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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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澳格列汀, SP2086, Retagliptin


Figure imgb0068 Figure imgb0002   澳格列汀, SP2086, Retagliptin 1174122-54-3(Retagliptin), 1174038-86-8 (Retagliptin Hydrochloride), 1256756-88-3(Retagliptin Phosphate) (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester Methyl (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo [1,5-a]pyrazine-1-carboxylate, DPP-4 inhibitor Type II diabetes

Jiangsu Hengrui Medicine Co., Ltd

  Nanjing Changao Pharmaceutical 澳格列汀 is a novel DPP-4 inhibitor (gliptin) for the treatment of type II diabetes. Because Shanghai Sun Sail Pharmaceutical, a wholly owned subsidiary of Nanjing Changao Pharmaceutical, has filed two patents to protect DPP-4 inhibitors (WO2011147207 and CN101786978), it is unknown which one covers this drug. Relevant data’s from WHO showed morbidity rate, disability rate, death rate of diabetes mellitus and overall health level of diabetes mellitus patients have already ranked the third place in non-infectious diseases, diabetes, together with tumors and cardiovascular diseases were the three main diseases which threats human health. Diabetes mellitus is usually classified into type 1 and type 2, there are more than 240 million diabetes patients, and 90% of them are suffering from type 2 diabetes, which also has a 1% growth rate every year, so, type 2 diabetes will be the main new growth point of diabetes drug market. The incidence of diabetes in China is about 5%, the number of patients of which ranks second place in the world just behind India. There are many antidiabetic drugs on the market, insulin injection, metformin, rosiglitazone, pioglitazone are representations of them. However, there is no drug alone can keep the HbA1c level of type 2 diabetes patients within the aimed range in a long term. Even though used in combination, the effect of the drugs will go down year by year after 3-4 years. Adverse reaction is one of the problems of many hypoglycemic drugs, wherein the fatal hypoglycemia is most worried by clinicians; secondly, many oral hypoglycemic drugs, such as sulfonylureas, α-glycosidase inhibitors and thiazolidinediones may all induce weight gain to patients, some of the drugs may also induce cardiovascular diseases. Therefore, developing new type hypoglycemic drugs with brand new mechanism of action, higher safety and effectiveness is an important task that should be completed quickly for the scientists. In the process of constantly finding new methods endocrine hormones were found to play an important role in the pathology and physiology of type 2 diabetes. Dipeptidyl peptidase-IV (DPP-IV) is an important enzyme related to diabetes, inhibiting the action of which to treat type 2 diabetes is a new method with good prospect. DPP-IV inhibitors can indirectly stimulate the secretion of insulin, the action of which is generated by inhibit DPP-IV to stabilize endocrine hormones such as incretin hormones, glucagons-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). GLP-1 is a production expressed by glucagon protogene after eating, and mainly secreted by intestinal mucosa L-cell, and it can stimulate the secretion of insulin by pancreatic β-cells, which plays a significant role in the stability of blood sugar. Experiments prove that GLP-1 has physiological functions as following: acting on pancreatic β-cells in a glucose-dependent manner, facilitating the transcription of insulin genes, increasing the biosynthesis and secretion of insulin, stimulating the proliferation and differentiation of β-cells, inhibiting the apoptosis of β-cells to increasing the number of pancreatic β-cells; inhibiting the secretion of glucagon; inhibiting the appetite and food intake; retarding the emptying of gastric contents, etc., all of these functions are helpful to reduce blood sugar after food intake and to keep blood sugar within constant level. In addition, it won’t cause the danger of severe hypoglycemia. GLP-1 well controlled the blood sugar of type 2 diabetes animal models and patients by multiple mechanisms. However, GLP-1 may lose biological activity through quick degradation by DPP-IV, and the half life of it is shorter than 2 minutes, which utterly limits the clinical use of GLP-1. It was found in researches that DPP-IV inhibitors can totally protect endogenous and even extraneous GLP-1 from inactivation by DPP-IV, improve activated GLP-llevel, and reduce the antagonistic effect of GLP-1 metabolites. Moreover, DPP-IV inhibitors can also delay the incidence of diabetes through stimulating the regeneration of pancreatic β-cells and the improving the glucose tolerance and insulin sensitivity. Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. For reviews on the application of DPP-IV inhibitors for the treatment of Type 2 diabetes, reference is made to the following publications: (1) H.-U.Demuth.et al. “Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors“, Biochim.Biophvs. Acta. 1751:33-44 (2005) and (2) K.Augustyns. et al. “Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes“, Expert Opin. Ther. Patents, 15:1387-1407 (2005). At present, some DPP-IV inhibitors have been disclosed ( US5462928 , US5543396 , WO9515309 ,WO2003004498 , WO2003082817 , WO2004032836 , WO2004085661 ), including MK-0431 as an DPP-IV inhibitor made by Merck which showed good inhibition activity and selectivity, and which has been on the market by 2006.

    • Figure imgb0001sitagliptin

      (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester of the following formula is compound A, the code of which is SP2086.

      Figure imgb0002

恒瑞医药旗下1.1类口服降糖药物瑞格列汀的制备方法 Synthesis of Hengrui Medicine’s diabetes drug Retagliptin courtesy yaopha see enlarged image at http://www.yaopha.com/2014/02/10/chemical-structure-and-synthesis-of-hengrui-medicines-diabetes-drug-retagliptin/ …………………………………………………………..

            EP2436684A1
                  Example 1. Preparation of hydrochloride of compound A (SP2086-HCL)
                  (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SM2086-15) (1.35kg, 2.40mol), HCL-ethyl acetate (greater than 2M) (12.3kg) were added into a 100L reaction kettle and stirred to dissolved. The mixture was reacted for more than 2 hours at normal temperature. Detected with TLC to reaction completely before evaporated and pumped to dryness with oil pump to give 1.15∼1.20kg of white to light yellow solid product with [α]

D20

                -28.0∼-33.0° (C=1, methanol), yield 96.0∼100%. The product was hydrochloride of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester (SP2086-HCL). (TLC detection: silica gel GF254plate; developing reagent: chloroform: methanol: ammonia= 40: 1: 0.1; raw material 15: Rf=0.80, product 1: Rf=0.50; ultraviolet visualization).

Example 2. Preparation of phosphate of compound A (SP2086-HPO4)

    • SP2086-HCL(1.20kg, 2.40mol) was added into 100L reaction kettle, and dissolved in dichloromethane (15.2kg), then washed with saturated sodium bicarbonate solution (5.8kg). The aqueous layer was extracted once with dichloromethane ( 6.0 kg). The organic layers were combined and washed once with water (5kg), dried with anhydrous sodium sulphate. The mixture was filtrated and concentrated to dryness under reduced pressure at 40°C to give 1.12 kg of oil. The oil was stirred and dissolved with 30 times amount of isopropanol (26.0kg). A solution of 85% phosphoric acid (305.2g, 2.65mol) in isopropanol (1.22kg) was added immidiately after the oil completely dissolved. The solid was separated out, filtered after stirring for 2 hours and washed with cold isopropanol. The wet product was dried under reduced pressure at 40°C to give 1.16∼1.24kg of white to light yellow solid with a yield of 86.0∼92.0% (the wet product could be directly suspended in isopropanol without drying).

……………………………………… http://www.google.com/patents/EP2230241A1?cl=en Example 1(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

        • Figure imgb0068
          Figure imgb0069

Step 1

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane under stirring, followed by addition of (2,4,5-trifluoro-phenyl)-acetic acid 1a (7.15 g, 37.6 mmol) and 4-dimethylaminopyridine (7.35 g, 60.2 mmol) in an ice-water bath. Then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g, 43.2 mmol) in 250 mL of dichloromethane was added dropwise slowly. After stirring at room temperature for 36 hours, the reaction mixture was washed with the solution of 5% potassium bisulfate (250 mL×7) and saturated brine (250 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2,2-dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (11.4 g, yield 96%) as a white solid. MS m/z (ESI): 315.5 [M-1]

Step 23-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

        • 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (15.72 g, 49.6 mmol) was dissolved in 280 mL of ethanol under stirring, then the reaction mixture was heated to 70 °C in an oil bath overnight. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (12 g, yield 88%) as a yellow oil. MS m/z (ESI): 259 [M-1]

Step 33-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester

        • 3-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added to the solution. The reaction mixture was heated to reflux for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, then 100 mL of water was added to the residue. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid. The resulting solid was dissolved in 50 mL of ethyl acetate at 80 °C, then 50 mL of n-hexane and seed-crystal were added to the solution. The mixture was cooled to room temperature, half an hour later, 100 mL of n-hexane was added. The mixture was stored in refrigerator overnight and then filtered under reduced pressure to obtain the title compound 3-amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d(19.5 g, yield 80%) as a white solid. MS m/z (ESI): 260.1 [M+1]Step 43-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester
        • 3-Amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d (4.1 g, 15.8 mmol) was added into an autoclave, followed by addition of 70 mL of methanol, di-tert-butyl dicarbonate (3.8 g, 17.4 mmol), chloro(1, 5-cyclooctadiene)rhodium( I ) dimer (32 mg, 0.0632 mmol) and (R)-1-[(S)-2-(diphenyl phosphino)ferrocenyl]-ethyl-tert-butylphosphine (68 mg, 0.126 mmol). The reaction mixture was hydrogenated for 24 hours under 6.67 atmosphere at 30 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. Then 34 mL of methanol was added to the residue at 50 °C, followed by addition of 12 mL of water until all dissolved. After cooling to room temperature, the mixture was stored in the refrigeratory overnight and then filtered. The solid product was washed with the solvent mixture of methanol/water (v:v = 3:2), dried in vacuo to obtain the title compound 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (4 g, yield 70%) as a light yellow solid. MS m/z (ESI): 362.4 [M+1]Step 5(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid
        • 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45 °C for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mLx3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M-1] Reference: Tetrahedron Asymmetry, 2006, 17(2), 205-209

Step 6C-Pyrazin-2-yl-methylamine

        • Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1]

Step 72,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide

        • C-Pyrazin-2-yl-methylamine 1h (10.9 g, 100 mmol) was added into a reaction flask, then 20 mL of trifluoroacetic anhydride was added dropwise slowly within an hour at 0 °C in an ice-water bath. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Then it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2,2,2-trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g) as a brown oil. MS m/z (ESI): 206.1 [M+1]

Step 83-Trifluoromethyl-imidazo[1,5-a]pyrazine

        • 2,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g, 100 mmol) was added into a reaction flask at room temperature, followed by addition of 100 mL of phosphorus oxychloride. After stirring at room temperature for 30 minutes, phosphorous pentoxide (17.8 g, 125 mmol) was added to the solution. The reaction mixture was heated to reflux for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Phosphorus oxychloride was removed, and the reaction system was quenched with deionized water. The mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath. The mixture was extracted with ethyl acetate (250 mL×4), and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, yield 65%) as a yellow solid. MS m/z (ESI): 188.0 [M+1] 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H)

Step 93-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

        • 3-Trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of anhydrous ethanol under stirring, then 10% Pd/C (500 mg) was added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through a pad of coarse silica gel and concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (12.2 g, yield 99%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 6.84 (s, 1H), 4.10 (m, 4H), 3.26 (m, 2H), 1.81 (s, 1H)

Step 10(R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester

        • Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1f (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H)

Step 11(R)-[3-(1-Bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acidtert-butyl ester

        • (R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 11 (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol under stirring, and 1-bromo-2,5-pyrolidinedione (14.1 g, 79.2 mmol) was then added to the solution at room temperature. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for an hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was filtered through a pad of coarse silica gel to remove potassium carbonate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-i midazo [1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1m (20.0 g, yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.063 (m, 1H), 6.88 (m, 1H), 4.72 (s, 1H), 4.56 (s, 1H), 4.13 (m, 3H), 3.88 (m, 2H), 2.94 (m, 2H), 2.62 (m, 2H), 1.36 (s, 9H)

Step 12(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester

      • Octacarbonyldicobalt (4.02 g, 11.76 mmol), ethyl chloroacetate (0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of methanol were added into the reaction flask. After stirring for 5 minutes, (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acidtert-butyl ester 1m (2.3 g, 3.92 mmol) was added. The reaction mixture was reacted at 60 °C in an oil bath, and the colour of the reaction mixture turned from puce to purple. 2 hours later, Electro-Spray Ionization (ESI) mass spectrometry showed the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (1.1 g, yield 50%) as a white solid. MS m/z (ESI): 565.0 [M+1] Reference: Journal of Organometallic Chemistry, 1985, 285(1-3), 293-303

Step 13(R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

  • [0064]
    (R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (0.12 g, 2.12 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 1 (0.12 g, yield 94.3%) as a light yellow solid. MS m/z (ESI): 465.2 [M+1] 1H NMR (400 MHz, CD3OD): δ 7.101-7.08 (m, 1H), 6.906-6.864 (m, 1H), 5.343-4.995 (m, 2H), 4.221-4.093 (m, 5H), 3.954 (s, 3H), 2.978-2.937 (m, 2H), 2.71-2.643 (m, 2H), 2.061 (s, 2H)
EP2230241A1 * Nov 27, 2008 Sep 22, 2010 Jiangsu Hengrui Medicine Co., Ltd. Tetrahydro-imidazoý1,5-a¨pyrazine derivatives, preparation methods and medical uses thereof
WO2003004498A1 * Jul 5, 2002 Jan 16, 2003 Merck & Co Inc Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2005003135A1 * Jun 18, 2004 Jan 13, 2005 Alex Minhua Chen Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

Zifaxaban, TY-602, Zhifeishaban 知非沙班……Tianjin Institute of Pharmaceutical Research China


 

zifa

 

Zifaxaban

Figure CN102464658AD00081

Zifaxaban

cas 1378266-98-8

rotation (-)

C20 H16 Cl N3 O4 S

C20H16ClN3O4 S, M = 429.87

Tianjin Institute of Pharmaceutical Research

Deep vein thrombosis; Lung embolism

Factor Xa antagonist

TY-602; zhifeishaban; zifaxaban

天津药物研究院

Chinese J Struc Chem. 2014, 33 (7), 1091-1095.

(S) -5- chloro -N- ((2- oxo _3_ (4_ (2_ oxo _2H_-1-yl) phenyl) oxazolidin-5 -1,3_ yl) methyl) thiophene-2-carboxamide

5-Chloro-N-(5S)-2-oxo-3-[4-(2-oxopyridin-1(2H)-yl)phenyl]oxazolidin-5-ylimethyllthiophene-2-carboxamide]

 

The title compound(zifaxaban 2, C20H16ClN3O4 S, Mr = 429.87) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900(12), b = 13.086(3), c = 12.889(3) A, β = 100.86(3)°, V = 959.1(3) A3, Z = 2, Dc = 1.489 g/cm3, F(000) = 444, μ = 0.342 mm-1, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections(I > 2σ(I)).

The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation.

Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.

zifaxaban (first disclosed in CN102464658), useful for treating thromboembolic disorders. Zifaxaban, a factor Xa antagonist, is being developed by Tianjin Institute of Pharmaceutical Research, for treating deep vein thrombosis and pulmonary embolism (preclinical, as of November 2014). In May 2014, an IND was filed in China. In June 2014, the institute was seeking to outlicense this product.

In vivo within the cardiovascular, blood coagulation or blood analysis some have formed out of the process of forming a solid mass with the aggregation, called thrombosis, the formation of a solid mass called a thrombus blocks. Thrombosis is an abnormal flow of blood coagulation status due to platelet activation and coagulation factors are activated in accordance therewith.

The blood coagulation was originally a protective mechanism of the organism, there is a mutual antagonism in blood coagulation system and the anti-clotting system. Under physiological conditions, blood clotting factors continue to be activated to produce thrombin, fibrin formation trace, calm on the vascular endothelium, but these traces of fibrin and constantly being activated fibrinolytic system dissolution, while being activated coagulation factors are constantly mononuclear phagocyte system swallowed. The dynamics of the coagulation system and fibrinolysis system, which ensures the blood coagulation potential can also always ensure that the fluid state of the blood.

 Sometimes, however, in certain factors can promote the coagulation process, breaking the above dynamic balance triggered the coagulation process, the blood can form a thrombosis or embolism, such as leading to myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and other thromboembolic disease.

Thromboembolic disease is cardiovascular disease against the most serious diseases, is the first killer of human health. In China, with the improvement and increased aging of the population’s living standards, the incidence of such diseases, mortality, morbidity is increasing every year.

The existing anti-thromboembolic diseases into anti-platelet drugs, anticoagulants and fibrinolytic drugs. Among them, the anti-clotting drugs are the main contents of antithrombotic therapy, mainly thrombin inhibitors and vitamin K antagonists. Heparin and low molecular weight heparin, represented by the presence of oral thrombin inhibitor invalid, non-selective inhibition and high risk of bleeding and other shortcomings. Although warfarin is representative of vitamin K antagonists can be administered orally, but there are narrow therapeutic index, high risk of bleeding and other shortcomings.

Studies have shown that the coagulation process is usually divided into intrinsic coagulation pathway and the extrinsic coagulation pathway. Coagulation process involves a lot of coagulation factors, coagulation factor activated are each the next inactive clotting factor precursor is converted into the activated form. Endogenous, exogenous pathway final summary, the blood coagulation factor X is converted to Xa.

Therefore, theoretically, the direct inhibition of ¾ factor activity should produce effective anti-clotting effect, without the side effects of thrombin inhibitors with. As direct inhibition) (a factor activity on normal hemostasis reaction / adjustment process produces minimal impact. For example, platelets remain low catalytic activity of thrombin on the ability to respond to, and thus does not affect the formation of platelet thrombi, so bleeding integrated minimize the risk of the levy.

  research also proved this point. Recently reported a variety of compounds can selectively inhibit efficient Xa, which play a preventive and / or treatment of thromboembolic disease effect (W003000256A1; CN00818966; US2007259913A1; US2007259913A1). Among them, rivaroxaban (Rivaroxaban) was listed in 2008 for hip or knee replacement surgery prophylaxis and treatment of venous thrombosis, with oral, fixed dose and other advantages.

  rivaroxaban drawback is the high price of raw materials, low yield preparation, purification of the product is difficult, high production costs. Patent CN00818966 8 reported rivaroxaban synthetic routes as follows:

4

Figure CN102464658AD00051

where the first reaction (Preparation of 4- (4-morpholino-3-yl) nitrobenzene) yield of only 17.6%, and rivaroxaban difficult purification.

 

Figure CN102464658AD00061

 

………………………………

Patent

http://www.google.com/patents/CN103232446A?cl=en

(S) -5- chloro -N- ((2- oxo-3- (4- (2_ oxo -2H- pyridin-1-yl) phenyl) -1, 3_ oxazolidine -5 – yl) methyl) thiophene-2-carboxamide.

[0011] Meanwhile, patent CN201110337461.4 described formula (I) Preparation of the compound:

[0012]

Figure CN103232446AD00041

 

……………………………………..

Patent

CN102464658

http://www.google.com/patents/CN102464658B?cl=en

Example 1

[0046] (S) -5- chloro -N- ((2- oxo-3- (4_ (2_ Batch oxo _2H_ piperidinyl) phenyl) _1,3_ oxazolidin-5-yl) methyl ) thiophene-2-carboxamide (II)

 

Figure CN102464658AD00081

[0048] A, 1- (4- amino-phenyl) -IH- pyridin _2_ -one (Compound VII) is

[0049] The reaction flask was charged with 104g of pyridine -2 (IH) – one (Compound IX), 200g of iodoaniline (compound VIII), 26gCuI, 151g of potassium carbonate, 18g8- hydroxyquinoline, 500mlDMF, nitrogen, heated to reflux, Insulation reaction was stirred 10h. Filtered hot, the filtrate evaporated under reduced pressure to make the solvent, the residue was added ethyl acetate, IL, 0 ° C incubated with stirring lh, filtered and the solid dried, 2L acetonitrile and purified to give 98g dark red solid. Refined liquor was concentrated to 500ml, the ice bath was stirred lh, filtered to give a dark red solid 19g. Total product were 117g, yield 68.9%.

[0050] 1H-NMR (DMSO-Cl6), δ (ppm):… 5 306 (s, 2H), 6 236 (d, 1H), 6 406 (d, 1H), 6 601 (d,. 2H), 6. 977 (d, 2H), 7. 459 (m, 2H).

[0051] B, (R) -2- (2- hydroxy-3- ((2-oxo–2H- pyridin-1-yl) phenyl) amino) propyl) isoindoline-1,3- -dione (Compound V) is

[0052] The reaction flask was added 40gl_ (4- aminophenyl) -IH- pyridin-2-one (Compound VII), 45g (S) _N_ glycidyl phthalimide (Compound VI), 300ml95% ethanol, heating to reflux, the gradual emergence of solid insulation mixing IOh, cooled to room temperature, filtered, and the filter cake washed with ethanol (150ml X 2), and dried to give an off-white solid 38g.

[0053] The mother liquor was taken, evaporated to dryness under reduced pressure, was added 15g (Q-N_ glycidyl phthalimide (Compound VII), 150ml95% ethanol, heated to reflux, stirred incubated 10h, concentrated under reduced pressure, cooled to room temperature , stirred at room temperature for 2h, washed with ethanol and dried to give an off-white solid 33g.

[0054] A total of an off-white solid 71g, yield of 84.8%, without purification, was used directly in the next step.

[0055] 1H-NMR (DMS0_d6), δ (ppm):… 3 053 (m, 1H), 3 194 (m, 1H), 4 644 (m, 2H), 4 020 (m, 1H). , 5. 168 (d, 1H), 5. 851 (t, 1H), 6. 230 (m, 1H), 6. 404 (d, 1H), 6. 665 (d, 2H), 7. 041 ( d, 2H), 7. 435 (m, 1H), 7. 537 (m, 1H), 7. 855 (m, 4H).

[0056] C, ⑶-2- ((2- oxo-3- (4- (2_ oxo _2H_ pyridyl) phenyl) oxazolidin _5_ -1,3_ yl) methyl ) Preparation of isoindoline-1,3-dione (Compound IV) of the

[0057] The reaction flask was charged 50g Compound V, 27gN, N’- carbonyldiimidazole (⑶I), 4_ catalytic amount of dimethylaminopyridine (DMAP), 150mlN, N- dimethylformamide (DMF), stirred for 90 temperature ° C, the reaction was kept for 8 hours to make the solvent was evaporated under reduced pressure, added to IL of water, stirred and dispersed, filtered, washed with water (150mlX “, washed with ethanol (100ml X 1), dried to give a white solid 48g, yield of 90%.

[0058] 1H-NMR (DMSo-CI6), δ (ppm):…. 3 984 (m, 3H), 4 251 (t, 1H), 4 968 (m, 1H), 6 301 (m, 1H), 6. 459 (d, 1H), 7. 423 (d, 2H), 7. 514 (m, 1H), 7. 615 (m, 3H), 7. 892 (m, 4H).

[0059] D, (S) -5- (aminomethyl) -3- (4- (2_ oxo _2H_-1-yl) phenyl) oxazolidin _2_ -1,3_ one hydrochloride (compound III) Synthesis of

[0060] The reaction flask was charged 50g compound IV, 200ml of ethanol, 60ml aqueous methylamine (40%), heated to reflux, stirred incubated 2h, cooled, evaporated under reduced pressure to make the solvent to give a sticky solid.

[0061] added to 300ml of ethanol, 20ml of hydrochloric acid, heated to reflux, stirred incubated lh, cooled to room temperature, incubated with stirring 2h, filtered, washed with ethanol, and dried to obtain;. 34 5g of white solid, yield 88.7%.

 1H-NMR (DMS0_d6), δ (ppm):…. 3 240 (m, 2H), 3 980 (m, 1H), 4 255 (m, 1H), 5 028 (m, 1H) , 6. 321 (m, 1H), 6. 475 (d, 1H), 7. 504 (m, 3H), 7. 634 (m, 3H), 8. 561 (s, 1H).

 Ε, (S) -5- chloro -N – ((2- oxo-3- (4- (2-oxo–2Η- pyridin-1-yl) phenyl) oxazolidin _1,3_ 5-yl) methyl) thiophene-2-carboxamide Preparation of thiophene (II) of

The reaction flask was charged 15g Compound III, 200ml of tetrahydrofuran, 40ml of water was added with stirring 6. 2g of sodium carbonate was added dropwise 10g5- chloro-thiophene-2-carbonyl chloride (Compound II-1) in tetrahydrofuran IOOml, 30~35 ° C insulation stirred 5h, point board to control the reaction was complete.

 to make the solvent was distilled off under reduced pressure, 50ml of water was added, stirring was filtered, the filter cake washed with water and dried to give 18. 5g of white solid.

 200ml of acetic acid and purified room temperature overnight, filtered, and the filter cake washed with ethanol and dried to give a white solid 16g, 80% yield.

Melting point: 204 8 ~205 8 ° C;

 1H-NMR (DMSo-CI6), δ (ppm):…. 3 623 (t, 2H), 3 893 (m, 1H), 4 230 (t, 1H), 4 871 (m, 1H), 6. 308 (t, 1H), 6. 468 (d, 1H), 7. 193 (d, 1H), 7. 426 (m, 2H), 7. 500 (m, 1H), 7. 637 (m, 4H), 8. 967 (t, 1H);

 MS (ESI): m / z = 430 (M + H);

 HPLC: rt (%) = 14. 38 (99. 62);

 [a] 20d = -37 6 ° (c 0. 3004, DMS0);

 

WO-2014183667Acetic acid solvate of oxazolidinone derivative, preparation method for the solvate, and application thereof

 

WO-2014183665Oxazolidinone derivative crystal form I and preparation method and use thereof

 

WO-2014183666Oxazolidinone derivate crystal form II, preparation method therefor, and application thereo

 

SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

/////////

 

TORCETRAPIB Revisted


Torcetrapib
Torcetrapib
CAS : 262352-17-0
(2R,4S)-4-[[[3,5-Bis(trifluoromethyl)phenyl]methyl](methoxycarbonyl)amino]-2-ethyl-3,4-dihydro-6-(trifluoromethyl)-1(2H)-quinolinecarboxylic acid ethyl ester
(2R,4S)-4-[(3,5-bis-trifluoromethylbenzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
Manufacturers’ Codes: CP-529414
Molecular Formula: C26H25F9N2O4
Molecular Weight: 600.47
Percent Composition: C 52.01%, H 4.20%, F 28.48%, N 4.67%, O 10.66%
Properties: Anhydrous, non-hygroscopic crystals, mp 89-90°. d 1.406.
Melting point: mp 89-90°
Density: d 1.406
 
Derivative Type: Ethanolate
CAS Registry Number: 343798-00-5
Molecular Formula: C26H25F9N2O4.C2H6O
Molecular Weight: 646.54
Percent Composition: C 52.02%, H 4.83%, F 26.45%, N 4.33%, O 12.37%
Properties: White crystalline powder, mp 54-58°. [a]D -93.3° (c = 1.08 in methanol). d 1.402. Non-hygroscopic. Higher aqueous soly than anhydrous form.
Melting point: mp 54-58°
Optical Rotation: [a]D -93.3° (c = 1.08 in methanol)
Density: d 1.402
Therap-Cat: Antilipemic; antiatherosclerotic.
 Torcetrapib.png

Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.

 

Medical uses

Torcetrapib has not been found to affect either cardiovascular disease or risk of death in those already taking a statin.[1]

Mechanism

Torcetrapib acts (as a CETP inhibitor) by inhibiting cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the “good” cholesterol-containing particle) and reduces LDL levels (the “bad” cholesterol).[vague][citation needed]

Development

The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.[2]

Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.[3]

Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer’s statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.[4]

Clinical trials

A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[5]

Nine phase III studies were completed.[6][7][8][9][10][11][12][13][14][15]

Early termination of study

On December 2, 2006 Pfizer cut off torcetrapib’s phase III trial because of “an imbalance of mortality and cardiovascular events” associated with its use.[16] This was a sudden and unexpected event and as late as November 30, 2006 Jeff Kindler, Pfizer’s chief executive, was quoted, “This will be one of the most important compounds of our generation.”[16] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.[17] Pfizer recommended that all patients stop taking the drug immediately.[18]

Six studies were terminated early.[6] One of the completed studies found it raised systolic blood pressure and concluded “Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.”[19]

The drug cost $800m+ to bring into Phase III development.[20]

 09008-cover-cetrapib
 Dec. 2, 2006, was a day drugmakers won’t soon forget. On that day, Pfizer, the world’s biggest drug company, faced devastating news: Its highest profile drug candidate, the cholesterol-targeted molecule torcetrapib, had increased the risk of death in a 15,000-patient clinical trial. In light of the data, Pfizer promptly pulled the plug on the cholesteryl ester transfer protein (CETP) inhibitor that already had cost more than $800 million to develop. The torcetrapib news rocked the cardiovascular research field and left Pfizer without a potential new medication to supplement the blockbuster cholesterol drug Lipitor (atorvastatin), which was careening toward the patent cliff.
 
 
……………………
A Concise Asymmetric Synthesis of Torcetrapib�, M. Guino, P. H. Phua, J-C. Caille and K. K. Hii, J. Org. Chem., 2007, 72, 6290-6293.doi:10.1021/jo071031gAbstract: Optically active torcetrapib was synthesized in seven steps from achiral precursors without the need for protecting groups, utilizing an enantioselective aza-Michael reaction to achieve asymmetry.

 ………………………..
PATENT

Example 9 Anhydrous, (-)-(2R,4S)-4-[(3,5-Bιs-trιfluoromethyl-benzyl)-methoxycarbonyl-amιnol-2- ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester.

A 2.6g portion of 4(S)-[(3,5-bιs-tπfluoromethyl-benzyl)-methoxycarbonyl-amιno]-2(R)- ethyl-6-tπfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester (a mixture of predominantly amorphous material with traces of ethanolate crystalline form; the title compound was also prepared in an analogous manner starting from pure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanes and heated to effect a solution at about 60°C The heat was removed and the reaction was allowed to cool to ambient over a one hour period The reaction was seeded with anhydrous (-)-(2R,4S)-4-[(3,5-bιs-tπfluoromethyl-benzyl)- methoxycarbonyl-amιno]-2-ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 – carboxylic acid ethyl ester and granulated for eighteen hours under ambient conditions. Alternately, the anhydrous crystals may be prepared from hexanes without seeding. The product was collected by filtration and air dried. The isolated product X-ray pattern matched the calculated powder pattern. Density: 1.406 Crystal System: Trigonal

Microscopy: Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C axis. The crystals demonstrate a cleavage plane perpendicular to the C axis Fusion Microsocopy In Type A oil dissolution at 50°C.

Dry — clear melt at 86°C.

NMR: No trace of ethanolate

Degree of crystallmity: Highly crystalline Hygroscopicity. Non-hygroscopic at 100% relative humidity over 48 hours.

Appearance: Free flowing white powder

 
Lit References:
Cholesteryl ester transfer protein (CETP) inhibitor. Prepn: M. P. DeNinno et al., WO 0017164; eidem, US6197786 (2000, 2001 both to Pfizer); of crystalline forms: D. J. M. Allen et al., WO 0140190 (2001 to Pfizer).
Mechanism of action study: R. W. Clark et al., J. Lipid Res. 47, 537 (2006).
Clinical evaluation of effects on HDL cholesterol levels: R. W. Clark et al.,Arterioscler. Thromb. Vasc. Biol. 24, 490 (2004); M. E. Brousseau et al., N. Engl. J. Med. 350, 1505 (2004).
Review of clinical development in combination with atorvastatin: J. R. Burnett, Curr. Opin. Invest. Drugs 6, 944-950 (2005).

References

Notes

  1.  Keene, D; Price, C; Shun-Shin, MJ; Francis, DP (Jul 18, 2014). “Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients.”. BMJ (Clinical research ed.) 349: g4379. PMID 25038074.
  2.  Buchwald, Stephen (July 23, 2004). “Research Projects”. Retrieved 2007-10-04.
  3. “Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility” (Press release). Pfizer. June 22, 2005. Retrieved 2006-12-03.
  4.  Berenson, Alex (July 26, 2006). “Heart Pill to Be Sold by Itself”. Business (The New York Times). Retrieved 2006-12-03.
  5. Brousseau, ME; Schaefer EJ; Wolfe ML; Bloedon LT; Digenio AG; Clark RW; Mancuso JP; Rader DJ (April 8, 2004). “Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol” (abstract). New England Journal of Medicine 350 (15): 1505–1515. doi:10.1056/NEJMoa031766. PMID 15071125. Retrieved 2006-12-03.
  6.  http://clinicaltrials.gov/ct2/results?term=torcetrapib
  7.  http://clinicaltrials.gov/ct2/show/NCT00139061 Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate
  8.  http://clinicaltrials.gov/ct2/show/NCT00134511 Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
  9.  http://clinicaltrials.gov/ct2/show/NCT00134485 Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
  10.  http://clinicaltrials.gov/ct2/show/NCT00134498 Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
  11.  http://clinicaltrials.gov/ct2/show/NCT00267254 Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol
  12.  http://clinicaltrials.gov/ct2/show/NCT00138762 Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol
  13. http://clinicaltrials.gov/ct2/show/NCT00134173 Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)
  14.  http://clinicaltrials.gov/ct2/show/NCT00137462 Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone.
  15.  http://clinicaltrials.gov/ct2/show/NCT00136981 Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)
  16.  Berenson, Alex (December 3, 2006). “Pfizer Ends Studies on Drug for Heart Disease”. The New York Times. Retrieved 2006-12-03. (registration required)
  17.  Theresa Agovino (Associated Press) (December 3, 2006). “Pfizer ends cholesterol drug development”. Yahoo! News. Retrieved 2006-12-03.[dead link] Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
  18. Associated Press (December 2, 2006). “Pfizer cuts off cholesterol drug trials”. Yahoo! News (Yahoo.com). Retrieved 2006-12-03.[dead link] (Link dead as of 15 January 2007)
  19.  Bots et al.; Visseren, Frank L; Evans, Gregory W; Riley, Ward A; Revkin, James H; Tegeler, Charles H; Shear, Charles L; Duggan, William T et al. (July 2007). “Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial”. The Lancet 370 (9582): 153–160. doi:10.1016/S0140-6736(07)61088-5.
  20. Cutler, D. M. (2007-03-29). “The Demise of the Blockbuster?”. The New England Journal of Medicine (Massachusetts Medical Society) 356 (13): 1292–1293. doi:10.1056/NEJMp078020.ISSN 1533-4406. PMID 17392299. Retrieved 2007-04-23.

External links

Keywords: Antilipemic; CETP Inhibitor; Antiatherosclerotic.

Troglitazone (Romglizone) an antidiabetic Revisted


Troglitazone svg.svg

Troglitazone, GR-92132X, CI-991, CS-045, Romozin, Prelay, Rezulin, Noscal

CAS 97322-87-7

C24 H27 N O5 S, 441.54
(±)-5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-ylmethoxy)benzyl]thiazolidine-2,4-dione
2,​4-​Thiazolidinedione, 5-​[[4-​[(3,​4-​dihydro-​6-​hydroxy-​2,​5,​7,​8-​tetramethyl-​2H-​1-​benzopyran-​2-​yl)​methoxy]​phenyl]​methyl]​-
  • CI 991
  • CS 045
  • Depotox
  • GR 92132X
  • Noscal
  • Rezulin
  • Romglizone
  • Troglitazone

Withdrawn – 2000

Crystals, m.p. 184-6 °C

Daiichi Sankyo Co., Ltd. INNOVATOR

Trademarks: Noscal (Sankyo); Prelay (Sankyo); Rezulin
Percent Composition: C 65.28%, H 6.16%, N 3.17%, O 18.12%, S 7.26%
Properties: Crystals from benzene-acetone, mp 184-186°.
Therap-Cat: Antidiabetic.
Insulin Sensitizer.

Troglitazone

Type-II diabetes mellitus (DM) is characterized by insulin resistance, glucose intolerance, increased hepatic glucose production, and decreased pancreatic insulin secretion. In the past, the drug classes used for type-II DM have targeted the last three of these abnormalities. Sulfonylurea agents bind to ATP-dependent potassium efflux channels to stimulate pancreatic insulin secretion at b-islet cells. The biguanides decrease hepatic glucose production, and thea-glucosidase inhibitors delay carbohydrate digestion to improve glucose tolerance. Until the recent advent of the thiazolidinedione drugs (ciglitazone was first synthesized in 1982), there was no therapy specifically targeting insulin resistance. Drugs of this class all share a common thiazolidine-2-4-dione structure. Marketed drugs of this class include pioglitazone, rosiglitazone, and troglitazone [Figure 1] – the first to reach the market.

The “glitazones” act to reduce insulin resistance and also correct hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Thiazolidinediones bind to the gisoform of the peroxisome proliferator-activated receptor (PPARg), a nuclear transcription factor that regulates the expression of several insulin-responsive genes involved in glucose and lipid metabolism, and the differentiation of fibroblasts into adipose tissue. The net effect is to reduce insulin resistance, mostly through increased glucose uptake by muscle tissue; however, the exact biochemical mechanism is unclear. Effects on lipid metabolism include decreased triglycerides and free fatty acids, and a slight increase or no change in high-density lipoprotein, low-density lipoprotein, and total cholesterol. There also appear to be acute increases in insulin-stimulated glucose uptake that are PPAR-independent. This effect is too rapid to occur via gene transcription, and in the case of troglitazone may result from action of its quinone metabolite. Troglitazone also decreases production of various inflammatory mediators and may antagonize TNFa.

Troglitazone�s most common adverse effect is fluid retention, which may increase preload and induce cardiac hypertrophy. Troglitazone is contraindicated in congestive heart failure, and cases of pulmonary edema have been reported. Troglitazone induces colon polyps in murine models and is therefore contraindicated for patients with familial polyposis coli. Troglitazone and pioglitazone (but not rosiglitazone) induce cytochrome P450 (CYP) 3A4. This enzyme induction can result in decreased drug levels or drug effects with estradiol, terfenadine, cyclosporine, simvistatin, tacrolimus, and other drugs metabolized by CYP 3A4. A small fraction of troglitazone is metabolized by CYP (not 3A4) to an active quinone metabolite, but it is mostly conjugated to sulfate and glucuronide. Troglitazone enhances the anticoagulant effect of warfarin, probably through competitive serum protein binding, and has other drug interactions at the PPAR level. Troglitazone interferes with gemfibrozil’s binding to PPARa, and may decrease NSAID effectiveness by competing for PPARg.

Rezulin (tradename troglitazone by Parke-Davis) was FDA approved January 29, 1997, and was first marketed in March 1997. Over 600,000 American patients received troglitazone, with an additional 200,000 in Japan. Pre-marketing studies showed 1.9% of patients on troglitazone developed serum alanine aminotransferase levels in excess of three times the upper limit of normal, vs. 0.6% with placebo. Such hepatotoxicity was typically asymptomatic and reversible. A few patients developed overt liver injury, and two liver biopsies among these patients showed hepatocellular injury pattern. It was estimated that only 1 patient in 50,000 to 60,000 would die from liver failure or require liver transplantation. On November 3, 1997, the FDA released a warning regarding 150 adverse events with troglitazone, 35 with acute liver injury, and 3 deaths in Japan from liver failure. The warnings and restrictions about troglitazone were extended in December 1997, July 1998, and June 1999. Troglitazone was voluntarily withdrawn from the US market on March 21, 2000, after it had been demonstrated that Rezulin was more toxic than either Avandia (rosiglitazone) or Actos(pioglitazone).

Troglitazone hepatotoxicity appears to be idiosyncratic. The onset is typically delayed, usually 2-5 months after initiating therapy, although one case was reported after only four doses. Although hypersensitivity has been suggested in several cases, the hallmarks of immune mechanisms, fever, rash, and eosinophilia, are usually absent. Histologic specimens usually show hepatocellular injury, bridging fibrosis and necrosis, intracanalicular cholestasis, and lack of regenerative activity. Samples vary in the amount of WBC infiltration (with or without eosinophils) and steatosis.

Idiosyncratic (or host-dependent) drug reactions are either due to hypersensitivity or to metabolic aberrations. It is not clear whether troglitazone hepatotoxicity is caused by hypersensitivity. Proposed metabolic aberrations include oxidation/reduction reactions with the a-tocopherol moiety on troglitazone (although it is usually considered an antioxidant), reactions from the quinone metabolite (similar to acetaminophen’s quinone metabolite), and genetic variations in cytokines and their receptors, the apoptosis cascade, mitochondrial respiration, and regenerative response. It is unlikely that CYP polymorphisms play a major role, as the incidence of troglitazone hepatotoxicity is too low. Two cases of hepatic toxicity associated with rosiglitazone have also been reported. Although the patients had co-morbidities, exposures to other drugs, and one case may have been due to shock, these cases suggest that hepatotoxicity may be an emerging “class-effect” of thiazolidinediones.

Troglitazone (Rezulin, Resulin, Romozin, Noscal) is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for patients with diabetes mellitus type 2.[1] It was developed by Daiichi Sankyo Co.(Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. One F.D.A. medical officer evaluating troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity,[2] but a full panel of experts approved it in January 1997.[3] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards. It didn’t get approval in the rest of Europe.

Approval history

Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin sensitivity. At the time it was widely believed that such drugs, by addressing the primary metabolic defect associated with Type 2 diabetes, would have numerous benefits including avoiding the risk of hypoglycemia associated with insulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate of cardiovascular disease that is associated with diabetes.[4][5]

Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for U.S. Food and Drug Administration (F.D.A.) review on July 31, 1996. The medical officer assigned to the review, Dr. John L. Gueriguian, cited Rezulin’s potential to harm the liver and the heart and he questioned its viability in lowering blood sugar for patients with adult-onset diabetes, recommending against the drug’s approval. After complaints from the drugmaker, Gueriguian was removed on November 4, 1996 and his review was purged by the F.D.A.[6][7]Gueriguian and the company had a single meeting, at which Gueriguian used “intemperate” language; The company said it’s objections were based on inappropriate remarks made by Gueriguian.[8] Parke-Davis said at the advisory committee that the risk of liver toxicity was comparable to placebo and that additional data of other studies confirmed this.[9] According to Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantial greater risk for liver toxicity.[10]

The F.D.A. approved the drug on January 29, 1997, and it appeared in pharmacies in late March. At the time Dr. Solomon Sobel, a director at the F.D.A., overseeing diabetes drugs, said in a New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[11]

Glaxo Wellcome P.L.C. received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.[12] After reports of sudden liver failure in patients receiving the drug, the Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels.[13] Glaxo removed troglitazone from the market in Britain on December 1, 1997.[6] Glaxo had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[14][15]

On May 17, 1998, a 55-year old patient named Audrey LaRue Jones died of acute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at the National Institutes of Health as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.[16][17] This called into question the efficacy of the monitoring strategy. The N.I.H. responded on June 4 by dropping troglitazone from the study.[7][18] Dr. David J. Graham, an F.D.A. epidemiologist charged with evaluating the drug, warned on March 26, 1999 of the dangers of using it and concluded that patient monitoring was not effective in protecting against liver failure. He estimated that the drug could be linked to over 430 liver failures and that patients incurred 1,200 times greater risk of liver failure when taking Rezulin.[7][19] Dr. Janet B. McGill, an endocrinologist who had assisted in the Warner–Lambert’s early clinical testing of Rezulin, wrote in a March 1, 2000 letter to Sen. Edward M. Kennedy (D-Mass.): “I believe that the company . . . deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies.”[20]

On March 21, 2000, the F.D.A. withdrew the drug from the market.[21] Dr. Robert I. Misbin, an F.D.A. medical officer, wrote in a July 3, 2000 letter to the House Energy and Commerce Committee of strong evidence that Rezulin could not be used safely, after having been threatened by the FDA with dismissal in March 2000.[6][22] By that time the drug had been linked to 63 liver-failure deaths and had generated sales of more than $2.1 billion for Warner-Lambert.[19] The drug cost $1,400 a year per patient in 1998.[15] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[23]

Lawsuits

In 2009 Pfizer Inc. resolved all but three of 35,000 claims over its withdrawn diabetes drug Rezulin for a total of about $750 million. Pfizer, which acquired rival Wyeth for almost $64 billion, paid about $500 million to settle Rezulin cases consolidated in federal court in New York, according to court filings. The company also paid as much as $250 million to resolve state-court suits. In 2004, it set aside $955 million to end Rezulin cases.[24]

Mode of action

Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating peroxisome proliferator-activated receptors (PPARs).

Troglitazone is a ligand to both PPARα and – more strongly – PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation:[25] troglitazone use was associated with a decrease of nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response.

 

 

 

rosiglitazone, ciglitazone, darglitazone, englitazone, rosiglitazone, pioglitazone, rosiglitazone, troglitazone

 

Systematic (IUPAC) name
(RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
Clinical data
Legal status
?
Pharmacokinetic data
Half-life 16-34 hours
Identifiers
CAS number 97322-87-7 
ATC code A10BG01
PubChem CID 5591
IUPHAR ligand 2693
DrugBank DB00197
ChemSpider 5389 Yes
UNII I66ZZ0ZN0E Yes
KEGG D00395 Yes
ChEBI CHEBI:9753 Yes
ChEMBL CHEMBL408 Yes
Chemical data
Formula C24H27NO5S 
Mol. mass 441.541 g/mol

………………….

 

………………..

 

A new synthesis of [14C]-labeled CS-045 has been reported: The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III), which is reduced with NaBH4 in methanol to the corresponding carbinol (IV). The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V), which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI). The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII), which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII). The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX), which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI). Finally, this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.

……………….

A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.

…………..

European Journal of Medicinal Chemistry, 51, 206-215; 2012

http://www.sciencedirect.com/science/article/pii/S0223523412001353

Full-size image (28 K)

……………………………………….

see       Indian Journal of Heterocyclic Chemistry, 15(4), 407-408; 2006

……………………………………………………….

Bioorganic & Medicinal Chemistry Letters, 14(10), 2547-2550; 2004

http://www.sciencedirect.com/science/article/pii/S0960894X04003038

Full-size image (3 K)

Figure 1.

 

Full-size image (7 K)

Scheme 2.

(a) t-Butyldimethylsilyl chloride, imidazole, DMF; (b) LAH, rt, 3 h (75.9%, two steps); (c) 4-fluorobenzaldehyde, KtOBu, DMF, 80 °C, 8 h; (d) 2,4-thiazolidinedione, AcOH, piperidine, toluene, reflux, 4 h (37%, two steps); (e) HCl, MeOH, 15 min; (f) CoCl2, DMG (84%).

 

………………………

Patent

http://www.google.co.in/patents/US5700820

EXAMPLE-1

A mixture of 70 g of ethyl-3- 4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl!-2-chloropropionate, 13.12 g of thiourea and 80.2 ml of sulpholane was reacted for 80 min., under a nitrogen stream at 115°-120° C. Subsequently, a 656.2 ml Acetic acid, 218.7 ml conc. hydrochloric acid and 109.4 ml water was added to this and the resulting mixture was further heated for 12 hrs at 85°-90° C. The reaction mixture was cooled to room temperature and 196.8 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 40 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ˜67-70%. The elution of column was continued further to yield 5- 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl!2-iminothiazolidine-4-one with HPLC purity of ˜70%.

Lit References:

Oral hypoglycemic agent which improves insulin sensitivity and decreases hepatic glucose production. Prepn: JP Kokai 85 51189; T. Yoshioka et al., US 4572912 (1985, 1986 both to Sankyo); T. Yoshioka et al.,

J. Med. Chem. 32,421 (1989).

Mechanism of action studies: T. P. Ciaraldi et al., Metabolism 39, 1056 (1990); M. Kellerer et al., Diabetes 43, 447 (1994).

Clinical evaluation: T. Kuzuya et al., Diabetes Res. Clin. Pract. 11, 147 (1991).

Clinical metabolic effects: S. L. Suter et al., Diabetes Care 15, 193 (1992).

References

  1.  Fisher, Lawrence (4 November 1997). “Adverse Diabetes Drug News Sends Warner-Lambert Down”. The New York Times. Retrieved 12 December 2012.
  2.  Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights, wired.com
  3.  Cohen, J. S. (2006). “Risks of troglitazone apparent before approval in USA”.Diabetologia 49 (6): 1454–5. doi:10.1007/s00125-006-0245-0. PMID 16601971.
  4.  Henry RR (September 1996). “Effects of troglitazone on insulin sensitivity”. Diabet. Med.13 (9 Suppl 6): S148–50. PMID 8894499.
  5.  Keen H (November 1994). “Insulin resistance and the prevention of diabetes mellitus”. N. Engl. J. Med. 331 (18): 1226–7. doi:10.1056/NEJM199411033311812. PMID 7935664.
  6. Willman, David (20 December 2000). “NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal”. The Los Angeles Times. Retrieved 12 December 2012.
  7.  Willman, David (4 June 2000). “The Rise and Fall of the Killer Drug Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
  8.  “Report: FDA Removes Medical Officer”.
  9.  Avorn, J (2005). Powerful medicines. New York: Vintage books.
  10.  Gøtzsche, Peter (2013). Deadly medicines and organised crime : how big pharma has corrupted healthcare. London [u.a.]: Radcliffe Publ. p. 185. ISBN 9781846198847.
  11. Leary, Warren (31 January 1997). “New Class of Diabetes Drug Is Approved”. The New York Times. Retrieved 12 December 2012.
  12. Sinclair, Neil (31 July 1997). “Glaxo Wellcome gets approval for Romozin”. ICIS News. Retrieved 12 December 2012.
  13. “www.accessdata.fda.gov”.
  14.  British Broadcasting Corporation (1 December 1997). “Diabetes drug withdrawn from sale”. BBC. Retrieved 12 December 2012.
  15.  Fisher, Lawrence (17 January 1998). “Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes”. The New York Times. Retrieved 12 December 2012.
  16.  Diabetes Prevention Research Group (April 1999). “Design and methods for a clinical trial in the prevention of type 2 diabetes”. Diabetes Care 22 (4): 623–634.doi:10.2337/diacare.22.4.623. Retrieved 12 December 2012.
  17.  Diabetes Prevention Program Research Group (7 February 2002). “Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin”. The New England Journal of Medicine 346 (6): 393–403. doi:10.1056/NEJMoa012512.PMC 1370926. PMID 11832527. Retrieved 12 December 2012.
  18.  Gale, Edwin (January 2006). “Troglitazone: the lesson that nobody learned?”.Diabetologia 49 (1): 1–6. doi:10.1007/s00125-005-0074-6.
  19.  Willman, David (16 August 2000). “FDA’s Approval and Delay in Withdrawing Rezulin Probed”. The Los Angeles Times. Retrieved 12 December 2012.
  20.  Willman, David (10 March 2000). “Fears Grow Over Delay in Removing Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
  21.  U.S. Food and Drug Administration. “2000 Safety Alerts for Human Medical Products”. U.S. Food and Drug Administration. Retrieved 12 December 2012.
  22.  Willman, David (March 17, 2000). “Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal”. Los Angeles Times.
  23.  Pfizer. “Pfizer Annual Report 2001”. Pfizer. Retrieved 12 December 2012.
  24.  Feeley, Jef (March 31, 2009). “Pfizer Ends Rezulin Cases With $205 Million to Spare”.Bloomberg. Retrieved 6 April 2014.
  25.  Aljada A, Garg R, Ghanim H, et al. (2001). “Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?”. J. Clin. Endocrinol. Metab. 86 (7): 3250–6.doi:10.1210/jc.86.7.3250. PMID 11443197.

External links

US4316849 * 11 Jul 1980 23 Feb 1982 Blasinachim S.P.A. Process for preparing a crystalline polymorphous type of chenodeoxycholic acid
US4572912 * 28 Aug 1984 25 Feb 1986 Sankyo Company Limited Treatment of hyperlipemia and hyperglycemia
US5248699 * 13 Aug 1992 28 Sep 1993 Pfizer Inc. Hydrochloride salt, antidepressant, anorectic
US5319097 * 11 Dec 1991 7 Jun 1994 Imperial Chemical Industries Plc Pharmaceutical agents
AU3255984A * Title not available
EP0014590A1 * 7 Feb 1980 20 Aug 1980 Eli Lilly And Company Crystalline forms of N-2-(6-methoxy)benzothiazolyl-N’-phenyl urea and process for their preparation
EP0022527A1 * 4 Jul 1980 21 Jan 1981 BLASCHIM S.p.A. Process for preparing a solvent-free crystalline polymorphous form of chenodeoxycholic acid
EP0490648A1 * 11 Dec 1991 17 Jun 1992 Zeneca Limited Pharmaceutical agents

Ragaglitazar ……..Dr. Reddy’s Research Foundation


Ragaglitazar

NNC-61-0029, (-) – DRF-2725, NN-622,

(−)DRF 2725

cas   222834-30-2

222834-21-1 (racemate)

Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes

PPAR alpha agonist; PPAR gamma agonist

(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,

(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx

Molecular Formula: C25H25NO5
Molecular Weight: 419.4697 g/mol
Dr. Reddy’s Research Foundation (Originator), Novo Nordisk (Licensee)
Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists
Phase III
…………………..
EP 1049684; JP 2001519422; WO 9919313
Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.
…………………………………………
……………………………………………………..
The synthesis of ragaglitazar (Scheme 1) was commenced by treating substrate 2 under optimized phase-transfer catalyzed conditions, using solid cesium hydroxide monohydrate as the base, a pivalate protected benzyl bromide and the Park and Jew triflurobenzyl-hydrocinchonidinium bromide salt 1. We were delighted to find that this reaction produced 3 in good yield with good selectivity. Subsequent removal of the diphenylmethyl (DPM) group under Lewis acidic conditions followed by a Baeyer-Villager like oxidation yielded the - hydroxy aryl ester 4. At this point, we were again pleased to find that this ester could be recrystalized from warm ether to give essentially enantiomerically pure products (~95% ee). The free hydroxyl was then alkylated using triethyloxonium tetrafluoroborate, and then transesterification under catalytic basic conditions produced 5. A mesylated phenoxazine alcohol reacted with 5 to yield the methyl ester of 6, which was obtained by treatment with sodium hydroxide in methanol. The overall synthesis proceeds with 47% overall yield (41% from commercially available reagents) and is eight linear steps from the alkoxyacetophenone substrate 2, including a recrystalization.

……………………………………………………………..

J Med Chem 2001,44(16),2675

http://pubs.acs.org/doi/abs/10.1021/jm010143b

 

Abstract Image

(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.

Figure

Scheme 1 a

 

a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.

Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.

Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull198735, 2394−2411

(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6).  as a white solid, mp: 89−90 °C.

[α]D 25 = − 12.6 (c = 1.0%, CHCl3).

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity):  419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).

Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).

…………………………………

http://www.google.com/patents/US6608194?cl=zh

EXAMPLE 23 (−) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

 

Figure US06608194-20030819-C00052

 

The title compound (0.19 g, 54%) was prepared as a white solid from diastereomer [(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenyl)ethylpropanamide (0.45 g, 0.84 mmol) obtained in example 21by an analogous procedure to that described in example 22. mp: 89-90° C.

[α]D 25=−12.6 (c=1.0% CHCl3)

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J=7.02 Hz, 3H), 1.42-1.91 (bs, 1H, D2O exchangeable), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H), 3.86-4.06 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.63-6.83 (complex, 10H), 7.13 (d, J=8.54 Hz, 2H).

………………………..

http://www.google.com/patents/EP1049684A1?cl=en

Example 23

(S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid :

 

Figure imgf000051_0002

The title compound (0.19 g, 54 %) was prepared as a white solid from diastereomer [(2S- N(lS)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l- phenyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp : 89 – 90 °C. [α]D 25 = – 12.6 (c = 1.0 %, CHC13)

*H NMR (CDC13, 200 MHz) : δ 1.16 (t, J = 7.02 Hz, 3H), 1.42 – 1.91 (bs, IH, D20 exchangeable), 2.94 – 3.15 (complex, 2H), 3.40 – 3.65 (complex, 2H), 3.86 – 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 – 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).

Patent Submitted Granted
Benzamides as ppar modulators [US2006160894] 2006-07-20
Novel tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US2002077320] 2002-06-20
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US7119198] 2006-07-06 2006-10-10
Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them [US6440961] 2002-08-27
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6548666] 2003-04-15
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6608194] 2003-08-19
CRYSTALLINE R- GUANIDINES, ARGININE OR (L) -ARGININE (2S) -2- ETHOXY -3-{4- [2-(10H -PHENOXAZIN -10-YL)ETHOXY]PHENYL}PROPANOATE [WO0063189] 2000-10-26
Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds [US6897199] 2002-11-14 2005-05-24
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6939988] 2005-09-06

WO-2014181362

  1. wo/2014/181362 a process for the preparation of 3 … – WIPO

    patentscope.wipo.int/search/en/WO2014181362

    Nov 13, 2014 – (WO2014181362) A PROCESS FOR THE PREPARATION OF 3-ARYL-2-HYDROXY PROPANOIC ACID COMPOUNDS …

A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

ragaglitazar; saroglitazar

Council of Scientific and Industrial Research (India)

Process for preparing enantiomerically pure 3-aryl-2-hydroxy propanoic acid derivatives (eg ethyl-(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate), using S-benzyl glycidyl ether as a starting material. Useful as intermediates in the synthesis of peroxisome proliferator activated receptor agonist such as glitazars (eg ragaglitazar or saroglitazar). Appears to be the first filing on these derivatives by the inventors; however see WO2014181359 (for a concurrently published filing) and US8748660 (for a prior filing), claiming synthesis of enantiomerically pure compounds.

  1. Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Efficient Catalytic Asymmetric Alkylations. 1. Enantioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. J. Am. Chem. Soc. 1984, 106, 446–447.
  2. Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Phase-Transfer Catalyzed Asymmetric Glycolate Alkylation. Org. Lett. 2004, 6, 2289–2292.
  3. Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation, Investigation of the Scope, and Application to the Synthesis of (-)-Ragaglitazar. J. Org. Chem. 2005, ASAP.
  4. Henke, B. R. Peroxisome Proliferator-Activated Receptor  Dual Agonists for the Treatment of Type 2 Diabetes. J. Med. Chem. 2004, 47, 4118–4127.
  5. Wilson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 2000, 46, 1306–1317.
  6. Uchida, R.; Shiomi, K.; Inokoshi, J.; Masuma, R.; Kawakubo, T.; Tanaka, H.; Iwai, Y.; Omura, A. Kurasoins A and B, New Protein Farnesyltrasferase Inhibitors Produced by Paecilomyces sp. FO-3684. J. Antibio. 1996, 49, 932–934.

TAK-733……. clinical studies for cancer treatment.


TAK-733

CAS: 1035555-63-5

Synonym: TAK-733; TAK 733; TAK733.

IUPAC/Chemical name: 

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

Chemical Formula: C17H15F2IN4O4

Exact Mass: 504.01060

Molecular Weight: 504.23

Elemental Analysis: C, 40.49; H, 3.00; F, 7.54; I, 25.17; N, 11.11; O, 12.69

Phase I clinical studies for cancer treatment.Takeda Pharmaceutical

Solid Tumors Therapy

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

Current developer: Millennium Pharmaceuticals, Inc./Takeda Pharmaceutical Company Limited.

TAK-733 is being developed at Millennium Pharmaceuticals for the treatment of adult patients with advanced non-hematological malignancies. Phase I clinical trials are ongoing for the treatment of advanced metastatic melanoma. In preclinical studies, the compound has been shown to bind to and potently inhibit MEK.

………………………………….

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

  • Takeda San Diego;10410 Science Center Drive, San Diego, CA 92121, United States

http://www.sciencedirect.com/science/article/pii/S0960894X11000941

Full-size image (17 K)

Scheme 3.

Synthesis of compounds 26 and 27 (Route 4). Reagents and conditions: (a) 1-chloro-2,4-dinitrobenzene, K2CO3, DMF; (b) (R)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine or 2,2-dimethyl-1,3-dioxan-5-amine, K2CO3 or Cs2CO3, DMF; (c) HCl, THF; (d) Selectfluor, CH3CN,DMF.

TAK-733 exhibited potent enzymatic and cell activity with an IC50 of 3.2 nM against constitutively active MEK enzyme and an EC50 of 1.9 nM against ERK phosphorylation in cells. TAK-733 did not inhibit any other kinases, receptors or ion channels that were tested with inhibitor concentrations up to 10 μM. TAK-733 was found to bind plasma protein moderately (ca. 97% for human and 96% for mouse), and exhibit high permeability and high microsomal stability across species. It did not inhibit P450s up to 30 μM.

The co-crystal structure of TAK-733 in the MEK1 allosteric site has been solved (Fig. 3). As predicted, the pyridone oxygen makes a hydrogen bond with the backbone NH of Ser212. The 2-fluoro-4-iodoaniline moeity sits in the deep lipophilic pocket. The pyrimidinone oxygen makes a hydrogen bond with Lys97, and the propanediol terminal hydroxyl interacts with both Lys97 and the ADP phosphate.

Full-size image (47 K)
Figure 3.

The X-ray co-crystal structure of TAK-733 in the MEK1 allosteric site.

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

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

Biological Activity of TAK-733:

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

References:

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

 

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

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

Information about this agent

TAK-733 is  currently in Phase I clinical trials and is being developed by Millennium Pharmaceuticals, Inc. (a part of Takeda Pharmaceutical Company Limited).

   

References

1: Acquaviva J, Smith DL, Jimenez JP, Zhang C, Sequeira M, He S, Sang J, Bates RC, Proia DA. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol Cancer Ther. 2014 Feb;13(2):353-63. doi: 10.1158/1535-7163.MCT-13-0481. Epub 2014 Jan 7. PubMed PMID: 24398428.

2: Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X. Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep. 2014 Jan;9(1):83-90. doi: 10.3892/mmr.2013.1781. Epub 2013 Nov 7. PubMed PMID: 24213221.

3: Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res. 2013 Dec 1;73(23):7043-55. doi: 10.1158/0008-5472.CAN-13-1825. Epub 2013 Oct 11. PubMed PMID: 24121489.

4: Garraway LA, Baselga J. Whole-genome sequencing and cancer therapy: is too much ever enough? Cancer Discov. 2012 Sep;2(9):766-8. doi: 10.1158/2159-8290.CD-12-0359. PubMed PMID: 22969114.

5: Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012 Sep;2(9):791-7. Epub 2012 Jul 13. PubMed PMID: 22798288; PubMed Central PMCID: PMC3449158.

6: von Euw E, Atefi M, Attar N, Chu C, Zachariah S, Burgess BL, Mok S, Ng C, Wong DJ, Chmielowski B, Lichter DI, Koya RC, McCannel TA, Izmailova E, Ribas A. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. Mol Cancer. 2012 Apr 19;11:22. PubMed PMID: 22515704; PubMed Central PMCID: PMC3444881.

7: Dong Q, Dougan DR, Gong X, Halkowycz P, Jin B, Kanouni T, O’Connell SM, Scorah N, Shi L, Wallace MB, Zhou F. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9. doi: 10.1016/j.bmcl.2011.01.071. Epub 2011 Jan 22. PubMed PMID: 21310613.

US8030317 Dec 18, 2007 Oct 4, 2011 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
US20080255160 Dec 18, 2007 Oct 16, 2008 Qing Dong Mapk/erk kinase inhibitors
WO2008000020A1 Jun 27, 2007 Jan 3, 2008 Gary L Corino Improved process

EP1894932A1 Jun 10, 2005 Mar 5, 2008 Japan Tobacco, Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
US20050222177 * Jul 29, 2004 Oct 6, 2005 Irm Llc Diseases with abnormal activation of the Abl, BCR-Abl, Bmx, CSK, TrkB, FGFR3, Fes, Lck, B-RAF, C-RAF, MKK6, alpha and beta SAPK2 kinases; antiproliferative; pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-phenylcarbamoyl-phenyl]-amides and pyrrolo[3,2-c]pyridine analogs

 

EMA Guideline on similar Biological Medicinal Products adopted


EMA Guideline on similar Biological Medicinal Products adopted
On 23 October, the CHMP adopted the revised Guideline on similar biological medicinal products. Get more details here.

http://www.gmp-compliance.org/enews_4577_EMA-Guideline-on-similar-Biological-Medicinal-Products-adopted_8524,8474,9183,9138,Z-BIOTM_n.html

 

 

Last year the “Draft Guideline on Similar Biological Medicinal Products” was published by EMA.

After agreement of the revised draft by the Biosimilar Medicinal Products Working Party and Biologics Working Party in July, the CHMP adopted and published the final Guideline on 23 October 2014. They summarized the outline of the document as follows:

“This Guideline outlines the general principles to be applied for similar biological medicinal products (also known as biosimilars) as referred to in Directive 2001/83/EC, as amended, where it is stated that ‘the general principles to be applied [for similar biological medicinal products] are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency’.
This Guideline describes and addresses the application of the biosimilar approach, the choice of the reference product and the principles for establishing biosimilarity.

The scope of the guideline is to fulfil the requirement of section 4, Part II, Annex I to Directive 2001/83/EC, as amended, which states that ‘the general principles to be applied [for similar biological medicinal products] are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency’.”

The date for coming into effect is 30 April 2015 (with the advice: After adoption by CHMP applicants may apply some or all provisions of this guideline in advance of this date.). The document replaces the Guideline on similar biological medicinal products (CHMP/437/04).

For further infromation please see the complete “Guideline on similar biological medicinal products“.

Aplaviroc, AK602, GSK-873140


Aplaviroc.svg

Aplaviroc

4-(4-{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid

for the treatment of HIV infection

461023-63-2 of hydrochloride

461443-59-4 (free base)

873140
AK-602
GW-873140
ONO-4128

ono…….innovator

Ono Pharmaceutical Co., Ltd.
Base
4-[4-[[(3R)-1-Butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl]methyl]phenoxy]benzoic acid
(3R)-1-butyl-2,5-dioxo-3-[(1R)-1-hydroxy-1-cyclohexylmethyl]-9-[4-(4-carboxyphenyloxy)phenylmethyl]-1,4,9-triazaspiro[5.5]undecane
Molecular Formula: C33H43N3O6
Molecular Weight: 577.71
Percent Composition: C 68.61%, H 7.50%, N 7.27%, O 16.62%
References: CCR5 chemokine receptor antagonist; inhibits HIV entry by blocking interaction of viral coat protein gp120 with the receptor. Prepn: H. Habashita et al., WO 02074770 (2002 to Ono); eidem, US 04082584 (2004).
Study of CCR5 binding and mechanism of action: C. Watson et al., Mol. Pharmacol. 67, 1268 (2005).
Antiretroviral activity in immunodeficient mice: H. Nakata et al., J. Virol. 79, 2087 (2005). Clinical pharmacokinetics: K. K. Adkison et al., Antimicrob. Agents Chemother. 49, 2802 (2005).
Derivative Type: Hydrochloride
CAS Registry Number: 461023-63-2
Manufacturers’ Codes: AK-602; GW-873140; ONO-4128
Molecular Formula: C33H43N3O6.HCl
Molecular Weight: 614.17
Percent Composition: C 64.53%, H 7.22%, N 6.84%, O 15.63%, Cl 5.77%
Therap-Cat: Antiviral.

aplaviroc.png

Identifiers
CAS number 461023-63-2 Yes
ATC code None
PubChem CID 3001322
ChemSpider 2272720 Yes
UNII 98B425P30V Yes
KEGG D06557 Yes
ChEMBL CHEMBL1255794
Chemical data
Formula C33H43N3O6 
Mol. mass 577.711 g/mol

 

Aplaviroc (INN, codenamed AK602 and GSK-873140) is a CCR5 entry inhibitor developed for the treatment of HIV infection.[1][2] It is developed by GlaxoSmithKline.

In October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns.[3][4] Some authors have claimed that evidence of poor efficacy may have contributed to termination of the drug’s development;[5] the ASCENT study, one of the discontinued trials, showed aplaviroc to be under-effective in many patients even at high concentrations.[6]

Aplaviroc hydrochloride, an orally-effective, long-acting chemokine CCR5 receptor antagonist, had been under development by Ono and GlaxoSmithKline for the treatment of HIV infection. In early 2006, the companies discontinued development of the antagonist based on reports of elevated liver function test values from clinical studies.

Originally developed at Ono, aplaviroc was licensed to GlaxoSmithKline in 2003 for development, manufacturing and marketing. GlaxoSmithKline also obtained rights to evaluate the agent in non-HIV conditions worldwide with the exception of Japan, South Korea and Taiwan.

A low-molecular-weight compound, aplaviroc prevents HIV viral infection by blocking the binding of the virus to the CCR5 receptor

……………….

WO 2002074770

0r

http://www.google.com/patents/EP1378510A1?cl=en

Reference example 3(3)

    (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride

  • [0136]
    Figure 00560002

    TLC:Rf 0.32 (butanol:acetic acid:water = 4:2:1);
    NMR (CD3OD): δ 4.16 (d, J = 2.0 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.46-1.93 (m, 6H), 1.80-1.64 (m, 5H), 1.48-1.15 (m, 6H), 1.02-0.87 (m, 5H);
    Optical rotation:[α]D +1.22 (c 1.04, methanol, 26°C).

 

Example 9(54)

    (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride

  • [0359]
    Figure 01740001

    TLC:Rf 0.43(chloroform:methanol = 5:1);
    NMR (CD3OD):δ 8.05 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.38 (s, 2H), 4.17 (d, J = 2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.56-1.86 (m, 6H), 1.82-1.60 (m, 5H), 1.52-1.16 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

………………….

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

Owing to the special properties of piperazines (increased solubility and H-bond acceptor capability etc.) it is often considered to be a privileged structure and therefore occurs widely, for instance in GlaxoSmithKlines investigational anti-HIV drug aplaviroc (4.37) which, despite being a promising CCR5 receptor antagonist, was discontinued due to hepatotoxicity concerns. In this compound the spirodiketopiperazine unit (4.35) was designed to mimic a type-1 β-turn (4.36) as present in G-protein coupled receptors (Figure 14) [117].

[1860-5397-9-265-14]
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).

The synthesis of aplaviroc and its analogues can be accomplished via the use of an Ugi multicomponent reaction (Ugi-MCR) [118]. The procedure involved the condensation of piperidone 4.38 and butylamine (4.39) followed by reaction of the resulting imine with isocyanide 4.41 and interception of the nitrilium intermediate with the amino acid4.40 (Scheme 47) [119]. This sequence was completed by structural rearrangement and acid-mediated ring closure to produce the spirocyclic diketopiperazine 4.43. Following debenzylation this material was subjected to a reductive amination finally affording aplaviroc analogues (Scheme 47).

[1860-5397-9-265-i47]
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  1. 117         Habashita, H.; Kokubo, M.; Hamano, S.; Hamanaka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem. 2006, 49, 4140–4152. doi:10.1021/jm060051s
  2. Dömling, A.; Huang, Y. Synthesis 2008, 2859–2883. doi:10.1055/s-0030-1257906
    ref 118
  3. Nishizawa, R.; Nishiyama, T.; Hisaichi, K.; Matsunaga, N.; Minamoto, C.; Habashita, H.; Takaoka, Y.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H.Bioorg. Med. Chem. Lett. 2007, 17, 727–731. doi:10.1016/j.bmcl.2006.10.084
    ref 119
Patent Submitted Granted
Triazaspiro[5.5]undecane derivative and pharmaceutical composition comprising the same as active ingredient [US7262193] 2005-09-29 2007-08-28
Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient [US7285552] 2004-06-03 2007-10-23
Triazaspiro[5.5]undecane derivatives and drugs containing the same as the active ingredient [US7053090] 2004-04-29 2006-05-30

 

WO1998031364A1 * Jan 20, 1998 Jul 23, 1998 Timothy Harrison 3,3-disubstituted piperidines as modulators of chemokine receptor activity
WO2000014086A1 * Jan 21, 1999 Mar 16, 2000 Kyowa Hakko Kogyo Kk Chemokine receptor antagonists and methods of use therefor
WO2002074769A1 * Mar 18, 2002 Sep 26, 2002 Kenji Maeda Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

References

  1.  Maeda, Kenji; Ogata, Hiromi; Harada, Shigeyoshi et al. (2004). “Determination of binding sites of a unique CCR5 inhibitor AK602 / ONO-4128/ GW873140 on human CCR5” (PDF). Conference on Retroviruses and Opportunistic Infections. Archived from the original on November 3, 2005.
  2.  Nakata, Hirotomo; Maeda, Kenji; Miyakawa, Toshikazu et al. (February 2005). “Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model”. Journal of Virology 79 (4): 2087–96.doi:10.1128/jvi.79.4.2087-2096.2005.
  3.  “Aplaviroc (GSK-873,140)”. AIDSmeds.com. October 25, 2005. Retrieved September 5, 2008.[dead link]
  4. Nichols WG, Steel HM, Bonny T et al. (March 2008). “Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)”.Antimicrobial Agents and Chemotherapy 52 (3): 858–65. doi:10.1128/aac.00821-07. PMC 2258506. PMID 18070967.
  5.  Moyle, Graeme (December 19, 2006). “The Last Word on Aplaviroc: A CCR5 Antagonist With Poor Efficacy”. The Body.Archived from the original on 6 October 2008. Retrieved September 5, 2008.
  6.  Currier, Judith; Lazzarin, Adriano; Sloan, Louis et al. (2008). “Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study”. Antiviral Therapy (Lond.) 13 (2): 297–306.PMID 18505181.

Further reading

  • Horster, S; Goebel, FD (April 2006). “Serious doubts on safety and efficacy of CCR5 antagonists: CCR5 antagonists teeter on a knife-edge”. Infection 34 (2): 110–13. doi:10.1007/s15010-006-6206-1. PMID 16703305.

FAMOTIDINE


Famotidine.svgFamotidine-from-xtal-polymorph-A-3D-balls.png

FAMOTIDINE

76824-35-6

3-(2-Guanidinothiazol-4-ylmethylthio)-N-sulfamoylpropanamidine

MK-208
YM-11170
YM-1170

Histamine H2 Receptor Antagonists

Gastroesophageal Reflux Disease,

Agents forGastric Antisecretory Drugs (GERD)

Astellas Pharma (Innovaator)Launched – 1985

Systematic (IUPAC) name
3-[({2-[(diaminomethylidene)amino]-1,3-thiazol-4-yl}methyl)sulfanyl]-N’-sulfamoylpropanimidamide
Clinical data
Trade names Pepcid
AHFS/Drugs.com monograph
MedlinePlus a687011
Licence data US FDA:link
Pregnancy cat.
Legal status
  • Pharmacist only S3/S4(AU), General Availability (OTC)(UK),
    Over the Counter(US)
Routes Oral (tablet form)
Pharmacokinetic data
Bioavailability 40-45% (Oral)[1]
Protein binding 15-20%[1]
Metabolism hepatic
Half-life 2.5-3.5 hours[1]
Excretion Renal (25-30% unchanged [Oral])[1]
Identifiers
CAS number 76824-35-6 Yes
ATC code A02BA03
PubChem CID 3325
DrugBank DB00927
ChemSpider 3208 Yes
UNII 5QZO15J2Z8 Yes
Chemical data
Formula C8H15N7O2S3 
Mol. mass 337.449 g/mol
3-[[[2-[(Aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)propanimidamide
Additional Names: [1-amino-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propylidene]sulfamide; N-sulfamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamide
Manufacturers’ Codes: YM-11170; MK-208
Trademarks: Amfamox (Merck & Co.); Fadul (Hexal); Famodil (Sigma-Tau); Famosan (ProMed); Famoxal (Silanes); Ganor (Boehringer, Ing.); Gaster (Yamanouchi); Gastridin (Merck & Co.); Gastropen (Schwarz); Lecedil (Zdravlje); Motiax (Neopharmed); Muclox (Sigma-Tau); Pepcid (Merck & Co.); Pepcidac (McNeil); Pepcidine (Merck & Co.); Pepdine (Merck & Co.); Pepdul (Merck & Co.); Peptan (Merck & Co.); Ulfamid (Krka)
Molecular Formula: C8H15N7O2S3
Molecular Weight: 337.45
Percent Composition: C 28.47%, H 4.48%, N 29.06%, O 9.48%, S 28.51%
Properties: mp 163-164°. Soly at 20° (%, w/v): 80 in DMF; 50 in acetic acid; 0.3 in methanol; 0.1 in water; <0.01 in ethanol, ethyl acetate, chloroform. LD50 i.v. in mice: 244.4 mg/kg (Yasufumi).
Melting point: mp 163-164°
Toxicity data: LD50 i.v. in mice: 244.4 mg/kg (Yasufumi)
Therap-Cat: Antiulcerative.

Famotidine is an H2-histamine antagonist that was first launched by Astellas Pharma (formerly Yamanouchi) in Japan in 1985 as an injectable for the treatment of upper gastrointestinal hemorrhage and for the treatment of Zollinger-Ellison syndrome. In 1986, the drug was launched pursuant to a collaboration between Merck Sharp & Dohme and Sigma-Tau for the oral prevention and treatment of gastroesophageal reflux disease (GERD).

Famotidine (INN) /fəˈmɒtɪdn/ is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD/GORD). It is commonly marketed byJohnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by Astellas under the trade name Gaster. Unlikecimetidine, the first H2 antagonist, famotidine has no effect on the cytochrome P450 enzyme system, and does not appear to interact with other drugs.[2]

Medical use

Certain preparations of famotidine are available over the counter (OTC) in various countries. In the US 20 or more mg, sometimes in combination with a more traditional antacid, are available OTC. Larger doses still require a prescription.

Famotidine is given to surgery patients before operations to prevent postoperative nausea and to reduce the risk of aspiration pneumonitis. Famotidine is also given to some patients taking NSAIDs, to prevent peptic ulcers.[3] It serves as an alternative toproton-pump inhibitors.[4]

It is also given to dogs and cats with acid reflux.

Famotidine has also been used in combination with an H1 antagonist to treat and prevent urticaria caused by an acute allergic reaction.[5]

Side-effects

Side-effects are associated with famotidine use. In clinical trials, the most common adverse effects were headache, dizziness, andconstipation or diarrhea.[6]

History

Famotidine was developed by Yamanouchi Pharmaceutical Co.[7] It was licensed in the mid-80s by Merck & Co.[8] and is marketed by a joint venture between Merck and Johnson & Johnson. The imidazole-ring of cimetidine was replaced with a 2-guanidinothiazole ring. Famotidine proved to be 30 times more active than cimetidine.[citation needed]

It was first marketed in 1981. Pepcid RPD orally-disintegrating tablets were released in 1999. Generic preparations became available in 2001, e.g.Fluxid (Schwarz) or Quamatel (Gedeon Richter Ltd.).

In the United States and Canada, a product called Pepcid Complete, which combines famotidine with an antacid in a chewable tablet to quickly relieve the symptoms of excess stomach acid, is available. In the UK, this product is known as Pepcidtwo.

Famotidine suffers from poor bioavailability (50%), as it is poorly soluble in the low pH of the stomach. Famotidine used in combination with antacids promotes local delivery of these drugs to the receptor of the parietal cell wall. Therefore, researchers are developing innovative formulations of tablets, such as gastroretentive drug delivery systems. Such tablets are retained in the stomach for a longer period of time, thereby improving the bioavailability of drugs. Local delivery also increases bioavailability at the stomach wall receptor site and increases the efficacy of drugs to reduce acid secretion.[9]

Research

Famotidine has been investigated as an adjunct in treatment-resistant schizophrenia. In one trial it caused a 10% reduction in schizophrenic symptom severity in treatment-resistant patients.[10]

Famotidine is also indicated in the treatment of duodenal and benign gastric ulcers, for the prevention of relapse of duodenal ulceration, for the treatment of gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis, for the treatment of heartburn associated with acid indigestion and sour stomach, for the prevention of meal-induced heartburn, and for the treatment of reflux esophagitis due to GERD, including ulcerative disease as diagnosed by endoscopy. The drug is currently marketed in tablet, film-coated tablet, orally-disintegrating tablet, powder, lyophilized powder for injection solution and injectable formulations. The compound had been in development for the treatment of non-erosive reflux disease (NERD), however, Astellas Pharma discontinued development for this indication in 2007.

Famotidine was developed by replacing the imidazole ring of GlaxoSmithKline’s cimetidine with a 2-guanidinothiazole ring, a modification proven to increase the activity of the drug 30-fold. Famotidine competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells. It suppresses the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid by two mechanisms: by blocking histamine released by enterochromaffin-like (ECL) cells in the stomach from binding to H2 receptors and stimulating acid secretion, and by reducing the effect that other compounds (such as gastrin, pentagastrin, caffeine, insulin and acetylcholine) have on the promotion of acid secretion due to H2 receptor blockade.

Famotidine was originally developed at Astellas Pharma. It was subsequently licensed in the U.S. to Merck & Co., known outside the U.S. and Canada as Merck Sharp & Dohme. In 2007, Salix acquired the U.S. rights to famotidine oral solution (Pepcid[R]) for the treatment of GERD and peptic ulcer. Sigma-Tau holds rights to the drug and is responsible for marketing activities in Italy. Famotidine is sold in over 110 countries worldwide, including France, Germany, Italy, Japan, the U.S. and the U.K.

……………………………..

US 4283408

http://www.google.co.in/patents/US4283408

The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol – water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone – methanol – water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.

Drugs Fut 1983, 8, 1, 14

US 4283408

DOS 2 951 675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).

DOS 3 008 056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 052 478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 055 800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).

synthesis of S-[2-aminothiazol-4-ylmethyl]isothiourea:

Spragne, J.M.; Lund, A.H.; Ziegler, C.: J. Am. Chem. Soc. (JACSAT) 68, 2155 (1946).

Figure 1: FTIR spectra of famotidine

FT IR OF FAMOTIDINE

http://link.springer.com/article/10.1007%2Fs00216-011-5599-6

[1H,13C] 2D NMR Spectrum

………………………..

DSC OF FAMOTIDINE

WILL BE ADDED

heating rate of 10C/min, and was run from 100 to 190C.The compound was found to melt at 166.4C

 

……………………………

 

…………………..

UV – range

Conditions : Concentration – 1 mg / 100 ml
The solvent designation graphics Methanol
Water
0.1М HCl
0.1M NaOH
Maximum absorption 287 nm 265 nm 286 nm
465 309 440
e 15700 10400 14850

 

FIG WILL BE ADDED

 

Ultraviolet spectroscopy
The UV spectrum of famotidine (5mg/ml) in methanol is shown inFig.ABOVE
. The spectrum was recorded using a Shimadzu UV–vis Spectro-photometer 1601 PC. Famotidine exhibited three maxima wavelengths
TABLE WILL BE ADDED

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

…………..

Synthesis pathway

Synthesis of a)


Trade names

Country Trade name Manufacturer
Germany Fadul Hexal
Famobeta betapharm
Famonerton Dolorgiet
Pepdul TEOFARMA
various generic drugs
France Peptsidak McNeil
Peptsidduo McNeil
Pepdin Merck Sharp & Dohme-Chibret
Great Britain Peptsid Merck Sharp & Dohme
Italy Famoudou Sigma-Tau
Gastridin Merck Sharp & Dohme
Motiaks Neopharmed
Japan Gaster Astellas
United States Peptsid Merck, 1986
– “- Johnson & Johnson; Merck
Ukraine Ulfamid Krka, dd, Novo mesto, Slovenia
Kvamatel JSC “Gedeon Richter”, Hungary
Famasan ABM. MED. CA AT Prague, Czech Republic
FamodinGeksal Salyutas Pharma GmbH, Germany, venture hexane AG, Germany
various generic drugs

Formulations

  • ampoule 10 mg, 20 mg;
  • Tablets coated with 10 mg, 20 mg, 40 mg;
  • oral suspension, 40 mg / 5 ml;
  • 2% powder, 10%;
  • 10 mg tablets, 20 mg;
  • vials (lyophilisate) 20 mg

Reference for above

  • DOS 2,951,675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).
  • DOS 3,008,056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).
  • GB 2052478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).
  • GB 2055800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).
  • US 4,283,408 (Yamanouchi; 11.8.1981; J-prior. 2.8.1979).

References

  1. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2.  Humphries TJ, Merritt GJ (August 1999). “Review article: drug interactions with agents used to treat acid-related diseases” (pdf). Aliment. Pharmacol. Ther. 13 (Suppl 3): 18–26.doi:10.1046/j.1365-2036.1999.00021.x. PMID 10491725.
  3. “Horizon Pharma, Inc. Announces FDA Approval of DUEXIS(R) for the Relief of the Signs and Symptoms of Rheumatoid Arthritis and Osteoarthritis and to Decrease the Risk of Developing Upper Gastrointestinal Ulcers” (Press release). Horizon Pharma. 2011-04-25.
  4.  Brauser D (Jul 13, 2009). “Famotidine May Prevent Peptic Ulcers, Esophagitis in Patients Taking Low-Dose Aspirin”. Medscape.
  5.  Fogg TB, Semple D (29 November 2007). “Combination therapy with H2 and H1 antihistamines in acute, non compromising allergic reactions”. BestBets. Manchester, England: Manchester Royal Infirmary. Retrieved 26 April 2011.
  6.  “Pepcid Side Effects & Drug Interactions”. RxList.com. 2008. Retrieved 2008-07-31.
  7.  US patent 4283408, HIRATA YASUFUMI; YANAGISAWA ISAO; ISHII YOSHIO; TSUKAMOTO SHINICHI; ITO NORIKI; ISOMURA YASUO; TAKEDA MASAAKI, “Guanidinothiazole compounds, process for preparation and gastric inhibiting compositions containing them”, issued 1981-08-11
  8.  “Sankyo Pharma”. Skyscape Mediwire. 2002. Retrieved 2009-10-30.[dead link]
  9.  “Formulation and Evaluation of Gastroretentive Floating Tablets of Famotidine”. Farmavita.Net. 2008. Retrieved 2009-01-30.
  10.  Meskanen, K; Ekelund, H; Laitinen, J; Neuvonen, PJ; Haukka, J; Panula, P; Ekelund, J (August 2013). “A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia.”. Journal of Clinical Psychopharmacology 33 (4): 472–478. doi:10.1097/JCP.0b013e3182970490. PMID 23764683.
References:
Histamine H2-receptor antagonist. Prepn, NMR and mass spectral data: H. Yasufumi et al., BE 882071;eidem, US 4283408; JP Kokai 81 55383, C.A. 95, 203930n (1980, 1981, 1981 all to Yamanouchi).
Inhibition of gastric acid and pepsin secretion in rats: M. Takeda et al., Arzneim.-Forsch. 32, 734 (1982); in man: M. Miwa et al., Int. J. Clin. Pharmacol. Ther. Toxicol. 22, 214 (1984).
Effect on disposition of antipyrine in liver: Ch. Staiger et al., Arzneim.-Forsch. 34, 1041 (1984). Chromatographic determn in plasma and urine: W. C. Vincek et al., J. Chromatogr. 338, 438 (1985). Pharmacokinetics: T. Takabatke et al., Eur. J. Clin. Pharmacol. 28, 327 (1985).
Clinical trial in Zollinger-Ellison syndrome: J. M. Howard et al.,Gastroenterology 88, 1026 (1985). Symposia on pharmacology and clinical efficacy: Am. J. Med. 81, Suppl. 4B, 1-64 (1986);Scand. J. Gastroenterol. 22, Suppl. 134, 1-62 (1987).
Web information on Famotidine
Mechanism of Action
H2-receptor antagonist
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature

Esoxybutynin, (S)-Oxybutynin


Chemical structure for Esoxybutynin [INN]

(S)-2-Cyclohexyl-2-phenylglycolic acid 4-diethylaminobut-2-ynyl ester

Drug name, 药物名称….. Esoxybutynin, (S)-Oxybutynin

 

(S)-Oxybutynin Structure

Sepracor (Originator)
RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Anticholinergics
Phase III

 

CAS No. 119618-22-3
Chemical Name: (S)-Oxybutynin
Synonyms: Esoxybutynin;(S)-Oxybutynin;(S)-OXYBUTYNIN HCL;(S)-OXYBUTYNIN CHLORIDE;(S)-OXYBUTYNIN HYDROCHLORIDE;(S)-Hydroxycyclohexylphenylacetic acid 4-(diethylamino)-2-butynyl ester;(S)-CYCLOHEXYL-HYDROXY-PHENYL-ACETIC ACID 4-DIETHYLAMINO-BUT-2-YNYL ESTER;(αS)-α-Cyclohexyl-α-hydroxybenzeneacetic acid 4-(diethylamino)-2-butin-1-yl ester;Benzeneacetic acid, a-cyclohexyl-a-hydroxy-, 4-(diethylamino)-2-butynyl ester, (S)-;(S)-α-Phenylcyclohexaneglycolic Acid 4-(Diethylamino)-2-butynyl Ester, Hydrochloride
CBNumber: CB1746039
Molecular Formula: C22H31NO3
Formula Weight: 357.49

Oxybutynin and its derivatives are applicable as a bronchodilator or a remedy for pollakisuria. Also, oxybutynin exerts a direct antispasmodic effect on various forms of smooth muscle, mainly by inhibiting the action of acetylcholine on smooth muscle as an anti-cholinergic drug and the like. Oxybutynin is marketed in hydrochloride form. Oxybutynin known as [α-cyclohexyl-hydroxy-benzeneaceticacid- 4-(diethyl amino)-2-butynyl ester] he US Patent No. 3,176,019 (‘019) discloses about 4-amino-2-butynol esters and their derivatives, particularly about oxybutynin hydrochloride. It also reveals about the synthesis of oxybutynin, wherein, the methyl phenyl cyclohexyl glycolate is reacted with 4-diethylamino-2-butynylacetate in presence of base to yield oxybutynin followed by further workup. Further, it is treated with 2N HCl solution to form hydrochloride salt. It is recrystallised by employing ethyl acetate or water to obtain pure oxybutynin hydrochloride. Further, the US Patent ‘019 unveils about the reaction of propargyl-2-cyclohexyl-2-hydroxy-2-phenyl acetate, /^-formaldehyde and diethyl amine in dry dioxane to obtain crude product of oxybutynin. The dry hydrogen chloride gas is passed through the ether solution of oxybutynin to yield the oxybutynin chloride as precipitate.

According to the prior art process oxybutynin is obtained as oil, which contains lot of impurities, therefore, it needs to purify high vacuum distillation. Also, the resultant oxybutynin base is having a low melting point, which may decompose during high vacuum distillation. Further, the existence of any polymorphism in oxybutynin is not disclosed in prior arts. In light of the foregoing, a need exists in the art for inventing a new form and the process thereof. Objects and Summary of the Invention

It is a principal object of the present invention is to provide a novel crystalline oxybutynin base in a solid state having improved quality.

Another object of the present invention is to provide a process for the preparation of novel crystalline oxybutynin base as a solid state. Further, object of the present invention is to provide a process for preparing an acid addition salt of oxybutynin employing crystalline oxybutynin base

In accordance with one preferred embodiment of the present invention, there is provided a crystalline oxybutynin base characterized by using different analytical tools including X-ray powder diffraction pattern, Thermo Gravimetric Analysis (TGA), and Differential Scanning Calorimetry (DSC).

Oxybutynin is used therapeutically in the treatment of intestinal hypermotility and in the treatment of urinary incontinence due to detrusor instability. Oxybutynin is sold for this purpose under the trade name of Ditropan®. Chemical names for oxybutynin are 4- (diethylamino)-2-butynyl-α-cyclohexyl-α-hydroxy benzeneacetate, and 4-(diethylamino)-2- butynylphenylcyclohexyl-glycolate. It is a racemic mixture of the R-enantiomer, R- oxybutynin, and the S-enantiomer, S-oxybutynin.

Use of the S-enantiomer of oxybutynin, S-oxybutynin, for the treatment of urinary incontinence has been described in U.S. Patent Numbers 5,532,278, and 5,736,577. The structure of S-oxybutynin (Registry Number 1 19618-22-3) is shown in formula I. S- oxybutynin is not commercially available at the present time.

 

Administration of racemic oxybutynin may result in a number of adverse effects. These adverse effects include, but are not limited to, xerostomia, mydriasis, drowsiness, nausea, constipation, palpitations and tachycardia. The amelioration of cardiovascular side effects of racemic oxybutynin, such as tachycardia and palpitations, is of particular therapeutic value.

The synthesis of S-oxybutynin has been described in the literature by Kacher et al, J. Pharmacol. Exp. Ther., 247, 867-872 (1988). An improved synthetic method is disclosed in copending U.S. patent application, serial number 09/21 1,646, the contents of which are incorporated in their entirety. In this method, an activated derivative of cyclohexylphenylglycolic acid (CHPGA), the mixed anhydride I, is prepared.

isobutylchloroforrnate

 

The mixed anhydride I is coupled with the propargyl alcohol derivative 4-N,N-diethylamino butynol (4-N,N-DEB)( III where R1 is -CH2R2; R2 is -ΝR3R4; and R3 and R4 are each ethyl.) Reaction of the optically active mixed anhydride with 4-NN-DEB produces a single enantiomer of oxybutynin, in this case, (S)-4-diethylamino-2- butynylphenylcyclohexylglycolate.

Improved syntheses of starting material CHPGA have been described in two copending U.S. Patent Applications, Serial Numbers 09/050,825 and 09/050,832. The contents of both are incorporated by reference in their entirety. In the first (09/050,825), phenylglyoxylic acid or cyclohexylglyoxylic acid is condensed with a single enantiomer of a cyclic vicinal aminoalcohol to form an ester of the phenylglyoxylic acid or the cyclohexylglyoxylic acid. The ester is reacted with an appropriate Grignard reagent to provide an α-cyclohexylphenylglycolate ester. A single diastereomer of the product ester is separated from the reaction mixture, and hydrolyzed to provide S-α- cyclohexylphenylglycolic acid (S-CHPGA). The second (09/050,832) discloses an alternate stereoselective process for preparing CHPGA. A substituted acetaldehyde is condensed with mandelic acid to provide a 5-phenyl-l,3-dioxolan-4-one, which is subsequently reacted with cyclohexanone to provide a 5-(l-hydroxy cyclohexyl)-5-phenyl-l,3-dioxolan-4-one. The product is dehydrated to a 5-(l-cyclohexenyl)-5-phenyl-l,3-dioxolan-4-one, hydrolyzed and reduced to CHPGA.

 

……………………………..

SYNTHESIS

Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50篊 in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.

US 5973182; US 6140529; WO 0023414

……………………………………………………………

 

 

The desired product is finally obtained by first formation of a mixed anhydride (XVI) by reaction of the cyclohexylphenyl glycolic acid (IV) with isobutylchloroformate (XV) in cyclohexane in the presence of Et3N, followed by treatment with 4-N,N-diethylamino butynol (XVII) (obtained on turn from reaction of propargyl alcohol (XVIII) with diethylamine (XIX) in the presence of paraformaldehyde and CuCl.

J Org Chem 2000,65(19),6283

Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50篊 in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.

CLIP

Tetrahedron Lett 2002,43(48),8647

The catalytic enantioselective cyanosilylation of the ketone (I) by means of Tms-CN catalyzed by gadolinium isopropoxide and the chiral ligand (II) in THF/propionitrile gives the silylated cyanohydrin (III), which is reduced by means of DIBAL in toluene to yield the carbaldehyde (IV). The desilylation of (IV) by means of HCl in aqueous THF affords the hydroxyaldehyde (V), which is finally oxidized by means of NaClO2 in tert-butanol/water to provide the target (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate (VI) (see Scheme no. 23604001a, intermediate (IV)).

PATENT

http://www.google.com/patents/WO2009122429A2?cl=en

Example-1 Preparation of 4-diethylamino-2-butyne-ol

A mixture of para formaldehyde (105.Og), N,N-diethyl amine(300g) and copper(II) acetate (7.5g) in 1,4 dioxane (900ml) was heated to 60-65° C. After 1.5 h, 2-propyne-l-ol (150g, 2.7 moles) was added and the mixture was heated at 90-95° C. after 2 hrs; excess solvent, 1,4 dioxane, evaporated at reduced pressure to afford 315g

(84%) of the product as an oil. Example-2

Preparation of diethylamino-2-butvnylacetate

A mixture of 4-diethylamino-2-butyne-l-ol (30Og), acetic acid (600ml); acetic anhydride (300ml) and con.sulphuric acid (15ml) was heated to 65-70° C. After 2hrs.of maintenance excess solvent mixture was evaporated at reduced pressure. The residue was cooled and poured in a mixture of dichloromethane (1800ml) and DM water (3000ml).The reaction mass was saturated with sodium bicarbonate (300g) solid slowly controlling effervescences. The organic layer was separated and washed with 2% sodium bicarbonate and 1% EDTA solution to afford 318g (81%) of product as oil.

Example-3

Preparation of 4-diethylamino-2-butvnyl phenyl cvclohexyl alveolate hydrochloride (Oxybutynin Hydrochloride)

A mixture of 150g of methyl phenyl cyclohexyl glycolate, 133g of 4- diethylamino-2-butynyl acetate was dissolved in 1.8 ltr of n-heptane. The solution was added with 1.2 g of sodium methoxide. The solution was heated with stirring to a temperature of 95-100° C and distillate was collected. After 30min of maintenance at 95-100° C, the solution was cooled to 65-70° C under nitrogen. The solution was added with 3.24 g of sodium methoxide. The solution was heated with stirring to a temperature of 95-100° C and distillate was collected. After 1 hr. maintenance at 95- 100° C, reaction mass cooled to room temperature, washed with water. n-Heptane layer was separated and added 300 ml of 2N Hydrochloric acid to give oxybutynin hydrochloride. The crude was recrystallised from ethyl acetate.

Example-4 Preparation of Oxybutvnin base

A mixture of 150g of methyl phenyl cyclohexyl glycolate, 133g of 4- diethylamino-2-butynyl acetate was dissolved in 1.8 ltr of n-heptane. The solution was added with 1.2 g of sodium methoxide. The solution was heated with stirring to a temperature of 95-100° C and distillate was collected. After 30min of maintenance at 95-100° C, the solution was cooled to 65-70° C under nitrogen. The solution was added with 3.24 g of sodium methoxide. The solution was heated with stirring to a temperature of 95-100° C and distillate was collected. After 1 hr. maintenance at 95-

100° C, reaction mass cooled to room temperature, washed with ‘water. n-Heptane layer was separated, concentrated under reduced pressure to give residue. n-Pentane (250ml) was added to the residue and stirred under nitrogen atmosphere at 25-30° C. The solid product was filtered and washed with chilled n-pentane. Wet cake was dried at 40-42° C. Dry weight = 160.O g

Example-5 Preparation of Oxybutvnin (Base)

Oxybutynin chloride (lOOgm) was treated with DM water (500ml) at 25-30° C and heated to 40-45° C to observe clear solution. n-Heptane (500ml) was added to the solution and adjusted the pH of the mass to 10.0-11.0 using 5% sodium hydroxide solution at 20-25° C. Layers obtained were separated and aqueous layer was extracted with heptane. Organic layers were combined and concentrated under vacuum at 40- 45° C to, give residue. n-Pentane (250ml) was added to the residue and stirred under nitrogen atmosphere at 25-30° C. The solid product was filtered and washed with chilled n-pentane. Wet cake was dried at 40-42° C. Dry weight = 85.0 gm

PATENT

http://www.google.com/patents/US3176019

Example XIX 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochl0ride.-A mixture of 394.2 g. of methyl phenylcyclohexylglycolate, 293.1 g. of 4-diethylamino-2-butynyl acetate was dissolved with Warming in 2.6 l. of n-heptane. The solution was heated with stirring to a temperature of 60-70 C. and 8.0 g. of sodium methoxide were added. The temperature of the mixture was then raised until the solvent began to distill. Distillation was continued at a gradual rate and aliquots of the distillate were successively collected and analyzed for the presence of methyl acetate by measurement of the refractive index. The reaction was completed when methyl acetate no longer distilled, and the refractive index observed was that of pure heptane (11 1.3855). About three and one-half hours were required for the reaction to be completed. The reaction mixture was then allowed to cool to room temperature, washed with Water, and extracted with four ml. portions of 2 N hydrochloric acid. The aqueous extracts Were combined and stirred at room temperature to permit crystallization of the hydrochloride salt of the desired product. Crystallization was completed by cooling the slurry in an ice bath, and the product was collected by filtration, pressed dry, and recrystallized from 750 ml. of water. Yield of pure crystalline material, 323 g.

PATENT

http://www.google.com/patents/EP1185498A2?cl=en

 

 

Background of the Invention Cyclohexylphenyl glycolic acid (also referred to herein as “CHPGA”) is used as a starting material for manufacturing compounds that have important biological and therapeutic activities. Such compounds include, for example, oxphencyclimine, oxyphenonium bromide, oxypyrronium bromide, oxysonium iodide, oxybutynin (4- diethylamino-2-butynyl phenylcyclohexylglycolate) and its metabolites, such as desethyloxybutynin (4-ethylamino-2-butynyl phenylcyclohexylglycolate). The important relation between stereochemistry and biological activity is well known. For example, the (S)-enantiomers of oxybutynin and desethyloxybutynin have been shown to provide a superior therapy in treating urinary incontinence, as disclosed in U.S. Patent Nos. 5,532,278 and 5,677,346. The (R) enantiomer of oxybutynin has also been suggested to be a useful drug candidate. [Noronha-Blob et al., J. Pharmacol. Exp. Ther. 256, 562-567 (1991)]. Racemic CHPGA is generally prepared by one of two methods: (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters, as shown in Scheme 1; or (2) cyclohexyl magnesium halide addition to phenylglyoxylate as shown in Scheme 2. Scheme 1.

R is hydrogen or lower alkyl.

Scheme 2.

Asymmetric synthesis of individual enantiomers of CHPGA has been approached along the lines of Scheme 2, by Grignard addition to a chiral auxiliary ester of glyoxylic acid to give a diastereomeric mixture of esters. In addition, multiple step asymmetric synthesis of (R)-CHPGA from fDJ-arabinose using Grignard reagents has been reported. In general, simple primary alkyl or phenyl Grignard (or alkyllithium) reagents are used for the addition, and the addition of inorganic salts (e.g. ZnCl2) appears to increase the diastereoselectivity of the products.

As outlined in Scheme 3 below, the simple chiral ester wherein R* is the residue of a chiral alcohol, can be directly converted to chiral drugs or drug candidates by trans-esterification (R’=acetate), or hydrolyzed to yield chiral CHPGA (R’=H).

Scheme 3

esterification

(S) or (R)-Oxybutynin

(S) or (R)-CYLOHEXYLPHENYL GLYCOLIC ACID VIA RESOLUTION The resolution process of the present invention provides an inexpensive and efficient method for preparing a single enantiomer from racemic CHPGA via the formation of the diastereomeric salt with (L) or (D) -tyrosine methyl ester, also referred to herein as “(Z) or (D)-TME”. The process consists of three parts, which are depicted and described below: Part 1: Preparation of (S)-CHPGA-(Z)-TME diastereomeric salt or (R)-CHPGA-(D)-TME diastereomeric salt; Part 2:

Preparation of (S) or (R) CHPGA; and Part 3 – Recovery of (L) or (D)-tyrosine methyl ester. The ability to recover the resolving agent in high yield is an advantageous feature of the process of the invention. It greatly reduces cost by allowing recycling of the resolving agent. For ease in understanding, the diastereomeric salt, (<S)-CHPGA-(E)-TME, and the pure enantiomer (S)-CHPGA are depicted in the reactions below. However, the (R) enantiomeric series could instead be depicted and is similarly produced using the opposite enantiomer of TME.

Part 1 : Preparation of (5VCHPGA-(XVTyrosine Methyl Ester Diastereomer Salt

* ( )-TME

(S, R)-CHPGA (S)-CHPGA – (J)-TME (MW= 234.3) (MW = 429.5)

For use in the process of Part 1, the racemic starting material, (S, R)- cyclohexylphenyl glycolic acid (CHPGA) can be prepared by the process described above, i.e. (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters or (2) cyclohexyl magnesium halide addition to phenylglyoxylate. Mandelic acid and phenylglyoxylic acid, also known as benzoylformic acid, are commercially available. Phenyl mandelic acid may be prepared by Grignard addition of phenyl magnesium bromide to diethyl oxalate followed by hydrolysis. The (L) enantiomer of tyrosine methyl ester is also readily available from commercial sources, as is (Z))-tyrosine, which can then be esterified to produce (_9)-tyrosine methyl ester using conventional techniques, such as acid-catalyzed esterification with methanol. The diastereomer of the present process is produced by dissolving racemic

CHPGA and an appropriate amount of an enantiomer of tyrosine methyl ester in a suitable solvent and then bringing about the insolubilization of one diastereomer. For example, racemic CHPGA and about 0.5 molar equivalents of (Z)-tyrosine methyl ester or (Z))-tyrosine methyl ester can be dissolved in a mixture of acetonitrile and water. When the solvent is about 10 wt % water in acetonitrile, solution may be achieved by heating, preferably by heating to reflux (approximately 78° C). After heating the solution for a sufficient time to achieve complete dissolution, usually about 5 minutes at reflux, followed by cooling, preferably to about 0-5° C, the diastereomeric salt (S)-CHPGA – (E)-TME or (R)-CHPGA – (£>)- TME, depending on the TME enantiomer used, crystallizes from solution. Better yields are obtained when the cooling temperature is maintained until crystallization of the diastereomer salt is complete, typically a period of about four hours. The salt crystals are then separated from the solution, for example by filtration. The crystalline product may be washed with solvent and dried. When the solvent is water/acetonitrile, drying under vacuum at about 40-50° C is effective. The mother liquor stream may be saved for later racemization and recovery of residual CHPGA. Racemization may be effected with aqueous mineral acids, particularly aqueous sulfuric acid in ethanol. Part 2: Preparation of (S.-CHPGA

(S)-CHPGA – (Z)-TME (S)-CHPGA

(MW = 429.5) (MW= 234.3)

In Part 2, the CHPGA enantiomer produced, (S) or (R)-CHPGA, is liberated from the diastereomeric salt. For the preparation of (S)-CHPGA, the (S)-CHPGA-(E)- TME salt from Part 1 is added to and dissolved to form a solution which is about 15 wt % substrate in toluene. The solution is treated with an excess of dilute mineral acid, such as 1.1 equivalents of 0.5 M HC1 or H2SO4. Upon dissolution of the diastereomeric salt, essentially all the TME enantiomer is converted to the hydrochloride salt. The diastereomeric salt mixture may be heated to about 40-50° C for about 10 minutes to facilitate dissolution of the solids. A phase split yields an aqueous solution containing (Z)-TME-HCl and an organic solution of (S)-CHPGA in toluene. The aqueous phase is separated from the organic solution and saved for recovery of the tryrosine methyl ester in Step 3 below. A common method of separation, which may be used throughout the processes described herein, is gravitational settling followed by drainage of the aqueous phase through a tap in the bottom of the reaction vessel.

The toluene organic phase containing (S)-CHPGA may be washed a second time with mineral acid, as specified above, and heated. The organic phase and aqueous phase are then separated, and the aqueous phase is discarded along with the rag layer, i.e. the layer separating the two phases. The retained toluene organic phase is then preferably concentrated, typically by vacuum distillation, to a weight that is about 2.1 to 2.3 times the weight of the diastereomeric salt originally present, followed by gradual cooling to 0-5° C to initiate crystallization of the single (S) enantiomer of CHPGA, as indicated by the formation of a thick slurry. The slurry is cooled for at least an hour to ensure that crystallization is complete, then filtered to isolate (S)-CHPGA. The (S)-CHPGA cake is then dried under vacuum while heating to a temperature of about (40-45° C).

Part 3 : Recovery of (X -Tyrosine Methyl Ester The aqueous phase containing (Z)-TME-HCl or (D)-TME-HCl saved from

Part 2 is cooled, preferably to about 0-5° C. While maintaining the cooling temperature, the aqueous solution is titrated with 0.5M NaOH to a pH of approximately 9.0. Typically, a thin slurry will form as the TME enantiomer precipitates. The TME enantiomer is isolated by filtration, washing with deionized water, and drying under vacuum at a temperature of about (40-50° C).

The resolution process of the present invention set forth above is illustrated by, but not limited to, the following example:

Example 1 Part 1 : Preparation of (S)-CHPGA-(E -Tyrosine Methyl Ester Diastereomer Salt A 2-liter reactor was charged with 100.0 g racemic CHPGA, 41.7 g (L)-

TME (0.5 equiv.), 549.2 g CH3CN, and 54.8 g deionized water. The reaction mixture was heated to reflux at approximately 78° C for about 5 min. The solution was then cooled to a temperature between 0-5° C over a period of 2 hours and remained cooling (0-5 ° C) for about 2 hours. The solution was filtered to isolate the (S)-CHPGA-(Z)-TME diastereomeric salt, and the salt cake was washed with 130 g chilled ( 0-5° C) CH3CN. The salt cake was dried in vacuo at 40-50° C , and the residual solvent remaining in the cake was < 0.5%. Yield = 77.1 g (42.1 mole %); ee > 99.0% (S).

Part 2: Preparation of .S.-CHPGA A 1000 mL reactor was charged with 77. 1 g (S)-CHPGA-(E)-TME from

Part 1, 447.0 g toluene, 339.2 g 0.5M HC1 (1.1 equiv.) and heated to 40-50°C while stirring until the solids dissolved (about 10 min). While maintaining the temperature at 40-50° C, the organic and aqueous phases separated after about 10 minutes. The phases were divided, and the aqueous (bottom) phase containing (L)- TME-HC1 was saved for recovery in Part 3 below. Approximately 370 g aqueous phase was recovered.

To the toluene organic phase an additional 169.6 g 0.5M HC1 (0.6 equiv.) were added, and the solution was heated to a temperature between 40-50° C while stirring for about 10 minutes. The toluene and aqueous phases were allowed to separate (~ 10 min.), while maintaining the temperature between 40-50° C. The phases were divided, and the aqueous (bottom) phase and rag layer were discarded. The organic phase was concentrated by vacuum distillation to a final weight of 168.0 g, then cooled to 0-5 °C over a period of about one hour during which time a thick slurry formed spontaneously. Agitation was adjusted as necessary. The slurry was cooled at 0-5 °C for an additional one hour. The slurry was filtered to recover the (S)-CHPGA. The (S)-CHPGA filter cake was dried in vacuo at 40-45° C , and the residual solvent remaining in the cake was < 0.2%. Yield = 35.8 g (85 mole %); ee > 99.0%; chemical purity (% HPLC area) > 99.0%.

Part 3: Recovery of (Z)-Tyrosine Methyl Ester

A 2-liter vessel was charged with the aqueous phase saved from Part 2 (370 g). The solution was cooled to 0-5 °C, and the cooling temperature was maintained while titrating with 0.5 M NaOH to a pH of 9.0 ±0.5 over approximately 30 min. A thin slurry formed as (Z)-TME precipitated. The slurry was filtered, and the (L)-

TME cake was washed with 154 g deionized water. The cake was dried in vacuo at 40-50°C , and the residual solvent remaining in the cake was < 1.0%. Yield = 30.5 g (E)-TME (87 mole %).

(S) OR fRVOXYBUTYNIN AND RELATED COMPOUNDS VIA DIRECT COUPLING

The synthesis of a single enantiomer of oxybutynin and oxybutynin analogs according to the present invention comprises coupling an enantiomer of cyclohexylphenyl glycolic acid with a propargyl alcohol derivative utilizing carboxylic acid activation. Optically active CHPGA may be prepared either by the resolution process described above or by asymmetric methods. The present invention also provides a process for converting the aforementioned enantiomers of oxybutynin and oxybutynin analogs to their corresponding hydrochloride salts. The synthetic process consists of two reactions, which are depicted and described below: Part 1: Formation of the Mixed Anhydride; Part 2: Formation of (S) or (R) oxybutynin and its related compounds. Again for ease in understanding, the (S) enantiomeric series is depicted, although the (R) series is produced similarly.

Part 1 : Formation of the Mixed Anhydride

isobut lchloroformate

 

(S)-CHPGA Mixed Anhydride MW=234.29

In Part 1, (S) or (R) cyclohexylphenyl glycolic acid (CHPGA) is reacted with an alkyl chloroformate in an organic solvent to form a mixed anhydride enantiomer, as shown above, which can then react to form the desired chiral product in Part 2 below.

It should be noted that, while mixed anhydrides are often employed for the synthesis of amides, their use for ester synthesis is quite unusual. It should also be noted that a surprising and unexpected aspect of the present process is that the mixed anhydride intermediate proceeds to a chiral product without affecting the tertiary carbinol of CHPGA, which would lead to impurity formation or racemization. One would expect reaction with an acyl halide at the benzylic hydroxyl resulting in the formation of a stable, but undesired compound, such as an ester. Alternatively, if the hydroxyl were activated (unintentionally) to form a good leaving group, as, for example, under acidic conditions, the dissociation of the leaving group would form a benzylic carbonium ion, leading to racemization. One would therefore expect a loss in optical activity of the oxybutynin or the extensive production of by-products. Surprisingly, the present process produces a high purity product, and no racemization is observed.

In the preparation of the mixed anhydride, two intermediates, in addition to the mixed anhydride shown above, were detected. The two were isolated and their structures were determined by NMR to be

carbonate-anhydride A carbonate-acid B wherein R5 was isobutyl. Both intermediates were smoothly converted to oxybutynin upon treatment with 4-N,N-DEB.

The reaction is preferably carried out in an inert atmosphere, such as nitrogen or argon, and the reaction solution is stirred using conventional techniques. In the depiction above, isobutyl chloroformate (IBCF) is shown as the preferred alkyl chloroformate for reaction with (S)-CHPGA forming the isobutyloxy mixed anhydride. However, other alkyl chloroformates, such as isopropenylchloroformate and 2-ethylhexylchloroformate, for example, may instead be used. The amount of alkyl chloroformate used in the reaction is preferably about 1.2 equivalents with respect to the CHPGA enantiomer.

Preferably, the reaction proceeds in the presence of a tertiary amine (2.5 equiv.), such as triethylamine (TEA), 4-N,N-dimethylaminopyridine (DMAP), pyridine, diisopropylethylamine, diethylmethylamine, Ν-methylpiperidine or Ν- methylmorpholine, which scavenges the HC1 produced. Organic solvents that may be used include, but are not limited to cyclohexane, heptane, toluene, tetrahydrofuran (THF), ethylene glycol dimethyl ether (DME), diethoxy methane (DEM), and methyl t-butyl ether (MTBE). Part 2: Formation of (S) or (R -Oxybutynin and its Analogs

Mixed Anhydride (S)-Oxybutynin or Analog

A sidechain propargyl alcohol derivative of formula (III), wherein R1 is as previously defined, is added to the mixed anhydride contained in the reaction mixture to produce the single enantiomer of oxybutynin or analog thereof (II). About 1.3 equivalents of the formula (III) compound relative to (S) or (R)-CHPGA is sufficient. Typically, the reaction mixture is heated to reflux at a temperature of about 65-80° C, but more preferably about 70-75° C, until the reaction is complete, as determined by HPLC.

Most preferably, the propargyl alcohol derivative of formula (III) is a 4- amino propargyl alcohol derivative, wherein R1 is represented as -CH2R2; R2 is – NR3R4; and R3 and R4 are each independently lower alkyl, benzyl or methoxybenzyl. For example, the compound of formula (III) is most preferably 4-N,N-diethylamino butynol (4-N,N-DEB), where R3 and R4 are each ethyl. Reaction of the mixed anhydride with 4-N.N-DEB produces the single enantiomer of oxybutynin, i.e. (S) or (R)-4-diethylamino-2-butynyl phenylcyclohexylglycolate. Another preferred embodiment is the reaction using an Ν-protected 4-N-ethylamino butynol, such as Ν-ethyl-Ν-(4-methoxybenzyl)butynol, as the propargyl alcohol derivative and then cleaving the protecting group (by methods well known in the art) to produce (S) or (R)-4-ethylamino-2-butynyl phenylcyclohexylglycolate, also known as desethyloxybutynin. In that case, R3 is ethyl, and R4 is converted to hydrogen in formula (III). Suitable protecting groups are described in Greene and Wuts Protecting Groups in Organic Synthesis. Second Edition Wiley, New York 1991, p. 362-371, which is incorporated herein by reference. In another preferred embodiment, the propargyl alcohol derivative of formula (III) is 4-N,N- ethylmethylamino butynol, which results in the formation of (Sf) or (R)-4- ethylmethylamino-2-butynyl phenylcyclohexylglycolate. In this case, R3 is ethyl, and R4 is methyl.

Other useful sidechain propargyl alcohol compounds in which R1 is -CH2R2 are those wherein R2 is azide, hydroxy, or halo. In addition, propargyl alcohol itself, also known as 2-propyn-l-ol, may be reacted with the mixed anhydride. In this case, R1 is hydrogen in formula (III). 4-N,N-Diethylamino butynol for use as the sidechain propargyl alcohol in the present invention may be prepared by reacting propargyl alcohol, paraformaldehyde, and diethylamine under standard Mannich conditions. Other amino and alkyl amino propargyl alcohol derivatives of structure (III) can be formed by the process disclosed in U.S. Patent No. 5,677,346. Briefly, a secondary amine, in which one or more substituents may be a protecting group, such as N-ethyl-4- methoxybenzenemethanamine for example, is reacted with propargyl alcohol and paraformaldehyde in the presence of cuprous chloride. After condensation with the activated CHPGA, the addition of α-chloroethyl carbonochloridate removes the protecting group. In this example, the 4-N-ethylaminobutynyl ester is the ultimate product. The remaining propargyl alcohol derivatives for use in the present invention are commercially available or can be synthesized by methods known in the art.

As stated above, the progress of the condensation of the mixed anhydride with the propargyl alcohol may be conveniently monitored by periodic HPLC analyses of the reaction mixture until the desired extent of conversion is reached. At >80% conversion, the reaction is preferably quenched by washing with 10-12% aqueous monobasic sodium phosphate and water. About 8.5 g of the phosphate per gram of enantiomeric CHPGA used is typical. After separation of the organic phase, the aqueous washes are then discarded. A final wash using deionized water may then be performed, after which the bottom aqueous phase is discarded. The retained organic phase containing the enantiomer of structure (II) in solution with the organic solvent can then be concentrated to remove most of the solvent, typically by vacuum distillation.

Formation of the Hvdrochloride Salt

(S)-Oxybutynin or Analog (S)-Oxybutynin or Analog-HCl

To promote crystallization, the organic solvent containing the enantiomer of oxybutynin or one of its analogs (II) produced by the process outlined above (also referred to herein as “free base enantiomer (II)”) is exchanged with ethyl acetate (EtOAc). Typically, the organic solvent is removed by vacuum distillation to contain about 20-25 wt % (S) or (R) enantiomer of structure (II), which is based on the theoretical amount of free base (II) formed from the coupling process above. Ethyl acetate is then added to obtain the original solution volume or weight. This step may be repeated substituting the removal of EtOAc for the organic solvent. The EtOAc solution may be filtered through a filtering agent, such as diatomaceous earth. The filter cake is washed with EtOAc as needed.

The filtrate is then concentrated by vacuum distillation, for example, to contain about 20-25 wt % (theoretical) of free base enantiomer (II) and < 0.3 wt % water. To maximize product yield and purity and to encourage crystallization, most of the water should be removed from the solution. If the foregoing concentration processes are insufficient to reduce the water to < 0.3%, the vacuum distillation may be repeated with fresh solvent or a drying agent, such as magnesium sulfate may be employed. Water content can be determined by KF (Karl Fisher method). Methyl t-butyl ethyl (MTBE) is then added to the concentrated EtOAc solution to a volume that reduces the concentration by weight of the free base enantiomer (II) by about one third, or optimally to between about 6.5 and 8.5 wt %. The hydrochloride salt is then formed by the addition of HC1, while stirring. A slight excess of HC1 in ethanol, for example about 1.1 equivalents of 35-40 wt % HC1, is generally sufficient. The temperature may be increased to 35-45° C. To initiate recrystallization, the solution may be seeded with the hydrochloride salt of the enantiomer of structure (II). After about an hour of stirring, which may be done at 35-45° C, a slurry forms. If the slurry is cooled to about 0-5° C and this temperature maintained for about two hours, filtration provides a very good recovery of the hydrochloride salt of the enantiomer of structure (II). The filter cake is typically a white to off-white crystalline solid, which can then be washed with ambient temperature methyl t-butyl ether (at least 2.2 g MTBE per gram free base enantiomer (II)), followed by vacuum drying at 40- 50° C.

The following example is illustrative, but the present invention is not limited to the embodiment described therein:

Example 2 Preparation of (S)-Oxybutvnin-HCl

A 3-neck round bottomed flask was charged with 50.0 g (S)-CHPGA (213.0 mmol) and 780 g (1000 mL) cyclohexane under nitrogen. While stirring, 54 g triethylamine (2.5 equiv.) and 35 g isobutyl chloroformate (IBCF)(1.2 equiv.) were slowly added while maintaining the temperature at 20-30° C. After about 0.5 hour, while continuing to stir the reaction mixture, 39.15 g 4-N,N-DEB (1.3 equiv.) were added, and the mixture was heated to 65 °C to reflux . Mixing continued at reflux until the formation of (S)-oxybutynin was complete by HPLC area normalization. Heating was discontinued, and the reaction mixture was cooled to between

20-30° C. At this time, 425 g of 11.5% ΝaH2PO4Η20 aqueous solution were added to the mixture, and the mixture was stirred for 10 min. Stirring was discontinued, and the organic and aqueous phases separated after about 15 minutes. The aqueous (bottom) phase was discarded. 425 g of 11.5% NaH2PO4Η20 aqueous solution were again added to the retained organic phase, and the mixture was stirred for about 10 min. The phases were then permitted to separate, which took about 15 minutes. The aqueous (bottom) phase was again discarded. To the remaining organic phase, deionized water (400 g) was added. The mixture was stirred for about 10 min, followed by phase separation after about 15 minutes. The aqueous (bottom) phase was discarded.

Cyclohexane was removed from the organic phase by vacuum distillation to about 350 g (~ 22 wt % (S)-oxybutynin based on the theoretical amount (76.29 g) of (S)-oxybutynin free base formed). Ethyl acetate (EtOAc) was added to obtain the original solution volume of about 1000 mL (or about 83 Og), followed by vacuum distillation to 20-25 wt % (S)-oxybutynin. EtOAc was then added a second time to a volume of about 1000 mL (or about 830g). The batch was then polish filtered through about 5.0 g CELITE® while washing the filter cake with EtOAc as needed. The filtered mixture was concentrated and dried by vacuum distillation to 339 g (~ 22.5 wt % (S)-oxybutynin) and < 03 wt % water, as measured by KF. Based on the theoretical amount of (S)-oxybutynin free base (76.29 g), methyl t-butyl ether was added to adjust the (S)-oxybutynin free base concentration to 8.0 wt % (953 g). With agitation, 23 g of 37 wt % HC1 in EtOH (1.1 equiv.) were slowly added to the solution, while maintaining the temperature between 20 and 45° C. The temperature of the solution was then adjusted to 35-45° C, and the solution was seeded with about 500 mg (S)-oxybutynin-HCl crystals (approximately 10 mg of seeds per g (S)-CHPGA ). The temperature was maintained, and the solution was stirred for about one hour. A slurry formed, which was then cooled to 0-5 °C over a minimum of 1 hour and held for 2 hours. The slurry was then filtered to recover the (S)-oxybutynin-HCl. The filter cake was a white to off-white crystalline solid. After washing with MTBE (a minimum of 167.84 g MTBE (2.2 g MTBE/g (S)-oxybutynin free base), the cake was dried in vacuo at 40-45 °C. The residual solvent remaining in the cake was < 0.5%. Dry weight = 57.9 g. Overall yield = 68.9%.

Example 3 Isolation of the two carbonate intermediates A and B To a racemic mixture of cyclohexylphenylglycolic acid [CHPGA] (5.0 g, 0.0213mol) in cyclohexane (100 mL) was added triethylamine (7.4 mL, 0.053 mol) and isobutylchloroformate (5.5mL, 0.0426mol). The slurry was allowed to stir at ambient temperature for approximately 0.5 h, at which time the reaction was quenched with a 10% aq. NaH2PO4 (50 ml). The organic phase was separated from the aqueous phase and washed with 10% aq. NaH2PO4 (50mL) followed by DI water (50mL). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford a colorless oil. The product was purified by flash chromatography eluting with 95:5 hexane-EtOAc [Rf = 0.2] to afford pure carbonate-anhydride A. The structure was confirmed by H and 13C NMR, IR, in sttw IR and MS.

To a racemic mixture of cyclohexylphenylglycolic acid [CHPGA] (5.0 g, 0.0213 mol) in cyclohexane (100 mL) was added triethylamine (7.4 mL, 0.053mol) or preferably 1-methyl piperidine (O.053mol), and isobutylchloroformate (3.3 mL, 0.026mol). The slurry was allowed to stir at ambient temperature for approximately 0.5 h, at which time the reaction was quenched with a 10% aq. solution of NaH2PO4 (50 mL) followed by DI water (50mL). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford a colorless oil as a 4:1 mixture of A and B by HPLC. The crude product was purified by passing the mixture through a plug of neutral alumina. Compound A was eluted first using

CHClj B was then washed off the alumina with acetone and concentrated in vacuo to afford pure carbonate-acid B. The structure was confirmed by H and 13C NMR, IR, in situ IR and MS.

 

PATENT

http://www.google.com/patents/US6294582

The synthesis of S-oxybutynin has been described in the literature by Kacher et al., J. Pharmacol. Exp. Ther., 247, 867-872 (1988). An improved synthetic method is disclosed in copending U.S. patent application, Ser. No. 09/211,646, now U.S. Pat. No. 6,140,529, the contents of which are incorporated in their entirety. In this method, an activated derivative of cyclohexylphenylglycolic acid (CHPGA), the mixed anhydride I, is prepared.

The mixed anhydride I is coupled with the propargyl alcohol derivative 4-N,N-diethylamino butynol (4-N,N-DEB)(III where R1 is —CH2R2; R2 is —NR3R4; and R3 and R4 are each ethyl.) Reaction of the optically active mixed anhydride with 4-N,N-DEB produces a single enantiomer of oxybutynin, in this case, (S)-4-diethylamino-2-butynylphenylcyclohexylglycolate.

Improved syntheses of starting material CHPGA have been described in two copending U.S. patent applications, Ser. No. 09/050,825, now U.S. Pat. No. 6,013,830, and 09/050,832. The contents of both are incorporated by reference in their entirety. In the first (09/050,825, now U.S. Pat. No. 6,013,830), phenylglyoxylic acid or cyclohexylglyoxylic acid is condensed with a single enantiomer of a cyclic vicinal aminoalcohol to form an ester of the phenylglyoxylic acid or the cyclohexylglyoxylic acid. The ester is reacted with an appropriate Grignard reagent to provide an a-cyclohexylphenylglycolate ester. A single diastereomer of the product ester is separated from the reaction mixture, and hydrolyzed to provide S-α-cyclohexylphenylglycolic acid (S-CHPGA). The second (09/050,832) discloses an alternate stereoselective process for preparing CHPGA. A substituted acetaldehyde is condensed with mandelic acid to provide a 5-phenyl-1,3-dioxolan-4-one, which is subsequently reacted with cyclohexanone to provide a 5-(1-hydroxy cyclohexyl)-5-phenyl-1,3-dioxolan-4-one. The product is dehydrated to a 5-(1-cyclohexenyl)-5-phenyl-1,3-dioxolan-4-one, hydrolyzed and reduced to CHPGA.

The magnitude of a prophylactic or therapeutic dose of S-oxybutynin in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration. The dose, and perhaps the dose frequency will also vary according to the age, body weight, and the response of the individual patient. In general, the daily dose ranges when administered by inhalation, for the conditions described herein, are from about 0.1 mg to about 100 mg in single or divided dosages. Preferably a daily dose range should be between about 10 mg to about 25 mg, in single or divided dosages, preferably in from 2-4 divided dosages. In managing the patient the therapy should be initiated at a lower dose, perhaps from 5 mg to about 10 mg, and increased up to about 2×20 mg or higher depending on the patient’s global response. When administered orally, preferably as a soft elastic gelatin capsule, the preferred dose range is from about 1 mg to about 1 g per day, more preferably, from about 25 mg to about 700 mg per day, and most preferably, from about 100 mg to about 400 mg per day. It is further recommended that children and patients over 65 years and those with apaired renal, or hepatic function, initially receive low dosages and that they be titrated based on individual responses and blood levels. It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician possesses knowledge of how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The terms “a therapeutically effective quantity”, and “a quantity sufficient to alleviate bronchospasms” are encompassed by the above described dosage amounts and dose frequency schedule.

The methods of the present invention utilize S-oxybutynin, or a pharmaceutically acceptable salt thereof. The term “pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable nontoxic acids including both inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluene sulfonic. The hydrochloride has particular utility.

Preferred unit dosage formulations are those containing an effective dose, as recited, or an appropriate fraction thereof, of S-oxybutynin or pharmaceutically acceptable salts thereof. The formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question. For example, formulations for oral administration may include carriers such as starches, sugars, microcystalline cellulose, diluents, granulating agents, flavoring agents and the like. Formulations suitable for oral, rectal and parenteral administration (including subcutaneous, transdermal, intramuscular, and intravenous) and inhalation may be used for treatment according to the present invention.

Any suitable route of administration may be employed for providing the patient with an effective dosage of S-oxybutynin. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration may be employed. Transdermal administration may be improved by the inclusion of a permeation enhancer in the transdermal delivery device, for example as described in PCT application WO 92/20377. Dosage forms include troches, dispersions, suspensions, solutions, aerosols, patches, syrups, tablets and capsules, including soft elastic gelatin capsules. Oral and parenteral sustained release dosage forms may also be used.

Because of their ease of administration, tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Soft elastic gel capsules are a preferred form of administration of S-oxybutynin.

Soft elastic gelatin capsules may be prepared by mixing S-oxybutynin with a digestible oil such as soybean oil, lecithin, cottonseed oil, or olive oil. The mixture is then injected into gelatin by means of a positive pressure pump, such that each dosage unit contains an effective dose of S-oxybutynin. The capsules are subsequently washed and dried.

Oral syrups, as well as other oral liquid formulations, are well known to those skilled in the art, and general methods for preparing them are found in most standard pharmacy school textbooks. An exemplary source is Remington: The Science and Practice of Pharmacy. Chapter 86 of the 19th edition of Remington entitled “Solutions, Emulsions, Suspensions and Extracts” describes in complete detail the preparation of syrups (pages 1503-1505) and other oral liquids. Similarly, sustained release formulation is well known in the art, and Chapter 94 of the same reference, entitled “Sustained-Release Drug Delivery Systems”, describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675.) The relevant disclosure, Chapters 86 and 94, is incorporated herein by reference.

Controlled release means and delivery devices are also described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, and in PCT application WO 92/20377. Because they reduce peak plasma concentrations, controlled release dosage forms are particularly useful for providing a therapeutic plasma concentration of S-oxybutynin while avoiding the side effects associated with peak plasma concentrations.

Formulations suitable for inhalation include sterile solutions for nebulization comprising a therapeutically effective amount of S-oxybutynin or a pharmaceutically acceptable salt thereof, dissolved in aqueous saline solution and optionally containing a preservative such as benzalkonium chloride or chlorobutanol, and aerosol formulations comprising a therapeutically effective amount of S-oxybutynin, or a pharmaceutically acceptable salt thereof, dissolved or suspended in an appropriate propellant (e.g., HFA-134a, HFA-227, or a mixture thereof, or a chlorofluorocarbon propellant such as a mixture of Propellants 11, 12 and/or 114) optionally containing a surfactant. Aerosols may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. The preparation of a particularly desirable aerosol formulation is described in European Patent No. 556239, the disclosure of which is incorporated herein by reference. Also suitable are dry powder formulations comprising a therapeutically effective amount of S-oxybutynin or a pharmaceutically acceptable salt thereof, blended with an appropriate carrier and adapted for use in connection with a dry-powder inhaler.

 

……………………….

CZ20013826A3 * Title not available
US3176019 * Jun 20, 1961 Mar 30, 1965 Mead Johnson & Co Substituted aminobutynyl acetates
* Cited by examiner
Non-Patent Citations
Reference
1 * DATABASE CAPLUS [Online] 13 November 2010 STN Database accession no. 2006:220682 & CZ 20 013 826 A3 18 June 2003
2 * DATABASE CAPLUS 13 January 2010 STN: ‘Syntheses of oxybutynin hydrochloride‘ Database accession no. 1997:395370 & ZHONGGUO YIYAO GONGYE ZAZHI vol. 27, no. 9, pages 387 – 389

Image result for oxytrol

CLIP

 

Racemic

Oxybutynin
Oxybutynin2DCSD.svg
Oxybutynin 3d balls.png
Systematic (IUPAC) name
4-Diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylethanoate
Clinical data
Trade names Ditropan
AHFS/Drugs.com monograph
MedlinePlus a682141
Pregnancy cat.
Legal status
Routes oral, transdermal gel, transdermal patch
Pharmacokinetic data
Protein binding 91%-93%
Half-life 12.4-13.2 hours
Identifiers
CAS number 5633-20-5 Yes
ATC code G04BD04
PubChem CID 4634
IUPHAR ligand 359
DrugBank DB01062
ChemSpider 4473 Yes
UNII K9P6MC7092 Yes
KEGG D00465 Yes
ChEBI CHEBI:7856 Yes
ChEMBL CHEMBL1231 Yes
Chemical data
Formula C22H31NO3 
Mol. mass 357.486 g/mol

Oxybutynin (Ditropan, Lyrinel XL, Lenditro (South Africa)) is an anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination (urge incontinence), by decreasing muscle spasms of the bladder.[1]

It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. It also has direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically.

Oxybutynin is also a possible treatment of hyperhidrosis (hyper-active sweating).[2][3][4]

Chemistry

Oxybutynin contains one stereocenter. Commercial formulations are sold as the racemate. The (R)-enantiomer is a more potent anticholinergic than either the racemate or the (S)-enantiomer, which is essentially without anticholinergic activity at doses used in clinical practice.[5][6] However, (R)-oxybutynin administered alone offers little or no clinical benefit above and beyond the racemic mixture. The other actions (calcium antagonism, local anesthesia) of oxybutynin are not stereospecific. (S)-Oxybutynin has not been clinically tested for its spasmolytic effects, but may be clinically useful for the same indications as the racemate, without the unpleasant anticholinergic side effects.

 

Clinical efficacy

In two trials of patients with overactive bladder, transdermal oxybutynin 3.9 mg/day decreased the number of incontinence episodes and increased average voided volume to a significantly greater extent than placebo. There was no difference in transdermal oxybutynin and extended-release oral tolterodine.[7]

Adverse effects

Common adverse effects associated with oxybutynin and other anticholinergics include: dry mouth, difficulty in urination, constipation, blurred vision, drowsiness, and dizziness.[8] Anticholinergics have also been known to induce delirium.[9]

These are dose-related and sometimes severe. In one population studied—after six months, more than half of the patients had stopped taking the medication because of side effects and calcium defects. An intake of calcium of 800 to 1000 mg is suggested.Dry mouth may be particularly severe; one estimate is that over a quarter of patients who begin oxybutynin treatment may have to stop because of dry mouth.

N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought responsible for much of the adverse effects associated with the use of oxybutynin.[10] N-Desethyloxybutynin plasma levels may reach as much as six times that of the parent drug after administration of the immediate-release oral formulation.[11] Alternative dosage forms have been developed in an effort to reduce blood levels of N-desethyloxybutynin and achieve a steadier concentration of oxybutynin than is possible with the immediate release form. The long-acting formulations also allow once-daily administration instead of the twice-daily dosage required with the immediate-release form. The transdermal patch, in addition to the benefits of the extended-release oral formulations, bypasses the first-pass hepatic effect that the oral formulations are subject to.[12] In those with overflow incontinence because of diabetes or neurological diseases like multiple sclerosis or spinal cord trauma, oxybutynin can worsen overflow incontinence since the fundamental problem is that the bladder is not contracting.

Clinical pharmacology

Oxybutynin chloride exerts direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. It exhibits one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

Sources say the drug is absorbed within one hour and has an elimination half-life of 2 to 5 hours.[13][14][15] There is a wide variation among individuals in the drug’s concentration in blood. This, and its low concentration in urine, suggest that it is eliminated through the liver.[14]

Contraindications

Oxybutynin chloride is contraindicated in patients with untreated angle closure glaucoma, and in patients with untreated narrow anterior chamber angles—since anticholinergic drugs may aggravate these conditions. It is also contraindicated in partial or complete obstruction of the gastrointestinal tract, hiatal hernia, gastroesophageal reflux disease, paralytic ileus, intestinal atony of the elderly or debilitated patient, megacolon, toxic megacolon complicating ulcerative colitis, severe colitis, and myasthenia gravis. It is contraindicated in patients with obstructive uropathy and in patients with unstable cardiovascular status in acute hemorrhage. Oxybutynin chloride is contraindicated in patients who have demonstrated hypersensitivity to the product.

Formulations

It is available orally in generic formulation or as the brand-names Ditropan, Lyrinel XL, or Ditrospam, as a transdermal patch under the brand name Oxytrol, and as a topical gel under the brand name Gelnique.

A 2009 Weill Cornell Medical College study concluded that patients switched to generic oxybutynin experienced a degradation in therapeutic value: “In women, there was a doubling of daytime frequency of urination, a slight 20% increase in nocturia, and a 46.3% increase in urge incontinence. In men, there was a 2.4-fold increase in daytime frequency, a 40% increase in nocturia, and a 40.6% increase in urge incontinence”.[16]

PATENT

http://www.google.com/patents/US3176019

Example XIX 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochl0ride.-A mixture of 394.2 g. of methyl phenylcyclohexylglycolate, 293.1 g. of 4-diethylamino-2-butynyl acetate was dissolved with Warming in 2.6 l. of n-heptane. The solution was heated with stirring to a temperature of 60-70 C. and 8.0 g. of sodium methoxide were added. The temperature of the mixture was then raised until the solvent began to distill. Distillation was continued at a gradual rate and aliquots of the distillate were successively collected and analyzed for the presence of methyl acetate by measurement of the refractive index. The reaction was completed when methyl acetate no longer distilled, and the refractive index observed was that of pure heptane (11 1.3855). About three and one-half hours were required for the reaction to be completed. The reaction mixture was then allowed to cool to room temperature, washed with Water, and extracted with four ml. portions of 2 N hydrochloric acid. The aqueous extracts Were combined and stirred at room temperature to permit crystallization of the hydrochloride salt of the desired product. Crystallization was completed by cooling the slurry in an ice bath, and the product was collected by filtration, pressed dry, and recrystallized from 750 ml. of water. Yield of pure crystalline material, 323 g.

 Oxybutynin chloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=91548

Oxybutynin

Title: Oxybutynin
CAS Registry Number: 5633-20-5
CAS Name: a-Cyclohexyl-a-hydroxybenzeneacetic acid 4-(diethylamino)-2-butynyl ester
Additional Names: a-phenylcyclohexaneglycolic acid 4-(diethylamino)-2-butynyl ester; 4-diethylamino-2-butynyl phenylcyclohexylglycolate; oxibutinina
Molecular Formula: C22H31NO3
Molecular Weight: 357.49
Percent Composition: C 73.91%, H 8.74%, N 3.92%, O 13.43%
Literature References: Muscarinic receptor antagonist. Prepn: GB 940540 (1963 to Mead Johnson). Physico-chemical properties: E. Miyamoto et al., Analyst 119, 1489 (1994). GC-MS determn in plasma: K. S. Patrick et al., J. Chromatogr. 487, 91 (1989). Toxicity: E. I. Goldenthal, Toxicol. Appl. Pharmacol. 18, 185 (1971). Review of pharmacodynamics and therapeutic use: Y. E. Yarker et al., Drugs Aging 6, 243-262 (1995).
Properties: pKa 8.04. Log P (n-octanol/water): 2.9 (pH 6). Soly in water (mg/ml): 77 (pH 1); 0.8 (pH 6); 0.012 (pH >9.6).
pKa: pKa 8.04
Log P: Log P (n-octanol/water): 2.9 (pH 6)
Derivative Type: Hydrochloride
CAS Registry Number: 1508-65-2
Additional Names: Oxybutynin chloride
Manufacturers’ Codes: MJ-4309-1
Trademarks: Cystrin (Sanofi-Synthelabo); Ditropan (Sanofi-Synthelabo); Dridase (Sanofi-Synthelabo); Kentera (UCB); Pollakisu (Kodama); Tropax (BMS)
Molecular Formula: C22H31NO3.HCl
Molecular Weight: 393.95
Percent Composition: C 67.07%, H 8.19%, N 3.56%, O 12.18%, Cl 9.00%
Properties: Crystals, mp 129-130°. Sol in water, acids. Practically insol in alkali. LD50 orally in rats: 1220 mg/kg (Goldenthal).
Melting point: mp 129-130°
Toxicity data: LD50 orally in rats: 1220 mg/kg (Goldenthal)
Therap-Cat: In treatment of urinary incontinence.
Keywords: Antimuscarinic.

References

  1. Chapple CR. “Muscarinic receptor antagonists in the treatment of overactive bladder”. Urology (55)5, Supp. 1:33-46, 2000.
  2. Tupker RA, Harmsze AM, Deneer VH (2006). “Oxybutynin therapy for generalized hyperhidrosis.”. Arch Dermatol 142 (8): 1065–6. doi:10.1001/archderm.142.8.1065. PMID 16924061.
  3. Mijnhout GS, Kloosterman H, Simsek S, Strack van Schijndel RJ, Netelenbos JC. (2006). “Oxybutynin: dry days for patients with hyperhidrosis.”. Neth J Med 64 (9): 326–8. PMID 17057269.
  4. Schollhammer M, Misery L. (2007). “Treatment of hyperhidrosis with oxybutynin.”. Arch Dermatol. 143 (4): 544–5. doi:10.1001/archderm.143.4.544. PMID 17438194.
  5. Kachur JF, et al. “R and S enantiomers of oxybutynin: pharmacological effects in guinea pig bladder and intestine.” Journal of Pharmacology and Experimental Therapeutics 247:867-72, 1988.
  6. Noronha-Blob L, Kachur JF. “Enantiomers of oxybutynin: in vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs.” Journal of Pharmacology and Experimental Therapeutics 256:562-7, 1991.
  7. Baldwin C, Keating GM.[1].Drugs 2009;69 (3):327-337. doi:10.2165/00003495-200969030-00008.
  8. Mehta D (Ed.) 2006. British National Formulary 51. Pharmaceutical Press. ISBN 0-85369-668-3
  9. Andreasen NC and Black DW, “Introductory Textbook of Psychiatry.” American Psychiatric Publishing Inc. 2006
  10. Allen B. Reitz, Suneel K. Gupta, Yifang Huang, Michael H. Parker, and Richard R. Ryan (2007). “The preparation and human muscarinic receptor profiling of oxybutynin and N-desethyloxybutynin enantiomers”. Med Chem 3 (6): 543–5. doi:10.2174/157340607782360353. PMID 18045203.
  11. Zobrist RH, et al. “Pharmacokinetics of the R- and S-Enantiomers of Oxybutynin and N-Desethyloxybutynin Following Oral and Transdermal Administration of the Racemate in Healthy Volunteers”. Pharmaceutical Research 18:1029-1034, 2001.
  12. Oki T, et al. “Advantages for Transdermal over Oral Oxybutynin to Treat Overactive Bladder: Muscarinic Receptor Binding, Plasma Drug Concentration, and Salivary Secretion”. Journal of Pharmacology and Experimental Therapeutics Fast Forward 316:1137-1145, 2006.
  13. [2] “Oxybutynin” Retrieved on 30 August 2012.
  14. [3] “The pharmacokinetics of oxybutynin in man. (Abstract)” Retrieved on 30 August 2012.
  15. [4] “Oxybutynin” Retrieved on 30 August 2012.
  16. Kerr, Martha (2009-05-03). “AUA 2009: Generics Not Equal to Brand-Name Drugs for Overactive Bladder”. American Urological Association (AUA) 104th Annual Scientific Meeting (Medscape). Retrieved 2013-04-20.

External links

Title: OxybutyninCAS Registry Number: 5633-20-5CAS Name: a-Cyclohexyl-a-hydroxybenzeneacetic acid 4-(diethylamino)-2-butynyl esterAdditional Names: a-phenylcyclohexaneglycolic acid 4-(diethylamino)-2-butynyl ester; 4-diethylamino-2-butynyl phenylcyclohexylglycolate; oxibutininaMolecular Formula: C22H31NO3Molecular Weight: 357.49Percent Composition: C 73.91%, H 8.74%, N 3.92%, O 13.43%Literature References: Muscarinic receptor antagonist. Prepn: GB 940540 (1963 to Mead Johnson). Physico-chemical properties: E. Miyamoto et al., Analyst 119, 1489 (1994). GC-MS determn in plasma: K. S. Patrick et al., J. Chromatogr. 487, 91 (1989). Toxicity: E. I. Goldenthal, Toxicol. Appl. Pharmacol. 18, 185 (1971). Review of pharmacodynamics and therapeutic use: Y. E. Yarker et al., Drugs Aging 6, 243-262 (1995).Properties: pKa 8.04. Log P (n-octanol/water): 2.9 (pH 6). Soly in water (mg/ml): 77 (pH 1); 0.8 (pH 6); 0.012 (pH >9.6).pKa: pKa 8.04Log P: Log P (n-octanol/water): 2.9 (pH 6)Derivative Type: HydrochlorideCAS Registry Number: 1508-65-2

Additional Names: Oxybutynin chloride

Manufacturers’ Codes: MJ-4309-1

Trademarks: Cystrin (Sanofi-Synthelabo); Ditropan (Sanofi-Synthelabo); Dridase (Sanofi-Synthelabo); Kentera (UCB); Pollakisu (Kodama); Tropax (BMS)

Molecular Formula: C22H31NO3.HCl

Molecular Weight: 393.95

Percent Composition: C 67.07%, H 8.19%, N 3.56%, O 12.18%, Cl 9.00%

Properties: Crystals, mp 129-130°. Sol in water, acids. Practically insol in alkali. LD50 orally in rats: 1220 mg/kg (Goldenthal).

Melting point: mp 129-130°

Toxicity data: LD50 orally in rats: 1220 mg/kg (Goldenthal)

 

Therap-Cat: In treatment of urinary incontinence.

Keywords: Antimuscarinic.

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