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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, 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...... , 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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Alogliptin is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.

Alogliptin (trade name Nesina in the US[1] and Vipidia in Europe[2]) is an orally administered anti-diabetic drug in the DPP-4 inhibitor class,[3] developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005. Like other medications for the treatment of Type 2 diabetes, alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of causing hypoglycemia, and exhibits relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in patients whose diabetes cannot adequately be controlled with metformin alone.[4]

Clinical study

Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) that is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). [5]

A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and vogliboseamong newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors.[6]

A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was “non-inferior” to a “very low fat/calorie traditional Japanese diet” among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI.[7]

A randomized clinical trial reporting in 2011 aimed to demonstrate the efficacy of alogliptin as an add-on agent in combination withmetformin and pioglitazone versus simply increasing the dosage of pioglitazone in combination with metformin; in other words, this was a study to look at a three-agent therapy versus a two-agent therapy. The outcome of this study suggested that the addition of alogliptin to metformin and pioglitazone provided superior impact on diabetes biomarkers (e.g. HbA1c) than increasing the dose of pioglitazone in a two agent therapy with metformin.[8]

Reported adverse events

Adverse events appear to be restricted to mild hypoglycemia based on clinical studies.[6][7][8]

Alogliptin is not associated with increased weight, increased risk of cardiovasular events, or heart failure.[9][10]

Market access

In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Adminiistration (USFDA),[11] after positive results from Phase III clinical trials.[1] In September of 2008, the company also filed for approval in Japan,[12] winning approval in April 2010.[11] The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data.[12] The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011.[11] In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.[11]

In 2013 the FDA approved the drug in three formulations: As a stand-alone with the brand-name Nesina. Combined with metforminusing the name Kazano, and when combined with pioglitazone as Oseni.

Diabetes affects millions of people worldwide and is considered one of the main threats to human health in the 21st century. In 2006, the World Health Organization (WHO) estimated that over 180 million people worldwide had diabetes, and the number is projected to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to the WHO, approximately 1.1 million people died from diabetes in 2005, and it is estimated that diabetes-related deaths will increase by more than 50% in the next decade. Globally, the socioeconomic burden of diabetes is substantial.

There are two main types of diabetes, designated type 1 and type 2, with type 2 diabetes accounting for over 90% of all diabetes cases globally. Type 1 diabetes is characterized by insulin deficiency, primarily caused by autoimmune-mediated destruction of pancreatic islet β-cells, and type 2 diabetes is characterized by abnormal insulin secretion and concomitant insulin resistance. To prevent the development of ketoacidosis, people with type 1 diabetes must take exogenous insulin for survival. Although those with type 2 diabetes are not dependent on exogenous insulin as much as subjects with type 1 diabetes, they may require exogenous insulin to control blood glucose levels.

As diabetes has become a global health concern, research interest in the condition has rapidly increased. In addition to studies on prevention, many studies with the aim of developing new interventions for the treatment of diabetes, especially type 2 diabetes, have been conducted. Currently available medications for the treatment and management of type 2 diabetes include metformin, sulfonylureas, thiazolidinediones and insulin. However, these therapies are commonly associated with secondary failure and may cause hypoglycemia. Insulin resistance and progressively worsening hyperglycemia caused by reduced β-cell function are major challenges in managing type 2 diabetes. Evidence suggests that patients with insulin resistance do not develop hyperglycemia until their β-cells are unable to produce enough insulin. New agents that can enhance insulin secretion from islet β-cells in a sustained glucose-dependent manner could therefore hold promise for the treatment of type 2 diabetes.

One promising approach is based on inhibition of the serine protease dipeptidyl- peptidase IV (DPP IV), a postproline dipeptidyl aminopeptidase that belongs to the S9b peptidase family of proteolytic enzymes. It is known that DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-I) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes.

Recently, a series of DPP IV inhibitors were developed. Among these highly potent compounds, alogliptin benzoate (SYR-322) and its analogs demonstrated encouraging antidiabetic efficacy (EP 1586571 (WO 2005/095381); WO 2008/067465; WO 2007/035379, and US 2004/097510).

Alogliptin benzoate can be prepared as described in EP 1586571 (WO 2005/095381) according to the process set forth in Scheme 1 :

Figure imgf000004_0001

Scheme 1

In accordance with this process, 6-Chlorouracil (1) is alkylated with 2- (bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF- DMSO to produce the TV-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1 ,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)- aminopiperidine dihydrochloride in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is -20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.

Intermediate 2-((6-chloro-3-methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl) benzonitrile (3) is alternatively obtained by alkylation of 6-chloro-3 methyluracil with 2-(bromomethyl)benzonitrile by means of diisopropylethylamine in hot NMP (WO 2007/035629). Although this process is more technological than the previously described process (EP 1586571), the overall yield is still moderate (50-55%). The problem of mixed solvents (toluene, NMP, diisopropylethylamine) separation persists for this process as well.



Preparation of (R)-2-((6-(3 -aminopiperidin-l-yl)-3 -methyl-2,4-dioxo-3 ,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 3):

Figure imgf000025_0001

Scheme 3

Preparation of l-(2-isocyanobenzyl)-3-methylurea

2-cyanobenzylamine hydrochloride (90 g) and Dichloromethane (800 ml) were taken into a round bottomed (RB) flask. Methyl isocyanate (45.6 g) was added at 5°C. Triethylamine (81 g) in Dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16h. Water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration and dried in oven at 50°C for 12h. The yield is 85% and the purity 99.8%.

Preparation of l-(2-isocyanobenzyl)-3-methyIpyrimidine-2,4,6(lH,3H,5H)-trione

a). To a stirred solution of 0.11 mol of sodium ethanolate in 80 ml of ethanol abs. was added 0.1 mol of l-(2-isocyanobenzyl)-3-methylurea and 0.1 mol diethyl malonate. The mixture was refluxed for 3-5 h. The cooled residue was acidified with 0.1 M hydrochloric acid (60 ml). The solid which separated was filtered off and recrystallized from ethanol or any suitable solvent. The yield is 78-85% and purity >95%.

b). In an alternate embodiment, l-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60°C. Acetic anhydride (60 ml) was added at 60°C and heating was continued for two hours at 80°C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.

The compound thus prepared can be used for the next step without purification or purified by crystallization or column chromatography.

Preparation of 6-chloro-l-(2-isocyanobenzyl)-3-methylpyriinidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(lH,3H,5H)-trione (30 g) was mixed with phosphorus oxychloride (300 ml) and cooled to 0°C. Water (9 ml) was added slowly, stirred for 10 min. and heated to reflux at 110°C for 5h. Progress of the reaction was monitored by TLC (50% Ethyl acetate/Hexane). On completion of the reaction, phosphorus oxychloride was distilled off. The crude compound was dissolved in dichloromethane (500 ml) and poured into ice water (500 ml) by small portions. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The mixture of two isomers (4-chloro and 6-chloro derivatives = 1:1) was isolated and separated by column chromatography using neutral alumina and eluent – 25-50% of ethylacetate and hexane). The off-white solid was obtained, yield – 37%, purity – 99.8%. 1H NMR corresponds to literature data (J. Med. Chem. 2007, 50, 2297-2300).

b). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5% yield.

c). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (13.1 mmol) in POCl3 (30 ml) was refluxed for 1-3 h. The solvent was concentrated and then partitioned with CH2Cl2 (100 ml) and water (100 ml). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 6-chloro compound as a solid (-95%). Compound can be also precipitated from concentrated methylene chloride solution by hexanes and used as a crude for the next step or purified by reslurring in isopropanol, filtered off, washed with isopropanol, and dried under vacuum at 55-60° C.

Preparation of (R)-tert-butyl l-(3-(2-isocyanobenzyI)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate

a). 6-chloro- l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (13 g), Dimethylformamide (130 ml), Potassium carbonate (13 g) and tert-butyl (R)-piperidin- 3-ylcarbamate (10.4 g) were heated to 80°C for 7 hrs. The mixture was then allowed to come to room temperature and poured over ice water (500 ml). The obtained solid was filtered and washed with cold water (500 ml). The solid thus obtained was taken in Methyl-tert-butylether (50 ml) stirred for 10 min. filtered and washed with Hexane (50 ml), to give the N-tert-butyloxycarbonyl protected compound in -75% yield. b). In an alternate embodiment, a flask charged with a stir bar, 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (4.10 mmol), (Λ)-3- terrtnityloxycarbonylaminopiperidine (4.64 mmol), K2CO3 (1.15 g, 8.32 mmol) and DMF (12 mL) was stirred at 75 °C for 6 h. Then, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the N-ter/butyloxycarbonyl protected compound in -93-96% yield.

Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile salts

a). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile hydrochloride

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from previous procedure was dissolved in THF and acidified with 6M hydrochloric acid while maintaining the temperature below 15° C. The resultant slurry was cooled to 0-5° C, stirred at this temperature for 3-5 h and then filtered. The filter cake was washed twice with isopropanol and dried in vacuum at 45-5O0C to provide hydrochloride as a white crystalline solid.

b). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile trifluoroacetate

TFA (ImL) was added into the methylene chloride solution of (R)-tert-butyl l-(3-(2- isocyanobenzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from the above-mentioned procedure. The solution was stirred at room temperature for 1 h and then the mixture was concentrated in vacuo. The residue was dissolved in a small amount of MeOH or isopropanol and the desired salt was precipitated by addition of diisopropyl ether. The solids were filtered off, washed with diisopropyl ether and dried in vacuum at 45-5O0C to provide trifluoroacetate as an off- white powder. c). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile benzoate (Alogliptin)

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate was dissolved in ethanol. A solution of benzoic acid in ethanol was added and the mixture was slowly heated to 65-70°C. The solution was stirred at this temperature for Ih and was then crystallized by cooling to 0-5° C and stirring for 12 hrs. The solution was filtered, washed with alcohol. The wet cake was then conditioned under nitrogen for 2 hours. The cake was dried for 8 hrs at 40-50° C to provide the benzoic acid salt of alogliptin as a white crystalline solid.


Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 4)

Figure imgf000029_0001
Figure imgf000029_0002

Scheme 4 Preparation of 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylurea (0.2 mol) and cyanoacetic acid (0.22 mol) were dissolved in acetic anhydride (400 ml), and the mixture was heated at 80°C for 2 hours. Acetic anhydride was distilled off under reduced pressure and water (200 ml) was added. The mixture was cooled to 0-5 0C and 2N NaOH solution (220 ml) was added and stirring was continued for 2 hours. The obtained solids were filtered off, washed with cold methanol and dried under vacuum. The yield of 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione was 72 %.

b). Under nitrogen atmosphere, l-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3- methyl-l-(2-isocyanobenzyl)-urea with 68% yield.

To 3-(2-cyano-acetyl)-3-methyl-l-(2-isocyanobenzyl)-urea (120 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-l-(2-isocyanobenzyl)-3- methylpyrimidine-2,4(lH,3H)-dione in 76% yield.

c). 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (0.1 mol) was mixed with (R)-piperidin-3-yl-carbamic acid tert.-butyl ester hydrochloride (0.1 mol) of the appropriate amine hydrochloride and (R)-piperidin-3-yl-carbamic acid tert.-butyl ester (0.1 mol). The mixture was heated at 100°C and bubbling continued for 3 hr. Water was added to the cooled mixture and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give N-tert-butyloxycarbonyl protected compound in ~93-96% yield.

d). Benzoate salt of alogliptin was prepared as described above. While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.


Patent EP2410855A1










  1.  “Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S.” (Press release). Takeda Pharmaceutical Company. January 4, 2008. Retrieved January 9, 2008.
  2.  Vipidia: EPAR summary for the public (European Medicines Agency)
  3. Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. (2007). “Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV”. J. Med. Chem.50 (10): 2297–2300.doi:10.1021/jm070104l.PMID 17441705.
  4.  “” (PDF).
  6.  Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei (September 2011), “Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only)”, Current Medical Research and Opinion 27 (9): 1781–1792,doi:10.1185/03007995.2011.599371,PMID 21806314, retrieved April 26,2012
  7.  Kutoh, Eiji; Ukai, Yasuhiro (2012),“Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only)”, Endocrine(January 17, 2012), doi:10.1007/s12020-012-9596-0, PMID 22249941, retrieved April 26, 2012
  8. Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R. (October 2011), “Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study”, Diabetes, Obesity and Metabolism (October 27, 2011) 13 (12): 1088–1096, doi:10.1111/j.1463-1326.2011.01463.x, retrieved April 26,2012
  9.  White WB, Cannon CP, Heller SR et al. (October 2013). “Alogliptin after acute coronary syndrome in patients with type 2 diabetes”. N. Engl. J. Med. 369(14): 1327–35.doi:10.1056/NEJMoa1305889.PMID 23992602.
  10.  White WB, Zannad F (January 2014). “Saxagliptin, alogliptin, and cardiovascular outcomes”. N. Engl. J. Med. 370 (5): 484.doi:10.1056/NEJMc1313880.PMID 24482824.
  11.  Grogan, Kevin (April 26, 2012),“FDA wants yet more data on Takeda diabetes drug alogliptin”,PharmaTimes (PharmaTimes), PharmaTimes online, retrieved April 26,2012
  12. “GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy”. Genetic Engineering & Biotechnology News. June 4, 2009.
EP1083172A1 * May 26, 1998 Mar 14, 2001 Rimma Iliinichna Ashkinazi N-substituted derivatives of 5-oxyiminobarbituric acid
US2598936 * Apr 13, 1950 Jun 3, 1952 Searle & Co Disubstituted cyanoalkanoylureas and thioureas and methods for their production
US6066641 * Dec 12, 1995 May 23, 2000 Euro-Celtique S.A. Aryl thioxanthines
US6248746 * Jan 7, 1999 Jun 19, 2001 Euro-Celtique S.A. 3-(arylalkyl) xanthines
US20080194593 * Jan 11, 2008 Aug 14, 2008 Rao Kalla A2b adenosine receptor antagonists
WO1994003456A1 * Aug 5, 1993 Feb 17, 1994 Boehringer Ingelheim Kg Asymmetrically substituted xanthine with adenosine-antagonistic properties
WO2001029010A1 * Oct 18, 2000 Apr 26, 2001 Amjad Ali Gram-positive selective antibacterial compounds, compositions containing such compounds and methods of treatment
WO2007035629A2 * Sep 15, 2006 Mar 29, 2007 Takeda Pharmaceutical Process for the preparation of pyrimidinedione derivatives
WO2007150011A2 * Jun 22, 2007 Dec 27, 2007 Smithkline Beecham Corp Prolyl hydroxylase inhibitors
Systematic (IUPAC) name
Clinical data
Trade names Nesina, Vipidia
Kazano, Vipidomet (withmetformin)
Oseni, Incresync (withpioglitazone)
  • US: B (No risk in non-human studies)
Legal status
  • (Prescription only)
Routes of
Pharmacokinetic data
Bioavailability 100%
Protein binding 20%
Metabolism Limited, hepatic (CYP2D6– and3A4-mediated)
Biological half-life 12–21 hours
Excretion Renal (major) and fecal (minor)
CAS Registry Number 850649-62-6 Yes BENZOATE850649-61-5 FREE BASE
ATC code A10BH04
PubChem CID: 11450633
ChemSpider 9625485 Yes
KEGG D06553 Yes
ChEBI CHEBI:72323 
Synonyms SYR-322
Chemical data
Formula C18H21N5O2
Molecular mass 339.39 g/mol


Alogliptin benzoate

MF: C18H21N5O2.C7H6O2
MW: 461.519
Melting Point: 185-188°C
Optical Rotation: -56.3° (c=1, MeOH)

Solubility:Soluble in MeOH; Insoluble in ACN

850649-62-6  CAS



    • Synonyms:SYR-322
    • ATC:A10BH04
  • Use:antidiabetic, DPP-4 inhibitor
  • Chemical name:2-[[5-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-2H-pyrimidin-1(2H)-yl]methyl]benzonitrile
  • Formula:C18H21N5O2
  • MW:339.40 g/mol
  • CAS-RN:850649-61-5



  • Formula:C19H19NO2
  • MW:293.37 g/mol
  • CAS-RN:850649-62-6

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN Formula Chemical Name CAS Index Name
22115-41-9 C8H6BrN 2-(bromomethyl)benzonitril
C12H8ClN3O2 2-[[6-chloro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
C13H10ClN3O2 2-[[6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
4270-27-3 C4H3ClN2O2 6-chloro-2,4(1H,3H)-pyrimidinedione
74-88-4 CH3I methyl iodide Methane, iodo-
127294-73-9 C5H12N2 (3R)-3-piperidinamine

Trade Names

Country Trade Name Vendor Annotation
J Nesina Takeda ,2010


  • tabl. 12.5 and 25 mg


    • Feng, J. et al.: J. Med. Chem. (JMCMAR) 50, 2297-2300 (2007).
    • WO 2 005 095 381 (SYRRX; 13.10.2005; appl. 15.12.2004; USA-prior. 15.3.2004).
    • WO 2 010 109 468 (MAPI Pharma; 30.9.2010; appl. 25.3.2010; USA-prior. 26.3.2009).
  • solid preparation comprising Alogliptin and Pioglitazone:

    • US 20 100 092 551 (Takeda Pharm.; 15.4.2010; appl. 30.1.2008; J-prior. 1.2.2007).
  • solid preparation comprising Alogliptin and Metformin:

    • US 20 200 136 127 (Takeda Pharm.; 3.6.2010; appl. 16.7.2008; J-prior. 19.7.2007).


09b37-misc2b027LIONEL MY SON

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CHINA MARKET-Takeda and Sanofi Sign Co-promotion Agreement to Expand Reach of Diabetes Treatment Alogliptin in China



• Alogliptin is a DPP-4 inhibitor that is designed to slow the inactivation of incretin hormones GLP-1 and GIP
• Agreement is part of Takeda’s strategy to complement capabilities through partnerships
• Agreement complements Sanofi’s diabetes portfolio and expand its offer of innovative diabetes treatment to Chinese patients
• The regulatory approval of alogliptin in China is expected in 2013

Shanghai, China, April 22, 2013 – Takeda and Sanofi today announced that they have entered into an agreement for the co-promotion of alogliptin in China for the treatment of type 2 diabetes. Alogliptin is Takeda’s new type 2 diabetes therapy, which has been filed for marketing authorization in China. It is a dipeptidyl peptidase-4 inhibitor (DPP-4i) that is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide).

Under the terms of the agreement, Takeda will grant Sanofi the exclusive right to co-promote alogliptin in China. Sanofi will utilize its commercial capabilities and experience to promote the product in defined territories in China. The commercial terms of the agreement were not disclosed.

“Diabetes has become a major public health problem in China with a rapid increase in the prevalence over recent years. China is now the country with the largest number of people with diabetes,” said Haruhiko Hirate, Corporate Officer and Head of North Asia of Takeda. “The collaboration will expand our reach to Chinese physicians treating patients with type 2 diabetes. Both Takeda and Sanofi have a long history and significant experience in diabetes and this makes for a win-win partnership, as we work together to advance patient care and help to meet the needs of this growing patient population.”

“We are pleased to announce the collaboration with Takeda,” said Fabrice Baschiera, General Manager, Pharmaceutical Operations, Sanofi China. “Alogliptin reinforces the strategic focus of Sanofi in the diabetes field. The new addition of alogliptin strengthens our offer of innovative diabetes treatment to Chinese patients, which includes best-in-class oral and insulin drugs. We look forward to working with Takeda to make alogliptin more widely available to patients with type 2 diabetes in China,” added Mr. Baschiera.

Alogliptin was approved and marketed in Japan in 2010 under the brand name of Nesina®, where it is currently the best-selling DPP-4i for type 2 diabetes. It was approved by the U.S. FDA as a monotherapy and also in fixed-dose combination with pioglitazone (Oseni®) and metformin (Kazano®) in January 2013 for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise.

In China, the rapid economic development has brought mass urbanization, changing diets and increasingly sedentary lifestyles. These factors greatly increase the risk of developing type 2 diabetes. China has the largest number of people with diabetes1, with approximately 92.4 million adults suffering from the disease, 60.7% of which are undiagnosed2. Over the next 20 years, an additional 40 million Chinese adults are expected to develop type 2 diabetes, surpassing the overall prevalence rate of the United States3.

Alogliptin is under registration review in China. Takeda is expecting to obtain the regulatory approval in 2013.

1 International Diabetes Federation. New diabetes figures in China: IDF press statement
2 Diabetes: Wenying Yang et al, N ENGL J MED, March 25, 2010;
3 Kantar Health. The Burden of the Complicated Type 2 Diabetes Patient in China.

About Alogliptin
Alogliptin is a DPP-4i for the treatment of type 2 diabetes as an adjunct to diet and exercise. DPP-4 is designed to slow the inactivation of incretin hormones GLP-1 and GIP. As a result, an increased amount of active incretins enables the pancreas to secrete insulin in a glucose-dependent manner, thereby assisting in the management of blood glucose levels. A New Drug Application (NDA) for NESINA (alogliptin) was approved in April 2010 by the Japanese Ministry of Health, Labour and Welfare for the treatment of type 2 diabetes, and the therapy is available under the same brand name in Japan. NESINA (alogliptin) was approved by the U.S. FDA as a monotherapy and also in fixed-dose combination with pioglitazone (OSENI) and metformin (KAZANO) in January 2013 for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise.
About Type 2 Diabetes
Type 2 diabetes is the most common form of diabetes affecting millions of people globally. Type 2 diabetes is a progressive and chronic condition and patients should work with a health care professional to manage and monitor their disease. In addition to diet and exercise, patients often need to take multiple medications in order to help them manage their blood glucose levels. According to the International Diabetes Federation, the global health care expenditures for diabetes (both type 1 and 2) were estimated at $471.6 billion in 2012. By 2030, this number is projected to exceed $595 billion. China is now the country with the largest number of people with diabetes and 92.4 million adults are suffering from the disease.

About Takeda
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website,

About Sanofi
Sanofi, a global and diversified healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).–alogliptin/


From a structural point has uracil (Uracil) structure, synthesis of these compounds are usually replaced with urea or urea and 1,3 – parents Electric reagent directly related ring, and substituted ureas from amines and isocyanate obtained. Compound 1 and methyl isocyanate urea derivatives obtained by reacting 2 , 2 and 1,3 – diethyl reaction 3 , 3 chlorination with phosphorus oxychloride to obtain 4 , 4 with a secondary amine 5 reaction of 6 , 6 de-Boc protected with acid reaction and generate benzoate Alogliptin benzoate.

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