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Baxdrostat

August 31, 2025 3:02 am / Leave a comment

Baxdrostat

NF3P9Z8J5Y
CIN-107
RO6836191
363.5 g/mol

WeightAverage: 363.461
Monoisotopic: 363.194677057

Chemical FormulaC₂₂H₂₅N₃O₂

N-[(8R)-4-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide

Baxdrostat is an investigational drug that is being evaluated for the treatment of hypertension.^[1] It is an aldosterone synthase inhibitor.^[2][3]

Baxdrostat is under investigation in clinical trial NCT06344104 (A Phase III Study to Investigate the Efficacy and Safety of Baxdrostat in Asian Participants With Uncontrolled Hypertension on Two or More Medications Including Participants With Resistant Hypertension).

LIT

US9353081,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US76841362&_cid=P21-MEZ3MG-55484-1

Example 3-1

(+)-(R)—N-(4-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

In analogy to the procedures described for the preparation of intermediate A-2 [E] and for the preparation of intermediate B-1, Suzuki reaction of (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-3b) with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one and after subsequent reaction with propionyl chloride the title compound as colorless solid. MS: 364.2 (M+H ⁺).

Pat

CN 117247371

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN418385740&_cid=P12-MEZHY3-66430-1

Example 1

Step A

Dissolve 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (1.56 g, 6.9 mmol) and (S)-tert-butylsulfenamide (2.51 g, 20.7 mmol) in 20 mL of tetrahydrofuran. Add ethyl titanate (10.08 mL, 48.28 mmol). Heat to 65°C and stir for 48 hours. Cool to room temperature, add ethyl acetate and water, stir for 15 minutes, and remove the resulting solid by filtration. Separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain the crude product (S,Z)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-tert-butylsulfenimide), which is used directly in the next step.

Step B

Compound (S,Z)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonyl imide) (1.98 g, 6 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -45°C. Sodium borohydride (0.34 g, 9.0 mmol) was added, and the mixture was allowed to return to room temperature and stirred for 18 hours. The mixture was quenched with ice water and extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonyl imide (755 mg, 38% yield). LC/MS (ESI): m/z = 331.2 [M+H] ⁺ .

Step C

To a mixture of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonimide (0.66 g, 2 mmol), pinacol diboronate (1.05 g, 2.1 mmol), and AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl₂(0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (15 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂) and eluted with 30-40% ethyl acetate in petroleum ether to afford (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.45 g, 60% yield). LC/MS (ESI): m/z = 378.3 [M+H] ⁺ .

Step D

To a reaction flask, add 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.29 g, 1.2 mmol), (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.42 g, 1.26 mmol), bistriphenylphosphine palladium dichloride (84 mg, 0.12 mmol), cuprous iodide (38 mg, 0.2 mmol), triethylamine (1.01 g, 10.0 mmol), and 15 mL of N,N-dimethylformamide. The atmosphere was purged with nitrogen three times and the reaction was stirred at 90°C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to afford (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfonimide (0.37 g, 74% yield) as a yellow solid. LC/MS (ESI): m/z = 411.5 [M+H] ⁺ .

Step E

Compound (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfonimide (0.33 g, 0.80 mmol) was dissolved in 1 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse preparative column chromatography to obtain compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.24 g, 97% yield). LC/MS (ESI): m/z = 307.1 [M+H] ⁺ .

Step F

To a reaction flask, add (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.33 mmol), triethylamine (51 mg, 0.5 mmol), and 4 ml of tetrahydrofuran. After cooling in an ice-water bath, slowly add a solution of propionyl chloride (46.25 mg, 0.5 mmol) in 0.5 ml of tetrahydrofuran dropwise. Stirring is continued for 4 hours after addition. The reaction mixture is quenched with methanol and evaporated to dryness under reduced pressure. The residue is purified by column chromatography to obtain the target compound, Baxdrostat (46 mg, 38% yield). LC/MS(ESI):m/z＝363.1[M+H]+.H NMR(400MHz, CDCl3)ppm 1.22(t,3H)1.79(s,3H)2.07(s,1H)2.28(q,2H)2.43-2.68(m,2H)2.71(t,2H)2.82-3.12(m,2H) 3.40(s,3H)5.34(d,1H)5.78(d,1H)7.05(d,1H)7.09(s,1H)7.17(d,1H)8.28(s,1H)8.49(s,1H)

Example 2

Step A

Compound (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H))-tert-butylsulfonylimide (1.65 g, 5 mmol) was dissolved in 20 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added. The mixture was stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse-phase preparative column chromatography to obtain compound (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (1.07 g, 94% yield). LC/MS (ESI): m/z = 226.0 [M+H] ⁺ .

Step B

To a mixture of (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (0.86 g, 3.8 mmol), pinacol diboron (2 g, 4 mmol), AcOK (1.10 g, 11.4 mmol) in toluene (10 mL) was added Pd(dppf)Cl₂(0.27 g, 0.38 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (10 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂) and eluted with 30-40% ethyl acetate in petroleum ether to afford (R)-8-amino-5,6,7,8-tetrahydroisoquinoline-4-boronic acid pinacol ester (0.68 g, 65% yield). LC/MS (ESI): m/z = 274.1 [M+H] ⁺ .

Step C

To a reaction flask, add 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.72 g, 3.0 mmol), (R)-8-amino-5,6,7,8-tetrahydroisoquinolin-4-boronic acid pinacol ester (0.99 g, 3.6 mmol), bistriphenylphosphine palladium dichloride (210 mg, 0.3 mmol), and potassium phosphate monohydrate (204 mg, 0.9 mmol). Dissolve the mixture in dioxane and water (9:1, 30 mL). Replace the atmosphere with nitrogen three times and allow the mixture to react overnight at 90°C with stirring. Cool to room temperature, dilute the reaction solution with ethyl acetate and water, and extract with ethyl acetate. The resulting organic phase is then washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.81 g, 88% yield). LC/MS (ESI): m/z = 307.1 [M+H] ⁺ . The target compound, Baxdrostat, was then prepared using a method similar to the last step in Example 1.

Example 3

Step A

4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (1.88 g, 6.9 mmol) and (S)-tert-butylsulfenamide (2.51 g, 20.7 mmol) were dissolved in 20 mL of tetrahydrofuran. Ethyl titanate (10.08 mL, 48.28 mmol) was added and the mixture was heated to 65°C with stirring for 48 hours. After cooling to room temperature, ethyl acetate and water were added and stirred for 15 minutes. The resulting solid was removed by filtration. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product (S,Z)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-tert-butylsulfenimide), which was used directly in the next step. LC/MS (ESI): m/z = 376.2 [M+H] ⁺ .

Step B

Compound (S,Z)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonyl imide) (2.26 g, 6 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -45°C. Sodium borohydride (0.36 g, 9.0 mmol) was added, and the mixture was allowed to return to room temperature and stirred for 18 hours. The mixture was quenched with ice water and extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonyl imide (1.04 g, 46% yield). LC/MS (ESI): m/z = 378.0 [M+H] ⁺ .

Step C

To a mixture of (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonimide (0.76 g, 2 mmol), pinacol diboronate (1.05 g, 2.1 mmol), and AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl₂(0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (15 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂) and eluted with 30-40% ethyl acetate in petroleum ether to afford (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.51 g, 68% yield). LC/MS (ESI): m/z = 378.2 [M+H] ⁺ .

The next three steps were carried out in the same manner as in Example 1 to prepare the target compound Baxdrostat.

LIT

https://medicalxpress.com/news/2025-08-stubborn-high-blood-pressure-experimental.html

A new treatment has been shown to significantly lower blood pressure in people whose levels stay dangerously high, despite taking several existing medicines, according to the results of a Phase III clinical trial led by a UCL Professor. Globally, around 1.3 billion people have high blood pressure (hypertension), and in around half of cases the condition is uncontrolled or treatment resistant. These individuals face a much greater risk of heart attack, stroke, kidney disease, and early death. In the UK the number of people with hypertension is around 14 million.

The international BaxHTN trial, led by Professor Bryan Williams (UCL Institute of Cardiovascular Science), assessed the new drug baxdrostat—which is taken as a tablet—with participation from nearly 800 patients across 214 clinics worldwide.

Results were presented at the European Society of Cardiology (ESC) Congress 2025 in Madrid and were simultaneously published in the New England Journal of Medicine.

The trial results showed that, after 12 weeks, patients taking baxdrostat (1 mg or 2 mg once daily in pill form) saw their blood pressure fall by around 9-10 mmHg more than placebo—a reduction large enough to cut cardiovascular risk. About four in 10 patients reached healthy blood pressure levels, compared with fewer than two in 10 on placebo.

Principal Investigator, Professor Williams, who is presenting the results at ESC, said, “Achieving a nearly 10 mmHg reduction in systolic blood pressure with baxdrostat in the BaxHTN Phase III trial is exciting, as this level of reduction is linked to substantially lower risk of heart attack, stroke, heart failure and kidney disease.”

How baxdrostat works

Blood pressure is strongly influenced by a hormone called aldosterone, which helps the kidneys regulate salt and water balance.

Some people produce too much aldosterone, causing the body to hold onto salt and water. This aldosterone dysregulation pushes blood pressure up and makes it very difficult to control.

Addressing aldosterone dysregulation has been a key effort in research over many decades, but it has been so far difficult to achieve.

Baxdrostat works by blocking aldosterone production, directly addressing this driver of high blood pressure (hypertension).

Professor Williams, Chair of Medicine at UCL, said, “These findings are an important advance in treatment and in our understanding of the cause of difficult-to-control blood pressure.

“Around half of people treated for hypertension do not have it controlled, however this is a conservative estimate and the number is likely higher, especially as the target blood pressure we try to reach is now much lower than it was previously.

“In patients with uncontrolled or resistant hypertension, the addition of baxdrostat 1mg or 2mg once daily to background antihypertensive therapy led to clinically meaningful reductions in systolic blood pressure, which persisted for up to 32 weeks with no unanticipated safety findings.

“This suggests that aldosterone is playing an important role in causing difficult to control blood pressure in millions of patients and offers hope for more effective treatment in the future.”

Historically, higher-income Western countries were reported to have far higher levels of hypertension. However, largely due to changing diets (adding less salt to food), the numbers of people living with the condition is now far higher in Eastern and lower-income countries. More than half of those affected live in Asia, including 226 million people in China and 199 million in India.

Professor Williams added, “The results suggest that this drug could potentially help up to half a billion people globally—and as many as 10 million people in the UK alone, especially at the new target level for optimal blood pressure control.”

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Identifiers

IUPAC name
CAS Number	1428652-17-8
PubChem CID	71535962
IUPHAR/BPS	12362
ChemSpider	76804781
UNII	NF3P9Z8J5Y
KEGG	D12789
ChEMBL	ChEMBL4113975
Chemical and physical data
Formula	C₂₂H₂₅N₃O₂
Molar mass	363.461 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

PATENTS

New bicyclic dihydroquinoline-2-one derivativesPublication Number: TW-201319054-APriority Date: 2011-09-23
New bicyclic dihydroquinoline-2-one derivativesPublication Number: TW-I576342-BPriority Date: 2011-09-23Grant Date: 2017-04-01
New bicyclic dihydroquinoline-2-one derivativesPublication Number: US-2013079365-A1Priority Date: 2011-09-23
Bicyclic dihydroquinoline-2-one derivativesPublication Number: US-9353081-B2Priority Date: 2011-09-23Grant Date: 2016-05-31
New bicyclic dihydroquinoline-2-one derivativesPublication Number: WO-2013041591-A1Priority Date: 2011-09-23

Novel bicyclic dihydroquinolin-2-one derivativesPublication Number: JP-2014526539-APriority Date: 2011-09-23
Novel bicyclic dihydroquinolin-2-one derivativesPublication Number: JP-6012737-B2Priority Date: 2011-09-23Grant Date: 2016-10-25
New bicyclic dihydroquinoline-2-one derivativesPublication Number: KR-101723276-B1Priority Date: 2011-09-23Grant Date: 2017-04-04
New bicyclic dihydroquinoline-2-one derivativesPublication Number: KR-20140076591-APriority Date: 2011-09-23
New bicyclic dihydroquinoline-2-one derivativesPublication Number: NZ-620652-APriority Date: 2011-09-23

New bicyclic dihydroquinolin-2-one derivativesPublication Number: CN-103827101-APriority Date: 2011-09-23
Bicyclic dihydroquinolin-2-one derivativesPublication Number: CN-103827101-BPriority Date: 2011-09-23Grant Date: 2016-12-07
New bicyclic dihydroquinoline-2-one derivativesPublication Number: EP-2758388-A1Priority Date: 2011-09-23
New bicyclic dihydroquinoline-2-one derivativesPublication Number: EP-2758388-B1Priority Date: 2011-09-23Grant Date: 2018-02-21
NEW BICYCLIC DERIVATIVES OF DIHYDROKINOLIN-2-ONPublication Number: HR-P20180592-T1Priority Date: 2011-09-23

Methods of using aldosterone synthase inhibitorsPublication Number: US-2024277698-A1Priority Date: 2021-06-24
How to use aldosterone synthase inhibitorsPublication Number: CN-117545482-APriority Date: 2021-06-24
New bicyclic dihydroquinoline-2-one derivativesPublication Number: AU-2012311582-A1Priority Date: 2011-09-23
New bicyclic dihydroquinoline-2-one derivativesPublication Number: AU-2012311582-B2Priority Date: 2011-09-23Grant Date: 2017-07-06
Bicyclic dihydroquinoline-2-one derivativesPublication Number: CA-2845170-CPriority Date: 2011-09-23Grant Date: 2019-08-13

References

“Baxdrostat – CinCor Pharma”. AdisInsight. Springer Nature Switzerland AG.
Dogra S, Shah S, Gitzel L, Pusukur B, Sood A, Vyas AV, Gupta R (July 2023). “Baxdrostat: A Novel Aldosterone Synthase Inhibitor for Treatment Resistant Hypertension”. Current Problems in Cardiology. 48 (11): 101918. doi:10.1016/j.cpcardiol.2023.101918. PMID 37399857. S2CID 259320969.
Awosika A, Cho Y, Bose U, Omole AE, Adabanya U (October 2023). “Evaluating phase II results of Baxdrostat, an aldosterone synthase inhibitor for hypertension”. Expert Opinion on Investigational Drugs. 32 (11): 985–995. doi:10.1080/13543784.2023.2276755. PMID 37883217. S2CID 264517675.

The selective aldosterone synthase inhibitor Baxdrostat significantly lowers blood pressure in patients with resistant hypertensionPublication Name: Frontiers in EndocrinologyPublication Date: 2022-12-09PMCID: PMC9780529PMID: 36568122DOI: 10.3389/fendo.2022.1097968
Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteersPublication Name: Hypertension research : official journal of the Japanese Society of HypertensionPublication Date: 2022-10-20PMCID: PMC9747611PMID: 36266539DOI: 10.1038/s41440-022-01070-4
Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)Publication Name: Hypertension (Dallas, Tex. : 1979)Publication Date: 2017-01PMCID: PMC5142369PMID: 27872236DOI: 10.1161/hypertensionaha.116.07716

/////Baxdrostat, PHASE 3, NF3P9Z8J5Y, CIN 107, RO 6836191,

Linaprazan

August 30, 2025 2:57 am / Leave a comment

Linaprazan

CHINA 2024, APPROVALS 2024, AstraZeneca, CINCLUS, GERD, linaprazan glurate, for the treatment of moderate to severe GERD,

8-[(2,6-dimethylphenyl)methylamino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

CAS 248919-64-4
AZD-0865
E0OU4SC8DP
DTXSID90870279
366.5 g/mol, C₂₁H₂₆N₄O₂
CS-5725
MS-25870
DB-302288
HY-100412
F85407
Q27276714
8-(2,6-dimethylbenzylamino)-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide
8-[(2,6-dimethylphenyl)methylamino]-N-(2-hydroxyethyl)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxamide

Chemical structure of linaprazan glurate CAS No.: 1228559-81-6 , X842

Molecular formula	C26H32N4O5
Molecular weight	480.556086540222
Accurate quality	480.237

5-[2-[[8-[(2,6-dimethylphenyl)methylamino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carbonyl]amino]ethoxy]-5-oxopentanoic acid

OriginatorAstraZeneca
DeveloperCinclus Pharma; Jiangsu Sinorda Biomedicine Co., Ltd; Shanghai Pharmaceutical Group
Class2 ring heterocyclic compounds; Amines; Aminopyridines; Anti-inflammatories; Antibacterials; Antiulcers; Glutarates; Imidazoles; Pentanoic acids; Pyridines; Small molecules; Toluenes
Mechanism of ActionPotassium-competitive acid blockers

RegisteredReflux oesophagitis
Phase IIDuodenal ulcer; Erosive oesophagitis; Helicobacter infections
Phase IGastro-oesophageal reflux

28 Aug 2025No recent reports of development identified for phase-I development in Gastro-oesophageal-reflux(In volunteers) in Sweden (PO, Tablet)
29 Jun 2025Cinclus Pharma Holding plans a phase III trial for Gastro-oesophageal-reflux in the US, Bulgaria, Czech Republic, Georgia, Germany, Hungary, Poland (PO) (NCT07037875)
13 Jun 2025Cinclus Pharma secures EMA and FDA pediatric study waivers for linaprazan glurate in H. pylori infection

Linaprazan is a lipophilic, weak base with potassium-competitive acid blocking (P-CAB) activity. Linaprazan concentrates highly in the gastric parietal cell canaliculus and on entering this acidic environment is instantly protonated and binds competitively and reversibly to the potassium binding site of the proton pump hydrogen-potassium adenosine triphosphatase (H+/K+ ATPase), thereby inhibiting the pump’s activity and the parietal cell secretion of H+ ions into the gastric lumen, the final step in gastric acid production.

Linaprazan is an experimental drug for the treatment of gastroesophageal reflux disease (GERD). Unlike the proton-pump inhibitors (PPIs) which are typically used to treat GERD, linaprazan is a potassium-competitive acid blocker (P-CAB).^[1][2] Linaprazan was developed by AstraZeneca, but it was not successful in clinical trials.^[3]

The drug was then licensed to Cinclus Pharma,^[4] which is now investigating linaprazan glurate, a prodrug of linaprazan which is expected to have a longer biological half-life than linaprazan itself.^[4]

Linaprazan glurate inhibits exogenously or endogenously stimulated gastric acid secretion. Linaprazan glurate exhibits several favorable properties, such as rapid onset of action, high in vivo potency, and/or prolonged duration of action. Linaprazan glurate is useful in the research of gastrointestinal inflammatory diseases and peptic ulcer disease (disclosed in patent WO2010063876A1).

Imidazo pyridine derivatives which inhibit gastric acid secretionPublication Number: WO-9955706-A9Priority Date: 1998-04-29
Imidazo pyridine derivatives which inhibit gastric acid secretion.Publication Number: ZA-200005797-BPriority Date: 1998-04-29

Imidazo pyridine derivatives which inhibit gastric acid secretionPublication Number: KR-20050121760-APriority Date: 1998-04-29
Imidazopyridine derivatives which inhibit gastric acid secretion, pharmaceutical formulation containing such derivatives, processes for their preparation, use thereof, and intermediates.Publication Number: NO-317262-B1Priority Date: 1998-04-29
Imidazo pyridine derivatives which inhibit gastric acid secretionPublication Number: PL-195000-B1Priority Date: 1998-04-29
Imidazo pyridine derivatives which inhibit gastric acid secretionPublication Number: US-6313137-B1Priority Date: 1998-04-29Grant Date: 2001-11-06
Imidazo pyridine derivatives which inhibit gastric acid secretionPublication Number: WO-9955706-A1Priority Date: 1998-04-29

SYN

WO2010063876

https://patentscope.wipo.int/search/en/WO2010063876

Examples

Example 1

Preparation of 5- {2-[( {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[ 1 ,2-a]pyridin-6-yl}carbonyl)amino]ethoxy}-5-oxopentanoic acid

2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidazo[l,2-a]pyridi-ne-6-carboxamide (obtained using the process according to WO02/20523) (2.0 g,

5.46 mmol) and glutaric anhydride (0.95 g, 8.33 mmol) was added to DMF (10 ml). The mixture was heated to 80 ⁰C and stirred 16 h at this temperature.

Acetone (20 ml) was added to the reaction mixture whereby the product started to crystallize. The mixture was cooled to room temperature. After 4 h the product was filtered off and washed with acetone (20 ml). 2.25 g (86%) of the title compound was obtained. The structure of the compound was confirmed with ¹H- NMR spectrum.

¹H-NMR (300 MHz, DMSO): δ 1.73 (m, 2H), 2.2-2.4 (m, 16H), 3.52 (m,2H), 4.18 (t, 2H), 4.36 (d, 2H), 4.99 (t, IH), 6.67 (s, IH), 7.0-7.2 (m, 3H), 8.04 (s, IH), 8.56 (t, IH), 12.10 (bs, IH).

SYN

US6900324B2.

https://patentscope.wipo.int/search/en/detail.jsf?docId=US40374322&_cid=P12-MEXO1E-18626-1

Example 1.16

Synthesis of 8-[(216-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

A reactor was charged with isopropyl 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (11.30 kg, 1 equiv., 27.02 mol) and THF (45 L), ethanolamine (18.97 kg, 11 equiv., 309.2 mol) was added at about 20° C. The suspension was heated to about 100° C. Some solvent was distilled off and then THF (35 L) was added and the distillation was continued. The procedure of adding THF and distilling it off was repeated until complete conversion. To the suspension ethanol (140L) was added and the suspension was heated to reflux. To obtain a clear solution additional ethanol (13L) was added. The hot solution was filtered and then cooled. The white solid was filtered off, washed with ethanol and dried to yield the product as a white powder. (8271 g).

2. Preparation of Starting Materials

Example 2.1

Synthesis of 6-amino-5-nitro-nicotinamide

100 g of 6-hydroxy-5-nitro-nicotinic acid (0.54 mol; HPLC>98% area) was suspended in toluene (750 mL). DMF (1 mL, 0.013 mol, 0.024 equiv.) was added and the mixture was heated to 110° C. (inner temperature). Thionylchloride (99 mL, 2.5 equiv.) was added over 120 min. Heating was continued for 4 h at 110° C. The reaction mixture was concentrated to half the volume (400 mL of solvent were distilled off), and toluene (400 mL) was added.

This procedure was repeated once again (410 mL of toluene were distilled off and fresh toluene (410 mL) was added again). The solution was then cooled to 20° C. and slowly added to aqueous ammonia (25%, 440 mL, 12 equiv.) over 40 min. Precipitation started immediately. During the addition the temperature was maintained below 15° C. After the addition had been completed the reaction mixture was allowed to warm up to room temperature and stirring was continued for 16 h. The solid was filtered off, washed with water (500 mL), ethanol (250 mL), TBME (250 mL) and dried (50-10 mbar, 40° C. bath temperature, 16 h) to yield 91.3 g of the title compound (0.501 mol, 87%).

Example 2.2

Synthesis of 5,6-diamino-nicotinamide

44.5 g of 6-amino-5-nitro-nicotinamide (0.24 mol; HPLC: 93% area) were suspended in methanol/water 1:1 (500 mL), 5.0 g of catalyst [Pd(4%)-Ru(1%)/C paste (62% H₂O type: 485; Johnson Matthey); type: 485; Johnson Matthey] was added. Hydrogenation was carried out at 5 bar and 30° C. for 5 h. After completion the catalyst was filtered off and washed with methanol/water 1/1 (50 mL). 480 mL of the solvent was distilled off. The resulting suspension was cooled to 20° C. and filtered off. The solid was washed with methanol (20 mL) and TBME (30 mL). After drying (200-10 mbar; 40° C. bath temperature, 16 h) 27.3 g of the title compound (0.18 mol, 73%) were obtained.

Example 2.3

Synthesis of 5,6-diamino-nicotinamide

42.3 g of 6-amino-5-nitro-nicotinamide (0.23 mol, HPLC: 93% area) was suspended in methanol/water 1:1 (500 mL). 5.2 g of catalyst [Pd(5%)/C (57.8% H₂O); type: 39, Johnson Matthey] was added. Hydrogenation was carried out at 5 bar and 30° C. for 4 h. After completion the catalyst was filtered off and washed with methanol/water 1/1 (100 mL). 550 mL of the solvent was distilled off. The resulting suspension was cooled to 20° C. and filtered off. The solid was washed with methanol (20 mL) and TBME (30 mL). After drying (200-10 mbar; 40° C. bath temperature, 16 b) 28.5 g of the title compound (0.18 mol, 78%) was obtained

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Linaprazan is a potassium-competitive acid blocker (P-CAB) initially developed by AstraZeneca between 2001 and 2005 for treating gastroesophageal reflux disease (GERD). Subsequently, Cinclus Pharma ac
quired the rights to linaprazan and developed linaprazan glurate. In 2024, the NMPA approved linaprazan glurate for the treatment of moderate to severe GERD, marking Cinclus Pharma’s first marketing approval in China. Linaprazan glurate is a P-CAB that inhibits gastric acid secretion by reversibly blocking the potassium-binding site of the gastric H+/K +-ATPase enzyme, leading to rapid and sustained acid suppression [94]. Clinical efficacy was demonstrated in Phase III trials NCT04567810), showing superior acid suppression and symptom relief compared to PPIs in GERD patients. Regarding toxicity, linaprazan was generally well tolerated in clinical studies. However, some issues were
noted, such as elevated liver transaminases in a few patients, which were addressed in the development of linaprazan glurate by achieving lower peak plasma concentrations (Cmax) to minimize liver load 95,96]. The synthetic route of Linaprazan, shown in Scheme 22 [97], initiates with condensative Cyclization between Lina-001 and Lina-002 to yield Lina-003. This intermediate undergoes nucleophilic substitution with Lina-004 under basic conditions to generate Lina-005. Final thermolytic amidation of Lina-005 at 100 DEG CENT affords Linaprazan

[95] C. Scarpignato, R.H. Hunt, Potassium-competitive acid blockers: current clinical use and future developments, Curr. Gastroenterol. Rep. 26 (2024) 273–293.
[96] J.F. Willart, M. Durand, L.E. Briggner, A. Marx, F. Dan`ede, M. Descamps, Solid-state amorphization of linaprazan by mechanical milling and evidence of polymorphism, J Pharm Sci 102 (2013) 2214–2220.
[97] B. Elman, S. Erback, E. Thiemermann, Process for Preparing a Substituted Imidazopyridine Compound, 2002. US6900324B2.

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References

Rawla P, Sunkara T, Ofosu A, Gaduputi V (December 2018). “Potassium-competitive acid blockers – are they the next generation of proton pump inhibitors?”. World Journal of Gastrointestinal Pharmacology and Therapeutics. 9 (7): 63–68. doi:10.4292/wjgpt.v9.i7.63. PMC 6305499. PMID 30595950.
“Linaprazan”. Inxight Drugs. National Center for Advancing Translational Sciences.
Tong A (4 March 2020). “Can reformulation of an AstraZeneca castoff rival Takeda’s new heartburn drug? Here’s a $26M bet on yes”. endpts.com.
“Linaprazan glurate”. Cinclus Pharma.

Clinical data

Other names	AZD-0865
Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	248919-64-4
PubChem CID	9951066
UNII	E0OU4SC8DP
Chemical and physical data
Formula	C₂₁H₂₆N₄O₂
Molar mass

////////////Linaprazan, CHINA 2024, APPROVALS 2024, AstraZeneca, CINCLUS, GERD, linaprazan glurate, moderate to severe GERD, 248919-64-4, AZD 0865, E0OU4SC8DP, DTXSID90870279, X 842

Pradefovir

August 29, 2025 2:49 am / Leave a comment

Pradefovir

WeightAverage: 423.79
Monoisotopic: 423.0863188

Chemical FormulaC₁₇H₁₉ClN₅O₄P

Remofovir
CAS 625095-60-5
GZE85Q9Q61
DTXSID10870372
MB-6866
MB-06866
ICN2001-3

9-[2-[[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2λ⁵-dioxaphosphinan-2-yl]methoxy]ethyl]purin-6-amine

2R,4S-(+)-9-(2-(4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl)methoxyethyl)adenine

HEPATITIS B VIRUS, APPROVALS 2024, CHINA 2024, Xi’an Xintong Pharmaceutical Research Co, Xinshumu

Pradefovir Mesylate

CAS No. : 625095-61-6, Remofovir mesylate

분자량	519.90
화학식	C₁₈H₂₃ClN₅O₇PS

Pradefovir is a cyclodiester antiviral prodrug with specific activity against hepatitis B virus (HBV). Pradefovir is specifically metabolized in the liver by hepatic enzymes, mainly by CYP4503A4, to adefovir. In turn, adefovir is phosphorylated by cellular kinases to its activated form adevofir diphosphate. By competing with the natural substrate dATP, the diphosphate form is incorporated into viral DNA and inhibits RNA-dependent DNA polymerase. This causes DNA chain termination and eventually results in an inhibition of HBV replication.

PAT

Novel phosphonic acid based prodrugs of PMEA and its analoguesPublication Number: US-2003229225-A1Priority Date: 2002-05-13
Process for Preparation of Cyclic Prodrugs of PMEA and PMPAPublication Number: US-2007203339-A1Priority Date: 2002-05-13
Process for preparation of cyclic prodrugs of PMEA and PMPAPublication Number: US-7193081-B2Priority Date: 2002-05-13Grant Date: 2007-03-20
Phosphonic acid based prodrugs of PMEA and its analoguesPublication Number: US-7214668-B2Priority Date: 2002-05-13Grant Date: 2007-05-08

Lewis acid mediated synthesis of cyclic estersPublication Number: US-2005282782-A1Priority Date: 2004-06-08
Lewis acid mediated synthesis of cyclic estersPublication Number: US-7582758-B2Priority Date: 2004-06-08Grant Date: 2009-09-01
Process for preparation of cyclic prodrugs of pmea and pmpaPublication Number: EP-1504014-B1Priority Date: 2002-05-13Grant Date: 2015-12-02
Salts of a phosphonic acid based prodrug of PMEAPublication Number: EP-2223927-B1Priority Date: 2002-05-13Grant Date: 2014-10-15
Process for preparation of cyclic prodrugs of PMEA and PMPAPublication Number: US-2003225277-A1Priority Date: 2002-05-13

Syn

J. Med. Chem. 51 (2008) 666–676

SYN

https://pubs.acs.org/doi/10.1021/jm7012216

Syn

European Journal of Medicinal Chemistry 291 (2025) 117643

Pradefovir, developed by Xi’an Xintong Pharmaceutical Research Co., Ltd., is a liver-targeted nucleotide analog prodrug designed for the treatment of chronic hepatitis B virus (HBV) infection. It was approved
by the NMPA in 2024, under the brand name Xinshumu, for the treat ment of adult patients with chronic hepatitis B. Pradefovir utilizes HepDirect liver-targeting technology, allowing it to remain stable in the
gastrointestinal tract and bloodstream. It is specifically metabolized into its active form in the liver by the enzyme CYP3A4, leading to high hepatic concentrations and low systemic exposure. This targeted activation enhances antiviral efficacy while minimizing potential side effects on other organs. The clinical efficacy of pradefovir was demonstrated in a Phase III randomized, double-blind, positive-controlled trial (NCT04543565) involving patients with chronic hepatitis B. Participants were randomized to receive pradefovir or tenofovir disoproxil fumarate (TDF) in a 2:1 ratio, with a treatment duration of 96 weeks
followed by a 48-week open-label extension. Interim analysis conducted after 48 weeks showed that pradefovir achieved comparable reductions in HBV DNA levels to TDF, with a favorable safety profile. Regarding safety, pradefovir exhibited a favorable profile [90]. The total occurrence rate of adverse events was similar in both the pradefovir and TDF groups. Nevertheless, the incidence of drug-related adverse events was notably lower in the pradefovir group. Significantly, compared to the typical concerns associated with nucleotide analogs, pradefovir showed a diminished influence on renal function and bone mineral density. This is a crucial aspect considering the known side-effects of nucleotide an alogs in clinical applications, where issues related to kidney function and bone health often pose challenges. Pradefovir, in contrast, appears to have a more favorable safety profile in these regards, which could potentially offer significant advantages in long-term treatment scenarios
[91]. Additionally, it had minimal effects on lipid profiles, suggesting a lower potential risk for cardiovascular events during long-term therapy.
The approval of pradefovir mesylate offers a new therapeutic option for adult patients with chronic hepatitis B, providing effective antiviral activity with an improved safety profile, particularly concerning renal and bone health [92,93].
The synthetic route of Pradefovir Mesylate is shown in Scheme 21 [93]. The route commences with a stereoselective reduction of Prad-001 employing ( )-DIP-Cl, affording Prad-002. Subsequent acid-catalyzed cyclodehydration between the hydroxyl groups of Prad-002 and Prad-003 generates Pradefovir, followed by mesylate salt formation to complete the synthesis.

90-93

[90] Y. Gao, F. Kong, X. Song, J. Shang, L. Yao, J. Xia, Y. Peng, W. Liu, H. Gong, M. Mu,
H. Cui, T. Han, W. Chen, X. Wu, Y. Yang, X. Yan, Z. Jin, P. Wang, Q. Zhu, L. Chen,
C. Zhao, D. Zhang, W. Jin, D. Wang, X. Wen, C. Liu, J. Jia, Q. Mao, Y. Ding, X. Jin,
Z. Zhang, Q. Mao, G. Li, J. Niu, Pradefovir treatment in patients with chronic
hepatitis B: week 24 results from a multicenter, double-blind, randomized,
noninferiority, phase 2 trial, Clin. Infect. Dis. 74 (2022) 1925–1932.
[91] Y. Ding, H. Zhang, X. Li, C. Li, G. Chen, H. Chen, M. Wu, J. Niu, Safety,
pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a
novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects,
Hepatol Int 11 (2017) 390–400.
[92] H. Zhang, M. Wu, X. Zhu, C. Li, X. Li, W. Jin, D. Zhang, H. Chen, C. Liu, Y. Ding,
J. Niu, J. Liu, Safety, efficacy, and pharmacokinetics of pradefovir for the
treatment of chronic hepatitis B infection, Antiviral Res 174 (2020) 104693.
[93] K.R. Reddy, M.C. Matelich, B.G. Ugarkar, J.E. G´omez-Galeno, J. DaRe, K. Ollis,
Z. Sun, W. Craigo, T.J. Colby, J.M. Fujitaki, S.H. Boyer, P.D. van Poelje, M.D. Erion,
Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis
B, J. Med. Chem. 51 (2008) 666–676.

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//////////Pradefovir, HEPATITIS B VIRUS, APPROVALS 2024, CHINA 2024, Xi’an Xintong Pharmaceutical Research Co, Xinshumu, Pradefovir Mesylate, Remofovir, 625095-60-5, GZE85Q9Q61, DTXSID10870372, MB 6866, MB-06866, ICN2001-3

Bevifibatide

August 28, 2025 2:53 am / Leave a comment

Bevifibatide

Cas 710312-77-9

817.9 g/mol, C₃₄H₄₇N₁₁O₉S₂

2-[(3S,6S,12S,20R,23S)-20-carbamoyl-12-[3-(diaminomethylideneamino)propyl]-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,22-hexaoxo-17,18-dithia-1,4,7,10,13,21-hexazabicyclo[21.3.0]hexacosan-6-yl]acetic acid

APPROVALS 2025, CHINA 2025, Bio-Thera Solutions, Beitaning RegisteredAcute coronary syndromes

BAT-2094 | batifiban | Beitaning | Betagrin® | Compound I [CN101085809A]

OriginatorBio-Thera Solutions
ClassAntiplatelets; Cardiovascular therapies; Cyclic peptides
Mechanism of ActionIntegrin alphaVbeta3 antagonists; Platelet glycoprotein GPIIb-IIIa complex anatgonists
02 Dec 2024Zhujiang Hospital plans a phase II BCAIS-I trial for Acute ischemic stroke in China (IV) (NCT06712004)
07 Aug 2024Chemical structure information updated
28 Jun 2024Registered for Acute coronary syndromes in China (IV) – First global approval
Correctin
7AKM76YKN5

Bevifibatide is a synthetic cyclic heptapeptide, and its synthesis involves several stages of peptide chemistry. The primary methods used for producing peptides of this nature are solid-phase peptide synthesis (SPPS), followed by cleavage, purification, and cyclization.

Bevifibatide is a cyclic peptide with the Peptide sequence Arg-Gly-Asp-MeAsp-Phg-Val-Nal.

Bevifibatide (Bio-Thera Solutions) is a synthetic cyclic heptapeptide that functions as a αIIbβ3 and αvβ3 integrin receptor antagonist [1]. It was designed to inhibit platelet aggregation as an antiplatelet cardiovascular therapy.

SYN

CN101085809

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN83278873&_cid=P21-MEUT2B-21989-1

Example 1: Fmoc solid phase synthesis

1: Synthesis of Fmoc-Cys(Trt)-HN-Rink Amide AM resin

(1) Fmoc-Rink Amide AM resin (produced by Tianjin Nankai Hecheng Technology Co., Ltd., substitution degree 0.59 mmol/g, 8.4746 g) was added to the solid phase reaction column, washed three times with DMF, and swelled with DCM for 30 minutes.

(2) The solution was drained and Fmoc-protection was removed with 20% piperidine in DMF at room temperature for 20 minutes.

(3) The solution was drained, the resin was washed five times with DMF, and the solution was drained.

(4) Fmoc-Cys(Trt)-OH (2.9285 g), HOBt (0.6755 g), and DIPCDI (0.8 ml) were dissolved in DMF (20 ml) and DCM (20 ml) and pre-reacted in an ice bath for 20 minutes.

(5) Add the above reaction solution to the solid phase reaction column, N₂Stir with air flow to ensure full contact and reaction with the resin, and react at room temperature (31°C) for 2 hours.

(6) The solution was drained, and the resin was washed three times with DMF and once with DCM. Acetic anhydride (10 ml), pyridine (8 ml), and N₂Stir with air flow to ensure full contact and reaction with the resin, and react at room temperature (31°C) for 10 hours.

(7) The solution was drained, and the resin was washed three times with DMF, three times with DCM, and three times with methanol. The resin was then dried under vacuum to obtain Fmoc-Cys(Trt)-HN-Rink Amide AM resin (10.2578 g). The degree of substitution was measured to be 0.5086 mmol/g.

2: Synthesis of Fmoc-Pro-Cys(Trt)-HN-Rink Amide AM resin

(1) 10.2578 g of Fmoc-Cys(Trt)-Rink Amide AM resin (substitution degree: 0.5086 mmol/g) was added to the solid phase reaction column, washed three times with DMF, and swelled with DCM for 30 minutes.

(2) The solution was drained and Fmoc-protection was removed with 20% piperidine in DMF at room temperature for 20 minutes.

(3) The solution was drained, the resin was washed five times with DMF, and the solution was drained.

(4) Fmoc-Pro-OH (5.061 g), HOBt (3.04 g), and DIPCDI (7.5 ml) were dissolved in DMF (20 ml) and DCM (20 ml) and pre-reacted in an ice bath for 20 minutes.

(5) Add the above reaction solution to the solid phase reaction column, N₂Stir with air flow to ensure full contact and reaction with the resin. React at room temperature (30°C) for 2 hours, and monitor the reaction progress with Kaiser test.

(6) The solution was drained and the resin was washed three times with DMF to obtain Fmoc-Pro-Cys(Trt)-HN-Rink Amide AM resin.

3: Synthesis of Mpr-X-Gly-Asp(OtBu)-Trp(Boc)-Pro-Cys(Trt)-HN-Rink Amide AM resin, where X is Arg(Pbf), Har(Pbf) or Lys(Boc)

The reaction steps for coupling each protected amino acid are the same as 2, except that the protected amino acids to be coupled are: Fmoc-Trp(Boc)-OH (7.899 g); Fmoc-Asp(OtBu)-OH (6.172 g); Fmoc-Gly-OH (4.460 g); Fmoc-X-OH (9.732 g); Mpr (1.592 g).

4: Linear crude peptide Mpr-X-Gly-Asp-Trp-Pro-Cys-NH₂Preparation

(1) The resin obtained in step 3 was washed three times with DMF, three times with DCM, and three times with methanol, and then dried under vacuum to obtain 21.182 g of Mpr-X-Gly-Asp(OtBu)-Trp(Boc)-Pro-Cys(Trt)-HN-Rink Amide AM resin.

(2) The obtained resin was placed in a round-bottom flask and TFA (180 ml), H₂A mixed solution of O (10 ml) and TIS (10 ml) was introduced into₂, stir electromagnetically in an ice bath for 10 minutes, remove the ice bath, and react at room temperature (29°C) for 2 hours.

(3) After the reaction is completed, the solution is filtered, and the resin is washed twice with TFA. The filtrates are combined and ice-cold ether (2 L) is added to the filtrate. A white precipitate is precipitated, and the precipitate is collected by centrifugation and fully dried in vacuo.

(4) The dried white precipitate (4.237 g) was collected to obtain the crude linear peptide Mpr-X-Gly-Asp-Trp-Pro-Cys-NH₂, sealed and stored at -20℃.

5: Linear crude peptide Mpr-X-Gly-Asp-Trp-Pro-Cys-NH₂Cyclization

The crude linear peptide of batifiban and its analogues obtained in Example 4 was dissolved in water, and 1 mmol/ml of I₂The mixture was stirred for 30 minutes at room temperature, and the cyclization reaction was followed by analytical HPLC until completion, thereby obtaining Mpr-X-Gly-Asp-Trp-Pro-Cys-NH₂(Disulfide bridge，Mpr1-Cys7)。

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Bevifibatide, developed by Bio-Thera Solutions, is a synthetic peptide that functions as a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor antagonist. It is marketed under the brand name Beitaning. In 2024, the
NMPA approved Bevifibatide citrate injection for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI), including coronary stent implantation, to reduce the risk of acute occlusion, in-stent thrombosis, no-reflow, and slow flow phenomena. Bevifibatide exerts its therapeutic effects by specifically binding to the GP IIb/IIIa receptors on platelets, thereby inhibiting the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to these receptors [80]. This inhibition prevents platelet aggregation, reducing the risk of thrombotic complications during and after PCI procedures. The clinical efficacy of Bevifibatide was demonstrated in a multicenter Phase III trial involving patients with acute coronary syndrome undergoing PCI (NCT04567890). The study achieved its primary efficacy endpoint, with the composite endpoint event rate at 30 days post-procedure being significantly lower in the Bevifibatide group (4.06%) compared to the control group (6.56 %), indicating superior antithrombotic efficacy. Regarding toxicity, Bevifibatide was generally well-tolerated. The most common adverse events included bleeding complications, which are consistent with the pharmacological action of GP IIb/IIIa inhibitors. These events were manageable with appropriate clinical interventions, and the overall safety profile was comparable to other agents in its class. The approval of Bevifibatide provides a new therapeutic option for patients undergoing PCI, aiming to enhance procedural safety by mitigating thrombotic risks associated with such
interventions [81].
The synthetic route of Bevifibatide, shown in Scheme 19, comprises sequential amidation reactions: Bevi-001 reacts with Bevi-002 to form Bevi-003, which undergoes deprotection and subsequent coupling with
Bevi-004 to generate Bevi-005 [82]. This intermediate undergoes consecutive amidation steps with Bevi-006 and Bevi-008, producing Bevi-007 and Bevi-009 respectively. Bevi-009 then reacts with Bevi-010
to form Bevi-011, followed by coupling with Bevi-012 to yield Bevi-013. Subsequent amidation with Bevi-014 produces Bevi-015, which undergoes TFA-mediated deprotection to give Bevi-016. The final synthesis involves oxidation of the sulfhydryl group in Bevi-016 followed by iodine-mediated coupling to afford Bevifibatide.

80-82

[80] G. Tonin, J. Klen, Eptifibatide, an older therapeutic peptide with new indications:
from clinical pharmacology to everyday clinical practice, Int. J. Mol. Sci. 24 (2023)5446.
[81] H. Patel, I. Lunn, S. Hameed, M. Khan, F.M. Siddiqui, A. Borhani, A. Majid, S.M. Bell, M. Wasay, Treatment of cerebral venous thrombosis: a review, Curr. Med.Res. Opin. 40 (2024) 2223–2236.
[82] S. Tan, Y. Yang, Y. Li, Synthesis of N2-(3-mercapto-1-oxopropyl)-L-arginylglycyl-L-α-aspartyl-L
α-tryptophyl-Lα-prolyl-L Its Analogues, 2007 CN101085809A.

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……

1. Zhao X, Yuan L, Gong Z, Li M, Yuan Y, Geng J. (2025)
New drugs approved by the NMPA in 2024: Synthesis and clinical applications.
Eur J Med Chem, 291: 117643. [PMID:40262297]

New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
Pharmacokinetic and pharmacodynamic properties of batifiban coadministered with antithrombin agents in Chinese healthy volunteersPublication Name: Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen banPublication Date: 2013-10-20PMID: 24142738DOI: 10.1007/s11596-013-1198-4
Safety, pharmacokinetic and pharmacodynamic studies of batifiban injection following single- and multiple-dose administration to healthy Chinese subjectsPublication Name: Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen banPublication Date: 2009-02-18PMID: 19224155DOI: 10.1007/s11596-009-0103-7

////////Bevifibatide, APPROVALS 2025, CHINA 2025, Bio-Thera Solutions, Beitaning, BAT 2094, batifiban, 710312-77-9, Correctin, 7AKM76YKN5

Tegileridine

August 27, 2025 10:42 am / Leave a comment

Tegileridine

YFJS8L4TGU
CAS 2095345-66-5
(9R)-N-((1S,4S)-4-Ethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-9-(2-pyridinyl)-6-oxaspiro(4.5)decane-9-ethanamine
434.6 g/mol

WeightAverage: 434.624
Monoisotopic: 434.293328472

Chemical FormulaC₂₈H₃₈N₂O₂

(1S,4S)-4-ethoxy-N-[2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethyl]-1,2,3,4-tetrahydronaphthalen-1-amine

Tegileridine fumarate

CAS#2245827-85-2 (fumarate)

Chemical Formula: C32H42N2O6

Exact Mass: 550.3000

Molecular Weight: 550.70

CHINA 2025, APPROVALS 2025, AISUTE, Jiangsu Hengrui

Tegileridine is under investigation in clinical trial NCT06458400 (To Evaluate the Efficacy and Safety of Tegileridine and Oliceridine Injections in the Treatment of Postoperative Pain).

Tegileridine is a drug which acts as a μ-opioid receptor agonist. It is closely related to compounds such as oliceridine, TRV734, and SHR9352, and shares a similar profile as a biased agonist selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment.^[1]

In January 2024, tegileridine was approved in China for the treatment of moderate to severe pain after abdominal surgery.^[2]

SYN

CN107001347

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN203399246&_cid=P20-METU4Y-21400-1

SYN

WO 2017/063509

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017063509&_cid=P20-METU6J-22458-1

[0183]Examples 1 and 2

[0184](S)-1-Ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine 1

[0185](R)-1-ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine 2

[0186]

[0187](R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4,5]decane-9-yl)acetaldehyde 1a (294 mg, 1.135 mmol, prepared by the method disclosed in patent application “WO2012129495”) and 1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine 1b (200 mg, 1.135 mmol, prepared by the method disclosed in patent application “WO2014078454”) were dissolved in 15 mL of dichloromethane, stirred for 1 hour, and sodium triacetoxyborohydride (1.203 g, 5.675 mmol) was added and stirred for 16 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the title product, 1-ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine. Chiral preparation was performed (separation conditions: chiral preparative column Superchiral S-AD (Chiralway), 2 cm ID*25 cm, 5 um; mobile phase: CO

₂ :methanol:diethanolamine=75:25:0.05, flow rate: 50 g/min). The corresponding fractions were collected and concentrated under reduced pressure to give the title products 1 (98 mg, brown oil) and 2 (95 mg, yellow solid).

[0188]Example 1:

[0189]MS m/z(ESI):420.3[M+1]；

[0190]Chiral HPLC analysis: retention time 4.028 minutes, chiral purity: 99.7% (chromatographic column: Superchiral S-AD (Chiralway), 0.46 cm ID*15 cm, 5 μm; mobile phase: CO2: methanol: diethanolamine = 75:25:0.05 (v/v/v))

[0191]

¹H NMR(400MHz,DMSO-d ₆)δ8.54(s,1H),7.72(s,1H),7.45(d,1H),7.20(s,1H),6.95(s,1H),6.78(d,1H),6.52(d,1H),6.37(s,1H),3.60(br,2H),3.18-3.43(m,3H),2.99(m,1H),2.33-2.45(m,3H),1.77-1.99(m,3H),1.19-1.60(m,12H),1.00-1.06(m,4H),0.63(m,1H).

[0192]Example 2:

[0193]MS m/z(ESI):420.3[M+1]；

[0194]Chiral HPLC analysis: retention time 3.725 minutes, chiral purity: 99.8% (chromatographic column: Superchiral S-AD (Chiralway), 0.46 cm ID*15 cm, 5 μm; mobile phase: CO2: methanol: diethanolamine = 75:25:0.05 (v/v/v))

[0195]

¹H NMR(400MHz,DMSO-d ₆)δ8.53(s,1H),7.72(s,1H),7.46(d,1H),7.20(s,1H),6.97(s,1H),6.85(d,1H),6.54(d,1H),6.40(s,1H),3.61(br,2H),3.17-3.25(m,3H),3.00-3.01(m,1H),2.33-2.46(m,3H),1.78-1.97(m,3H),1.24-1.65(m,12H),1.01-1.06(m,4H),0.61(m,1H).

SYN

US11111236

https://patentscope.wipo.int/search/en/detail.jsf?docId=US306969245&_cid=P20-METUA8-25189-1

Embodiment 1: Preparation of (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step One: Synthesis of Intermediate (D-1)

The compound represented by the formula (E1) (25 g), potassium hydroxide (22.4 g) and ethylene glycol (150 mL) were mixed and the resulting mixture was stirred at 150° C. for 16 hours, and then the reaction was stopped. The reaction solution was cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (150 mL×2). The aqueous phase was adjusted to pH=6-7 with 3M hydrochloric acid and extracted with dichloromethane (200 mL×4). The combined organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (26.1 g, pale yellow oil) with a yield of 97.4% and a HPLC purity of 92%.

Step Two: Synthesis of Intermediate (D2-1)

The compound represented by the formula (D-1) (28 g) was dissolved in anhydrous ethanol (100 mL) and the temperature was raised to 50° C. The resolving agent S-phenylethylamine (6.2 g) was dissolved in anhydrous ethanol (100 mL) and the resulting S-phenylethylamine solution was added dropwise into the above solution at 50° C. The mixture was heated to reflux and stirred for 2 hours. Then the mixture was allowed to cool to 10° C. naturally, and solid was precipitated. The mixture was filtered, and the filter cake was washed to give the product (13 g, solid) with an enantiomeric excess (ee) value of 96.7%;

recrystallization: the obtained 13 g solid product was added to anhydrous ethanol (80 mL), heated to reflux and stirred for 6 hours. Then the mixture was naturally cooled to 10° C. and solid was precipitated. The mixture was filtered, the filter cake was washed and dried to give the product (10.6 g) with an ee value of 99.0%.

Step Three: Synthesis of Intermediate (D2)

KOH (2.18 g) was dissolved in water (120 mL), and then the compound represented by formula (D2-1) was dissolved in the solution. The mixture was extracted with dichloromethane (100 mL×3). The aqueous phase was adjusted to pH=6-7 with IN HCl solution and then extracted with dichloromethane (150 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (7 g) with a yield of 50% and an ee value of 99.4%.

MS m/z (ESI): 276.71 [M+H] ⁺, 298.68 [M+Na] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 8.50-8.51 (m, 1H), 7.73-7.77 (m, 1H), 7.51-7.53 (d, 1H), 7.21-7.24 (m, 1H), 3.73-3.84 (m, 2H), 2.78-2.81 (d, 1H), 2.58-2.63 (m, 1H), 2.53-2.56 (d, 1H), 2.39-2.43 (m, 1H), 1.98-2.02 (d, 1H), 1.87-1.94 (m, 1H), 1.76-1.80 (m, 1H), 1.61-1.65 (m, 1H), 1.39-1.58 (m, 4H), 1.14-1.19 (m, 1H), (m, 1H), (m, 1H).

Step Four: Synthesis of Intermediate (C2)

Dichloromethane (8.5 kg) was added to a reaction flask, and then the raw material (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetic acid (350 g), N,O-dimethylhydroxylamine hydrochloride (148.8 g), EDCI (292.3 g) and DMAP (15.5 g) were added under stirring. After the resulting mixture was stirred for 15-25 minutes, DIPEA (492.4 g) was added. Then the mixture was stirred under argon protection at room temperature for 16-18 hours. A saturated ammonium chloride aqueous solution (2.8 kg) was added to the reaction solution, and the resulting mixture was stirred for 5-10 minutes and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.8 kg×2) and saturated brine (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then dichloromethane (2.5 kg) was added. The mixture was concentrated to dryness under reduced pressure to give an oil (372.03 g) with a yield of 92.0%.

MS m/z (ESI): 319.1 [M+H] ⁺, 341.3 [M+Na] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 8.50-8.51 (m, 1H), 7.66-7.71 (m, 1H), 7.43-7.45 (d, 1H), 7.15-7.18 (m, 1H), 3.63-3.66 (m, 2H), 3.47 (s, 3H), 2.86-2.88 (d, 3H), 2.62-2.65 (d, 1H), 2.50-2.57 (m, 1H), 2.36-2.39 (d, 1H), 1.96-2.00 (d, 1H), 1.80-1.86 (m, 1H), 1.68-1.72 (m, 1H), 1.48-1.55 (m, 1H), 1.31-1.46 (m, 4H), 1.03-1.07 (m, 1H), 0.63-0.71 (m, 1H).

Step Five: Synthesis of Intermediate (B2)

The compound represented by formula (C2) (334.4 g) was dissolved in toluene (2.2 kg) in a reaction flask. The solution was cooled to −45° C. to −35° C. and purged with argon, and then red aluminum (348.76 g) was added dropwise while maintaining the temperature between −45° C. to −35° C. After completion of the addition, the reaction solution was stirred at −45° C. to −35° C. for 3-4 hours, and then 10% citric acid aqueous solution (1 kg) was added to the reaction solution at −45° C. to −35° C. Then concentrated hydrochloric acid solution was added to adjust the pH to 2-3, followed by addition of ethyl acetate (1.8 kg). The mixture was stirred and allowed to stand to partition. The aqueous phase was adjusted to pH=11-13 with 5N sodium hydroxide solution, and then extracted with dichloromethane (3.3 kg×2). The combined dichloromethane phase was washed with saturated sodium chloride solution (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then dichloromethane (3.3 kg) was added. The mixture was concentrated again under reduced pressure to give a pale red oil, which was directly used in the next step.

Step Six: Synthesis of the Compound Represented by Formula (III)

The above oil was added to a reaction flask, followed by addition of dichloromethane (8.5 kg) and the compound represented by formula (A1) (134.56 g). The resulting mixture was stirred for 2-3 hours, followed by addition of sodium triacetoxyborohydride (373.86 g). The mixture was stirred at room temperature for 16-18 hours, followed by addition of saturated sodium carbonate solution (2.66 kg). Then the mixture was adjusted to pH=11-13 by addition of 5N sodium hydroxide aqueous solution and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.83 kg) and saturated sodium chloride aqueous solution (2.74 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and then acetonitrile (120 g) was added. The mixture was stirred at room temperature for 16-18 hours to crystallize, and then filtered. The filter cake was dried to give the product (206.87 g) with a yield of 68.0%.

MS m/z (ESI): 435.3 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 9.74 (d, 1H), 9.58 (d, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.47 (t, 1H), 4.46-4.49 (m, 1H), 4.30-4.33 (m, 1H), 3.84-3.87 (m, 1H), 3.66-3.70 (m, 2H), 3.53-3.56 (m, 2H), 2.82-2.85 (d, 2H), 2.67 (s, 2H), 2.39-2.41 (m, 4H), 2.30-2.33 (m, 4H), 1.85 (s, 2H), 1.48-1.52 (m, 6H), 1.27 (m, 3H).

SYN

US20200054594A1

SYN

Tegileridine fumarate, developed by Jiangsu Hengrui Pharmaceuti
cals Co., Ltd., is a novel small-molecule analgesic that functions as a
complete opioid receptor agonist with relative selectivity for -opioid
receptors (MOR). It is marketed under the brand name Aisute. In 2024,
the NMPA approved Tegileridine fumarate injection for the treatment of moderate to severe pain following abdominal surgery. Tegileridine ex
erts its analgesic effects by activating MOR, leading to inhibition of
adenylate cyclase activity, decreased intracellular cAMP levels, and
subsequent modulation of ion channel conductance. This results in hy
perpolarization of neuronal membranes and reduced neuronal excit
ability, effectively alleviating pain. The clinical efficacy of Tegileridine
was evaluated in a Phase III randomized, double-blind, placebo-
controlled trial (NCT05012516) involving patients experiencing mod
erate to severe pain after abdominal surgery. The research indicated that
Tegileridine offered substantial alleviation of pain in contrast to the
placebo. It manifested a quick-acting property, and its analgesic effects
endured throughout the period of observation. In terms of toxicity,
Tegileridine was typically well-tolerated by the subjects. The most
frequently encountered adverse reactions were nausea, vomiting, and
dizziness, all of which were of mild to moderate intensity. Importantly,
Tegileridine exhibited a favorable safety profile with a lower incidence
of gastrointestinal adverse reactions compared to traditional MOR ag
onists, potentially offering an improved therapeutic window for post
operative pain management. The approval of Tegileridine provides a
new treatment option for patients suffering from moderate to severe
postoperative pain, particularly following abdominal surgeries,
addressing a significant clinical need in pain management [72,73].
The synthesis of Tegileridine fumarate, illustrated in Scheme 17,
begins with nucleophilic substitution reaction involving Tegi-001 to
yield Tegi-002 [74]. Tegi-002 is subsequently acidified to produce
Tegi-003. Finally, Tegi-003 undergoes reductive amination with
Tegi-004 to synthesize Tegileridine.

[72] S. Dhillon, Correction: tegileridine: first approval, Drugs 84 (2024) 1011.
[73] S. Dhillon, Tegileridine: first approval, Drugs 84 (2024) 717–720.
[74] X. Li, B. Feng, Y. Chen, T. Liu, F. He, M. He, W. Tao, P. Sun, Oxa Spiro Derivative
Useful in Treatment of Pain and pain-related Disease and Its Preparation, 2017.
CN107001347A.

AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

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References

WO 2017/063509, “Oxa spiro derivative, preparation method therefor, and applications thereof in medicines”, published 10 April 2018, assigned to Jiangsu Hengrui Medicine Company and Shanghai Hengrui Pharmaceutical Company Ltd .
Dhillon S (June 2024). “Tegileridine: First Approval”. Drugs. 84 (6): 717–720. doi:10.1007/s40265-024-02033-4. PMID 38771484.

Clinical data

Trade names	艾苏特
Legal status
Legal status	Rx in China
Identifiers
IUPAC name
CAS Number	2095345-66-5
PubChem CID	129049969
UNII	YFJS8L4TGU
Chemical and physical data
Formula	C₂₈H₃₈N₂O₂
Molar mass	434.624 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
Tegileridine: First ApprovalPublication Name: DrugsPublication Date: 2024-05-21PMID: 38771484DOI: 10.1007/s40265-024-02033-4
Study of the mass balance, biotransformation and safety of [14C]SHR8554, a novel μ-opioid receptor injection, in healthy Chinese subjectsPublication Name: Frontiers in PharmacologyPublication Date: 2023-09-14PMCID: PMC10538116PMID: 37781692DOI: 10.3389/fphar.2023.1231102

Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: US-2018297988-A1Priority Date: 2015-10-15
Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: WO-2017063509-A1Priority Date: 2015-10-15
Oxaspiro derivatives, methods of their manufacture, and their application in pharmaceuticalsPublication Number: JP-6824502-B2Priority Date: 2015-10-15Grant Date: 2021-02-03
Oxa spiro derivatives, their preparation, and their applications in medicinePublication Number: KR-102703513-B1Priority Date: 2015-10-15Grant Date: 2024-09-06

Opioid Receptor (MOR) Agonist Salt, Its Fumarate Salt I Crystalline Form, and Process for Making SamePublication Number: JP-7153030-B6Priority Date: 2017-04-14Grant Date: 2023-07-24
Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: EP-3354649-A1Priority Date: 2015-10-15
Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: EP-3354649-B1Priority Date: 2015-10-15Grant Date: 2019-12-04
Oxaspiro derivative, process for its production and its application in medicinePublication Number: JP-2018534257-APriority Date: 2015-10-15
Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: US-10442793-B2Priority Date: 2015-10-15Grant Date: 2019-10-15

////////////Tegileridine, CHINA 2025, APPROVALS 2025, AISUTE, Jiangsu Hengrui, YFJS8L4TGU, 2095345-66-5, Tegileridine FUMARATE

Velagliflozin

August 27, 2025 2:37 am / Leave a comment

Velagliflozin

VETERINARY DRUG

Cas 946525-65-1
FV2YU8SL0P
2-((4-cyclopropylphenyl)methyl)-4-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl)benzonitrile
2-((4-Cyclopropylphenyl)methyl)-4-beta-D-glucopyranosylbenzonitrile
395.4 g/mol, C₂₃H₂₅NO₅

2-[(4-cyclopropylphenyl)methyl]-4-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]benzonitrile

Velagliflozin L-proline H2O

Velagliflozin, sold under the brand name Senvelgo, is an antidiabetic medication used for the treatment of cats.^[2][4][5] Velagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor.^[6] It is taken by mouth.^[2]

Velagliflozin is the active ingredient of the first oral liquid medication approved by the Food and Drug Administration for the treatment of diabetes in cats. This compound belongs to the known class of sodium-glucose cotransporter 2 inhibitors approved to treat diabetes in human.

Application: NADA 141-568Drug: Senvelgo®Active Ingredient(s): VelagliflozinCompany: Boehringer lngelheim Animal Health USA Inc.Patent(s): 7776830 (Exp: 05/01/2027); 8557782 (Exp: 05/01/2027); 9145434 (Exp: 09/07/2033); 10617666 (Exp: 06/06/2035); 11896574 (Exp: 12/17/2034); 10220017 (Exp: 09/29/2036); 10709683 (Exp: 08/24/2036); 11225500 (Exp: 12/17/2038)
[Indication for Use] To improve glycemic control in otherwise healthy cats with diabetes mellitus not previously treated with insulin.Application: NADA 141-568Active Ingredient(s): VelagliflozinCompany: Boehringer lngelheim Animal Health USA Inc.Freedom of Information: FOIA Summary 14320Approval Date: August 10, 2023

APPROVALS 2023, GDA 2023, EU 2023, EMA 2023, SENVELGO

Velagliflozin (brand name Senvelgo) is a veterinary medication approved for treating diabetes in cats, not humans.

Approved countries and years for velagliflozin:

United States (US): Approved by the FDA in August 2023.
European Union (EU): Received marketing authorization in November 2023.
Switzerland: Approved in 2023.
Great Britain: Approved in 2023.

SYN

US20200352968

https://patentscope.wipo.int/search/en/detail.jsf?docId=US310904480&_cid=P11-METCZG-99171-1

SYN

US7776830

https://patentscope.wipo.int/search/en/detail.jsf?docId=US41880220&_cid=P11-METD0X-00376-1

The following compound is obtained analogously to Example XXIV:

(1) 1-Cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

Mass spectrum (ESI ⁻): m/z=413 [M+H] ⁺

Advantageously, the reduction of the anomeric carbon center of the appropriate intermediate obtained during the synthesis of this compound is conducted with the oxygen functionalities on the pyranose ring protected. Preferred protective groups are benzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, triisopropylsilyl and allyl.

EXAMPLE 17

2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Mass spectrum (ESI ⁺): m/z=413 [M+NH ₄] ⁺

The compound is obtained according to example 6 using 4-cyclopropyl-phenylboronic acid as the coupling partner.

Yield: 83% of theory

Alternatively this compound is obtained as described in Example XXIV(1).

The compound of example 17 is also obtained by employing the following procedure:

A solution of 2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile (0.80 g) in methanol (5 mL) and THF (5 mL) is treated with aqueous potassium hydroxide solution (4 mol/l, 5 mL). The reaction solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The organic solvents are evaporated and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried (sodium sulphate) and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->9:1).

Yield: 0.54 g (96% of theory)

SYN

WO2007128749

https://patents.google.com/patent/WO2007128749A1/en

The following compound is obtained analogously to Example XXIV:

(1 ) 1 -Cvano-2-(4-cvclopropyl-benzyl)-4-(3-D-glucopyranos-1 -vD-benzene

Mass spectrum (ESI^“): m/z = 413 [M+H] ⁺ Advantageously, the reduction of the anomeric carbon center of the appropriate intermediate obtained during the synthesis of this compound is conducted with the oxygen functionalities on the pyranose ring protected. Preferred protective groups are benzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, terfbutyldimethylsilyl, triisopropylsilyl and allyl.

Example XXV

1-Cyano-2-(4-cyclopropyl-benzyl)-4-(tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene To a flask charged with a stir bar, 4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile (4.4 g), degassed toluene (12 ml.) and degassed water (8 ml.) and kept under argon atmosphere is added cyclopropylboronic acid (0.20 g), potassium phosphate (5.0 g), tricyclohexylphosphine (0.19 g) and at last palladium(ll)acetate (76 mg). The mixture is stirred at 1 10 °C for 6 h meanwhile cyclopropylboronic acid is added after each hour (5x 0.20 g). After cooling to room temperature, the mixture is diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts are dried (sodium sulphate) and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1 -> 1 :1 ). Yield: 3.2 g (87% of theory ) Mass spectrum (ESI⁺): m/z = 581 [M+NH₄] ⁺

Example XXVI

4-(1 -Hvdroxy-cvclopropyD-phenylboronic acid A 3.0 M solution of ethylmagnesium bromide in diethylether (7.6 ml.) is added to a stirred solution of titanium(IV) isopropoxide (2.2 ml.) in diethylether (70 ml.) chilled to -78 °C. The resultant solution is stirred at -78 °C for 1.5 h, before 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa borolan-2-yl)-benzoic acid methyl ester (2.0 g) is added. The reaction mixture is warmed to ambient temperature and stirred for an additional 12 h. Then, 1 M aqueous hydrochloric acid is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is dissolved in acetone (60 ml.) and 0.1 M aqueous NH₄OAc solution (50 ml.) followed by NaIO₄ (2.3 g) is added. The resulting reaction mixture is stirred at room temperature for 18 h. After removal of the acetone, the residue is extracted with ethyl acetate. The combined extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is purified by chromatography on silicagel (cyclohexane/ethyl acetate). Yield: 0.45 g (33% of theory) Mass spectrum (ESI^“): m/z = 223 [M+HCOO]^“ Preparation of the end compounds:

Example 17: 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

Mass spectrum (ESI⁺): m/z = 413 [M+NH₄]⁺

The compound is obtained according to example 6 using 4-cyclopropyl-phenylboronic acid as the coupling partner.

Yield: 83% of theory

Alternatively this compound is obtained as described in Example XXIV(I ).

The compound of example 17 is also obtained by employing the following procedure:

A solution of 2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1 -yl)- benzonitrile (0.80 g) in methanol (5 ml.) and THF (5 ml.) is treated with aqueous potassium hydroxide solution (4 mol/l, 5 ml_). The reaction solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The organic solvents are evaporated and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried (sodium sulphate) and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1 :0 -> 9:1 ). Yield: 0.54 g (96% of theory)

SYN

Synthesis 2024, 56, 906–943

In 2007, Boehringer-Ingelheim Vetmedica GmbH pioneered the development of velagliflozin (15), subsequently submitting a patent application in the United States with the identification number US7776830B2.72a More recently, through clinical investigations, this compound has demonstrated its efficacy as an SGLT2 inhibitor, proving adept at curtailing glucose reabsorption, encouraging glucosuria,
and leading to reductions in both blood glucose and insulin levels.
The initial synthesis of velagliflozin (15) was also disclosed in the above patent,72a and in patent
WO2007128749A1.72b The synthesis, depicted in Scheme46, comprises of nine-steps starting with the readily available raw material 2-bromo-5-iodobenzoic acid (250), which undergoes reduction using LiBH4 to form the corresponding alcohol 251. Subsequently, chlorination is carried out using thionyl chloride, resulting in the formation of chloride 252. O-Alkylation of phenol with compound 252 is
then conducted in a basic medium, yielding intermediate 253.The C-glycosylation of 253 with 2,3,4,6-tetrakis-O(trimethylsilyl)-D-glucopyranone 22 in the presence of turbo Grignard reagent (isopropylmagnesium chloride and LiCl) and methanesulfonic acid in methanol gives compound
254 with an impressive 93% yield. The hydroxy group of in termediate 254 is protected using acetic anhydride, and themethoxy group is subsequently removed via Lewis acid (BF3·Et2O, Et3SiH) treatment, providing compound 255 in a yield of 60%. A metal-catalyzed cyano group installation is then performed on intermediate 255, leading to the formation of compound 256 in 84% yield. The subsequent steps involve benzylic bromination followed by coupling with cyclopropylphenyl boronic acid 260, resulting in the formation of intermediate 258. Finally, deacetylation of intermediate 258 using aqueous KOH produces the desired product

The overall yield obtained for velagliflozin (15) is calculated to be 11.3%, with this synthetic route providing a systematic and efficient approach. The highlight of the route is high-yielding chemical transformations. However, the drawback is the use of two palladium-mediated couplings
that increase the possibility of leaching of the toxic metal in scale-up batches. Additionally, the synthetic route requires a large number of chemical transformations and not best suited for commercial production.
The same authors reported an alternative method (Scheme 47) for the synthesis of velagliflozin (15) in the product patent.72 The aglycone intermediate 265 is accessed in two steps starting from ethyl 2-(4-bromophenyl)acetate (262). O-Glycosylation takes place with the aglycone

4-bromo-2-(4-cyclopropylbenzyl)benzonitrile (265) using 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone 22 in the presence of tert-butyllithium in pentane (1.7 M), resulting in the formation of compound 266. Reduction of compound 266 using boron trifluoride–diethyl etherate yields
the final API velagliflozin (15). This truncated synthetic route is well suited for scale-up due to the significantly low er number of transformations compared to the previous route. Unfortunately, the specific yields were not clearly in dicated for this process. This method presents an alternative approach to the synthesis of velagliflozin (15), providing a potential pathway for its preparation in 5 steps with
an overall yield of 40%.

(72) (a) Eckhardt, M.; Himmelsbach, F.; Eickelmann, P.; Sauer, A.;
Thomas, L. US7776830B2, 2010. (b) Eckhardt, M.; Himmelsbach,
F.; Eickelmann, P.; Sauer, A.; Thomas, L. WO2007128749A1,
2007.

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Medical uses

Velagliflozin is indicated to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.^[2]^[4]^[6]

References

“Notice: Multiple additions to the Prescription Drug List (PDL) [2024-10-18]”. Health Canada. 18 October 2024. Retrieved 25 October 2024.
“Senvelgo- velagliflozin solution”. DailyMed. 8 November 2023. Retrieved 13 December 2023.
“Senvelgo Product information”. Union Register of veterinary medicinal products. 22 November 2023. Retrieved 29 August 2024.
“NADA 141-568 Senvelgo (velagliflozin oral solution) Cats”. This article incorporates text from this source, which is in the public domain.
Cook AK, Behrend E (January 2025). “SGLT2 inhibitor use in the management of feline diabetes mellitus”. Journal of Veterinary Pharmacology and Therapeutics. 48 Suppl 1 (Suppl 1): 19–30. doi:10.1111/jvp.13466. PMC 11736986. PMID 38954371.
“Dear Veterinarian Letter regarding important safety conditions associated with the use of Senvelgo (velagliflozin oral solution) for improving glycemic control in certain cats with diabetes mellitus”. U.S. Food and Drug Administration. 4 December 2023. Retrieved 13 December 2023. This article incorporates text from this source, which is in the public domain.

Clinical data

Trade names	Senvelgo
License data	US DailyMed: Velagliflozin
Routes of administration	By mouth
ATCvet code	QA10BK90 (WHO)
Legal status
Legal status	CA: ℞-only^[1]US: ℞-only^[2]EU: Rx-only^[3]
Identifiers
IUPAC name
CAS Number	946525-65-1
PubChem CID	24862817
ChemSpider	58827717
UNII	FV2YU8SL0P EQE2P2T77I
Chemical and physical data
Formula	C₂₃H₂₅NO₅
Molar mass	395.455 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

SGLT2 inhibitors: a novel therapy for cognitive impairment via multifaceted effects on the nervous systemPublication Name: Translational NeurodegenerationPublication Date: 2024-08-09PMCID: PMC11312905PMID: 39123214DOI: 10.1186/s40035-024-00431-y
Demographic, morphologic, hormonal and metabolic factors associated with the rate of improvement from equine hyperinsulinaemia-associated laminitisPublication Name: BMC Veterinary ResearchPublication Date: 2022-01-18PMCID: PMC8764787PMID: 35042535DOI: 10.1186/s12917-022-03149-z
The efficacy and safety of velagliflozin over 16 weeks as a treatment for insulin dysregulation in poniesPublication Name: BMC Veterinary ResearchPublication Date: 2019-02-26PMCID: PMC6390376PMID: 30808423DOI: 10.1186/s12917-019-1811-2
The sodium-glucose co-transporter 2 inhibitor velagliflozin reduces hyperinsulinemia and prevents laminitis in insulin-dysregulated poniesPublication Name: PLOS ONEPublication Date: 2018-09-13PMCID: PMC6136744PMID: 30212530DOI: 10.1371/journal.pone.0203655
Effects of the sodium‐glucose cotransporter 2 (<scp>SGLT</scp>2) inhibitor velagliflozin, a new drug with therapeutic potential to treat diabetes in catsPublication Name: Journal of Veterinary Pharmacology and TherapeuticsPublication Date: 2017-11-15PMID: 29139146DOI: 10.1111/jvp.12467

/////////Velagliflozin, APPROVALS 2023, GDA 2023, EU 2023, EMA 2023, SENVELGO, DIABETES, SENVELGO,

Cetagliptin

August 26, 2025 3:19 am / Leave a comment

Cetagliptin

CAS No. FREE FORM : 2243737-33-7 C₁₈H₁₈F₆N₄O, 420.4 g/mol

[ Cetagliptin Phosphate 2243737-33-7 ]

분자량 MW	518.35
화학식 MF	C₁₈H₂₁F₆N₄O₅P

(3R)-3-amino-1-[(8R)-8-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one

CHINA 2024, APPROVALS 2024, CGeneTec, DIABETES,

GTPL13952
CGT8012

OriginatorCGeneTech
Class2 ring heterocyclic compounds; Amines; Antihyperglycaemics; Fluorobenzenes; Imidazoles; Ketones; Pyrazines; Small molecules
Mechanism of ActionDipeptidyl peptidase 4 inhibitors

RegisteredType 2 diabetes mellitus CHINA 2024

01 Dec 2024Registered for Type 2 diabetes mellitus in China (PO) – First global approval
20 Mar 2024Chemical structure information added
28 Jun 2023No recent reports of development identified for phase-I development in Type-2-diabetes-mellitus(In volunteers) in China (PO, Tablet)
Cetagliptin is an orally active inhibitor for dipeptidyl peptidase 4 (DPP-4) and CYP2D6 (IC₅₀ of 6 µM). Cetagliptin is a substrate for P-glycoprotein. Cetagliptin reduces the GLP-1 degradation, maintains the level of postprandial blood sugar, and can be used in type 2 diabetes mellitus research.

Cetagliptin (CGT-8012) is an orally bioavailable, dipeptidyl peptidase 4 enzyme (DPP-4) inhibitor (‘gliptin’) class drug. It was designed as an antihyperglycemic agent to treat type 2 diabetes mellitus (T2DM) via inhibition of DPP-4-mediated catbolism of incretin hormones including glucagon-like peptide-1 (GLP-1) [2].

A DPP-4 inhibitor pharmaceutical composition and its preparation method and usePublication Number: CN-118557538-APriority Date: 2024-08-01
A kind of preparation method of DPP-IV inhibitor and its key intermediatePublication Number: CN-114057751-APriority Date: 2022-01-17
A kind of preparation method of DPP-IV inhibitor and its key intermediatePublication Number: CN-114057751-BPriority Date: 2022-01-17Grant Date: 2022-04-12
A kind of preparation method of DPP-IV inhibitor and key intermediate thereofPublication Number: TW-202330535-APriority Date: 2022-01-17
A preparation method of a DPP-IV inhibitor and its key intermediatePublication Number: TW-I842342-BPriority Date: 2022-01-17Grant Date: 2024-05-11

Salt of cetagliptin, preparation method thereof, pharmaceutical composition, and use thereofPublication Number: US-2020123164-A1Priority Date: 2018-04-26
Salt of cetagliptin, preparation method therefor, pharmaceutical composition, and use thereofPublication Number: EP-3785713-A1Priority Date: 2018-04-26
Salt of cetagliptin, preparation method thereof, pharmaceutical composition, and use thereofPublication Number: US-11046701-B2Priority Date: 2018-04-26Grant Date: 2021-06-29
Tetrahydro-imidaz0[1,5-a]pyrazine derivatives, preparation process and medicinal use thereofPublication Number: US-2010273786-A1Priority Date: 2007-12-26
Tetrahydro-imidazo[1,5-Î±]pyrazine derivatives, preparation process and medicinal use thereofPublication Number: US-8207161-B2Priority Date: 2007-12-26Grant Date: 2012-06-26

SYN

CN101899047

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84092509&_cid=P20-MERZ31-36806-1

SYN

CN103351391

https://patents.google.com/patent/CN103351391A/en

Synthetic route and the concrete steps of compound (I) are as follows:

Step 1: synthetic compound 2

With 11.8 gram (0.037 mole) compound 1{DL N-[(1,1-dimethyl oxyethyl group) carbonyl]-2,4; 5-trifluorophenyl-L-Ala, DL N-[(1,1-dimethylethoxy) carbonyl]-2; 4; 5-trifluorophen yl-alanine, CAS:1367740-01-9, reference: synthetic chemistry; 2011; 19 (4), 557-560} is dissolved among 40 milliliters of THF, adds 5.8 milliliters of triethylamines (0.042 mole) again; reaction is cooled to 0 ℃; add 4.0 milliliters of Vinyl chloroformates (0.041 mole), 0 ℃ was reacted 1 hour under nitrogen protection, after the filtration filtered liquid was cooled to 0 ℃; slowly add sodium borohydride (1.4 grams; 0.057 the mole) mixed solution in 15 ml waters, stirring is spent the night, and adds 1N HCl acidifying; ethyl acetate extraction three times; merge organic phase, sodium hydrogen carbonate solution is washed, the saturated salt washing; anhydrous sodium sulfate drying; the concentrated 7.6 gram products that obtain, namely compound 2, yield 67%.Repeat this step, make more compound 2, use for subsequent step.

Step 2: synthetic compound 3

8.2 gram (0.027 mole) compounds 2 are dissolved in 40 milliliters of methylene dichloride; add again 4.2 milliliters of triethylamines (0.030 mole); the catalytic amount DMAP; reaction is cooled to 0 ℃; add Tosyl chloride (6.8 grams; 0.035 mole); 0 ℃ is arrived room temperature reaction 2 hours under nitrogen protection, adds 1N HCl acidifying, dichloromethane extraction three times; merge organic phase; sodium hydrogen carbonate solution is washed, saturated salt washing, anhydrous sodium sulfate drying; concentrate and obtain crude product, namely compound 3.Repeat this step, make more compound 3, use for subsequent step.

Step 3: synthetic compound 4

12.4 gram (0.027 mole) compounds 3 are dissolved in 40 milliliters of dimethyl formamides, slowly add the mixed solution of sodium cyanide (4.5 grams, 0.092 mole) in 30 milliliters of dimethyl formamides, room temperature reaction 48 hours, pour in 100 milliliters of frozen water, ethyl acetate extraction three times merges organic phase, the saturated salt washing, anhydrous sodium sulfate drying, concentrated rear column chromatography purification obtains 7.8 gram products, be compound 4, yield 92%.

Step 4: synthetic compound

3.1 gram (0.010 mole) compounds 4 are dissolved in 15 milliliters of 6N hydrochloric acid, and reflux is spent the night, and adds the neutralization of 2N sodium hydroxide solution, cooling drying.The gained solid is dissolved among 30 milliliters of THF, adds 20 milliliters of 0.5N sodium hydroxide solutions, adds tert-Butyl dicarbonate (2.4 grams again, 0.011 mole), room temperature reaction

16 hours, concentrated, add the neutralization of 10% sodium bisulfate, ethyl acetate extraction three times merges organic phase, the saturated salt washing, anhydrous sodium sulfate drying, the concentrated 3.3 gram products that obtain, namely, compound

5, yield 99%.

Step 5: synthetic compound 7

Compound 6{5; 6; 7; 8-tetrahydrochysene-8-methyl-3-(trifluoromethyl)-imidazo [1,5-a] pyrazine, 5; 6; 7,8-tetrahydro-8-methyl-3-(trifluoromethyl)-imidazo[1,5-a] pyrazine; synthesize and see CN103087067; 2.1 gram, 0.010 mole } be dissolved in 8 milliliters of methylene dichloride, add triethylamine 1.2 grams (0.012 mole); compound 5 (3.3 grams; 0.010 mole), EDCI2.3 restrains (0.012 mole), room temperature reaction is 24 hours under nitrogen protection; pour in 100 milliliters of frozen water; organic phase is washed saturated salt washing, anhydrous sodium sulfate drying; the concentrated crude product that obtains; be dissolved in 100 milliliters of the 2N HCl/ methanol solutions (anhydrous HCl gas is dissolved in the solution of methyl alcohol), room temperature reaction 4 hours is spin-dried for; cooling; pour in 100 milliliters of frozen water, transfer PH to 9, ethyl acetate extraction three times; merge organic phase; and wash saturated salt washing, anhydrous sodium sulfate drying; concentrated; column chromatography purification obtains 2.8 gram products, and namely compound 7, yield 66%.

Compound 7 comprises four optical isomers, and route and the concrete steps of their separation and purification are as follows:

Step 6: preparation compound 9A and 9B

2.8 gram (6.67 mmole) compounds 7 are dissolved in 50 milliliters of acetonitriles; add triethylamine 1.2 grams (8.0 mmole); add again compound 8 (1.9 grams; 6.67 mmole; reference: J.Org.Chem.1995; 60 (3); 730), reflux is spent the night under nitrogen protection, and is concentrated; add ethyl acetate; the 1N sodium hydroxide solution is washed, and ethyl acetate milliliter extraction three times merges organic phase; the saturated salt washing; anhydrous sodium sulfate drying, the evaporating column chromatography purification obtains 1.6 gram 9A (43%) and 1.4 gram 9B (39%) products (de＞98%); structural analysis determines that tentatively 9A is RR and SS mixture of enantiomers, and 9B is RS and SR mixture of enantiomers.Gained compound 9A and 9B give over to respectively next step and use.

Step 7: preparation compound 10A and 10B

1.5 gram (2.64 mmole) compound 9A are dissolved in 50 milliliters of methylene dichloride, reaction is cooled to 0 ℃, adds HBr solution (2M, 2.6 milliliters, 5.2 mmole), be dissolved in ethyl acetate after concentrated, sodium hydrogen carbonate solution is washed, the saturated salt washing, anhydrous sodium sulfate drying, the concentrated product that obtains, namely compound 10A (RR and SS mixture of enantiomers) gives over to next step and uses.

According to same reaction principle, condition and step, take compound 9B as starting raw material, obtain compound 10B (RS and SR mixture of enantiomers), give over to next step and use.

Step 8: preparation compound 11A, 11B and 11C, 11D

Resulting compound 10A in the step 7 (1.1 gram) is dissolved in 20 milliliters of ethanol, adds D-tartrate 0.4 gram (2.64 moles), reflux 0.5 hour, cooling, filter, obtain white solid, again with behind ten times of amount ethyl alcohol recrystallizations 2 times, obtain white solid, free with saturated sodium bicarbonate aqueous solution, obtain 0.29 and digest compound 11A, be i.e. compound (I), yield 26% is surveyed ee value＞95%.

PAPER

https://www.tandfonline.com/doi/full/10.1080/00498254.2022.2091494

SYN

https://patents.google.com/patent/US11046701B2/en

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Cetagliptin phosphate, developed by CGeneTec, is a DPP-4 inhibitor designed for the treatment of T2DM. In 2024, the NMPA approved cetagliptin phosphate for managing T2DM. As a member of the DPP-4inhibitor, Cetagliptin exerts its effect on glycemic regulation by impeding the breakdown of incretin hormones. This action leads to a glucose-dependent increase in insulin secretion and a concurrent decrease in glucagon levels. Multiple clinical investigations have attested to the effectiveness and safety profile of sitagliptin. In a particular instance, a randomized, double-blind, placebo-controlled Phase 3 study was carried out to assess the use of sitagliptin as a single-agent treatment in patients diagnosed with type 2 diabetes [67]. The study found that cetagliptin significantly reduced HbA1c levels compared to placebo, with a greater proportion of patients achieving target glycemic control.
The treatment was generally well tolerated, with a safety profile comparable to placebo [68,69]. Regarding toxicity, cetagliptin was well tolerated in clinical studies, with no significant increase in adverse effects compared to placebo. No drug-related hypoglycemia was reported,
indicating a favorable safety profile [70].
The synthesis of Cetagliptin, depicted in Scheme 16, initiates with Ceta-001 cyanidation affording Ceta-002, whose hydrogenative reduction yields Ceta-003 [71]. Subsequent amidation constructs Ceta-004,
followed by cyclization rearrangement producing Ceta-005. Hydrogenation delivers Ceta-006, which undergoes coupling with Ceta-007 assembling Ceta-008. Final TFA-mediated deprotection achieves
Cetagliptin. Concurrently, the side route involves Ceta-009 nucleophilic substitution forming Ceta-010. Sequential imine hydrolysis/protection converts Ceta-010 to Ceta-011, whose controlled hydrolysis ultimately delivers Ceta-007

67-70

[67] J. Lu, J. Zhao, D. Xie, J. Ding, Q. Yu, T. Wang, Use of a PK/PD model to select
Cetagliptin dosages for patients with type 2 diabetes in phase 3 trials, Clin.
Pharmacokinet. 63 (2024) 1463–1476.
[68] L. Guo, F. Tian, L. Liu, M. Chen, C. Jiang, S. Li, C. Liu, Y. Zhang, J. Qin, D. Yu,
Y. Zong, W. Dai, Retagliptin as add-on therapy to metformin in Chinese patients
with type 2 diabetes inadequately controlled with metformin: a multicentre,
randomized, double-blind, placebo-controlled, phase 3 trial, Diabetes Obes Metab
26 (2024) 2830–2838.
[69] C. Hu, J. Zheng, J. Miao, F. Liu, T.T. Hu, J.K. Gu, S.Q. Shu, Y. Wang, X.H. Zhu, M.
Z. Liang, [Pharmacokinetics of Phosphate Retagliptin Tabletin in Patients with
Renal Dysfunction], Sichuan Da Xue Xue Bao Yi Xue Ban 49 (2018) 74–80.
[70] A. Cahn, S. Cernea, I. Raz, An update on DPP-4 inhibitors in the management of
type 2 diabetes, Expert Opin Emerg Drugs 21 (2016) 409–419.

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https://en.cgenetech.com.cn/news/55.html

Since the listing application of a class of innovative drug Cetagliptin independently developed by CGeneTech was accepted by the State Food and Drug Administration, it has received great attention in the industry. Recently, the well-known industry media “Shell News Agency” also took this opportunity to comprehensively sort out the hot track and broad market prospects of domestic DPP-4 inhibitors. This article is shared with you. In the face of the high expectations given by the industry, CGeneTech will continue to run the last “one kilometer” of product launch with a scientific and rigorous attitude.
Diabetes (DM), as a chronic disease, has attracted much attention. Diabetes drugs have become the second largest drug market after tumor drugs, and it is also a place for pharmaceutical enterprises to compete.
With the development of medicine, some new drugs with different mechanism of action from traditional oral hypoglycemic drugs have emerged in recent years. Dipeptidyl peptidase-4 (DPP-4) inhibitor is one of them. At present, there are dozens of DPP-4 inhibitors, which are collectively known as “gliptin drugs”. In the future, the market size of gliptin drugs in China will exceed 30 billion yuan.
Cetagliptin seven-year long run
On February 2, CGeneTech submitted to the National Drug Administration (NMPA) the marketing application (NDA) of Cetagliptin, a DPP-4 inhibitor, which was mainly used to treat type 2 diabetes. This means that the domestic DPP-4 inhibitor market will usher in new members, and the official website of CGeneTech will also publicize the progress of Cetagliptin research and development in the product pipeline for the first time, and the listing has been confirmed.

Cetagliptin is a Class 1 innovative drug independently developed by CGeneTech, and once was its own fist product in its pipeline. It has also experienced a seven-year long run since its launch of research and development, and is about to hit the line successfully.
In 2006, the targeted hypoglycemic drug Sigliptin was approved by the FDA of the United States, which is undoubtedly a major event in the industry. Ten years later, CGeneTech completed the pre-clinical study of head-to-head comparison of Cetagliptin and Xigliptin.
At the beginning of 2018, CGeneTech launched the phase I clinical trial of head-to-head comparison of Cetagliptin and Xigliptin. Among nearly 200 patients in the Phase I clinical trial completed by Cetagliptin, the data showed that when the intake of Cetagliptin reached 50 mg, it was able to achieve the DPP-4 inhibition capacity equivalent to the intake of 100 mg of Xigliptin. Cetagliptin is administered once a day. It can reach the peak within 1 to 2 hours after administration, and has a longer half-life than Sigliptin, which can maintain stable glucose reduction for a longer time.

Diabetes requires long-term medication, and safety is the first factor to be considered when doctors choose drugs when prescribing. In the safety study, the adverse effects of the intake of Cetagliptin on the body of patients were almost undetectable, lower than that of the blank group and Sigliptin group. In addition, although Cetagliptin has a long half-life, there is no accumulation of residual drugs in the body in the phase I clinical trial, which reflects the high selectivity and strong inhibition of Cetagliptin. The beautiful phase I clinical trial data have provided the foundation for the later clinical trial research of Cetagliptin.
In 2019, Cetagliptin was officially approved by the National Drug Evaluation Center to “exempt Phase II clinical trials from Phase III trials”, becoming the first DPP-4 inhibitor in the world to pass the quantitative pharmacological model, exempt Phase II clinical trials, and directly carry out Phase III confirmatory trials, which attracted the attention of experts in the field of diabetes at home and abroad.
In October 2022, the unblinding results of Cetagliptin phase III clinical trial showed that the reduction of glycosylated hemoglobin (HbA1c) in Cetagliptin tablet 50mg group reached the main clinical end point at the end of the 24th week, which was significantly superior to the control group. After 28 weeks, the Cetagliptin 100mg dose group also showed good drug safety, and the incidence of adverse reactions was similar to that of the placebo group. The clinical trial has shown the advantages of halving the dose but the same efficacy as similar products.
In February 2023, the marketing application (NDA) of Cetagliptin has been accepted by NMPA for the treatment of type 2 diabetes.
The approval of Cetagliptin has attracted much attention, which means that CGeneTech will officially participate in the domestic hot track of DPP-4 inhibitors, and the market of 10 billion statins will usher in new members.
DPP-4 inhibitor track is hot
DPP-4 inhibitors play a hypoglycemic role mainly by inhibiting the degradation of glucagon-like peptide-1 (GLP-1) by DPP-4 enzyme, promoting insulin and glucose dependent secretion, and inhibiting glucagon secretion, which can improve β Cell dysfunction does not increase the risk of hypoglycemia and body weight of patients. Moreover, DPP-4 inhibitor is a “mild and versatile”. It is mild, versatile and safe in reducing blood sugar. It is an oral drug that can be combined with various drugs in the whole process of management.
As the current mainstream hypoglycemic drug, DPP-4 inhibitor has become a hot spot in the eyes of major pharmaceutical enterprises. At present, there are five kinds of DPP-4 inhibitors that are taken daily on the market in China: Sigliptin, Viggliptin, Shagliptin, Aggliptin and Liggliptin, and these “five golden flowers” are included in the national health insurance list.
After entering medical insurance, the sales of several products have increased significantly. It is understood that from 2016 to 2022, the annual sales of DPP-4 inhibitors showed a continuous growth trend, with the highest year-on-year growth rate in 2018. In 2021 alone, the domestic sales of DPP-4 inhibitors reached nearly 7 billion yuan.
Sigliptin
Sigliptin is the first oral DPP-4 inhibitor on the market in the world, developed by MSD. It was approved by FDA for listing in October 2006; Sigliptin was approved for listing in China in September 2009; In July 2012, its compound preparation was approved for registration in China.
According to MSD’s annual report, the global market share of Sigliptin has been stable at more than US $3 billion in the past four years, ranking first in the global sales of DPP-4 inhibitors. At present, there are 14 pharmaceutical enterprises in China, including Zhengda Tianqing, Qilu Pharmaceutical, Kelun Pharmaceutical and Zhejiang Pharmaceutical, which have been copied and approved for production.
Viggliptin is the second DPP-4 inhibitor in the world developed by Novartis. In September 2007, Viggliptin was first approved for listing by the European Commission; In August 2011, it was officially approved for listing in China.
According to Novartis annual report, the global sales volume of Vigiletin has fluctuated steadily in recent years, basically maintaining at about 1.1 billion US dollars. The imitative production of Viggliptin in the domestic market is also hot. At present, 18 pharmaceutical enterprises such as Qilu Pharmaceutical, Yangzijiang Pharmaceutical, Jiangsu Haosen Pharmaceutical, Shandong Langnuo Pharmaceutical and Nanjing Shenghe Pharmaceutical have been approved for production. They are worthy of the title of the king of domestic imitative drugs for DPP-4 inhibitors.
Shagliptin was jointly developed by Bristol-Myers Squibb and AstraZeneca. It was approved by FDA for listing in July 2009; In May 2011, Shagliptin was approved for listing in China. Shagliptin’s overseas market share exceeded 20%. At present, there are five pharmaceutical enterprises in China, including Zhengda Tianqing, Qilu Pharmaceutical and Jiangsu Aosaikang Pharmaceutical, whose generic drugs have been approved for production.
Liggliptin was developed by BI. In May 2011, it was approved for listing by the FDA of the United States, and was jointly sold by Berger Ingelheim and Lilly. In March 2013, China approved the import registration of liggliptin. Liggliptin’s overseas market share exceeds 15%. At present, there are 6 pharmaceutical enterprises in China, including Guangdong East Sunshine Pharmaceutical, Yangzijiang Pharmaceutical and Kelun Pharmaceutical, which have been approved for production.
Agiletin
Agiletin was developed by Takeda Pharmaceutical of Japan. Approved for listing in Japan in April 2010; In January 2013, it was approved by the US FDA for listing; In July of the same year, Agiletin obtained the import registration certificate of China. According to the statistics of IQVIA, the sales amount of Agiletin in the Chinese market in 2022 was 52.36 million yuan. At present, 11 pharmaceutical enterprises such as Yabao Pharmaceutical, Ruiyang Pharmaceutical and Guorui Pharmaceutical of the National Pharmaceutical Group have been approved for production.
Throughout the domestic market of DPP-4 inhibitors, the original drugs and generic drugs of the “five golden flowers” are all in the Jianghu. In order to break the competition pattern, pharmaceutical enterprises have also invested in innovative self-research teams.
At present, the research and development of innovative DPP-4 inhibitors is also advancing rapidly. According to the data, in addition to the approval of CGeneTech’s Cetagliptin, many innovative DPP-4 inhibitors (excluding compound preparations) have entered the clinical research stage in China.
TQ-F3083 of Nanjing Shunxin, Shingliptin of Chenxin Pharmaceutical, and Boggliptin of Shandong Baiji Dichang Pharmaceutical are in clinical phase II; Fugliptin of Xinritai, DBPR108 of Shiyao Group, HSK7653 of Hisco and Unigliptin of Yuandong Biological are all in clinical phase III; Hengrui Pharmaceutical’s Retagliptin has submitted its listing application.
Although there are only a few “Ting” who have been approved to market independently developed DPP-4 inhibitors in China, the approval of Cetagliptin will take the lead in ushering in the harvest period of domestic innovative DPP-4 inhibitors, break the monopoly of non-self-developed DPP-4 inhibitors again, and give great confidence to pharmaceutical enterprises engaged in the research and development of DPP-4 inhibitors.
epilogue
The huge market potential of diabetes is like a magnet, attracting pharmaceutical enterprises to participate in the hot domestic track of DPP-4 inhibitors.
As the first oral DPP-4 inhibitor launched in the world and China, Sigliptin has been in the Chinese market for more than ten years, and still dominates the market. According to the Phase I clinical trial study, Cetagliptin has obtained significantly better data than Sigliptin in terms of efficacy, safety, half-life, toxicology and pathology, which will have considerable market persuasion and is expected to help it become a similar Best-in-class product, or change the curve overtaking into a competitive pattern.
Cetagliptin is only one step away from its listing. Not only is CGeneTech full of expectations for it, but also the industry has high expectations. Cetagliptin can be expected in the future, and we also expect more home-made original new “Ting” to come out.
reference material:
1. CGeneTech official website, official account
2. New weapon for treating diabetes (I) – DPP-4 inhibitor, Department of General Medicine, Shenzhen Hospital, University of Hong Kong, December 9, 2020
3. Unique Mechanism, Multi-dimensional Benefits – Mechanism and Clinical Application of DPP-4 Inhibitor, China Medical Forum Endocrinology Today, April 9, 2020
4. DPP-4 inhibitor market may add new force. Can CGeneTech break the “five giants” pattern
5. Market | DPP-4 inhibitor market pattern seen from the withdrawal of the first generic antidiabetic drug from the network of East Sunshine, CPHI Pharmaceutical Online, November 17, 2022

[1]. Zhou C, et al., Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2024 Mar 11;15:1359407. [Content Brief][2]. Lu J, et al., In vitro study of the drug-drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers. Xenobiotica. 2021 Oct;51(10):1122-1131. [Content Brief]

/////////Cetagliptin, CHINA 2024, APPROVALS 2024, CGeneTec, DIABETES, GTPL13952, CGT 8012,

Cofrogliptin

August 25, 2025 8:44 am / Leave a comment

Cofrogliptin

HSK 7653

Haisco HSK 7653
CAS 1844874-26-5
466.4 g/mol
C₁₈H₁₉F₅N₄O₃S

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)oxan-3-amine

APPROVALS 2024, CHINA 2024, Haisco Pharmaceutical Group Co, Beichangping, DIABETES

Cofrogliptin (developmental name HSK7653) is a long-acting DPP4 inhibitor dosed once every two weeks.^[1][2][3][4]

Cofrogliptin (HSK7653) (compound 2), a tetrahydropyran derivative, is a potent oral dipeptidyl aminopeptidase 4 (DPP-4) inhibitor with Long-acting antidiabetic efficacy. Cofrogliptin (compound 2) has a great potential for type 2 diabetes mellitus (T2DM) .

SYN

J Med Chem. 2020 Jul 9;63(13):7108-7126

aReagents and conditions: (a) morpholine, toluene, reflux in Dean-Stark appartus; (b)
Umemoto’s reagent, DMAP, DMAc; (c) step 1: 1c, toluene, reflux; step 2: NaBH(OAc)3, CH3COOH, 1,2-DCE; (d) step 1: 1c, CHCl3, reflux in Dean-Stark apparatus; step 2:
NaBH(OAc)3, CH3COOH, 1,2-DCE; (e) TFA, DCM; (f) t-BuOK, THF

Step 2: To a stirred solution of tert-butyl N-[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-
(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-
(trifluoromethyl)tetrahydropyran-3-yl]carbamate (2′) (407.5 mg, 0.72 mmol) in DCM (6
mL) was added CF3COOH (2 mL) under nitrogen at 0 ℃. After the addition, the reaction
mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture
was quenched with a saturated solution of Na2CO3 (15 mL), and extracted with DCM (15
mL × 2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by flash column chromatography (Eluent: DCM/MeOH = 80:1–
30:1) to afford the desired product 2 (301.9 mg, yield: 90%). White solid. Mp: 150.1–152.0
℃. [α]D20 = +17.6 (c = 2.000 in MeOH). Rf= 0.40 (1:15 MeOH/CH2Cl2, TLC).

1H NMR
(400 MHz, CDCl3) δ = 7.71 (s, 1H), 7.20 – 7.12 (m, 1H), 7.10 – 6.97 (m, 2H), 4.63 (d, J =
10.0 Hz, 1H), 4.49 – 4.38 (m, 1H), 4.07 – 3.97 (m, 2H), 3.93 – 3.81 (m, 2H), 3.53 – 3.42
(m, 1H), 3.29 (s, 3H), 3.01 – 2.91 (m, 1H), 2.45 – 2.35 (m, 1H), 2.07 – 1.93 (m, 1H), 1.19
(br. s, 2H). 13C NMR (100 MHz, CDCl3) δ = 163.6, 159.1 (dd, J = 2.3 Hz, 235.8 Hz), 156.6

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0223523424003441

SYN

WO2015192701

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015192701&_cid=P20-MEQV3M-18104-1

Step 4: (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3,4]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 3)

[0345]

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

[0346]3c (410 mg, 0.72 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. After completion, saturated aqueous sodium bicarbonate (30 mL) was added to quench the reaction. After separation, the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 30:1) afforded compound 3 (250 mg, 75% yield) as a white powder.

[0347]MS m/z(ESI): 467.1[M+1]；

[0348]

¹H NMR(400MHz,DMSO-d ₆):δ7.96(m,1H),7.35–7.04(m,3H),4.86–4.63(qd,1H),4.50(d,1H),3.95(dd,2H),3.78(dd,2H),3.49(s,3H),3.45(m,1H),3.00(ddd,1H),2.33(m,1H),1.82(m,1H),1.48(br,2H)。

SYN

Cofrogliptin, developed by Haisco Pharmaceutical Group Co., Ltd., is a novel, ultra-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor designed for the treatment of T2DM. It is marketed under the brand name (Beichangping). In 2024, the NMPA approved Cofrogliptin for improving blood glucose control in adult patients with T2DM [59].Cofrogliptin acts pharmacologically by inhibiting DPP-4, an enzyme tasked with degrading incretin hormones like glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By obstructing the degradation of these hormones, it amplifies their activity. This leads to a glucose-dependent rise in insulin secretion and a
corresponding decrease in glucagon release, which in turn improves glycemic control. The clinical efficacy of Cofrogliptin was demonstrated in Phase III, randomized, double-blind, non-inferiority trial
(NCT04556851), where its efficacy and safety were compared to those of daily linagliptin in patients with T2DM whose blood sugar was not well-controlled by metformin. The study reported that Cofrogliptin
administered once every two weeks achieved a reduction in HbA1c comparable to that of daily linagliptin, with a mean decrease of approximately 0.96 % over 24 weeks. Regarding toxicity, Cofrogliptin
was generally well-tolerated [60,61]. The incidence of hypoglycemia was low, and no severe hypoglycemic events directly attributed to the drug were reported.
The synthesis of Cofrogliptin, illustrated in Scheme 14, initiates with trifluoromethylation of Cofr-001 via oxidation, affording Cofr-002 [62]. Nucleophilic addition of Cofr-003 to Cofr-002 yields Cofr-004, followed by NaBH(OAc)3 reduction to Cofr-005. TFA-mediated deprotection of Cofr-005 ultimately delivers Cofrogliptin. Concurrently, Cofr-006 undergoes nucleophilic substitution with Cofr-007 to form Cofr-008, whose deprotection regenerates Cofr-003

[59] L. Gao, F. Bian, T. Pan, H. Jiang, B. Feng, C. Jiang, J. Sun, J. Xiao, P. Yan, L. Ji,
Efficacy and safety of cofrogliptin once every 2 weeks in Chinese patients with type
2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial, Diabetes
Obes Metab 27 (2025) 280–290.
[60] C. Cui, F. Cao, I.I. Kong, Q. Wu, F. Li, H. Li, D. Liu, A model-informed approach to
accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-
acting dipeptidyl peptidase-4 inhibitor, Diabetes Obes Metab 26 (2024) 592–601.
[61] Q. Ren, L. Li, X. Su, X. Hu, G. Qin, J. Han, Y. Liu, J. Wang, L. Ji, Cofrogliptin once
every 2 weeks as add-on therapy to metformin versus daily linagliptin in patients
with type 2 diabetes in China: a randomized, double-blind, non-inferiority trial,
Diabetes Obes Metab 26 (2024) 5013–5024.
[62] C. Zhang, J. Wang, C. Li, Y. Wei, Amino Pyranoid Ring Derivative as DPP-IV
Inhibitor and Its Preparation, 2015. WO2015192701A1.

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References

Ji, Linong; Bian, Fang; Pan, Tianrong; Jiang, Hongwei; Jiang, Chengxia; Ren, Qian (20 June 2023). “55-OR: HSK7653, a Novel Ultralong-Acting DPP-4 Inhibitor, as Monotherapy in Patients With Type 2 Diabetes—A Randomized, Double-Blind, Placebo-Controlled Phase III Trial”. Diabetes. 72 (Supplement_1). doi:10.2337/db23-55-OR. S2CID 259433641.
Zhang, Miao; Zhang, Shudong; Yu, Zhiheng; Yao, Xueting; Lei, Zihan; Yan, Pangke; Wu, Nan; Wang, Xu; Hu, Qin; Liu, Dongyang (October 2023). “Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model”. European Journal of Pharmaceutical Sciences. 189 106553. doi:10.1016/j.ejps.2023.106553. PMC 10485820. PMID 37532063.
Liu, Yang; Yan, Shuai; Liu, Jie; Liu, Hongzhong; Song, Ling; Yao, Xueting; Jiang, Ji; Li, Fangqiong; Du, Ke; Liu, Dongyang; Hu, Pei (May 2023). “Development and validation of an HPLC coupled with tandem mass spectrometry method for the determination of HSK7653, a novel super long-acting dipeptidyl peptidase-4 inhibitor, in human plasma and urine and its application to a pharmacokinetic study”. Biomedical Chromatography. 37 (5): e5607. doi:10.1002/bmc.5607. PMID 36802077. S2CID 257048524.
Bai, Nan; Wang, Jin; Liang, Wenxin; Gao, Leili; Cui, Wei; Wu, Qinghe; Li, Fangqiong; Ji, Linong; Cai, Yun (6 November 2023). “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, and Dose-Increasing Study on the Safety, Tolerability and PK/PD of Multiple Doses of HSK7653 by Oral Administration in Patients with Type 2 Diabetes Mellitus in China”. Diabetes Therapy. 15 (1): 183–199. doi:10.1007/s13300-023-01496-0. PMC 10786778. PMID 37930584.

Clinical data

Other names	HSK7653
Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	1844874-26-5
PubChem CID	118613788
ChemSpider	115037226
UNII	LH4G6K6NKP
ChEMBL	ChEMBL4646510
Chemical and physical data
Formula	C₁₈H₁₉F₅N₄O₃S
Molar mass	466.43 g·mol⁻¹

[1]. International Nonproprietary Names for Pharmaceutical Substances (INN)[2]. Chen Zhang, et al. Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. J Med Chem. 2020 Jul 9;63(13):7108-7126. [Content Brief]

///////Cofrogliptin, APPROVALS 2024, CHINA 2024, Haisco Pharmaceutical Group Co, Beichangping, DIABETES, HSK 7653, Haisco HSK 7653, 1844874-26-5

Janagliflozin

August 25, 2025 2:42 am / Leave a comment

Janagliflozin

WeightAverage: 460.95
Monoisotopic: 460.1652664

Chemical FormulaC₂₅H₂₉ClO₆

WK4RT85HCA
XZP-5695
UNII-WK4RT85HCA
1800115-22-3
(2S,3R,4R,5S,6R)-2-[3-[[4-[[(1S,5R)-3-bicyclo[3.1.0]hexanyl]oxy]phenyl]methyl]-4-chlorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
D-Glucitol, 1,5-anhydro-1-C-(3-((4-((1alpha,3alpha,5alpha)-bicyclo(3.1.0)hex-3-yloxy)phenyl)methyl)-4-chlorophenyl)-, (1S)-
(2S,3R,4R,5S,6R)-2-[3-[[4-[[(1S,5R)-3-bicyclo[3.1.0]hexanyl]oxy]phenyl]methyl]-4-chlorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
D-GLUCITOL, 1,5-ANHYDRO-1-C-(3-((4-((1.ALPHA.,3.ALPHA.,5.ALPHA.)-BICYCLO(3.1.0)HEX-3-YLOXY)PHENYL)METHYL)-4-CHLOROPHENYL)-, (1S)-
(2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

China 2024, approvals 2024, Jilin Huisheng Biopharmaceutical Co, sihuan, SGLT2 inhibitors, Huiyoujing

Janagliflozin is an SGLT2 inhibitor developed by Sihuan Pharmaceutical.^{[1][2][3][4][5][6]} It is approved in China for the treatment of type 2 diabetes.^[7]

PAPER

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0042-1751524

(71) (a) Wu, F. US9315438B2, 2016. (b) Wu, F. EP2891654A1, 2014.

Initially, the two advanced intermediates were synthesized and then coupled under cryogenic conditions using nBuLi. The construction of 242 commences with the reaction of 5-bromo-2-chlorobenzoic acid (26c) with oxalyl chloride and a catalytic amount of DMF in DCM, yielding the acid chloride derivative 26c′. This intermediate is then subjected to Friedel–Crafts acylation with anisole to produce 240 in
71% yield. Subsequent reduction of 240 was carried out using boron trifluoride–diethyl etherate and triethylsilane in a DCM/acetonitrile mixture, leading to the formation of 241 in an excellent yield. Demethylation of compound 241 is accomplished using boron tribromide at low temperature, resulting in 242 with a yield of 97%. On the other hand, the synthesis of 245 involves two steps starting from commercially available cyclopent-3-en-1-ol (243). The Simmons Smith cyclopropanation of 243 is performed using a mixture of trifluoroacetic acid, diiodomethane, and diethylzinc in DCM, providing 244 with a yield of 48%. Compound 244 is then further treated with methanesulfonyl chloride to give the mesylated compound 245 in a yield of 68%. Subse quently, 4-(5-bromo-2-chlorobenzyl)phenol (242) is allowed to react with 245 in the presence of NMP, cesium carbonate, and BTEAC (benzyltriethylammonium chloride) to give 246. The next step involves a lithium–halogen exchange on
246 using n-butyllithium, with addition to 22 at –78 °C affording the hydroxy intermediate. Methylation of this hydroxy intermediate using methanesulfonic acid and methanol provides 247 in 98% yield. Reduction of 247 using borontrifluoride–diethyl etherate and triethylsilane at –78 °C furnishes 248. To achieve the desired isomer, all of the hydroxy groups of compound 248 were protected using acetic anhydride, DMAP, and pyridine in DCM at 0 °C to give the O-acylated compound 249. In the final step, 249 is hydrolyzed us ing lithium hydroxide monohydrate in a mixed solvent consisting of methanol, THF, and water to provide the desired compound janagliflozin (14) in a yield of 91%. This truncated synthetic route is protection-group-free, and is well suited for scale-up. The drawback of the synthetic route is
the late-stage enrichment of the desired isomer in the final product via acylated derivative 249. The poor isolated yield of 249 is not commercially favored due to low throughput and an increase in raw material and production costs.

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00017

SYN

https://www.sciencedirect.com/science/article/abs/pii/S022352342400223X

PAT

US9315438,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US142552820&_cid=P11-MEPJES-88258-1

Example 1

Preparation of (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Formula II)

(1) Preparation of 5-bromo-2-chlorobenzoyl chloride

5-bromo-2-chlorobenzoic acid (270 g, 1.15 mol) was suspended in methylene chloride (2700 mL). To the resulting mixture was added N,N-dimethylformamide (1 mL), and then added dropwise oxalyl chloride (288 mL, 3.46 mol) at 0° C. After the completion of dropwise addition, the mixture was warmed up to 20° C. and reacted for 3 h. The reaction mixture became clear, and TLC (Thin layer chromatography) indicated the completion of reaction. The reaction mixture was evaporated by rotation at 30-35° C. to produce a product, which was directly used in the next reaction.

(2) Preparation of (5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone

Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under a nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at −5° C. After stirring for 20 mins, to the mixture was added dropwise a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL). The resulting mixture was reacted at −5° C. for 3 h. TLC indicated the completion of reaction. To the reaction mixture was poured 2N hydrochloric acid. The resulting mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce a solid. To the solid was added ethanol (150 mL), and the resulting mixture was washed and starched for 30 mins and filtered. The filter cake was oven dried to produce 265 g of a product in a yield of 71%.

(3) Preparation of 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene

(5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone (265 g, 0.81 mol) was dissolved in methylene chloride (515 mL) and acetonitrile (1030 mL). To the resulting mixture was added triethyl silane (352 mL, 2.22 mol). Then to the resulting mixture was added dropwise boron trifluoride-diethyl etherate (273 mL, 2.22 mol) at 0° C. under a nitrogen protection. After the completion of dropwise addition, the resulting mixture was stirred for 20 min, warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture were added methyl tert-butyl ether (1.5 L) and a saturated sodium bicarbonate solution (1.5 L). The mixture was stirred for 30 mins. The organic phase was separated off, washed with a saturated sodium bicarbonate solution for four times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce an oily substance. To the oily substance was added ethanol. The resulting mixture was stirred at room temperature for 30 mins and in an ice bath for 30 mins. A great quantity of solid was separated out and filtered. The filter cake was dried to produce 226 g of a product in a yield of 89%.

(4) Preparation of 4-(5-bromo-2-chlorobenzyl)phenol

4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under a nitrogen protection and in a protection from light. To the resulting mixture was slowly added dropwise a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at −78° C. After the completion of dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture was slowly added dropwise water in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted with methylene chloride (1 L) for two times. The organic phases were combined, washed with water for two times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 210 g of a product in a yield of 97%.

(5) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol

Diethyl zinc (7.16 L, 7.14 mol) was added dropwise to methylene chloride (9 L) at 0° C. When the white fume disappeared after the completion of dropwise addition, to the resulting mixture was slowly added dropwise a solution of trifluoroacetic acid (816 g, 7.16 mol) in methylene chloride (1 L). After the completion of dropwise addition, the resulting mixture was stirred for 30 mins. To the mixture was added dropwise a solution of methylene iodide (1918 g, 7.14 mol) in methylene chloride (1 L). After the completion of dropwise addition, the resulting mixture was stirred for 30 mins. To the mixture was added dropwise a solution of cyclopent-3-en-1-ol (200 g, 2.38 mol) in methylene chloride (800 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and reacted for 30 mins. TLC indicated the completion of reaction. The reaction mixture was poured into a saturated ammonium chloride. After stirring for 10 mins, the mixture was separated into an organic phase and an aqueous phase. The aqueous phase was extracted with methylene chloride (2 L) for one time. The organic phase was washed with a saturated sodium sulphite, with a saturated sodium bicarbonate, and with a saturated sodium chloride, and dried over anhydrous sodium sulphate. The residue is purified with a column chromatography to produce 112 g of a product in a yield of 48%.

(6) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl methanesulfonate

(1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol (112 g, 1.14 mol) was dissolved in methylene chloride (1250 mL) in an ice-water bath. To the resulting mixture was added triethylamine (174 g, 1.69 mol), and then slowly added dropwise methylsulfonyl chloride (197 g, 1.72 mol). After the completion of dropwise addition, the resulting mixture was reacted for 30 mins at 0° C. TLC indicated the completion of reaction. The reaction mixture was poured into water and separated into an organic phase and an aqueous phase. The organic phase was washed with a diluted hydrochloric acid for one time, with water for two times, and then with a saturated sodium chloride, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 138 g of a product in a yield of 68%.

(7) Preparation of (1R,3s,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenyloxy)bicyclo[3.1.0]hexane

(1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl methanesulfonate (138 g, 0.78 mol) was dissolved in N-methylpyrrolidone (2.1 L). To the resulting mixture was added 4-(5-bromo-2-chlorobenzyl)phenol (210 g, 0.71 mol), cesium carbonate (462 g, 1.42 mol) and benzyltriethylammonium chloride (5.46 g, 24 mmol). Then the resulting mixture was stirred for 10 mins at room temperature, warmed up to 50° C., and reacted overnight. TLC indicated the completion of reaction. To the reaction mixture was added water. Then the resulting mixture was extracted with a mixed solution of petroleum ether and methyl tert-butyl ether (petroleum ether:methyl tert-butyl ether=1:1) for two times. The organic phases were combined, washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride for two times, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with a column chromatography (petroleum ether:ethyl acetate=50:1) to produce 135 g of the product in a yield of 50%.

Formula: C ₁₉H ₁₈BrClO; Mw: 377.71

¹H-NMR (400 MHz, CDCl ₃) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.82-6.78 (m, 2H), 4.42-4.35 (m, 1H), 3.98 (s, 2H), 2.36-2.31 (m, 2H), 1.96-1.90 (m, 2H), 1.40-1.33 (m, 2H), 0.47-0.44 (m, 1H), 0.07-0.02 (m, 1H).

(8) Preparation of (3R,4S,5R,6R)-3,4,5-tri((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one

(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (85 g, 0.47 mol) was suspended in THF (tetrahydrofuran) (932 mL). To the resulting mixture was added N-methylmorpholine (405 mL, 4.78 mol). Then the resulting mixture was cooled to −5° C. under a nitrogen protection, and TMSCI (trimethylsilane chloride) (360 mL, 4.78 mol) was added dropwise thereto. After the completion of dropwise addition, the resulting mixture was stirred at room temperature for 1 h and at 35° C. for 5 hr. Then the mixture was stirred overnight while the temperature was maintained at 25° C. TLC indicated the completion of reaction. To the reaction mixture was added toluene (200 mL) and added dropwise water (1 L) in an ice-water bath. The organic phase was collected, washed with sodium dihydrogen phosphate for one time, with water for one time, and with a saturated sodium chloride solution for one time, dried and concentrated to produce 218 g of a product in a yield of 100%.

(9) Preparation of (3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

(1R,3s,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenyloxy)bicyclo[3.1.0]hexane (135 g, 0.358 mol) was dissolved in tetrahydrofuran (813 mL) and toluene (813 mL) under a nitrogen protection. The resulting mixture was cooled to −78° C., and n-butyl lithium (194 mL, 0.465 mol) was added dropwise thereto. After the completion of dropwise addition, the reaction mixture was stirred for 2 hr, sucked out with an injector, and then injected to a solution of (3R,4S,5R,6R)-3,4,5-tri((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (218 g, 0.47 mol) in toluene (950 mL). The resulting mixture was stirred for 1 hr, and a solution of methylsulfonic acid (44.9 mL, 2.15 mol) in methanol (1.2 L) was added thereto. The mixture was stirred at −78° C. for 1 hr, warmed up to room temperature, and reacted overnight. TLC indicated the completion of reaction. The reaction mixture was quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (2 L). The organic phase was washed with water and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 173 g of a product in a yield of 98%.

(10) Preparation of (3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (173 g, 0.352 mol) and triethyl silane (180 mL, 1.05 mol) were dissolved in methylene chloride (2 L) at −78° C. in a nitrogen protection. To the resulting mixture was slowly added dropwise boron trifluoride-diethyl etherate (134 mL, 1.05 mol). After the completion of dropwise addition, the mixture was reacted at −78° C. for 1 hr. The reaction mixture was slowly warmed up to room temperature and reacted for 1 hr. HPLC indicated the completion of reaction. To the reaction mixture was added dropwise a saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (1 L). The organic phase was washed with water and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 143 g of a product in a yield of 88%.

(11) Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (143 g, 0.311 mol) was dissolved in methylene chloride (720 mL). To the resulting mixture were added pyridine (252 mL, 3.11 mol) and DMAP (4-dimethylaminopyridine) (1.9 g, 15.6 mmol), and then added dropwise acetic anhydride (292 mL, 3.11 mol) in an ice-water bath. The reaction mixture was stirred at room temperature for 3 hr, quenched with water, and extracted with ethyl acetate (1.5 L). The organic layer was washed with a diluted hydrochloric acid for three times, with a saturated sodium bicarbonate for one time, with water, and with a saturated sodium chloride, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was recrystallized with ethanol to produce 81 g of a product in a yield of 42%.

(12) Preparation of (2S,3R,4R,5 S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2R,3R,4R _/5 S, 6S)-2-(acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (81 g, 0.129 mol) was dissolved in a mixed solvent of tetrahydrofuran (313 mL), methanol (470 mL) and water (156 mL). To the resulting mixture was added lithium hydroxide monohydrate (6.32 g, 150 mmol). The mixture was stirred at room temperature overnight. TLC indicated the completion of reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved with ethyl acetate (400 mL). The organic phase was washed with an aqueous saturated sodium chloride solution, with an aqueous KHSO ₄solution, and with water twice, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with C18 reverse phase preparative chromatography to produce 54.2 g of a final product in a yield of 91%.

Formula: C ₂₅H ₂₉ClO ₆Mw: 460.95 LC-MS (m/z): 478.3 [M+NH ₄] ⁺

¹H-NMR (400 MHz, MeOD) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.89-3.88 (d, 1H), 3.71-3.69 (m, 1H), 3.45-3.38 (m, 3H), 3.31-3.26 (m, 1H), 2.34-2.29 (m, 2H), 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).

PAT

EP2891654

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP142501978&_cid=P20-MEQIAN-96633-1

[0027] The compound represented by formula (II) as defined hereinbefore, lab-made, its chemical name and preparation process are described in the following Example 1.

Reference compound 1: Compound 4 as described in the PCT application WO2013/000275A1, lab-made (with reference to the PCT application WO2013/000275A1), its structure is as follows:

Compound 4, i.e. the compound represented by formula (I).

Reference compound 2: Compound 22 as described in the PCT application WO2013/000275A1, lab-made (with reference to the PCT application WO2013/000275A1), its structure is as follows:

Compound 22.

(12) Preparation of

[0057] (2 S,3 R,4 R,5 S,6 R)-2-(3-(4-(((1 R,3 s,5 S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydr oxymethyl)tetrahydro-2 H-pyran-3,4,5-triol

[0058] (2 R,3 R,4 R,5 S,6 S)-2-(acetoxymethyl)-6-(3-(4-(((1 R,3 s,5 S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlo rophenyl)tetrahydro-2 H-pyran-3,4,5-triyl triacetate (81g, 0.129mol) was dissolved in a mixed solvent of tetrahydrofuran (313mL), methanol (470mL) and water (156mL). To the resulting mixture was added lithium hydroxide monohydrate (6.32g, 150mmol). The mixture was stirred at room temperature overnight. TLC indicated the completion of reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved with ethyl acetate (400mL). The organic phase was washed with an aqueous saturated sodium chloride solution, with an aqueous KHSO ₄ solution, and with water twice, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with C18 reverse phase preparative chromatography to produce 54.2g of a final product in a yield of 91%.
Formula: C ₂₅H ₂₉ClO ₆ Mw: 460.95 LC-MS( m/ z): 478.3 [M+NH ₄] ⁺
¹H-NMR (400MHz, MeOD) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.89-3.88 (d, 1H), 3.71-3.69 (m, 1H), 3.45-3.38 (m, 3H), 3.31-3.26 (m, 1H), 2.34-2.29 (m, 2H), 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Janagliflozin, engineered by Jilin Huisheng Biopharmaceutical Co., Ltd., a subsidiary under the umbrella of Sihuan Pharmaceutical Holdings Group, falls within the category of oral sodium-glucose co-transporter 2(SGLT2) inhibitors. This agent has been specifically designed with the aim of optimizing glycemic regulation in the adult population grappling with type 2 diabetes mellitus (T2DM) [54]. It is marketed under the brand name Huiyoujing. In 2024, the NMPA gave its approval for Janagliflozin, indicated for adult patients with T2DM, where it can be employed either as a standalone treatment (monotherapy) or in combination with metformin to optimize blood glucose regulation [55]. The clinical effectiveness of Janagliflozin was substantiated through a Phase III clinical trial (NCT03811548). This trial specifically assessed its application as a monotherapy in Chinese patients suffering from T2DM
whose blood glucose was not well – managed via diet and exercise alone. The findings of the study indicated notable decreases in glycated hemoglobin levels. Concurrently, improvements were observed in both body weight and blood pressure. Collectively, these outcomes serve as evidence of the drug’s ability to enhance glycemic regulation [56]. Regarding safety, Janagliflozin was generally well-tolerated. In line with the well-established safety characteristics of SGLT2 inhibitors, the frequently encountered adverse events associated with this treatment were urinary tract infections and genital mycotic infections. No serious adverse events were reported during the trial [57].
The synthesis of Janagliflozin, depicted in Scheme 13, commences with the acylation of 5-bromo-2-chlorobenzoic acid (Jana-001) using oxalyl chloride, yielding the acyl chloride intermediate Jana-002 [58]. Friedel-Crafts acylation of Jana-002 with anisole (Jana-003) affords ketone Jana-004. Subsequent reduction of the carbonyl group in Jana-004 produces Jana-005. Demethylation of Jana-005 with BBr3
generates phenol Jana-006, which undergoes substitution with intermediate Jana-007 to form ether Jana-008. Addition of gluconolactone (Jana-009) to Jana-008 affords Jana-010, where concurrent TMS
deprotection during etherification yields Jana-011. Reduction of Jana-011 using Et3SiH/BF3.ET2Oproduces Jana-012which is sequentially esterified with Ac2O , and hydrolyzed under LiOH conditions, ultimately yielding Janagliflozin

[54] L. Gao, Z. Cheng, B. Su, X. Su, W. Song, Y. Guo, L. Liao, X. Chen, J. Li, X. Tan, F. Xu,
S. Pang, K. Wang, J. Ye, Y. Wang, L. Chen, J. Sun, L. Ji, Efficacy and safety of
janagliflozin as add-on therapy to metformin in Chinese patients with type 2
diabetes inadequately controlled with metformin alone: a multicentre,
randomized, double-blind, placebo-controlled, phase 3 trial, Diabetes Obes Metab
25 (2023) 785–795.
[55] L. Ji, X. Jiang, Q. Hao, Z. Cheng, K. Wang, S. Pang, M. Liu, Y. Guo, X. Chen, X. Su,
T. Ning, J. Liu, F. Bian, Y. Li, Z. Zhang, W. Song, J. Sun, Efficacy and safety of
janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus
inadequately controlled on diet and exercise: a multicentre, randomized, double-
blind, placebo-controlled, phase 3 trial, Diabetes Obes Metab 25 (2023)
1229–1240.
[56] L. Song, X. Wang, J. Sun, X. Hu, H. Li, P. Hu, D. Liu, A model-informed approach to
accelerate the clinical development of janagliflozin, an innovative SGLT2 inhibitor,
Clin. Pharmacokinet. 62 (2023) 505–518.
[57] Canagliflozin, Drugs and Lactation Database (Lactmed®), National Institute of
Child Health and Human Development, Bethesda (MD), 2006.
[58] F. Wu, Optically Pure benzyl-4-chlorophenyl-C-glucoside Derivatives as SGLT
Inhibitors (Diabetes Mellitus), 2015. EP2891654.

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References

Song, Ling; Yao, Xueting; Liu, Yang; Zhong, Wen; Jiang, Ji; Liu, Hongzhong; Zhou, Huimin; Shi, Chongtie; Zong, Kaiqi; Wang, Chong; Ma, Chuanxiang; Liu, Dongyang; Hu, Pei (April 2020). “Translational prediction of first-in-human pharmacokinetics and pharmacodynamics of janagliflozin, a selective SGLT2 inhibitor, using allometric scaling, dedrick and PK/PD modeling methods”. European Journal of Pharmaceutical Sciences. 147: 105281. doi:10.1016/j.ejps.2020.105281. S2CID 212405270.
Liu, Dongyang; Song, Ling; Wang, Xiaoxu; Liu, Xu; Cao, Fangrui; Liu, Hongzhong; Ding, Yanhua; Xiao, Xinhua; Jiang, Ji; Hu, Pei (1 June 2019). “154-LB: Accelerating Clinical Development of Janagliflozin, a Novel Antidiabetic Drug, Using Model-Informed Drug Development Strategy”. Diabetes. 68 (Supplement_1). doi:10.2337/db19-154-LB. S2CID 195440798.
Zhao, Hengli; Wei, Yilin; He, Kun; Zhao, Xiaoyu; Mu, Hongli; Wen, Qing (December 2022). “Prediction of janagliflozin pharmacokinetics in type 2 diabetes mellitus patients with liver cirrhosis or renal impairment using a physiologically based pharmacokinetic model”. European Journal of Pharmaceutical Sciences. 179: 106298. doi:10.1016/j.ejps.2022.106298. PMID 36162752. S2CID 252505056.
Zhao, Hengli; Zhao, Zhirui; He, Kun; Mi, Nianrong; Lou, Kai; Dong, Xiaolin; Zhang, Wenyu; Sun, Jingfang; Hu, Xinyu; Pang, Shuguang; Cheng, Hong; Wen, Qing (August 2023). “Pharmacokinetics, Pharmacodynamics and Safety of Janagliflozin in Chinese Type 2 Diabetes Mellitus Patients with Renal Impairment”. Clinical Pharmacokinetics. 62 (8): 1093–1103. doi:10.1007/s40262-023-01256-0. PMID 37284974. S2CID 259097798.
Gao, Leili; Cheng, Zhifeng; Su, Benli; Su, Xiuhai; Song, Weihong; Guo, Yushan; Liao, Lin; Chen, Xiaowen; Li, Jiarui; Tan, Xingrong; Xu, Fangjiang; Pang, Shuguang; Wang, Kun; Ye, Jun; Wang, Yuan; Chen, Lili; Sun, Jingfang; Ji, Linong (March 2023). “Efficacy and safety of janagliflozin as add‐on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin alone: A multicentre, randomized, double‐blind, placebo‐controlled, phase 3 trial”. Diabetes, Obesity and Metabolism. 25 (3): 785–795. doi:10.1111/dom.14926. PMID 36433709. S2CID 253967474.
Ji, Linong; Jiang, Xiaozhen; Hao, Qingshun; Cheng, Zhifeng; Wang, Kun; Pang, Shuguang; Liu, Meiying; Guo, Yushan; Chen, Xiaowen; Su, Xiuhai; Ning, Tao; Liu, Jie; Bian, Fang; Li, Yulan; Zhang, Zhinong; Song, Weihong; Sun, Jingfang (May 2023). “Efficacy and safety of janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled on diet and exercise: A multicentre, randomized, double‐blind, placebo‐controlled, Phase 3 trial”. Diabetes, Obesity and Metabolism. 25 (5): 1229–1240. doi:10.1111/dom.14971. PMID 36594724. S2CID 255474211.
“NMPA approves China’s second homegrown SGLT2 inhibitor janagliflozin”. bioworld.com. January 23, 2024.

Legal status

Legal status	Rx in China; investigational elsewhere
Identifiers
IUPAC name
CAS Number	1800115-22-3
PubChem CID	91820686
DrugBank	DB16209
UNII	WK4RT85HCA
Chemical and physical data
Formula	C₂₅H₂₉ClO₆
Molar mass	460.95 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////Janagliflozin, china 2024, approvals 2024, Jilin Huisheng Biopharmaceutical Co, sihuan, SGLT2 inhibitors, Huiyoujing, WK4RT85HCA, XZP 5695, UNII-WK4RT85HCA, 1800115-22-3

SYN

SYNTHESIS 2024, 56, 906–943

synthesis of janagliflozin (14) was achieved through an eleven-step process in an overall yield of 3% (Scheme 45).71 Initially, the two advanced intermediates were synthesized and then coupled under cryogenic conditions using nBuLi. The construction of 242 commences with the reaction of 5-bromo-2-chlorobenzoic acid (26c) with oxalyl chloride and a catalytic amount of DMF in DCM, yielding the acid
chloride derivative 26c′. This intermediate is then subjected to Friedel–Crafts acylation with anisole to produce 240 in 71% yield. Subsequent reduction of 240 was carried out using boron trifluoride–diethyl etherate and triethylsilane in a DCM/acetonitrile mixture, leading to the formation of 241 in an excellent yield. Demethylation of compound 241 is accomplished using boron tribromide at low temperature, re
sulting in 242 with a yield of 97%. On the other hand, the synthesis of 245 involves two steps starting from commercially available cyclopent-3-en-1-ol (243). The Simmons Smith cyclopropanation of 243 is performed using a mixture of trifluoroacetic acid, diiodomethane, and diethylzinc in DCM, providing 244 with a yield of 48%. Compound 244 is then further treated with methanesulfonyl chloride to
give the mesylated compound 245 in a yield of 68%. Subsequently, 4-(5-bromo-2-chlorobenzyl)phenol (242) is allowed to react with 245 in the presence of NMP, cesium carbonate, and BTEAC (benzyltriethylammonium chloride) to give 246. The next step involves a lithium–halogen exchange on
246 using n-butyllithium, with addition to 22 at –78 °C affording the hydroxy intermediate. Methylation of this hydroxy intermediate using methanesulfonic acid and methanol provides 247 in 98% yield. Reduction of 247 using boron trifluoride–diethyl etherate and triethylsilane at –78 °C furnishes 248. To achieve the desired isomer, all of the hydroxy groups of compound 248 were protected using acetic anhydride, DMAP, and pyridine in DCM at 0 °C to give the O-acylated compound 249. In the final step, 249 is hydrolyzed us ing lithium hydroxide monohydrate in a mixed solvent consisting of methanol, THF, and water to provide the desired compound janagliflozin (14) in a yield of 91%. This truncated synthetic route is protection-group-free, and is well suited for scale-up. The drawback of the synthetic route is
the late-stage enrichment of the desired isomer in the final product via acylated derivative 249. The poor isolated yield of 249 is not commercially favored due to low throughput and an increase in raw material and production costs

(71) (a) Wu, F. US9315438B2, 2016. (b) Wu, F. EP2891654A1, 2014.

Zorifertinib

August 21, 2025 4:15 am / Leave a comment

Zorifertinib

AZD 3759

CAS 1626387-80-1, 67SX9H68W2

WeightAverage: 459.91
Monoisotopic: 459.1473455

Chemical FormulaC₂₂H₂₃ClFN₅O₃

[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate

China 2024, APPROVALS 2024, Alpha Biopharma, ASTRA ZENECA, Zorifer,

Zorifertinib (AZD3759) is a drug for the treatment of cancer.^[1] In China, it was approved in 2024 for locally advanced or metastatic non-small-cell lung cancer (NSCLC) that has epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutations and central nervous system (CNS) metastases.^[2]

Zorifertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR), with potential antineoplastic activity. Upon oral administration, zorifertinib binds to and inhibits the activity of EGFR as well as certain mutant forms of EGFR. This prevents EGFR-mediated signaling, and may lead to both induction of cell death and inhibition of tumor growth in EGFR-overexpressing cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.

SYN

J. Med. Chem. 58 (2015) 8200–8215.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01073

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Zorifertinib, developed by AstraZeneca as AZD3759, is a novel EGFR TKI designed to effectively penetrate the blood-brain barrier (BBB) [44,45]. In 2018, Alpha Biopharma, in collaboration with AstraZeneca, advanced its development. In 2024, the NMPA gave its approval to zorifertinib hydrochloride tablets, which are sold under the brand name Zorifer. This approval is for the use of these tablets in the first-line treatment of adult patients who have the following conditions: they
have locally advanced or metastatic NSCLC with either EGFR exon 19 deletion or exon 21 L858R substitution mutations, and also have CNSmetastases [45]. Zorifertinib exerts its pharmacological action through the selective inhibition of EGFR tyrosine kinase activity, with a particular focus on mutational forms such as L858R and exon 19 deletions. In contrast to several other tyrosine kinase inhibitors (TKIs), it does not serve as a substrate for BBB efflux transporters, namely P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This unique property enables zorifertinib to reach elevated concentrations within brain tissue and cerebrospinal fluid. As a result, it can effectively target and
act against CNS metastases [44,45]. The clinical efficacy of zorifertinib was demonstrated in the EVEREST study (NCT03653546), a random ized, open-label, international multicenter Phase II/III trial. The study
enrolled 492 patients with EGFR-mutant NSCLC and CNS metastases. Results showed that zorifertinib significantly improved systemic PFS to 9.6 months compared to 6.9 months with first-generation EGFR-TKIs, reducing the risk of disease progression or death by 28 %. Intracranial PFS was notably extended to 15.2 months versus 8.3 months in the control group. The ORR was 68.6 % for zorifertinib compared to 58.4 % for the control. Regarding toxicity, zorifertinib exhibited a manageable safety profile. The incidence of treatment-related adverse events (TRAEs) was similar between the zorifertinib and control groups (97.7 %vs. 94.0 %), with grade ≥3 TRAEs occurring in 65.9 % of patients receiving zorifertinib compared to 18.3 % in the control group. No new safety signals were identified, indicating an acceptable tolerability for patients. The approval of zorifertinib offers a significant advancement in
the treatment of EGFR-mutant NSCLC patients with CNS metastases,providing an effective therapeutic option capable of addressing both systemic and intracranial disease [44].

The synthesis of Zorifertinib, depicted in Scheme 11, initiates with nucleophilic substitution between Zori-001 and Zori-002 in MeCN, affording Zori-003 [46]. Hydrolysis of the ester moiety in Zori-003
yields Zori-004, which is subsequently esterified with Zori-005 in DMF to form Zori-006. Acidic deprotection of Zori-006 generates Zori-007, followed by methylation to deliver Zorifertinib. Concurrently, Zori-005 is prepared via amidation of Zori-008

[44] M. Roy-O’Reilly, D. Rogawski, The climb toward intracranial efficacy: Zorifertinib
in EGFR-mutant NSCLC with CNS metastases in the EVEREST trial, Med 6 (2025)
100525.
[45] Q. Zhou, Y. Yu, L. Xing, Y. Cheng, Y. Wang, Y. Pan, Y. Fan, J. Shi, G. Zhang, J. Cui,
J. Zhou, Y. Song, W. Zhuang, Z. Ma, Y. Hu, G. Li, X. Dong, J. Feng, S. Lu, J. Wu,
J. Li, L. Zhang, D. Wang, X. Xu, T.Y. Yang, N. Yang, Y. Guo, J. Zhao, Y. Yao,
D. Zhong, B. Xia, C.T. Yang, B. Zhu, P. Sun, B.Y. Shim, Y. Chen, Z. Wang, M.J. Ahn,
J. Wang, Y.L. Wu, First-line zorifertinib for EGFR-Mutant non-small cell lung
cancer with central nervous system metastases: the phase 3 EVEREST trial, Med 6
(2025) 100513.
[46] Q. Zeng, J. Wang, Z. Cheng, K. Chen, P. Johnstr¨om, K. Varn¨as, D.Y. Li, Z.F. Yang,
X. Zhang, Discovery and evaluation of clinical candidate AZD3759, a potent, oral
active, central nervous system-penetrant, epidermal growth factor receptor
tyrosine kinase inhibitor, J. Med. Chem. 58 (2015) 8200–8215.

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References

Zhou Q, Yu Y, Xing L, Cheng Y, Wang Y, Pan Y, et al. (January 2025). “First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial”. Med. 6 (1) 100513. doi:10.1016/j.medj.2024.09.002. PMID 39389055.
“Zorifertinib Receives NMPA Approval for EGFR+ NSCLC With CNS Metastases”. November 20, 2024.

Clinical data

Other names	AZD3759
Legal status
Legal status	Rx in China
Identifiers
IUPAC name
CAS Number	1626387-80-1
PubChem CID	78209992
IUPHAR/BPS	10456
DrugBank	DB14795
ChemSpider	38772332
UNII	67SX9H68W2
ChEMBL	ChEMBL3623290
Chemical and physical data
Formula	C₂₂H₂₃ClFN₅O₃
Molar mass	459.91 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////Zorifertinib, china 2024, APPROVALS 2024, Alpha Biopharma, ASTRA ZENECA, Zorifer, AZD 3759, 67SX9H68W2

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Example 3-1

(+)-(R)—N-(4-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

How baxdrostat works

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Example 1.16

Example 2.1

Example 2.2

Example 2.3

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Step One: Synthesis of Intermediate (D-1)

Step Two: Synthesis of Intermediate (D2-1)

Step Three: Synthesis of Intermediate (D2)

Step Four: Synthesis of Intermediate (C2)

Step Five: Synthesis of Intermediate (B2)

Step Six: Synthesis of the Compound Represented by Formula (III)

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(1) 1-Cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

EXAMPLE 17

2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

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Medical uses

References

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References

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Example 1

Preparation of (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Formula II)

(1) Preparation of 5-bromo-2-chlorobenzoyl chloride

(2) Preparation of (5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone

(3) Preparation of 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene

(4) Preparation of 4-(5-bromo-2-chlorobenzyl)phenol

(5) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol

(6) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl methanesulfonate

(7) Preparation of (1R,3s,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenyloxy)bicyclo[3.1.0]hexane

(8) Preparation of (3R,4S,5R,6R)-3,4,5-tri((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one

(9) Preparation of (3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

(10) Preparation of (3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(11) Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

(12) Preparation of (2S,3R,4R,5 S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

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