Home » Posts tagged 'PHASE 3' (Page 14)

Tag Archives: PHASE 3

With Persistence And Phase 3 Win, Amicus Nears First Drug Approval …….Migalastat

August 21, 2014 10:56 am / Leave a comment

Migalastat hydrochloride

CAS Number: 75172-81-5 hydrochloride

CAS BASE….108147-54-2

ABS ROT = (+)

+53.0 °

Conc: 1 g/100mL; Solv: water ; 589.3 nm; Temp: 24 °C

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.

Chemical Name:	DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE
Synonyms:	DGJ;Amigal;Unii-cly7m0xd20;GALACTOSTATIN HCL;DGJ, HYDROCHLORIDE;Migalastat hydrochloride;Galactostatin hydrochloride;DEOXYGALACTONOJIRIMYCIN HCL;1-DEOXYGALACTONOJIRIMYCIN HCL;1,5-dideoxy-1,5-imino-d-galactitol

DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE Structure

………………………..

Links

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.

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).

………………………

Links

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:

Example 1: Preparation and Purification of DGJ

A protected crystalline galactofuranoside obtained from the technique described by Santoyo-Gonzalez. 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-α-D- galactofuranoside (1250 g), was hydrogenated for 1-2 days using methanol (10 L) with palladium on carbon (10%, wet, 44 g) at 50 psi of H₂. Sodium methoxide (25% in methanol, 1.25 L) was added and hydrogenation was continued for 1-2 days at 100 psi ofH₂. Catalyst was removed by filtration and the reaction was acidified with methanolic hydrogen chloride solution (20%, 1.9 L) and concentrated to give crude mixture of DGJ • HCl and sodium chloride as a solid. The purity of the DGJ was about 70% (w/w assay), with the remaining 30% being mostly sodium chloride.

The solid was washed with tetrahydrofuran (2 x 0.5 L) and ether (I x 0.5 L), and then combined with concentrated hydrochloric acid (3 L). DGJ went into solution, leaving NaCl undissolved. The obtained suspension was filtered to remove sodium chloride; the solid sodium chloride was washed with additional portion of hydrochloric acid (2 x 0.3 L). All hydrochloric acid solution were combined and slowly poured into stirred solution of tetrahydrofuran (60 L) and ether (11.3 L). The precipitate formed while the stirring was continued for 2 hours. The solid crude DGJ* HCl, was filtered and washed with tetrahydrofuran (0.5 L) and ether (2 x 0.5 L). An NMR spectrum is shown in FIGS. 2A-2B.

The solid was dried and recrystallized from water (1.2 mL /g) and ethanol (10 ml/1 ml of water). This recrystallization step may be repeated. This procedure gave white crystalline DGJ* HCl, and was usually obtained in about 70- 75% yield (320 – 345 g). The product of the purification, DGJ-HCl is a white crystalline solid, HPLC >98% (w/w assay) as shown in FIG. 1. FIGS. 3A-3D and FIG. 4 show the NMR spectra of purified DGJ, showing the six sugar carbons.

Example 2: Purification of 1-deoxymannojirimycin 1 -deoxymannojirimycin is made by the method described by Mariano

(J. Org. Chem., 1998, 841-859, see pg. 859, herein incorporated by reference). However, instead of purification by ion-exchange resin as described by Mariano, the 1-deoxymannojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the 1-deoxymannojirimycin hydrochloride is precipitated crystallized using solvents known for recrystallization of 1- deoxymannojirimycin (THF for crystallization and then ethanol/water.

Example 3: Purification of (+)-l-deoxynojirimycin

(+)-l-deoxynojirimycin is made by the method Kibayashi et al. (J. Org. Chem., 1987, 3337-3342, see pg. 334I₅ herein incorporated by reference). It is synthesized from a piperidine compound (#14) in HCl/MeOH. The reported yield of 90% indicates that the reaction is essentially clean and does not contain other sugar side products. Therefore, the column chromatography used by Kibayashi is for the isolation of the product from non-sugar related impurities. Therefore, instead of purification by silica gel chromatography, the (+)-l-deoxynojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

Example 4: Purification of Nojirimycin

Nojirimycin is made by the method described by Kibayashi et al. (J.

Org. Chem., 1987, 3337-3342, see pg. 3342). However, after evaporating of the mixture at reduced pressure, instead of purification by silica gel chromatography with ammonia-methanol-chloroform as described by Kibayashi, the nojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the impurities not dissolved in HCl and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

……………………….

Links

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.

………………………

Links

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

……………………………..

Links

SEE

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

Chem Ber 1980, 113(8): 2601

…………………………

Links

Org. Lett., 2010, 12 (17), pp 3957–3959

DOI: 10.1021/ol101556k

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

+53.0 °

Conc: 1 g/100mL; Solv: water ; 589.3 nm; Temp: 24 °C

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%.

Figure 1. Structures of nojirimycin (1) and DGJ (2).

SEE SUPP INFO

http://pubs.acs.org/doi/suppl/10.1021/ol100037c/suppl_file/ol100037c_si_001.pdf

(-)-1-deoxygalactojirimycin hydrochloride as transparent colorless needles.

[α]D -51.4 (D2O, c 1.0)

1H-NMR (D2O) δ ppm 4.09 (dd, 1H, J 2.9 Hz, 1.3 Hz), 4.00 (ddd, 1H, J = 11.3 Hz, 9.7 Hz, 5.3 Hz),

3.80 (dd, 1H, J = 12,1 Hz, 8.8 Hz), 3.73 (dd, 1H, J = 12.1 Hz, 8.8 Hz), 3.56 (dd, 1H, J = 9.7 Hz, 2.9

Hz), 3.44 (dd, 1H, J = 12.4 Hz, 5.3 Hz), 3.34 (ddd, 1H, J = 8.7 Hz, 4.8 Hz, 1.0 Hz), 2.8 (app. t, 1H,

J = 12.0 Hz)

13C-NMR (D2O, MeOH iSTD) δ 73.6, 67.5, 65.3, 60.7, 59.7, 46.7

HRMS Measured 164.0923 (M + H – Cl) Calculated 164.0923 (C6H13NO4 + H – Cl)

…………………………………………………..

Links

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.

…………………………………………..

Links

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.

……………………………………………

Links

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.

…………………..

Links

J. Org. Chem., 1991, 56 (2), pp 815–819

DOI: 10.1021/jo00002a057

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

………………

Links

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.

Amat et al., “Eantioselective Synthesis of 1-deoxy-D-gluonojirimycin From A Phenylglycinol Derived Lactam,” Tetrahedron Letters, pp. 5355-5358, 2004.
2		Chernois, “Semimicro Experimental Organic Chemistry,” J. de Graff (1958), pp. 31-48.
3		Encyclopedia of Chemical Technology, 4th Ed., 1995, John Wiley & Sons, vol. 14: p. 737-741.
4		Heiker et al., “Synthesis of D-galacto-1-deoxynojirimycin (1, 5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin.” Carbohydrate Research, 203: 314-318, 1990.
5		Heiker et al., 1990, “Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin,” Carbohydrate Research, vol. 203: p. 314-318.
6	*	Joseph, Carbohydrate Research 337 (2002) 1083-1087.
7	*	Kinast et al. Angew. Chem. Int. Ed. Engl. 20 (1998), No. 9, pp. 805-806.
8	*	Lamb, Laboratory Manual of General Chemistry, Harvard University Press, 1916, p. 108.
9		Linden et al., “1-Deoxynojirimycin Hydrochloride,” Acta ChrystallographicaC50, pp. 746-749, 1994.
10		Mellor et al., Preparation, biochemical characterization and biological properties of radiolabelled N-alkylated deoxynojirimycins, Biochem. J. Aug. 15, 2002; 366(Pt 1):225-233.
11	*	Mills, Encyclopedia of Reagents for Organic Synthesis, Hydrochloric Acid, 2001 John Wily & Sons.
12		Santoyo-Gonzalez et al., “Use of N-Pivaloyl Imidazole as Protective Reagent for Sugars.” Synthesis 1998 1787-1792.
13		Schuller et al., “Synthesis of 2-acetamido-1, 2-dideoxy-D-galacto-nojirimycin (2-acetamido-1, 2, 5-trideoxy-1, 5-imino-D-galacitol) from 1-deoxynojirimycin.” Carbohydrate Res. 1990; 203: 308-313.
14		Supplementary European Search Report dated Mar. 11, 2010 issued in corresponding European Patent Application No. EP 06 77 2888.
15		Uriel et al., A Short and Efficient Synthesis of 1,5-dideoxy-1,5-imino-D-galactitol (1-deoxy-D-galactostatin) and 1,5-dideoxy-1,5-dideoxy-1,5-imino-L-altritol (1-deoxy-L-altrostatin) From D-galactose, Synlett (1999), vol. 5, pp. 593-595.

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.

(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.

Cortendo AB: First Patient Enrolled into NormoCort Phase 3 SONICS Trial Following a Successful EU Investigator Meeting

August 13, 2014 7:37 am / Leave a comment

KETOCONAZOLE 2S 4R

ALSO

142128-57-2
228850-16-6 (tartrate)

(-)-cis-1-Acetyl-4-[4-[2(S)-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4(R)-ylmethoxy]phenyl]piperazine

531.431, C26 H28 Cl2 N4 O4

COR-003
DIO-902
LDKTZ

CORTENDO

licensee DiObex

Biological Role(s):	antifungal agent An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.

Application(s):	antifungal agent An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.

Ketoconazole, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3– dioxolan-4-yl]methoxy]phenyl]piperazine, is a racemic mixture of the cis enantiomers (-)-(2S,4R) and (+)-(2R,4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis.(-)-Ketoconazole, the (2S,4R) enantiomer contained in the racemate of ketoconazole, is in phase III clinical trials at Cortendo for the treatment of endogenous Cushing’s syndrome. The company and licensee DiObex had also been developing the drug candidate for the treatment of type 2 diabetes; however, no recent development has been reported for this research.Preclinical studies have demonstrated the drug candidate’s ability to inhibit the synthesis of cortisol, resulting in substantial clinical benefits including lowering both blood pressure and cholesterol in addition to controlling glucose levels. It has also been shown that (-)-ketoconazole is responsible for virtually all of the cortisol synthesis inhibitory activity present in the racemate. Rights to the compound are shared with Cortendo.In 2012, orphan drug designation was assigned in the U.S. for the treatment of endogenous Cushing’s syndrome.

August 12, 2014 02:30 AM Eastern Daylight Time

GÖTEBORG, Sweden.–(BUSINESS WIRE)–Cortendo AB (OSE:CORT) today announced that the first patient has been enrolled into the Phase 3 SONICS trial, i.e., “Study Of NormoCort In Cushing’s Syndrome.”

“The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”

The patient was enrolled by one of the trial’s lead principal investigators at a Pituitary Center from a prestigious institution in Baltimore, Maryland. “The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”, said Dr. Theodore R Koziol. ”The SONICS clinical trial team is acutely focused on the implementation of the trial following a successful EU Investigator’s meeting in Barcelona in July, which we believe further solidified the foundation for the trial.”

Cortendo successfully completed its European Investigator meeting supporting SONICS held in Barcelona, Spain on July 17-18. More than 35 investigators/study coordinators, including many of the world’s leading Cushing’s experts from 24 study sites, were in attendance and received training for the trial. Based on the positive feedback from the meeting, Cortendo has gained further confidence that NormoCort (COR-003) has the potential to be an important future treatment option for patients afflicted with Cushing’s Syndrome. A second US Investigator meeting is also being planned for later this year.

”It was gratifying to participate in the NormoCort SONICS trial investigator meeting in my home town of Barcelona with so many esteemed colleagues dedicated to treating patients with Cushing’s Syndrome”, said Susan Webb M.D. Ph.D. Professor of Medicine Universitat Autonoma de Barcelona. ”There remains a significant unmet medical need for patients, and I am delighted to be part of the development of this new therapy”.

Cortendo has also further strengthened its internal as well as external teams to support the study and to position the trial for an increased recruitment rate. In July, Cortendo added both an experienced physician and internal Clinical Operations Director to the NormoCort development team. Cortendo, working in concert with its CROs supporting the SONICS trial, now has a team of approximately 20 personnel on the NormoCort development program.

Cortendo has previously communicated its plan to meet the recruitment goal by increasing the number of study sites from 38 to 45 worldwide. The company is at various levels of activation with more than 30 study sites to date. Therein, Cortendo expects a large proportion of the sites to be activated by the end of the third quarter this year and remains confident that essentially all sites will be open by the end of 2014.

Risk and uncertainty

The development of pharmaceuticals carries significant risk. Failure may occur at any stage during development and commercialization due to safety or clinical efficacy issues. Delays may occur due to requirements from regulatory authorities not anticipated by the company.

About Cortendo

Cortendo AB is a biopharmaceutical company headquartered in Göteborg, Sweden. Its stock is publicly traded on the NOTC-A-list (OTC) in Norway. Cortendo is a pioneer in the field of cortisol inhibition and has completed early clinical trials in patients with Type 2 diabetes. The lead drug candidate NormoCort, the 2S, 4R-enantiomer of ketoconazole, has been re-focused to Cushing’s Syndrome, and has entered Phase 3 development. The company’s strategy is to primarily focus its resources within orphan drugs and metabolic diseases and to seek opportunities where the path to commercialization or partnership is clear and relatively near-term. Cortendo’s business model is to commercialize orphan and specialist product opportunities in key markets, and to partner non-specialist product opportunities such as diabetes at relevant development stages.

Cortendo AB (publ)

Sweden: Box 47 SE-433 21 Partille Tel. / Fax: +46 (0)31-263010

USA: 555 East Lancaster Ave Suite 510 Radnor, PA 19087 Tel: +1 610-254-9200 Fax: +1 610-254-9245

This information was brought to you by Cision http://news.cision.com

Contacts

Alexander Lindström
Chief Financial Officer Office
+1 610 254 9200
Mobile : +1 917 349 7210
E-mail : alindstrom@cortendo.com

Ketoconazole, 1-acetyl-4- [4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl] methoxy] phenyl] piperazine, is a racemic mixture of the cis enantiomers (-)-(2S, 4R) and (+)-(2R, 4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis. Ergosterol is a key component of fungal cell walls.
More recently, ketoconazole was found to decrease plasma cortisol and to be useful, alone and in combination with other agents, in the treatment of a variety of diseases and conditions, including type 2 diabetes, Metabolic Syndrome (also known as the Insulin Resistance Syndrome, Dysmetabolic Syndrome or Syndrome X), and other medical conditions that are associated with elevated cortisol levels. SeeU.S. Patent Nos. 5,584,790 ; 6,166,017 ; and 6,642,236 , each of which is incorporated herein by reference. Cortisol is a stress-related hormone secreted from the cortex of the adrenal glands. ACTH (adenocorticotropic hormone) increases cortisol secretion. ACTH is secreted by the pituitary gland, a process activated by secretion of corticotropin releasing hormone (CRH) from the hypothalamus.
Cortisol circulates in the bloodstream and activates specific intracellular receptors, such as the glucocorticoid receptor (GR). Disturbances in cortisol levels, synthetic rates or activity have been shown to be associated with numerous metabolic complications, including insulin resistance, obesity, diabetes and Metabolic Syndrome. Additionally, these metabolic abnormalities are associated with substantially increased risk of cardiovascular disease, a major cause of death in industrialized countries. See Mårin P et al., “Cortisol secretion in relation to body fat distribution in obese premenopausal women.” Metabolism 1992; 41:882-886, Bjorntorp, “Neuroendocrine perturbations as a cause of insulin resistance.” Diabetes Metab Res Rev 1999; 15(6): 427-41, and Rosmond, “Role of stress in the pathogenesis of the metabolic syndrome.” Psychoneuroendocrinology 2005; 30(1): 1-10, each of which is incorporated herein by reference.
While ketoconazole is known to inhibit some of the enzymatic steps in cortisol synthesis, such as, for example, 17α hydroxylase (Wachall et al., “Imidazole substituted biphenyls: a new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer.” Bioorg Med Chem 1999; 7(9): 1913-24, incorporated herein by reference) and 11b-hydroxylase (Rotstein et al., “Stereoisomers of ketoconazole: preparation and biological activity.” J Med Chem 1992; 35(15): 2818-25) and 11β-hydroxy steroid dehydrogenase (11β-HSD) (Diederich et al., “In the search for specific inhibitors of human 11β-hydroxysteroid-dehydrogenases (11β-HSDs): chenodeoxycholic acid selectively inhibits 11β-HSD-L” Eur J Endocrinol 2000; 142(2): 200-7, incorporated herein by reference) the mechanisms by which ketoconazole decreases cortisol levels in the plasma have not been reported. For example, there is uncertainty regarding the effect of ketoconazole on the 11β-hydroxy steroid dehydrogenase (11β-HSD) enzymes. There are two 11β-HSD enzymes. One of these, 11β-HSD-I, is primarily a reductase that is highly expressed in the liver and can convert the inactive 11-keto glucocorticoid to the active glucocorticoid (cortisol in humans and corticosterone in rats). In contrast, the other, 11β-HSD-II, is primarily expressed in the kidney and acts primarily as an oxidase that converts active glucocorticoid (cortisol in humans and corticosterone in rats) to inactive 11-keto glucocorticoids. Thus, the plasma concentration of active glucocorticoid is influenced by the rate of synthesis, controlled in part by the activity of adrenal 11β-hydroxylase and by the rate of interconversion, controlled in part by the relative activities of the two 11β-HSD enzymes. Ketoconazole is known to inhibit these three enzymes (Diederich et al., supra) and the 2S,4R enantiomer is more active against the adrenal 11β-hydroxylase enzyme than is the 2R,4S enantiomer (Rotstein et al., supra). However, there are no reports describing the effect of the two ketoconazole enantiomers on either of 11β-HSD-I or 11β-HSD-II, so it is not possible to predict what effects, if any, the two different ketoconazole enantiomers will each have on plasma levels of the active glucocorticoid levels in a mammal.
Ketoconazole has also been reported to lower cholesterol levels in humans (Sonino et al. (1991). “Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients.” Clin Endocrinol (Oxf). 35(4): 347-52; Gylling et al. (1993). “Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia.” J Lipid Res. 34(1): 59-67) each of which is incorporated herein by reference). The 2S,4R enantiomer is more active against the cholesterol synthetic enzyme 14 αlanosterol demethylase than is the other (2R,4S) enantiomer (Rotstein et al infra). However, because cholesterol level in a human patient is controlled by the rate of metabolism and excretion as well as by the rate of synthesis it is not possible to predict from this whether the 2S,4R enantiomer of ketoconazole will be more effective at lowering cholesterol levels.
The use of ketoconazole as a therapeutic is complicated by the effect of ketoconazole on the P450 enzymes responsible for drug metabolism. Several of these P450 enzymes are inhibited by ketoconazole (Rotsteinet al., supra). This inhibition leads to an alteration in the clearance of ketoconazole itself (Brass et al., “Disposition of ketoconazole, an oral antifungal, in humans.” Antimicrob Agents Chemother 1982; 21(1): 151-8, incorporated herein by reference) and several other important drugs such as Glivec (Dutreix et al., “Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.” Cancer Chemother Pharmacol 2004; 54(4): 290-4) and methylprednisolone (Glynn et al., “Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion.” Clin Pharmacol Ther 1986; 39(6): 654-9). As a result, the exposure of a patient to ketoconazole increases with repeated dosing, despite no increase in the amount of drug administered to the patient. This exposure and increase in exposure can be measured and demonstrated using the “Area under the Curve” (AUC) or the product of the concentration of the drug found in the plasma and the time period over which the measurements are made. The AUC for ketoconazole following the first exposure is significantly less than the AUC for ketoconazole after repeated exposures. This increase in drug exposure means that it is difficult to provide an accurate and consistent dose of the drug to a patient. Further, the increase in drug exposure increases the likelihood of adverse side effects associated with ketoconazole use.
[0008]

Rotstein et al. (Rotstein et al., supra) have examined the effects of the two ketoconazole cis enantiomers on the principal P450 enzymes responsible for drug metabolism and reported “…almost no selectivity was observed for the ketoconazole isomers” and, referring to drug metabolizing P450 enzymes: “[t]he IC50 values for the cis enantiomers were similar to those previously reported for racemic ketoconazole”. This report indicated that both of the cis enantiomers could contribute significantly to the AUC problem observed with the ketoconazole racemate.
One of the adverse side effects of ketoconazole administration exacerbated by this AUC problem is liver reactions. Asymptomatic liver reactions can be measured by an increase in the level of liver specific enzymes found in the serum and an increase in these enzymes has been noted in ketoconazole treated patients (Sohn, “Evaluation of ketoconazole.” Clin Pharm 1982; 1(3): 217-24, and Janssen and Symoens, “Hepatic reactions during ketoconazole treatment.” Am J Med 1983; 74(1B): 80-5, each of which is incorporated herein by reference). In addition 1:12,000 patients will have more severe liver failure (Smith and Henry, “Ketoconazole: an orally effective antifungal agent. Mechanism of action, pharmacology, clinical efficacy and adverse effects.” Pharmacotherapy 1984; 4(4): 199-204, incorporated herein by reference). As noted above, the amount of ketoconazole that a patient is exposed to increases with repeated dosing even though the amount of drug taken per day does not increase (the “AUC problem”). The AUC correlates with liver damage in rabbits (Ma et al., “Hepatotoxicity and toxicokinetics of ketoconazole in rabbits.” Acta Pharmacol Sin 2003; 24(8): 778-782 incorporated herein by reference) and increased exposure to the drug is believed to increase the frequency of liver damage reported in ketoconazole treated patients.
Additionally, U.S. Patent No. 6,040,307 , incorporated herein by reference, reports that the 2S,4R enantiomer is efficacious in treating fungal infections. This same patent application also reports studies on isolated guinea pig hearts that show that the administration of racemic ketoconazole may be associated with an increased risk of cardiac arrhythmia, but provides no data in support of that assertion. However, as disclosed in that patent, arrhythmia had not been previously reported as a side effect of systemic racemic ketoconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic ketoconazole was administered concurrently with terfenadine. Furthermore several published reports (for example, Morganroth et al. (1997). “Lack of effect of azelastine and ketoconazole coadministration on electrocardiographic parameters in healthy volunteers.” J Clin Pharmacol. 37(11): 1065-72) have demonstrated that ketoconazole does not increase the QTc interval. This interval is used as a surrogate marker to determine whether drugs have the potential for inducing arrhythmia. US Patent Number 6,040,307 also makes reference to diminished hepatoxicity associated with the 2S,4R enantiomer but provides no data in support of that assertion. The method provided in US Patent Number 6,040,307 does not allow for the assessment of hepatoxicity as the method uses microsomes isolated from frozen tissue.

…………………………

http://www.google.com/patents/EP1853266B1?cl=en

DIO-902 is the single enantiomer 2S,4R ketoconazole and is derived from racemic ketoconazole. It is formulated using cellulose, lactose, cornstarch, colloidal silicon dioxide and magnesium stearate as an immediate release 200 mg strength tablet. The chemical name is 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxyl]phenyl] piperazine, the formula is C₂₆H₂₈Cl₂N₄O₄, and the molecular weight is 531.44. The CAS number is 65277-42-1, and the structural formula is provided below. The chiral centers are at the carbon atoms 2 and 4 as marked.

[0132]

Ketoconazole is an imidazole-containing fungistatic compound. DIO-902 is an immediate release tablet to be taken orally and formulated as shown in the table below.

Component	Percentage
2S,4R ketoconazole; DIO-902	50%
Silicified Microcrystalline Cellulose, NF (Prosolv HD 90)	16.5
Lactose Monohydrate, NF (316 Fast-Flo)	22.4
Corn Starch, NF (STA-Rx)	10
Colloidal Silicon Dioxide, NF (Cab-O-Sil M5P)	0.5
Magnesium Stearate, NF	0.6

The drug product may be stored at room temperature and is anticipated to be stable for at least 2 years at 25° C and 50% RH. The drug is packaged in blister packs.

ketoconazole 2S,4R enantiomer

ketoconazole 2S,4S enantiomer

ketoconazole 2R,4R enantiomer

ketoconazole 2R,4S enantiomer

……………………..

Journal of Medicinal Chemistry (Impact Factor: 5.61). 08/1992; 35(15):2818-25. DOI: 10.1021/jm00093a015

http://pubs.acs.org/doi/abs/10.1021/jm00093a015

…………………….

Enantioselective separation of ketoconazole enantiomers by membrane extraction

http://www.sciencedirect.com/science/article/pii/S1383586611001638

A new process has been developed to separate ketoconazole (KTZ) enantiomers by membrane extraction, with the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively. This system is established by adding hydrophobic l-isopentyl tartrate (l-IPT) in organic strip phase (shell side) and hydrophilic sulfobutylether-β-cyclodextrin (SBE-β-CD) in aqueous feed phase (lumen side), which preferentially recognizes (+)-2R,4S-ketoconazole and (−)-2S,4R-ketoconazole, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where KTZ enantiomers form four complexes with SBE-β-CD in aqueous phase and l-IPT in organic phase, respectively. The membrane is permeable to the KTZ enantiomers but non-permeable to the chiral selector molecules. Fractional chiral extraction theory, mass transfer performance of hollow fiber membrane, enantioselectivity and some experimental conditions are investigated to optimize the separation system. Mathematical model of I/II = 0.893e^0.039NTU for racemic KTZ separation by hollow fiber extraction, is established. The optical purity for KTZ enantiomers is up to 90% when 9 hollow fiber membrane modules of 30 cm in length in series are used.

Full-size image (10 K)

I, (−)-2S,4R-ketoconazole;
II, (+)-2R,4S-ketoconazole;
CDs, cyclodextrin derivatives;
l-IPT, l-isopentyl tartrate;
d-IPT, d-isopentyl tartrate;
HP-β-CD, hydroxypropyl-β-cyclodextrin;
Me-β-CD, methyl-β-cyclodextrin;
β-CD, β-cyclodextrin;
NTU, number of transfer units;
HTU, height of a transfer unit;
PVDF,polyvinylidene fluoride

…………………….

Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-

Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-epichlorohydrin

Original Research Article
Pages 1283-1294
Pelayo Camps, Xavier Farrés, Ma Luisa García, Joan Ginesta, Jaume Pascual, David Mauleón, Germano Carganico
Bromobenzoates (2R,4R)- and (2S,4S)-18, prepared stereoselectively from (R)- and (S)-epichlorohydrin, were transformed into (2R,4S)-(+)- and (2S,4R)-(−)-Ketoconazole, respectively, following the known synthetic protocols for the racemic mixture.

Tetrahedron Asymmetry 1995, 6(6): 1283

Stereoselective syntheses of both enantiomers of ketoconazole (1) from commercially available (R)- or (S)-epichlorohydrin has been developed. The key-step of these syntheses involves the selective substitution of the methylene chlorine atom by benzoate on a mixture of and or of their enantiomers, followed by crystallization of the corresponding cis-benzoates, (2S,4R)-18 or(2S,4S)-18, from which (+)- or (−)-1 were obtained as described for (±)-1. The ee’s of (+)- and (−)-ketoconazole were determined by HPLC on the CSP Chiralcel OD-H.

………………..

WO 1996029325

http://www.google.com/patents/WO1996029325A1?cl=en

The incidence of fungal infections has considerably increased over the last decades. Notwithstanding the utility of the antifungal compounds commercialized in the last 15 years, the investigation in this field is however very extensive. During this time, compounds belonging to the azole class have beer, commercialized for both the topical and oral administrations, such a class including imidazoles as well as 1,2,4-triazoles. Some of these compounds car. show m some degree a low gastrointestinal tolerance as well as hepatotoxycity.

A large number of pharmaceutically active compounds are commercialized as stereoisomeric mixtures. On the other hand, the case in which only one of said stereoisomers is pharmaceutically active is frequent.

The undesired enantiomer has a lower activity and it sometimes may cause undesired side-effects.

Ketoconazole (1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine), terconazole (1-[4-[[2(2,4-dichlorophenyl)-2-[(1H-1 , 2 ,4-triazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine) and other related azole antifungal drugs contain in their structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four possible stereoisomers are possible. These compounds are commercialized in the form or cis racemates which show a higher antifungal activity than the corresponding trans racemates.

The cis homochiral compounds of the present invention, which are intermediates for the preparation of enantiomerically pure antifungal drugs, have been prepared previously in the racemic form and transformed into the different azole antifungal drugs in the racemic form [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979). J . Med . Chem . , 26, 611 (1983), J . Med . Chem . , 27 , 894 (1984) and US 4,144,346, 4,223,036, 4,358,449 and 4,335,125].

Scheme 1 shows the synthesis described for racemic ketoconazole [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979)]. Scheme 1

)

The synthesis of racemic terconazole [J. Heeres et al., J. Med . Chem . , 26 , 611 11983)] is similar. differing in the introduction of a 1 H- 1 , 2,4-triazol-1-yl substituent in place of 1H-imidazol-1-yl and in the nature of the phenol used in the last step of the synthetic sequence, which phenol is 1-methylethyl-4-(4- hydroxyphenyl)piperazme instead of 1-acetyl-4-(4-nydroxyphenyl)piperazine.

The preparation of racemic itraconazole [J. Heeres et al., J. Med . Chem. , 27 , 894 (1984)] is similar to that of terconazole, differing only in the nature of the phenol used in the last step of the synthetic sequence.

In the class of azoles containing a 1,3-dioxolane ring and a piperazine ring and moreover they are pure enantiomers, only the preparation of (+)- and (-)-ketoconazole has been described [D. M. Rotstein et al., J. Med . Chem . , 35, 2818 (1992)] (Scheme 2) starting from the tosylate of (+)- and (-) 2,2-dimethyl-1,3-dioxolane-4-methanol.

Scheme 2

This synthesis suffers from a series of drawbacks, namely: a) the use of expensive, high molecular weight starting products which are available only on a laboratory scale, and b) the need for several chromatographies during the process in order to obtain products of suitable purity, which maKes said synthesis economically unattractive and difficult to apply industrially.

Recently (N. M. Gray, WO 94/14447 and WO 94/14446) the use of (-)-ketoconazole and (+)-ketoconazole as antifungal drugs causing less side-effects than (±)-ketoconazole has been claimed.

The industrial preparation of enantiomerically pure antifungal drugs with a high antifungal activity and less side-effects is however a problem in therapy. The present invention provides novel homochiral compounds which are intermediates for the industrial preparation of already known, enantiomerically pure antifungal drugs such as ketoconazole enantiomers, or of others which have not yet been reported in literature, which are described first in the present invention, such as (+)-terconazole and (-)-terconazoie, which show the cited antifungal action, allowing to attain the same therapeutical effectiveness using lower dosages than those required for racemic terconazole

Example 14 : (2S,4R)-(-)-1-acetyl-4-[4-[ [2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine, (2S,4R) -(- )-ketoconazole.

This compound is prepared following the process described above for (2R,4S)-(+)-ketoconazole. Starting from HNa (60-65% dispersion in paraffin, 32 mg, 0.80 mmol), 1-acetyl-4-(4-hydroxyphenyl)piperazine (153 mg, 0.69 mol) and (2S,4S)-(-)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH₃) (250 mg, 0.61 mmol), upon crystallization from an acetone:ethyl acetate mixture, (2S,4R) -(-)-ketoconazole is obtained [(2S,4R)-V Ar = 2,4-dichlorophenyl, Y = CH, Z = COCH₃] (196 mg, 61% yield) as a solid, m.p. 153-155ºC (lit. 155-157ºC); [α]_D ²⁰ = -10.50 (c = 0.4, CHCl₃) (lit. [α]_D ²⁵ = -10.58. c = 0.4, CHCl₃) with e.e. > 99% (determined by HPLC using the chiral stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1 % diethylamine as the eluent).

Figure imgf000007_0001

+ KETOCONAZOLE…. UNDESIRED

Example 7: (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.

To a suspension of NaH (dispersed in 60-65% paraffin, 19.2 mg, 0.48 mmol) in anhydrous DMSO (3 ml),

1-acetyl-4-(hydroxyphenyl)piperazine (102 mg, 0.46 mmol) is added and the mixture is stirred for 1 hour at room temperature. Then, a solution of (2R,4R) – (+)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH₃) (160 mg, 0.39 mmol) in anhydrous DMSO (5 ml) is added, and the mixture is heated at 80ºC for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with water

(20 ml) and extracted with CH₂Cl₂ (3 × 25 ml). The combined organic phases are washed with water (3 × 25), dried with Na₂SO₄ and the solvent is evaporated off under vacuum. The oily residue thus obtained is crystallized from an acetone:ethyl acetate mixture to give (2R,4S)-(+)-ketoconazole ( (2R, 4 S) -V , Ar 2,4-dichlorophenyl, Y = CH , Z = COCH₃ ) ( 110 mg , 5 3 % yie ld ) as a white solid, m.p. 155-156°C (lit. 154-156ºC), [α]_D ²⁰ = + 8.99 (c = 0.4, CHCl₃) (lit. [α]_D ²⁵ = + 8.22, c = 0.4, CHCl₃), with e.e. > 99% (determined by HPLC using the chirai stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1% of diethylamine, as the eluent; (+)-Ketoconazole retention time 73,28 min. (-)-Ketoconazole, retention time 79.06 min).

IR (KBr), ʋ : 2875, 1645, 1584, 1511, 1462, 1425, 1250, 103S, 313 cm^-1.

¹H NMR (500 MHz, CDCl₃), δ : 2.12 (s, 3H, COCH₃),

3.02 (m, 2H, 3-H₂), 3.05 (m, 2H, 5-H₂), 3.27 (dd, J= 9.5

Hz, J’=7.0 Hz, 1H) and 3.70 (dd, J=9.5 Hz, J’=5.0 Hz, 1 H) (4″-CH₂), 3.60 (m, 2H, 6-H₂), 3.76 (m, 2H, 2-H₂), 3.73 (dd, J=8.0 Hz, J’=5.0 Hz, 1H) and 3.86 (dd, J=8.0 Hz, J’=6.5 Hz, 1H) (5″-H₂), 4.34 (m, 1H, 4″-H), 4.40 (d, J=15.0 Hz, 1H) and 5.00 (d, J=15.0 Hz, 1H) (CH₂-N), 4.34

(m, 1H, 4″-H), 6.76 [d, J = 9.0 Hz, 2H, 2′(C6′ )-H], 6.88

[d, J=9.0 Hz, 2H, C3′(C5)-H], 6.96 (s, 1H, imidazole 5- H), 6.99 (s, 1H, imidazole 4-H), 7.25 (dd, J=8.5 Hz, J’=2.0 Hz, 1H, 5″‘-H), 7.46 (d, J=2.0 Hz, 1H, 3″‘-H),

7.53 (s, 1H, imidazole 2-H), 7.57 (d, J=8.5 Hz, 1H,

6″‘-H).

¹³C NMR (75.4 MHz, CDCI₃), δ : 21.3 (CH₃, COCH₃), 41.4 (CH₂, C₂), 46.3 (CH₂, C6), 50.6 (CH₂, C3), 51.0 (CH₂, C5), 51.2 (CH₂, CH₂-N), 67.6 [CH₂, C5″ and 4″-CH₂), 74.7 (CH, C4″), 108.0 (C, C2″), 115.2 [CH, C2′(6′)], 118.8 [CH, C3′(5′)], 121.2 (CH, imidazole C5), 127.2 (CH, C5″‘), 128.5 (CH, imidazole C4), 129.5 (CH, C6′”), 131.3 (CH, C3″‘), 133.0 (C, C2″‘), 134.6 (C, C1′”), 135.8 (C, C4″‘), 138.8 (CH, imidazole C2), 145.6 (C, C1′), 152.8 (C, C4’), 168.9 (C, CO).

…………………………

Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid
J Pharm Sci 1999, 88(6): 599

Experimental and theoretical analysis of the interaction of (±)-cis-ketoconazole with β-cyclodextrin in the presence of (+)-l-Tartaric acid (pages 599–607)

Enrico Redenti, Paolo Ventura, Giovanni Fronza, Antonio Selva, Silvia Rivara, Pier Vincenzo Plazzi and Marco Mor

Article first published online: 12 JUN 2000 | DOI: 10.1021/js980468o

http://onlinelibrary.wiley.com/doi/10.1021/js980468o/pdf

¹H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using β-cyclodextrin in the presence of (+)-l-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by ¹H and ¹³C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.

WO1993019061A1 *	Mar 10, 1993	Sep 30, 1993	Janssen Pharmaceutica Nv	Itraconazole and saperconazole stereoisomers
WO1994025452A1 *	Apr 28, 1994	Nov 10, 1994	Ashit K Ganguly	Process for preparing intermediates for the synthesis of antifungal agents
EP0050298A2 *	Oct 13, 1981	Apr 28, 1982	Hoechst Aktiengesellschaft	1-(1,3-Dioxolan-2-ylmethyl) azoles, process for their preparation and their use
EP0052905A1 *	Nov 19, 1981	Jun 2, 1982	Janssen Pharmaceutica N.V.	Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives
US5208331 *	Jun 18, 1992	May 4, 1993	Syntex (U.S.A.) Inc.	Process for preparing 1,3-dioxolane derivatives

Decernotinib … JAK inhibitor for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis.

July 21, 2014 5:12 am / Leave a comment

Decernotinib

Chemical structure for Decernotinib

Decernotinib

N2-[2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]-N-(2,2,2-trifluoroethyl)-D-isovalinamide

(R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2- trifluoroethyl)butanamide

Vertex Pharmaceuticals Inc

Vertex Pharma,

UNII-MZK2GP0RHK, VX-509, VRT-831509, cas 944842-54-0

Molecular Formula: C₁₈H₁₉F₃N₆O

Molecular Weight: 392.37827

In phase 3 for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis.

DECERNOTINIB

The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as psoriasis. Moreover, JAK kinases represent an established therapeutic target for this disease.

For example, JAK kinases are an established therapeutic target for treating psoriasis. Stump K. L., et al., Arthritis Res. Ther. (201 1) 13:R68; Fridman J.S., et al., J Immunol. (2010) 184:5298-5307; West K., Curr. Op. Investig. Drugs (2009) 10:491-504; Kremer J. M. et al., Arthritis Rheumatism (2009) 60(7):1895- 1905; Xiong, W. et al., Ther Adv Musculoskelet Dis. (201 1) 3(5): 255-266; Panes, J. et al. 19^th Ann. Eur. Gastroenterology Week (Oct 22-26, 2011) Stockholm, SE, PI 456; and Drugs in R & D “Tofacitinib” (2010) 10(4):271-84.

Compounds described as kinase inhibitors, particularly the JAK family kinases, are disclosed in WO 2005/095400 and WO 2007/084557. Also disclosed in these publications are processes and intermediates for preparing these compounds

Decernotinib ( VX-509 ) is an oral selective JAK3 inhibitor being evaluated for the treatment of rheumatoid arthritis ( RA ). This was a 24-week, randomized, placebo-controlled, double-blind, phase 2 study of four dosing regimens of Decernotinib, administered to patients with RA with inadequate response to Methotrexate ( MTX ).

The aim of the study was to assess the efficacy and safety of four dosing regimens of VX-509 administered to patients with rheumatoid arthritis on stable background Methotrexate therapy.

Patients with active rheumatoid arthritis ( C-reactive protein [ CRP ] greater than ULN, greater than or equal to 6 swollen joints [ of 66 ], and greater than or equal to 6 tender joints [ of 68 ] ) taking stable doses of MTX were randomized 1:1:1:1:1 to receive placebo or one of four dosing regimens of Decernotinib ( 100 mg QD, 150 mg QD, 200 mg QD, or 100 mg BID ) for a duration of 24 weeks.

The primary efficacy endpoints at week 12 were met and have previously been reported; 24-week efficacy and safety results are now reported.

A total of 358 patients were randomized and received greater than or equal to 1 dose of study drug; 81% of patients were female, with a mean age of 53 years.
At baseline, the mean tender joint count was 23.8, the mean swollen joint count was 16.1, and the average disease duration was 7.3 years.

After 24 weeks of treatment the proportion of patients achieving ACR20, ACR50, ACR70, DAS28 ( CRP ) less than 2.6 and DAS28 ( ESR ) less than 2.6 and the decrease from baseline in DAS28 ( CRP ) were statistically significantly greater in each of the Decernotinib dose groups than in the placebo group.

Over 24 weeks, the percentage of patients with any adverse event was higher in the Decernotinib group ( all Decernotinib dose groups combined ) ( 59.9% ) relative to placebo ( 42.3% ) and led to study discontinuation in 9.1% and 8.5% of patients in the Decernotinib and placebo groups, respectively.
The most common adverse reactions in the Decernotinib group were headache ( 8.7% ), hypercholesterolemia ( 5.2% ), and diarrhea ( 4.5% ).
Serious adverse reactions occurred in similar proportions of patients receiving Decernotinib ( 7.3% ) or placebo ( 5.6% ), but there were more serious infections in the Decernotinib group ( 3.5% ) compared with placebo ( 1.4% ).
Through 24 weeks there were two serious adverse effects that resulted in death; one was cardiac failure in the Decernotinib 100 mg BID group ( previously reported ) and one was pancytopenia in a patient with pneumonia in the Decernotinib 200 mg QD group.
Elevations in transaminase levels and decreases in median neutrophil and lymphocyte counts were observed in the Decernotinib groups and were generally mild.

Safety profiles were comparable across groups receiving Decernotinib.

In conclusion, all tested doses of Decernotinib significantly improved signs and symptoms of rheumatoid arthritis versus placebo when administered in combination with stable background Methotrexate therapy for 24 weeks.
Decernotinib was associated with small increases in adverse reactions rates, serious infections, and mostly minor laboratory abnormalities. ( Xagena )

Source: EULAR Meeting – van Vollenhoven R et al, Ann Rheum Dis 2014;73(Suppl2)

see

WO 2007084557

http://www.google.com/patents/WO2007084557A2?cl=en

………………………………………

WO 2013006634

http://www.google.com/patents/WO2013006634A2?cl=en

Figure imgf000060_0002

Formula I is:

The present invention provides a process for preparing (R)-2-(2-(lH-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide of Formula la:

comprising the steps of:

ivb) reacting lH-pyrrolo[2,3-b]pyridine (5a) with p-toluenesulfonyl chloride in the presence of an organic solvent to generate l-tosyl-lH-pyrrolo[2,3-b]pyridine (9a)

5a 9a

vb) reacting l-tosyl-lH-pyrrolo[2,3-b]pyridine (9a) in an organic solvent with N-bromosuccinimide to generate 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (7a)

vi) reacting 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (7a) with triisopropyl borate in the presence of a strong lithium base in an organic solvent to generate

l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) 0^H

vii) esterifying l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) with pinacolate alcohol in an organic solvent to generate

3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -tosyl- 1 H-pyrrolo[2,3 -bjpyridine (la) :

viiib) reacting 2,4-dichloropyrimidine (11a) with a hydrochloride salt of D-isovaline (15a) under coupling condition to generate a compound of Formula 2a

11a 2a

ixb) reacting the compound of Formula 2a with HC1 to generate the hydrochloride salt of the compound of Formula 2a;

i) reacting the compound of Formula la with the compound of Formula 2a with in the presence of water, an organic solvent, an inorganic base, and a transition metal catalyst to generate a compound of Formula 3a,

ii) deprotecting the compound of Formula 3a under basic conditions to generate a compound of Formula 4a

4a ; and iii) reacting the compound of Formula 4a with 2,2,2-trifluoroethylamine in the presence of a coupling agent and an organic solvent to generate the compound of Formula la.

Figure imgf000093_0002

– l¹³C₄, ¹⁵N₂]

……………………………………………………………….

WO 2013070606

http://www.google.com/patents/WO2013070606A1?cl=en

………………………………………………….

patent WO2014074471

WO2014074471 claiming use of heterocyclic compound (preferably decernotinib) for treating psoriasis. Vertex is developing decernotinib, an oral JAK 3 inhibitor, for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis. As of July 2014, the drug is Phase 3 trials.

http://www.google.com/patents/WO2014074471A1?cl=en

Table 1:

COMPD 1 IS DECERNOTINIB

Example 1: Analytical Methods Used

[0260] (A) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (60:40:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm. Run time was 25-26 minutes.

[0261] (B) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (90: 10:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm.

[0262] (C) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9:1). Gradient 5 % to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 245 nm.

T = 25 °C.

[0263] (D) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9: 1). Gradient 15% to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 220 nm.

T = 35 °C.

[0264] Example 2: Preparation of Compounds of Formula I [0265] General Synthetic Scheme

[0266] The Boc-protected amino acid starting material (1) undergoes amidation in the presence of an activating agent, a coupling reagent, and the acid salt of the amine HNR⁷R¹⁷ to generate the Boc-protected amide intermediate (2). The amide intermediate (2) is

deprotected under acidic conditions and reacted with the halogenated heteroaryl (3) to generate the aminoheteroaryl intermediate (4). Boronated azaindole (5) is coupled with the aminoheteroaryl intermediate (4) under cross-coupling condition to generate the compound of Formula I.

………………………………………………………………………….

Patent

http://www.google.com/patents/US8163917

346	M+H393.20	RT 1.60	(DMSO-d6, 300 MHz) 11.95 (bs, 1H), 8.7 (d,
			1H), 8.25 (m, 2H), 8.12 (d, 1H), 8.02 (d, 1H),
			7.28 (s, 1H), 7.13 (dd, 1H), 6.38 (bd, 1H), 3.75
			(m, 2H), 2.06 (m, 1H), 1.83 (m, 1H), 1.46 (s,
			3H), 0.8 (t, 3H);

346

Example 1 Preparation of Compounds of the Invention

General Synthetic Scheme

Step 1

To a stirred solution of Boc-valine (1; R₁is Me; 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol) in 100 mL of DCM is added trifluoroethylamine HCl (2.92 g, 0.022 mol). The reaction mixture is stirred for 16 h. It is concentrated to dryness and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO₃and brine. The organic layer is dried (Na₂SO₄) and concentrated in vacuo to give 5.4 g (98%) of 2 as a white solid.

Step 2

Compound 2 (5.32 g, 0.0197 mol) is deprotected with a 1:1 mixture of DCM/TFA at rt for 45 min. Concentration to dryness gives the intermediate amine that is used directly for the next step. A mixture of 5-fluoro-2,4-dichloropyrimidine (3; R is F; 3.28 g, 0.0197 mol), the crude amine TFA salt (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol) are stirred in isopropanol at rt for 16 h. The reaction mixture is concentrated in vacuo and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO₃and brine. The organic layer is dried (Na₂SO₄) and concentrated in vacuo to give a crude oil that is subjected to chromatography (50% EtOAc/50% hexanes) to yield the desired compound 4.

Step 3

A mixture of 5 (30 mg, 0.075 mmol; prepared according to WO 2005/095400), 4 (23 mg, 0.075 mmol), Pd (Ph₃P)₄(9 mg, 0.0078 mmol) and sodium carbonate 2M (115 uL, 0.23 mmol) in 1 mL of DME is microwaved at 150° C. for 10 minutes. The reaction mixture is filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, the crude intermediate that is used directly for the next step.

The crude intermediate is dissolved in 1 mL of dry methanol and 200 uL of sodium methoxide in methanol 25% was added. The reaction mixture is stirred at 60° C. for 1 h and quenched with 6N HCl (154 uL). The mixture is dried under a flow of nitrogen and purified by reverse phase HPLC (10-60 MeCN/water w/0.5% TFA) to provide the desired material of formula 6a.

Compounds of formulae 6b and 6c may be prepared in an analogous manner using the appropriate starting reagents. For instance, a compound of formula 6b may generally be made by substituting Cert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)pyrrolidine-1-carboxylate for compound 1, while a compound of formula 6c may generally be made by substituting tert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)propan-2-ylcarbamate for compound 1.

Example 2 Analytical Results

Tables 4, 5 and 6 below depicts exemplary ¹H-NMR data (NMR) and liquid chromatographic mass spectral data, reported as mass plus proton (M+H), as determined by electrospray, and retention time (RT) for certain compounds of the present invention, wherein compound numbers in Tables 4, 5 and 6 correspond to the compounds depicted in Tables 1, 2 and 3, respectively (empty cells indicate that the test was not performed):

PATENTS

US8163917	4-25-2012	Azaindoles Useful as Inhibitors of Janus Kinases
US7767816	8-4-2010	Azaindoles useful as inhibitors of janus kinases

new patent

WO-2014110259

US8450489 *	Mar 1, 2012	May 28, 2013	Vertex Pharmaceuticals Incorporated	Azaindoles useful as inhibitors of janus kinases
US8530489 *	May 22, 2012	Sep 10, 2013	Vertex Pharmaceuticals Incorporated	5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8686143 *	Oct 25, 2011	Apr 1, 2014	Vertex Pharmaceuticals Incorporated	Compounds useful as inhibitors of Janus kinases
US20120157429 *	Oct 25, 2011	Jun 21, 2012	Wannamaker Marion W	Compounds useful as inhibitors of janus kinases
US20120165307 *	Mar 1, 2012	Jun 28, 2012	Vertex Pharmaceuticals Incorporated	Azaindoles useful as inhibitors of janus kinases
US20120309963 *	May 22, 2012	Dec 6, 2012	Vertex Pharmaceuticals Incorporated	5-cyano-4- (pyrrolo [2,3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
US20130237516 *	Apr 25, 2013	Sep 12, 2013	Vertex Pharmaceuticals Incorporated	Azaindoles useful as inhibitors of janus kinases
WO2013173506A2	May 15, 2013	Nov 21, 2013	Rigel Pharmaceuticals, Inc.	Method of treating muscular degradation

WO2005095400A1	Mar 30, 2005	Oct 13, 2005	Vertex Pharma	Azaindoles useful as inhibitors of jak and other protein kinases
WO2007084557A2	Jan 17, 2007	Jul 26, 2007	Vertex Pharma	Azaindoles useful as inhibitors of janus kinases
WO2013070606A1 *	Nov 6, 2012	May 16, 2013	Vertex Pharmaceuticals Incorporated	Methods for treating inflammatory diseases and pharmaceutical combinations useful therefor

PARP Inhibitor.. Veliparib (ABT-888) 维利帕尼

July 7, 2014 4:22 am / Leave a comment

Veliparib

Abbott Laboratories

2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide

CAS number: 912444-00-9 (Veliparib),

912445-05-7 (Veliparib dihydrochloride)

Mechanism of Action:poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor
Indiction:cancer treatment

Development Status:Phase III

Drug Company: AbbVie

PARP Inhibitor Veliparib (ABT-888)

Also known as: ABT-888, 912444-00-9, ABT 888, carboxamide, CHEBI:62880, 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT888, Veliparib

Molecular Formula: C₁₃H₁₆N₄O Molecular Weight: 244.29234

Systematic (IUPAC) name
2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide
Clinical data
Legal status	experimental
Identifiers

ATC code	None
PubChem	CID 11960529
DrugBank	DB07232
ChemSpider	10134775
UNII	01O4K0631N
ChEMBL	CHEMBL506871
Chemical data
Formula	C₁₃H₁₆N₄O
Mol. mass	244.29 g/mol

US2012035244	2-10-2012	PARP1 TARGETED THERAPY
US2009099245	4-17-2009	2-{(R)-2-METHYLPYRROLIDIN-2-YL)-1H-BENZIMIDAZOLE-4-CARBOXAMIDE CRYSTALLINE FORM 1

Veliparib (ABT-888)^[1] is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC.

It inhibits both PARP1 and PARP2.^[2]^[3]

AbbVie’s Veliparib (ABT-888,), an inhibitor of poly ADP-ribose polymerase 1 and 2 (PARP 1 and PARP 2), is being investigated in multiple tumor types, including 3 phase III studies, all initiated this year, in neoadjuvant treatment of triple-negative breast cancer (clinical trial number:NCT02032277), non-small cell lung cancer (NSCLC, clinical trial number:NCT02106546) and HER2-negative, BRCA1 and/or BRCA2-positive breast cancer (clinical trial number:NCT02163694).

AbbVie, which was spun off from Abbott Laboratories in early 2013, is currently looking to buy Irish drug maker Shire for $46 billion. The proposed deal follows Pfizer’s failed $120 billion attempt to buy AstraZeneca. Humira, AbbVie’s rheumatoid arthritis drug and the world’s top-selling drug last year, accounts for 60% of company revenue and is going off-patent in at the end of 2016. The threat of growing competition for Humira may be a major motivation for AbbVie.

Synthesis of Veliparib_ABT-888_PARP inhibitor_cancer drug_ AbbVie 艾伯维抗肿瘤药物维利帕尼的化学合成

Chemical structure for Veliparib

Clinical trials

Numerous phase I clinical trials are in progress.^[4]

A phase I/II clinical trial for use with/out doxorubicin (for Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma) started in 2008 and is due to complete in 2010.^[5] Results (inc MTD) with topotecan.^[6]

A phase II clinical trial for metastatic melanoma has started recruiting.^[7] Due to end Dec 2011.

A phase II clinical trial for metastatic breast cancer has started recruiting.^[8] Due to end Nov 2011.

A phase II clinical trial for add-on to Radiation Therapy for Patients with Brain Metastases from Non-Small Cell Lung Cancer.

It was included in the I-SPY2 breast cancer trial,^[9] and there are encouraging data from that study ^[10]

A phase I clinical trial for prostate cancer in men who carry the BRCA mutation is underway and is now recruiting (as of May 2013).^[11]

……………….

http://www.google.com/patents/US20060229289

EXAMPLE 1

2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide EXAMPLE 1A 1-benzyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate

A solution of 1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate (15.0 g, 57 mmol) and iodomethane (7.11 ml, 114 mmol) in THF (100 mL) was treated with NaN(TMS)₂(1.0 M solution in THF, 114 mL, 114 mmol) at −75° C. under nitrogen. The temperature of the cooling bath was then slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for another 3 h. After quenching with water, the mixture was acidified with 2 N HCl (˜100 mL) and was partitioned between water (400 mL) and EtOAc (400 mL). The organic phase was washed with brine and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc/hexane) to give Example 1A (15.15 g, Yield: 96%). MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 1B

1-[(benzyloxy)carbonyl]-2-methylpyrrolidine-2-carboxylic acid

A solution of Example 1A (15.15 g, 54.63 mmol) in a mixture of THF (100 mL) and water (50 mL) was treated with LiOH.H₂O (4.58 g, 109.26 mmol) in water (50 mL). Methanol was added until a transparent solution formed (60 mL). This solution was heated at 60° C. for overnight and the organic solvents were removed under vacuum. The residual aqueous solution was acidified with 2 N HCl to pH 2 and was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO₄), filtered and concentrated to give Example 1B as a white solid (13.72 g, 95.4% yield). MS (DCI/NH₃) m/z 264 (M+H)⁺.

EXAMPLE 1C

benzyl 2-({[2-amino-3-(aminocarbonyl)phenyl]amino}carbonyl)-2-methylpyrrolidine-1-carboxylate

A solution of Example 1B (13.7 g, 52 mmol) in a mixture of pyridine (60 mL) and DMF (60 mL) was treated with 1,1′-carbonyldiimidazole (9.27 g, 57.2 mmol) at 45° C. for 2 h. 2,3-Diamino-benzamide dihydrochloride (11.66 g, 52 mmol), which was synthesized as described in previous patent application WO0026192, was added and the mixture was stirred at rt overnight. After concentration under vacuum, the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1C (16.26 g). Extraction of the aqueous phase with ethyl acetate followed by concentration, filtration and water-EtOAc wash, provided additional 1.03 g of Example 1C. Combined yield: 84%. MS (APCI) m/z 397 (M+H)⁺.

EXAMPLE 1D

benzyl 2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate

A suspension of Example 1C (17.28 g, 43.6 mmol) in acetic acid (180 mL) was heated under reflux for 2 h. After cooling, the solution was concentrated and the residual oil was partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic phase was washed with water and concentrated. The residue was purified by flash column chromatography (silica gel, 3-15% CH₃OH in 2:1 EtOAc/hexane) to provide Example 1D (16.42 g, Yield: 99%).

MS (APCI) m/z 379 (M+H)⁺.

EXAMPLE 1E 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide

A solution of Example 1D (15.0 g, 40 mmol) in methanol (250 ml) was treated with 10% Pd/C (2.8 g) under 60 psi of hydrogen for overnight. Solid material was filtered off and the filtrate was concentrated. The residual solid was recrystallized in methanol to give 7.768 g of Example 1E as free base. The bis-HCl salt was prepared by dissolving the free base in warm methanol and treating with 2 equivalents of HCl in ether (10.09 g). MS (APCI) m/z 245 (M+H)⁺; ¹H NMR (500 MHz, D₂O): δ 1.92 (s, 3 H), 2.00-2.09 (m, 1 H), 2.21-2.29 (m, 1 H), 2.35-2.41 (m, 1 H), 2.52-2.57 (m, 1 H), 3.54-3.65 (m, 2 H), 7.31 (t, J=7.93 Hz, 1 H), 7.68 (dd, J=8.24, 0.92 Hz, 1 H), 7.72 (dd, J=7.63, 0.92 Hz, 1 H); Anal. Calcd for C₁₃H₁₆N₄O.2 HCl: C, 49.22; H, 5.72N, 17.66. Found: C, 49.30; H, 5.60; N, 17.39.

EXAMPLE 3 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide EXAMPLE 3A benzyl(2R)-2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate

Example 1D (1.05 g, 2.8 mmol) was resolved on chiral HPLC (Chiralcel OD, 80/10/10 hexane/EtOH/MeOH). The faster eluting peak was collected and concentrated to provide Example 3A (99.4% e.e., 500 mg). MS (APCI) m/z 379 (M+H)⁺.

EXAMPLE 3B 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide

A solution of Example 3A (500 mg, 1.32 mmol) in methanol (10 ml) was treated with 10% Pd/C (150 mg) under hydrogen for overnight (balloon). Solid material was filtered off and the filtrate was concentrated. The residual solid was further purified by HPLC (Zorbax C-18, CH₃CN/H₂O/0.1%TFA) and was converted to bis-HCl salt to provide Example 4 as white solid (254 mg). Co-crystallization of the free base with 1 equivalent of L-tartaric acid in methanol gave a single crystal that was suitable for X-ray study. The X-ray structure with L-tartaric acid was assigned the R-configuration. MS (APCI) m/z 245 (M+H)⁺; ¹H NMR (500 MHz, D₂O): δ 2.00 (s, 3 H), 2.10-2.19 (m, 1 H), 2.30-2.39 (m, 1 H), 2.45-2.51 (m, 1 H), 2.61-2.66 (m, 1 H), 3.64-3.73 (m, 2 H), 7.40 (t, J=7.95 Hz, 1 H), 7.77 (d, J=8.11 Hz, 1 H), 7.80 (d, J=7.49 Hz, 1 H); Anal. Calcd for C₁₃H₁₆N₄O.2 HCl: C, 49.22; H, 5.72; N, 17.66. Found: C, 49.10; H, 5.52; N, 17.61.

……………….

WO2009049111

http://www.google.com/patents/WO2009049111A1?cl=en

EXAMPLE 1 Preparation of ABT-888 Crystalline Form 1 A mixture of ABT-888 dihydrochloride (10 g) was stirred in saturated potassium bicarbonate (50 mL) and n-butanol (50 mL) until the ABT-888 dihydrochloride completely dissolved. The aqueous layer was extracted with a second portion of n-butanol then discarded. The extracts were combined, washed with 15% sodium chloride solution (50 mL) and concentrated. The concentrate was chase distilled three times with heptane (50 mL),dissolved in refluxing 2-propanol (45 mL) and filtered hot. The filtrate was cooled to ambient temperature with stirring over 18 hours, cooled to 0-5⁰C, stirred for 1 hour, and filtered. The filtrant was washed with 2-propanol and dried in a vacuum oven at 45-50⁰C with a slight nitrogen purge.

EXAMPLE 2

Preparation of ABT-888 Crystalline Form 2

A mixture of ABT-888 in methanol, in which the ABT-888 was completely dissolved, was concentrated at about 35 ⁰C, and the concentrate was dried to a constant weight.

EXAMPLE 3 Preparation of ABT-888 Crystalline Form 1

15 16

Step 1 : 2-(2-methyl-2-pyrrolidino)-benzimidazole-4-carboxamide 2 HCl (15) is dissolved in water (3.5 kg / kg 15) at 20 + 5 ⁰C. Dissolution of 15 in water results in a solution of pH 0 – 1.

Step 2: The reaction is run at 20 – 25 ⁰C. One equivalent of sodium hydroxide is added, raising the pH to 2 – 3 with only a mild exotherm (10⁰C observed with rapid addition of 1.0 equiv.). This generates a solution that remains clear for several days even when seeded with free base crystals. 3N NaOH (1.0 equiv., 1.25 kg / kg 15) is charged and the solution polish filtered into the crystallizer/ reactor.

Step 3: 5% Na₂CO₃ (1.5 equiv., 10.08 kg / kg 15) is then filtered into the crystallizer over 2 hours. Nucleation occurs after approximately l/6th of the Na₂CO₃ solution is added (-0.25 equiv.)

Step 4: The slurry is mixed for NLT 15 min before sampling (typically 1 to 4 hours (2.5 mg/mL product in the supernatant)). The slurry is filtered at 20⁰C and washed with 6 portions of water (1.0 kg / kg 15 each). Each wash was applied to the top of the cake and then pressured through. No mixing of the wetcake was done.

Step 5 : The solids are then dried. Drying was performed at 50⁰C keeping the Cogeim under vacuum while applying a slight nitrogen bleed. The agitator blade was left in the cake to improve heat transfer to the cake. It was rotated and lifted out of the cake once per hour of drying to speed the drying process while minimizing potential crystal attrition that occurs with continuous agitator use. In one embodiment of Step 1, the volume of water for dissolution of the Dihydrochloride (15) is about 1.3 g water/g 15. In another embodiment of Step 1,, the volume of water for dissolution is about 1.3 g to about 4 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 1.3 g to 3.5 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 3.5 g water/g 15.

……………………

J. Med. Chem., 2009, 52 (2), pp 514–523

DOI: 10.1021/jm801171j

http://pubs.acs.org/doi/abs/10.1021/jm801171j

Abstract Image

(2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide

excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a Ki of 5 nM and in a C41 whole cell assay with an EC50 of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.

References

23481647

4-1-2013

Design, synthesis and biological evaluation of novel imidazo[4,5-c]pyridinecarboxamide derivatives as PARP-1 inhibitors.

Bioorganic & medicinal chemistry letters

23850199	8-15-2013	Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.	Bioorganic & medicinal chemistry letters
23787099	8-1-2013	Identification of potent Yes1 kinase inhibitors using a library screening approach.	Bioorganic & medicinal chemistry letters

20071126

5-1-2010

A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS.

Journal of pharmaceutical and biomedical analysis

19143569

1-22-2009

Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer.

Journal of medicinal chemistry

External links

http://kdwn.com/2013/12/16/new-drug-study-method-show-breast-cancer-promise/

US8013168	Oct 10, 2008	Sep 6, 2011	Abbott Laboratories	Veliparib crystal structure; an anticancer PARP inhibitor
US8372987	Oct 10, 2008	Feb 12, 2013	Abbvie Inc.	Title compound is Veliparib, a Poly(ADP-ribose) polymerase i.e. PARP inhibitor; anticancer agent

US20060229289 *	Apr 11, 2006	Oct 12, 2006	Gui-Dong Zhu	2-(2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, aka veliparib, for example; poly(ADP-ribose)polymerase inhibitors; antiinflammatory, antitumor agents; Parkinson’s disease

Penning, Thomas D. et al. Discovery of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the Treatment of Cancer. Journal of Medicinal Chemistry, 52(2), 514-523; 2009

Zhu, Guidong. 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide crystalline form 2 compositions and preparation for treating cancer. PCT Int. Appl. (2009), WO2009049109 A1 20090416

Kolaczkowski, Lawrence . 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide (ABT-888) crystalline form I and its pharmaceutical composition for cancer treatment. PCT Int. Appl. (2009), WO2009049111 A1 20090416.
Zhu, Gui-Dong; Gong, Jianchun; Gandhi, Virajkumar B.; Penning, Thomas D.; Giranda, Vincent L. Preparation of 1H-benzimidazole-4-carboxamides as poly(ADP-ribose)polymerase (PARP) inhibitors. U.S. Pat. Appl. Publ. (2006), US20060229289 A1 20061012.

Luseogliflozin, TS 071…………. strongly inhibited SGLT2 activity,

July 1, 2014 5:44 am / 2 Comments on Luseogliflozin, TS 071…………. strongly inhibited SGLT2 activity,

LUSEOGLIFLOZIN, CAS 898537-18-3
An antidiabetic agent that inhibits sodium-dependent glucose cotransporter 2 (SGLT2).

(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol

(1S)-1,5-anhydro-1-[3-(4-ethoxybenzyl)-6-methoxy-4-methylphenyl]-1-thio-D-glucitol

Taisho Pharmaceutical Co., Ltd

Taisho (Originator), PHASE 3

Click to access 2013041801-e.pdf

TS-071

Taisho Pharmaceutical Holdings Co. Ltd.
Description	Oral sodium-glucose cotransporter 2 (SGLT2) inhibitor

Links

WO 2010119990

WO2006073197

TS-071, an SGLT-2 inhibitor, is in phase III clinical development at Taisho for the oral treatment of type 1 and type 2 diabetes

In 2012, the product was licensed to Novartis and Taisho Toyama Pharmaceutical by Taisho in Japan for comarketing for the treatment of type 2 diabetes.

Diabetes is a metabolic disorder which is rapidly emerging as a global health care problem that threatens to reach pandemic levels. The number of people with diabetes worldwide is expected to rise from 285 million in 2010 to 438 million by 2030. Diabetes results from deficiency in insulin because of impaired pancreatic β-cell function or from resistance to insulin in body, thus leading to abnormally high levels of blood glucose.

Diabetes which results from complete deficiency in insulin secretion is Type 1 diabetes and the diabetes due to resistance to insulin activity together with an inadequate insulin secretion is Type 2 diabetes. Type 2 diabetes (Non insulin dependent diabetes) accounts for 90-95 % of all diabetes. An early defect in Type 2 diabetes mellitus is insulin resistance which is a state of reduced responsiveness to circulating concentrations of insulin and is often present years before clinical diagnosis of diabetes. A key component of the pathophysiology of Type 2 diabetes mellitus involves an impaired pancreatic β-cell function which eventually contributes to decreased insulin secretion in response to elevated plasma glucose. The β-cell compensates for insulin resistance by increasing the insulin secretion, eventually resulting in reduced β-cell mass. Consequently, blood glucose levels stay at abnormally high levels (hyperglycemia).

Hyperglycemia is central to both the vascular consequences of diabetes and the progressive nature of the disease itself. Chronic hyperglycemia leads to decrease in insulin secretion and further to decrease in insulin sensitivity. As a result, the blood glucose concentration is increased, leading to diabetes, which is self-exacerbated. Chronic hyperglycemia has been shown to result in higher protein glycation, cell apoptosis and increased oxidative stress; leading to complications such as cardiovascular disease, stroke, nephropathy, retinopathy (leading to visual impairment or blindness), neuropathy, hypertension, dyslipidemia, premature atherosclerosis, diabetic foot ulcer and obesity. So, when a person suffers from diabetes, it becomes important to control the blood glucose level. Normalization of plasma glucose in Type 2 diabetes patients improves insulin action and may offset the development of beta cell failure and diabetic complications in the advanced stages of the disease.

Diabetes is basically treated by diet and exercise therapies. However, when sufficient relief is not obtained by these therapies, medicament is prescribed alongwith. Various antidiabetic agents being currently used include biguanides (decrease glucose production in the liver and increase sensitivity to insulin), sulfonylureas and meglitinides (stimulate insulin production), a-glucosidase inhibitors (slow down starch absorption and glucose production) and thiazolidinediones (increase insulin sensitivity). These therapies have various side effects: biguanides cause lactic acidosis, sulfonylurea compounds cause significant hypoglycemia, a-glucosidase inhibitors cause abdominal bloating and diarrhea, and thiazolidinediones cause edema and weight gain. Recently introduced line of therapy includes inhibitors of dipeptidyl peptidase-IV (DPP-IV) enzyme, which may be useful in the treatment of diabetes, particularly in Type 2 diabetes. DPP-IV inhibitors lead to decrease in inactivation of incretins glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP), thus leading to increased production of insulin by the pancreas in a glucose dependent manner. All of these therapies discussed, have an insulin dependent mechanism.

Another mechanism which offers insulin independent means of reducing glycemic levels, is the inhibition of sodium glucose co-transporters (SGLTs). In healthy individuals, almost 99% of the plasma glucose filtered in the kidneys is reabsorbed, thus leading to only less than 1% of the total filtered glucose being excreted in urine. Two types of SGLTs, SGLT-1 and SGLT-2, enable the kidneys to recover filtered glucose. SGLT-1 is a low capacity, high-affinity transporter expressed in the gut (small intestine epithelium), heart, and kidney (S3 segment of the renal proximal tubule), whereas SGLT-2 (a 672 amino acid protein containing 14 membrane-spanning segments), is a low affinity, high capacity glucose ” transporter, located mainly in the S 1 segment of the proximal tubule of the kidney. SGLT-2 facilitates approximately 90% of glucose reabsorption and the rate of glucose filtration increases proportionally as the glycemic level increases. The inhibition of SGLT-2 should be highly selective, because non-selective inhibition leads to complications such as severe, sometimes fatal diarrhea, dehydration, peripheral insulin resistance, hypoglycemia in CNS and an impaired glucose uptake in the intestine.

Humans lacking a functional SGLT-2 gene appear to live normal lives, other than exhibiting copious glucose excretion with no adverse effects on carbohydrate metabolism. However, humans with SGLT-1 gene mutations are unable to transport glucose or galactose normally across the intestinal wall, resulting in condition known as glucose-galactose malabsorption syndrome.

Hence, competitive inhibition of SGLT-2, leading to renal excretion of glucose represents an attractive approach to normalize the high blood glucose associated with diabetes. Lower blood glucose levels would, in turn, lead to reduced rates of protein glycation, improved insulin sensitivity in liver and peripheral tissues, and improved cell function. As a consequence of progressive reduction in hepatic insulin resistance, the elevated hepatic glucose output which is characteristic of Type 2 diabetes would be expected to gradually diminish to normal values. In addition, excretion of glucose may reduce overall caloric load and lead to weight loss. Risk of hypoglycemia associated with SGLT-2 inhibition mechanism is low, because there is no interference with the normal counter regulatory mechanisms for glucose.

The first known non-selective SGLT-2 inhibitor was the natural product phlorizin

(glucose, 1 -[2-P-D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)- 1 – propanone). Subsequently, several other synthetic analogues were derived based on the structure of phlorizin. Optimisation of the scaffolds to achieve selective SGLT-2 inhibitors led to the discovery of several considerably different scaffolds.

C-glycoside derivatives have been disclosed, for example, in PCT publications

W_.O20040131 18, WO2005085265, WO2006008038, WO2006034489, WO2006037537, WO2006010557, WO2006089872, WO2006002912, WO2006054629, WO2006064033, WO2007136116, WO2007000445, WO2007093610, WO2008069327, WO2008020011, WO2008013321, WO2008013277, WO2008042688, WO2008122014, WO2008116195, WO2008042688, WO2009026537, WO2010147430, WO2010095768, WO2010023594, WO2010022313, WO2011051864, WO201 1048148 and WO2012019496 US patents US65151 17B2, US6936590B2 and US7202350B2 and Japanese patent application JP2004359630. The compounds shown below are the SGLT-2 inhibitors which have reached advanced stages of human clinical trials: Bristol-Myers Squibb’s “Dapagliflozin” with Formula A, Mitsubishi Tanabe and Johnson & Johnson’s “Canagliflozin” with Formula B, Lexicon’s “Lx-421 1″ with Formula C, Boehringer Ingelheim and Eli Lilly’s “Empagliflozin” with Formula D, Roche and Chugai’s “Tofogliflozin” with Formula E, Taisho’s “Luseogliflozin” with Formula F, Pfizer’ s “Ertugliflozin” with Formula G and Astellas and Kotobuki’s “Ipragliflozin” with Formula H.

Formula G Formula H

In spite of all these molecules in advanced stages of human clinical trials, there is still no drug available in the market as SGLT-2 inhibitor. Out of the potential candidates entering the clinical stages, many have been discontinued, emphasizing the unmet need. Thus there is an ongoing requirement to screen more scaffolds useful as SGLT-2 inhibitors that can have advantageous potency, stability, selectivity, better half-life, and/ or better pharmacodynamic properties. In this regard, a novel class of SGLT-2 inhibitors is provided herein

………………………

SYNTHESIS

Links

EP1845095A1

Example 5

Synthesis of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose

Five drops of 1,2-dibromoethane were added to a mixture of magnesium (41 mg, 1.67 mmol), 1-bromo-3-(4-ethoxybenzyl)-6-methoxy-4-methylbenzene (0.51 g, 1.51 mmol) and tetrahydrofuran (2 mL). After heated to reflux for one hour, this mixture was allowed to stand still to room temperature to prepare a Grignard reagent. A tetrahydrofuran solution (1.40 mL) of 1.0 M i-propyl magnesium chloride and the prepared Grignard reagent were added dropwise sequentially to a tetrahydrofuran (5 mL) solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (0.76 g, 1.38 mmol) while cooled on ice and the mixture was stirred for 30 minutes. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate =4:1) to obtain (0.76 g, 68%) a yellow oily title compound.
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=6.92 Hz, 3 H) 2.21 (s, 3 H) 3.51 – 4.20 (m, 12 H) 3.85 – 3.89 (m, 3 H) 4.51 (s, 2 H) 4.65 (d, J=10.72 Hz, 1 H) 4.71 (d, J=5.75 Hz, 1 H) 4.78 – 4.99 (m, 3 H) 6.59 – 7.43 (m, 26 H)

Example 6

[0315]

Synthesis of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

An acetonitrile (18 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (840 mg, 1.04 mmol) was added sequentially with Et₃SiH (0.415 mL, 2.60 mmol) and BF₃·Et₂O (0.198 mL, 1.56 mmol) at -18°C and stirred for an hour. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (640 mg, 77%).
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=6.88 Hz, 3 H) 2.21 (s, 3 H) 3.02 – 3.21 (m, 1 H) 3.55 (t,J=9.40 Hz, 1 H) 3.71 (s, 1 H) 3.74 – 3.97 (m, 10 H) 4.01 (s, 1 H) 4.45 – 4.56 (m, 3 H) 4.60 (d, J=10.55 Hz, 2 H) 4.86 (s, 2 H) 4.90 (d, J=10.55 Hz, 1H) 6.58 – 6.76 (m, 5 H) 6.90 (d, J=7.34 Hz, 1 H) 7.09 – 7.19 (m, 5 H) 7.23 – 7.35 (m, 15 H).
ESI m/z = 812 (M+NH₄).

Example 7

Synthesis of (1S)-1,5-anhydro-1-[3-(4-ethoxybenzyl)-6-methoxy-4-methylphenyl]-1-thio-D-glucitol

A mixture of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol (630 mg, 0.792 mmol), 20% palladium hydroxide on activated carbon (650 mg) and ethyl acetate (10 mL) – ethanol (10 mL) was stirred under hydrogen atmosphere at room temperature for 66 hours. The insolubles in the reaction mixture were filtered off with celite and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol =10:1) to obtain a colorless powdery title compound (280 mg, 81%) as 0.5 hydrate. 1H NMR (600 MHz, METHANOL- d₄) δ ppm 1.35 (t, J=6.9 Hz, 3 H) 2.17 (s, 3 H) 2.92 – 3.01 (m, 1 H) 3.24 (t, J=8.71 Hz, 1 H) 3.54 – 3.60 (m, 1 H) 3.72 (dd, J=11.5, 6.4 Hz, 1 H) 3.81 (s, 3 H) 3.83 (s, 2 H) 3.94 (dd, J=11.5, 3.7 Hz, 1 H) 3.97 (q, J=6.9 Hz, 2 H) 4.33 (s, 1 H) 6.77 (d, J=8.3 Hz, 2 H) 6.76 (s, 1 H) 6.99 (d, J=8.3 Hz, 2 H) 7.10 (s, 1 H). ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). mp 155.0-157.0°C. Anal. Calcd for C₂₃H₃₀O₆S·0.5H₂O: C, 62.28; H, 7.06. Found: C, 62.39; H, 7.10.

………………………………..

PAPER

Links

(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment
(Journal of Medicinal Chemistry) Saturday March 20th 2010
Author(s): ,
DOI:10.1021/jm901893x Links
GO TO: [Article]

http://pubs.acs.org/doi/abs/10.1021/jm901893x

(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (3p)

Compound 3p (0.281 g, 81%) was prepared as a colorless powder from 21p (0.630 g, 0.792 mmol) according to the method described for the synthesis of 3a. (Method A)

mp 155.0−157.0 °C.

¹H NMR (600 MHz, MeOH-d₄) δ 1.35 (t, J = 6.9 Hz, 3 H), 2.17 (s, 3 H), 2.92−3.01 (m, 1 H), 3.24 (t, J = 8.7 Hz, 1 H), 3.54−3.60 (m, 1 H), 3.72 (dd, J = 6.4, 11.5, Hz, 1 H), 3.81 (s, 3 H), 3.83 (s, 2 H), 3.94 (dd, J = 3.7, 11.5 Hz, 1 H), 3.97 (q, J = 6.9 Hz, 2 H), 4.33 (brs, 1 H), 6.77 (d, J = 8.3 Hz, 2 H), 6.76 (s, 1 H), 6.99 (d, J = 8.3 Hz, 2 H), 7.10 (s, 1 H).

MS (ESI) m/z 452 (M+NH₄).

Anal. Calcd for (C₂₃H₃₀O₆S·0.5H₂O) C, 62.28; H, 7.06. Found C, 62.39; H, 7.10.

3p is compd

cmpds	R¹	R²	R³	SGLT2 (nM) mean (95% CI)	SGLT1 (nM) mean (95% CI)	T1/T2 selectivity
1				27.8 (21.8−35.3)	246 (162−374)	8.8
3a	H	H	OEt	73.6 (51.4−105)	26100 (20300−33700)	355
3b	H	OH	OEt	283 (268−298)	14600 (11500−18500)	51.6
3c	H	OMe	OEt	13.4 (11.3−15.8)	565 (510−627)	42.2
3d	H	F	OEt	9.40 (5.87−15.0)	7960 (7180−8820)	847
3e	H	Me	OEt	2.29 (1.76−2.99)	671 (230−1960)	293
3f	H	Cl	OEt	1.77 (0.95−3.30)	1210 (798−1840)	684
3g	OH	H	OEt	17.4 (15.9−19.0)	4040 (1200−13600)	232
3h	OMe	H	OEt	37.9 (26.4−54.4)	100000 (66500−151000)	2640
3i	OMe	OMe	OEt	10.8 (6.84−17.1)	4270 (1560−11600)	395
3j	H	Cl	OMe	1.68 (1.08−2.60)	260 (72.5−931)	155
3k	H	Cl	Me	1.37 (0.97−1.95)	209 (80.2−545)	153
3l	H	Cl	Et	1.78 (0.88−3.63)	602 (473−767)	338
3m	H	Cl	iPr	4.01 (1.75−9.17)	8160 (4860−13700)	2040
3n	H	Cl	tBu	18.8 (11.0−32.1)	35600 (31900−39800)	1890
3o	H	Cl	SMe	1.16 (0.73−1.85)	391 (239−641)	337
3p	OMe	Me	OEt	2.26 (1.48−3.43)	3990 (2690−5920)	1770
3q	OMe	Me	Et	1.71 (1.19−2.46)	2830 (1540−5200)	1650
3r	OMe	Me	iPr	2.68 (2.15−3.34)	17300 (14100−21100)	6400
3s	OMe	Cl	Et	1.51 (0.75−3.04)	3340 (2710−4110)	2210

Links

PATENT

Patent	Filing date	Publication date	Applicant	Title
WO2004014930A1 *	Aug 8, 2003	Feb 19, 2004	Asanuma Hajime	PROCESS FOR SELECTIVE PRODUCTION OF ARYL 5-THIO-β-D- ALDOHEXOPYRANOSIDES

* Cited by examiner

NON-PATENT CITATIONS

Reference
1	*	AL-MASOUDI, NAJIM A. ET AL: “Synthesis of some novel 1-(5-thio-.beta.-D-glucopyranosyl)-6-azaur acil derivatives. Thio sugar nucleosides” NUCLEOSIDES & NUCLEOTIDES , 12(7), 687-99 CODEN: NUNUD5; ISSN: 0732-8311, 1993, XP008091463
2	*	See also references of WO2006073197A1

EP2419097A1 *	Apr 16, 2010	Feb 22, 2012	Taisho Pharmaceutical Co., Ltd.	Pharmaceutical compositions
EP2455374A1 *	Oct 15, 2009	May 23, 2012	Janssen Pharmaceutica N.V.	Process for the Preparation of Compounds useful as inhibitors of SGLT
EP2601949A2 *	Apr 16, 2010	Jun 12, 2013	Taisho Pharmaceutical Co., Ltd.	Pharmaceutical compositions
EP2668953A1 *	May 15, 2009	Dec 4, 2013	Bristol-Myers Squibb Company	Pharmaceutical compositions comprising an SGLT2 inhibitor with a supply of carbohydrate and/or an inhibitor of uric acid synthesis
WO2009143020A1	May 15, 2009	Nov 26, 2009	Bristol-Myers Squibb Company	Method for treating hyperuricemia employing an sglt2 inhibitor and composition containing same
WO2010043682A2 *	Oct 15, 2009	Apr 22, 2010	Janssen Pharmaceutica Nv	Process for the preparation of compounds useful as inhibitors of sglt
WO2010119990A1	Apr 16, 2010	Oct 21, 2010	Taisho Pharmaceutical Co., Ltd.	Pharmaceutical compositions
WO2013152654A1 *	Mar 14, 2013	Oct 17, 2013	Theracos, Inc.	Process for preparation of benzylbenzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors

Links

Luseogliflozin: Phase III data 10/21/2013

Week in Review, Clinical Results

Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose…
Luseogliflozin: Phase III data 10/21/2013

Week in Review, Clinical Results

Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose…
Luseogliflozin regulatory update 05/13/2013

Week in Review, Regulatory

Taisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Last month, Taisho’s Taisho Pharmaceutical Co. Ltd. subsidiary submitted a regulatory …
Strategy: Doubling down in diabetes 05/06/2013
Merck shoring up slowing diabetes franchise with Pfizer, Abide deals

BioCentury on BioBusiness, Strategy

As sales flatten for Merck’s sitagliptin franchise and a new class of oral diabetes drugs comes to market, the pharma has tapped Pfizer and Abide to shore up its position.

see

http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=cd5f5c06-c07f-4dc8-8922-44f431e2a6bb&cKey=1a3e5ff0-564c-4606-99a0-5dd71879bc5c&mKey=%7BBAFB2746-B0DD-4110-8588-E385FAF957B7%7D Links

SEE

http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132352

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF)

July 1, 2014 3:28 am / Leave a comment

ATALUREN

PTC 124

3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

MF C₁₅H₉FN₂O₃
Molecular Weight		284.24
CAS Registry Number		775304-57-9

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF) – MarketWatch

SOUTH PLAINFIELD, N.J., June 30, 2014 /PRNewswire/ — PTC Therapeutics, Inc. /quotes/zigman/16944148/delayed/quotes/nls/ptct PTCT -0.01% today announced the initiation of a global confirmatory Phase 3 clinical trial of Translarna™ (ataluren), an investigational new drug, in patients with nonsense mutation cystic fibrosis (nmCF). Nonsense mutations within cystic fibrosis are categorized as Class I mutations, a severe form of CF that results in little or no production of the CFTR protein. The Phase 3 confirmatory trial is referred to as ACT CF (ataluren confirmatory trial in cystic fibrosis) and the primary endpoint is lung function as measured by relative change in percent predicted forced expiratory volume in one second, or FEV1.read at

http://www.marketwatch.com/story/ptc-therapeutics-initiates-confirmatory-phase-3-clinical-trial-of-translarna-ataluren-in-patients-with-nonsense-mutation-cystic-fibrosis-nmcf-2014-06-30?reflink=MW_news_stmp

Ataluren, formerly known as PTC124, is a small-molecular agent designed by PTC Therapeutics and sold under the trade nameTranslarna. It makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.^[1]

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,^[2]^[3] such as some people with cystic fibrosis and Duchenne muscular dystrophy. In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.^[4] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. However, other phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.^[5] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.^[6]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.^[7]

Ataluren appears to be most effective for the stop codon ‘UGA’.^[2]

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).^[8]

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

References

Derek (2013-09-18). “The Arguing Over PTC124 and Duchenne Muscular Dystrophy. In the Pipeline:”. Pipeline.corante.com. Retrieved 2013-11-28.
Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91.doi:10.1038/nature05756. PMID 17450125.
Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 2007). “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers”. Journal of clinical pharmacology 47 (4): 430–444. doi:10.1177/0091270006297140. PMID 17389552.
“PTC THERAPEUTICS AND GENZYME CORPORATION ANNOUNCE PRELIMINARY RESULTS FROM THE PHASE 2B CLINICAL TRIAL OF ATALUREN FOR NONSENSE MUTATION DUCHENNE/BECKER MUSCULAR DYSTROPHY (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271. edit Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272.doi:10.1164/rccm.201001-0137OC. PMID 20622033. edit
“PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved 2013-11-28.
Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115. edit
http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23

External links

Ataluren’s official page on PTC Therapeutics’s website

other sources

rINN: Ataluren

Other Names

PTC124^®, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

Pharmacological Information

Pharmacology Images

Ataluren Molecule

Web information on Ataluren

NHS Evidence on Ataluren

DrugBank on Ataluren

Relevant Clinical Literature

Pubmed on Ataluren

RCT with Ataluren

Systematic reviews of Ataluren

Ataluren in N Eng J Med, Lancet, JAMA, BMJ

Ataluren in Cochrane Collaboration

TRIP Database on Ataluren

Google Scholar on Ataluren

Bandolier on Ataluren

UK Guidance

Nice Guidance on Ataluren

BNF-registration required
BNF for children-registration required

UK directory of medicines

UK Medicine Guide (eg pictures of capsules)

Centre for Reviews and Dissemination databases -DARE & NHS EED (evaluates reliability of research)

SNOMED search

Prodigy Guidance on Ataluren

Regulatory Literature

UK SPCs of medicines with marketing authorisation

EMEA search

FDA search

Other Literature

PubChem on Ataluren

CTD (Comparative Toxicogenomics Database) link

ChemIndustry.com link

Protein Structural Information

Biological Information (GenomeNet)

Protein Knowledgebase (UniProtKB)

Orphan drug under investigation for treatment of genetic conditions where nonsense mutations result in premature termination of polypeptides. This drug, which is convenient to deliver orally, appears to allow ribosomal transcription ofRNA to continue past premature termination codon mutations with correct reading of the full normal transcript which then terminates at the proper stop codon. Problematically it has been postulated that assay artifact may have complicated evaluation of its efficacy which appears to be less than gentamicin.^[1] Faults of this class in the transcription process are involved in several inherited diseases.

Some forms of cystic fibrosis and Duchenne muscular dystrophy are being targeted in the development stage of the drug.^[2] Phase I and II trials are promising for cystic fibrosis.^[3]^[4] In a mouse model of Duchenne muscular dystrophy, restoration of muscle function occurred.^[5]

A potential issue is that there may be parts of the human genome whose optimal gene function through evolution has resulted from relatively recent in evolutionary terms insertion of a premature termination codon and so functional suboptimal transcripts of other proteins or functional RNAs might result.

References

old cut paste

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation — also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

PTC124 has been developed by PTC Therapeutics.

Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

June 26, 2014 5:37 am / 3 Comments on Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

http://seekingalpha.com/article/2283763-mast-therapeutics-mstminus-188-would-fit-well-in-mercks-drug-development-pipeline

MST-188 (purified poloxamer 188)

MST-188 is an investigational agent, formulated using a purified form of poloxamer 188. Substantial research has demonstrated that poloxamer 188 has cytoprotective and hemorrheologic properties and inhibits inflammatory processes and thrombosis. We believe the pharmacologic effects of poloxamer 188 support the development of MST-188 in multiple clinical indications for diseases and conditions characterized by microcirculatory insufficiency (endothelial dysfunction and/or impaired blood flow). We are enrolling patients in EPIC, a pivotal phase 3 study of MST-188 in sickle cell disease. In addition, our MST-188 pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation (i.e., restoration of circulating blood volume and pressure) following major trauma.

What is MST-188 and How Does it Work?

POTENTIAL APPLICATIONS OF MST-188

We believe the pharmacodynamic properties of MST-188 (cytoprotective, hemorheologic, anti-inflammatory, antithrombotic/pro-fibrinolytic) enable it simultaneously to address, or prevent activation of, multiple biochemical pathways that can result in microcirculatory insufficiency, a multifaceted condition principally characterized by endothelial dysfunction and impaired blood flow. The microcirculation is responsible for the delivery of blood through the smallest blood vessels (arterioles and capillaries) embedded within tissues. A healthy endothelium is critical to a functional microcirculation. Without the regular delivery of blood and transfer of oxygen to tissue from the microcirculation, individual cells (in both the endothelium and tissue) are unable to maintain aerobic metabolism and, through a series of complex and interrelated events, eventually die. If microcirculatory insufficiency continues, the patient will suffer tissue necrosis, organ damage and, eventually, death.

Microcirculatory Insuffiency

Sickle Cell Disease (SCD)

MST-188 for Sickle Cell Disease

Sickle cell disease is an inherited genetic disorder that affects millions of people worldwide. It is the most common inherited blood disorder in the U.S., where it is estimated to affect approximately 90,000 to 100,000 people, including approximately 1 in 500 African American births. The estimated annual cost of medical care for patients with sickle cell disease in the U.S. exceeds $1.0 billion.

Sickle cell disease is characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the walls of blood vessels. The hallmark of the disease is recurring episodes of severe pain commonly known as crisis or vaso-occlusive crisis. Vaso-occlusive crisis occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This obstruction results in intense pain and tissue damage, including tissue death. Over a lifetime, the accumulated burden of damaged tissue frequently results in the loss of vital organ function and a greatly reduced lifespan. In fact, organ failure is the leading cause of death in adults with sickle cell disease¹ and the average life expectancy is around 45 years.²

We estimate that, in the U.S., sickle cell disease results in approximately 100,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. Further, although the number is difficult to measure, we estimate that the number of untreated vaso-occlusive crisis events is substantial and in the hundreds of thousands in the U.S. each year.

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

Complications of Arterial Disease

MST-188 for Complications of Arterial Disease

Data from experimental models demonstrate the potential for MST-188, when used alone or in combination with thrombolytics, to improve outcomes in patients experiencing complications of arterial disease resulting from atherosclerotic and thromboembolic processes. We believe that, based on the similar pathophysiology of atherosclerotic arterial disease, an agent that is effective in one form of occlusive arterial disease also may be effective in its other manifestations. We plan to first demonstrate the potential of MST-188 in patients with acute limb ischemia, a complication of peripheral arterial disease.

Arterial disease resulting from atherosclerotic and thromboembolic processes is associated with significant morbidity and mortality. It is a common circulatory problem in which plaque-obstructed arteries reduce the flow of blood to tissues. Atherosclerosis occurs with advanced age, smoking, hypertension, diabetes and dyslipidemia. Peripheral arterial disease, or PAD, refers to disease affecting arteries outside the brain and heart and often refers to blockage of arteries in the lower extremities. Progression of PAD is associated with ongoing obstruction, or occlusion, of the peripheral arteries, which can occur slowly over time or may lead to a sudden, acute occlusion. Acute limb ischemia, or ALI, is a sudden decrease in perfusion of a limb, typically in the legs, that often threatens viability of the limb. The condition is considered acute if clinical presentation occurs within approximately two weeks after symptom onset. ALI rapidly threatens limb viability because there is insufficient time for new blood-vessel growth to compensate for loss of perfusion.

A Brief History of MST-188

Definitions

RheothRx – A first-generation product with unpurified, excipient-grade poloxamer 188 as the active ingredient. Associated with elevated serum creatinine.

MST-188 (formerly known as ANX-188, FLOCOR and CRL-5861) – A second-generation product with purified poloxamer 188 as the active ingredient. Certain low molecular weight substances present in excipient-grade poloxamer 188 that are associated with elevated serum creatinine are not present in MST-188. No clinically significant elevations in creatinine have been observed in clinical studies conducted with the purified material (>300 administrations).

Early Development: The CytRx Corporation/Burroughs Wellcome Alliance

Poloxamer 188 is a well studied compound. It was originally used as an emulsifying agent in topical wound cleansers and parenteral nutrition products. However, the therapeutic use of poloxamer 188 was largely conceived by Dr. Robert Hunter, MD, PhD (Distinguished Professor and Chairman, Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston). Dr. Hunter (then at Emory University) identified the compound’s rheologic, cytoprotective and antithrombotic activities through an extensive series of laboratory studies. His work led to the formation of CytRx Corporation, a start-up company that licensed Dr. Hunter’s inventions from Emory. CytRx conducted a wide range of pre-clinical and clinical studies with first-generation poloxamer 188, then known as RheothRx. These studies led to a major alliance with Burroughs Wellcome (today, GSK). Burroughs also performed an extensive series of nonclinical studies and 8 clinical trials, primarily focused on acute myocardial infarction (AMI). Early studies investigating RheothRx were promising. The largest AMI trial planned to enroll approximately 20,000 patients. However, during the 3,000-patient lead-in phase of this study, elevations in serum creatinine were observed, particularly in those patients aged 65 years and older and in subjects with elevated creatinine at baseline. This phenomenon was referred to as “acute renal dysfunction” and resulted in the discontinuation of the program by Glaxo, which had recently merged with Burroughs Wellcome.

Addressing Renal Toxicity and Pursuing Sickle Cell Disease

After Glaxo returned the RheothRx program, CytRx investigated the source of the renal dysfunction and determined the elevation in serum creatinine was attributable to preferential absorption of certain low molecular weight substances by the proximal tubule epithelial cells in the kidney. CytRx developed a proprietary method of manufacture based on supercritical fluid chromatography that reduced the level of these low molecular weight substances present in poloxamer 188, creating what is now known as purified poloxamer 188. Nonclinical testing of purified poloxamer 188 (now known as MST-188), demonstrated less accumulation in kidney tissue, less pronounced vacuolization of proximal tubular epithelium, more rapid recovery from vacuolar lesions, and less effect on serum creatinine. A full report of the differential effects of commercial-grade and purified poloxamer 188 on renal function has been published.¹

Subsequently, CytRx sought to re-introduce MST-188 into the clinic. However, CytRx lacked the resources to conduct a 20,000-patient heart attack study. Instead, they focused the development of MST-188 in sickle cell disease (SCD), a rare disease with a huge unmet need and in which RheothRx had demonstrated positive results in a pilot Phase 2 study conducted by Burroughs Wellcome. In that Phase 2 study (n=50), RheothRx significantly reduced the duration of crisis, pain intensity, and total analgesic use and showed trends to shorter days of hospitalization in the subgroup of patients who received the full dose of study drug (n=31). These data were reported more fully by Adams-Graves et al.² Notably, CytRx conducted safety studies in both adult and pediatric sickle cell patients and, even at significantly higher levels of exposure than anticipated therapeutic doses, there were no clinically significant changes in serum creatinine observed and no acute kidney failure reported. Based on these promising Phase 1 and 2 results, CytRx subsequently launched a randomized, double-blind, placebo-controlled Phase 3 study of MST-188 in 350 patients with sickle cell disease. The primary endpoint was a reduction in the duration of a painful crisis. However, CytRx concluded the study at 255 patients, in part due to capital constraints. Nonetheless, the study demonstrated treatment benefits in favor of MST-188. However, it did not achieve statistical significance in the primary study endpoint (p=0.07). Mast believes that enrolling fewer than the originally-planned number of patients and key features of the study’s design negatively affected the outcome of the primary endpoint. In particular, the study assumed that most patients would resolve their crisis within one week (168 hours). However, a substantial number of patients did not achieve crisis resolution within 168 hours and were assigned a “default” value of 168 hours, which had a potentially significant effect on the primary endpoint. Notably, in a post hoc “responder’s analysis” of the intent-to-treat population (n=249), which analyzed the proportion of patients who achieved crisis resolution at 168 hours (excluding those who had been assigned the default of 168 hours), over 50% of subjects receiving MST-188 achieved crisis resolution within 168 hours, compared to 37% in the control group (p=0.02). Data from the Phase 3 study are reported more fully by Orringer et al.³ Following conclusion of the Phase 3 study, CytRx merged with a private company and modified its business strategy by discontinuing development of all of its existing programs (including MST-188) to focus on assets held by the private company with which it merged.

SynthRx

After the corporate reorganization at CytRx, a group of individuals, including Dr. Hunter, formed a private entity, which they named SynthRx, Inc., to acquire rights to the data, know-how, and extensive clinical and pre-clinical and manufacturing information necessary to continue development of MST-188. SynthRx developed new intellectual property and conducted additional analyses of the existing data. However, they were unable to raise capital to fund development of MST-188 during the “great recession.”

Mast Therapeutics

In 2010, Mast Therapeutics met with Dr. Hunter and his colleagues to negotiate the acquisition of SynthRx and continue the development of MST-188. The merger was finalized in April 2011.

Since April 2011, Mast Therapeutics has re-established the unique manufacturing process through a partnership with Pierre Fabre (FRA) and met with the FDA multiple times to discuss a pivotal study protocol for MST-188 in sickle cell disease. In 2013, Mast initiated the EPIC study, a 388-patient pivotal Phase 3 trial of MST-188 in sickle cell disease, and, in 2014, Mast initiated its second MST-188 clinical program with a Phase 2, proof-of-concept study of MST-188 in combination with rt-PA in patients with acute limb ischemia. In addition, based on recent nonclinical study data showing improvements in cardiac ejection fraction and key biomarkers and prior studies showing MST-188 improved cardiac function without increasing cardiac energy requirements, Mast has announced its intent to pursue clinical development of MST-188 in heart failure.

1. Emanuele, M. and Balasubramaniam, B. Differential Effects of Commercial-Grade and Purified Poloxamer 188 on Renal Function. Drugs in R&D April 2014. Available at http://link.springer.com/article/10.1007/s40268-014-0041-0
2. Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997;90:2041-6
3. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286(17):2099-106

EPIC’s study drug, MST-188, is a new class of drug that acts by attaching to the damaged surfaces of the cell membranes, potentially improving blood flow and oxygen delivery.

Improving blood flow and oxygen delivery may reduce the duration and severity of pain crises faced by sickle cell patients.

Selexipag Meets Primary Endpoint in Pivitol Phase III Griphon Outcome Study in Patients with Pulmonary Arterial Hypertension

June 18, 2014 4:30 am / Leave a comment

June 16, 2014

Actelion Ltd today announced the top-line results of the pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial hypertension (PAH) with selexipag, the first selective oral prostacyclin IP receptor agonist. Initial analysis shows that the event-driven outcome study has met its primary efficacy endpoint with high statistical significance.

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

June 16, 2014

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

Selexipag

N-[2-[4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy]acetyl]methanesulfonamide
2-[4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy]-N-(methylsulfonyl)acetamide

phase 3 pulmonary hypertention

Nippon Shinyaku Co Ltd

Selexipag (ACT-293987, NS-304) is a drug currently in development by Actelion as a treatment of pulmonary arterial hypertension. Selexipag and its active metabolite, ACT-333679, are agonists at the PGI₂ prostaglandin receptor, which leads to vasodilation in the pulmonary circulation

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.

In April 2008, Actelion and Nippon Shinyaku signed a licensing agreement, under which Actelion will be responsible for the global development and commercialization of selexipag outside Japan, and the two companies will co-develop and co-commercialize the drug in Japan.

http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpbs

http://www1.actelion.com/sites/en/scientists/development-pipeline/phase-3/selexipag.page

ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE

Actelion and Nippon Shinyaku entered into an exclusive worldwide alliance in April 2008 to collaborate on selexipag, a first-in-class orally-available, selective IP receptor agonist for patients suffering from pulmonary arterial hypertension (PAH). This compound was originally discovered and synthesized by Nippon Shinyaku. Phase II evaluation has been completed, and a Phase III program in PAH patients has been initiated. Actelion is responsible for global development and commercialization of selexipag outside Japan, while the two companies will co-develop and co-commercialize in Japan. Nippon Shinyaku will receive milestone payments based on development stage and sales milestones as well as royalties on any sales of selexipag.

Selexipag

IUPAC name 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
Identifiers
CAS number	475086-01-2
PubChem	9913767
ChemSpider	8089417
UNII	5EXC0E384L
KEGG	D09994

Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C₂₆H₃₂N₄O₄S
Molar mass	496.6 g·mol⁻¹

NS-304 (ACT-293987), an orally available long acting non-prostanoid prostaglandin I2 (PGI-2) receptor agonist, is in phase III clinical trials at Actelion for the oral treatment of pulmonary hypertension. Nippon Shinyaku is conducting phase III clinical trials with NS-304 for this indication in Europe. In Japan, phase II clinical trials are ongoing for the treatment of pulmonary hypertension and chronic thromboembolic pulmonary hypertension.

Originally discovered and synthesized by Nippon Shinyaku, NS-304 stimulates PGI-2 receptors in blood vessels and exerts vasodilating effects.

In 2008, the compound was licensed to Actelion by Nippon Shinyaku on a worldwide basis with the exception of Japan for the oral treatment of pulmonary arterial hypertension (PAH). According to the final licensing agreement, Actelion will be responsible for global development and commercialization of NS-304 outside Japan, while the two companies will codevelop and co-commercialize the product candidate in Japan. In 2005, orphan drug designation was assigned in the E.U. by Nippon Shinyaku for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

…………………….

US2012/101276

http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en

The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).

BACKGROUND OF THE INVENTION

Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).

Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).

In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).

Production of Compound A

Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.

Step 1:

6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.

Step 2:

5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.

Step 3:

Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.

The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.

…………………………………

WO 2002088084

and

http://www.google.fm/patents/WO2009157398A1?cl=en

………………………

Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 21 p. 6692 – 6704

compd 31

……………………

Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 24 p. 7720 – 7725

Full-size image (5 K) 2a isthe drug

N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

http://www.sciencedirect.com/science/article/pii/S0968089607007614

References

Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.

ABOUT SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.

Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [2,4,5]

Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [6]

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.

– See more at: http://www.orphan-drugs.org/2014/06/17/selexipag-meets-primary-endpoint-pivitol-phase-iii-griphon-outcome-study-patients-pulmonary-arterial-hypertension/#sthash.PI3PzVZd.dpuf

ScinoPharm to Provide Active Pharmaceutical Ingredient 英文名称 Burixafor to F*TaiGen for Novel Stem Cell Drug

June 9, 2014 3:53 am / 1 Comment on ScinoPharm to Provide Active Pharmaceutical Ingredient 英文名称 Burixafor to F*TaiGen for Novel Stem Cell Drug

英文名称Burixafor

TG-0054

(2-{4-[6-amino-2-({[(1r,4r)-4-({[3-(cyclohexylamino)propyl]amino}methyl)cyclohexyl]methyl}amino)pyrimidin-4-yl]piperazin-1-yl}ethyl)phosphonic acid

[2-[4-[6-Amino-2-[[[trans-4-[[[3-(cyclohexylamino)propyl]amino]methyl]cyclohexyl]methyl]amino]pyrimidin-4-yl]piperazin-1-yl]ethyl]phosphonic acid

1191448-17-5

C₂₇H₅₁N₈O₃P, 566.7194

chemokine CXCR 4 receptor antagonist;

	Taigen Biotechnology Co., Ltd.

Taigen Biotechnology Co., Ltd.

ScinoPharm to Provide Active Pharmaceutical Ingredient to F*TaiGen for Novel Stem Cell Drug
MarketWatch
The drug has received a Clinical Trial Application from China’s FDA for the initiation of … In addition, six products have entered Phase III clinical trials.

read at

http://www.marketwatch.com/story/scinopharm-to-provide-active-pharmaceutical-ingredient-to-ftaigen-for-novel-stem-cell-drug-2014-06-08

2D chemical structure of 1191448-17-5

TAINAN, June 8, 2014 — ScinoPharm Taiwan, Ltd. (twse:1789) specializing in the development and manufacture of active pharmaceutical ingredients, and TaiGen Biotechnology (4157.TW; F*TaiGen) jointly announced today the signing of a manufacturing contract for the clinical supply of the API of Burixafor, a new chemical entity discovered and developed by TaiGen. The API will be manufactured in ScinoPharm’s plant in Changshu, China. This cooperation not only demonstrates Taiwan’s international competitive strength in new drug development, but also sees the beginning of a domestic pharmaceutical specialization and cooperation mechanisms, thus establishing a groundbreaking milestone for Taiwan’s pharmaceutical industry.

Dr. Jo Shen, President and CEO of ScinoPharm said, “This cooperation with TaiGen is of representative significance in the domestic pharmaceutical companies’ upstream and downstream cooperation and self-development of new drugs, and indicates the Taiwanese pharmaceutical industry’s cumulative research and development momentum is paving the way forward.” Dr. Jo Shen emphasized, “ScinoPharm’s Changshu Plant provides high-quality API R&D and manufacturing services through its fast, flexible, reliable competitive advantages, effectively assisting clients of new drugs in gaining entry into China, Europe, the United States, and other international markets.”

According to Dr. Ming-Chu Hsu, Chairman and CEO of TaiGen, “R&D is the foundation of the pharmaceutical industry. Once a drug is successfully developed, players at all levels of the value chain could reap the benefit. Burixafor is a 100% in-house developed product that can be used in the treatment of various intractable diseases. The cooperation between TaiGen and ScinoPharm will not only be a win-win for both sides, but will also provide high-quality novel dug for patients from around the world.”

Burixafor is a novel stem cell mobilizer that can efficiently mobilize bone marrow stem cells and tissue precursor cells to the peripheral blood. It can be used in hematopoietic stem cell transplantation, chemotherapy sensitization and other ischemic diseases. The results of the ongoing Phase II clinical trial in the United States are very impressive. The drug has received a Clinical Trial Application from China’s FDA for the initiation of a Phase II clinical trial in chemotherapy sensitization under the 1.1 category. According to the pharmaceutical consultancy company JSB, with only stem cell transplant and chemotherapy sensitizer as the indicator, Burixafor’s annual sales are estimated at USD1.1 billion.

ScinoPharm currently has accepted over 80 new drug API process research and development plans, of which five new drugs have been launched in the market. In addition, six products have entered Phase III clinical trials. Through the Changshu Plant’s operation in line with the latest international cGMP plant equipment and quality management standards, the company provides customers with one stop shopping services in professional R&D, manufacturing, and outsourcing, thereby shortening the customer development cycle of customers’ products and accelerating the launch of new products to the market.

TaiGen’s focus is on the research and development of novel drugs. Besides Burixafor, the products also include anti-infective, Taigexyn®, and an anti-hepatitis C drug, TG-2349. Taigexyn® is the first in-house developed novel drug that received new drug application approval from Taiwan’s FDA. TG-2349 is intended for the 160 million global patients with hepatitis C with huge market potential. TaiGen hopes to file one IND with the US FDA every 3-4 years to expand TaiGen’s product line.

About ScinoPharm

ScinoPharm Taiwan, Ltd. is a leading process R&D and API manufacturing service provider to the global pharmaceutical industry. With research and manufacturing facilities in both Taiwan and China, ScinoPharm offers a wide portfolio of services ranging from custom synthesis for early phase pharmaceutical activities to contract services for brand companies as well as APIs for the generic industry. For more information, please visit the Company’s website at http://www.scinopharm.com

About TaiGen Biotechnology

TaiGen Biotechnology is a leading research-based and product-driven biotechnology company in Taiwan with a wholly-owned subsidiary in Beijing, China. The company’s first product, Taigexyn®, have already received NDA approval from Taiwan’s FDA. In addition to Taigexyn®, TaiGen has two other in-house discovered NCEs in clinical development under IND with US FDA: TG-0054, a chemokine receptor antagonist for stem cell transplantation and chemosensitization, in Phase 2 and TG-2349, a HCV protease inhibitor for treatment of chronic hepatitis infection, in Phase 2. Both TG-0054 and TG-2349 are currently in clinical trials in patients in the US.

SOURCE ScinoPharm Taiwan Ltd.

TG-0054 is a potent and selective chemokine CXCR4 (SDF-1) antagonist in phase II clinical studies at TaiGen Biotechnology for use in stem cell transplantation in cancer patients. Specifically, the compound is being developed for the treatment of stem cell transplantation in multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and myocardial ischemia.

Preclinical studies had also been undertaken for the treatment of diabetic retinopathy, critical limb ischemia (CLI) and age-related macular degeneration. In a mouse model, TG-0054 efficiently mobilizes stem cells (CD34+) and endothelial progenitor cells (CD133+) from bone marrow into peripheral circulation.

BACKGROUND

Chemokines are a family of cytokines that regulate the adhesion and transendothelial migration of leukocytes during an immune or inflammatory reaction (Mackay C.R., Nat. Immunol, 2001, 2:95; Olson et al, Am. J. Physiol. Regul. Integr. Comp. Physiol, 2002, 283 :R7). Chemokines also regulate T cells and B cells trafficking and homing, and contribute to the development of lymphopoietic and hematopoietic systems (Ajuebor et al, Biochem. Pharmacol, 2002, 63:1191). Approximately 50 chemokines have been identified in humans. They can be classified into 4 subfamilies, i.e., CXC, CX3C, CC, and C chemokines, based on the positions of the conserved cysteine residues at the N-terminal (Onuffer et al, Trends Pharmacol ScI, 2002, 23:459). The biological functions of chemokines are mediated by their binding and activation of G protein-coupled receptors (GPCRs) on the cell surface.

Stromal-derived factor- 1 (SDF-I) is a member of CXC chemokines. It is originally cloned from bone marrow stromal cell lines and found to act as a growth factor for progenitor B cells (Nishikawa et al, Eur. J. Immunol, 1988, 18:1767). SDF-I plays key roles in homing and mobilization of hematopoietic stem cells and endothelial progenitor cells (Bleul et al, J. Exp. Med., 1996, 184:1101; and Gazzit et al, Stem Cells, 2004, 22:65-73). The physiological function of SDF-I is mediated by CXCR4 receptor. Mice lacking SDF-I or CXCR4 receptor show lethal abnormality in bone marrow myelopoiesis, B cell lymphopoiesis, and cerebellar development (Nagasawa et al, Nature, 1996, 382:635; Ma et al, Proc. Natl. Acad. ScI, 1998, 95:9448; Zou et al, Nature, 1998, 393:595; Lu et al, Proc. Natl. Acad. ScI, 2002, 99:7090). CXCR4 receptor is expressed broadly in a variety of tissues, particularly in immune and central nervous systems, and has been described as the major co-receptor for HIV- 1/2 on T lymphocytes. Although initial interest in CXCR4 antagonism focused on its potential application to AIDS treatment (Bleul et al, Nature, 1996, 382:829), it is now becoming clear that CXCR4 receptor and SDF-I are also involved in other pathological conditions such as rheumatoid arthritis, asthma, and tumor metastases (Buckley et al., J. Immunol., 2000, 165:3423). Recently, it has been reported that a CXCR4 antagonist and an anticancer drug act synergistically in inhibiting cancer such as acute promuelocutic leukemia (Liesveld et al., Leukemia

Research 2007, 31 : 1553). Further, the CXCR4/SDF-1 pathway has been shown to be critically involved in the regeneration of several tissue injury models. Specifically, it has been found that the SDF-I level is elevated at an injured site and CXCR4-positive cells actively participate in the tissue regenerating process.

………………………………………………………………………..

http://www.google.com/patents/WO2009131598A1?cl=en

Compound 52

Example 1 : Preparation of Compounds 1

1-1 1-Ii 1-m

^ ^–\_{\ Λ x}CUNN ^H ‘ ‘₂2.. P ^rd^u/’C^ ^. , _Λ>\_V>_v

Et₃N, TFAA , _H_, r [ Y I RRaanneeyy–NNiicckkeell _{u H} f [ Y | NH₂

CH₂CI₂, -10 ⁰C _Boc^ ‘^NNA/ 11,,44–ddιιooxxaannee B Boocer”¹^”–^^ LiOH, H₂O, 50 ⁰C

1-IV 1-V

Water (10.0 L) and (BoC)₂O (3.33 kgg, 15.3 mol) were added to a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (compound 1-1, 2.0 kg, 12.7 mol) and sodium bicarbonate (2.67 kg, 31.8 mol). The reaction mixture was stirred at ambient temperature for 18 hours. The aqueous layer was acidified with concentrated hydrochloric acid (2.95 L, pH = 2) and then filtered. The resultant solid was collected, washed three times with water (15 L), and dried in a hot box (60 ⁰C) to give trα/?5-4-(tert-butoxycarbonylamino-methyl)-cyclo-hexanecarboxylic acid (Compound l-II, 3.17 kg, 97%) as a white solid. R_f = 0.58 (EtOAc). LC-MS m/e 280 (M+Na⁺). ¹H NMR (300 MHz, CDCl₃) δ 4.58 (brs, IH), 2.98 (t, J= 6.3 Hz, 2H), 2.25 (td, J = 12, 3.3 Hz, IH), 2.04 (d, J= 11.1 Hz, 2H), 1.83 (d, J= 11.1 Hz, 2H), 1.44 (s, 9H), 1.35-1.50 (m, 3H), 0.89-1.03 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 181.31, 156.08, 79.12, 46.41, 42.99, 37.57, 29.47, 28.29, 27.96. M.p. 134.8-135.0 ⁰C. A suspension of compound l-II (1.0 kg, 3.89 mol) in THF (5 L) was cooled at

-10 ⁰C and triethyl amine (1.076 L, 7.78 mol) and ethyl chloroformate (0.441 L, 4.47 mol) were added below -10 ⁰C. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled at -10 ⁰C again and NH₄OH (3.6 L, 23.34 mol) was added below -10 ⁰C. The reaction mixture was stirred at ambient temperature for 18 hours and filtered. The solid was collected and washed three times with water (10 L) and dried in a hot box (6O⁰C) to give trans-4- (tert-butoxycarbonyl-amino-methyl)-cyclohexanecarboxylic acid amide (Compound l-III, 0.8 kg, 80%) as a white solid. Rf= 0.23 (EtOAc). LC-MS m/e 279, M+Na⁺. ¹H NMR (300 MHz, CD₃OD) δ 6.63 (brs, IH), 2.89 (t, J= 6.3 Hz, 2H), 2.16 (td, J = 12.2, 3.3 Hz, IH), 1.80-1.89 (m, 4H), 1.43 (s, 9H), 1.37-1.51 (m, 3H), 0.90-1.05 (m, 2H). ¹³C NMR (75 MHz, CD₃OD) δ 182.26, 158.85, 79.97, 47.65, 46.02, 39.28, 31.11, 30.41, 28.93. M.p. 221.6-222.0 ⁰C.

A suspension of compound l-III (1.2 kg, 4.68 mol) in CH₂Cl₂ (8 L) was cooled at -1O⁰C and triethyl amine (1.3 L, 9.36 mol) and trifluoroacetic anhydride (0.717 L, 5.16 mol) were added below -10 ⁰C. The reaction mixture was stirred for 3 hours. After water (2.0 L) was added, the organic layer was separated and washed with water (3.0 L) twice. The organic layer was then passed through silica gel and concentrated. The resultant oil was crystallized by methylene chloride. The crystals were washed with hexane to give £rαns-(4-cyano-cyclohexylmethyl)-carbamic acid tert-butyl ester (Compound 1-IV, 0.95 kg, 85%) as a white crystal. R_f = 0.78 (EtOAc). LC-MS m/e 261, M+Na⁺. ¹H NMR (300 MHz, CDCl₃) δ 4.58 (brs, IH), 2.96 (t, J = 6.3 Hz, 2H), 2.36 (td, J= 12, 3.3 Hz, IH), 2.12 (dd, J= 13.3, 3.3 Hz, 2H), 1.83 (dd, J = 13.8, 2.7 Hz, 2H), 1.42 (s, 9H), 1.47-1.63 (m, 3H), 0.88-1.02 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 155.96, 122.41, 79.09, 45.89, 36.92, 29.06, 28.80, 28.25, 28.00. M.p. 100.4~100.6°C.

Compound 1-IV (1.0 kg, 4.196 mol) was dissolved in a mixture of 1 ,4-dioxane (8.0 L) and water (2.0 L). To the reaction mixture were added lithium hydroxide monohydrate (0.314 kg, 4.191), Raney-nickel (0.4 kg, 2.334 mol), and 10% palladium on carbon (0.46 kg, 0.216 mol) as a 50% suspension in water. The reaction mixture was stirred under hydrogen atmosphere at 5O⁰C for 20 hours. After the catalysts were removed by filtration and the solvents were removed in vacuum, a mixture of water (1.0 L) and CH₂Cl₂ (0.3 L) was added. After phase separation, the organic phase was washed with water (1.0 L) and concentrated to give £rα/?s-(4-aminomethyl- cyclohexylmethyl)-carbamic acid tert- butyl ester (compound 1-V, 0.97 kg, 95%) as pale yellow thick oil. R_f = 0.20 (MeOH/EtOAc = 9/1). LC-MS m/e 243, M+H⁺. ¹H NMR (300 MHz, CDCl₃) δ 4.67 (brs, IH), 2.93 (t, J= 6.3 Hz, 2H), 2.48 (d, J= 6.3 Hz, 2H), 1.73-1.78 (m, 4H), 1.40 (s, 9H), 1.35 (brs, 3H), 1.19-1.21 (m, IH), 0.77-0.97 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 155.85, 78.33, 48.27, 46.38, 40.80, 38.19, 29.87, 29.76, 28.07. A solution of compound 1-V (806 g) and Et₃N (1010 g, 3 eq) in 1-pentanol

(2.7 L) was treated with compound 1-VI, 540 g, 1 eq) at 90⁰C for 15 hours. TLC showed that the reaction was completed. Ethyl acetate (1.5 L) was added to the reaction mixture at 25°C. The solution was stirred for 1 hour. The Et₃NHCl salt was filtered. The filtrate was then concentrated to 1.5 L (1/6 of original volume) by vacuum at 50⁰C. Then, diethyl ether (2.5 L) was added to the concentrated solution to afford the desired product 1-VII (841 g, 68% yield) after filtration at 25⁰C .

A solution of intermediate 1-VII (841 g) was treated with 4 N HCl/dioxane (2.7 L) in MeOH (8.1 L) and stirred at 25°C for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated to 1.5 L (1/7 of original volume) by vacuum at 50⁰C. Then, diethyl ether (5 L) was added to the solution slowly, and HCl salt of 1-VIII (774 g) was formed, filtered, and dried under vacuum (<10 torr). For neutralization, K₂CO3 (2.5 kg, 8 eq) was added to the solution of HCl salt of 1-VIII in MeOH (17 L) at 25°C. The mixture was stirred at the same temperature for 3 hours (pH > 12) and filtered (estimated amount of 1-VIII in the filtrate is 504 g). Aldehyde 1-IX (581 g, 1.0 eq based on mole of 1-VII) was added to the filtrate of 1-VIII at 0-10⁰C. The reaction was stirred at 0-10⁰C for 3 hours. TLC showed that the reaction was completed. Then, NaBH₄ (81 g, 1.0 eq based on mole of 1-VII) was added at less than 10⁰C and the solution was stirred at 10-15⁰C for Ih. The solution was concentrated to get a residue, which then treated with CH₂Cl₂ (15 L). The mixture was washed with saturated aq. NH₄Cl solution (300 mL) diluted with H₂O (1.2 L). The CH₂Cl₂ layer was concentrated and the residue was purified by chromatography on silica gel (short column, EtOAc as mobile phase for removing other components; MeOH/28% NH₄OH = 97/3 as mobile phase for collecting 1-X) afforded crude 1-X (841 g). Then Et₃N (167 g, leq) and BoC₂O (360 g, leq) were added to the solution of

1-X (841 g) in CH₂Cl₂ (8.4 L) at 25°C. The mixture was stirred at 25°C for 15 hours. After the reaction was completed as evidenced by TLC, the solution was concentrated and EtOAc (5 L) was added to the resultant residue. The solution was concentrated to 3L (1/2 of the original volume) under low pressure at 50⁰C. Then, n-hexane (3 L) was added to the concentrated solution. The solid product formed at 50⁰C by seeding to afford the desired crude product 1-XI (600 g, 60% yield) after filtration and evaporation. To compound 1-XI (120.0 g) and piperazine (1-XII, 50.0 g, 3 eq) in 1- pentanol (360 niL) was added Et₃N (60.0 g, 3.0 eq) at 25°C. The mixture was stirred at 120⁰C for 8 hours. Ethyl acetate (480 mL) was added to the reaction mixture at 25°C. The solution was stirred for Ih. The Et₃NHCl salt was filtered and the solution was concentrated and purified by silica gel (EtOAc/MeOH = 2:8) to afforded 1-XIII (96 g) in a 74% yield.

A solution of intermediate 1-XIII (100 mg) was treated with 4 N HCl/dioxane (2 mL) in CH₂Cl₂ (1 mL) and stirred at 25°C for 15 hours. The mixture was concentrated to give hydrochloride salt of compound 1 (51 mg). CI-MS (M⁺ + 1): 459.4

Example 2: Preparation of Compound 2

Compound 2 Intermediate 1-XIII was prepared as described in Example 1.

To a solution of 1-XIII (120 g) in MeOH (2.4 L) were added diethyl vinyl phosphonate (2-1, 45 g, 1.5 eq) at 25°C. The mixture was stirred under 65°C for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH₂Cl₂ = 8/92) to get 87 g of 2-11 (53% yield, purity > 98%, each single impurity <1%) after analyzing the purity of the product by HPLC.

A solution of 20% TFA/CH₂C1₂ (36 mL) was added to a solution of intermediate 2-11 (1.8 g) in CH₂Cl₂ (5 mL). The reaction mixture was stirred for 15 hours at room temperature and concentrated by removing the solvent to afford trifluoracetic acid salt of compound 2 (1.3 g). CI-MS (M⁺ + 1): 623.1

Example 3 : Preparation of Compound 3

TMSBr _H H

s U

Intermediate 2-11 was prepared as described in Example 2. To a solution of 2-11 (300 g) in CH₂Cl₂ (1800 mL) was added TMSBr (450 g, 8 eq) at 10-15⁰C for 1 hour. The mixture was stirred at 25°C for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 40⁰C.

CH₂Cl₂ was added to the mixture to dissolve the residue. TMSBr and solvent were removed under vacuum again to obtain 36O g crude solid after drying under vacuum (<1 torr) for 3 hours. Then, the crude solid was washed with 7.5 L IPA/MeOH (9/1) to afford compound 3 (280 g) after filtration and drying at 25°C under vacuum (<1 torr) for 3 hours. Crystallization by EtOH gave hydrobromide salt of compound 3 (19Og). CI-MS (M⁺ + 1): 567.0.

The hydrobromide salt of compound 3 (5.27 g) was dissolved in 20 mL water and treated with concentrated aqueous ammonia (pH=9-10), and the mixture was evaporated in vacuo. The residue in water (30 mL) was applied onto a column (100 mL, 4.5×8 cm) of Dowex 50WX8 (H⁺ form, 100-200 mesh) and eluted (elution rate, 6 mL/min). Elution was performed with water (2000 mL) and then with 0.2 M aqueous ammonia. The UV-absorbing ammonia eluate was evaporated to dryness to afford ammonia salt of compound 3 (2.41 g). CI-MS (M⁺ + 1): 567.3.

The ammonia salt of compound 3 (1.5 g) was dissolved in water (8 mL) and alkalified with concentrated aqueous ammonia (pH=l 1), and the mixture solution was applied onto a column (75 mL, 3×14 cm) of Dowex 1X2 (acetate form, 100-200 mesh) and eluted (elution rate, 3 mL/min). Elution was performed with water (900 mL) and then with 0.1 M acetic acid. The UV-absorbing acetic acid eluate was evaporated, and the residue was codistilled with water (5×50 mL) to afford compound 3 (1.44 g). CI-MS (M⁺ + 1): 567.4. Example 4: Preparation of Compound 4

Compound 4

Intermediate 1-XIII was obtained during the preparation of compound 1. To a solution of diethyl vinyl phosphonate (4-1, 4 g) in CH₂Cl₂ (120 mL) was added oxalyl chloride (15.5 g, 5 eq) and the mixture was stirred at 30⁰C for 36 hours. The mixture were concentrated under vacuum on a rotatory evaporated to give quantitatively the corresponding phosphochloridate, which was added to a mixture of cyclohexyl amine (4-II, 5.3 g, 2.2 eq), CH₂Cl₂ (40 mL), and Et₃N (6.2 g, 2.5 eq). The mixture was stirred at 35°C for 36 hours, and then was washed with water. The organic layer was dried (MgSO₄), filtered, and evaporated to afford 4-III (4.7 g, 85% yield) as brown oil.

Compound 4-III (505 mg) was added to a solution of intermediate 1-XIII (500 mg) in MeOH (4 mL). The solution was stirred at 45°C for 24 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/ MeOH = 4: 1) to afford intermediate 4-IV (420 mg) in a 63% yield.

A solution of HCl in ether (5 mL) was added to a solution of intermediate 4- IV (420 mg) in CH₂Cl₂ (1.0 mL). The reaction mixture was stirred for 12 hours at room temperature and concentrated by removing the solvent. The resultant residue was washed with ether to afford hydrochloride salt of compound 4 (214 mg). CI-MS (M⁺ + 1): 595.1

Preparation of compound 51

TMSBr

Intermediate l-II was prepared as described in Example 1. To a suspension of the intermediate l-II (31.9 g) in toluene (150 mL) were added phosphorazidic acid diphenyl ester (51-1, 32.4 g) and Et₃N (11.9 g) at 25°C for 1 hour. The reaction mixture was stirred at 80⁰C for 3 hours and then cooled to 25°C. After benzyl alcohol (51-11, 20 g) was added, the reaction mixture was stirred at 80⁰C for additional 3 hours and then warmed to 120⁰C overnight. It was then concentrated and dissolved again in EtOAc and H₂O. The organic layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with 2.5 N HCl, saturated aqueous NaHCO₃ and brine, dried over anhydrous MgSO₄, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/Hexane = 1 :2) to give Intermediate 51-111 (35 g) in a 79% yield. A solution of intermediate 51-111 (35 g) treated with 4 N HCl/dioxane (210 rnL) in MeOH (350 mL) was stirred at room temperature overnight. After ether (700 mL) was added, the solution was filtered. The solid was dried under vacuum. K2CO3 was added to a suspension of this solid in CH₃CN and ώo-propanol at room temperature for 10 minutes. After water was added, the reaction mixture was stirred at room temperature for 2 hours, filtered, dried over anhydrous MgSO₄, and concentrated. The resultant residue was purified by column chromatography on silica gel (using CH₂Cl₂ and MeOH as an eluant) to give intermediate 51-IV (19 g) in a 76% yield. Intermediate 1-IX (21 g) was added to a solution of intermediate 51-IV (19 g) in CH₂Cl₂ (570 mL). The mixture was stirred at 25°C for 2 hours. NaBH(OAc)₃ (23 g) was then added at 25°C overnight. After the solution was concentrated, a saturated aqueous NaHCO₃ solution was added to the resultant residue. The mixture was then extracted with CH₂Cl₂. The solution was concentrated and the residue was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 51-V (23.9 g) in a 66% yield.

A solution of intermediate 51-V (23.9 g) and BoC₂O (11.4 g) in CH₂Cl₂ (200 mL) was added to Et₃N (5.8 mL) at 25°C for overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (using EtOAc and Hexane as an eluant) to give intermediate 51-VI (22 g) in a 77% yield.

10% Pd/C (2.2 g) was added to a suspension of intermediate 51-VI (22 g) in MeOH (44 mL). The mixture was stirred at ambient temperature under hydrogen atmosphere overnight, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 51-VII (16.5 g) in a 97% yield.

Intermediate 51-VII (16.5 g) and Et₃N (4.4 mL) in 1-pentanol (75 mL) was allowed to react with 2,4-dichloro-6-aminopyrimidine (1-VI, 21 g) at 120⁰C overnight. The solvent was then removed and the residue was purified by column chromatography on silica gel (using EtOAc and hexane as an eluant) to afford intermediate 51-VIII (16.2 g) in a 77% yield.

A solution of intermediate 51-VIII (16.2 g) and piperazine (1-XII, 11.7 g) in 1-pentanol (32 mL) was added to Et₃N (3.3 mL) at 120⁰C overnight. After the solution was concentrated, the residue was treated with water and extracted with CH₂Cl₂. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc/ MeOH to 28% NH₄0H/Me0H as an eluant) to afford Intermediate 51-IX (13.2 g) in a 75% yield. Diethyl vinyl phosphonate (2-1) was treated with 51-IX as described in

Example 3 to afford hydrobromide salt of compound 51. CI-MS (M⁺ + 1): 553.3

………………………………….

Preparation of Compound 1

Water (10.0 L) and (Boc)₂O (3.33 kgg, 15.3 mol) were added to a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (compound 1-I, 2.0 kg, 12.7 mol) and sodium bicarbonate (2.67 kg, 31.8 mol). The reaction mixture was stirred at ambient temperature for 18 hours. The aqueous layer was acidified with concentrated hydrochloric acid (2.95 L, pH=2) and then filtered. The resultant solid was collected, washed three times with water (15 L), and dried in a hot box (60° C.) to give trans-4-(tert-butoxycarbonylamino-methyl)-cyclo-hexanecarboxylic acid (Compound 1-II, 3.17 kg, 97%) as a white solid. R_f=0.58 (EtOAc). LC-MS m/e 280 (M+Na⁺). ¹H NMR (300 MHz, CDCl₃) δ 4.58 (brs, 1H), 2.98 (t, J=6.3 Hz, 2H), 2.25 (td, J=12, 3.3 Hz, 1H), 2.04 (d, J=11.1 Hz, 2H), 1.83 (d, J=11.1 Hz, 2H), 1.44 (s, 9H), 1.35˜1.50 (m, 3H), 0.89˜1.03 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 181.31, 156.08, 79.12, 46.41, 42.99, 37.57, 29.47, 28.29, 27.96. M.p. 134.8˜135.0° C.

A suspension of compound 1-II (1.0 kg, 3.89 mol) in THF (5 L) was cooled at 10° C. and triethyl amine (1.076 L, 7.78 mol) and ethyl chloroformate (0.441 L, 4.47 mol) were added below 10° C. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled at 10° C. again and NH₄OH (3.6 L, 23.34 mol) was added below 10° C. The reaction mixture was stirred at ambient temperature for 18 hours and filtered. The solid was collected and washed three times with water (10 L) and dried in a hot box (60° C.) to give trans-4-(tert-butoxycarbonyl-amino-methyl)-cyclohexanecarboxylic acid amide (Compound 1-III, 0.8 kg, 80%) as a white solid. R_f=0.23 (EtOAc). LC-MS m/e 279, M+Na⁺. ¹H NMR (300 MHz, CD₃OD) δ 6.63 (brs, 1H), 2.89 (t, J=6.3 Hz, 2H), 2.16 (td, J=12.2, 3.3 Hz, 1H), 1.80˜1.89 (m, 4H), 1.43 (s, 9H), 1.37˜1.51 (m, 3H), 0.90˜1.05 (m, 2H). ¹³C NMR (75 MHz, CD₃OD) δ 182.26, 158.85, 79.97, 47.65, 46.02, 39.28, 31.11, 30.41, 28.93. M.p. 221.6˜222.0° C.

A suspension of compound 1-III (1.2 kg, 4.68 mol) in CH₂Cl₂(8 L) was cooled at 10° C. and triethyl amine (1.3 L, 9.36 mol) and trifluoroacetic anhydride (0.717 L, 5.16 mol) were added below 10° C. The reaction mixture was stirred for 3 hours. After water (2.0 L) was added, the organic layer was separated and washed with water (3.0 L) twice. The organic layer was then passed through silica gel and concentrated. The resultant oil was crystallized by methylene chloride. The crystals were washed with hexane to give trans-(4-cyano-cyclohexylmethyl)-carbamic acid tent-butyl ester (Compound 1-IV, 0.95 kg, 85%) as a white crystal. R_f=0.78 (EtOAc). LC-MS m/e 261, M+Na⁺. ¹H NMR (300 MHz, CDCl₃) δ 4.58 (brs, 1H), 2.96 (t, J=6.3 Hz, 2H), 2.36 (td, J=12, 3.3 Hz, 1H), 2.12 (dd, J=13.3, 3.3 Hz, 2H), 1.83 (dd, J=13.8, 2.7 Hz, 2H), 1.42 (s, 9H), 1.47˜1.63 (m, 3H), 0.88˜1.02 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 155.96, 122.41, 79.09, 45.89, 36.92, 29.06, 28.80, 28.25, 28.00. M.p. 100.4˜100.6° C.

Compound 1-IV (1.0 kg, 4.196 mol) was dissolved in a mixture of 1,4-dioxane (8.0 L) and water (2.0 L). To the reaction mixture were added lithium hydroxide monohydrate (0.314 kg, 4.191), Raney-nickel (0.4 kg, 2.334 mol), and 10% palladium on carbon (0.46 kg, 0.216 mol) as a 50% suspension in water. The reaction mixture was stirred under hydrogen atmosphere at 50° C. for 20 hours. After the catalysts were removed by filtration and the solvents were removed in vacuum, a mixture of water (1.0 L) and CH₂Cl₂(0.3 L) was added. After phase separation, the organic phase was washed with water (1.0 L) and concentrated to give trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (compound 1-V, 0.97 kg, 95%) as pale yellow thick oil. R_f=0.20 (MeOH/EtOAc=9/1). LC-MS m/e 243, M+H⁺. ¹H NMR (300 MHz, CDCl₃) δ 4.67 (brs, 1H), 2.93 (t, J=6.3 Hz, 2H), 2.48 (d, J=6.3 Hz, 2H), 1.73˜1.78 (m, 4H), 1.40 (s, 9H), 1.35 (brs, 3H), 1.19˜1.21 (m, 1H), 0.77˜0.97 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 155.85, 78.33, 48.27, 46.38, 40.80, 38.19, 29.87, 29.76, 28.07.

A solution of compound 1-V (806 g) and Et₃N (1010 g, 3 eq) in 1-pentanol (2.7 L) was treated with compound 1-VI, 540 g, 1 eq) at 90° C. for 15 hours. TLC showed that the reaction was completed.

Ethyl acetate (1.5 L) was added to the reaction mixture at 25° C. The solution was stirred for 1 hour. The Et₃NHCl salt was filtered. The filtrate was then concentrated to 1.5 L (1/6 of original volume) by vacuum at 50° C. Then, diethyl ether (2.5 L) was added to the concentrated solution to afford the desired product 1-VII (841 g, 68% yield) after filtration at 25° C.

A solution of intermediate 1-VII (841 g) was treated with 4 N HCl/dioxane (2.7 L) in MeOH (8.1 L) and stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated to 1.5 L (1/7 of original volume) by vacuum at 50° C. Then, diethyl ether (5 L) was added to the solution slowly, and HCl salt of 1-VIII (774 g) was formed, filtered, and dried under vacuum (<10 ton). For neutralization, K₂CO₃(2.5 kg, 8 eq) was added to the solution of HCl salt of 1-VIII in MeOH (17 L) at 25° C. The mixture was stirred at the same temperature for 3 hours (pH>12) and filtered (estimated amount of 1-VIII in the filtrate is 504 g).

Aldehyde 1-IX (581 g, 1.0 eq based on mole of 1-VII) was added to the filtrate of 1-VIII at 0-10° C. The reaction was stirred at 0-10° C. for 3 hours. TLC showed that the reaction was completed. Then, NaBH₄(81 g, 1.0 eq based on mole of 1-VII) was added at less than 10° C. and the solution was stirred at 10-15° C. for 1 h. The solution was concentrated to get a residue, which then treated with CH₂Cl₂(15 L). The mixture was washed with saturated aq. NH₄Cl solution (300 mL) diluted with H₂O (1.2 L). The CH₂Cl₂layer was concentrated and the residue was purified by chromatography on silica gel (short column, EtOAc as mobile phase for removing other components; MeOH/28% NH₄OH=97/3 as mobile phase for collecting 1-X) afforded crude 1-X (841 g).

Then Et₃N (167 g, 1 eq) and Boc₂O (360 g, 1 eq) were added to the solution of 1-X (841 g) in CH₂Cl₂(8.4 L) at 25° C. The mixture was stirred at 25° C. for 15 hours. After the reaction was completed as evidenced by TLC, the solution was concentrated and EtOAc (5 L) was added to the resultant residue. The solution was concentrated to 3 L (1/2 of the original volume) under low pressure at 50° C. Then, n-hexane (3 L) was added to the concentrated solution. The solid product formed at 50° C. by seeding to afford the desired crude product 1-XI (600 g, 60% yield) after filtration and evaporation.

To compound 1-XI (120.0 g) and piperazine (1-XII, 50.0 g, 3 eq) in 1-pentanol (360 mL) was added Et₃N (60.0 g, 3.0 eq) at 25° C. The mixture was stirred at 120° C. for 8 hours. Ethyl acetate (480 mL) was added to the reaction mixture at 25° C. The solution was stirred for 1 h. The Et₃NHCl salt was filtered and the solution was concentrated and purified by silica gel (EtOAc/MeOH=2:8) to afforded 1-XIII (96 g) in a 74% yield.

To a solution of 1-XIII (120 g) in MeOH (2.4 L) were added diethyl vinyl phosphonate (1-XIV, 45 g, 1.5 eq) at 25° C. The mixture was stirred under 65° C. for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH₂Cl₂=8/92) to get 87 g of 1-XV (53% yield, purity>98%, each single impurity<1%) after analyzing the purity of the product by HPLC.

A solution of 20% TFA/CH₂Cl₂(36 mL) was added to a solution of intermediate 1-XV (1.8 g) in CH₂Cl₂(5 mL). The reaction mixture was stirred for 15 hours at room temperature and concentrated by removing the solvent to afford trifluoracetic acid salt of compound 1 (1.3 g).

CI-MS (M⁺+1): 623.1.

(2) Preparation of Compound 2

Intermediate 1-XV was prepared as described in Example 1.

To a solution of 1-XV (300 g) in CH₂Cl₂(1800 mL) was added TMSBr (450 g, 8 eq) at 10-15° C. for 1 hour. The mixture was stirred at 25° C. for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 40° C. CH₂Cl₂was added to the mixture to dissolve the residue. TMSBr and solvent were removed under vacuum again to obtain 360 g crude solid after drying under vacuum (<1 torr) for 3 hours. Then, the crude solid was washed with 7.5 L IPA/MeOH (9/1) to afford compound 2 (280 g) after filtration and drying at 25° C. under vacuum (<1 ton) for 3 hours. Crystallization by EtOH gave hydrobromide salt of compound 2 (190 g). CI-MS (M⁺+1): 567.0.

The hydrobromide salt of compound 2 (5.27 g) was dissolved in 20 mL water and treated with concentrated aqueous ammonia (pH=9-10), and the mixture was evaporated in vacuo. The residue in water (30 mL) was applied onto a column (100 mL, 4.5×8 cm) of Dowex 50WX8 (H⁺ form, 100-200 mesh) and eluted (elution rate, 6 mL/min). Elution was performed with water (2000 mL) and then with 0.2 M aqueous ammonia. The UV-absorbing ammonia eluate was evaporated to dryness to afford ammonia salt of compound 2 (2.41 g). CI-MS (M⁺+1): 567.3.

The ammonia salt of compound 2 (1.5 g) was dissolved in water (8 mL) and alkalified with concentrated aqueous ammonia (pH=11), and the mixture solution was applied onto a column (75 mL, 3×14 cm) of Dowex 1×2 (acetate form, 100-200 mesh) and eluted (elution rate, 3 mL/min). Elution was performed with water (900 mL) and then with 0.1 M acetic acid. The UV-absorbing acetic acid eluate was evaporated, and the residue was codistilled with water (5×50 mL) to afford compound 2 (1.44 g). CI-MS (M⁺+1): 567.4.

(3) Preparation of Compound 3

Intermediate 1-XIII was obtained during the preparation of compound 1.

To a solution of diethyl vinyl phosphonate (3-I, 4 g) in CH₂Cl₂(120 mL) was added oxalyl chloride (15.5 g, 5 eq) and the mixture was stirred at 30° C. for 36 hours. The mixture were concentrated under vacuum on a rotatory evaporated to give quantitatively the corresponding phosphochloridate, which was added to a mixture of cyclohexyl amine (3-II, 5.3 g, 2.2 eq), CH₂Cl₂(40 mL), and Et₃N (6.2 g, 2.5 eq). The mixture was stirred at 35° C. for 36 hours, and then was washed with water. The organic layer was dried (MgSO₄), filtered, and evaporated to afford 3-III (4.7 g, 85% yield) as brown oil.

Compound 3-III (505 mg) was added to a solution of intermediate 1-XIII (500 mg) in MeOH (4 mL). The solution was stirred at 45° C. for 24 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=4:1) to afford intermediate 3-IV (420 mg) in a 63% yield.

A solution of HCl in ether (5 mL) was added to a solution of intermediate 3-IV (420 mg) in CH₂Cl₂(1.0 mL). The reaction mixture was stirred for 12 hours at room temperature and concentrated by removing the solvent. The resultant residue was washed with ether to afford hydrochloride salt of compound 3 (214 mg).

CI-MS (M⁺+1): 595.1.

(4) Preparation of Compound 4

Compound 4 was prepared in the same manner as that described in Example 2 except that sodium 2-bromoethanesulfonate in the presence of Et₃N in DMF at 45° C. was used instead of diethyl vinyl phosphonate. Deportations of amino-protecting group by hydrochloride to afford hydrochloride salt of compound 4.

CI-MS (M⁺+1): 567.3

(5) Preparation of Compound 5

Compound 5 was prepared in the same manner as that described in Example 2 except that diethyl-1-bromopropylphosphonate in the presence of K₂CO₃in CH₃CN was used instead of diethyl vinyl phosphonate.

CI-MS (M⁺+1): 581.4

(6) Preparation of Compound 6

Compound 6 was prepared in the same manner as that described in Example 5 except that 1,4-diaza-spiro[5.5]undecane dihydrochloride was used instead of piperazine.

CI-MS (M⁺+1): 649.5

(7) Preparation of Compound 7

Intermediate 1-II was prepared as described in Example 1.

To a suspension of the intermediate 1-II (31.9 g) in toluene (150 mL) were added phosphorazidic acid diphenyl ester (7-I, 32.4 g) and Et₃N (11.9 g) at 25° C. for 1 hour. The reaction mixture was stirred at 80° C. for 3 hours and then cooled to 25° C. After benzyl alcohol (7-II, 20 g) was added, the reaction mixture was stirred at 80° C. for additional 3 hours and then warmed to 120° C. overnight. It was then concentrated and dissolved again in EtOAc and H₂O. The organic layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with 2.5 N HCl, saturated aqueous NaHCO₃and brine, dried over anhydrous MgSO₄, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/Hexane=1:2) to give Intermediate 7-III (35 g) in a 79% yield.

A solution of intermediate 7-III (35 g) treated with 4 N HCl/dioxane (210 mL) in MeOH (350 mL) was stirred at room temperature overnight. After ether (700 mL) was added, the solution was filtered. The solid was dried under vacuum. K₂CO₃was added to a suspension of this solid in CH₃CN and iso-propanol at room temperature for 10 minutes. After water was added, the reaction mixture was stirred at room temperature for 2 hours, filtered, dried over anhydrous MgSO₄, and concentrated. The resultant residue was purified by column chromatography on silica gel (using CH₂Cl₂and MeOH as an eluant) to give intermediate 7-IV (19 g) in a 76% yield.

Intermediate 1-IX (21 g) was added to a solution of intermediate 7-IV (19 g) in CH₂Cl₂(570 mL). The mixture was stirred at 25° C. for 2 hours. NaBH(OAc)₃(23 g) was then added at 25° C. overnight. After the solution was concentrated, a saturated aqueous NaHCO₃solution was added to the resultant residue. The mixture was then extracted with CH₂Cl₂. The solution was concentrated and the residue was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 7-V (23.9 g) in a 66% yield.

A solution of intermediate 7-V (23.9 g) and Boc₂O (11.4 g) in CH₂Cl₂(200 mL) was added to Et₃N (5.8 mL) at 25° C. for overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (using EtOAc and Hexane as an eluant) to give intermediate 7-VI (22 g) in a 77% yield. 10% Pd/C (2.2 g) was added to a suspension of intermediate 7-VI (22 g) in MeOH (44 mL). The mixture was stirred at ambient temperature under hydrogen atmosphere overnight, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 7-VII (16.5 g) in a 97% yield.

Intermediate 7-VII (16.5 g) and Et₃N (4.4 mL) in 1-pentanol (75 mL) was allowed to react with 2,4-dichloro-6-aminopyrimidine (1-VI, 21 g) at 120° C. overnight. The solvent was then removed and the residue was purified by column chromatography on silica gel (using EtOAc and hexane as an eluant) to afford intermediate 7-VIII (16.2 g) in a 77% yield.

A solution of intermediate 7-VIII (16.2 g) and piperazine (1-XII, 11.7 g) in 1-pentanol (32 mL) was added to Et₃N (3.3 mL) at 120° C. overnight. After the solution was concentrated, the residue was treated with water and extracted with CH₂Cl₂. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc/MeOH to 28% NH₄OH/MeOH as an eluant) to afford Intermediate 7-IX (13.2 g) in a 75% yield.

Diethyl vinyl phosphonate (2-I) was treated with 7-IX as described in Example 3 to afford hydrobromide salt of compound 7.

CI-MS (M⁺+1): 553.3

(8) Preparation of Compound 8

Cis-1,4-cyclohexanedicarboxylic acid (8-I, 10 g) in THF (100 ml) was added oxalyl chloride (8-II, 15.5 g) at 0° C. and then DMF (few drops). The mixture was stirred at room temperature for 15 hours. The solution was concentrated and the residue was dissolved in THF (100 ml). The mixture solution was added to ammonium hydroxide (80 ml) and stirred for 1 hour. The solution was concentrated and filtration to afford crude product 8-III (7.7 g).

Compound 8-III (7.7 g) in THF (200 ml) was slowly added to LiAlH₄(8.6 g) in THF (200 ml) solution at 0° C. The mixture solution was stirred at 65° C. for 15 hours. NaSO₄.10H₂O was added at room temperature and stirred for 1 hours. The resultant mixture was filtered to get filtrate and concentrated. The residue was dissolved in CH₂Cl₂(100 ml). Et₃N (27 g) and (Boc)₂O (10 g) were added at room temperature. The solution was stirred for 15 h, and then concentrated to get resultant residue. Ether was added to the resultant residue. Filtration and drying under vacuum afforded solid crude product 8-IV (8.8 g).

A solution of compound 8-IV (1.1 g) and Et₃N (1.7 g) in 1-pentanol (10 ml) was reacted with 2,4-dichloro-6-aminopyrimidine (1-VI, 910 mg) at 90° C. for 15 hours. TLC showed that the reaction was completed. Ethyl acetate (10 mL) was added to the reaction mixture at 25° C. The solution was stirred for 1 hour. The Et₃NHCl salt was removed. The filtrate was concentrated and purified by silica gel (EtOAc/Hex=1:2) to afford the desired product 8-V (1.1 g, 65% yield).

A solution of intermediate 8-V (1.1 g) was treated with 4 N HCl/dioxane (10 ml) in MeOH (10 ml) and stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated, filtered, and dried under vacuum (<10 ton). For neutralization, K₂CO₃(3.2 g) was added to the solution of HCl salt in MeOH (20 ml) at 25° C. The mixture was stirred at the same temperature for 3 hours (pH>12) and filtered. Aldehyde 1-IX (759 mg) was added to the filtrate at 0-10° C. The reaction was stirred at 0-10° C. for 3 hours. TLC showed that the reaction was completed. Then, NaBH₄(112 mg) was added at less than 10° C. and the solution was stirred at 10-15° C. for 1 hour. The solution was concentrated to get a residue, which was then treated with CH₂Cl₂(10 mL). The mixture was washed with saturated NH₄Cl (aq) solution. The CH₂Cl₂layer was concentrated and the residue was purified by chromatography on silica gel (MeOH/28% NH₄OH=97/3) to afford intermediate 8-VI (1.0 g, 66% yield).

Et₃N (600 mg) and Boc₂O (428 mg) were added to the solution of 8-VI (1.0 g) in CH₂Cl₂(10 ml) at 25° C. The mixture was stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The solution was concentrated and purified by chromatography on silica gel (EtOAc/Hex=1:1) to afford intermediate 8-VII (720 mg, 60% yield).

To a solution compound 8-VII (720 mg) and piperazine (1-XII, 1.22 g) in 1-pentanol (10 mL) was added Et₃N (1.43 g) at 25° C. The mixture was stirred at 120° C. for 24 hours. TLC showed that the reaction was completed. Ethyl acetate (20 mL) was added at 25° C. The solution was stirred for 1 hour. The Et₃NHCl salt was removed and the solution was concentrated and purified by silica gel (EtOAc/MeOH=2:8) to afford 8-VIII (537 mg) in 69% yield.

To a solution of 8-VIII (537 mg) in MeOH (11 ml) was added diethyl vinyl phosphonate (2-I, 201 mg) at 25° C. The mixture was stirred under 65° C. for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH₂Cl₂=1:9) to get 8-IX (380 mg) in a 57% yield.

To a solution of 8-IX (210 mg) in CH₂Cl₂(5 ml) was added TMSBr (312 mg) at 10-15° C. for 1 hour. The mixture was stirred at 25° C. for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 40° C., then, CH₂Cl₂was added to dissolve the residue. Then TMSBr and solvent were further removed under vacuum and CH₂Cl₂was added for four times repeatedly. The solution was concentrated to get hydrobromide salt of compound 8 (190 mg).

CI-MS (M⁺+1): 566.9

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA
web link

ABOUTME

BRAND ANTHONYCRASTO

COLLECTION OF SITE LINKS

http://amcrasto.bravesites.com/

http://anthonycrasto.jimdo.com/

Congratulations! Your presentation titled “Anthony Crasto Glenmark scientist, helping millions with websites” has just crossed MILLION views.

アンソニー安东尼 Энтони 안토니 أنتوني

join my process development group on google

organic-process-development group

you can post articles and will be administered by me on the google group which is very popular across the world

https://sites.google.com/site/amcrasto/

SKILLPAGES

MIXXT

APNACIRCLE

LinkedIn group

SYNTHETIC ORGANIC CHEMISTRY

blogs are

MY BLOG ON MED CHEM
New Drug Approvals
ALL ABOUT DRUGS
WORLD DRUG TRACKER
MEDICINAL CHEM INTERNATIONAL
DRUG SYN INTERNATIONAL
SCALEUP OF DRUGS
ALL FOR DRUGS ON WEB
http://scholar.google.co.uk/citations?user=bxm3kYkAAAAJ

MY CHINA AND JAPAN BLOGS

http://amcrasto.blog.fc2.com/

http://blog.sina.com.cn/u/5030268874

http://ameblo.jp/medchem-amcrasto/

VIETNAM
http://me.zing.vn/u/amcrasto

ICELAND
http://amcrasto.bland.is/
RUSSIA
http://www.100zakladok.ru/amcrasto/
http://bobrdobr.ru/people/amcrasto/

AbbVie’S Investigational Oncology Compound ABT-199/GDC-0199, Venetoclax

June 3, 2014 2:55 am / Leave a comment

ChemSpider 2D Image | 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide | C45H50ClN7O7S

ABT 199, RG 7601, GDC 0199

Venetoclax

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

SYNTHESIS UPDATED BELOW …………..

CAS 1257044-40-8 [RN]

2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

ABT 199

Molecular Formula: C₄₅H₅₀ClN₇O₇S
Average mass: 868.439209 Da
Monoisotopic mass: 867.318115 Da
4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

NORTH CHICAGO, Ill., May 31, 2014/NEWS.GNOM.ES/ — AbbVie (NYSE: ABBV) released interim results from a Phase Ib clinical trial of ABT-199/GDC-0199, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, in combination with rituximab (Abstract 7013). Results showed anoverall response rate (ORR) of 84 percent, in patients with relapsed/refractory chronic lymphocytic leukemia(CLL), the most common leukemia in the UnitedStates. These results were presented at the 50^thAnnual Meeting of the American Society of ClinicalOncology (ASCO), May 30 – June 3 in Chicago.

http://news.gnom.es/pr/abbvie-presents-new-results-from-studies-of-investigational-oncology-compound-abt-199gdc-0199-at-the-2014-american-society-of-clinical-oncology

ABT-199 is a so-called BH3-mimetic drug, which is designed to block the function of the protein Bcl 2. In 1988, it was discovered that Bcl-2 allowed leukaemia cells to become long-lived, a discovery made at the Walter and Eliza Hall Institute by Professors David Vaux, Suzanne Cory and Jerry Adams. Subsequent research led by them and other institute scientists, including Professors Andreas Strasser, David Huang, Peter Colman and Keith Watson, has explained much about how Bcl-2 and related molecules function to determine if a cell lives or dies. These discoveries have contributed to the development of a new class of drugs called BH3-mimetics that kill, and thereby rapidly remove, leukaemic cells by blocking Bcl-2. (source:http://www.wehi.edu.au).

Highlights of recent research using this agent

GDC-0199 (RG7601) is a novel small molecule Bcl-2 selective inhibitor designed to restore apoptosis, also known as programmed cell death, by blocking the function of a pro-survival Bcl-2 family protein. The Bcl-2 family proteins, which are expressed at high levels in many tumors, play a central role in regulating apoptosis and, consequently, are thought to impact tumor formation, tumor growth and resistance.

Venetoclax (previously: GDC-0199, ABT-199, RG7601 )^[1] is a small molecule oral drug being investigated to treat chronic lymphocytic leukemia (CLL).^[2]^[3]

In 2015, the FDA granted Breakthrough Therapy Designation to venetoclax for CLL in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation.^[3]

Mechanism of action

Venetoclax (a BH3-mimetic^[4]) acts as a Bcl-2 inhibitor, ie. it blocks the anti-apoptotic B-cell lymphoma-2 (BCL2) protein, leading toprogrammed cell death in CLL cells.^[2]

Clinical trials

A phase 1 trial established a dose of 400mg/day.^[2]

A trial of venetoclax in combination with rituximab had an encouraging complete response rate.^[5]

A phase 2 trial met its primary endpoint which was overall response rate.^[3] Interim results from a Phase 2b trial are encouraging, especially in patients with the 17p deletion.^[2]

A phase 3 trial (NCT02005471)^[1] has started.^[3]

NOW IN PHASE 3 UPDATED…………

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (hereafter, “Compound 1”) is a potent and selective Bcl-2 inhibitor having, inter alia, antitumor activity as an apoptosis-inducing agent. Compound 1 has the formula:

Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1. The disclosures of U.S. 2010/0305122; 2012/0108590; 2012/0157470 and 2012/0277210 are hereby incorporated by reference in their entireties.

str1

PATENT

US 2015183783

http://www.google.com/patents/US20150183783

PATENT

CN 104370905

http://www.google.com/patents/CN104370905A?cl=en

str1

ABT-199 is developed AbbVie Bel-2 inhibitors, I trial (NCT01328626) enrolled 84 patients with relapsed type / refractory CLL / SLL patients and 44 cases of relapsing / refractory non-Hodgkin lymphoma patients. ABT-199 treatment response CLL / SLL rate of 79% (complete response rate of 22%), median duration of response time was 20.5 months; ABT-199 treatment of non-Hodgkin’s lymphoma response rate of 48% (complete response rate was 7.5%). The efficacy of ABT-199 is capable of obinutuzumab, idelalisib, ibrutinib rival, is expected to become the first listed Bcl_2 inhibitors, ABT-199 is currently ongoing Phase III clinical study.

ABT-199 compound CAS number 1257044-40-8, the compound is structured as follows:

Patent W02012058392, W02012071336, W02010138588 et al. Discloses the preparation of ABT-199 in order to -IH- 5-bromo-pyrrolo [2, 3-b] pyridine as raw material to protect hydroxylation, after replacing the compound 5, and reaction of compound 6, hydrolysis to give compound 9, compound 10 and compound 9 obtained by condensation of ABT-199, a specific line as follows:

Figure CN104370905AD00052

use of 2-fluoro-4-nitrobenzoate (A) as a raw material, and substituted 5-hydroxy-7-aza-indole (B), reduction to produce compound ( D), the compound (D) with the compound by cyclization after (H) substitution, hydrolysis to yield compound (J), and then with the compound (K) to afford ABT-199.

Figure CN104370905AC00021

Preparation of a compound of Example (F) of the

Example

First step: Synthesis of Compound (C)

2-fluoro-4-nitrobenzoate in IL three-necked flask 50. 0g, dissolved with dimethylformamide N’N- 250ml, was added successively 5-hydroxy-7-aza-indole indole 33. 6g, potassium carbonate 34. 7g, the reaction was heated to 50 degrees under nitrogen gas protection for 2 hours, poured into 2L of ice water was added and extracted three times with ethyl acetate, the organic phase was dried with saturated sodium chloride spin dry to give Compound (C) crude 82. 0g, crude without purification in the next reaction direct investment.

Step two: Synthesis of Compound (D)

The compound of the previous step (C) of the crude product was dissolved in methanol 400ml, was added 10% palladium on carbon 4. 0g, through the reaction of hydrogen at atmospheric pressure, after the end of the reaction by TLC spin solvent to give compound (D) The crude product 73. 2g, crude without purification in the next reaction direct investment.

The third step: Synthesis of compound (F)

Take the previous step the compound (D) crude 20. 0g, t-butanol were added 150ml, compound (E) 10. g, potassium carbonate 9. 7g, completion of the addition the reaction was refluxed for 48 hours the reaction solution was cooled, added acetic acid ethyl ester was diluted, washed with water three times, the combined aqueous phases extracted once with ethyl acetate, the combined ethyl acetate phases twice, dried over anhydrous sodium sulfate and the solvent was spin, the crude product obtained was purified by silica gel column chromatography to give 13. 9g, three-step overall yield of 57.4%.

Preparation Example II Compound (H),

[0029] Take compound (G) (prepared according to W02012058392 method) 5. 0g, dissolved with 50ml of dichloromethane, was added triethylamine 5. 6ml, the reaction solution was cooled to 0-5 ° with stirring, was added dropwise methanesulfonyl chloride 2. 7g, the addition was complete the reaction was warmed to room temperature overnight, after the end of the reaction by TLC the reaction was quenched with water, the organic phase was dried over anhydrous sodium sulfate and the solvent was spin, purified by silica gel column chromatography to give compound (H) 6. 5g , a yield of 99%.

Three ABT-199 Preparation of Example

First step: Synthesis of Compound (I)

In IOOml three-necked flask were added the compound (F) 2. 5g, compound ⑶2. 3g, potassium carbonate I. 9g, Ν ‘was added and reacted at 50 degrees N- dimethylformamide 15ml, nitrogen atmosphere, TLC detection After the reaction, the reaction solution was poured into ice-water, extracted with ethyl acetate twice added ethyl acetate phase was dried over anhydrous sodium sulfate spin, and purified by silica gel column chromatography to give compound (I) 3. 6g, yield 88 %.

Step two: Synthesis of Compound (J)

In IOml single jar Compound (I) I. 0g, followed by adding water 5ml, ethanol 5ml, tetrahydrofuran 5ml, sodium hydroxide 136mg, the reaction was stirred at room temperature the reaction, ethyl acetate was added after dilution of the reaction by TLC, adjusted with IN hydrochloric acid PH4-5, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and spin dried to give compound (J) 907mg, 93% yield.

Step two: Synthesis of ABT-199

In a 25ml single neck flask was added the compound (J) 100mg, EDCI67mg, dichloromethane 10ml, the reaction was stirred for 30 minutes, was added the compound (K) (prepared in accordance with W02012058392) 55mg, finally added a catalytic amount of DMAP, the force After opening the reaction was stirred overnight, after the end of the reaction by TLC the solvent was spin, HPLC purified preparation obtained by pure ABT-199 ^ 9811, 65% yield.

PATENT

WO 2014165044

http://www.google.com/patents/WO2014165044A1?cl=en

PATENT

US 2014275540

http://www.google.com/patents/US20140275540

Figure US20140275540A1-20140918-C00031

An exemplary reaction according to Scheme 2 is shown below.

Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. Pat. No. 3,813,443 and Proceedings of the Chemical Society, London, 1907, 22, 302.
Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 and J. Am. Chem. Soc., 1950, 72, 1215-1218.
In another embodiment, the compound of formula (1) is prepared from compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in WO 2009/117626 and Organometallics, 2008, 27 (21), 5605-5611.
Example 1 Synthesis of tert-butyl 4-bromo-2-fluorobenzoate (Compound (C))

To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro1-iodobenzene, “Compound (A)” (5 g, 1.0 eq) and THF (25 ml). The solution was cooled to −5° C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 1 h. Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10% citric acid (10 ml), and then diluted with 25% NaCl (10 ml). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3×10 ml). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency=67%, potency adjusted yield=88%) was taken to the next step without further purification. ¹H NMR (DMSO-d₆): δ 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (t, J=8.2 Hz, 1H).
Example 2 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (Compound (D))
To a 3 L three-neck Morton flask were charged 1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20° C. for 15 min. The resulting solution was cooled to about zero to 5° C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10° C., and rinsed with DMF (30 mL). The reaction mixture was stirred at 10° C. for 1 hour (an off-white slurry) and adjusted the internal temperature to ˜45° C. over 30 min. The reaction mixture was stirred at 45-50° C. for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion % by HPLC). The solution was cooled to ˜20° C. The solution was stirred at 20° C. overnight.
Water (1200 mL) was added slowly to the reaction mixture at <30° C. over 1 hour (slightly exothermic). The product slurry was adjusted to ˜20° C., and mixed for NLT 2 hours. The crude product was collected by filtration, and washed with water (400 mL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50° C. overnight to give the crude product (236.7 g).
Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted: 200.7 g) was charged back to a 3 L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over 1 hr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78° C.). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to ˜−10° C. at a rate of approximate 10° C./hour), and mixed for 2 hr. The product was collected by filtration, and rinsed with heptane (200 ml).
The solid was dried under vacuum at ˜50° C. overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191° C. (uncorrected). ¹H NMR (DMSO-d₆): δ 1.40 (s, 9H), 6.41 (dd, J=3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3, 1.8 Hz, 1H), 7.51 (t, J=3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
Example 3 Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde (Compound (F))
To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456 mol) and CH₂Cl₂(80 mL). The solution was cooled down <−5° C., and POCl₃(64.7 g, 0.422 mol) added slowly over 20 min @<20° C. (exothermic), rinsed with CH₂Cl₂(6 mL). The slightly brown solution was adjusted to 20° C. over 30 min, and mixed at 20° C. for 1 hour. The solution was cooled back to <5° C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ˜0.292 mol) was added, and rinsed with in CH₂Cl₂(10 mL) (slightly exothermic) at <20° C. The solution was heated to refluxing temperature, and mixed overnight (21 hours).
To a 1000 mL three neck RB flask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12% brine, and 130 mL of CH₂Cl₂. The mixture was stirred and cooled down to <5° C. The above reaction mixture (clear and brown) was transferred, quenched into it slowly while maintaining the internal temperature <10° C. The reaction vessel was rinsed with CH₂Cl₂(10 mL). The quenched reaction mixture was stirred at <10° C. for 15 min. and allowed to rise to 20° C. The mixture was stirred 20° C. for 15 min and allowed to settle for 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extracted with CH₂Cl₂(50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K₃PO₄aq. solution (40 g). The organic was dried over MgSO₄, filtered and rinsed with CH₂Cl₂(30 ml). The filtrate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency=90.9 wt % by qNMR, ˜100%). ¹H NMR (CDCl₃): δ 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H), 2.31 (tt, J=6.4, 2.2 Hz, 2H), 2.36 (t, J=2.2 Hz, 2H), 10.19 (s, 1H).
Example 4 Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde (Compound (G))
To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). The mixture was stirred at 20° C. for 5 min. 21.0 wt % K₂CO₃aq. solution (76.0 g) was added. The mixture was stirred at room temperature (rt) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N₂for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N₂. The reaction mixture was evacuated and purged with N₂for three times (an orange colored mixture). The bottle was back filled with N₂and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixture was stirred at 30° C. overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material <2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO₃-2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20° C. for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO₃aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. ¹HNMR (CDCl₃): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
Example 5 Synthesis of tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate (Compound (H))
To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20° C. for NLT 30 min and allowed to settle for NLT 15 min. The lower aq. phase (˜560 mL) was separated (note: leave any emulsion in the upper organic phase). The organic phase was washed with 10% citric acid solution (500 g×2). 500 g of 5% NaHCO₃aq. solution was charged slowly into the flask. The mixture was stirred at 20° C. for NLT 30 min., and allowed to settle for NLT 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20° C. for NLT 15 min., and allowed to settle for NLT 15 min. The upper organic phase was concentrated to ˜200 mL volume under vacuum. The solution was adjusted to −30° C., and filtered off the inorganic salt. Toluene (50 mL) was used as a rinse. The combined filtrate was concentrated to ˜100 mL volume. Acetonitrile (400 mL) was added, and the mixture heated to ˜80° C. to achieve a clear solution. The solution was cooled down slowly to 20° C. slowly at rate 10° C./hour, and mixed at 20° C. overnight (the product is crystallized out at ˜45-50° C., if needed, seed material may be added at 50° C.). The slurry was continued to cool down slowly to ˜−10° C. at rate of 10° C./hours. The slurry was mixed at ˜−10° C. for NLT 6 hours. The product was collected by filtration, and rinsed with pre-cooled acetonitrile (100 mL). The solid was dried under vacuum at 50° C. overnight (72.0 g, 85%). MS-ESI: 419 (M+1); mp: 109-110° C. (uncorrected); ¹H NMR (CDCl₃): δ 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).
Example 6 Synthesis of 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine dihydrochloride (Compound (I))
To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the Boc reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3 g of concentrated hydrochloride aq. solution added to the slurry. The reaction mixture was adjusted to an internal temperature of ˜65° C. (a clear and colorless solution achieved). The reaction mixture was agitated at ˜65° C. for NLT 12 hours.
The product slurry was cooled down to −5° C. slowly (10° C./hour). The product slurry was mixed at ˜−5° C. for NLT 2 hours, collected by filtration. The wet cake was washed with IPA (72 mL) and dried at 50° C. under vacuum overnight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm). MS-ESI: 319 (M+1); ¹HNMR (CDCl₃): δ 0.86 (s, 6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).
Example 7 Synthesis of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-benzenesulfonamide (Compound (N))
To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80° C. and agitated for no less than 12 hours.
The product solution was cooled down to 40° C. and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20° C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10° C. and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40° C. for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75° C. under vacuum to give 12.7 g of the desired product in 99.9% purity and in 91% weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH₂, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).
Example 8 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (Compound (K))
General Considerations:
this chemistry is considered air and moisture sensitive. While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.
To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K₃PO₄(285 ml) was added and the biphasic mixture was stirred for 30 min. The layers were separated and the organic layer was washed with 25% NaCl (145 ml). The organic layer concentrated to 120 g and used in the coupling reaction without further purification.
NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution −30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd₂dba₃(0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 μm inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml).
The resulting mixture was heated to 55° C. with stirring for NLT 16 h, then cooled to 22° C. The mixture was diluted with 12% NaCl (300 g) followed by THF (300 ml). The layers were separated.
The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO₃(23 g), and water (262 ml). After 1 h the layers were separated.
The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO₃(23 g), and water (262 ml). After 1 h the layers were separated. The organic layer was washed with 12% NaCl (300 g), then filtered through a 0.45 μm inline filter. The filtered solution was concentrated in vacuo to ˜300 mL, and chased three times with heptane (600 mL each) to remove THF.
The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 ml). The mixture was heated to 75° C., held for 15 min, and then cooled to 65° C. over NLT 15 min. Seed material was charged and the mixture was held at 65° C. for 4 hours. The suspension was cooled to 25° C. over NLT 8 h, then held at 25° C. for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50° C. under vacuum.
Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155° C. ¹H NMR (DMSO-d₆): δ 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J=6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02-3.19 (m, 4H), 6.33 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.72 (dd, J=9.0, 2.4 Hz, 1H), 6.99-7.06 (m, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, J=6.7 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 11.53 (s, 1H).
Example 9 Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Compound (L))
Solution preparation: 10% KH₂PO₄(aq): KH₂PO₄(6 g) in water (56 g); 2:1 heptane/2-MeTHF:heptane (16 mL) in 2-MeTHF (8 mL).
Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55° C. until reaction completion. The reaction mixture was cooled to 22° C., washed with the 10% KH₂PO₄solution (31 g) twice. The organic layer was then washed with water (30 g).
After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (˜19 mL) and heated to no less than 50° C. Heptane (23 ml) was slowly added. The resulting suspension was cooled to 10° C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane/2-MeTHF (24 ml). Drying of the solids at 80° C. under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 0.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J=3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
Example 10 Synthesis of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (Compound (I))
Solution preparation prior to reaction: 10% Acetic Acid:Acetic Acid (37 mL) in water (333 g); 5% NaHCO₃:NaHCO₃(9 g) in water (176 g); 5% NaCl:NaCl (9 g) in water (176 g).
Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25° C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et₃N (8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion.

STR1

N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35° C. and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL). The organic, product layer was then washed with 5% NaHCO₃solution (185 mL) and then washed with 5% NaCl solution (185 mL) at 35° C. The lower, organic layer was separated and then concentrated to 8 vol (˜256 mL) diluted with methanol (26 mL) and warmed to 38° C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10° C. and then filtered. The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (˜2 vol, 64 mL). After drying the wet cake at 90° C., 32 g (84%) of Compound (I) was isolated.
¹H NMR (DMSO-d₆): δ 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J=3.4, 1.9 Hz, 1H), 6.66 (dd, J=9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J=9.3, 2.3 Hz, 1H), 8.02 (d, J=2.61 Hz, 1H), 8.54 (d, J=2.33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).

PATENT

str1

Patent	Submitted	Granted
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2014275082]	2014-02-10	2014-09-18
Processes For The Preparation Of An Apoptosis-Inducing Agent [US2014275540]	2014-03-12	2014-09-18
APOPTOSIS INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES [US2010305122]	2010-12-02
Panel of micrornas that silence the MCL-1 gene and sensitize cancer cells to ABT-263 [US8742083]	2010-12-23	2014-06-03
Treatment Of Cancers Using PI3 Kinase Isoform Modulators [US2014377258]	2014-05-30	2014-12-25
METHODS OF TREATMENT USING SELECTIVE BCL-2 INHIBITORS [US2012129853]	2011-11-22	2012-05-24
INHIBITION OF MCL-1 AND/OR BFL-1/A1 [US2015051249]	2013-03-14	2015-02-19
COMBINATION THERAPY OF A TYPE II ANTI-CD20 ANTIBODY WITH A SELECTIVE BCL-2 INHIBITOR [US2014248262]	2013-09-06	2014-09-04

References

New Drugs Online Report for venetoclax
Hard-to-Treat CLL Yields to Investigational Drug. ASH Dec 2015 refs: Roberts AW, et al “Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia” N Engl J Med 2015; DOI: 10.1056/NEJMoa1513257.
Phase 2 Study of Venetoclax in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion Meets Primary Endpoint
ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia. 2011
For Refractory CLL, Venetoclax’s Complete Response Rate Is Tops. 2015

External links

ABT-199 inc formula and structure

References

1: Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2
inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Jan 6. doi: 10.1038/nm.3048. [Epub ahead of print] PubMed PMID: 23291630.

Venetoclax
Systematic (IUPAC) name

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Identifiers
CAS Number	1257044-40-8
PubChem	CID: 49846579
ChemSpider	29315017
Chemical data
Formula	C₄₅H₅₀ClN₇O₇S
Molecular mass	868.44 g/mol

/////////

CC1(CCC(=C(C1)c2ccc(cc2)Cl)CN3CCN(CC3)c4ccc(c(c4)Oc5cc6cc[nH]c6nc5)C(=O)NS(=O)(=O)c7ccc(c(c7)[N+](=O)[O-])NCC8CCOCC8)C

CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Tag Archives: PHASE 3

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Share this:

Contacts

Enantioselective separation of ketoconazole enantiomers by membrane extraction

Share this:

Share this:

2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide

CAS number: 912444-00-9 (Veliparib),

912445-05-7 (Veliparib dihydrochloride)

Mechanism of Action:poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor Indiction:cancer treatment

Development Status:Phase III

Drug Company: AbbVie

PARP Inhibitor Veliparib (ABT-888)

Clinical trials

References

External links

Share this:

Luseogliflozin: Phase III data 10/21/2013

Luseogliflozin: Phase III data 10/21/2013

Luseogliflozin regulatory update 05/13/2013

Strategy: Doubling down in diabetes 05/06/2013 Merck shoring up slowing diabetes franchise with Pfizer, Abide deals

Share this:

References

External links

References

Share this:

MST-188 (purified poloxamer 188)

POTENTIAL APPLICATIONS OF MST-188

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376. 2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

Share this:

June 16, 2014

June 16, 2014

Share this:

Share this:

Mechanism of action

Clinical trials

PATENT

PATENT

PATENT

PATENT

PATENT

References

External links

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

Mechanism of Action:poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor
Indiction:cancer treatment

Strategy: Doubling down in diabetes 05/06/2013
Merck shoring up slowing diabetes franchise with Pfizer, Abide deals

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.