(WO2015139602) Sofosbuvir New Patent

(WO2015139602) 2'-SUBSTITUTED-2,2'-DEHYDRATED URIDINE OR 2'-SUBSTITUTED-2,2'-DEHYDRATED CYTIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF

ZHANG, Rongxia

A further object of the present invention to provide a method for preparing a compound of formula I.

The present invention provides a process for preparing a compound I 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-cytidine using the following formula or 2'-deoxy-2'-substituted 2'-2'-substituted nitrile or uridine 2'-deoxy-2'-substituted-2'-carbonitrile The method of cytidine compound,

2'-deoxy-2'-fluoro-2'-methyl-uridine (IIIa) is the preparation of anti-hepatitis C drugs Sofosbuvir key intermediate.

Sofosbuvir developed by Gilead Science Company, FDA on December 6, 2013 Sofosbuvir formally approved for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is first used to treat certain types of HCV infection without the use of interferon effective and safe drugs. Clinical trials have shown, sofosbuvir can achieve very high proportion of sustained virologic response (clinical cure). More revolutionary breakthrough that, sofosbuvir without joint peginterferon α situation is still very significant effect, such as sofosbuvir ribavirin genotype 2 and genotype 3 patients with previously untreated chronic hepatitis C continued virological response rate of 100%. Sofosbuvir is a prodrug is metabolized in vivo to 2'-deoxy-2'-fluoro-2'-methyl-uridine-5'-monophosphate.

Currently reported 2'-deoxy-2'-fluoro-2'-methyl uridine synthetic methods are as follows:

In the literature (Journal of Medicinal Chemistry, 2005,48,5504) in order cytidine as a raw material, first selectively protected 3 ', 5'-hydroxyl group, and then oxidizing the 2'-hydroxyl to a carbonyl group, and the reaction of methyllithium get the 2'-hydroxyl compound, and then removing the protective group, use benzoyl protected 3 ', 5'-hydroxyl group, and then reacted with DAST fluorinated compound, followed by hydrolysis and aminolysis reaction products, such as the following Reaction Scheme. The method of route length, the need to use expensive silicon ether protecting group molecule relatively poor economy; conducting methylation time will generate a non-methyl enantiomer beta bits.

In Patent (WO2005003147, WO2006031725A2, US20040158059) using 2'-fluoro-2'-methyl - ribose derivative with N- benzoyl cytosine for docking the reaction, then after the hydrolysis, aminolysis reaction to obtain the final product, As shown in the following reaction scheme. Raw material of the process is not readily available, synthetic steps cumbersome, expensive; the reaction product obtained contained docking base for the alpha position isomers, need purification removed to form waste.

SUMMARY OF THE INVENTION

The present inventors have designed and synthesized a compound of formula I as shown, the compound may be a fluorinated or nitrile reaction of 2'-deoxy-2'-fluoro-2'-get-substituted uridine or 2 under appropriate conditions' - 2'-deoxy-2'-fluoro-2'-deoxy-2'-substituted cytidine or nitrile uridine or 2'-substituted-2'-deoxy-2'-substituted-2'-cytidine nitrile compound; or a compound of formula I or a nitrile group by fluoro reaction, followed by deprotection reaction to give 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro--2 '- cytidine or 2'-substituted-2'-deoxy-2'-nitrile-substituted uridine or 2'-deoxy-2'-substituted-2'-cytidine compound nitrile group; or a compound of formula I through the opening cyclization reaction, and then through the group of fluoro or nitrile, and finally deprotection reaction to give 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-2'-substituted Cellular glycoside or 2 'substituted-2'-deoxy-2'-carbonitrile 2'-deoxy-uridine or 2'-substituted-2'-cytidine compound nitrile group; or a compound of formula I through a ring-opening reaction, and then 2 '- hydroxyl forming a leaving group, and then after a nitrile group or a fluorinated reaction, the final deprotection reaction of 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'- cytidine or 2'-fluoro-2'-substituted-2'-deoxy-2'-nitrile-substituted uridine or 2'-deoxy-2'-substituted-2'-cytidine nitrile compound.

It is therefore an object of the present invention is to provide a compound of the general formula I prepared 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-2'-substituted cytidine or 2'-substituted-2'-deoxy-2'-carbonitrile uridine or 2'-deoxy-2'-substituted-2'-carbonitrile The method of cytidine compound.

Example 1:

The 2'-C- methyl uridine (18.4g, 0.07mol), N, N'- carbonyldiimidazole (216.2g, 0.10mol), sodium bicarbonate (8.4g, 0.10mol) was suspended N, N- two dimethylformamide (50ml), the temperature was raised to 130 ℃, reaction for 4 hours, cooled and filtered to remove inorganic salts, the filtrate was added ethyl acetate (200ml), analyze the material at room temperature, suction filtered, washed with ethyl acetate cooled to, drying to give a yellow solid (19.9g, yield: 83%).

Ia: ¹ H NMR (300 MHz, CD ₃ OD): [delta] 7.80 (d, 1H, J = 7.5 Hz), 6.05 (d, 1H, J = 7.5 Hz), 5.91 (s, 1H), 4.34 (d, 1H, J = 4.8Hz), 4.07 (m, 1H), 3.56 (m, 2H), 1.63 (s, 3H); ESI-MS m / z (M + 1) 241.

Example 2:

The compound of Example 1 Ia (0.24g, 1mmol)) was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure, the residue was added acetone, beating, and filtered to give solid (0.18g, yield: 70%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

Example 3:

Compound Ib (0.45g, 1mmol) was dissolved in a mixture of dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2), dried over anhydrous dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the residue was subjected to column chromatography to give the product (0.36g, yield: 78%).

IIa: ¹ H NMR (400 MHz, CDCl ₃ and DMSO-d ₆ ): [delta] 7.99 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 7.34 ~ 7.61 (m, 7H ), 6.10 (brs, 1H), 5.64 (brs, 1H), 5.42 (d, J = 8.0Hz, 1H), 4.53-4.68 (m, 3H), 1.40 (d, J = 22.8Hz, 3H); ESI -MS m / z (M + 1) 469.

Example 4:

The compound of Example 3 IIa (0.47g, 1mmol) dissolved in 10% methanol solution of ammonia and stirred overnight, the solvent was removed under reduced pressure, and the residue was slurried in ethyl acetate, filtered to give a white solid (0.2g, yield : 77%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

Example 5:

Compound IVa (0.57g, 1mmol) was dissolved in dichloroethane (20ml) was added trifluoromethanesulfonic acid trimethylsilyl ester (1ml), was heated for 12 hours, cooled, and the reaction solution was concentrated dryness, added two dichloromethane (100ml) was dissolved, washed successively with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give an oil which was purified by column chromatography to give a white solid (0.3g, yield : 67%).

Ib: ¹ H NMR (300 MHz, CDCl ₃ ): δ7.96-8.10 (m, 6H), 7.41-7.65 (m, 9H), 7.32 (d, 1H, J = 5.4 Hz), 6.09 (d, 1H, J = 5.4Hz), 5.79 (m, 2H), 4.67 (m, 1H), 4.48 (m, 2H), 1.81 (s, 3H); ESI-MS m / z (M-1) 447.

Example 6:

N The compound of Example 1 Ia (1.3g, 5.4mmol) dissolved in dry, N- dimethylformamide (10ml) was added p-toluenesulfonic acid monohydrate (1.12g, 5.9mmol) and 3,4- dihydropyran (1.28ml, 14.04mmol), The reaction was stirred for 5 hours at room temperature, water was added and the methylene chloride solution was separated, the organic layer was concentrated and purified by silica gel chromatography to give the product 1.3g.

Ic: ¹ H NMR (300 MHz, CDCl ₃ ): [delta] 7.29 (m, 1H), 6.08 (m, 1H), 5.61 (m, 1H), 4.33-4.72 (m, 4H), 3.37-3.90 (m, 6H), 1.43-1.82 (m, 12H), 1.25 (s, 3H); ESI-MS m / z (M + 1) 427.

Example 7:

The solvent was removed, the residue was purified compound of Example 6 Ic (0.43g, 1mmol) was dissolved in 70% HF in pyridine was heated to 100 ~ 120 ℃, stirred for 5 hours, cooled, reduced pressure was purified through silica gel column to give a solid ( 0.18g, yield: 72%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

Example 8:

The compound of Example 6 Ic (50mg, 0.122mmol) was dissolved in methanol (1ml) was added 1N sodium hydroxide solution (0.2ml), stirred at room temperature overnight, water was added and the methylene chloride solution was separated, the organic layer was concentrated after purified by column chromatography to give the product (45mg, yield: 87%).

VA: ¹ H NMR (300 MHz, CDCl ₃ ): [delta] 7.89 (d, 1H, J = 4.5Hz), 6.01 (s, 1H), 5.95 (d, 1H, J = 4.5Hz), 5.65 (m, 2H ), 4.73 (m, 3H), 4.59 (m, 1H), 3.52-4.30 (m, 4H), 1.56-1.80 (m, 12H), 1.32 (s, 3H); ESI-MS m / z (M + 35) 461.

Example 9:

The mixture of Example 8 Compound Va (0.43g, 1mmol) was dissolved in dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2) and washed , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound IIb. Compound IIb is dissolved in methanol (10ml) was added p-toluenesulfonic acid (200mg), stirred for 6 hours at room temperature, the methanol was removed under reduced pressure, silica gel column chromatography to give the product IIIa (180mg, yield: 75%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

Example 10:

The 2'-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added N, N'- carbonyldiimidazole (0.194g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), was heated to 130 ℃, stirred for 4 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled, The solvent was removed under reduced pressure, the residue was added to acetone and filtered to obtain a solid IIIa (0.12g, yield: 60%).

Example 11:

The 2'-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate ( 55mg, 0.66mmol), was heated to 150 ℃, stirred for 6 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure The residue was added to acetone and filtered to obtain a solid IIIa (0.13g, yield: 65%).

Example 12:

Under nitrogen, the compound of Example 9 Example Va (4.26g, 10mmol) was dissolved in dry tetrahydrofuran (100ml) was added triethylamine (6g, 60mmol), cooled to -78 ℃, was added trifluoromethanesulfonic anhydride (4.23g , 15mmol), stirred for 1 hour, the reaction system was added saturated ammonium chloride solution, extracted three times with methylene chloride, organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product Vb ( 4g, yield: 72%). ESI-MS m / z (M-1) 557.

Compound Vb (4g) was dissolved in dry tetrahydrofuran, was added tetrabutylammonium fluoride (1.87g, 7.1mmol), warmed to reflux, cooled to room temperature after heating for 1 hour, water was added to the reaction system, and extracted with methylene chloride three times, the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product IIb (2.7g, yield: 88%). ESI-MS m / z (M-1) 427.

Compound IIb (2.7g) was dissolved in methanol (20ml) was added 3M hydrochloric acid (10ml), 50 ℃ stirred for 8 hours, and concentrated to give a solid, was added acetonitrile, beating, and filtered to give the product IIIa (1g, yield: 61%).

IIIa: ¹ H NMR (300 MHz, DMSO-d ₆ ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.

////////////////

Pregabalin

15 16 (S)-Pregabalin

Example 7: Preparation of (S) Pregabalin from compound 19

1Og of compound 19 is dissolved in 440 ml 6 N HCl, and the solution is warmed to 125°C for 15 hours. After cooling, the mixture is diluted with water, and extracted three times with dichloromethane, then the aqueous phase is evaporated. After drying under high vacuum, the (S)-Pregabalin hydrochloride is obtained as crystals. (S)-Pregabalin is further resolved by dissolving (S)-Pregabalin hydrochloride in isobutanol, and then adding triethyl amine. The mixture is stirred for 45 minutes, and the product is filtered, washed with isobutanol.

http://www.google.com/patents/WO2006110783A2?cl=en

Publication number	WO2006110783 A2
Publication type	Application
Application number	PCT/US2006/013565
Publication date	Oct 19, 2006
Filing date	Apr 11, 2006
Priority date	Apr 11, 2005
Also published as	CA2603215A1, 4 More »
Inventors	Asher Maymon, Vinod Kumar Kansal, Lilach Hedvati
Applicant	Teva Pharma, Asher Maymon, Vinod Kumar Kansal, Lilach Hedvati
Export Citation	BiBTeX, EndNote, RefMan
Patent Citations (1), Non-Patent Citations (3), Referenced by (23),Classifications (13), Legal Events (6)
External Links: Patentscope, Espacenet Citing Patent Filing date Publication date Applicant Title WO2008007145A2 * Jul 12, 2007 Jan 17, 2008 Generics Uk Ltd Process of preparing a gamma-amino acid WO2008117305A2 * Mar 3, 2008 Oct 2, 2008 Venkata Siva Kumar Bobba A novel process for preparing pregabalin and its acid addition salts WO2009010554A1 * Jul 17, 2008 Jan 22, 2009 Esteve Labor Dr Process for the enantioselective preparation of pregabalin WO2009022839A2 * Aug 11, 2008 Feb 19, 2009 Korea Advanced Inst Sci & Tech Novel method for preparing pregabalin WO2009080365A1 * Dec 18, 2008 Jul 2, 2009 Synthon Bv Pregabalin salts WO2009081208A1 * Dec 19, 2008 Jul 2, 2009 Generics Uk Ltd Processes to pregabalin WO2009087650A2 * Oct 14, 2008 Jul 16, 2009 Sundeep Aurora A novel process for synthesis of pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic pregabalin WO2009141362A2 * May 19, 2009 Nov 26, 2009 Sandoz Ag Process for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester WO2009147434A1 * Jun 3, 2009 Dec 10, 2009 Generics [Uk] Limited A novel and efficient method for the synthesis of an amino acid WO2009149928A1 * Jun 10, 2009 Dec 17, 2009 Synthon B.V. Processes for making pregabalin and intermediates therefor WO2014005494A1 * Jun 28, 2013 Jan 9, 2014 Sunshine Lake Pharma Co., Ltd. Method of preparing lactam compound EP2017273A1 * Jul 18, 2007 Jan 21, 2009 Laboratorios del Dr. Esteve S.A. Process for the enantioselective preparation of pregabalin US7586005 Oct 28, 2008 Sep 8, 2009 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US7619112 Aug 14, 2007 Nov 17, 2009 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid US7678938 Aug 14, 2007 Mar 16, 2010 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid US7763749 May 10, 2006 Jul 27, 2010 Teva Pharmaceutical Industries Ltd. Method for the preparation of Pregabalin and salts thereof US7851651 Oct 28, 2008 Dec 14, 2010 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US7923575 Oct 19, 2009 Apr 12, 2011 Teva Pharmaceutical Industries Limited Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US7960583 Oct 28, 2008 Jun 14, 2011 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US7973196 Aug 30, 2010 Jul 5, 2011 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US8097754 Mar 24, 2008 Jan 17, 2012 Teva Pharmaceutical Industries Ltd. Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid US8212071 Nov 4, 2008 Jul 3, 2012 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US8546112 May 19, 2009 Oct 1, 2013 Sandoz Ag Process for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester

India rejects patent on Pfizer's arthritis drug

read at .http://www.firstpost.com/business/india-rejects-patent-on-pfizers-arthritis-drug-2424070.html?trk=pulse-det-art_view_ext

Mumbai: India has again denied Pfizer Inc a patent on its rheumatoid arthritis drug tofacitinib, the latest setback for a multinational drugmaker seeking to enforce its intellectual property rights in the country.

Representational image. AFP

Pfizer sought a patent that covers an important chemical formulation of the active compound in the medicine, but the Indian Patent Office said the company would have to establish that the compound for which it is seeking a patent is therapeutically more effective than the active compound.

WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban

WO 2015129603

HIGH-PURITY CRYSTALS OF ACTIVE BLOOD COAGULATION FACTOR X (FXA) INHIBITOR

DAIICHI SANKYO COMPANY,LIMITED [JP/JP]; 3-5-1,Nihonbashi Honcho,Chuo-ku, Tokyo 1038426 (JP)

Claims highly pure crystalline form of edoxaban p-toluenesulfonate monohydrate. Useful for treating thrombotic diseases. Daiichi Sankyo had developed and launched edoxaban for treating non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism, the drug was recently launched in US (in February 2015) and approved in Europe (in June 2015).

The present invention addresses the problem of providing high-purity crystals of a compound which is represented by formula (1a) and is an active blood coagulation factor X (FXa) inhibitor. High-purity crystals of a compound represented by formula (1a) which: are characterised by being obtained by a step for dissolving crystals in a solvent and thereafter performing recrystallisation; have a 0.03% or less maximum content of one impurity as the impurity content by percentage; and have a 0.13% or less total impurity content.

It shows the inhibitory effect of activated blood coagulation factor X (FXa), a compound useful as a prophylactic and / or therapeutic agent for thrombotic diseases, the following formula (1a)[Formula 1]

In N represented ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl-4 , 5,6,7-tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate [hereinafter, may be referred to as compound (1a) is there

　(Reference Example 1) N ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7 Synthesis of tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate (1a) (WO 07 / the method described in 032 498 pamphlet)　Was prepared by the method described in WO 07/032498 pamphlet, N ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - the {[(5-methyl-4,5,6,7-tetra-hydro thiazolopyridine [5,4-c] pyridine-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido (86.8g), at 60 ℃, it was dissolved in 30% aqueous ethanol (418ml), p- 30% aqueous ethanol solution of toluene sulfonic acid monohydrate (29.0g) a (167ml) was added. The reaction mixture, after stirring for 1 hour at 70 ℃, was gradually cooled to room temperature, ethanol was added, and the mixture was stirred for 16 hours. The reaction solution under ice-cooling, after stirring for 1 hour, The crystals were collected by filtration to give the title compound 102.9g.

　The resulting compound, the absorption peak of the same intensity at the same wave number standard and the (known compound) was observed in the IR.
The obtained compound, in analysis using HPLC, as impurities, a peak of more impurities (both 0.03 wt%) is confirmed, the total of the impurities was 0.16 wt.% Since, its purity was 99.84% (Note that the content of% refers to% of the HPLC area value of the free form of formula (1a) compound).

¹ H-NMR (DMSO-d6) delta: 1.45-1.54 (1H, M), 1.66-1.78 (3H, M), 2.03-2.10 (2H, M), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3 .13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m) , 7.11 (2H, d, J = 7.8Hz), 7.46 (2H, d, J = 8.2Hz), 8.01 (2H, d, J = 1.8Hz), 8.46 ( 1H, t, J = 1.8Hz), 8.75 (1H, d, J = 6.9Hz), 9.10-9.28 (1H, br.s), 10.18 (1H, br.s ), 10.29 (1H, s).

Elemental analysis: Anal. Calcd. For: C; 50.43%, H; 5.46%, N; 13.28%.
Found: C; 50.25%, H; 5.36%, N; 13.32%

/////////////WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban

EUTICALS SPA WO2015128440 New patent CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE

WO2015128440
CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE

EUTICALS SPA [IT/IT]; Viale Bianca Maria, 25 I-20121 Milano (IT)

A tiotropium bromide and cocrystal of lactose monohydrate is Disclosed HEREIN. In the tiotropium bromide cocrystal the components and lactose are preferably present in stoichiometric ratio An almost. Said cocrystal: has a single endothermic event at about 191-3 ° C Determined by DSC. A process for the preparation of the cocrystal est Disclosed. Preferably, the particle size cocrystal: has a distribution of D90 <10μ. The cocrystal est Disclosed for use as medicine, in Particular for the treatment of a respiratory complaint, Such As chronic obstructive pulmonary disease (COPD), bronchitis, emphysema and asthma.A pharmaceutical composition comprenant the active ingredient as cocrystal est Disclosed, in Particular for administration by inhalation. In the lathing box, Said: has a mean particle cocrystal size of 0.5 to 10 .mu.m, preferably 1 to 6 .mu.m, more preferably 1.5 to 5 microns.


Tiotropium bromide (compound identified by CAS registry number 136310-93-5) was described for the first time in 1991 by Boheringer Inghelheim (EP 0418716) and presents the following structural formula:

Tiotropium bromide is an anticholinergic bronchodilator with a long-lasting effect, 24 hours, which may be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease), bronchitis, emphisema and asthma.
Tiotropium bromide is preferably administered by inhalation: suitable inhalable powders packed into appropriate capsules may be used (Spiriva^®; US7694676 and US8022082) or alternatively, it may be administered by the use of inhalable aerosols (EP2201934).
The correct manufacture of the above mentioned compositions, suitable for the administration of a pharmaceutically active substance by inhalation, is based on the definition of physical parameters, like a particular crystalline form (see for example US6608055 and US677423) and a defined particle size distribution (US7070800), which are connected with the nature of the active substance itself.
From literature data, Tiotropium Bromide is described to exist in different polymorphic forms as well as in an amorphous form. In more details, Tiotropium Bromide is described to exist in a crystalline monohydrate form (US6777423), in several anhydrous (US6608055, WO2006/1 17300, EP1682542) and solvate (US7879871 , W02010/101538, WO201 1/015882) polymorphic forms. Some of these polymorphic forms are unstable and may change. For example, the monohydrate form described in US6777423 may be easily transformed after a mild heating at 40°C for few hours into the corresponding anhydrous form described in US6608055.
Since the quality of a pharmaceutical formulation requires that an active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent regulatory requirements.
There is the need of a crystalline form of tiotropium bromide which is stable to humidity and to mechanical treatments, like the micronization or other milling techniques, and which meets the high demands mentioned above for any pharmaceutically active substance.
It has now surprisingly been found that a crystal modification of tiotropium bromide meeting the above requirements can be obtained in the form of a cocrystal with lactose. Unexpectedly, this cocrystal is stable towards the influence of moisture and humidity and to physical treatments like the micronization.
In the novel cocrystal the components tiotropium bromide and lactose are present in an almost stoichiometric ratio, as determined for example by NMR spectroscopy. Therefore, the present invention relates to a tiotropium bromide-lactose cocrystal in which the components tiotropium bromide and lactose are present, with the limit of resolution of the employed analytical technique (ie H-NMR), in a ratio of about 1 : 1.
This novel cocrystal is characterized by a single endothermic event at about 191-3°C determined by DSC and by an X-Ray spectrum with characteristic 2theta values at 13.08; 14.16; 14.68; 17.90; 18.58; 19.06; 19.44; 21.02; 22.58; 23.24; 25.26; 26.20; 27.24; 28.08; 28.42; 29.96; 30.18; 31.80; 34.50; 34.82; 35.58; 38.70; 39.26; 41.52 and 50.06.
The present invention also relates to the cocrystal herein disclosed for use as a medicament, in particular for the treatment of respiratory complaints, particularly for the treatment of COPD and/or asthma.

Example 1
Preparation of Tiotropium Bromide Cocrystal with lactose in dimethylsulfoxide and acetone
Tiotropium Bromide (4.25g; 8.99 mmoles) and lactose monohydrate (3.58g; 9.9 mmoles) were dispersed at room temperature in dimethylsulfoxide (7.2 ml). The mixture was heated under stirring at the temperature of 50-55°C to obtain a limpid solution. Then acetone (55 ml) was added dropwise in 30' maintaining the reaction mixture under stirring at 50-55°C. The obtained solution was cooled down at 20-25°C and kept at this temperature under stirring for 2 hours. After this period a suspension was obtained. The precipitate was recovered by suction and the wet product slurried in acetone (14.9 ml) under stirring for 90'. The product was recovered by filtration, washed on the filter with acetone (4 times with 8.5 ml each) and dried under vacuum at 40°C for 48 hours to afford 6.76g (8.1 1 mmoles; 90% molar yields) of dry product.
The obtained crystals were analysed by X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and H-NMR (500 MHz) indicating that a new crystalline form, namely a cocrystal of Tiotropiumbromide with lactose is formed.
A representative DRX spectrum of Tiotropium Bromide cocrystal with lactose is shown in Figure 1 (third DRX spectrum from the bottom) overlapped with the DRX spectra of the employed starting materials (from the top respectively the DRX spectra of lactose monohydrate and of Tiotropium Bromide). The list of the characteristic diffraction peaks including normalised intensities of Tiotropium Bromide cocrystal is shown in table 1.
Table 1
2theta Intensity l/lo
11.360 420 21
12.340 453 23
13.080 366 18
13.520 843 42
14.160 1026 51
14.680 1098 54
15.280 659 33
theta Intensity l/lo 5.960 696 35 6.300 524 26 6.960 872 43 7.900 1472 73 8.580 1897 93 9.060 1847 91 9.440 1938 95 0.460 791 39 1.020 826 41 1.720 819 41 2.580 1712 84 3.240 2044 100 3.980 919 45 4.380 853 42 5.260 1499 74 6.200 1156 57 7.240 1240 61 8.080 1554 77 8.420 1935 95 9.960 1043 52 0.180 1024 51 0.500 819 41 0.900 924 46 1.800 1399 69 2.340 960 47 2.980 839 42 3.440 937 46 theta Intensity l/lo 4.500 1032 51 4.820 1424 70 5.580 1196 59 6.380 899 44 6.880 964 48 7.220 917 45 7.740 913 45 7.960 982 49 8.700 1163 57 9.260 1035 51 9.880 833 41 1.520 1396 69 1.940 976 48 3.400 1005 50 3.600 989 49 4.900 1074 53 5.360 893 44 6.920 1001 49 7.480 932 46 8.060 958 47 9.540 1107 55 0.060 1023 51 1.820 995 49 4.440 990 49 5.220 946 47 6.340 960 47 8.100 926 46 The DSC-thermograms of the lactose cocrystal with Tiotropium bromide shows an endothermic event at ca. 191-193°C indicating melting of this material. The obtained DSC-diagram is depicted in Figure 2.
In order to get an idea on the stoichiometry of the obtained cocrystal H-NMR spectra (500 MHz) were recorded. The samples were dissolved in d6-DMSO for analysis. The corresponding spectrum is shown in Figures 3 and 3A. In addition to the characteristic H-NMR signals of tiotropium there is a signal at 4,17 and 4, 18 ppm which is indicative of H1 ' of lactose (integration 1 H; ref Hyunnsook Ko et al. Bull. Korean Chem. Soc. 2005, Vol 26, No12, 2001-6). Integration of this signal compared to the signal at 4,12 ppm of CH 1 and 5 (integration 2H; ref. Zhenguang Lin et al. Spectrochimica Acta Part A 75 (2010), 1 159-1162) of Tiotropium shows that the cocrystal has a stoichiometry which is close to 1 : 1.

EUTICALS SPA





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