxyethylene)oxy(1-oxoethylene)))tetraglycinate tetrakis(trifluoroacetate)

NKTR-102 is currently being developed by Nektar. According to the company’s news release, this agent exhibits a very high response rate and excellent clinical benefit rate in patients with metastatic breast cancer, and importantly, this anti-tumor activity is maintained in each of the poor prognosis subsets within the study. The data from the Phase 2 study also shows highly promising PFS of 5.3 months and OS of 13.1 months in the every three week dose schedule, which was also very well-tolerated. As a novel topoisomerase I inhibitor in breast cancer, NKTR-102 holds great therapeutic potential and allows us to address the challenge of resistance in this setting

NKTR-102 (PEG-irinotecan), a PEGylated form of irinotecan, is in clinical development by Nektar Therapeutics for the treatment of multiple solid tumors, including colorectal cancer, metastatic or locally advanced breast cancer, metastatic or locally advanced ovarian cancer and gastrointestinal cancer. No recent development has been reported for phase I clinical trials for the treatment of gastrointestinal cancer.

In preclinical studies, NKTR-102 resulted in significantly higher reduction in tumor growth than irinotecan in colon, lung and breast tumors. The company believes that following intravenous administration of NKTR-102, irinotecan will be released slowly, resulting in prolonged systemic exposure of irinotecan. Irinotecan is a cytotoxic anticancer agent used extensively to treat colorectal, lung, esophageal and other solid tumors. In 2011, orphan drug designation was assigned to the compound in the U.S. for the treatment of ovarian cancer.

In 2011, orphan drug designation was assigned in the E.U. for the treatment of ovarian cancer. In 2012, fast track designation was assigned by the FDA for the treatment of locally recurrent or metastatic breast cancer progressing after treatment with an anthracycline, a taxane and capecitabine.

Therapeutic Area	Nektar Discovered	Indication	Phase
Oncology
Etirinotecan pegol (NKTR-102)
		Metastatic Breast Cancer	Phase 3
		Platinum-Resistant Ovarian Cancer	Phase 2 Completed
		Second-Line Colorectal Cancer	Phase 2 Completed
		Bevacizumab (Avastin)-refractory high-grade glioma	Phase 2
		Non-Small Cell Lung Cancer (NSCLC)	Phase 2
		Small Cell Lung Cancer (SCLC)	Phase 2
		GI and solid tumors In combination with 5-FU	Phase 1 Completed

http://www.nektar.com/product_pipeline/all_phases.html#BAX855

Market Overview

Etirinotecan pegol is in Phase 3 clinical development for patients with metastatic or locally recurrent breast cancer and Phase 2 clinical development for patients with solid tumor malignancies, including ovarian, colorectal, glioma, small cell and non-small cell lung cancers. Each year, approximately 5.3 million patients worldwide are diagnosed with one of these types of cancer.¹

Etirinotecan Pegol Clinical Data and Product Profile

Etirinotecan pegol (NKTR-102) is the first long-acting topoisomerase I-inhibitor (Topo I) designed to concentrate in tumor tissue, provide sustained tumor suppression throughout the entire chemotherapy cycle, and to reduce the peak exposures that are associated with toxicities of other cytotoxics. Etirinotecan pegol was invented by Nektar using its advanced polymer conjugate technology platform, and is the first oncology product candidate to leverage Nektar’s releasable polymer technology platform.

Topo I-inhibitors are important chemotherapeutic agents used to treat cancer. Immediately after dosing, however, standard topo I-inhibitors reach high peak concentrations and diffuse quickly throughout the body—penetrating and damaging healthy tissue, such as bone marrow, as well as tumor tissue. Subsequent rapid metabolism limits topo I exposure in tumor cells, reducing the duration of their effect and resulting in a much lower tumor exposure to the active metabolite that may limit their efficacy.

Etirinotecan pegol is a novel chemotherapeutic designed to enhance the anti-cancer effects of topo I-inhibition while minimizing its toxicities. Unlike first generation topo I-inhibitors that exhibit a high initial peak concentration and short half-life, etirinotecan pegol’s unique pro-drug design results in a lowered initial peak concentration of active topo I inhibitor in the blood. The large etirinotecan pegol molecule is inactive when administered. Over time, the body’s natural enzymatic processes slowly metabolize the linkers within the molecule, continuously freeing active drug that then works to stop tumor cell division through inhibition of topo I.

Clinical and preclinical studies have shown that the half-life of active drug generated from etirinotecan pegol is greatly extended to 50 days (compared to 48 hours for irinotecan) and that active drug remains in circulation throughout the entire chemotherapy cycle, providing sustained exposure to topo I inhibition. In preclinical models, etirinotecan pegol achieved a 300-fold increase in tumor concentration as compared to a first generation topo I-inhibitor. Because etirinotecan pegol is a large molecule, it is believed to penetrate the leaky vasculature within the tumor environment more readily than normal vasculature, concentrating and trapping etirinotecan pegol in tumor tissue.

Etirinotecan pegol is currently in development for the treatment of breast, ovarian, colorectal, glioma, small cell and non-small cell lung cancers.

Ongoing clinical development for etirinotecan pegol:

• In metastatic breast cancer, a Phase 3 randomized, head to head study (The BEACON Study) of etirinotecan pegol compared to Treatment of Physician’s Choice (TPC) completed enrollment of 864 patients in August 2013. Data from the study on the primary endpoint of overall survival is expected by the end of 2014 or early 2015.
• In ovarian cancer, an expanded Phase 2 study of single-agent etirinotecan pegol in platinum refractory/resistant ovarian cancer in 177 women who failed prior Doxil therapy was completed at the end of 2012.
• In colorectal cancer, a 174-patient Phase 2 randomized, head-to-head study of etirinotecan pegol compared to irinotecan in patients with second-line colorectal cancer with the KRAS gene mutation is in progress.
• Etirinotecan pegol is also being evaluated in glioma, small cell and non-small cell lung cancers.

Highlighted Data Presentations:

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were published in the November 2013 issue of The Lancet Oncology (click here to view manuscript) These data were previously presented at the 2011 ASCO Annual meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in platinum-resistant/refractory ovarian cancer were published in the September 30, 2013 online edition of the Journal of Clinical Oncology (click here to view abstract). These data were previously presented at the 2010 ASCO Meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented in an oral abstract session at the 2011 ASCO Breast Cancer Symposium by Agustin Garcia, MD. View presentation slides.

Data from a Phase 2 clinical study of NKTR-102 in a subpopulation of patients with platinum-resistant/refractory ovarian cancer and prior Doxil® (pegylated liposomal doxorubicin or PLD) treatment were presented at the 2011 ASCO Annual Meeting by Agustin Garcia, MD. (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented at the 2010 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium by Amad Awada, MD. (click here to download this presentation).

2014 events related to this product

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http://www.google.com.ar/patents/US7744861?cl=pt-PT

Example 1 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K

A. Synthesis of t-Boc-Glycine-Irinotecan

 

In a flask, 0.1 g Irinotecan (0.1704 mmoles), 0.059 g t-Boc-Glycine (0.3408 mmoles), and 0.021 g DMAP (0.1704 mmoles) were dissolved in 13 mL of anhydrous dichloromethane (DCM). To the solution was added 0.070 g DCC (0.3408 mmoles) dissolved in 2 mL of anhydrous DCM. The solution was stirred overnight at room temperature. The solid was removed through a coarse frit, and the solution was washed with 10 mL of 0.1N HCL in a separatory funnel. The organic phase was further washed with 10 mL of deionized H₂O in a separatory funnel and then dried with Na₂SO₄. The solvent was removed using rotary evaporation and the product was further dried under vacuum. ¹H NMR (DMSO): δ 0.919 (t, CH₂CH ₃), 1.34 (s, C(CH₃)₃), 3.83 (m, CH₂), 7.66 (d, aromatic H).

B. Deprotection of t-Boc-Glycine-Irinotecan

 

0.1 g t-Boc-Glycine-Irinotecan (0.137 mmoles) was dissolved in 7 mL of anhydrous DCM. To the solution was added 0.53 mL trifluoroacetic acid (6.85 mmoles). The solution was stirred at room temperature for 1 hour. The solvent was removed using rotary evaporation. The crude product was dissolved in 0.1 mL MeOH and then precipitated in 25 mL of ether. The suspension was stirred in an ice bath for 30 minutes. The product was collected by filtration and dried under vacuum. ¹H NMR (DMSO): δ 0.92 (t, CH₂CH ₃), 1.29 (t, CH₂CH ₃), 5.55 (s, 2H), 7.25 (s, aromatic H).

C. Covalent Attachment of a Multi-Armed Activated Polymer to Glycine Irinotecan.

 

0.516 g Glycine-Irinotecan (0.976 mmoles), 3.904 g 4arm-PEG(20K)-CM (0.1952 mmoles), 0.0596 g 4-(dimethylamino)pyridine (DMAP, 0.488 mmoles), and 0.0658 g 2-hydroxybenzyltriazole (HOBT, 0.488 mmoles) were dissolved in 60 mL anhydrous methylene chloride. To the resulting solution was added 0.282 g 1,3-dicyclohexylcarbodiimide (DCC, 1.3664 mmoles). The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a coarse frit and the solvent was removed using rotary evaporation. The syrup was precipitated in 200 mL of cold isopropanol over an ice bath. The solid was filtered and then dried under vacuum. Yield: 4.08 g. ¹H NMR (DMSO): δ 0.909 (t, CH₂CH ₃), 1.28 (m, CH₂CH ₃), 3.5 (br m, PEG), 3.92 (s, CH₂), 5.50 (s, 2H).

Example 2 ANTI-TUMOR ACTIVITY OF PENTAERYTHRITOLYL-4-ARM-(PEG -1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K, “4-ARM-PEG-GLY-IRINO-20K” IN A COLON CANCER MOUSE XENOGRAFT MODEL

Human HT29 colon tumor xenografts were subcutaneously implanted in athymic nude mice. After about two weeks of adequate tumor growth (100 to 250 mg), these animals were divided into different groups of ten mice each. One group was dosed with normal saline (control), a second group was dosed with 60 mg/kg of irinotecan, and the third group was dosed with 60 mg/kg of the 4-arm PEG-GLY-Irino-20K (dose calculated per irinotecan content). Doses were administered intraveneously, with one dose administered every 4 days for a total of 3 administered doses. The mice were observed daily and the tumors were measured with calipers twice a week. FIG.1 shows the effect of irinotecan and PEG-irinotecan treatment on HT29 colon tumors in athymic nude mice.

As can be seen from the results depicted in FIG. 1, mice treated with both irinotecan and 4-arm-PEG-GLY-Irino-20K exhibited a delay in tumor growth (anti-tumor activity) that was significantly improved when compared to the control. Moreover, the delay in tumor growth was significantly better for the 4-arm-PEG-GLY-Irino-20K group of mice when compared to the group of animals administered unconjugated irinotecan.

Example 3 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-40K, “4-ARM-PEG-GLY-IRINO-40K”

4-arm-PEG-GLY-IRINO-40K was prepared in an identical fashion to that described for the 20K compound in Example 1, with the exception that in step C, the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 4 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-20K, “4-ARM-PEG-GLY-SN-38-20K”

4-arm PEG-GLY-SN-38-20K was prepared in a similar fashion to its irinotecan counterpart as described in Example 1, with the exception that the active agent employed was SN-38, an active metabolite of camptothecin, rather than irinotecan, where the phenolic-OH of SN-38 was protected with MEMCI (2-methoxyethoxymethyl chloride) during the chemical transformations, followed by deprotection with TEA to provide the desired multi-armed conjugate.

Example 5 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-40K, “4-ARM-PEG-GLY-SN-38-40K”

4-arm PEG-GLY-SN-38-40K was prepared in a similar fashion to the 20K version described above, with the exception that the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 8 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-2-{2-[2-1-HYDROXY-2-OXO-VINYLOXY)-ETHOXY]-ETHYLAMINO}-PROPEN-1-ONE LINKED-IRINOTECAN)-20K AND -40K

 

A. 2-(2-t-Boc-aminoethoxy)ethanol (1)

2-(2-Aminoethoxy)ethanol (10.5 g, 0.1 mol) and NaHCO₃ (12.6 g, 0.15 mol) were added to 100 mL CH₂Cl₂ and 100 mL H₂O. The solution was stirred at RT for 10 minutes, then di-tert-butyl dicarbonate (21.8 g, 0.1 mol) was added. The resulting solution was stirred at RT overnight, then extracted with CH₂Cl₂ (3×100 mL). The organic phases were combined and dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was subjected to silica gel column chromatography (CH₂Cl₂:CH₃OH=50:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethanol (1) (16.0 g, 78 mmol, yield 78%)

B. 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-Irinotecan (2)

2-(2-t-Boc-aminoethoxy)ethanol (1) (12.3 g, 60 mmol) and 4-dimethylaminopyridine (DMAP) (14.6 g, 120 mmol) were dissolved in 200 ml anhydrous CH₂Cl₂. Triphosgene (5.91 g, 20 mmol) was added to the solution while stirring at room temperature. After 20 minutes, the solution was added to a solution of irinotecan (6.0 g, 10.2 mmol) and DMAP (12.2 g, 100 mmol) in anhydrous CH₂Cl₂ (200 mL). The reaction was stirred at RT for 2 hrs, then washed with HCI solution (pH=3, 2L) to remove DMAP. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was evaporated under vacuum and subjected to silica gel column chromatography (CH₂Cl₂:CH₃OH=40:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.9 g, 6.0 mmol, yield 59%).

C. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3)

2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.7 g, 5.75 mmol) was dissolved in 60 mL CH₂Cl₂, and trifluoroacetic acid (TFA) (20 mL) was added at RT. The reaction solution was stirred for 2 hours. The solvents were removed under vacuum and the residue was added to ethyl ether and filtered to give a yellow solid as product 3 (4.3 g, yield 90%).

D. 4-arm-PEG_20k-carbonate-inotecan (4)

4-arm-PEG_20k-SCM (16.0 g) was dissolved in 200 mL CH₂Cl₂. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to a solution of 4-arm-PEG_20k-SCM. The reaction was stirred at RT for 12 hrs then precipitated in Et₂O to yield a solid product, which was dissolved in 500 mL IPA at 50° C. The solution was cooled to RT and the resulting precipitate collected by filtration to give 4-arm-PEG_20k-glycine -irinotecan (4) (16.2 g, drug content 7.5% based on HPLC analysis). Yield: 60%.

E. 4-arm-PEG_40k-carbonate-irinotecan (5)

4-arm-PEG_40k-SCM (32.0 g) was dissolved in 400 mL CH₂Cl₂. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to the solution of 4-arm -PEG_40k-SCM. The reaction was stirred at RT for 12 hrs and then precipitated in Et₂O to get solid product, which was dissolved in 1000 mL isopropyl alcohol (IPA) at 50° C. The solution was cooled to RT and the precipitate collected by filtration to gave 4-arm-PEG_40k-glycine-irinotecan (4) (g, drug content 3.7% based on HPLC analysis). Yield: 59%.

 

References

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13: Atyabi F, Farkhondehfai A, Esmaeili F, Dinarvand R. Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice. Acta Pharm. 2009 Jun;59(2):133-44. PubMed PMID: 19564139.

14: Liu Z, Robinson JT, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J Am Chem Soc. 2008 Aug 20;130(33):10876-7. Epub 2008 Jul 29. PubMed PMID: 18661992; PubMed Central PMCID: PMC2597374.

15: Scott LC, Yao JC, Benson AB 3rd, Thomas AL, Falk S, Mena RR, Picus J, Wright J, Mulcahy MF, Ajani JA, Evans TR. A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother Pharmacol. 2009 Jan;63(2):363-70. Epub 2008 Apr 9. PubMed PMID: 18398613.

16: Almubarak M, Newton M, Altaha R. Reinduction of bevacizumab in combination with pegylated liposomal Doxorubicin in a patient with recurrent glioblastoma multiforme who progressed on bevacizumab/irinotecan. J Oncol. 2008;2008:942618. Epub 2008 Sep 2. PubMed PMID: 19259336; PubMed Central PMCID: PMC2648641.

17: Krauze MT, Noble CO, Kawaguchi T, Drummond D, Kirpotin DB, Yamashita Y, Kullberg E, Forsayeth J, Park JW, Bankiewicz KS. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts. Neuro Oncol. 2007 Oct;9(4):393-403. Epub 2007 Jul 24. PubMed PMID: 17652269; PubMed Central PMCID: PMC1994096.

18: Li YF, Fu S, Hu W, Liu JH, Finkel KW, Gershenson DM, Kavanagh JJ. Systemic anticancer therapy in gynecological cancer patients with renal dysfunction. Int J Gynecol Cancer. 2007 Jul-Aug;17(4):739-63. Epub 2007 Feb 16. Review. PubMed PMID: 17309673.

19: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2006 Dec;28(10):719-40. PubMed PMID: 17235418.

20: Lokich J. Same-day pegfilgrastim and chemotherapy. Cancer Invest. 2005;23(7):573-6. PubMed PMID: 16305982.

21: Honig A, Rieger L, Sutterlin A, Kapp M, Dietl J, Sutterlin MW, Kämmerer U. Brain metastases in breast cancer–an in vitro study to evaluate new systemic chemotherapeutic options. Anticancer Res. 2005 May-Jun;25(3A):1531-7. PubMed PMID: 16033055.

Irinotecan

Systematic (IUPAC) name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy- 3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin- 9-yl-[1,4’bipiperidine]-1’-carboxylate
Clinical data
Trade names	Camptosar
AHFS/Drugs.com	monograph
MedlinePlus	a608043
Pregnancy cat.	D (Australia, United States)
Legal status	POM (UK), ℞-only (U.S.)
Routes	Intravenous
Pharmacokinetic data
Bioavailability	NA
Metabolism	Hepatic glucuronidation
Half-life	6 to 12 hours
Excretion	Biliary and renal
Identifiers
CAS number	100286-90-6
ATC code	L01XX19
PubChem	CID 60838
DrugBank	DB00762
ChemSpider	54825
UNII	7673326042
KEGG	D08086
ChEMBL	CHEMBL481
Chemical data
Formula	C33H38N4O6 e
Mol. mass	586.678 g/mol (Irinotecan) 623.139 g/mol (Irinotecan hydrochloride) 677.185 g/mol (Irinotecan hydrochloride trihydrate))

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Irinotecan (Camptosar, Pfizer; Campto, Yakult Honsha) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1.^[1] In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996^[2] and full approval in 1998.^[3] During development, it was known as CPT-11.

Mechanism

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

[[File:

 

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Irinotecan Pathway edit

1. The interactive pathway map can be edited at WikiPathways: “IrinotecanPathway_WP46359″.

Side-effects

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or Lomotil with the first loose bowel movement.

Immunosuppression

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia (a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

*28 variant patients

People with variants of the UGT1A1 called TA₇, also known as the “*28 variant”, express fewer UGT1A1 enzymes in their liver and often suffer from Gilbert’s syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.^[4]

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.^[4]

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses.^[5] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient’s genotype.^[6]

Research

Recently it was shown that antitumor activity of irinotecan against glioblastoma can be enhanced by co-treatment with statins.^[7] Similarly, it was shown that berberine may enhance chemosensitivity to irinotecan in colon cancercells. ^[8]

References

External links

• Pfizer website
• Irinotecan Pathway on PharmGKB

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See more at: http://worlddrugtracker.blogspot.in/2014/08/fda-approves-eliquis-apixaban-for.html

Plerixafor

cas 110078-46-1

CXCR4 chemokine antagonist

Stem cell mobilization [CXCR4 receptor antagonist]

A bicyclam derivate, highly potent & selective inhibitor of HIV-1 & HIV-2.

Bone marrow transplantation; Chronic lymphocytic leukemia; Chronic myelocytic leukemia; Myelodysplastic syndrome; Neutropenia; Sickle cell anemia

Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required.

Plerixafor is a hematopoietic stem cell mobilizer with a chemical name l, 1′-[1,4phenylenebis (methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. It has the molecular formula C₂₈H₅₄N₈. The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1.

Figure 1: Structural Formula

 

 

Plerixafor is a white to off-white crystalline solid. It is hygroscopic. Plerixafor has a typical melting point of 131.5 °C. The partition coefficient of plerixafor between 1octanol and pH 7 aqueous buffer is < 0.1.

Plerixafor (rINN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients. The stem cells are subsequently transplanted back to the patient. The drug was developed by AnorMED which was subsequently bought by Genzyme.

History

The molecule 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane], consisting of two cyclam rings linked at the amine nitrogen atoms by a 1,4-xylyl spacer, was first synthesised by Fabbrizzi et al. in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds.^[1] Then, it was serendipitously discovered by De Clercq that such a molecule, could have a potential use in the treatment of HIV[2] because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the virus’s main cellular receptor, CD4).^[2]Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients.^[3]

Indications

Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation.^[4] The drug is approved for patients with lymphoma and multiple myeloma.^[5]

Contraindications

Pregnancy and lactation

Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.^[5]

Adverse effects

Nausea, diarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient.^[5][6]

The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor.^[7]

Phase III clinical development in combination with G-CSF (granulocyte colony-stimulating factor) is under way at Genzyme (which acquired the product through its acquisition of AnorMED in late 2006) in a stem cell mobilization regimen in non-Hodgkin’s lymphoma (NHL). The trials are designed to evaluate the potential of plerixafor in combination with G-CSF, to rapidly increase the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target and, as a result, reducing the number of apheresis sessions required for patients to collect a target number of peripheral blood stem cells. A phase I safety trial had been under way for the treatment of renal cancer, however, no recent development for this indication has been reported. An IND has been filed in the U.S. seeking approval to initiate clinical evaluation of the drug candidate to help repair damaged heart tissue in patients who have suffered heart attacks. Currently, an investigator-sponsored study is ongoing to evaluate plerixafor as a single agent in allogeneic transplant. AMD-3100, in combination with mitoxantrone, etoposide and cytarabine, is also in phase I/II clinical trials at the University of Washington for the treatment of acute myeloid leukemia (AML).

The University has also been conducting early clinical trials for increasing the stem cells available for transplantation in patients with advanced hematological malignancies, however, no recent developments on this trial have been reported. Genzyme has completed a phase I/II clinical study of plerixafor hydrochloride in combination with rituximab for the treatment of chronic lymphocytic leukemia. The former AnorMED had been developing plerixafor for the treatment of rheumatoid arthritis (RA), but no clinical development has been reported as of late. AnorMED was also developing plerixafor for the treatment of HIV, but discontinued the trials in 2001 due to abnormal cardiac activity and lack of efficacy.

By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. Once in the circulating blood, the stem cells can be collected for use in stem cell transplant. In terms of use for cardiac applications, there is clinical evidence that the presence of stem cells circulating in the bloodstream or directly injected into the hearts of patients who have suffered a heart attack may result in improved cardiac function.

Chemical properties

Plerixafor is a macrocyclic compound and a bicyclam derivative.^[4] It is a strong base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc, copper and nickel, as well as cobalt and rhodium. The biologically active form of plerixafor is its zinc complex.^[8]

Synthesis

Three of the four nitrogen atoms of the macrocycle 1,4,8,11-tetraazacyclotetradecan are protected with tosyl groups. The product is treated with 1,4-dimethoxybenzene or 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained.^[9]

SEE   CHINESE JOURNAL OF MEDICINAL CHEMISTRY    2010 20 (6): 511-513   ISSN: 1005-0108   CN: 21-1313/R

DOWNLOAD………http://download.bioon.com.cn/upload/201207/24113552_9395.pdf

http://www.zgyhzz.cn/qikan/epaper/zhaiyao.asp?bsid=14753

( 1 ) BASE FORM
0155g ( 8016% ), m p 129 ~ 131 e 。
1H-NM R
( CDC l3 ) D: 7.28( s, 4H, A r-H ), 3.55 ( br s, 4H,A r-CH2 ), 2.82 ~ 2.52( m, 32H, NCH2, NHCH2 ),
1.86 ~ 1.68 ( m, 8H, CCH2C )。 ESI-M S m /z:
503.55 [M + H]+ 。

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SEE

http://doc.sciencenet.cn/upload/file/2011531154034454.pdf

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http://www.google.com/patents/US5756728

U.S. Pat. No. 5,021,409 is directed to a method of treating retroviral infections comprising administering to a mammal in need of such treatment a therapeutically effective amount of a bicyclic macrocyclic polyamine compound. Although the usefulness of certain alkylene and arylene bridged cyclam dimers is generically embraced by the teachings of the reference, no arylene bridged cyclam dimers are specifically disclosed.

WO 93/12096 discloses the usefulness of certain linked cyclic polyamines in combating HIV and pharmaceutical compositions useful therefor. Among the specifically disclosed compounds is 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11 tetraazacyclotetradecane (and its acid addition salts), which compound is a highly potent inhibitor of several strains of human immune deficiency virus type 1 (HIV-1) and type 2 (HIV-2).

European Patent Appln. 374,929 discloses a process for preparing mono-N-alkylated polyazamacrocycles comprising reacting the unprotected macrocycle with an electrophile in a non-polar, relatively aprotic solvent in the absence of base. Although it is indicated that the monosubstituted macrocycle is formed preferentially, there is no specific disclosure which indicates that linked bicyclams can be synthesized by this process.

U.S. Pat. No. 5,047,527 is directed to a process for preparing a monofunctionalized (e.g., monoalkylated)cyclic tetramine comprising: 1) reacting the unprotected macrocycle with chrominum hexacarbonyl to obtain a triprotected tetraazacyloalkane compound; 2) reacting the free amine group of the triprotected compound prepared in 1) with an organic (e.g., alkyl) halide to obtain a triprotected monofunctionalized (e.g., monoalkylated) tetraazacycloalkane compound; and 3) de-protecting the compound prepared in 2) by simple air oxidation at acid pH to obtain the desired compound. In addition, the reference discloses alternative methods of triprotection employing boron and phosphorous derivatives and the preparation of linked compounds, including the cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, by reacting triprotected cyclam prepared as set forth in 1) above with an organic dihalide in a molar ratio of 2:1, and deprotecting the resultant compound to obtain the desired cyclam dimer.

J. Med. Chem., Vol. 38, No. 2, pgs. 366-378 (1995) is directed to the synthesis and anti-HIV activity of a series of novel phenylenebis(methylene)-linked bis-tetraazamacrocyclic analogs, including the known cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane. The cyclam dimers disclosed in this reference, including the afore-mentioned cyclam dimer, are prepared by: 1) forming the tritosylate of the tetraazamacrocycle; 2) reacting the protected tetraazamacrocycle with an organic dihalide, e.g., dibromo-p-xylene, in acetonitrile in the presence of a base such as potassium carbonate; and 3) de-protecting the bis-tetraazamacrocycle prepared in 2) employing freshly prepared sodium amalgam, concentrated sulfuric acid or an acetic acid/hydrobromic acid mixture to obtain the desired cyclam dimer, or an acid addition salt thereof.

Although the processes disclosed in U.S. Pat. No. 5,047,527 and the J. Med. Chem. reference are suitable to prepare the cyclam dimer 1,1′- 1,4-phenylene bis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, they involve the use of cyclam as a starting material, a compound which is expensive and not readily available. Accordingly, in view of its potent anti-HIV activity, a number of research endeavors have been undertaken in an attempt to develop a more practical process for preparing 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane.

EXAMPLE 1

a) Preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acylic precursor of formula III

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 43.5 g (0.25 mol) of N,N’-bis(3-aminopropyl) ethylenediamine and 250 ml of tetrahydrofuran. To the resultant solution is added, over a period of 30 minutes with external cooling to maintain the temperature at 20° C., 113.6 g (0.8 mol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 4 hours, after which time 52.25 ml. (0.3 mol) of diisopropylethylamine is added. The resultant reaction mixture is warmed to 60° C. and, over a period of 2 hours, is added a solution of 33.0 g (0.125 mol) of α,α’-dibromoxylene in 500 ml. of tetrahydrofuran. The reaction mixture is then maintained at a temperature of 60° C., with stirring, for an additional 2 hours after which time a solution of 62.0 g. (1.55 mol) of sodium hydroxide in 250 ml. of water is added. The resultant mixture is then stirred vigorously for 2 hours, while the temperature is maintained at 60° C. A solution of 152.5 g. (0.8 mol) of p-toluenesulfonyl-chloride in 250 ml. of tetrahydrofuran is then added, over a period of 30 minutes, while the temperature is maintained at between 20° C. and 30° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 1 liter of isopropyl acetate, the layers are separated and the organic layer is concentrated to dryness under vacuum to yield the desired compound as a foamy material.

b) Preparation of the hexatosyl cyclam dimer of formula IV

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 114.6 g. (0.10 mol) of the compound prepared in a) above and 2.5 liters of dimethylformamide. After the system is degassed, 22.4 g. (0.56 mol) of NaOH beads, 27.6 g (0.2 mol) of anhydrous potassium carbonate and 5.43 g. (0.016 mol) of t-butylammonium sulfate are added to the solution, and the resultant mixture is heated to 100° C. and maintained at this temperature for 2.5 hours. A solution of 111.0 g (0.3 mol) of ethyleneglycol ditosylate in 1 liter of dimethylformamide is then added, over a period of 2 hours, while the temperature is maintained at 100° C. After cooling the reaction mixture to room temperature, it is poured into 4 liters of water with stirring. The suspension is then filtered and the filter cake is washed with 1 liter of water. The filter cake is then thoroughly mixed with 1 liter of water and 2 liters of ethyl acetate. The solvent is then removed from the ethyl acetate solution and the residue is re-dissolved in 500 ml. of warm acetonitrile. The precipitate that forms on standing is collected by filtration and then dried to yield the desired compound as a white solid.

c) Preparation of 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane

In a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 26.7 g.(0.02 mol) of the compound prepared in b) above, 300 ml. of 48% hydrobromic acid and 1 liter of glacial acetic acid. The resultant mixture is then heated to reflux and maintained at reflux temperature, with stirring, for 42 hours. The reaction mixture is then cooled to between 22° C. and 23° C. over a period of 4 hours, after which time it is stirred for an additional 12 hours. The solids are then collected using suction filtration and added to 400 ml. of deionized water. The resultant solution is then stirred for 25 to 30 minutes at a temperature between 22° C. and 23° C. and filtered using suction filtration. After washing the filter pad with a small amount of deionized water, the solution is cooled to between 10° C. and 15° C. 250 g. of a 50% aqueous solution of sodium hydroxide is then added, over a period of 30 minutes, while the temperature is maintained at between 5° C. and 15° C. The resultant suspension is stirred for 10 to 15 minutes, while the temperature is maintained at between 10° C. and 15° C. The suspension is then warmed to between 22° C. and 23° C. and to the warmed suspension is added 1.5 liters of dichloromethane. The mixture is then stirred for 30 minutes, the layers are separated and the organic layer is slurried with 125 g. of sodium sulfate for 1 hour. The solution is then filtered using suction filtration, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. To the slurry is then added 1.25 liters of acetone, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. The slurry is then cooled to between 22° C. and 23° C. and the solids are collected using suction filtration. The solids are then washed with three 50 ml. portions of acetone and dried in a vacuum oven to obtain the desired compound as a white solid.

EXAMPLE 2

The following is an alternate procedure for the preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acyclic precursor of formula III.

To a 3-necked, round-bottomed flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 3.48 g. (20 mmol) of N,N’-bis-(3-aminopropyl)ethylenediamine and 20 ml. of tetrahydrofuran. To the resultant solution is added, over a period of 20 minutes with external cooling to maintain the temperature at 20° C., 5.2 ml. (42 mmol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 1 hour, after which time a solution of 2.64 g. (10 mmol) of α,α’-dibromoxylene in 20 ml. of tetrahydrofuran is added. The resultant reaction mixture is then stirred at room temperature for 4 hours. A solution of 4.8 g. (120 mmol) of sodium hydroxide in 20 ml. of water is then added and the resultant mixture is warmed to 60° C. and maintained at this temperature, with vigorous stirring, for 2 hours. Over a period of 20 minutes, 13.9 g. (73 mmol) of p-toluenesulfonylchloride is then added portionwise, while the temperature is maintained at 20° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 100 ml. of isopropyl acetate, the layers are separated and the organic layer is washed with saturated sodium bicarbonate aqueous solution. The solution is then condensed to 40 ml., cooled to 4° C. and kept at that temperature overnight. The resultant suspension is filtered and the solid is washed with 10 ml. of isopropyl acetate. The solvents are then removed from the filtrate to yield the desired compound as a brown gel.

…………………………

see

Synthesis and structure-activity relationships of phenylenebis(methylene)linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker
J Med Chem 1995, 38(2): 366

http://pubs.acs.org/doi/abs/10.1021/jm00002a019

…………………………………………………

see

New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor
J Med Chem 1999, 42(2): 229

http://pubs.acs.org/doi/full/10.1021/jm980358u

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CN 102584732

 http://www.google.com/patents/CN102584732B?cl=en

[0003]

[0004] plerixafor (trade name Mozobil ™) was developed by the U.S. company Genzyme chemokine receptor 4 (CXCR4) antagonist specificity. The drug is a hematopoietic stem (progenitor) cell activator, and can stimulate hematopoietic stem cell proliferation and differentiation into functional blood circulation.

[0005] As the non-Hodgkin’s lymphoma (NHL) and multiple myeloma (Korea) most of the cases and the progress of cases to alleviate the need for autologous peripheral blood stem cell transplantation, and plerixafor joint G-CSF can significantly improve the number of patients with ⑶ 34 + cells, about 60% of the patient’s peripheral blood can ⑶ 34 + cells increased to ensure that the NHL and MM patients with autologous hematopoietic stem cell transplantation success.

[0006] U.S. FDA approval on December 15, 2008 its listing, clinical studies showed that the drug can greatly increase the number of white blood cells of patients and to promote hematopoietic stem cells from bone marrow to the blood flow, and granulocyte colony-stimulating factor (G-CSF ) have a synergistic effect; has been used in multiple myeloma and Hodgkin’s lymphoma patients with stem cell transplantation in clinical trials.

[0007] About plerixafor or synthetic analogs have some at home and abroad reported in the literature, there are J.0rg.Chem.2003, 68,6435-6436; J.Med Chem.1995, 38 (2): 366-378; J.SynthCommun.1998 ,28:2903-2906; Tetrahedron, 1989,45 (1) :219-226; Chinese Journal of Pharmaceuticals 2007,38 (6); World Patent W09634860A1; W09312096A1; U.S. Patent US5047527, US5606053, US5801281, US5064956, Chinese patent CN1466579A.

[0008] J.Med Chem.1995, 38 (2) = 366-378 relates to a preparation method comprises the following steps: a) forming a salt of trimethoxy benzene tetraaza macrocycles; 2) reacting the protected tetrazole hetero macrocycle in acetonitrile under the presence of a base such as potassium carbonate as dibromo-p-xylene is reacted with an organic dihalide; 3) using freshly prepared sodium amalgam, concentrated sulfuric acid or acetic acid / hydrobromic acid mixture deprotected target product.

[0009] US 5047527 relates to preparation of the cyclic four monofunctional amine, the method comprising: a) reacting the unprotected macrocycle of reaction with chromium hexacarbonyl to obtain protection tetraazadecalin three compounds; 2) 3 Protection of the free amino compound with an organic halide to obtain three-protected monofunctional tetraaza naphthenic compounds; 3) simple air oxidation, deprotection to obtain the desired product. [0010] J.Synth Commun.1998 ,28:2903-2906 describes an improved method for synthesizing intermediates Plerixafor, the method using phosphor protection, deprotection to give a smooth 1,1 ‘- [1,4 - phenylene bis (methylene)] _ two _1, 4,8,11 – tetraazacyclododecane fourteen burn.

[0011] US 5606053 relates to a process for preparing dimers 1, I ‘- [1,4 - phenylene bis (methylene)] – two -1,4,8,11 – tetraazacyclododecane-tetradecane method. The preparation of compounds include: 1) the four-amine as the starting material, obtained by acylation of toluene Juan acyclic intermediates and three xylene sulfonate and toluene sulfonate and toluene intermediates; 2) and xylene sulfonate and intermediates trimethylbenzene toluenesulfonic acid intermediates after alkylation separation dibromo xylene, toluene sulfonate and then obtain a non-cyclic dimers of six toluenesulfonic acylated; 3) six isolated bridged acyclic toluenesulfonic acid dimer form is reacted with ethylene glycol ditosylate three equivalents of cyclization; 4) deprotection to obtain the objective product was purified by hydrobromic acid and acetic acid.

[0012] US 5801281 relates to preparation of dimer 1, I ‘- [1,4 _-phenylene bis (methylene)] – two _1, 4,8,11

[0013] – tetraazacyclo tetradecane, comprising: a) reacting the acyclic tetraamine with 3 equivalents of ethyl trifluoroacetate, the reaction; 2) with 0.5 equivalents of the tri-dibromo-p-xylene-protected acyclic alkylation of the amine obtained form four non-cyclic dimers; 3) hydrolysis to remove the six trifluoroacetyl compound group; 4) acylation of the compound toluenesulfonic bridged tetraamine dimer; 5) B Juan xylene glycol ester cyclization; 6) and glacial acetic acid mixed with hydrobromic acid deprotection was the target product.

Under the [0014] US 5064956 discloses a multi-alkylated single-ring nitrogen of the compound prepared, the method involves reacting the unprotected macrocycle in an aprotic, relatively non-polar solvent in presence of alkali electrophilic reagent. Not mentioned in this document similar to the embodiment Seclin dimer synthesis.

[0015] Through the open Plerixafor synthetic route research and meta-analysis of the literature, mainly in the following four synthetic routes:

[0016] Route One, is 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, NI, N4, N8 three protected with 1,4 – bis (halomethyl) benzene-bridged deprotection to obtain the finished product. The following reaction scheme, wherein R is p-toluenesulfonyl group, a methanesulfonyl group, a trifluoroacetyl group, a tert-butoxycarbonyl group and the like:

[0017]

[0018] Route II is di (2 – aminopropyl) ethylenediamine as raw material, the ring and the reaction with 1,4 – bis (halomethyl) benzene-bridged, and then deprotection Bullock Suffolk.

[0019] Route 3 to 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, under anhydrous, anaerobic conditions, after the ring protection with 1,4 – bis (halomethyl ) benzene bridging, and then deprotection plerixafor. Synthesis scheme below, wherein R is P, Ni, etc.;

[0021] line four, based on acrylate as starting material, first with ethylene diamine as raw material by Michael addition of the amine solution, then with malonate cyclization 1,4,8,11 – Tetraaza _5, 7,12 – three oxo cyclotetradecane by α, α ‘- dibromo-p-xylene bridging, the final deprotection plerixafor. Reaction Roadmap follows:

[0022]

[0023] The above synthesis route and the existing methods have the following disadvantages:

[0024] In an intermediate of the synthesis route, the existing technology, the need for column purification of the intermediates, low yield.

[0025] route to protect the stability of the two because of the strong, leading to the final deprotection step difficult, long production cycle, low yield, and finished organic residues can not be achieved within the standard limits.

Higher dry anaerobic demands [0026] Route 3 on, harsh reaction conditions, deprotection is not complete, intermediates need to repeatedly purified, low yield, after repeated recrystallization, finished monohetero difficult to control in 0.1% less.

[0027] Anhydrous ethylene diamine route and need four anhydrous THF, more stringent requirements on the process, and to use dangerous borane dimethyl sulfide, while the second step is only about 35% lower yield. Selectivity of the reaction is not high shortcomings, so do not be the most economical and reasonable synthetic route.

[0028] We prepared by Plerixafor prepared by methods disclosed above may Plerixafor single impurity of 0.1% or less is difficult to achieve, it is difficult to meet the quality requirements of the injection material, the same techniques can not reach the European Quality of ICH guidelines of the relevant technical requirements, low yield, high cost required for each step of the intermediate column to afford a large amount of solvent, time consuming, and the greater the elution solvent toxicity, is not suitable for industrial production.

(I) Preparation of 1,4,8 _ tris (p-toluenesulfonyl) -1,4,8,11 – tetraazacyclododecane-tetradecane: the raw 1,4,8,11 – tetraazacyclododecane cyclotetradecane suspended in methylene chloride, in the role of acid binding agent, at a temperature 10 ~ 30 ° C, p-toluenesulfonyl chloride and 3 ~ 8h, filtered, and the filtrate was collected and concentrated to dryness to obtain a residue; will have The residue of said C ^ C3 alkyl group in a mixed solvent of alcohol and an aprotic solvent, purification, crystallization segment greater than 95% purity of 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraaza cyclotetradecane;

[0032] (2) Preparation of 1,1 ‘- [1,4 - (phenylene methylene)] – two – [4,8,11 - tris (p-toluenesulfonyl)] -1,4, 8,11 – tetraazacyclododecane-tetradecane: A (I) the resulting 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane, α, α two bromo-p-xylene in place of anhydrous acetonitrile, was added acid-binding agent, the reaction was refluxed under nitrogen for 5 to 24 hours; After the reaction was cooled to room temperature, the reaction mixture was then collected by filtration and the filter cake was purified to obtain a mixed solvent I , I, – [1,4 - (phenylene methylene)] – two – [4,8,11 - tris (p-toluenesulfonyl)] _1, 4,8,11 – tetraazacyclododecane ten four alkyl;

[0033] (3) Synthesis Plerixafor: A (2) the resultant I, 1′-[1,4 _ (phenylene methylene)] – two – [4,8,11 - tris (p-toluene sulfonyl)] -1,4,8,11 – tetraazacyclododecane myristic acid solution was added to the mixture, stirred and dissolved, the reaction was warmed to reflux for 10 to 24 hours, cooled, filtered, and filter cake was collected; the filter cake was dissolved in purified water, adjusted with sodium hydroxide solution or potassium hydroxide solution to the PH-12, filtered, and the filtrate was extracted with a halogenated solvent, and the organic layer was dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure P Le Suffolk crude;

[0034] (4) Purification Plerixafor: Plerixafor the crude was dissolved into a solvent and heated to reflux to dissolve, filtered, and the crystallization solvent is added dropwise at 40 ~ 45 ° C crystallization 30min, filtered and the filtrate then cooled to 20 ~ 25 ° C crystallization I hour at O ​​~ 5 ° C crystallization three hours, filtered, and the filter cake was dried Plerixafor.

Plerixafor Preparation: 6 [0075] Implementation

[0076] The starting material 1,4,8,11 – tetraazacyclo tetradecane (5g, 25mmol) was suspended in dichloromethane (50g) was added N, N-diisopropylethylamine (7.5ml) , a solution of p-toluenesulfonyl chloride (10.8g, 56.5mmol) and methylene chloride (50g) in a solution of, at 25 ~ 30 ° C reaction temperature 3h, filtered, and the filtrate was collected and concentrated to dryness and to the residue in methanol (30g), toluene (IOg) was heated to reflux, filtered, and the filtrate was cooled to 40 ° C crystallization 30min, filtered to remove impurities little over protection, and the filtrate was added methyl tert-butyl ether (30g), stirring rapidly cooled to O ~ 5 ° C crystallization 3h, filtered, and dried to give 1,4,8 – tris (p-toluenesulfonyl) -1, 4,8,11 – tetraazacyclododecane-tetradecane (9.6g, 61.9%), purity of 97.2%.

[0077] The 4,8 _ tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane (9g, 13.6mmol) α, α ‘- dibromo-p-xylene (1.81 g, 6.8mmol) in dry acetonitrile was placed (90ml) was added potassium carbonate (15.0g, 108.5mmol), the reaction was refluxed under nitrogen for 5 hours. Cooled to room temperature and filtered to collect the filter cake, was added anhydrous methanol (10ml), ethyl acetate (30ml), dichloromethane (IOml) hot melt, whereby the cooling crystallization, filtration, and dried under reduced pressure to obtain white solid (16. lg, 83%), purity 97.5%.

[0078] The intermediate obtained above (5g, 3.5mmol) was added to glacial acetic acid (25ml) and concentrated hydrochloric acid (25ml) was stirred until dissolved in the mixed solution was heated to reflux for 24 hours, cooled, collected by filtration cake. The filter cake was dissolved in purified water (20ml), adjusting the PH value of the solution with sodium hydroxide to 12, filtered, and the filtrate was extracted with dichloromethane (50mlX3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain sand Bullock Fu crude (1.4g, 79.5%), purity 98.6%.

[0079] The crude Plerixafor (1.4g) is placed in tetrahydrofuran (14g), heated to reflux to dissolve, filtered, and added dropwise n-hexane (42g), and 40 ~ 45 ° C crystallization 30min, filtered little solid, The filtrate was rapidly cooled to 20 ~ 25 ° C crystallization I hour and then at O ​​~ 5 ° C crystallization three hours, filtered, 45 ° C and dried under reduced pressure to obtain the finished Plerixafor (1.2g, 85.7%), purity 99.93 %, the largest single miscellaneous 0.04%.

………………………………….

http://www.google.com/patents/US8420626?cl=en

wherein, n is 0 or 1, Ts is tosyl radical, P is trifluoroacetyl or p-tosyl radical;
To the NaOH solution of the starting material 7 is dropwise added ether solution of tosyl chloride. The system is stirred over night. A white solid is formed and filtrated. The filter cake is washed with water and ethyl ether, respectively, recrystallized to give a white solid intermediate of formula 8. To the dried acetonitrile solution of the compound of formula 8 is slowly dropwise added dried acetonitrile solution of 1,2-di-p-tosyloxypropane under reflux state, refluxed for 2-4 days, stood until room temperature. A white solid is precipitated and filtrated. The filter cake is washed with water and ethyl acetate, respectively, recrystallized to give a white solid compound of formula 9. The compound of formula 9 is dissolved in 90% concentrated sulfuric acid, allowed to react at 100° C. for 24-48 hours, stood until room temperature. To the reaction solution are dropwise added successively ethanol and ethyl ether. A white solid is precipitated, filtrated, dried, and dissolved in NaOH solution. The aqueous phase is extracted with chloroform. The chloroform phase is combined, concentrated, recrystallized to give a white solid compound of formula 10. To the chloroform solution of the compound of formula 10 and triethylamine is dropwise added chloroform solution of tosyl chloride. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: dichloromethane/methanol system) to give a white solid compound of formula 11 (protective group is tosyl); or to the methanol solution of the compound of formula 10 is dropwise added ethyl trifluoroacetate. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: ethyl acetate) to give a white solid compound of formula 11 (protective group is trifluoroacetyl);

Pharmacokinetics

Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours.^[5]

Pharmacodynamics

In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist ofCXCR7.^[10] The CXCR4 alpha-chemokine receptor and one of its ligands, SDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells.^[11]

Interactions

No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs.^[5]

Legal status

Plerixafor has orphan drug status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008.^[12] In Europe, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009.^[7] The drug was approved for use in Canada by Health Canada on December 8, 2011.^[13]

Research

Small molecule cancer therapy

Plerixafor was seen to reduce metastasis in mice in several studies.^[14] It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer surviving radiation are critically depended on bone marrow derived cells for vasculogenesis whose recruitment mediated by SDF-1 CXCR4 interaction is blocked by plerixafor.^[15]

Use in generation of other stem cells

Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can produce mesenchymal stem cells andendothelial progenitor cells in mice.^[16]

Other uses

Blockade of CXCR4 signalling by plerixafor (AMD3100) has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with morphine, though only animal studies have been conducted as yet.^[17]

Plerixafor

Systematic (IUPAC) name
1,1′-[1,4-Phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a609018
Pregnancy cat.	D (US)
Legal status	℞-only (US)
Routes	Subcutaneous injection
Pharmacokinetic data
Protein binding	Up to 58%
Metabolism	None
Half-life	3–5 hours
Excretion	Renal
Identifiers
CAS number	110078-46-1
ATC code	L03AX16
PubChem	CID 65015
IUPHAR ligand	844
DrugBank	DB06809
ChemSpider	58531
UNII	S915P5499N
Synonyms	JM 3100, AMD3100
Chemical data
Formula	C28H54N8
Mol. mass	502.782 g/mol

http://www.google.com/patents/CN102653536A?cl=en

(Plerixafor), chemical name: 1, I ‘- [I, 4_ phenylene ni (methylene)] – ni -1,4,

8,11 – tetraazacyclo tetradecane, its molecular structure is as follows:

[0004]

Synthesis of domestic and foreign literature in general, all require 1,4,8,11 – tetraazacyclo-tetradecane for 3 protection (eg of formula I), of the three methods are used to protect the p-toluenesulfonamide chloride, trifluoroacetic acid ko ko cool, tert-butyl carbonate ni. Use of p-toluenesulfonamide-protected deprotection step into strict step because deprotecting reagent (such as hydrobromic acid / glacial acetic acid, concentrated sulfuric acid, etc.) side reactions often occur.The use of trifluoroacetic acid ko ko ester protecting, since the trifluoromethyl group strongly polar ko, resulting fourth-NH unprotected decrease in activity, usually not fully reflect the subsequent reaction, thereby further into ー is introduced after deprotection difficult to remove impurities 1,4,8,11 – tetraazacyclo-tetradecane.

[0006] tert-butyl carbonate ni selective protection of the amino group is widely used (polyamines, amino acids, p printed tidic chains, etc.), but to use it for 1,4,8,11 – tetraazacyclo tetradecane rarely reported, abroad it for 1,4,8,11 – tetraazacyclo tetradecane protection coverage, we use the t-butyl carbonate brother attempted 3 protection, he was surprised to find that in certain conditions, the three protection up to 90% (see Figure I), with high selectivity, significantly higher than the reported domestic Boc protected

Selectivity of the reaction (see table below).

[0007]

[0008] 2 by three protection product with quite different polarity protection products, flash column chromatography using silica gel column to separate the protector 3 of sufficient purity, and deprotection conditions milder (only hydrochloric acid solution), in a certain extent reduce the incidence of side effects, so capable of synthesizing high purity products.

[0009]

SUMMARY OF THE INVENTION

xample I: 3Boc protection 1,4,8,11 _ tetraazacyclo Preparation tetradecane

[0048] 1,4,8,11 taken tetraazacyclo tetradecane _ 10g (0.05mol), and acetone – water (2: l) 50ml, tris ko amine 10. 119g (0. Lmol), ni ko isopropyl amine 3. 225g (0. 025mol), at room temperature was added dropwise tert-butyl carbonate, brother 38. 194g (0. 175mol), dropwise at room temperature after stirring for 24 hours, HPLC monitoring of the reaction. After completion of the reaction 50 ° C under reduced pressure to dryness to give a pale yellow oil, 150g on a silica gel column, and eluted with ko acid esters ko collecting ko ko acid ester liquid evaporated to dryness under reduced pressure to give a white foam 23. 12g, yield of 92.36%. 1HNMR (400MHz, CDCl3, 6 ppm): 1. 74 (2H, q, 5. 5);

I. 96 (2H, q, 6. 5); 2. 66 (2H, t, 5. 5); 2. 82 (2H, t, 5. 5); 3. 33 (4H, m); 3. 34 (2H, m); 3. 37 (2H, m), 3. 43 (4H, m).

[0049] Implementation Example 2: 6Boc protection Bullock Suffolk Preparation

[0050] Take 3Boc protection 1,4,8,11 _ tetraazacyclo tetradecane 20. 03g (0. 04mol), dissolved in anhydrous ko nitrile 400ml, anhydrous potassium carbonate 20g, aa ‘ni chlorine ni toluene 3.5012g (0.02mol), sodium iodide 75mg, at reflux for 24 hours under nitrogen, TLC monitoring of the reaction. After completion of the reaction, cooled to room temperature, filtered, the filter cake was washed with 200ml of ko nitrile, nitrile ko combined solution was evaporated to dryness under reduced pressure to give the protected Bullock 6Boc Suffolk 21. 20g, yield of 96.06%. Alcohol with ko – a mixed solvent of water and recrystallized to give a white solid. [0051] Implementation Example 3: Bullock Suffolk • 8HC1 • 3H20 Preparation of compounds

[0052] Protection Bullock Suffolk take 6Boc 20g, add methanol 200ml, stirring to dissolve, concentrated hydrochloric acid was added dropwise at room temperature, 60ml, was stirred at room temperature after the addition was complete 48 inches, TLC monitoring of the reaction. After completion of the reaction, filtration, the filter cake was dried 50 ° C under reduced pressure to give a white solid 13. 54g, yield of 88.04%.

[0053] Implementation Example 4: Preparation of Suffolk Bullock…………Plerixafor BASE

[0054] Take Bullock Suffolk • 8HC1 • 3H20 compound 13. 54g, add water 40ml ultrasound to dissolve after stirring constantly with 50% sodium hydroxide solution to adjust the pH to 12 and filtered, the filter cake 50 ° C minus pressure and dried to give a white solid 7. 24g, yield 90.24 V0o

1H NMR (400MHz, CDCl3, 6 ppm): 1. 75 (4H, bs); 1. 87 (4H, bs); 2. 95-2. 51 (32H, m); 3. 54 (4H, s); 4. 23 (4H, bs); 7. 30 (4H, s). 

IR (KBr) 3280,2927,2883,2805,1458,1264,1117 cm,

NEW PATENT…………….WO-2014125499

Improved and commercially viable process for the preparation of high pure plerixafor base

Process for the preparation of more than 99.8% pure plerixafor base by HPLC. Also claims solid forms of plerixafor base and composition comprising the same. Appears to be the first filing from the assignee on this API. FDA Orange book lists US6987102 and US7897590, expire in July 2023.

References

External links

• MeSH JM+3100

http://pubs.rsc.org/en/content/articlehtml/2012/dt/c2dt31137b

http://www.thno.org/v03p0047.htm

SEE ALSO……….http://www.scipharm.at/download.asp?id=1427

SEE…………..https://www.academia.edu/5549712/2011531154034454SCHEME 15 IS SYNTHESIS OF PLEXIXAFOR

read

ncur_powerpoint Courtney.ppt

FDA Gives Insys Pharmaceutical Cannabidiol Orphan Status

Insys Therapeutics Inc., a specialty pharmaceutical company that is developing and commercializing innovative drugs and novel drug delivery systems, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its pharmaceutical cannabidiol (CBD) for the treatment of glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in humans.

 

 

read at

http://www.dddmag.com/news/2014/08/fda-gives-insys-pharmaceutical-cannabidiol-orphan-status?et_cid=4117613&et_rid=523035093&type=cta

- See more at: http://worlddrugtracker.blogspot.in/#sthash.mFuiI6Hm.dpuf

FDA allows marketing of first ZnT8Ab autoantibody test to help diagnose type 1 diabetes

 

 

Today, August 20, 2014, the U.S. Food and Drug Administration allowed marketing of the first zinc transporter 8 autoantibody (ZnT8Ab) test that can help determine if a person has type 1 diabetes and not another type of diabetes. When used with other tests and patient clinical information, the test may help some people with type 1 diabetes receive timely diagnosis and treatment for their disease.

Type 1 diabetes is the most common type of diabetes diagnosed in children and adolescents, but in some instances it may also develop in adults. People with the disease produce little or no insulin because their immune system attacks and destroys the cells in the pancreas that produce insulin, a hormone that converts sugars (glucose) in food to the energy the bodyneeds. People with type 1 diabetes mustinject insulinto regulate their blood glucose because proper regulation is critical to lower their risk of long-term complications such as blindness, kidney failure and cardiovascular disease.

The immune system of many people with type 1 diabetes produces ZnT8Ab, but patients with other types of diabetes (type 2 and gestational) do not. The KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay detects the presence of the ZnT8 autoantibody in a patient’s blood.

“Early treatment of type 1 diabetes is important in helping to prevent further deterioration of insulin producing cells,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the Center for Devices and Radiological Health at the FDA. “This test can help patients get a timely diagnosis and help start the right treatment sooner.”

The KRONUS ZnT8Ab ELISA Assay was reviewed through the de novo premarket review pathway, a regulatory pathway for some low- to moderate-risk medical devices that are not substantially equivalent to an already legally marketed device.

 

 

The agency reviewed data from a clinical study of 569 blood samples — 323 from patients with diagnosed type 1 diabetes and 246 samples from patients diagnosed with other kinds of diabetes, other autoimmune diseases, and other clinical conditions. The test was able to detect the ZnT8 autoantibody in 65 percent of the samples from patients with diagnosed type 1 diabetes and incorrectly gave a positive result in less than two percent of the samples from patients diagnosed with other disease.

A negative result from the test does not rule out a diagnosis of type 1 diabetes. The test should not be used to monitor the stage of disease or the response to treatment.

KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay is manufactured by KRONUS Market Development Associates, Inc. in Star, Idaho.

 

- See more at: http://worlddrugtracker.blogspot.in/#sthash.RfMvYLLf.dpuf

Aripiprazole

7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]- 3,4-dihydro-2(1H)-quinolinone.

END AUG 2014

The US Food and Drug Administration (FDA) has received a new drug application (NDA) from Ireland-based Alkermes for its aripiprazole lauroxil to treat schizophrenia.

Aripiprazole lauroxil is an injectable atypical antipsychotic with one-month and two-month formulations, developed for the treatment of schizophrenia, which is a chronic, severe and disabling brain disorder.

The company has submitted the application based on positive results from the pivotal phase three study that assessed the efficacy and safety of aripiprazole lauroxil, where the drug demonstrated significant improvements in schizophrenia symptoms when compared to a placebo.

Alkermes CEO Richard Pops said: “We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options, to help meet the individual needs of patients and their healthcare providers.

“These attributes, together with the robust clinical data observed in the pivotal study, position aripiprazole lauroxil to be a meaningful new entrant in the growing long-acting injectable antipsychotic market, and we look forward to working with the FDA to bring this important new medication to patients and physicians as quickly as possible.”

The study, in which both doses of aripiprazole lauroxil tested, including 441mg and 882mg, reached the primary endpoint with statistically significant and clinically meaningful reductions in positive and negative syndrome scale (PANSS) scores, according to the company.

In addition, it met all secondary endpoints and demonstrated significant improvements in schizophrenia symptoms against the placebo.

• ALKS 9070
• ALKS 9072
• Aripiprazole lauroxil
• RDC 3317
• RDC-3317
• UNII-B786J7A343

Aripiprazole lauroxil [USAN]  CAS  1259305-29-7

Systematic (IUPAC) name
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Trade names	Abilify
AHFS/Drugs.com	monograph
MedlinePlus	a603012
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
Pharmacokinetic data
Bioavailability	87%[1][2][3][4]
Protein binding	>99%[1][2][3][4]
Metabolism	Hepatic (liver; mostly via CYP3A4 and CYP2D6[1][2][3][4])
Half-life	75 hours (active metabolite is 94 hours)[1][2][3][4]
Excretion	Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)[1][2][3][4]
Identifiers
CAS number	129722-12-9
ATC code	N05AX12
PubChem	CID 60795
IUPHAR ligand	34
DrugBank	DB01238
ChemSpider	54790
UNII	82VFR53I78
KEGG	D01164
ChEBI	CHEBI:31236
ChEMBL	CHEMBL1112
Chemical data
Formula	C23H27Cl2N3O2
Mol. mass	448.385

Aripiprazole (/ˌɛərɨˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an add on to other treatment), tic disorders, and irritability associated with autism.^[5]

It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;^[6] and to treat irritability in children with autism on 20 November 2009.^[7] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.^[1]

Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Regulator status

In the United States, the FDA has approved aripiprazole for the treatment of schizophrenia in adults and adolescents (aged 13–17), of manic and mixed episodes associated with Bipolar I (One) Disorder with or without psychotic features in adults, children and adolescents (aged 10–17),^[59] of irritability associated with autism in pediatric patients (aged 6–17),^[60] and of depression when used along with antidepressants in adults.^[61]

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.^[62]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.^[63] It has not been FDA-approved for use as monotherapy in unipolar depression.

Patent status

Otsuka’s US patent on aripiprazole expires on October 20, 2014;^[64] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[62] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.^[65] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]

Dosage forms

Abilify 2mg tablets (US)

• Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
• Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
• Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
• Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

Synthesis

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:^[66]

U.S. Patent No.4, 734, 416 and U.S. Patent No.5,006,528 discloses the Aripiprazole, 7-{4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy}- 3,4-dihydro-2 (IH) -quinolinone or 7-{4-[4- (2, 3-dichlorophenyl) -1- piperazinyl] butoxy}-3, 4-dihydro carbostyril, is a typical antipsychotic agent useful for the treatment of Schizophrenia, having the formula as given below.

Aripiprazole

U.S. patent No.5,006,528 discloses preparation of Aripiprazole and its pharmaceutically acceptable acid-addition salts. The process for the preparation of acid salts involves reaction of Aripiprazole with a pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; organic acids such as oxalic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, . benzoic acid and the like as per Scheme-1. Scheme- 1

 

a. K₂CO₃, Water K CH₂CI₂ c. Column chromatographic purification d. n-Hexane – Ethaπol

ARIPIPRAZOLE ACID SALT

The product Aripiprazole _.obtained by the above process has melting point of 139.0° – 139.5°C.

The process involves purification of the intermediate, 7-(4- bromobutoxy) -3, 4-dihydrocarbostyril (III) by silica gel column chromatography to remove impurities formed during the reaction. The process further involves two recrystallizations of Aripiprazole from ethanol to obtain the pure Aripiprazole though compromising on yields by increasing the operational cost of the product. PCT publication WO 03/026659 discloses low hygroscopic forms of

Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form ^SA’ . It further states that the anhydrous

Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per PCT publication WO 03/026659 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals. Further discloses that the type-I crystals are prepared -by recrsytallization from ethanol solution of

Aripiprazole or by heating Aripiprazole hydrate at 80⁰C and type-II crystals by heating type-I crystals at 130 to 140⁰C for 15 hrs.

PCT application Publication WO 03/026659 discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate

‘A’ at 90 – 125°C for about 3 – 50 hrs. The process for Polymorphic

Form-C is by heating the Aripiprazole anhydrous to a temperature of 140

- 150⁰C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 170⁰C for at least 2 weeks in a sealed tube, which is a glassy mass.

PCT publication WO 03/026659 further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G.It further reported the melting point of Aripiprazole anhydrous Form B as 139.7°C-

Research

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behavior in animal models without significantly affecting other rewarding behaviors (such as food self-administration).^[67] Aripiprazole may be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine’s stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine.^[68]

http://www.google.com/patents/WO2006030446A1?cl=en

Scheme-3

Aripiprazole Acid addition salt

Form-A, B, C , D , E , F Type-I & Type-II Aripiprazole acid salts used for the preparation of polymorphs

…………………………….

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2 (1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U.S. Pat. No. 4,74,416 and U.S. Pat. No. 5,006,528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent, than Alzheimer’s disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.

Aripiprazole (Aripiprazole) is an atypical antipsychotic, on 15 November 2002 by the U.S. FDA clearance to market, its efficacy is through the dopamine D2 receptor and serotonin 5HT1A receptor partial agonist activity and serotonin 5HT2A receptor antagonism activity mediated common. With its unique mechanism of action and safety assessment, aripiprazole known as third-generation antipsychotic drugs.

[0003] Aripiprazole is a quinolinone derivative, developed by the Japanese company Otsuka Pharmaceutical, the chemical name

Is: 7 – {4 – [4 - (2,3 - dichlorophenyl)-1_ piperazinyl] butoxy} -3,4 – dihydro-quinolone, the following structural formula:

[0004]

[0005] For the preparation of aripiprazole, Japanese OtsukaPharmaceutical’s patent EP 0367141A2, and related patents US4234585, CN89108934 preparation methods described in 5. In addition, the patent CN1450056A, CN1562973A, CN1784385A, CN1680328A, CN1576273A, etc. describe some of these five Preparation

Method is very similar way. These preparation methods are direct or indirect use of 7 – hydroxy -3,4 – dihydro – quinolin-2 – one (HCS) that the key to higher prices of raw materials, and some methods involve harsh reaction conditions, poor selectivity, low yield, but also increases the cost of industrial production of the product.

[0006] Chinese patent CN1304373C preparation method is not described in the 7 – hydroxy-3 ,4 _ dihydro-2_ (1H) – quinoline

Quinolone intermediates for their preparation of the core reaction is as follows:

[0007]

[0008] This reaction is Friedel-Crafts alkylation reaction, there is a harsh reaction conditions, the yield is low, the reaction selectivity is poor, the shortcomings of high emissions, is not conducive to industrial mass production. SUMMARY OF THE INVENTION

[0009] In order to solve the above problems, the present invention provides a simple, high selectivity, high yield, low cost, environmentally friendly, easy to prepare industrialization aripiprazole and intermediates thereof.

[0010] The technical solution of the present invention, the present invention provides in one aspect a process for preparingaripiprazole novel intermediates.

[0011] The present invention, on the other hand provides a method for the preparation of intermediates.

[0012] The present invention provides the use of the other intermediates for preparing aripiprazole two new preparation methods.

[0013] Specifically, the present invention relates to novel intermediates, compounds of formula ⑴:

[0014]

[0015] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl and other common alkyl groups in any one, and preferably is ethyl.

[0016] Compound of formula ⑴: 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate, is the following prepared by the procedure:

[0017] Step one, the acylation reaction: with 4 – methyl – 3 – nitro-phenol (VIII) and acetic anhydride as the raw material, DMAP as catalyst, to give 4 – methyl – 3 – nitrophenyl acetate ( VII).

[0018] wherein 4 – methyl – 3 – nitro-phenol (VIII), acetic anhydride, DMAP molar ratio is preferably 1: 1.0 to 1.4: 0.05, at room temperature, the reaction time is preferably 0.5 to 3 hours.

[0019] Step two, the bromination reaction: The resulting product, 4 to Step one – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide and benzoyl peroxide as a raw material , carbon tetrachloride solvent reflux, to give 4 – bromomethyl-3 – nitrophenyl acetate (VI).

[0020] wherein 4 – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide, benzoyl peroxide molar ratio is preferably 1: 1 to 1.2: 0.05, reaction time is preferably 4-18 hours.

[0021] Step three, instead of the reaction: in an appropriate solvent, adding an alkaline agent and diethyl malonate was stirred in an ice bath, was added dropwise step two the resulting product, 4 – bromomethyl-3 – nitrophenyl yl acetate (VI) solution after completion of the addition reaction of 1 to 3 hours to obtain a brown liquid product, 2 – (4_ acetoxy-2 – nitrobenzyl) malonate (V).

[0022], wherein the alkali agent is a common organic or inorganic base selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the solvent is selected from tetrahydrofuran, methanol, ethanol, butanol, tert-butanol, toluene or N, N-dimethylformamide; 4 – bromomethyl-3 – nitrophenyl acetate (VI), alkaline agent and lipid diethyl molar ratio is preferably 1: 1.0 to 1.8: 1.0 to 1.4.

[0023] Step 4 Hydrolysis decarboxylation: the product obtained in Step Three 2 – (4_ acetoxy-2 – nitro-benzyl)-malonic acid diethyl ester (V) was added concentrated hydrochloric acid and a suitable solvent, heating and stirring reflux, to give a yellow solid product 3 – (4_ hydroxy-2 – nitrophenyl) propionic acid (IV).

[0024] wherein the solvent is selected from water, methanol, ethanol or acetic acid, water soluble solvent, was heated with stirring under reflux time is preferably 3 to 18 hours. [0025] Step five, the esterification reaction: the product obtained in step 4, 3 – (4 – hydroxy-2 – nitrophenyl) propionic acid (IV) was added to an appropriate solvent, the mixture was stirred in an ice bath, was added dropwise thionyl sulfone, after completion of the addition reaction of 1 to 3 hours, to give a pale brown liquid product 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III).

[0026] wherein the solvent is selected from anhydrous methanol, ethanol, propanol, isopropanol, butanol, t-butanol, benzyl alcohol, alcohol and other common solvents.

[0027] Step VI substitution reaction: 1,4 – dibromobutane was added to an appropriate solvent and an alkaline reagent, heated to 50 ~ 100 ° C, the product obtained was added dropwise Step Five 3 – (4_ hydroxy – nitrophenyl) propionate (III) solution, after the addition was complete the reaction was kept 2 to 4 hours to obtain a brown liquid product 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II).

[0028] wherein the solvent is selected from methanol, 95% ethanol, ethanol, acetonitrile and N, N-dimethylformamide, and the like; said alkaline agent is a common organic or inorganic weak base, such as triethylamine, pyridine, potassium carbonate, sodium carbonate, etc..

[0029] Step 7 condensation reaction: the product obtained in Step Six 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II) adding a suitable solvent, (2,3 – dichlorophenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, to obtain

The intermediate product 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl)-piperazin-1 – yl) butoxy)-2 – nitrophenyl) propionate ⑴.

[0030] Among them, 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate (I), (2, 3 – dichloro-phenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, the four molar ratio is preferably 1: 0.9 to 1.0: 2.0 to 2.2: 0.05 to 0.5. The solvent is selected from methanol, ethanol and N, N-dimethylformamide, acetonitrile and the like. Step six of the alkaline reagent and alkaline reagent used in the same, said catalyst is a common low-iodine salts, such as sodium iodide, potassium iodide.

[0031] The present invention provides two other hand, the use of a compound of formula ⑴ preparing aripiprazole new method.

[0032] Method one: ⑴ intermediate compound of formula in an appropriate solvent in the acid or salt or a base in the presence of a reducing agent under the action of restoring ring closure reaction to obtain aripiprazole.

[0033] Method one reductive cyclization of the reducing agent used is iron, zinc, sodium sulfide, stannous chloride, and preferably iron; reaction solvent is selected from water, methanol, ethanol, ethyl acetate or in one or more of the mixed solvent; said acid is a common organic or inorganic acid, preferably acetic acid or hydrochloric acid; said salt is a common inorganic or organic salts selected from chloride, ferrous chloride, , ammonium sulfate, calcium chloride, zinc chloride, sodium chloride, sodium bromide or sodium acetate and the like; common said base is an inorganic base selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate; the reduction ring-closing reaction temperature range of 30 ~ 140 ° C, preferably about 80 ° C; reaction time ranges from about 0.5 to 8 hours, preferably 2 hours.

[0034] Method two: ⑴ intermediate compound of formula in an appropriate solvent in the first catalyst, the reduction reaction, and then carried out in a suitable solvent can be prepared by cyclization of aripiprazole.

[0035] The reduction reaction of the second approach, the reducing agent is hydrogen or a carboxylic acid; the catalyst is selected from molybdenum, molybdenum dioxide or Raney nickel, preferably Raney nickel; the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid, preferably ethanol; said ring-closing reaction of the solvent is selected from N, N-dimethylformamide, trichlorobenzene or xylene; reaction temperature range of 50 ~ 180 ° C, preferably about 70 ~ 150 ° C; reaction time the range of about 1 to 8 hours.

[0036] In summary, the present invention is described for preparing aripiprazole method in 4– methyl – 3 – nitro-phenol (VIII) as a starting material, by acetylation protected hydroxy, radical instead of 4 – bromomethyl-3 – nitrophenyl acetate (VI), the diethyl malonate and a nucleophilic substitution reaction to obtain 2 – (4_ acetoxy-2 – nitrobenzyl ) malonic acid diethyl ester (V), which is decarboxylated by hydrolysis, esterification, to give 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III), the reaction product with dibromobutane an ether compounds, and with (2,3 – dichlorophenyl)-piperazine hydrochloride 1_ condensation, to give 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl) piperazine -1 – yl) butoxy) -2 – nitrophenyl) propionate (I), and then by reductive cyclization step, or first reduced and then ring-closing reaction of aripiprazole. The synthetic route of the present invention is as follows: [0037]

According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, anhydrous aripiprazole crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting raw anhydrousaripiprazole with ethanol. Also, according to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996), anhydrousaripiprazole crystals are manufactured by heating aripiprazole hydrate at 80° C. However, the anhydrous aripiprazole crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.

The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must be taken in order ensure they are not exposed to moisture during process and formulation. Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages. First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms ofaripiprazole. Second, the variation in the amount of hydrous versus anhydrousaripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may cause the drug substance, Conventional Anhydrous Aripiprazole, to adhere so manufacturing equipment which may further result in processing delay, increased operator involvement, increased cost, increased maintenance, and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic crystals, the potential for absorbance of moisture during storage and handling would adversely affect the dissolubility of aripiprazole drug substance. Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopicity thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.

Also, Proceedings of the 4 the Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystals exist as type-I crystals and type-II crystals; the type-I crystals of anhydrous aripiprazolecan be prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C.; and the type-II crystals of anhydrousaripiprazole can be prepared by heating the type-I crystals of anhydrousaripiprazole at 130 to 140° C. for 15 hours.

By the aforementioned methods, anhydrous aripiprazole type-II crystals having high purity can not be easily prepared in an industrial scale with good repeatability.

Chemical Synthesis of Aripiprazole (active ingredient for Abilify)

Experimental Procedures for the preparation of Aripiprazole (Abilify, aripiprazole)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps The first step comprises synthesis of 7 -. (4-bromobutoxy) -3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3, 4 -dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield The resulting 7-BBQ is further reacted with 1 -. (2,3 – dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7 – (4-Bromobutoxy) 3 ,4-dihydro-2 (1H) quinolinon ( 7 – (4-Bromobutoxy) 3 ,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3 ,4-dihydro-2 (1H)-quinolinone (aka 7-Hydroxy-3 ,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40 – 45 ° C for 24 hours Reaction mass was cooled upto room temperature and was filtered off The resulting filtrate was distilled off.. under vacuum. The resultant mass was cooled to 25-30 ° C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The . solid was filtered and dried under vacuum at 55-60 ° C for 20 hours to obtain title compound mp 110.5-111 ° C; 1H NMR (DMSO-d6) ä 1.81 (2H, m,-CH2-), 1.95 (2H , m,-CH2-), 2.41 (2H, t, J) 7 Hz,-CH2CO-), 2.78 (2H, t, J) 7 Hz,-CH2-C-CO-), 3.60 (2H, t, J) 6 Hz,-CH2Br), 3.93 (2H, t, J) 6 Hz, O-CH2-), 6.43 (1H, d, J) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz ), 7.04 (1H, d, J) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7 – {4 – [4 - (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One)

7 – (4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30 ° C. To this potassium carbonate (67.2 gm) and l – (2,3 – dichlorophenyl). piperazine hydrochloride (44.9gm) were added under stirring The reaction mixture was refluxed at 80-85 ° C for 8 hours The reaction mass was cooled to room temperature, filtered and the resulting solid was washed. with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80 ° C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to . obtain title compound Yield: 75-80%; Dimer Impurity: <0.1% 1H NMR:. DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar ]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t,-CH2-O-]; 2.97 [4H, bb, 2 ( -CH2-)]; 2.78 [2H, t,-CH2-N2-)]; 2.39 [4H, m, 2 (-CH2-)]; 1.73 [2H, m, - CH2-]; 1.58 [2H, m .,-CH2-] IR: cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588 .

No Generic Abilify in the US until April 2015

On May 7, 2012, The US Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. In its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify ®.. The Federal Circuit Affirmed a Decision of the U.S. District Court for the District of New Jersey Holding that the asserted claims ofU.S. Patent No. 5,006,528 Covering aripiprazole, the active Ingredient in Abilify ®, are Valid, THUS Maintaining Patent and Regulatory Protection for Abilify ® in the U.S. until at least April 20, 2015 . The Case is Otsuka Pharma Co.. V. sand Inc.., 2011-1126 and 2011-1127, US Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, US District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole (Abilify for active Ingredient): 7 – {4 – [4 - (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One
CAS Number 129722 -12-9
aripiprazole chemical name 7 – [4 – [4 - (2,3 - dichlorophenyl) -1 - piperazinyl] butoxy] -3,4 – dihydro-2 ( 1H) – quinolinone

Aripiprazole (, Aripiprazole, Abilify) is an atypical antipsychotic medication for the quinoline derivatives, aripiprazole is a dopamine system stabilizer first, positive and schizophrenia negative symptoms have a significant effect. For the treatment of schizophrenia, the development of Otsuka Pharmaceutical Co., Ltd., in November 15, 2002 by the U.S. Food and Drug Administration (FDA) approval in the U.S., domestic aripiprazole has (Booz clear (brisking, manufacturers : Chengdu Nakasone Pharmaceutical), Austrian (Manufacturer: Shanghai Pharmaceutical Co., Ltd. and Western)) have been approved by the listing in China. On sale in the United States where the law by Bristol-Myers Squibb is responsible. An law where the main patent protection in the United States, and more than three-quarters of its sales from the U.S., patent will expire in April 2015.

Aripiprazole synthetic route

7 – hydroxy-3 ,4. Dihydro -2 (1H) – quinolinone as a starting material, 1,4. Dibromobutane ether to give 7 – (4 – Bromo-butoxy) -3,4 – dihydro – 2 (1H) quinolinone, and then with 1 – (2,3 – dichlorophenyl) piperazine acid condensation aripiprazole (7 – [4 – [4 - (2,3 - dichlorophenyl) -1 - piperazinyl] butoxy] -3,4 – dihydro -2 (1H) – quinolinone)

Aripiprazole preparation method

7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone
A reaction flask was added 7 – hydroxy – 3,4 – dihydro -2 (1H) – quinolone 32.6 g (0.2mol), 1,4 – dibromo butane 129.5g (0.6mol), 11.2% KOH solution 250ml (0.5mol) and DMF975ml, was heated to 60 º C for 2h diluted with 1L water, the aqueous layer with ethyl acetate. acetate (300ml × 2) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover the solvent, the residue was recrystallized from isopropanol, to give 7 – (4 – Bromo-butoxy) – 3,4 – dihydro -2 (1H) – quinolone 38.7g, yield 68%, mp108 ~ 110 º C.

Synthesis of aripiprazole
in the reaction flask was added 7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone, 29.8g (0.1mol), KI25g (0.15mol) 95% Ethanol 596ml, stirred and heated to 60 º C, was added N-2 30min after 3 – dichlorophenyl piperazine 23.1g (0.1mol) and triethylamine 20ml (0.15mol), stirred for 8h at 60 º C the mixture is filtered. crystallization filtrate was cooled, filtered and the filter cake was recrystallized twice from ethanol and dried to obtain aripiprazole 25.6g, yield 57%, mp138.9 ~ 139.6 º C.

References

External links

• Abilify website
• Abilify Full Prescribing Information (for Health Care Professionals)
• U.S. National Library of Medicine: Drug Information Portal – Aripiprazole
• Abilify adverse events reported to the FDA
• Mechanism of Action Of Aripiprazole