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FDA approves new treatment for diabetic retinopathy in patients with diabetic macular edema

March 27, 2015 12:59 am / Leave a comment

FDA approves new treatment for diabetic retinopathy in patients with diabetic macular edema

03/25/2015

The U.S. Food and Drug Administration today expanded the approved use for Eylea (aflibercept) injection to treat diabetic retinopathy in patients with diabetic macular edema.

March 25, 2015

Release

The U.S. Food and Drug Administration today expanded the approved use for Eylea (aflibercept) injection to treat diabetic retinopathy in patients with diabetic macular edema.

Diabetic retinopathy (DR) is the most common diabetic eye disease and is a leading cause of blindness in adults in the United States. According to the Centers for Disease Control and Prevention, diabetes (type 1 and type 2) affects more than 29 million people in the United States and is the leading cause of new blindness among people ages 20 to 74 years. In 2008, 33 percent of adults with diabetes aged 40 years or older had some form of DR. In some cases of DR with diabetic macular edema (DME), abnormal new blood vessels grow on the surface of the retina. Severe vision loss or blindness can occur if the new blood vessels break.

“Diabetes is a serious public health crisis, affecting more patients every year,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval gives patients with diabetic retinopathy and diabetic macular edema another therapy to treat this vision-impairing complication.”

In February, the FDA approved Lucentis (ranibizumab injection) 0.3 mg to treat DR in patients with DME.

Eylea is administered by a physician as an injection into the eye once a month for the first five injections and then once every two months. It is intended to be used along with appropriate interventions to control blood sugar, blood pressure and cholesterol.

The safety and efficacy of Eylea to treat DR in patients with DME were evaluated in 679 participants in two clinical studies where participants were randomly assigned to receive Eylea or macular laser photocoagulation, a laser-based treatment used to burn small areas of the retina. At week 100, participants being treated with Eylea showed significant improvement in the severity of their DR, compared to patients who did not receive Eylea.

The most common side effects associated with Eylea include bleeding of the conjunctiva (the tissue that lines the inside of the eyelids and covers the white part of the eye); eye pain; cataracts; floaters; increased pressure inside the eye (increased intraocular pressure); and separation of the interior jelly of the eye from the retina (vitreous detachment). Serious adverse reactions include infection within the eye (endophthalmitis) and retinal detachments.

The FDA granted breakthrough therapy designation to Eylea for the treatment of DR with DME. The FDA can designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening conditions. The FDA also reviewed the new use for Eylea under the agency’s priority review program, which provides for an expedited review of drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition.

The FDA previously approved Eylea to treat wet (neovascular) age-related macular degeneration, a condition in which abnormal blood vessels grow and leak fluid into the macula. Eylea is also approved to treat DME and macular edema secondary to retinal vein occlusions, both of which cause fluid to leak into the macula resulting in blurred vision.

Eylea is marketed by Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. Lucentis is marketed by South San Francisco, California-based Genentech, a subsidiary of Roche Pharmaceuticals.

GSK 923295, a CENP-E Inhibitor

March 25, 2015 3:59 am / Leave a comment

GSK-923295A

1088965-37-0

Synonym: GSK-923295; GSK 923295; GSK923295.

CENP-E Inhibitor

IUPAC/Chemical name:

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-chloro-N-[(1S)-2-[[2-(dimethylamino)acetyl]amino]-1-[[4-[8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]methyl]ethyl]-4-(1-methylethoxy)- Benzamide,

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[1-(N,N-dimethylglycinamido)-3-[4-[8-[1(S)-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2(S)-yl]-4-isopropoxybenzamide

C32H38ClN5O4
Exact Mass: 591.26123
Molecular Weight: 592.12822
Elemental Analysis: C, 64.91; H, 6.47; Cl, 5.99; N, 11.83; O, 10.81

Kinesin-like protein KIF11 inhibitor; Centromere protein E inhibitor

GSK-923295 is a novel antimitotic inhibitor of centromere-associated protein E (CENP-E) with potential anticancer activity. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts.

GSK-923295, a small-molecule inhibitor of centromere associated protein (CENP), is in early clinical development at Cytokinetics for the treatment of refractory cancer. No recent development has been reported for early clinical research which had been ongoing at GlaxoSmithKline.

Clinical study showed that GSK923295 had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with K_i of 3.2 nM, and less potent to mutant I182 and T183. Phase 1.

The compound potently inhibits CENP-E ATPase activity and exerts broad-spectrum antiproliferative activity against cancer cells and xenografts. GSK-923295 has demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors.

Cytokinetics was developing GSK-923295, the lead from a series of small-molecule mitotic kinesin spindle protein inhibitors, for treating cancer including advanced solid tumors. However, since October 2014, the program was no longer listed on the Cytokinetics’ website

In 2001, a strategic alliance was established between Cytokinetics and GlaxoSmithKline to discover, develop and commercialize novel small-molecule therapeutics targeting mitotic kinesins for applications in the treatment of cancer and other diseases.

…………………….

PATENT

US8772507

http://www.google.com/patents/US8772507

1,1-Dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate

To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution and were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]⁺: 331.2.

1,1-Dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]⁺: 460.4.

1,1-Dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-d oxo-1,3-dihydro-21′-isoindol-2-yl)methyl]ethyl}carbamate

A solution of 1,1-dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (5 mol %) were stirred in anhydrous dioxane (300 mL) at 100° C. for 3 h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400 mL). The mixture was treated with N-bromosuccinimide (108.8 mmol) and stirred at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL). Precipate formed upon addition of hexanes (350 mL) and was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+H]⁺: 502.4.

1,1-Dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate

A mixture of 1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na₂SO₄), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]⁺.

3-Chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of 1,1-dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness and redissolved in DMF (30 mL). To this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na₂SO₄), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]⁺.

N-[(1S)-2-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

A mixture of 3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound (1.67 g, 100%) as a pale yellow powder. MS (ES+) m/e 507 [M+H]⁺.

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH₂Cl₂) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS (ES+) ink 592 [M+H]⁺.

………………….

WO2005107762

https://www.google.im/patents/WO2005107762A2

Example 1

cheme E:

ide

NaHCO_j, IPA 100 ‘C

1 , 1 -Dimethylethyl [( 1 S)-2-(4-bromophenyl)- 1 -(hydroxymethyl)ethyl]carbamate:

To a solution of 4-bromo-N-{[(l ,1 -dimethylethyl)oxy] carbonyl }-L- phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0 °C was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stiπed for an additional 2 h at 0 °C, The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stiπed at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%).

ESMS [M+H]⁺: 331.2.

1,1 -Dimethylethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]ethyl}carbamate:

To a solution of 1 ,1 -dimethylethyl [(lS)-2-(4-bromophenyl)-l –

(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0 °C was added dropwise diisopropyl azodi carboxyl ate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to wai to RT over 5h, The reaction was then concentrated in vacuo and product was tritarated out of solution usingl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3 x 100 mL), and dried to afford the title product as a white solid (57%).

ESMS [M+H]⁺: 460.4.

1 ,1 -Dimethylethyl {(15)-2-[4-(bromoacetyl)phenyl]-l -[(l,3-dioxo-l ,3-dihydro-2H-isoindol- 2-yl)methyl]ethyl}carbamate:

A solution of 1,1 -dimethyl ethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and /ra/?s–dichlorobis(triphenylphospine)palladιum(II) (5 mol%) were stiπed in anhydrous dioxane (300 mL) at 100 °C for 3h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400mL) and treated with N- bromosuccinimide (108.8 mmol) and stined at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+Η]+: 502.4. l,l-Dimethylethyl [(lS)-2-(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]carbamate:

A mixture of l_!l-dimethylethyl{(lS)-2-{4-(biOinoacetyl)phenyl]-l-[(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), l-(2- amino-3-pyτidinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4,72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na₂S0₄), and concentrated to give the title compound (1.79 g, S7%) as a light pink solid. MS(ES+) m/e 541 [M+Η]⁺.

3-Chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-Λ]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l – methylethyl)oxy]benzamide:

A mixture of 1,1 -dimethylethyl [(15)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-fl]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M ΗC1 in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness ,redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16,55 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na SO ), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]⁺.

N-[(lS)-2-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]p>tidin-2- yl]phenyl}methyl)eth)’l]-3-chloro-4-[(l-methylethyl)oxy]benzamide:

A mixture of 3-chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2N-isoindol-2-yl)-l-

({4-[8-(l -hydiOxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l- methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57°C ovemight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound(1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]⁺.

3-Chloro-N-[(15)-2-[(7VN-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l ,2- «]pyitdin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide:

A mixture ofN-[(lS)-2-amino-l-({4-[S-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]phenyl)methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide (0.912 g, 1 ,80 mmol), EDCI (0.69 g, 3,6 mmol), NN-diisopropylethylamine (0.466 g, 3,6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Νa₂S0 ), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH₂Cl₂) to give the title compound ( 0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]⁺.

SEE

WO2008 / 138561

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Organic Process Research & Development (2010), 14(5), 1254-1263

Org. Process Res. Dev., 2010, 14 (5), pp 1254–1263

DOI: 10.1021/op100186c

http://pubs.acs.org/doi/abs/10.1021/op100186c

The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel−Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.

¹H NMR (400 MHz, CD₃OD) δ_H 1.34 (6H, d, J = 6.0, (CH₃)₂), 1.59 (3H, d, J = 7.0, CH₃CH), 2.21 (6H, s, N(CH₃)₂), 2.87−3.01 (4H, m, CH₂Ph and CH₂N(CH₃)₂), 3.49 (2H, m, CH₂NPhthal), 4.50 (1H, m, CHNH), 4.70 (1H, m, (CH₃)₂CHO)), 5.49 (1H, q, J = 7.0, CHOH), 6.88 (1H, t, J = 7.0, H-j), 7.08 (1H, d, J = 7.5, H-b), 7.33−7.37 (3H, m, H-k and H-d), 7.63 (1H, dd, J = 7.5 and 2.0, H-c), 7.78 (1H, s, H-a), 7.83 (2H, d, J = 7.0, H-e), 8.09 (1H, m, H-h), 8.27 (1H, d, J = 8.0, H-i);

¹³C NMR (100 MHz, CD₃OD) δ_C 22.2, 24.1, 39.3, 43.8, 46.1, 53.0, 63.7, 66.2, 73.0, 110.4, 113.8, 115.3, 121.2, 124.5, 126.1, 127.5, 128.4, 128.5, 130.6, 130.7, 133.3, 136.0, 139.4, 145.1, 146.1, 157.6, 168.5 and 173.6;

HRMS (ESI⁺) m/z calculated for [M+H]⁺ C₃₂H₃₉N₅O₄Cl 592.2691, found 592.2684.

…………………….

PREDICTIONS

http://orgspectroscopyint.blogspot.in/2015/03/gsk-923295.html

1H NMR PREDICT

see http://orgspectroscopyint.blogspot.in/2015/03/gsk-923295.html

ACS Medicinal Chemistry Letters (2010), 1(1), 30-34

http://pubs.acs.org/doi/abs/10.1021/ml900018m

Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.

SEE

WO-2015037460

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=F8D2DAAA427F9EBAB6B7CE67A7EE0772.wapp1nC?docId=WO2015037460&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Method for producing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol

Process for preparing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol, useful as an intermediate in the synthesis of pharmaceuticals described in WO2005107762 and WO2008138561 (such as GSK-923295 and tubulysin derivatives respectively). Appears to be a new area of interest to the assignee.

…………..

WO2010118207

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010118207&recNum=278&docAn=US2010030350&queryString=%28SYK%29%2520&maxRec=1655

References

1: Mayes PA, Degenhardt YY, Wood A, Toporovskya Y, Diskin SJ, Haglund E, Moy C, Wooster R, Maris JM. Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E inhibition. Int J Cancer. 2013 Feb 1;132(3):E149-57. doi: 10.1002/ijc.27781. Epub 2012 Sep 28. PubMed PMID: 22948716.

2: Chung V, Heath EI, Schelman WR, Johnson BM, Kirby LC, Lynch KM, Botbyl JD, Lampkin TA, Holen KD. First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer. Cancer Chemother Pharmacol. 2012 Mar;69(3):733-41. doi: 10.1007/s00280-011-1756-z. Epub 2011 Oct 22. PubMed PMID: 22020315.

3: Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Wozniak AW, Gorlick R, Kolb EA, Houghton PJ, Smith MA. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jun;58(6):916-23. doi: 10.1002/pbc.23176. Epub 2011 May 16. PubMed PMID: 21584937; PubMed Central PMCID: PMC3163687.

4: Balamuth NJ, Wood A, Wang Q, Jagannathan J, Mayes P, Zhang Z, Chen Z, Rappaport E, Courtright J, Pawel B, Weber B, Wooster R, Sekyere EO, Marshall GM, Maris JM. Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma target. Cancer Res. 2010 Apr 1;70(7):2749-58. doi: 10.1158/0008-5472.CAN-09-3844. Epub 2010 Mar 16. PubMed PMID: 20233875; PubMed Central PMCID: PMC2848992.

5: Wood KW, Lad L, Luo L, Qian X, Knight SD, Nevins N, Brejc K, Sutton D, Gilmartin AG, Chua PR, Desai R, Schauer SP, McNulty DE, Annan RS, Belmont LD, Garcia C, Lee Y, Diamond MA, Faucette LF, Giardiniere M, Zhang S, Sun CM, Vidal JD, Lichtsteiner S, Cornwell WD, Greshock JD, Wooster RF, Finer JT, Copeland RA, Huang PS, Morgans DJ Jr, Dhanak D, Bergnes G, Sakowicz R, Jackson JR. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. doi: 10.1073/pnas.0915068107. Epub 2010 Feb 18. PubMed PMID: 20167803; PubMed Central PMCID: PMC2851928.

Uprosertib (GSK-2141795)

March 24, 2015 8:13 am / Leave a comment

Uprosertib (GSK-2141795)

GSK 2141795C

N-[(1S)-1-(aminomethyl)-2-(3,4-difluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide

N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide

2-Furancarboxamide, N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-

Λ/-{(1 S)-2-amino-1-r(3,4-difluorophenyl)methyllethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.

Cas 1047634-65-0 (GSK-2141795); BASE

CAS 1047635-80-2 (GSK-2141795 HCl salt)

Synonym: GSK-2141795; GSK2141795; GSK 2141795; GSK795; GSK-795; GSK 795. Uprosertib. UNII ZXM835LQ5E

IUPAC/Chemical name:

N-((S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide

C18H16Cl2F2N4O2
Exact Mass: 428.06184
Molecular Weight: 429.25

Elemental Analysis: C, 50.37; H, 3.76; Cl, 16.52; F, 8.85; N, 13.05; O, 7.45

Mechanims of Action:Akt inhibitor
Indication:Cancer Treatment
Drug Company:GlaxoSmithKline

PHASE 2… CANCER

Uprosertib, also known as GSK2141795 and GSK795, is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity.

The National Cancer Institute (NCI) is evaluating the compound in phase II clinical studies for the treatment of endometrial carcinoma and multiple myeloma in combination with trametinib.

GSK-2141795, an oral AKT inhibitor, is in early clinical trials at GlaxoSmithKline for the treatment of solid tumors and lymphoma. The company is conducting phase II clinical trials for the treatment of patients with BRAF wild-type mutation melanoma and for the treatment of recurrent or persistent cervical cancer in combination with trametinib.

Akt inhibitor GSK2141795 binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.

QC data:

View NMR, View HPLC, View MS …… MEDKOO

PATENT

Patent	Submitted	Granted
Inhibitors of AKT Activity [US2011071182]	2011-03-24
INHIBITORS OF Akt ACTIVITY [US2010267759]	2010-10-21
INHIBITORS OF AKT ACTIVITY [US2009209607]	2009-08-20
INHIBITORS OF Akt ACTIVITY [US2010041726]	2010-02-18

More information about this drug

The chemical structures of Afuresertib (GSK-2110183) and GSK-2141795 are very similar as shown below:

Fig 1. chemical structures of Afuresertib (GSK-2110183) and GSK-2141795

PATENT

WO 2008098104 OR EP2117523

http://www.google.com/patents/EP2117523A1?cl=en

Scheme 2

11-1 I-2

II-3 II-4

Reagents: (a) PyBrop, (i-Pr)₂NEt, 1 ,1-dimethylethyl (2-amino-3- phenylpropyl)carbamate, DCM, RT; (b) 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1- methyl-1 H-pyrazole, K₂CO₃, Pd(PPh₃)₄, dioxane/H₂O; (c) TFA / DCM, RT.

Preparation 7

Preparation of 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole

To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 ml.) at 0⁰C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 ml_, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 0⁰C over 1 hour. The reaction was diluted with saturated NH₄CI solution and extracted with DCM. The organic fractions were washed with H₂O (2 x 100 ml_), dried over Na₂SO₄ and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)⁺ for [RB(OH)₂]; ¹H NMR (CDCI₃, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).

Example . .24

UPROSERTIB

Preparation Λ/-{(1 S)-2-amino-1-r(3,4-difluorophenyl)methyllethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1584 mg, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in 1 ,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80 ⁰C. After 1 hr, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and purified via column chromatography (30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol, 26 % yield) as a white powder: LCMS (ES) m/e 206 (M+H)⁺.

b) methyl 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate (412 mg, 2.0 mmol) and N-chlorosuccinimide (267 mg, 2.0 mmol) in DMF (10 ml.) was heated at 75 ⁰C for 30 minutes. Another batch of N-chlorosuccinimide (267 mg, 2.0 mmol) was added. After 1 hr, the mixture was concentrated and purified using silica gel and eluting with 0-55% ethyl acetate / hexane to afford the title compound as a white solid (225 mg, 0.82 mmol, 71 % yield) : LCMS (ES) m/e 276 (M+H)⁺.

c) 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (224 mg, 0.82 mmol) in 6N sodium hydroxide (1.36 ml, 8.2 mmol) and tetrahydrofuran (5 ml) was stirred at 70 ⁰C in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H₂O-DCM. The aqueous phase was adjusted to pH ~4 and then washed several times with DCM. The combined organic fractions were dried over Na₂SO₄ and concentrated affording the title compound (201 mg, 0.77 mmol, 94 % yield) as a yellow oil: LCMS (ES) m/e 262 (M+H)⁺.

d) 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1- [(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylic acid (200 mg, 0.77 mmol)[prepared according to the procedure of Preparation 6], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1 H-isoindole-1 ,3(2H)- dione (254 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.30 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (536 mg, 1.15 mmol). After stirring at ambient temperature for 20 hrs, the mixture was concentrated and purified with silica gel column eluting with gradient (0-50% ethyl acetate/hexanes) to afford the title compounds as an off-white foamy solid (304 mg, 0.54 mmol, 71 % yield): LCMS (ES) m/e 560(M+H)+.

e) Λ/-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1- methyl-1 /-/-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-N-{(1S)-2- (3,4-difluorophenyl)-1 -[(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2- furancarboxamide (304 mg, 0.54 mmol) in methanol (5 ml) at 25 ⁰C was added hydrazine (0.08 ml, 2.7 mmol) dropwise. After 12h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1 % NH₄OH)). The free base was converted to the HCI salt by addition of excess 4M HCI in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCI salt of the title compound as a yellow solid:

LC-MS (ES) m/z 430(M+H)⁺,

¹H NMR (400 MHz, MeOD) δ ppm 2.91 – 3.05 (m, 2 H) 3.17 – 3.28 (m, 2 H) 3.81 (s, 3 H) 4.57 (d, J=9.60 Hz, 1 H) 7.12 (br. s., 1 H) 7.18-7.28 (m., 2 H) 7.36-7.39 (m, 1 H) 7.58 (s, 1 H).

SYNTHESIS ELABORATED

STEP A

4,5-dibromo-2-furancarboxylic acid in methanol , sulfuric acid methyl 4,5-dibromo-2-furancarboxylate LCMS (ES) m/e 283 (M+H)+

STEP B

methyl 4,5-dibromo-2-furancarboxylate and isopropylmagnesium chloride ,to give methyl 4-bromo-2-furancarboxylate

LCMS (ES) m/e 204,206 (M, M+2)+

STEP C

methyl 4-bromo-2-furancarboxylate and NCS in N,N-dimethylformamide methyl 4-bromo-5-chloro-2-furancarboxylate LCMS (ES) m/e 238,240,242 (M, M+2, M+4)+

STEP D

methyl 4-bromo-5-chloro-2-furancarboxylate , 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole prepared according toPreparation 7], potassium carbonate and bis(tri-t-butylphosphine)paliadium(0) in 1,4-dioxane (19.14 ml) and water ……methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate obtained. LCMS m/e ES 240, 242 (M, M+2)+

STEP E

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid.

A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate [prepared according to Example

127] and n-chlorosuccinimide (166 mg, 1.25 mmol) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid. LCMS (ES) m/e 261,263 (M, M+2)+

STEP F

Reacting 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid [prepared according to the procedure of Preparation 6], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione and N,N-diisopropylethylamine in DCM was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate …….obtd

5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide. the uproserib precursor

LCMS (ES) m/e 560(M+H)+

NOTE STRUCTURE OF 2-[(2S)-2-amino-3-(2,4-difluoro phenyl)propyl]-1H-isoindole-1,3(2H)-dione

SEE http://www.google.com/patents/WO2010093885A1?cl=en

Preparation 1

Preparation of 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl1-1 /-/-isoindole-1 ,3(2H)-dione a) 1 ,1-dimethylethyl [(1 S)-2-(3,4-difluorophenyl)-1-(hydroxymethyl)ethyl]carbamate

To a solution of Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3,4-difluoro-L-phenylalanine (2.0 g, 6.7 mmol) in THF (35 ml.) at 0 ⁰C stirred was added BH₃-THF (30 ml_, 30 mmol- 1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (1 :4, 20 ml.) and partitioned between saturated aqueous NaHCO₃ and CHCI₃. The aqueous phase was then extracted several times with CHCI₃. The combined organic fractions were concentrated and the resulting white solid (7.0 g, 74%) used without further purification: LCMS (ES) m/e 288 (M+H)⁺.

b) 1 ,1-dimethylethyl {(1 S)-2-(3,4-difluorophenyl)-1-[(1 ,3-dioxo-1 ,3-dihydro-2/-/-isoindol-2- yl)methyl]ethyl}carbamate

To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3,4-difluorophenyl)-1-

(hydroxymethyl)ethyl]carbamate (2.65 g, 9.22 mmol), polymer bound triphenylphosphine (5.33 g, 1 1.5 mmol, 2.15 mmol/g) and phthalimide (1.63 g, 10.9 mmol) in THF (50 ml.) at 25 ⁰C was added diisopropyl azodicarboxylate (1.85 ml_, 11.3 mmol). After stirring at RT for 1 h, the reaction solution was filtered and concentrated. The residue was adsorbed onto silica and purified via column chromatography to yield product (0.33 g) as a white solid: LCMS (ES) m/z 417 (M+H)⁺.

c) 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1 H-isoindole-1 ,3(2H)-dione

To a solution of 1 ,1-dimethylethyl {(1S)-2-(3,4-difluorophenyl)-1-[(1 ,3-dioxo-1 ,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (0.33 g, 0.79 mmol) in CHCI₃:MeOH (10:3, 13 mL) at RT was added 4M HCI in dioxane (5 mL, 20 mmol). After 12h, the solvents were removed and affording the title compound (0.29 g, quant.) as a white HCI salt which was used without further purification: LCMS (ES) m/z 317 (M+H)⁺.

FINAL STEP

conversion of precursor to uprosertb

UPROSERTIB PRECURSOR GIVES

UPROSERTIB

N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.

5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)methyl]ethyl}-2-furancarboxamide in methanol (5 ml) AND hydrazine …..N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1Hpyrazol-5-yl)-2-furancarboxamide.

SYNTHESIS OF INTERMEDIATES

Example 127

a) methyl 4,5-dibromo-2-furancarboxylate

To a solution of 4,5-dibromo-2-furancarboxylic acid (25 g, 93 mmol) in methanol (185 ml) was added sulfuric acid (24.7 ml, 463 mmol). The resulting solution stirred at 50 ⁰C over 12h. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (23.67 g, 83 mmol, 90 % yield), LCMS (ES) m/e 283, 285, 287 (M, M+2, M+4)⁺.b) methyl 4-bromo-2-furancarboxylate Br

To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 1 1.62 mmol) in tetrahydrofuran (46 ml) at -40 ⁰C was added isopropylmagnesium chloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added and the solution warmed to 25 ⁰C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SOφ concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56 % yield) as a yellow solid: LCMS (ES) m/e 205, 207 (M, M+2)⁺.

c) methyl 4-bromo-5-chloro-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) and NCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirred in a sealed tube for 1 h at 100 ⁰C. After 1 h, the solution was partitioned between DCM- H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over I^^SOφ concentrated and purified via column chromatography (2-10% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2- furancarboxylate (1.348 g, 5.12 mmol, 75 % yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M, M+2, M+4)⁺.

d) methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.05 g, 5.05 mmol)[prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1 ,4- dioxane (19.14 ml) and water (3.83 ml) was stirred at 80 ⁰C in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SOφ concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (800 mg, 2.53 mmol, 55 % yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)⁺.

e) 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2- furancarboxylate (300 mg, 1.25 mmol) in 6N sodium hydroxide (4.16 ml, 24.93 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70 ⁰C in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ~4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-chloro-4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylic acid (267 mg, 0.59 mmol, 47 % yield) as a white foam: LCMS (ES) m/e 265 (M+H)⁺.

References

1: Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, Rouse MB, Rabindran SK, Heerding DA, Kumar R. Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor. PLoS One. 2014 Jun 30;9(6):e100880. doi: 10.1371/journal.pone.0100880. eCollection 2014. PubMed PMID: 24978597; PubMed Central PMCID: PMC4076210.

2: Pachl F, Plattner P, Ruprecht B, Médard G, Sewald N, Kuster B. Characterization of a chemical affinity probe targeting Akt kinases. J Proteome Res. 2013 Aug 2;12(8):3792-800. doi: 10.1021/pr400455j. Epub 2013 Jul 3. PubMed PMID: 23795919.

3: Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs. 2010 Nov;19(11):1355-66. doi: 10.1517/13543784.2010.520701. Epub 2010 Sep 16. Review. PubMed PMID: 20846000; PubMed Central PMCID: PMC3244346.

Brexpiprazole ブレクスピプラゾール

March 23, 2015 8:39 am / Leave a comment

Brexpiprazole

ブレクスピプラゾール

OPC-34712, UNII-2J3YBM1K8C, OPC34712,

CAS 913611-97-9,

Molecular Formula:C₂₅H₂₇N₃O₂S

Molecular Weight:433.56578 g/mol

7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one

7-[4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy]quinolin-2(1H)-one

2(1H)-Quinolinone, 7-[4-(4-benzo[b]thien-4-yl-1-piperazinyl)butoxy]-

7- [ 4- ( 4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

UNII-2J3YBM1K8C

Otsuka Pharma Co Ltd,

Otsuka Pharma Co Ltd,

OTSUKA ……………INNOVATOR

NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.

UPDATE JULY 2015 ON STATUS OF APPROVAL

Approval Status:

Approved July 2015

Specific Treatments:

depression and schizophrenia

Therapeutic Areas

Psychiatry/Psychology

Brexpiprazole (/brɛksˈpɪprəzoʊl/ breks-pip-rə-zohl; also called OPC-34712) is a novel D2 dopamine partial agonist investigational product currently in clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder(ADHD).^[1]Although it failed Stage 2 trials for ADHD, it has been designed to provide improved efficacy and tolerability (e.g., lessakathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).^[2]

OPC-34712 is an antidepressant and antipsychotic drug candidate awaiting approval in the U.S. for the treatment of schizophrenia and also as adjunctive treatment of major depressive disorder (MDD). The product is in phase III clinical trials for the treatment of agitation associated with Alzheimer’s disease. Phase III clinical trials are also underway for the treatment of post-traumatic stress disorder (PTSD).

brexpiprazole (pre-registration, as of April 2015), which is being developed by Otsuka and Lundbeck, useful for treating schizophrenia, agitation associated with Alzheimer’s disease, major depressive disorder and attention deficit hyperactivity disorder. Family members of the product case, WO2006112464, hold protection in EU states until 2026 and its US equivalent, US7888362, has US154 extension, expiring in 2027. Suzhou Vigonvita Life Sciences appears to be new to patenting and is the first collaborative filing from the three assignees.

Phase II clinical trials are also ongoing for use as adjunctive therapy in adults with attention deficit hyperactivity disorder (ADHD). The compound is being developed by Otsuka Pharmaceutical. In 2011, a codevelopment and commercialization agreement was signed by Lundbeck and Otsuka Pharmaceutical in Latin and North America, Australia and Europe for the treatment of psychiatric disorders.

The drug is being developed by Otsuka, and is considered to be a successor^[3] of its top-selling antipsychotic agent aripiprazole(brand names: Abilify, Aripiprex). Otsuka’s US patent on aripiprazole expired on October 20, 2014;^[4] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[5]

Brexpiprazole (1) , a serotonin–dopamine activity modulator, is an investigational new drug currently in phase-III clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder.(1A) Brexpiprazole is also considered to be a possible successor to the top-selling antipsychotic agent aripiprazole.(2A)

1A……….Phase II and Phase III Drugs in U.S. Development for Depression, Anxiety, Sleep Disorders, Psychosis & ADHD, 2011. http://www.neurotransmitter.net/newdrugs.html(accessed Jan 27, 2015).
2A…………FDA accepts new schizophrenia drug filing, 2014.http://www.pharmafile.com/news/194878/fda-accepts-new-schizophrenia-drug-filing(accessed Jan 27, 2015).

Brexpiprazole

In the clinical program, brexpiprazole demonstrated improvement in symptoms in both schizophrenia and as adjunctive therapy in major depressive disorder (MDD)

July 2015 is the anticipated completion timing of the FDA’s review (based on PDUFA timeline)Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) today announced that the U.S. Food and Drug Administration (FDA) has determined that the New Drug Application (NDA) for brexpiprazole for monotherapy in adult patients with schizophrenia and for adjunctive treatment of major depressive disorder (MDD) in adult patients is sufficiently complete to allow for a substantive review, and the NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.The NDA is supported by seven completed placebo-controlled clinical phase II or III studies in the proposed indications – three studies in schizophrenia and four studies with brexpiprazole as adjunctive therapy in MDD. The dossier included data from more than 6,000 participants of whom more than 5,000 received brexpiprazole.

Brexpiprazole in adult patients with schizophreniaOne clinical phase II and two clinical phase III placebo-controlled studies have been completed using brexpiprazole in adult patients suffering from schizophrenia. Across the three studies more than 1,700 patients have been randomized.In the first pivotal phase III study randomizing approximately 625 patients, brexpiprazole 2mg/day and 4 mg/day both demonstrated greater improvement of symptoms relative to placebo as measured by change from baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at week 6 (p<0.05). Results of the key secondary endpoint supported primary results.In the second pivotal phase III study randomizing approximately 650 patients, brexpiprazole 4 mg/day again demonstrated greater improvement of symptoms relative to placebo (p<0.05) in change from baseline in the PANSS Total Score at Week 6. Brexpiprazole 2 mg/day showed numerical improvement (p>0.05) over placebo at Week 6.The results from the clinical phase II studyi were presented at the 24th Annual US Psychiatric and Mental Health Congress in November 2011. The study showed a clinically meaningful improvement from baseline measured by PANSS total score at week 6, although it did not achieve statistical separation from placeboii.In the placebo-controlled phase II and III studies, the rates of discontinuation due to adverse events were 8.1% for patients receiving brexpiprazole compared to 12.7% of patients receiving placebo; the only adverse event that occurred in more than 5% of brexpiprazole patients and more frequently than placebo was akathisia (5.8% vs. 4.5%).

Brexpiprazole as adjunctive therapy in major depressive disorder (MDD) Four studies have been included in the dossier using brexpiprazole as adjunctive therapy for adult patients suffering from MDD who had demonstrated a consistent, inadequate response to at least two regimens of prior antidepressant treatment. Patients with MDD and an inadequate response to one to three antidepressants were enrolled and received antidepressants for 8 weeks, single blinded, in the two phase III studies. Patients with an inadequate response during this prospective phase were provided antidepressant therapy and randomized adjunctive treatment with either brexpiprazole or placebo for 6 weeks. The primary efficacy endpoint was the change in MADRS (Montgomery–Åsberg Depression Rating Scale) Total Score from baseline at week 6. MADRS is a commonly used scale to assess the range of symptoms in patients with MDD. Across the four studies, more than 3,900 patients entered the prospective phase and more than 1,800 patients were included in the randomized phase of the studies.The first pivotal phase III results were presented in a poster session at the 22nd European Psychiatry Association Congress (EPA) in March 2014. This two-arm phase III study randomized approximately 380 patients and demonstrated an improvement of symptoms with an antidepressant plus 2 mg brexpiprazole that was greater than an antidepressant plus placebo (p<0.001)The second pivotal phase III study was a three-arm study in which approximately 675 patients were randomized to treatment with an antidepressant plus either placebo, 1 mg brexpiprazole or 3 mg brexpiprazole.v Patients in both brexpiprazole treatment groups showed greater improvement in symptoms as measured by the MADRS compared to placebo (1 mg p>0.05, 3 mg p<0.05). Results of the second pivotal phase III study in MDD have not yet been published.

The first clinical phase IIvi study randomized approximately 425 patients in four arms and was presented at the 164th Annual Meeting of the American Psychiatric Association in May 2011. Patients exhibited greater improvements than adjunctive placebo in MADRS Total score with the 1.5 (±0.5) mg/day dose of brexpiprazole after six weeks of treatment (p

About brexpiprazole (OPC-34712)Brexpiprazole is a novel investigational psychotropic compound discovered by Otsuka and under co-development with Lundbeck. Brexpiprazole is a serotonin-dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.

Partnership with Lundbeck

In November 2011, Otsuka and Lundbeck have announced a global alliance.^[6] Lundbeck has given Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

The partnership has been presented by Otsuka to its investors as a good fit for several reasons:^[7]

Geographic strategy: Otsuka in Japan, Asia, US; Lundbeck in Europe, South America and emerging markets
Research strategy: Otsuka has knowledge in antipsychotics, Lundbeck in anti-depressant and anxiolytic.
CNS strategy: Otsuka has a robust portfolio in next-generation CNS drugs, while Lundbeck covers a wide range of CNS conditions from Alzheimer’s to schizophrenia.
Similar corporate culture

Clinical trials

OPC-34712 is currently in clinical trials for adjunctive treatment of MDD, adjunctive treatment of adult ADHD and schizophrenia.^[8]

Major depression

Phase II

The Phase 2 multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three ADTs in the current episode. The study was designed to assess the efficacy and safety of OPC-34712 as an adjunctive treatment to standard ADT. The ADTs included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.^[9]

Phase III

A new Phase III study is currently in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”.^[10] Its goal is “to compare the effect of OPC-34712 to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrollment is 1250 volunteers.

Brexpiprazole, code: OPC-34712) is Otsuka Pharmaceutical Co., Ltd. developed a new generation of anti-psychotic drug candidates, and its role in multiple receptors, dopamine D2 receptor partial agonist (improving positive and negative symptoms, cognitive impairment and depressive symptoms), 5-HT2A receptor antagonist (improving negative symptoms, cognitive dysfunction, symptoms of depression, insomnia), α1 adrenoceptor antagonists (improving positive symptoms of schizophrenia), 5 – serotonin uptake / reuptake inhibitors (improve depressive symptoms); at the same time, but also a 5-HT1A partial agonist (anxiolytic and antidepressant activity) and 5-HT7 antagonist (temperature, circadian rhythms, learning and memory, sleep) . Currently, in the United States and Europe as adjuvant treatment of severe depression (MDD) Phase III clinical trial; III clinical trial for the treatment of schizophrenia in the United States, Europe and Japan, meanwhile, is still the United States Phase II adult ADHD Clinical Trials.

Adult ADHD

Phase II

Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)^[11] The company did not move the product to Phase III, and it is presumed this drug failed Phase II trials for the disorder.

Schizophrenia

Phase I

Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder^[12]

Phase II

A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia^[13]

Phase III

Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)^[14]
Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)^[15]
Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)^[16]
A Long-term Trial of OPC-34712 in Patients With Schizophrenia^[17]

Conferences

Phase II results were presented at the American Psychiatric Association’s 2011 annual meeting in May 2011.^[18]

The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology^[19] in September 2011.

At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia^[20]

Pharmacology

Brexpiprazole acts as a partial agonist of the 5-HT_1A, D₂, and D₃ receptors, and as an antagonist of the 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A–, α_1B–, α_1D–, and α_2C-adrenergic, and H₁receptors.^[22] It has negligible affinity for the mACh receptors.^[22]

Patents

U.S. Patent 8,071,600
WIPO PCT/JP2006/317704
Canadian patent: 2620688^[24]
WO 2013162046
WO 2013161830
WO 2013162048
WO 2013015456
JP 2008115172
WO 2006112464
WO2015054976 NEW

Patent	Submitted	Granted
PIPERAZINE-SUBSTITUTED BENZOTHIOPHENES FOR TREATMENT OF MENTAL DISORDERS [US2011152286]	2011-06-23
Piperazine-substituted benzothiophenes for treatment of mental disorders [US7888362]	2010-07-15	2011-02-15

Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2006112464A1 in the preparation route see Scheme 1, the difficulty of the route is the first reaction generates byproducts easily separated by column chromatography is not easy to obtain high-purity intermediates, thus affecting the final product Bray prazosin purity and yield.Scheme 1:

Subsequently, Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2013015456A1 in the alternative method of preparing the reaction of this step, see Scheme 2, the route the reagents are more expensive, high-cost, environmentally unfriendly and not suitable for industrial production.

Reaction Scheme 2:

Due to the above production process there is a high cost, and difficult to separate impurities and other shortcomings, it is necessary to find an economical, practical, environmental protection, new routes to improve process stability, reduce costs, improve product quality.

Synthesis

WO 2013015456

IN THIS BELOW PIC WE SEE

click on pics below to view

Synthesis of A

1 BROMO 4 CHLORO BUTANE WAS REACTED WITH 7 HYDROXY 1H QUINOLINE -2-ONE TO GIVE A

7 ( 4 CHLORO BUTOXY)-1H -QUINOLINE-2-ONE, WHICH WILL BE USED FOR COUPLING AT LAST STAGE

1 BROMO 4 CHLORO BUTANE

IN THE BELOW PIC 2,6-Dichlorobenzaldehyde AND RHODANINE WERE REACTED TO GIVE 2,6-dichlorobenzylidenerhodanine.

2,6-Dichlorobenzaldehyde

RHODANINE

NEXT WAS
2,6-dichlorobenzylidenerhodanine, GAVE (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid.

1H-NMR (DMSO-d6) d
ppm; 7.23-7.67 (4H, m), 3.5-5.7 (1H, br.), 11.7-14.5 (1H, br.).

Next was prepration of K salt

(Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid and potassium hydroxide gave ((Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid potassium salt).

Next stage

((Z)-3-(2,6-dichlorophenyl-2-mercapto-2-propenoic acid potassium
salt) GAVE 2-carboxy-4-chlorobenzo[b]thiophene.
Yield: 48.8 g. 1H-NMR (DMSO-d6) d ppm; 7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3
Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

NEXT IS DECARBOXYLATION

A mixture of 2-carboxy-4-chlorobenzo[b]thiophene, 1,3-dimethyl-2-imidazolidinone, and 1,8-
diazabicyclo[5.4.0]-undec-7-ene GAVE compound. 4-chlorobenzo[b]thiophene. 1H-NMR (DMSO-d6) d ppm; 7.38 (1H, t, J = 8.4
Hz), 7.51 (1H, dd, J = 5.5, 0.8 Hz), 7.48 (1H, dd, J = 7.7, 0.9 Hz), 7.94 (1H, dd, J = 5.5, 0.4
Hz), 8.02 (1H, dt, J = 8.0, 0.9 Hz).

BETTER REPRESENTATION OF ABOVE PIC

CLIPS FROM PATENT

Synthesis of 2,6-dichlorobenzylidenerhodanine

2,6-Dichlorobenzaldehyde (77.0 g) , rhodanine (58.6 g) , and acetic acid (539 ml) were suspended with stirring at room temperature. Anhydrous sodium acetate (116 g) was added to the suspension, and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 45°C, and ice water (700 ml) was added. After the mixture was stirred for 0.2 hours, the precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2,6- dichlorobenzylidenerhodanine. Even in non-dried form, this product could be subjected to the subsequent step.

Yield: 125.4 g^- MR (CDC1₃) 6ppm;7.30-7.44 (3H, m) , 7.70 (1H. s), 9.6 (1H, br.).

Reference Example 3

• Synthesis of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid

A suspension of 2,6- dichlorobenzylidenerhodanine (160.4 g) and water (800 ml) was stirred at room temperature, and sodium hydroxide (83.0 g) was added over a period of 1 hour. The resulting mixture was heated with stirring for another 0.5 hours. The reaction mixture was cooled with ice (10°C), and concentrated hydrochloric acid (192 ml) was added. After the mixture was stirred while cooling with ice for 0.5 hours, the precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with water and then dried to obtain an equivalent amount of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2- propenoic acid.

Yield: 138.9 g l-NMR (DMSO-de) δρρπΐ;7.23-7.67 (4H, m) , 3.5-5.7 (1H, br.), 11.7-14.5 (1H, br.).

Reference Example 4

• Synthesis of 2-carboxy-4-chlorobenzo[b] thiophene

A suspension of (Z)-3-(2,6-dichlorophenyl-2-mercapto-2- propenoic acid (72.4 g) and water (362 ml) was stirred at room temperature. Further, potassium hydroxide (40.8 g) was added, and the mixture was heated under reflux for 4 hours . After the mixture was allowed to cool, the mixture was stirred for 1 hour while cooling with ice. The precipitated crystals ((Z)-3-(2,6- dichlorophenyl-2-mercapto-2-propenoic acid potassium salt) were collected by filtration and washed with cold water. After the crystals were suspended in water, 35% concentrated hydrochloric acid (32 ml) was added (pH = 1), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and dried to obtain 2-carboxy-4- chlorobenzo[b] thiophene.

Yield of 48.8 g ^- MRiDMSO-de) 6ppm; 7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3 Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

Reference Example 5

• Synthesis of K salt 4-chlorobenzo[b] thiophen-2-carboxylate

Reference Example 6

· Synthesis of 2-carboxy-4-chlorobenzo[b]thiophene

Sodium 4-chlorobenzo[b] thiophen-2-carboxylate (2.40 g) was dissolved in water (33 ml) at 60°C. Concentrated hydrochloric acid (1.3 ml) was added to the solution at the same temperature, and the resulting mixture was stirred. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2-carboxy-4-chlorobenzo[b] thiophene.

Yield: 1.61 g ^- MR (DMS0-d₆);7.53 (1H, t, J = 7.7 Hz), 7.58 (1H, dd, J = 7.7, 1.3 Hz), 8.03 (1H, d, J = 0.5 Hz), 8.07 (1H, d, J = 7.6 Hz).

Elaborate description

IN THIS BELOW PIC WE SEE

Synthesis of 4-(1-piperazinyl)benzo[b]thiophene

4-Chlorobenzo[b]thiophene and xylene , Subsequently, piperazine, sodium tert-butoxide, palladium acetate (II), and 2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′-biphenyl (RuPhos) …… producing 4-(1-piperazinyl)benzo[b]thiophene.

NEXT IS PREPARATION OF HYDROCHLORIDE

4-(1-piperazinyl)benzo[b]thiophene hydrochloride. 1H-NMR (DMSO-d6) d ppm;
3.30 (4H, br.s), 3.61 (4H, br.s), 6.97 (1H, d, J = 7.8 Hz), 7.32 (1H, br. dd, J = 8.4, 7.8 Hz),
7.53 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 5.6 Hz), 9.37 (1H, br.s).

NEXT IS REACTION WITH A TO GIVE BREXPIPRAZOLE

1-benzo[b]thiophen-4-yl-piperazine hydrochloride, potassium carbonate
and DMF and 7-(4-chlorobutoxy)-1H-quinolin-2-one A FROM PIC 1 and potassium iodide GAVE BREXPIPRAZOLE, ie 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.

1H-NMR (DMSO-d6) d ppm; 1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44
(2H, t, J = 7.0 Hz), 2.55-2.70 (4H, m), 3.00-3.15 (4H, m), 4.06 (2H, t, J = 6.3 Hz), 6.30 (1H,
d, J = 9.5 Hz), 6.75-6.85 (2H, m), 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz),
7.40 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5
Hz), 7.80 (1H, d, J = 9.5 Hz), 11.58 (1H, bs).

BETTER REPRESENTATION OF PIC

Example 2

• Synthesis of 4- (l-piperazinyl)benzo[b]thiophene hydrochloride

4-Chlorobenzo[b] thiophene (5.00 g), piperazine (5.11 g) , palladium acetate (II) (2.7 mg), tri-tert-butylphosphonium

tetraphenylborate (6.2 mg), sodium tert-butoxide (8.548 g), and xylene (70 ml) were stirred at 120 to 130°C for 5 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the layers were separated. The xylene layer was washed with water, and then with saline. After addition of activated carbon, the mixture was stirred at room temperature for 30 minutes. After filtration of the mixture, concentrated

hydrochloric acid was added to the filtrate, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and dried to obtain 4- ( l-piperazinyl)benzo[b] thiophene hydrochloride.

Yield: 6.94 g !H-NMRiDMSO-de) 6ppm; 3.30 (4H, br.s), 3.61 (4H, br.s), 6.97 (1H, d, J= 7.8 Hz), 7.32 (1H, br.dd, J= 8.4. 7.8 Hz), 7.53 (1H, d, J= 5.6 Hz), 7.70 (1H, d, J= 8.4 Hz), 7.76 (1H, d, J= 5.6 Hz), 9.37 (1H, br.s).

Example 3

• Synthesis of 4- ( 1-piperazinyl)benzo[b] thiophene hydrochloride

4-Chlorobenzo[b] thiophene (10.0 g) and xylene (100 ml) were placed in a reaction vessel. The reaction vessel was

evacuated and then purged with argon. Subsequently, piperazine (15.3 g) , sodium tert-butoxide (17.1 g) , palladium acetate (II) (13.0 mg) , and 2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′- biphenyl (RuPhos) (69.0 mg) were added. After evacuation and purging with argon, the mixture was refluxed for 2 hours. After the reaction mixture was cooled to about 80°C, water (50 ml) and silica #600H (0.65 g) were added. The mixture was stirred at approximately 60°C for about 10 minutes, and then filtered. After the filtrate was separated into layers, the xylene layer was washed with water. Subsequently, the xylene layer was placed into the reaction vessel again. After addition of water (200 ml) and concentrated hydrochloric acid (8.0 ml) , the mixture was heated with stirring for dissolution. The layers were separated at 75°C or more. After the aqueous layer was collected, toluene (150 ml) and 25% aqueous sodium hydroxide solution (16 ml) were added, and the mixture was stirred. The layers were separated, and the organic layer was collected. The organic layer was washed with water and concentrated with an evaporator. Methanol (150 ml) was added to the concentrated oil to dissolve the oil, thus producing a methanol solution. 2-Propanol (150 ml) and concentrated

hydrochloric acid (7 ml) were placed into another reaction vessel, and the methanol solution was added dropwise over a period of 15 minutes or more. After completion of the dropwise addition, the mixture was cooled and stirred at 10°C or less for about 30 minutes, and then filtered (washed with a mixture of 5 ml of methanol and 5 ml of 2-propanol) . The crystals were collected, and then dried to obtain 4-(l-piperazinyl)benzo[b]thiophene hydrochloride.

Yield: 11.61 g

^-NMRfDMSO-de) oppm;

3.25-3.40 (8H, br.s), 6.96 (1H, d, J = 7.5 Hz), 7.32 (1H, dd, J = 8.0, 7.5 Hz), 7.52 (1H, d, J = 5.5 Hz ) . 7.70 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 9.35 (1H, br.s).

Reference Example 9

· Synthesis of 7- ( 4-chlorobutoxy) -lH-quinolin-2-one

After 7-hydroxy-lH-quinolin-2-one (10 g) and DMF (50 ml) were heated to approximately 30°C, an aqueous potassium carbonate solution (potassium carbonate: 8.6 g, water: 10 ml) was added. After the mixture was stirred at 30 to 40°C for about 15 minutes, l-bromo-4-chlorobutane (14.3 ml) was added and stirred at approximately 40°C for 5 hours. Water (100 ml) was added dropwise over a period of 30 minutes or more while the

temperature was maintained at 30°C or more. After the mixture was stirred at approximately 30°C for 30 minutes, stirring was continued at 10°C or less for 1 hour, after which the precipitated crystals were collected by filtration. After methanol (100 ml) was added to the precipitated crystals, the mixture was stirred under reflux to ensure dissolution. This solution was cooled and stirred at 30 to 40°C for 30 minutes and then at 5°C or less for about 1 hour, after which the precipitated crystals were

collected by filtration. The crystals were dried at 60°C to obtain 7- (4-chlorobutoxy) -lH-quinolin-2-one as white powder.

Yield: 12.3 g

^I-NMR (300 MHz; CDC1₃) oppm; 1.95-2.05 (4H, m) , 3.64 (2H, t, J = 6.0Hz), 4.10 (2H, t. J = 5.5 Hz), 6.56 (1H, d, J = 9.5 Hz), 6.80 (1H. dd, J = 9.0 Hz, 2.5 Hz), 6.84 (1H, d, J = 2.5 Hz), 7.45 (1H, d, J = 9.0 Hz), 7.73 (1H, d, J = 9.5 Hz), 12.45 (1H, brs).

Example 4

· Synthesis of 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one

After 1-benzo[b] thiophen-4-yl-piperazine hydrochloride (10.6 g), potassium carbonate (5.8 g) , and DMF (50 ml) were stirred at 30 to 40°C for about 30 minutes, 7-(4-chlorobutoxy) -1H- quinolin-2-one (10.0 g) and potassium iodide (6.9 g) were added. The mixture was stirred at 90 to 100°C for 2 hours. While the temperature of the mixture was maintained at 60°C or more, water (150 ml) was added dropwise over a period of 10 minutes or more.

After the mixture was cooled to 10°C or less, the precipitated crystals were collected by filtration, and washed with water and then with ethanol.

After ethanol (325 ml) and acetic acid (25 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. Concentrated hydrochloric acid (3.6 ml) was added at around 70°C, and the mixture was cooled. After confirming the precipitation of crystals, the mixture was heated again and stirred under reflux for 1 hour. After the mixture was cooled to 10°C or less, the precipitated crystals were collected by filtration and washed with ethanol.

After ethanol (191 ml) and water (127 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. After activated carbon (0.89 g) was added, the mixture was stirred under reflux for 30 minutes and then hot filtered. After activated carbon was removed, the mixture was heated again for dissolution. After 25% aqueous sodium hydroxide solution (5.8 ml) was added at approximately 70°C, the mixture was stirred under reflux for 30 minutes, after which water (64 ml) was added at approximately 70°C. After the mixture was stirred at 40°C for 30 minutes, the precipitated crystals were collected by filtration at 40°C or less, then washed with water, and dried to obtain 7- [4-(4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one as white crystals.

Yield: 14.30 g ^-NMRfDMSO-de) 6ppm; 1.6-1.75 (2H, m) . 1.75-1.9 (2H, m) , 2.44 (2H, t, J = 7.0 Hz),2.55-2.70 (4H, m) , 3.00-3.15 (4H, m) , 4.06 (2H, t, J = 6.3 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.75-6.85 (2H, m) , 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.58 (1H, bs) .

SEE http://www.molbase.com/en/index.html

IH NMR PREDICT

7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one NMR spectra analysis, Chemical CAS NO. 913611-97-9 NMR spectral analysis, 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one H-NMR spectrum

13 C NMR PREDICT

Patent

Reaction Scheme 3:

WO2015054976

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Wherein, X is halogen, such as fluorine, chlorine, bromine, iodine; R and R ₁ as defined above in the definition of the compounds of formula I the same;

Scheme 4:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ as defined above, with a compound of formula I as defined for the same;

Reaction Scheme 5:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ is the same as defined in the compounds shown above, and R are as defined for formula I. The present invention also provides processes for preparing key intermediates Bray prazosin/ Brexpiprazole or a salt thereof, the method as shown in Scheme 6:

Scheme 6:

Example 26

7- [4- (benzothiazol-4-yl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone

Preparation of

The product (400mg, 0.83mmol) of Example 25 will be implemented, silver carbonate (46mg, 0.16mmol) was dissolved in DMSO (5mL) and the acetic acid was heated to 120 ℃ overnight. Cooling, water was added, extracted with ethyl acetate, ethyl acetate layer was washed with saturated sodium bicarbonate and brine each wash again, dried over anhydrous sodium sulfate, and silica gel column chromatography, to give a solid (80mg, yield 22%).

¹ HNMR (400 MHz, DMSO-d ₆ ): δ10.00 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 7.27 (t, 1H), 7.04 ( d, 1H), 6.89 (d, 1H), 6.50 (dd, 1H), 6.45 (d, 1H), 3.93 (t, 2H), 3.06 (br, 4H), 2.78 (t, 2H), 2.60 (br , 4H), 2.41 (t, 4H), 1.74 (t, 2H), 1.60 (t, 2H) ESI: [M + 1] ⁺ = 436.3.

Example 27

7- [4- (2-carboxy-benzothiophen-4-yl-1-piperazinyl) butoxy] -2 (1H) – quinolinone

Preparation of

A mixture of 2-chloro-6- (4- (4 – ((2-oxo-1,2-dihydro-quinolin-7-yl) oxy) butyl) piperazin-1-yl) benzaldehyde (80mg , 0.18mmol) was dissolved in DMF (5mL) was added sodium hydroxide (29mg, 0.73mmol) and thioglycolic acid (0.025mL, 0.36mmol), 120 ℃ stirred for 16 hours. Cooling, water was added, adjusted with 1N HCl aqueous solution is about pH = 5, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and silica gel column chromatography, to give a solid (40mg, yield 46 %).

ESI: [M + 1] ⁺ = 478.0.

Piperazine hydrochloride – (2-carboxy-benzothiophen-4-yl)

Example 28 1-

The product of Example 17 (100mg, 0.25mmol) was dissolved in acetic acid (3mL) and concentrated hydrochloric acid (0.5 mL) in, 100 ℃ stirred for 10 hours. The reaction solution was poured into ice water, stirred for 10min after filtration, to obtain the target substance (38mg, 50% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 8.04 (s, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.00 (d, 1H), 3.30 ( bs, 8H) ESI: [M + 1] ⁺ = 262.9.

Preparation of tert-butyl piperazine-1 – Example 224- (2-carboxy-benzothiophen-4-yl)

Under nitrogen, to N, at room temperature was added N- dimethylformamide (5mL) within the reference product (200g, 0.62mmol) of Example 1, thioglycolic acid (114mg, 1.23mmol), sodium methoxide (133mg, 2.45mmol ), and the mixture was stirred at 105 ℃ 18 hours. Cooling, water was added, extracted with ethyl acetate, separated and the aqueous phase was adjusted pH = 5 or so, the precipitated solid was filtered and dried to obtain the target substance (130mg, 58% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.98 (s, 1H), 7.64 (d, 1H), 7.42 (t, 1H), 6.95 (d, 1H), 3.53 (bs, 4H), 3.035 ( bs, 4H) ESI: [M-1] ^– = 361.1.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – (2-carboxy-benzothiophen-4-yl) Example 234-

Under nitrogen, to N, at room temperature was added N- dimethylformamide (5mL) within the reference product (200g, 0.62mmol) of Example 1, thioglycolic acid (114mg, 1.23mmol), sodium hydroxide (99mg, 2.45 mmol), the mixture was stirred at 105 ℃ 18 hours. Cooling, water was added, extracted with ethyl acetate, separated and the aqueous phase was adjusted pH = 5 or so, the precipitated solid was filtered and dried to obtain the target substance (180mg, yield 81%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.98 (s, 1H), 7.64 (d, 1H), 7.42 (t, 1H), 6.95 (d, 1H), 3.53 (bs, 4H), 3.035 ( bs, 4H) ESI: [M-1] ^– = 361.1.

Example 24 7- [4- (2-ethoxycarbonyl-4-phenyl and thienyl-1-piperazinyl) butoxy] -2 (1H) – quinolinone Preparation of

A mixture of 2-chloro-6- (4- (4 – ((2-oxo-1,2-dihydro-quinolin-7-yl) oxy) butyl) piperazin-1-yl) benzaldehyde (80mg , 0.18mmol) was dissolved in DMF (5mL) was added DIPEA (94mg, 0.73mmol) and ethyl mercaptoacetate (0.024mL, 0.22mmol), 110 ℃ stirred for 16 hours. Cooling, water was added, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and silica gel column chromatography, to give a solid (40mg, 46% yield).

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 184- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen, was added at room temperature to DMF (5mL) within the reference product (200mg, 0.62mmol) of Example 1, ethyl mercaptoacetate (0.081ml, 0.74mmol), DIPEA (342mg, 2.48mmol), the mixture was at 105 ℃ stirred for 18 hours, 1N HCl aqueous solution was added adjust pH = 7, and extracted with methyl tert-butyl ether, the ether layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, the drying agent was filtered off, and concentrated by column chromatography to obtain the target (170mg, yield 71%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 194- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen at room temperature was added the product of Reference Example 1 to ethanol (5mL) inside (200mg, 0.62mmol), ethyl mercaptoacetate (0.081ml, 0.74mmol), sodium hydroxide (100mg, 2.48mmol), the mixture 85 ℃ stirred for 6 hours, and concentrated by column chromatography to obtain the target substance (70mg, 30% yield).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Piperazine hydrochloride – (2-carboxy-benzothiophen-4-yl) Example 201-

The product of Example 2 (200mg, 0.55mmol), was dissolved in THF (5mL) was added concentrated hydrochloric acid (0.5mL), 50 ℃ heated 6h.Cooling, methyl tert-butyl ether (5mL), filtered to give the target (130mg, yield 79%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 8.04 (s, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.00 (d, 1H), 3.30 ( bs, 8H) ESI: [M + 1] ⁺ = 262.9.

Piperazine hydrochloride – (benzothiophen-4-yl) Example 211-

The product of Example 20 (130mg, 0.43mmol) was added to diphenyl ether (3mL) in, 260 ℃ heating 0.5h. Cooling, filtration object (60mg, 55% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 7.75 (d, 1H), 7.69 (d, 1H), 7.53 (t, 1H), 7.31 (t, 1H), 6.97 ( t, 1H), 3.30 (bs, 8H) ESI: [M + 1] ⁺ = 219.2.

PAPER

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00027

http://pubs.acs.org/doi/full/10.1021/acs.oprd.5b00027

Figure 1. Brexpiprazole (1) and intermediate 18.

2-Chloro-6-fluorobenzaldehyde was converted to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18), an intermediate in the synthesis of brexpiprazole, via a five-step sequence in 54% overall yield. This procedure requires no expensive catalyst and avoids the side products produced in the coupling step in the reported process. Several kilograms of compound 18 were prepared using this economical and scalable process.

1-(Benzo[b]thiophen-4-yl)piperazine Dihydrochloride (18)

Compound 10 (1.5 kg, 4.71 mol) was dissolved in ………………..DELETED…………………, and then dried to give compound 18 (1.17 kg, 85% yield). HPLC for compound 18 (t_R = 6.3 min, identical to authentic sample) 99.8% purity; HPLC method B.

18:

¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.65 (s, 2H), 7.75 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 5.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 3.30 (s, 8H).

¹³C NMR (100 MHz, DMSO-d₆): δ 146.92, 140.62, 133.40, 126.50, 125.06, 121.91, 117.73, 112.56, 48.52, 43.00.

MS (ESI, eV): m/z = 219.1 [M + H]⁺.

………..

PATENT

http://www.google.com/patents/US20140187782

A 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (1):

is useful for various medicines such as antipsychotic drugs. Moreover, a 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (4):

wherein R¹is a hydrogen atom or a protecting group, is useful as an intermediate for synthesizing the compound represented by Formula (1).

Reference Example 30 and Example 1 of PTL 1 specifically disclose a method for producing a benzo[b]thiophene compound (the reaction scheme shown below). In Reference Example 30, 4-(1-piperazinyl)benzo[b]thiophene is produced by heating under reflux a mixture comprising 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of anhydrous piperazine, 9.3 g of sodium tert-butoxide, 0.65 g of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (0), and 250 ml of toluene (step X).

However, the reaction of the step X produces a relatively large amount of by-products that can hardly be separated, and the purity of the compound (4a) is thus inevitably reduced. Moreover, although column purification is performed to increase the purity of the compound (4a), it is very difficult to completely remove by-products, even by column chromatography purification. For this reason, there is a demand for the development of a novel method for producing the compound (4a) with high yield and high purity.

Furthermore, by-products contained in the compound (4a) inevitably reduce the purity of the compound (1) in the subsequent step Y. Since the method described in PTL 1 requires purification by column chromatography to obtain the target compound (1) with high purity, the method is not suitable for the industrial process of mass production. In addition, according to the method, incorporation of by-products that can hardly be separated is inevitable, and high-purity products usable as active pharmaceutical ingredients cannot be produced without purification by column chromatography.

CITATION LISTPatent Literature

PTL 1: Japanese Unexamined Patent Publication No. 2006-316052 Non Patent Literature
NPL 1: Tetrahedron Lett., 2004, 45, 9645

Example 4

Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

After 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (10.6 g), potassium carbonate (5.8 g), and DMF (50 ml) were stirred at 30 to 40° C. for about 30 minutes, 7-(4-chlorobutoxy)-1H-quinolin-2-one (10.0 g) and potassium iodide (6.9 g) were added. The mixture was stirred at 90 to 100° C. for 2 hours. While the temperature of the mixture was maintained at 60° C. or more, water (150 ml) was added dropwise over a period of 10 minutes or more. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration, and washed with water and then with ethanol.

After ethanol (325 ml) and acetic acid (25 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. Concentrated hydrochloric acid (3.6 ml) was added at around 70° C., and the mixture was cooled. After confirming the precipitation of crystals, the mixture was heated again and stirred under reflux for 1 hour. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration and washed with ethanol.

After ethanol (191 ml) and water (127 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. After activated carbon (0.89 g) was added, the mixture was stirred under reflux for 30 minutes and then hot filtered. After activated carbon was removed, the mixture was heated again for dissolution. After 25% aqueous sodium hydroxide solution (5.8 ml) was added at approximately 70° C., the mixture was stirred under reflux for 30 minutes, after which water (64 ml) was added at approximately 70° C. After the mixture was stirred at 40° C. for 30 minutes, the precipitated crystals were collected by filtration at 40° C. or less, then washed with water, and dried to obtain 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one as white crystals.

Yield: 14.30 g

¹H-NMR (DMSO-d₆) δ ppm;

1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44 (2H, t, J=7.0 Hz), 2.55-2.70 (4H, m), 3.00-3.15 (4H, m), 4.06 (2H, t, J=6.3 Hz), 6.30 (1H, d, J=9.5 Hz), 6.75-6.85 (2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.61 (1H, d, J=8 Hz), 7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.58 (1H, bs).

………………………

PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

Example 1

Preparation of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one

A mixture of 9.0 g of 7- ( 4-chlorobutoxy) -IH- quinolin-2-one, 10 g of 1-benzo [b] thiophene-4-yl- piperazine hydrochloride, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred for 2 hours at 😯⁰C. Water was added to the reaction solution and precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane .-methanol = 100:3). Recrystallized from ethanol, 13.6 g of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one in the form of a white powder was obtained.

Melting point 183.5-184.5⁰C

¹H-NMR ( DMSO-dg) δppm:

1.6-1.75 (2H, m) , 1.75-1.9(2H, m) , 2.44(2H, t, J=7Hz) , 2.5-2.8(4H, m) , 2.9-3.2(4H, m) , 4.06(2H, t, J=6.5Hz), 6.3O(1H, d, J=9.5Hz), 6.75-6.85 (2H, m) , 6.88(1H, d, J=7.5Hz), 7.27 (IH, dd, J=8Hz, 8Hz), 7.40 (IH, d, J=5.5Hz), 7.55 (IH, d, J=9.5Hz), 7.61(1H, d, J=8Hz) , 7.69(1H, d, J=5.5Hz), 7.8O(1H, d, J=9.5Hz), 11.59(1H, bs) .

……………….

PATENT

7- [ 4- ( 4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one

The dihydrate of the benzothiophene compound represented by Formula (I) or of a salt thereof according to the present invention can be produced from an anhydride of the benzothiophene compound or of a salt thereof.

The benzothiophene compound (in the form of an

anhydride) of Formula (I), from which the dihydrate of the present invention is produced, is a known compound, and can be obtained by the production method disclosed in Example 1 of

JP2006-316052A or according to Reference Examples 1 and 2

Fig. 1 shows the ^-NMR spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 2 shows the X-ray powder diffraction pattern of the dihydrate of the benzothiophene compound represented by

Formula (I) prepared in Example 1.

Fig. 3 shows the infrared absorption spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 4 shows the Raman spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 5 shows the ^XH- MR spectrum of the benzothiophene compound represented by Formula (I) prepared in Example 2.

Reference Example 1: Synthesis of 7-(4-chlorobutoxy)-lH-quinolin- 2-one Methanol (149 L) , 7-hydroxy-lH-quinolin-2-one (14.87 kg), and potassium hydroxide (6.21 kg) were mixed and stirred. After dissolution, l-bromo-4-chlorobutane (47.46 kg) was further added thereto and the resulting mixture was stirred under reflux for seven hours. Thereafter, the mixture was stirred at 10° C for one hour. The precipitated crystal was centrifuged and washed with methanol (15 L). The wet crystal was collected and placed in a tank. Water (149 L) was added thereto, followed by stirring at room temperature. After centrifugation, the resulting solid was washed with water (30 L). The wet crystal was collected and placed in a tank. After adding methanol (74 L), the mixture was stirred under reflux for one hour, cooled to 10° C, and then stirred. The precipitated crystal was centrifuged and washed with methanol (15 L). The separated crystal was dried at 60° C to obtain 7- (4-chlorobutoxy) -lH-quinolin-2-one (15.07 kg).

Reference Example 2: Synthesis of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one

Water (20 L), potassium carbonate (1.84 kg), 1- benzo[b] thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol (8 L) were mixed and stirred at 50° C. 7- ( 4-Chlorobutoxy) – lH-quinolin-2-one (2.80 kg) obtained in Reference Example 1 was added to the mixture and stirred under reflux for nine hours.

After concentrating the solvent (8 L) under ordinary pressure, the mixture was stirred at 90° C for one hour and then cooled to 9° C . The precipitated crystal was centrifuged and then

sequentially washed with water (8 L) and ethanol (6 L). The separated crystal was dried at 60° C to obtain a crude product. The crude product (4.82 kg) and ethanol (96 L) were mixed in a reaction vessel, and acetic acid (4.8 L) was introduced into the reaction vessel. The mixture was stirred under reflux for one hour to dissolve the crude product. After introducing

hydrochloric acid (1.29 kg), the mixture was cooled to 10° C. The mixture was heated again, refluxed for one hour, and cooled to 7° C. The precipitated crystal was centrifuged and washed with ethanol (4.8 L). The separated crystal was dried at 60° C to obtain 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one hydrochloride (5.09 kg). The resulting 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -lH-quinolin-2-one hydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were mixed in a reaction vessel. The mixture was stirred under reflux to dissolve the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one hydrochloride. Activated carbon (500 g) and water (5 L) were added thereto, and an activated carbon treatment was conducted under reflux for 30 minutes. After performing hot filtration, a solution containing sodium hydroxide (511 g) dissolved in water (1.5 L) was flowed into the reaction vessel while stirring the filtrate under reflux. After stirring under reflux for 30 minutes, water (10 L) was introduced thereto and the mixture was cooled to approximately 40° C. The

precipitated crystal was centrifuged and washed with water (125 L). The separated crystal was dried at 80° C to obtain 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (3.76 kg).

Example 1: Preparation of 7- [ 4- ( 4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

The 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-1- yl)butoxy] -lH-quinolin-2-one (3.2 kg) obtained in Reference

Example 2, ethanol (64 L) , water (74 L) , and acetic acid (1.77 kg) were mixed in a reaction vessel to prepare an acidic liquid mixture. The mixture was stirred under reflux to dissolve the 7- [ 4- ( 4-benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2- one (reflux temperature: 84° C). After cooling to -5°C, the solution obtained above was introduced, over a period of 30 minutes, into a solution containing 25% sodium hydroxide (5.9 kg) and water (54 L) that was cooled to 0°C, to prepare a liquid mixture with pHlO. After being stirred at 5° C or below for one hour, the mixture was heated to 20 to 30° C and further stirred for-seven hours . The precipitated crystal was filtered and washing with water (320 L) was performed, until alkali in the solid component disappeared (i.e.. until the pH value of the filtrate became 7 ) . The solid component was then air-dried until its weight became constant to obtain a white solid 7-[4-(4- benzofb] thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate (unground, 3.21 kg).

Fig. 1 shows the ^XH-NMR spectrum (D SO-d₆, TMS) of the dihydrate prepared by the aforesaid method. As shown in Fig. 1, in the ^- MR spectrum (DMSO-d₆, TMS) , peaks were observed at 1.64 ppm (tt, J = 7.4 Hz, J = 7.4 Hz, 2H) , 1.80 ppm (tt, J = 7.0 Hz, J = 7.0 Hz, 2H), 2.44 ppm (t, J = 7.5 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H), 6.80 ppm (d, J = 2.5 Hz, 1H) , 6.80 ppm (dd, J = 2.5 Hz, J = 9.0 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 7.8 Hz, J = 7.8 Hz, 1H) , 7.40 ppm (dd, J = 0.5 Hz, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.0 Hz, 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H) , 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5 Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured using an X-ray diffractometer (D8 ADVANCE, available from Bruker AXS). Fig. 2 shows the X-ray powder diffraction spectrum. As shown in Fig. 2, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.1° , 8.9° , 15.1° , 15.6° , and 24.4° . Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 11.6°.. 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°, 20.5°, 21.5°, 22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°. 28.1°, 28.5°, 28.9°, 29.8°, 30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°, 36.7°, 37.4° , and 38.3°.

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 3 shows the IR (KBr) spectrum. As shown in Fig. 3, in the IR (KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3509 cm^“1, 2934 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1, 1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 4 shows the Raman spectrum. As shown in Fig. 4, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 781 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1613 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1096 cm^“1, 1070 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer method. As a result, the dihydrate had a water content of 7.79% by weight.

Example 2; Preparation of finely ground dihydrate

Dihydrate crystal (2.73 kg) obtained in Example 1 was ground using a jet mill. Here, the air pressure was set at 5 kgf/cm², and the rotational speed of the feeder was set at 20 rpm. As a result, finely ground 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-1-yl)butoxy] -1H-quinoli -2-one dihydrate (2.61 kg,

95.6%) was obtained.

The dihydrate (finely ground product) thus obtained had a mean particle diameter of 5.5 um. The mean particle diameter was measured using a Microtrack HRA, manufactured by Nikkiso Co., Ltd.

Fig. 5 shows the ^-NMR spectrum (DMSO-d₆, TMS) of the dihydrate prepared by the above method. As shown in Fig. 5, in the ^- MR spectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J = 7.3 Hz, J = 7.3 Hz, 2H), 1.80 ppm (tt, J = 6.9 Hz, J = 6.9 Hz, 2H), 2.44 ppm (t, J = 7.3 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H) , 6.80 ppm (d, J = 2.5 Hz , 1H) , 6.80 ppm (dd, J = 2.3 Hz, J = 9.3 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 8.0 Hz, J = 8.0 Hz, 1H) , 7.40 ppm (d, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.5 Hz , 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H), 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5

Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1. Fig. 6 shows the X-ray powder diffraction spectrum. As shown in Fig. 6, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.2° , 8.9° ,

15.2° , 15.7° and 24.4° .

Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 6.8°, 12.2°, 14.0°, 14.5″, 17.4°,

18.1°, 18.5°, 19.0°, 19.2°, 19.6°, 20.3°, 20.6°, 21.5°, 22.7°,

23.4°, 25.0°, 26.1°, 27.1°, 28.6°, 29.0°, 30.4°, 34.0°, 34.5°,

35.3° , and 36.7° .

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1.

Fig. 7 shows the IR (KBr) spectrum. As shown in Fig. 7, in the IR

(KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3507 cm^“1, 2936 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1,

1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 8 shows the Raman spectrum.

As shown in Fig. 8, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1496 cm^‘1, 1376 cm^“1, 1323 cm^‘1, 1311 cm^“1, 1286 cm^“1, 1223 cm^“1, and 781cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1467 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1,

1095 cm^“1, 1069 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the

Karl Fischer method. As a result, the dihydrate had a water content of 6.74% by weight . Example 3 : Preparation of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

7- [ 4- ( 4-Benzo[ ] thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid (2.29 kg) were mixed to prepare an acidic liquid mixture. The liquid mixture was stirred under reflux to dissolve the 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one (reflux temperature: 82° C). After cooling to -5°C, the solution obtained above was introduced, over a period of about 15 minutes, into a solution containing sodium hydroxide (1.48 kg) and water (135 L) that was cooled to 1°C, to prepare a liquid mixture with pHll. After being stirred at approximately 2 to 5° C for three hours, the mixture was heated to 45° C and

further stirred at 45 to 50° C for two hours. The precipitated crystal was filtered and washing with water (200 L) was performed until alkali in the solid component disappeared (i.e., until the pH value of the filtrate became 7). The solid component was further washed with a liquid mixture of ethanol (15 L) and water (20 L). The solid component was then dried at room temperature until its weight became constant to obtain a white solid 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one dihydrate (unground, 5.11 kg).

The dihydrate thus obtained was the same as that obtained in Example 1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 9 shows the Raman spectrum. As shown in Fig. 9, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 782 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1126 cm^“1, 1096 cm^“1, 1070 cm^“1, 972 cm^“1, and 822 cm^“1.

…………………….

PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

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PATENT

http://www.google.com/patents/US20110152286

References

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^ Jump up to:^a ^b “Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)”. Retrieved10 February 2012.
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Jump up^ “Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)”. Retrieved 10 February 2012.
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Maeda K, Sugino H, Akazawa H et al. (September 2014). “Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator”. J. Pharmacol. Exp. Ther. 350 (3): 589–604. doi:10.1124/jpet.114.213793.PMID 24947465.
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http://zliming2004.blog.163.com/blog/static/6456372120149963644472/

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JP2006316052A				Title not available
US20110152286 *	Dec 16, 2010	Jun 23, 2011	Otsuka Pharmaceutical Co., Ltd.	Piperazine-substituted benzothiophenes for treatment of mental disorders

UPDATED

WO-2015054976

SUZHOU VIGONVITA LIFE SCIENCES CO., LTD. [CN/CN]; 398, Ruoshui Road, Suzhou Industrial Park Suzhou, Jiangsu 215123 (CN).
TOPHARMAN SHANGHAI CO., LTD. [CN/CN]; 1088, Chuansha Road, Pudong Shanghai 201209 (CN).
SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES [CN/CN]; 555, Zuchongzhi Road, Zhangjiang, Pudong Shanghai 201203 (CN)

(EN)The present invention relates to methods of preparing brexpiprazole, analogs thereof, key intermediates and salts thereof. Specifically, the present invention relates to new methods of preparing brexpiprazole, analogs thereof, key intermediates and salts thereof, and to the key intermediates and salts thereof used in the methods. The methods involve mild reaction conditions, stable intermediates, easy operations, and widely available reagents, thereby allowing for reduced synthesis costs, a shortened production cycle, high yield, and high product quality. The methods are suited for use in large-scale production.

Bray prazosin (Brexpiprazole, code: OPC-34712) is Otsuka Pharmaceutical Co., Ltd. developed a new generation of anti-psychotic drug candidates that act on more than one receptor, dopamine D2 receptor partial agonist (improving positive and negative symptoms, cognitive impairment and depressive symptoms), 5-HT2A receptor antagonist (improving negative symptoms, cognitive dysfunction, symptoms of depression, insomnia), α1 adrenoceptor antagonists (improving positive symptoms of schizophrenia), 5 – serotonin uptake / reuptake inhibitors (symptoms of depression); at the same time, but also a 5-HT1A partial agonist (anxiolytic and antidepressant activity) and 5-HT7 antagonist (temperature, circadian rhythms, learning and memory, sleep) . Currently, in the United States and Europe as an adjunctive treatment of severe depression (MDD) Phase III clinical trials; III clinical trials the treatment of schizophrenia in the United States, Europe and Japan, meanwhile, is still the United States II Adult ADHD clinical trials.

Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2006112464A1 in the preparation route Bray prazosin, see Scheme 1, the difficulty of the route is the first step in the reaction by-products easily separated by column chromatography is not easy to obtain high-purity intermediates, thus affecting the final product Bray prazosin purity and yield.

Scheme 1:

Subsequently, Otsuka Pharmaceutical Co., Ltd. are disclosed in PCT Application WO2013015456A1 in the alternative method of preparing the reaction of this step, see Scheme 2, along the route of the reagents are more expensive, high-cost, environmentally unfriendly and not suitable for industrial production.

Reaction Scheme 2:

DISCLOSURE

In response to these deficiencies, an object of the present invention is to provide a new, simple operation, high yield, low cost, environmentally friendly and suitable for industrial mass production Bray prazosin and the like, key intermediates and preparing a salt thereof.

Another object of the present invention is to provide novel compounds and salts thereof of the manufacturing process.

To achieve the above objects, the present invention provides compounds of formula I, the structure is as follows:

Wherein, R is C1 ~ C6 straight or branched chain alkyl, benzyl; preferably, R is C1 ~ C4 straight or branched chain alkyl group; most preferably, R is methyl, ethyl, t-butyl group;

R ₁ is acyl amino-protecting groups (e.g. formyl ( ), an acetyl group, a propionyl group, a benzoyl group, haloacetyl group, phthaloyl) or class alkoxycarbonyl amino-protecting group (e.g. t-butoxycarbonyl , benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl); said haloacetyl group is a fluorinated acetyl, bromoacetyl, chloroacetyl or iodoacetyl group; preferably, R ₁ is formyl, acetyl and tert-butoxycarbonyl groups;

The present invention also provides a method for preparing a compound of formula I, the compound of formula II with a thioglycolate as shown in the reaction, the compound, the method shown in Formula I as shown in Scheme 3,

Reaction Scheme 3:

Wherein, X is halogen, such as fluorine, chlorine, bromine, iodine; R and R ₁ are as defined above, the compound of formula I as defined the same;

The above reaction in the presence of a base, in particular, is an inorganic base (e.g. sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium hydrogen carbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydroxide, etc.) or an organic base (e.g. sodium alkoxide, potassium alkoxide, butyl lithium, 1,8-diazabicyclo [5,4 0] undecene -7 (DBU), pyridine, quinoline, 4-dimethylaminopyridine (DMAP) or an organic amine, etc.) performed in the presence of, wherein the sodium alkoxide may be sodium methoxide, sodium ethoxide, propoxy sodium alkoxide, sodium isopropoxide, n-butoxide, sodium tert-butoxide and the like; may be the potassium alkoxide, potassium methoxide, potassium ethoxide, potassium-propanol, potassium isopropoxide, n-butoxide, potassium tert-butoxide , the organic amine may be triethylamine, diethylamine, n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, etc., preferably, the base may be an inorganic alkali sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide, sodium hydroxide, or organic bases as sodium methoxide, sodium ethoxide, tert-butoxide potassium, triethylamine, diethylamine, diisopropylamine or diisopropylethylamine;

The above reaction is carried out in a suitable solvent, the solvent is water, C ₁ ~ C ₅ lower alcohol (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-amyl alcohol, amyl alcohol, ethylene glycol, propylene glycol, glycerol), N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, N- methylpyrrolidone, methylene chloride, chloroform, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or ethylene glycol monomethyl ether, and the like, one or more, preferably, the solvent is water , methanol, ethanol, N, N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane or ethylene glycol dimethyl ether or a species; the reaction time from 1 hour to 24 hours, preferably 2 hours to 12 hours. The reaction temperature is 0 ℃ ~ 150 ℃, preferably room temperature ~ 100 ℃.

To achieve the above object, the present invention also provides a compound of formula III, is structured as follows:

Wherein, R ₁ is acyl amino protecting groups (e.g. formyl, acetyl, propionyl, benzoyl, halo acetyl, phthaloyl) or class alkoxycarbonyl amino-protecting group (e.g. t-butoxycarbonyl , benzyloxycarbonyl, 9-fluorenyl methoxycarbonyl), said haloacetyl group is a fluorinated acetyl, bromoacetyl, chloroacetyl or iodoacetyl;

Preferably, R ₁ is formyl, acetyl or t-butoxycarbonyl;

The present invention also provides a method of preparing compounds of Formula III are shown, thioglycolic acid compound and reacting compound of formula III as shown in the method shown by the formula II as shown in Scheme 4,

Scheme 4:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ as defined above, with a compound of formula I as defined the same;

Scheme 5:

Wherein, X is fluorine, chlorine, bromine or iodine; R ₁ are the same as defined in the compounds illustrated and R are as defined above for formula I. The present invention also provides processes for preparing key intermediates Bray prazosin or a salt thereof, the method as shown in Scheme 6:

Scheme 6:

14- (3-chloro-2-carboxaldehyde-phenyl-1 -) – Reference Example Synthesis of piperazine-1-carboxylic acid tert-butyl ester

A mixture of 2-chloro-6-fluorobenzaldehyde (500mg, 3.15mmol), piperazine-1-carboxylate (646mg, 3.47mmol) was dissolved in N, N- dimethylformamide (5mL), and nitrogen at, at room temperature was added potassium carbonate (2.18g, 15.77mmol), the mixture was stirred for 4 hours at 80 ℃, cooled and filtered, water (20mL), ethyl acetate (3 × 5mL) was extracted, dried over anhydrous sodium sulfate, filtered The desiccant was concentrated to give a solid, after with petroleum ether (50mL) beating 1h, filtered to give a pale yellow solid (750mg, 75% yield).

¹ HNMR (400 MHz, CDCl ₃ ): δ10.37 (s, 1H), 7.40 (t, 1H), 7.01 (d, 1H), 6.99 (d, 1H), 3.20 (m, 4H), 3.00 (s, 4H), 1.47 (s, 9H) ESI: [M + 1] ⁺ = 325.8.

Reference Example 21- carboxylic acid (3-chloro-2-carboxaldehyde-phenyl-1 -) – -4- piperazine

A mixture of 2-chloro-6-fluorobenzaldehyde (500mg, 3.15mmol), 1- formyl piperazine (396mg, 3.47mmol) was dissolved in DMF (5mL), and under nitrogen at room temperature was added potassium carbonate (2.18g, 15.77mmol). The mixture was stirred for 4 hours at 80 ℃, cooled water (20mL), ethyl acetate (3 × 5mL) was extracted, dried over anhydrous sodium sulfate, and concentrated to give a solid with petroleum ether (50mL) After beating 1h, filtered to give a pale yellow solid (588mg, yield 70%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 10.45 (s, 1H), 8.13 (s, 1H), 7.44 (t, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 3.80 (s, 2H), 36.4 (s, 2H), 3.10 (m, 4H) ESI: [M + 1] ⁺ = 253.1.

Acetyl-31- (3-chloro-2-carboxaldehyde-phenyl-1 -) – 4- Reference piperazine

A mixture of 2-chloro-6-fluorobenzaldehyde (500mg, 3.15mmol), 1- acetyl-piperazine (444mg, 3.47mmol) was dissolved in DMF (5mL), and under nitrogen at room temperature was added potassium carbonate (2.18g, 15.77 mmol), the mixture was stirred at 80 ℃ 4 hours, cooled and filtered, water (20mL), ethyl acetate (3 × 5mL) was extracted, dried over anhydrous sodium sulfate, and concentrated to give a solid, after with petroleum ether (50mL) beating 1h, filtered to give a pale yellow solid (588mg, yield 70%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 10.44 (s, 1H), 7.44 (t, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 3.79 (bs, 4H), 3.10 (m, 4H), 2.18 (s, 3H) ESI: [M + 1] ⁺ = 267.1.

Piperazine-1-carboxylic acid tert-butyl ester – 14- (2-ethoxycarbonyl phenyl and thien-4-yl) Example

Under nitrogen, to N, was added the product (1.0g, 3.08mmol) of Reference Example 1 N- dimethylformamide (5mL) at room temperature within, ethyl thioglycolate (388mg, 3.20mmol), potassium carbonate (1.38 g, 10mmol), the mixture was stirred for 4 hours at 80 ℃, cooled and filtered, water (20mL), ethyl acetate (3x5mL) was extracted, dried over anhydrous sodium sulfate, the drying agent filtered, and concentrated to give a solid with petroleum ether (50mL ) after beating 1h, filtered to give a pale yellow solid (900mg, 75% yield).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Example 24- (2-carboxy-benzothiophen-4-yl) – piperazine-1-carboxylate Synthesis of

Of the product (1.0g, 2.5mmol) in Example 1 was dissolved into 1,4-dioxane (5mL), was added 4N aqueous sodium hydroxide solution (1.8mL, 7.2mmol), the mixture was stirred for 3h at 80 ℃, cooled to room temperature, water (5mL) and ethyl acetate (10mL), separated and the aqueous phase with 1N HCl at 0 ℃ pH was adjusted to about 4.0, the resulting solid was filtered, dried to give a pale yellow solid.

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.98 (s, 1H), 7.64 (d, 1H), 7.42 (t, 1H), 6.95 (d, 1H), 3.53 (bs, 4H), 3.035 ( bs, 4H) ESI: [M-1] ^– = 361.1.

34- (benzothiophen-4-yl) Example – Synthesis of piperazine-1-carboxylic acid tert-butyl ester

The product of Example 2 (20g, 54mmol) will be implemented, cuprous oxide (1g, 7mmol) was dissolved in quinoline (50mL) inside, heated to 140 ℃ overnight. After cooling and filtration, the filtrate was added water, extracted with ethyl acetate, the organic phase was washed with 1N HCl to slightly acidic, saturated aqueous sodium bicarbonate solution, purified by silica gel column chromatography, the concentrated solid slurried with petroleum ether to give an off-white solid (13g, yield 70%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 7.57 (d, 1H), 7.41 (s, 2H), 7.27 (t, 1H), 6.88 (d, 1H), 3.66 (m, 4H), 3.01 (m, 4H), 1.50 (s, 9H) ESI: [M + 1] ⁺ = 319.1.

44- (benzothiophene-4-yl) Example – Synthesis of piperazine-1-carboxylic acid tert-butyl ester

The product of Example 2 (500mg, 1.35mmol) will be implemented, silver carbonate (40mg, 0.135mmol) and acetic acid (8mg) was dissolved in dimethylsulfoxide (5mL) inside, heated to 120 ℃, the reaction overnight, cooled and filtered, and the filtrate Water was added, extracted with ethyl acetate, and concentrated by column chromatography to obtain the target substance.

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 7.57 (d, 1H), 7.41 (s, 2H), 7.27 (t, 1H), 6.88 (d, 1H), 3.66 (m, 4H), 3.01 (m, 4H), 1.50 (s, 9H) ESI: [M + 1] ⁺ = 319.1.

Piperazine hydrochloride – 51- (benzothiophen-4-yl) Example

At room temperature, the product of Example 3 will be implemented (2g, 6.2mmol) was dissolved in dioxane (6mL) was added 4N HCl / dioxane (6mL), stirred 3h, concentrated to dryness, the residue was beating ethyl acetate, filtered to obtain the target substance (1.3g, 95% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 7.75 (d, 1H), 7.69 (d, 1H), 7.53 (t, 1H), 7.31 (t, 1H), 6.97 ( t, 1H), 3.30 (bs, 8H) ESI: [M + 1] ⁺ = 219.2.

Example 61- formyl-4- (2-ethoxycarbonyl phenyl and thien-4-yl) – piperazine Synthesis

In N ₂ protected, at room temperature was added the product of Reference Example 2 to DMF (5mL) inside (1.0g, 3.7mmol), ethyl thioglycolate (410mg, 3.80mmol), potassium carbonate (1.38g, 10mmol), the mixture 80 ℃ stirred for 4 hours. Cooling water was added (20mL), ethyl acetate (3 × 5mL) was extracted, dried over anhydrous sodium sulfate, and concentrated to give a solid with petroleum ether (50mL) After beating 1h, filtered to give a pale yellow solid (1.0 g, yield 83%).

¹ HNMR (400 MHz, CDCl3): [delta] 8.15 (d, 2H), 7.59 (d, 1H), 7.41 (t, 1H), 6.94 (d, 1H), 4.44 (q, 2H), 3.85 (t, 2H ), 3.68 (t, 2H), 3.21-3.15 (m, 4H), 1.44 (t, 3H) ESI: [M + 1] ⁺ = 319.1.

Example 71- formyl-4- (2-carboxy-benzothiophen-4-yl) – piperazine

The product (1.0g, 3.1mmol) of Example 6 was dissolved in methanol (5mL) and water (2mL) the addition of lithium hydroxide (420mg, 10mmol), the mixture was stirred at room temperature for 5h, was added water (5mL) and acetic acid ethyl ester (10mL), extracted, the aqueous phase was collected, the pH was adjusted to about 4.0 at 0 ℃ with 1N HCl solution, the precipitated solid was filtered and dried to give a pale yellow solid (510mg, 56% yield).

ESI: [M-1] ^– = 289.1.

Example 81- formyl (benzothiophen-4-yl) -4 – piperazine

The product (1.0g, 3.4mmol) Example 7 will be implemented, cuprous oxide (50mg) was dissolved in quinoline (5mL) inside, heated to 140 ℃ overnight. After cooling and filtration, water was added, extracted with ethyl acetate, the organic phase was washed with aqueous 1N HCl to slightly acidic, then with saturated aqueous sodium bicarbonate solution, and concentrated by silica gel column chromatography, the resulting solid was slurried with petroleum ether to give white solid (520mg, 62% yield).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.15 (s, 1H), 7.62 (d, 1H), 7.42 (m, 2H), 7.31 (t, 1H), 6.04 (d, 1H), 3.82 (t, 2H), 3.63 (t, 2H), 3.19-3.12 (m, 4H) ESI: [M + 1] ⁺ = 247.1.

Example 91- (benzothiophen-4-yl) – piperazine hydrochloride

A mixture of the product of Example 8 (500mg) was dissolved in dioxane (2mL) was added 4N HCl / dioxane (3mL), stirred 3h, concentrated to dryness, slurried with ethyl acetate, filtered to give the target (470mg, yield 90%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 7.75 (d, 1H), 7.69 (d, 1H), 7.53 (t, 1H), 7.31 (t, 1H), 6.97 ( t, 1H), 3.30 (bs, 8H) ESI: [M + 1] ⁺ = 219.2.

Example 10 1-Acetyl-4- (2-ethoxycarbonyl phenyl and thien-4-yl) – piperazine Synthesis

Under the protection of N2, at room temperature was added the product of Reference Example 3 (1.0g, 3.74mmol) to DMF (5mL) inside, ethyl thioglycolate (388mg, 3.20mmol), potassium carbonate (1.38g, 10mmol), the mixture was 80 ℃ stirred for 4 hours, cooled water was added (20mL), ethyl acetate (3 × 5mL) was extracted, dried over anhydrous sodium sulfate, and concentrated to give a solid with petroleum ether (50mL) beating 1h, filtered to give a pale yellow solid (863mg, yield 70%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.17 (s, 1H), 7.60 (d, 1H), 7.42 (t, 1H), 7.01 (d, 1H), 4.44 (q, 2H), 3.94 (br, 2H), 3.80 (br, 2H), 3.21 (br, 4H), 2.19 (s, 3H), 1.44 (t, 3H) ESI: [M + 1] ⁺ = 333.3.

Example 11 1-Acetyl-(2-carboxy-benzothiophen-4-yl) -4 – piperazine

The product (1.0g, 3.0mmol) from Example 10 was dissolved in methanol (5mL) and water (2mL) the addition of lithium hydroxide (300mg, 7.2mmol), the mixture was stirred at rt for 3h, water was added (5mL) and ethyl acetate ester (10mL), separated and the aqueous phase was collected, the pH adjusted with aqueous 1N HCl at 0 ℃ to about 4.0, and the precipitated solid was filtered, dried to give a pale yellow solid (820mg, yield 90%).

ESI: [M-1] ^– = 303.1.

Example 12 1-Acetyl-4- (benzothiazol-4-yl) – piperazine

The product of Example 11 (1.0g, 3.2mmol), cuprous oxide (50mg) was dissolved in quinoline (5mL) inside, heated to 140 ℃ overnight. After cooling and filtration, water was added, extracted with ethyl acetate, washed with 1N HCl solution was added to a weak acid, a saturated aqueous solution of sodium bicarbonate, silica gel column chromatography, and concentrated to give a solid slurried with petroleum ether to give a white solid (600mg , yield 70%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.95 (s, 1H), 7.65 (d, 1H), 7.41 (t, 1H) 6.95 (d, 1H), 3.69 (q, 4H), 3.10 (t , 2H), 3.02 (t, 2H), 2.06 (s, 3H) ESI: [M + 1] ⁺ = 261.1.

EXAMPLE 131- (benzothiophen-4-yl) – piperazine hydrochloride

A mixture of the product of Example 12 (1g, 3.8mmol) was dissolved in dioxane (6mL) was added 4N HCl / dioxane (6mL), stirred 3h, concentrated dry, with ethyl beating, filtered to give the product (870mg, yield 90%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 7.75 (d, 1H), 7.69 (d, 1H), 7.53 (t, 1H), 7.31 (t, 1H), 6.97 ( t, 1H), 3.30 (bs, 8H) ESI: [M + 1] ⁺ = 219.2.

141- (benzothiophen-4-yl) Example – piperazine

The product of (500mg, 1.38mmol) of Example 2 was dissolved in quinoline (3mL) the addition of cuprous oxide (20mg), the reaction temperature was raised to 140 ℃ After 2h, the reaction continues to heat up to 240 ℃ 3h, cooled to room temperature, filtered , water was added, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, silica gel column chromatography, and concentrated to give the desired product. ¹ HNMR (300 MHz, DMSO-d ₆ ): [delta] 8.74 (bs, 1H), 7.75 (d, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.31 (t, 1H), 6.95 ( d, 1H), 3.24 (m, 8H) ESI: [M + 1] ⁺ = 219.2.

Example 15 7- [4- (2-carboxy-4-yl-benzothiophene-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone Preparation of

7- [4- (2-ethoxycarbonyl-4-phenyl and thienyl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone (300mg, 0.59 mmol) was dissolved in methanol (3mL) and water (1mL) was added lithium hydroxide (76mg, 1.8mmol), stirred at rt for 3h, ethyl acetate was added, the aqueous phase was adjusted with 1N dilute hydrochloric acid to about pH 4.0, using bis dichloromethane: methanol (10: 1) extraction, concentration did a white solid (210mg, 46% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 10.01 (s, 1H), 7.88 (s, 1H), 7.61 (d, 1H), 7.38 (t, 1H), 7.03 (q, 1H), 6.93 ( d, 1H), 6.48 (m, 2H), 3.92 (m, 4H), 3.35 (s, 4H), 2.84 (s, 4H), 2.77 (s, 2H), 2.62 (s, 2H), 1.72 (m , 4H), ESI: [M-1] ^– = 478.3.

EXAMPLE 167- [4- (benzothiazol-4-yl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone Preparation of

The product (500mg, 1.04mmol) of Example 15 will be implemented, cuprous oxide (50mg) was dissolved in quinoline (5mL) inside, heated to 140 ℃ overnight. After cooling and filtration, water was added, extracted with ethyl acetate, washed with 1N HCl solution was added until pH = 4.0, dichloromethane: methanol (10: 1) extracted, dried over anhydrous sodium sulfate, and silica gel column chromatography to give a solid (320mg , yield 70%).

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 17 4- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen at room temperature was added to ethanol (5mL) within the reference product (200mg, 0.62mmol) of Example 1, ethyl mercaptoacetate (0.081ml, 0.74mmol), potassium carbonate (342mg, 2.48mmol), the mixture was 85 ℃ stirred for 18 hours, concentrated, and column chromatography to obtain the target substance (100mg, 42% yield).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 18 4- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen, was added at room temperature to DMF (5mL) within the reference product (200mg, 0.62mmol) of Example 1, ethyl mercaptoacetate (0.081ml, 0.74mmol), DIPEA (342mg, 2.48mmol), the mixture was at 105 ℃ stirred for 18 hours, 1N HCl solution was added adjust the pH = 7, and extracted with methyl tert-butyl ether, the ether layer was then washed three times with saturated brine, dried over anhydrous sodium sulfate, the drying agent filtered, and concentrated by column chromatography to obtain the target (170mg, yield 71%).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – Example 19 4- (2-ethoxycarbonyl phenyl and thien-4-yl)

Under nitrogen at room temperature was added the product of Reference Example 1 to ethanol (5mL) inside (200mg, 0.62mmol), ethyl mercaptoacetate (0.081ml, 0.74mmol), sodium hydroxide (100mg, 2.48mmol), the mixture 85 ℃ stirred for 6 hours, concentrated to column chromatography to obtain the target substance (70mg, 30% yield).

¹ HNMR (400 MHz, CDCl ₃ ): [delta] 8.40 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 6.95 (d, 1H), 4.44 (q, 2H), 3.64 (m, 4H), 3.15 (m, 4H) ESI: [M + 1] ⁺ = 391.1.

Piperazine hydrochloride – (2-carboxy-benzothiophen-4-yl) Example 201-

The product of Example 2 (200mg, 0.55mmol), was dissolved in THF (5mL), concentrated hydrochloric acid (0.5mL), 50 ℃ heated 6h. Cooling, methyl tert-butyl ether (5mL), filtered to give the target (130mg, yield 79%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 8.04 (s, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.00 (d, 1H), 3.30 ( bs, 8H) ESI: [M + 1] ⁺ = 262.9.

Piperazine hydrochloride – (benzothiophene-4-yl) Example 211-

The product of Example 20 (130mg, 0.43mmol) was added to diphenyl ether (3mL) in, 260 ℃ heating 0.5h. Cooled and filtered to give the object (60mg, 55% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 7.75 (d, 1H), 7.69 (d, 1H), 7.53 (t, 1H), 7.31 (t, 1H), 6.97 ( t, 1H), 3.30 (bs, 8H) ESI: [M + 1] ⁺ = 219.2.

Preparation of tert-butyl piperazine-1 – Example 224- (2-carboxy-benzothiophen-4-yl)

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.98 (s, 1H), 7.64 (d, 1H), 7.42 (t, 1H), 6.95 (d, 1H), 3.53 (bs, 4H), 3.035 ( bs, 4H) ESI: [M-1] ^– = 361.1.

Preparation of piperazine-1-carboxylic acid tert-butyl ester – (2-carboxy-benzothiophen-4-yl) Example 234-

Under nitrogen, to N, at room temperature was added N- dimethylformamide (5mL) within the reference product (200g, 0.62mmol) of Example 1, thioglycolic acid (114mg, 1.23mmol), sodium hydroxide (99mg, 2.45 mmol), the mixture was stirred at 105 ℃ 18 hours. Cooling, water was added, extracted with ethyl acetate, separated and the aqueous phase was adjusted pH = 5 or so, the precipitated solid was filtered and dried to obtain the target substance (180mg, yield 81%).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 7.98 (s, 1H), 7.64 (d, 1H), 7.42 (t, 1H), 6.95 (d, 1H), 3.53 (bs, 4H), 3.035 ( bs, 4H) ESI: [M-1] ^– = 361.1.

Example 24 7- [4- (2-ethoxycarbonyl-4-phenyl and thienyl-1-piperazinyl) butoxy] -2 (1H) – quinolinone Preparation of

2-chloro-6- (4- (4 – ((2-oxo-1,2-dihydro-quinolin-7-yl) oxy) butyl) piperazin-1-yl) benzaldehyde (80mg , 0.18mmol) was dissolved in DMF (5mL) was added DIPEA (94mg, 0.73mmol) and ethyl mercaptoacetate (0.024mL, 0.22mmol), 110 ℃ stirred for 16 hours.Cooling, water was added, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and silica gel column chromatography to give a solid (40mg, 46% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): δ11.69 (s, 1H), 11.24 (s, 1H), 8.09 (s, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.57 ( d, 1H), 7.48 (t, 1H), 7.04 (d, 1H), 6.82 (m, 2H), 6.30 (d, 1H), 4.32 (m, 4H), 4.06 (t, 2H), 3.67-3.16 (m, 8H), 1.96 (m, 2H), 1.84 (m, 2H), 1.32 (t, 3H) ESI: [M + 1] ⁺ = 506.4.

Example 25 7- [4- (2-carboxy-4-yl-benzothiophene-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone Preparation of

7- [4- (2-ethoxycarbonyl-4-phenyl and thienyl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone (100mg, 0.19 mmol) was dissolved in acetic acid (3mL) and concentrated hydrochloric acid (0.5mL), 100 ℃ stirred for 10 hours. The reaction mixture was poured into ice water, stirred for 10min after filtration, to obtain the target substance (40mg, 43% yield).

Example 26 7- [4- (benzothiazol-4-yl-1-piperazinyl) butoxy] -3,4-dihydro -2 (1H) – quinolinone Preparation of

The product (400mg, 0.83mmol) of Example 25 will be implemented, silver carbonate (46mg, 0.16mmol) was dissolved in DMSO (5mL) and the acetic acid was heated to 120 ℃ overnight. Cooling, water was added, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine again each wash, dried over anhydrous sodium sulfate, and silica gel column chromatography to give a solid (80mg, yield 22%).

Example 27 7- [4- (2-carboxy-4-yl-benzothiophene-1-piperazinyl) butoxy] -2 (1H) – quinolinone Preparation of

2-chloro-6- (4- (4 – ((2-oxo-1,2-dihydro-quinolin-7-yl) oxy) butyl) piperazin-1-yl) benzaldehyde (80mg , 0.18mmol) was dissolved in DMF (5mL) was added sodium hydroxide (29mg, 0.73mmol) and thioglycolic acid (0.025mL, 0.36mmol), 120 ℃ stirred for 16 hours. Cooling, water was added, adjusted with 1N HCl aqueous solution is about pH = 5, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and silica gel column chromatography to give a solid (40mg, yield 46 %).

ESI: [M + 1] ⁺ = 478.0.

Piperazine hydrochloride – (2-carboxy-benzothiophen-4-yl) Example 28 1-

The product of Example 17 (100mg, 0.25mmol) was dissolved in acetic acid (3mL) and concentrated hydrochloric acid (0.5 mL) in, 100 ℃ stirred for 10 hours. The reaction mixture was poured into ice water, stirred for 10min after suction filtration to give the object (38mg, 50% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ): [delta] 9.46 (bs, 2H), 8.04 (s, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.00 (d, 1H), 3.30 ( bs, 8H) ESI: [M + 1] ⁺ = 262.9.

uUpdate july 2015

On July 10, the U.S. Food and Drug Administration approved Rexulti (brexpiprazole) tablets to treat adults with schizophrenia and as an add-on treatment to an antidepressant medication to treat adults with major depressive disorder (MDD).

Schizophrenia is a chronic, severe, and disabling brain disorder affecting about one percent of Americans. Typically, symptoms are first seen in adults younger than 30 years of age and include hearing voices; believing other people are reading their minds or controlling their thoughts; and being suspicious or withdrawn.

MDD, commonly referred to as depression, is also a severe and disabling brain disorder characterized by mood changes and other symptoms that interfere with a person’s ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person’s lifetime, although some may experience a single occurrence. Other signs and symptoms of MDD include loss of interest in usual activities; significant change in weight or appetite; insomnia or excessive sleeping (hypersomnia); restlessness/pacing (psychomotor agitation); increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; and suicide attempts or thoughts of suicide. Not all people with MDD experience the same symptoms.

“Schizophrenia and major depressive disorder can be disabling and can greatly disrupt day-to-day activities,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Medications affect everyone differently so it is important to have a variety of treatment options available for patients with mental illnesses.”

The effectiveness of Rexulti in treating schizophrenia was evaluated in 1,310 participants in two 6-week clinical trials. Rexulti was shown to reduce the occurrence of symptoms of schizophrenia compared to placebo (inactive tablet).

The effectiveness of Rexulti as an add-on treatment for MDD was evaluated in two 6-week trials that compared Rexulti plus an antidepressant to placebo plus an antidepressant in 1,046 participants for whom an antidepressant alone did not adequately treat their symptoms. The participants taking Rexulti reported fewer symptoms of depression than those taking the placebo.

Rexulti and other drugs used to treat schizophrenia have a Boxed Warning alerting health care professionals about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

The Boxed Warning also alerts health care professionals and patients to an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. Rexulti must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The most common side effects reported by participants taking Rexulti in clinical trials included weight gain and an inner sense of restlessness, such as feeling the need to move.

Rexulti is manufactured by Tokyo-based Otsuka Pharmaceutical Company Ltd.

update………….

4-Chlorobenzo[b]thiophene a key intermediate in brexpiprazole synthesis

We established an improved synthetic route to 4-chlorobenzo[b]thiophene, a key intermediate in brexpiprazole synthesis, via a practical decarboxylation process in three steps. Thermal analysis demonstrated that the coexistence of the decarboxylated product with DBU should be avoided and that removal of the product outside the reactor was vital. Our process yields the target compound by distillation under reduced pressure and is safe, highly batch efficient, cost-effective, and high yielding. Furthermore, manufacturing on a pilot scale was also accomplished through our approach.

4-Chlorobenzo[b]thiophene-2-carboxylic Acid (4)

4 as a white solid

mp 260 °C.

1H NMR (300 MHz, DMSO-d6) δ 7.54 (d, 1H, J = 11.6, 7.7 Hz), 7.56 (dd, 1H, J = 17.8, 7.7 Hz), 8.03 (d, 1H, J = 0.7 Hz), 8.07 (td, 1H, J = 7.6, 0.9 Hz), 13.19 (brs, 1H).

13C NMR (75 MHz, DMSO-d6) δ 122.21, 125.01, 126.84, 127.99, 128.96, 136.50, 136.57, 142.55, 163.10.

Elemental analysis calcd for C: 50.83%, H: 2.37%, found C: 50.84%, H: 2.21%.

2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium 4-Chlorobenzo[b]thiophene-2-carboxylate 5

5 as a white solid

Mp 182.5 °C.

1H NMR (300 MHz, CDCl3) δ 1.66 (m, 6H), 1.80–1.75 (m, 2H), 2.98–2.94 (m, 2H), 3.45–3.39 (m, 4H), 3.55–3.51 (m, 2H), 7.31–7.20 (m, 2H), 7.69 (dd, 1H, J = 3.9, 0.6 Hz), 7.97 (s, 1H), 13.19 (brs, 1H).

13C NMR (75 MHz, CDCl3) δ 19.51, 24.03, 26.70, 28.88, 31.99, 38.01, 48.36, 53.94, 121.04, 123.00, 125.17, 126.61, 128.98, 138.21, 142.43, 146.85, 165.91, 167.20.

Elemental analysis calcd for C: 59.25%, H: 5.80%, N: 7.68%, found C: 59.10%, H: 5.44%, N: 7.53%.

4-Chlorobenzo[b]thiophene (2)

1H NMR (300 MHz, CDCl3) δ 7.26 (t, 1H, J = 7.8 Hz), 7.36 (dd, 1H, J = 7.8, 0.9 Hz), 7.50 (d, 1H, J = 5.7 Hz), 7.52 (d, 1H, J = 5.7 Hz), 7.76 (d, 1H, J = 7.8 Hz).

13C NMR (75 MHz, CDCl3) δ 121.12, 122.40, 125.02, 127.43, 128.93, 138.06, 141.07.

Elemental analysis calcd for C: 56.98%, H: 2.99%, found C: 56.76%, H: 2.94%.

SEE

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00340

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00340/suppl_file/op5b00340_si_001.pdf

Safe and Efficient Decarboxylation Process: A Practical Synthetic Route to 4-Chlorobenzo[b]thiophene

Masahiro Miyake^*, Masamichi Shimizu, Koichi Tsuji, and Keiichi Ikeda

Bulk Pharmaceutical Chemicals Department, Second Tokushima Factory, Production Headquarters, Otsuka Pharmaceutical Co., Ltd., 224-18, Hiraishi Ebisuno, Kawauchi-cho, Tokushima 771-0182, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00340

Japanese filing for Amgen’s PCSK9 inhibitor Repatha

March 23, 2015 7:39 am / Leave a comment

Amgen has filed its closely watched PCSK9 inhibitor Repatha (evolocumab) in Japan for the treatment of high cholesterol.

Repatha is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C), or ‘bad’ cholesterol, from the blood.

Evolocumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	PCSK9
Clinical data
Legal status	Investigational
Routes of administration	Subcutaneous injection
Identifiers
CAS Registry Number	1256937-27-5
ATC code	C10AX13
Chemical data
Formula	C₆₂₄₂H₉₆₄₈N₁₆₆₈O₁₉₉₆S₅₆
Molecular mass	141.8 kDa

Evolocumab^[1] (also known as compound number AMG-145 or AMG145)^[2] is a monoclonal antibody designed for the treatment of hyperlipidemia.^[3] Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).

PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver’s ability to remove LDL-C, or “bad” cholesterol, from the blood.

Evolocumab, being developed by Amgen scientists, is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.

Clinical trials

Two trials have been in progress as at mid-2014:

On 23 January 2014 Amgen announced that the Phase 3 GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial evaluating evolocumab in patients with high cholesterol who cannot tolerate statins met its co-primary endpoints: the percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. The mean percent reductions in LDL-C, or “bad” cholesterol, compared to ezetimibe were consistent with results observed in the Phase 2 GAUSS study.^[4]^[5]

The GAUSS-2 trial evaluated safety, tolerability and efficacy of evolocumab in 307 patients with high cholesterol who could not tolerate effective doses of at least two different statins due to muscle-related side effects. Patients were randomly assigned to one of four treatment groups: subcutaneous evolocumab 140 mg every two weeks and oral placebo daily; subcutaneous evolocumab 420 mg monthly and oral placebo daily; subcutaneous placebo every two weeks and oral ezetimibe 10 mg daily; or subcutaneous placebo monthly and oral ezetimibe 10 mg daily.

Safety was generally balanced across treatment groups. The most common adverse events (> 5 percent in evolocumab combined group) were headache (7.8 percent evolocumab; 8.8 percent ezetimibe), myalgia (7.8 percent evolocumab; 17.6 percent ezetimibe), pain in extremity (6.8 percent evolocumab; 1.0 percent ezetimibe), and muscle spasms (6.3 percent evolocumab; 3.9 percent ezetimibe).

Cholesterol-lowering treatment with a statin as part of follow-up care can help reduce a patient’s risk after myocardial infarction, ischaemic stroke or TIA.

The FOURIER Phase 3 clinical study http://www.fourierstudy.com/ seeks to find out whether lowering cholesterol by an additional 50% might reduce this risk even further. Several sites in the UK are part of this very large clinical study, lasting up to five years, and it is hoped that the study will help guide future clinical practice.

Evolocumab (also formerly known as AMG145, from Amgen) binds to PCSK9, a natural protein produced by the liver. By binding to PCSK9, evolocumab allows the LDL receptor (a protein present in the liver) to move LDL-cholesterol out of the bloodstream more efficiently. This study is designed to see whether treatment of dyslipidemia with evolocumab in people who have experienced a prior myocardial infarction, ischaemic stroke or TIA, and who are taking a highly effective dose of a statin, reduces the risk of recurring or additional cardiovascular events. Participants in this study have clinically evident cardiovascular disease.

READ AT

https://newdrugapprovals.org/2014/03/19/amgen-drug-evolocumab-hits-endpoint-of-cholesterol-reduction/

MY EARLIER ARTICLE

DR ANTHONY CRASTO

https://newdrugapprovals.org/

References

World Health Organization (2012). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 108” (PDF). WHO Drug Information 26 (4).
2
Sheridan, C (2013). “Phase 3 data for PCSK9 inhibitor wows”. Nature Biotechnology 31 (12): 1057–8. doi:10.1038/nbt1213-1057. PMID 24316621. edit
3
Statement On A Nonproprietary Name Adopted By The USAN Council – Evolocumab
4
Estel Grace Masangkay, “Amgen Phase III GAUSS-2 Trial of Evolocumab (AMG 145) Meets Co-Primary Endpoints Of LDL Cholesterol Reduction”, Bioresearch Online (January 24 2014)
5

Pierson, Ransdell (17 March 2014). “Amgen drug meets goal for those with high genetic cholesterol”. Associated Press. Retrieved 19 March 2014.

Daiichi partners with AZ to sell Movantik in US…….Pharmatimes, Selina McKee

March 23, 2015 7:24 am / Leave a comment

Naloxegol

Daiichi partners with AZ to sell Movantik in US

March 19, 2015

http://www.pharmatimes.com/Article/15-03-19/Daiichi_partners_with_AZ_to_sell_Movantik_in_US.aspx

Selina McKee

News editor, Selina McKee

Selina McKee

Follow @PTselinamckee

Qualified from King’s College London with BSc (hons) in Human Biology in 1999 with an interest in medical journalism. Has since held positions as a database analyst managing a portfolio of companies at Evaluate Pharma, and as news editor at Pharma Marketletter. Fluent German speaker, interests include music, piano, reading, astronomy, photography and Formula 1.

Daiichi partners with AZ to sell Movantik in US

AstraZeneca has chosen Daiichi Sankyo to help sell its novel constipation drug Movantik (naloxegol) in the US, as the firm gears up for its launch in April.

First-in-class Movantik was cleared in the US last September for the treatment of opioid-induced constipation in adults with chronic non-cancer pain, for which there is still significant unmet need.

PharmaTimes Magazine and Digital offer a unique blend of news stories, interviews, features, case studies, analysis and comment on the critical issues facing the pharma and healthcare sectors. Our wide editorial lens combined with our editorial philosophy to deliver sharp, informed and entertaining coverage from the perspective of the industry, the payer and the patient, allows PharmaTimes to help kickstart conversations that matter most to our audience of decision makers within pharma and the healthcare profession.PharmaTimes Competitions are a critical facet of our business, providing a unique opportunity for industry to showcase its most talented people in marketing, communications, sales and clinical research. No other competitions offer entrants the chance to compete head-to-head in real-life challenges devised by independent industry and healthcare experts, to test their skill sets against their peers in real time, and receive feedback to ensure the whole experience is a valuable learning process.

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Editor, UK News at PharmaTimes

London, United Kingdom

Pharmaceuticals

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Pleasures of Process Development

March 22, 2015 1:40 am / Leave a comment

Org Prep Daily

A reflux in 12 molar HCl
Carefully watched for a frothing,
Painstakingly drained from the reactor,
To strip down and scrub off that gross thing.

My bosses, I tried please believe me,
I’m doing my best as you insist,
I’m ashamed of the material I burned through,
I’m ashamed of the deadlines I missed.

But if you could just see the beauty,
These things I could never describe,
These pleasures of process perfection,
This is my one lucky prize.

refrain: Product isolation…

My apologies to Joy Division

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Sri Lankan traditional medicine

March 21, 2015 8:49 am / 2 Comments on Sri Lankan traditional medicine

Sri Lanka has its own indigenous scheme of traditional medicine (Ayurveda).^[1]^[2] This system has been practised for many centuries in the island nation. The Sri Lankan Ayurvedic tradition is a mixture of the Sinhala traditional medicine, Ayurveda and Siddha systems of India, Unani medicine of Greece through the Arabs, and most importantly, theDesheeya Chikitsa, which is the indigenous medicine of Sri Lanka.

History

Sri Lanka developed its own Ayurvedic system based on a series of prescriptions handed down from generation to generation over a period of 3,000 years. The ancient kings, who were also prominent physicians, sustained its survival and longevity. King Buddhadasa (398 AD), the most influential of these physicians, wrote the Sarartha Sangrahaya, a comprehensive manuscript which Sri Lankan physicians still use today for reference.

Sri Lanka

Ancient inscriptions on rock surfaces reveal that organized medical services have existed within the country for centuries. In fact, Sri Lanka claims to be the first country in the world to have established dedicated hospitals. The Sri Lankan mountain Mihintale still has the ruins of what many believe to be the first hospital in the world. Old hospital sites now attract tourists, who marvel at the beautiful ruins. These places have come to symbolize a traditional sense of healing and care, which was so prevalent at that time.

Historically the Ayurvedic physicians enjoyed a noble position in the country’s social hierarchy due to their royal patronage. From this legacy stems a well-known Sri Lankan saying: “If you can not be a king, become a healer.” Along with Buddhism, the interrelationship between Ayurveda and royalty continues to influence politics in Sri Lanka.

Four systems of traditional medicine have been adopted in Sri Lanka: Ayurveda, Siddha, Unani and Deshiya Chikitsa. The Ayurveda and Deshiya Chikitsa systems use mainly plant and herbal preparations for the treatment of diseases–the former uses about 2000 species, the latter about 500. The plants are used singly or as mixtures.

Sri Lanka Traditional Medicine පාරම්පරික සිංහල වෙදකම

The traditional systems of medicine have a vast literature, mainly in the form of manuscripts. The principle of the Ayurvedic system is to consider the body as a whole, ailments of different organs not being treated separately as in modern medicine. Similarly, Ayurveda takes into account the actions of the drug in its entirety.

Research therefore must be carried out in hospitals or biological laboratories and not in chemical laboratories where plant extracts are subject inevitably to chemical reactions. Therefore the chemical approach to identify active principles is a complete deviation from the principles of traditional medicine. Research on plants should be carried out for the further development of traditional systems of medicine and not to their detriment.

The threat of extinction of certain species of plants and herbs is stressed, the causes being the destruction of jungles, the greater demand for raw materials for increased manufacture of traditional medicinal preparations, the absence of organised cultivation of medicinal plants, and unscientific harvesting. The compilation of encyclopaedias of plants used in traditional medicine is highly recommended for every country interested in preserving the traditional systems of medicine.

Traditional medicine has been practiced in Sri Lanka for 3,000 years. At present, there are four systems of traditional medical systems in Sri Lanka viz. Ayurveda, Siddha, Unani and Deshiya Chikitsa (Sri Lankan traditional treatment). The most important among them is Ayurveda, which also forms part of the national health services provided by the government of Sri Lanka including separate ministry for Indigenous Medicine. At present, Ayurveda serves a large proportion of the population with one Ayurvedic physician per 3,000 people in Sri Lanka. About 60 to 70% of the rural population relies on traditional and natural medicine for their primary health care. Therefore Herbal drugs are essential components of traditional medical system in Sri Lanka. Sri Lanka is identified as one of the most biologically diverse countries in Asia with about 20% of the area under forest. It has the highest species diversity per unit area in Asia and is one of the mega biodiversity hot spots. Therefore it is an urgent need to rationally utilize medicinal plants for curative purposes with proper maintenance of biodiversity. The government of Sri Lana has taken several initiatives to develop technology for the effective conservation and efficient utilization of medicinal plants, to coordinate research and developmental activities through the Department of Ayurveda, Bandaranayake Memorial Ayurvedic Research Institute and the Institute of Indigenous Medicine – University of Colombo. But lack of funding and some problems and constraints knowledge of herbal medical systems and its applications to cure illnesses has not been effectively explored fully by Sri Lanka. If this happens successfully, Sri Lanka could gain a very significant competitive edge in the global market, especially in the herbal medical drugs, beauty care and nutraceuticals.

There is a lot of scope for Sri Lanka to achieve higher rank in global market through export of quality products from medicinal and aromatic plants. But Sri Lanka seems to be lagging behind using advanced technology and standardization procedures in herbal products and is ranked lower in the herbal medicine global market share, while China occupies nearly 30% of the global market with high tech issues. Therefore Sri Lanka need to be focused on the quality assurance with multidisciplinary researches with in the country and collaborative works with other high tech used countries. Further Good laboratory practices (GLP) and Good manufacturing practices (GMPs) are also needed to apply for produce good quality medicinal products in Sri Lanka. Without overcoming these entire measures current scenario is not sufficient to increase the global market share of herbal drug industry and herbal medical practice for Sri Lanka.

Pathirage Kamal Perera, Guest invited speaker, Topic: Current scenario of herbal medicine in Sri Lanka, ASSOCHAM , 4th annual Herbal International Summit cum Exhibition on Medicinal & Aromatic Products, Spices and finished products(hi-MAPS) at NSIC, Okhla Industrial Estate, New Delhi on 14 -15 April,2012.

TRAVEL TO SRILANKA……..http://www.kumc.edu/Documents/history%20of%20med/Abeykoon.pdf

Works Cited 1. Waxler-Morrison NE. “Plural Medicine in Sri Lanka: Do Ayurvedic and Western Medical Practices Differ?” 1988. Web. 27 Jan. 2012. . 2. Glynn, J. R. “Factors That Influence Patients in Sri Lanka in Their Choice between Ayurvedic and Western Medicine.” British Medical Journal 291 (1985): 470-72. . 3. Jeyarajah R. “Factors That Influence Patients in Sri Lanka in Their Choice between Ayurvedic and Western Medicine.” 28 Sept. 1985. Web. 27 Jan. 2012. . 4. Ediriweera ER ER. “Clinical Study on the Efficacy of Chandra Kalka with Mahadalu Anupanaya in the Management of Pakshaghata (Hemiplegia).” Jan. 2011. Web. 27 Jan. 2012. . 5. Mano H. “Mechanisms of Blood Glucose-lowering Effect of Aqueous Extract from Stems of Kothala Himbutu (Salacia Reticulata) in the Mouse.” Jan. 2009. Web. 27 Jan. 2012. . 6. Nordstrom CR. “Exploring Pluralism–the Many Faces of Ayurveda.” 1988. Web. 27 Jan. 2012. . 7. Weerasinghe MC. “Paradox in Treatment Seeking: An Experience from Rural Sri Lanka.” Mar. 2011. Web. 27 Jan. 2012. .

The contacts of mentors and other respective sources

Commissioner of western province, Ministry of Indigenous Medicine, Sri Lanka Name- Dr. Nimal Karunasiri, Designation – Commissioner of Western Province, Ministry of Indigenous Medicine Sri Lanka Address- Ministry of Indigenous Medicine, Sri Lanka Contact information- Tel 01194777675679 Email- Nimalskl@gmail.com

National Ayurvedic Medical College and hospitals Name- Dr. R.A. Jayasinghe Designation – Director of indigenous medicine – Rajagiriya Address- National Ayurvedic Medical College, Rajagiriya, Sri Lanka Contact information- Tel +94775412312

National Ayurvedic research center Name- K.D.S. Ranaweera Designation- Professor Address- Institute Bandaranayaka Memorial Research Institute, Navinna, Sri Lanaka Contact information- Tel +942850302 or 333 /0712413537

Licensed Ayurvedic medical practitioners Name- Dr. H.A.M Sriyani Designation- Doctor of Ayurvedic Medicine Institute- Ayurvedic Hospital Address- Minipe Pradeshiya Saba (provincial level hospital), Hasalaka, Sri Lanka Contact information- Tel- 01194772865364

Name- Dr. H.P Jayadasa Designation- Doctor of Ayurvedic Medicine Institute- Gampaha Ayurvedic dispensary Address- 40. A, Rahula Road, Katubadda, Moratuwa, Sri Lanka Contact information- Tel- 01194777551389

Address of the hospital where the shadowing of doctors and interviewing patients will take placeMinipe Pradeshiya Saba (provincial level hospital) Hasalaka

References

Plunkett, Richard; Ellemor, Brigitte (2003). Sri Lanka. Lonely Planet. p. 174. ISBN 1-74059-423-1.
Petitjean, Patrick; Jami, Catherine; Moulin, Anne + – Marie (1992). Science and Empires. Springer. p. 112. ISBN 0-7923-1518-9.

Sri Lankan traditional medicine

http://www.indigenousmedimini.gov.lk/

Retosiban, GSK221149A

March 20, 2015 5:53 am / 1 Comment on Retosiban, GSK221149A

Retosiban, GSK221149A

820957-38-8

MW 494.5827, MF C27 H34 N4 O5

Oxytocin antagonist

Threatened pre-term labour

PHASE 3 GSK

UNII-GIE06H28OX, GSK 221149A, 820957-38-8,

(3R,6R)-6-((S)-sec-butyl)-3-(2,3-dihydro-1H-inden-2-yl)-1-((R)-1-(2-methyloxazol-4-yl)-2-morpholino-2-oxoethyl)piperazine-2,5-dione

3(R)-(2,3-Dihydro-1H-inden-2-yl)-1-[1(R)-(2-methyloxazol-4-yl)-2-(4-morpholinyl)-2-oxoethyl]-6(R)-[1(S)-methylpropyl]piperazine-2,5-dione

(3R.6R)-3-(2,3-dihvdro-1 H-inden-2-v0-1 -\( R)-1 -(2-methyl-1 ,3-oxazol-4- yl)-2-(4-morpholinyl)-2-oxoethyll-6-r(1S -1-methylpropyn-2.5- piperazinedione

2,5-Piperazinedione, 3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-4-oxazolyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-, (3R,6R)-

Morpholine, 4-[(2R)-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl](2-methyl-4-oxazolyl)acetyl]-

Retosiban (GSK-221,149-A)^[1]^[2] is an oral drug which acts as a selective, sub-nanomolar (K_i = 0.65 nM) oxytocin receptor antagonist with >1400-fold selectivity^[3] over the related vasopressin receptors and is being developed by GlaxoSmithKline for the treatment of preterm labour.^[4]^[5]

Retosibanis an oxytocin (OT) antagonist in phase III clinical trials at GlaxoSmithKline for the prevention of preterm labor. OT antagonism is widely known to inhibit spontaneous uterine contractions.

Retosiban is a diketopiperazine nonpeptide compound with high potency and selectivity for the OT receptor over vasopressin receptors.

This candidate has been shown to block oxytocin-induced uterine contractions when administered intravenously and to exhibit oral activity

Preterm labor is a major clinical problem leading to death and disability in newborns and accounts for 10% of all births and causes 70% of all infant mortality and morbidity.(Goldenberg, R. L.; Rouse, D.Prevention of premature birth N. Engl. J. Med. 1998, 339, 313)

Oxytocin (OT) is a potent stimulant of uterine contractions and is responsible for the initiation of labor via the interaction with the OT receptors in the mammalian uterus. OT antagonists have been shown to inhibit uterine contractions and delay preterm delivery. So there is increasing interest in OT antagonists because of their potential application in the prevention of preterm labor.

Although several tocolytics have already been approved in clinical practice, they have harmful maternal or fetal side effects.(Enkin, M.; Kierse, M.; Neilson, J.; Preterm Labour: A Guide to Effective Care in Pregnancy and Childbirth, 3rd ed.; Oxford University Press: Oxford, UK, 2000; pp 211– 225. )

The first clinically tested OT antagonist atosiban has a much more tolerable side effect profile and has recently been approved for use in Europe.

ATOSIBAN

However, atosiban is a peptide and a mixed OT/vasopressin V1a receptor antagonist that has to be given by iv infusion and is not suitable for long-term maintenance treatment, as it is not orally bioavailable.((a) Bossmar, T.Treatment of preterm labor with the oxytocin and vasopressin antagonist atosiban J. Perinat. Med. 1998, 26, 458– 465

See also,(b) Coomarasamy, A.; Knox, E. M.; Gee, H.; Khan, K. S.Oxytocin antagonists for tocolysis in preterm labour—a systematic review Med. Sci. Monit. 2002, 8, RA268– RA273)

Hence there has been considerable interest in overcoming the shortcomings of the peptide OT antagonists by identifying orally active nonpeptide OT antagonists with a higher degree of selectivity toward the vasopressin receptors (V1a, V1b, V2) with good oral bioavailability. Although several templates have been investigated as potential selective OT antagonists, few have achieved the required selectivity for the OT receptor vs the vasopressin receptors combined with the bioavailability and physical chemical properties required for an efficacious oral drug.(Borthwick, A. D.Oral Oxytocin Antagonists J. Med. Chem. 2010, 53, 6525– 6538)

Therefore the objective was to design a potent, orally active OT antagonist with high levels of selectivity over the vasopressin receptor with good oral bioavailability in humans that would delay labor safely by greater than seven days and with improved infant outcome, as shown by a reduced combined morbidity score.

R ecently reported(Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Hatley, R. J. D.; Hughes, J. A.; Irving, W. R.; Livermore, D. G.; Sollis, S. L.; Nerozzi, F.; Valko, K. L.; Allen, M. J.; Perren, M.; Shabbir, S. S.; Woollard, P. M.; Price, M. A.2,5-Diketopiperazines as Potent, Selective and Orally Bioavailable Oxytocin Antagonists 3: Synthesis, Pharmacokinetics and in Vivo Potency J. Med. Chem. 2006, 49, 4159– 4970) the identification of a novel series of (3R,6R,7R)-2,5-diketopiperazine (2,5-DKP) derivatives with antagonist activity at the human oxytocin receptor (hOTR).

The most potent of these was the 2,4-difluorophenyl dimethylamide 1, which has good in vitro (pK_i = 9.2) and in vivo (IC₅₀ = 227 nM) potency and is 20-fold more potent than atosiban in vitro. Compound 1 also has good pharmacokinetics with bioavailability >50% in both the rat and the dog.

Moreover, it is >500-fold selective over all three human vasopressin receptors (hV1aR, hV2R, and hV1bR) and has an acceptable P450 profile. In addition, it has a satisfactory safety profile in the genotoxicity screens and in the four day oral toxicity test in rats.

RETOSIBAN 106

However, 1 had poor aqueous solubility and high intrinsic clearance in human and cynomolgus monkey liver microsomes, so a compound was required that retained high antagonist potency and excellent pharmacokinetics in animal species seen with 1 but was more soluble and with improved human intrinsic clearance to decrease the risk of low bioavailability in humans.

first approach was to replace the 7-aryl ring with a five-membered heterocycle, which led to the oxazole Retosiban (106) a clinical candidate.(Borthwick, A. D.; Liddle, J.The design of orally bioavailable 2,5 diketopiperazine oxytocin antagonists: from concept to clinical candidate for premature labour Med. Res. Rev. 2011, 31, 576– 604)

As a backup to 106, an alternative replacement of the 7-aryl ring with a six-membered heterocycle was considered and in this report we describe how we investigated the modification of the 7-aryl ring to the 7(3′-pyridyl) ring and optimized substitution in this ring as well as modifying the isobutyl group to obtain good potency, lower intrinsic clearance in human microsomes, and good pharmacokinetics in animal species.

BARUSIBAN

L-368899

L-371257

PAPER

Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: Synthesis, pharmacokinetics, and in vivo potency
J Med Chem 2012, 55(2): 783

http://pubs.acs.org/doi/abs/10.1021/jm201287w

PAPER

The discovery of GSK221149A: A potent and selective oxytocin antagonist
Bioorg Med Chem Lett 2008, 18(1): 90

http://www.sciencedirect.com/science/article/pii/S0960894X07013170

Scheme

Reagents and conditions: (a) triethylamine, MeOH; (b) H₂, Pd/C, ethanol/acetic acid; (c) carbonyl diimidazole, CH₂Cl₂ 3 h then acetone/2 N HCl; (d) benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, dichloromethane 1 h then morpholine.

GSK221149A and other tertiary amides were prepared in four steps via the Ugi reaction as outlined in Scheme . A 2:1 mixture of diastereoisomers 24 was formed with the desirable (R)-diastereoisomer being the minor product. Hydrogenation of crude 24 furnished the cyclised phenol 25, again enriched with the undesirable (S)-diastereoisomer.

Activation of the mixture 25 with carbonyl diimidazole followed by the addition of 2 N HCl promoted epimerisation at the exocyclic position and yielded the acids 26 with the required (R)-diastereoisomer as the major product.

Acid activation with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate followed by the addition of morpholine and subsequent column chromatography yielded homo-chiral GSK221149A.

PATENT

WO 2005000840

http://www.google.co.in/patents/EP1641787A1?cl=en

Example 3

(3R.6R)-3-(2,3-dihvdro-1 H-inden-2-v0-1 -\( R)-1 -(2-methyl-1 ,3-oxazol-4- yl)-2-(4-morpholinyl)-2-oxoethyll-6-r(1S -1-methylpropyn-2.5- piperazinedione ( 2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1 H-inden-2-yl)ethanoic acid (35.84g, 0.110mol) in a 500mL round bottomed flask was treated with 2,2,2-trifluoroethanol (165mL) followed by methanol (55ml) and triethylamine (11.13g, 15.33mL, 0.110mmol) the slurry was stirred for 3.5hrs until dissolution was observed. The solution was then added to (D)- allo Isoleucine methyl ester hydrochloride (20g, .110mol) in a separate flask. The slurry was stirred until dissolution was observed. 2-methyl-4- formyloxazole (12.24g, 0.110mmol) was then added followed by 2- benzyloxyphenylisocynanide (23.04g, 0.110mmol). The dark brown reaction mixture was then stirred at 20-25°C for 24hrs. The solution was then concentrated to a volume of ca. 130mL by distillation at reduced pressure.

The solution was the diluted with dichloromethane (200mL) and washed with water (2 x 200mL). The organic phase was then diluted with N-methyl pyrrolidinone (460mL) was and the dichloromethane removed by stirring at 40°C under vacuum for 2hrs. Acetic acid 46mL) was then added followed by palladium on carbon catalyst (69. Og of 10% Pd wt, 57% water, Johnson Matthey type 87L) and the mixture hydrogenated under balloon pressure of hydrogen with rapid stirring for 2hrs. The reaction mixture was then filtered, washed through with ethyl acetate (960mL) and washed with 3%w/v aq sodium chloride solution (960mL). The biphasic mixture was filtered and the organic phase separated and washed with 3%w/v aq sodium chloride solution (2 x 960mL). The organic solution was then diluted with ethyl acetate (200mL) and concentrated by distillation at atmospheric pressure by distilling out 385mL of solvent. The concentrated solution at 20-25°C was treated with 1 ,1′-carbonyldiimidazoIe (21.46g, 0.132mol) and stirred at 20-25°C for 1 hr then treated with water (290mL) and stirred rapidly at 20-25°C for 24hr. The mixture was allowed to settle and the ethyl acetate layer separated and discarded. The aqueous phase was washed with ethyl acetate (290mL) and the mixture allowed to settle and the aqueous phase was separated and acidified to pH 1-2 by the addition of concentrated hydrochloric acid (18mL).

The aqueous phase was then extracted into ethyl acetate (290mL and then 145mL). The combined ethyl acetate solution was then concentrated by distillation at atmospheric pressure to a volume of ca. 93mL. This solution was then diluted with tetrahydrofuran (62mL) and treated with triethylamine (11.02g, 15.20mL, 0.109mol) and cooled to -78°C. The solution was then treated with trimethylacetyl chloride (4.81 g, 4.92mL, 39.90mmol) and stirred at – 78°C for 7hr. The reaction mixture was then treated with a solution of morpholine (15.82g, 15.83mL, 0.181 mol) in tetrahydrofuran (23mL) and stirred at -78°C for 1hr 20mins before being allowed to warm to 20-25°C. The solution was then diluted with ethyl acetate (76mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 153mL) followed by water (153mL). The organic solution was then diluted with ethyl acetate (54mL) and distilled down to a volume of 69mL at atmospheric pressure. The solution was then cooled to 20-25°C at which point crystallisation of the title compound occurred. The slurry of was then cooled further to 0°C before the title compound was isolated by filtration and sucked dry. Yield 8.92g.

SYN WILL BE UPDATED.. ……………KEEP WATCHING

References

1 Liddle J, Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, Exall AM, Hamlett C, Irving WR, Mason, AM, McCafferty GP, Nerozzi F, Peace S, Philp J, Pollard D, Pullen MA, Shabbir SS, Sollis SL, Westfall TD, Woollard PM, Wu C, Hickey DM (January 2008). “The discovery of GSK221149A: A potent and selective oxytocin antagonist”. Bioorganic & Medicinal Chemistry Letters 18 (1): 90–94. doi:10.1016/j.bmcl.2007.11.008. PMID 18032036.
2
Borthwick, A. D.; Liddle, J. (January 2013). “Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists”. In Domling, A. Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN 978-3-527-33107-9.
3
McCafferty GP, Pullen MA, Wu C, Edwards RM, Allen M.J, Woollard PM, Borthwick AD, Liddle J, Hickey DM, Brooks DP, Westfall TD (March 2007). “Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat”. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 293: R299–R305. doi:10.1152/ajpregu.00057.2007. PMID 17395790.
4
USAN Council (2007). “Statement on a Nonproprietary Name Adopted by the USAN Council” (PDF).
5 Borthwick AD, Liddle J (July 2011). “The Design of Orally Bioavailable 2,5-Diketopiperazine Oxytocin Antagonists: From Concept to Clinical Candidate for Premature Labour”. Medicinal Research Reviews 31 (4): 576–604. doi:10.1002/med.20193. PMID 20027670.

…………..

OTHER INFO

http://pubs.acs.org/doi/abs/10.1021/jm201287w

A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK_i > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl R–sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK_i = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

EPELSIBAN

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69)

69 as a white solid (2.4 g, 45%). Recystallisation from ethyl acetate/hexane (1:3) gave colorless needles (75%) mp 140 °C. ¹H NMR (CDCl₃) δ 7.49 (d, J = 7.8 Hz, 1H, pyridyl-4H), 7.26–7.15 (m, 4H, indanyl-arylH), 7.10 (d, J =8.1 Hz, 1H, pyridyl-5H), 6.68 (s, 1H, NCHpyridyl), 6.49 (d, J = 2.8 Hz, 1H, lactam-NH), 4.10 (dd, J = 10.1 Hz, 4.0 Hz, 1H, NCHindanyl), 4.01 (d, J = 4.5 Hz, NCHsec-butyl), 3.75–2.71 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H), 2.62 and 2.58 (2s, 6H, pyridyl-2Me,-6Me), 1.64–1.52 (m, 1H, CHHMe), 0.98–0.79 (m, 2H, CHHMe, CHMeCH₂), 0.70 (t, J = 7.1 Hz, 3H, CH₂Me), 0.45 (d, J = 6.8 Hz, 3H, CHMe). LCMS m/z 519 (MH⁺) single component, gradient 2 (t_R 2.70 min). HRMS calcd for C₃₀H₃₈N₄O₄ (MH⁺) 519.29658, found 519.29667. HPLC: 100% (t_R 10.388 min).

To a warm solution of 69 (2.66 g, 5.1 mmol) in acetone (40 mL) was added a solution of benzene sulfonic acid (0.81 g, 5.1 mmol) in acetone (40 mL), and the resulting solution was heated to boiling and allowed to cool to room temperature during 48 h. The resulting crystals were filtered off, air-dried on the filter pad to give the besylate (3.214 g, 92.6%) as white crystals of 69B mp 179–183 °C. ¹H NMR (CD₃OD) δ 8.30 (d, 1H, J = 8.1 Hz, pyridyl-4H), 7.84–7.80 (m, 2H, PhSO₃^– 2× ortho-H), 7.78 (d, J = 8.3 Hz, 1H, pyridyl-5H), 7.45–7.38 (m, 3H, PhSO₃^– 2× meta-H, para-H), 7.23–7.09 (m, 4H, indanyl-arylH), 6.08 (broad s, 1H, NCHpyridyl), 4.00 (d, J = 4.6 Hz, 1H, NCHsec-butyl), 3.92 (d, J = 9.9 Hz, 1H, NCHindanyl), 3.78–3.39 and 3.14–2.80 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H)), 2.79 and 2.78 (2s, 6H, pyridyl-2Me, -6Me), 1.85–1.74 (m, 1H, CHHMe), 1.59–1.48 (m, 1H, CHHMe), 1.15–1.01 (m, 1H, CHMeCH₂), 0.92 (d, J = 6.3 Hz, 3H, CHMe), 0.85 (t, J = 7.3 Hz, 3H, CH₂Me). LCMS m/z 519 MH⁺ single components, t_R 2.72 min; circular dichroism (CH₃CN) λ_max 225.4 nm, dE −15.70, E15086; λ_max 276 nm, dE 3.82, E5172. HRMS calcd for C₃₀H₃₈N₄O₄ (MH⁺) 519.2971, found 519.2972. Anal. (C₃₀H₃₈N₄O₄·C₆H₆O₃S·3.0H₂O) C, H, N, S.

…………..

Updates

Inline image 1

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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

Retosiban
Systematic (IUPAC) name

(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-(morpholin-4-yl)-2-oxoethyl]piperazine-2,5-dione
Clinical data
Legal status	Non-regulated
Identifiers
CAS number	820957-38-8
ATC code	None
PubChem	CID 96025669
ChemSpider	23323798
UNII	GIE06H28OX
KEGG	D08986
Synonyms	GSK-221,149-A
Chemical data
Formula	C₂₇H₃₄N₄O₅
Molecular mass	494.58 g/mol

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References

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4-Chlorobenzo[b]thiophene a key intermediate in brexpiprazole synthesis

Safe and Efficient Decarboxylation Process: A Practical Synthetic Route to 4-Chlorobenzo[b]thiophene

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Selina McKee

Selina McKee

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DR ANTHONY MELVIN CRASTO

ORGANIC SPECTROSCOPY

amcrasto@gmail.com

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Sri Lankan traditional medicine

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