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Myself, NIPER-G and NDTL Collaborate to Synthesize ‘Methandienone LTM’ for Global Anti-Doping Efforts
A proud moment for me [ ANTHONY MELVIN CRASTO ] as Scientific Advisor at Niper-G Dept Pharma Ministry of Chemicals and Fertilizers Govt of India 
Congrats team Niper-G and team National Dope Testing Lab Govt of India Prof. (Dr.) P. L. Sahu and Myself being a part of it as Scientific Advisor Niper-G for few years in Medicinal chem dept. Launched by Union minister Mansukh Mandaviya on 4th sept 2025 in Delhi
will be distributed across the world via World Anti-Doping agency WADA
Methandienone LTM is high purity rare reference material
Hope my interactions and guidance has given fruitful results. Thanks to Dr Murty for appointing me as advisor. Methandienone LTM will make India proud across the World 
A great achievement for India as nation and advanced capability demonstration
https://www.pib.gov.in/PressReleasePage.aspx?PRID=2163812
India Develops Rare Reference Material for Enhanced Anti-Doping Testing in Sports
NIPER Guwahati and NDTL Collaborate to Synthesize ‘Methandienone Long-Term Metabolite’ for Global Anti-Doping Efforts
//////////NIPER-G, NDTL, Methandienone LTM, Global Anti-Doping, INDIA
Sergliflozin Etabonate
Sergliflozin Etabonate
408504-26-7 Cas no
Ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[2-[(4-methoxyphenyl)methyl]phenoxy]oxan-2-yl]methyl carbonate
2-(4-methoxybenzyl)phenyl 6-O-ethoxycarbonyl-beta-D-glucopyranoside
ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[2-[(4-methoxyphenyl)methyl]phenoxy]tetrahydropyran-2-yl]methyl carbonate
ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-{2-[(4-methoxyphenyl)methyl]phenoxy}oxan-2-yl]methyl carbonate
PHASE 2……….TYPE 3 DIABETES AND OBESITY
A SGLT-2 inhibitor potentially for the treatment of type 2 diabetes and obesity.
GW-869682; GW-869682X; KGT-1251
- etabonate de sergliflozine
- etabonato de sergliflozina
MW 448.4, C23H28O9
KISSEI INNOVATOR
GSK DEVELOPER
Sergliflozin Etabonate is a benzylphenol glucoside and selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor with antihyperglycemic activity. Its prodrug form, sergliflozin etabonate, is orally available and is converted to sergiflozin upon absorption.
Sergliflozin etabonate (INN/USAN,[1][2] codenamed GW869682X) is an investigational anti-diabetic drug being developed by GlaxoSmithKline. It did not undergo further development after phase II
Sergliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine.[3][4]
Chemistry
Etabonate refers to the ethyl carbonate group. The remaining structure, which is the active substance, is called sergliflozin.
Sergliflozin
[PDF] Design, Syntheses, and SAR Studies of Carbocyclic Analogues of …onlinelibrary.wiley.com974 × 740Search by imageDesign, Syntheses, and SAR Studies of Carbocyclic Analogues of Sergliflozin as Potent SodiumDependent Glucose Cotransporter 2 In
Sergliflozin Etabonate is a benzylphenol glucoside and selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor with antihyperglycemic activity. Its prodrug form, sergliflozin etabonate, is orally available and is converted to sergiflozin upon absorption.
sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.
The compounds are described in EP 1 329 456 A1 and a crystalline form ofSergliflozin etabonate is described in EP 1 489 089 A1.
PATENT
US6872706B2
https://patentscope.wipo.int/search/en/detail.jsf?docId=US40677423&_cid=P20-MF4ZUQ-42384-1
PATENT
WO2001068660A1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001068660&_cid=P20-MF4ZXC-45172-1
SYN
Heterocycles 2016, 92, 1599
Our initial synthetic route of Serglifrozin etabonate (1) in early development consisted of six steps,
including synthesis of tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate (9), as shown in Scheme 1
and Scheme 2 The first step is the coupling reaction of phenol (3) and 4-methoxybenzyl chloride (4) in the presence of
lithium hydroxide monohydrate (LiOH·H2O) to provide the aglycon 5 in a 30% yield following
chromatographic purification (Scheme 1). We prepared 9 separately by mono-deacetylation of
penta-O-acetyl-β-D-glucopyranose (7) with N,N-dimethylethylenediamine in THF followed by reaction of
the crude product of 8 with trichloroacetonitrile in the presence of potassium carbonate (K2CO3) in ethyl
acetate (EtOAc) (Scheme 2). Next, we carried out glycosylation of 5 with 9 in the presence of boron
trifluoride diethyl etherate (BF3·OEt2) in EtOAc to produce 6 in a 77% yield. The obtained 6 was
deacetylated with sodium methoxide (NaOMe) in MeOH to produce Serglifrozin (2) in a 73% yield, and
reaction of the isolated 2 with ethyl chloroformate in the presence of 2,6-lutidine in acetone provided 1 in
a 66% yield. The overall yield from 3 was 11%. While this route was capable of supplying small
amounts of 1, it suffered from several disadvantages.
The coupling reaction between 3 and 4 provided the aglycon 5 in low yield (30%); thus, chromatographic
purification was required to obtain highly pure 5. The trichloroimidation reaction of 8 is too hazardous
for large-scale manufacturing, because an excess amount of trichloroacetonitrile, a volatile and highly
toxic reagent, is required to obtain the trichloroacetimidate 9. Furthermore, 9 is too unstable to use
conveniently in large-scale manufacturing. Trichloroacetamide, a sublimation compound, is formed as a
by-product from the glycosylation of 5 with 9. Thus, the vacuum line and the vacuum pump of the
manufacturing equipment would be polluted by trichloroacetamide.
Because of these issues, this synthetic method is unsuitable for large-scale manufacturing. Therefore,
we investigated alternative processes for the preparation of 1, suitable for large-scale manufacturing. An improved synthetic method for 1 was achieved in a five-step procedure without purification of 6
(intermediate), as shown in Scheme 3.
The Friedel-Crafts acylation of anisole (10) with 2-methoxybenzoyl chloride (11) in the presence of
aluminum chloride (AlCl3) at 110 °C provided benzophenone (12), which was selectively demethylated
on the methoxy group at the 2-position. The crude product of 12 was crystallized from MeOH to
provide highly pure 12 in a 78% yield. Hydrogenation of 12 in EtOH with 0.3–0.4 MPa H2 at room
temperature in the presence of 10% Pd/C provided 5. The crude product of 5 was crystallized from
toluene/n-heptane to provide highly pure 5 in an 88% yield.
The key step of the synthesis was the formation of the O-glycosylated product 6. In the initial synthesis,
it was necessary to isolate 6 to remove trichloroacetamide. Consequently, 2 was provided in a 56%
yield from 5. To obtain 6 efficiently without using the trichloroacetimidate (9), we evaluated several
conditions for the direct O-glycosylation of 5 with 7. The results are summarized in Table 1. The
O-glycosylation of 5 with 7 (200 mol%) in the presence of boron trifluoride diethyl etherate (BF3·OEt2;
100 mol%) in dichloromethane (DCM) at room temperature provided the crude product of 6 with a good
yield (80%) and β-selectivity (94/6), and then the deacetylation of the crude product of 6 in the presence
of sodium methoxide (NaOMe) in MeOH proceeded almost quantitatively to provide 2 in a 71% isolated
yield from 5 (run 1). Using this method, it was not necessary to isolate 6 because the excess amount of
7 was converted to glucose and removed to the aqueous layers in the deacetylation step. Use of DCM is
undesirable for large-scale manufacturing because quenching of O-glycosylation with water is highly
exothermic and washing of the DCM layer with water is a complicated procedure. Additionally, it is
strongly desirable to avoid using DCM in a manufacturing process due to environmental issues. For the reasons mentioned above, we attempted to use toluene as an alternative solvent. The O-glycosylation in
the presence of BF3·OEt2 (100 mol%) in toluene at 30 °C did not proceed completely, and the yield of 6
was lower than run 1 (run 2). We concluded that the lower solubility of 7 in toluene, compared with
DCM, caused the low yield. Because it was difficult to increase the amount of toluene from the
perspective of manufacturing efficiency, we tried to improve its solubility by optimizing the reagent
equivalent. Fortunately, we found that an excess amount of BF3·OEt2 enhanced the solubility of 7 in
toluene, and using 300 mol% of BF3·OEt2 in toluene provided 6 in a good yield (80%), similar to that
when using DCM (run 3). In contrast, reducing the amount of 7 provided 6 in an insufficient yield, and
2 was consequently provided in a lower yield (60%) (run 4). To achieve higher β-selectivity and an
increased yield, triethylamine (Et3N) was added to the O-glycosylation of 5 with 7 in the presence of
BF3·OEt2, according to the method of Lee et al.
9 Addition of Et3N (30 mol%) at 30 °C resulted in both
higher yield (89%) and higher β-selectivity (97/3) to provide 2 with a 79% isolated yield (run 5).
Increasing the amount of Et3N to 60 mol% at 30 °C resulted in a lower yield (85%) of 6 compared with
run 5, and the yield of 2 decreased (74%) (run 6). Increasing the reaction temperature to 40 °C in the
presence of 60 mol% of Et3N achieved the best results for both high yield (90%) and high β-selectivity
(99/1) to provide 2 in an 80% yield (run 7).
6-O-Ethoxycarbonyl-2-[(4-methoxyphenyl)methyl]phenyl-β-D-glucopyranoside (1). Ethyl
chloroformate (407 mg, 3.75 mol) was added drop-wise to the mixture of 2 (1.13 g, 3.0 mmol) and
2,6-lutidine (563 mg, 5.25 mmol) in acetone (4 mL) while maintaining the temperature between 12 and
18 °C. The reaction mixture was stirred at 15 °C for 23 h. Water (5 mL) was added drop-wise while
maintaining the temperature below 30 °C, and EtOAc (10 mL) was then added to the mixture. The
biphasic solution was transferred to a separating funnel for phase separation. The aqueous layer was
extracted with EtOAc (5 mL). The EtOAc layers were combined, washed successively with an aqueous
solution of 10% citric acid (5 mL × 2), an aqueous solution of 10% NaCl (5 mL), an aqueous solution of
5% NaHCO3 (5 mL × 2), and an aqueous solution of 10% NaCl (5 mL). They were then dried over
Na2SO4 and the filtrate was concentrated under reduced pressure. EtOH was added to the residue, and
the weight was adjusted to 7.2 g. The mixture was heated to 65 °C to dissolve solids. The solution was
cooled to 55 °C and seeded with 1. The solution was aged for 1 h at 50 °C, during which time the
product began to crystallize. After the slurry was cooled to 25 °C, n-heptane (11 mL) was added
drop-wise to the slurry at 25 °C followed by stirring for 1 h at 25 °C. The slurry was cooled to 3 °C and
then stirred for 2 h at 3 °C. The slurry was filtered, and the wet cake was washed with a mixed solvent
of EtOH (1.5 mL) and n-heptane (3 mL). The precipitate was dried in vacuo at 70 °C to give 888 mg
(66% yield) of 1 as a white solid. [α]
20
D -43.5 (c 1.0, DMSO). IR (KBr) cm-1
: 3495, 1744, 1514, 1488,
1454, 1467, 1411, 1372, 1340, 1266. 1H-NMR (CDCl3) δ: 1.27 (3H, t, J=7.0 Hz), 2.00 (1H, d, J=1.6
Hz), 3.46–3.54 (3H, m), 3.56–3.61 (2H, m), 3.72 (1H, d, J=2.1 Hz), 3.75 (3H, s), 3.82 (1H, d, J=15.5 Hz),
4.03 (1H, d, J=15.5 Hz), 4.11–4.22 (2H, m), 4.42 (2H, d, J=3.8 Hz), 4.69 (1H, d, J=7.4 Hz), 6.79–6.83
(2H, m), 6.97–7.02 (2H, m), 7.04–7.07 (2H, m), 7.15–7.22 (2H, m). 13C-NMR (CDCl3) δ: 14.2 (q), 36.1
(t), 55.4 (q), 64.4 (t), 66.4 (t), 69.6 (d), 73.4 (d), 73.8 (d), 75.7 (d), 100.8 (d), 114.1 (d×2), 114.4 (d), 122.7
(d), 128.0 (d), 129.2 (d×2), 130.0 (s), 131.1 (d), 133.4 (s), 155.2 (s), 155.4 (s), 157.8 (s). HRMS (ESI)
m/z: 466.2070 [M+NH4]
+
(Calcd for C23H32NO9: 466.2072)
6-O-Ethoxycarbonyl-2-[(4-methoxyphenyl)methyl]phenyl-β-D-glucopyranoside (1). Ethyl
chloroformate (21.6 g, 0.199 mol) was added drop-wise to the mixture of 2 (65.0 g, 0.173 mol),
2,6-lutidine (27.8 g, 0.259 mol) and pyridine (0.33 g, 4.2 mmol) in acetone (210 mL), maintaining the
temperature between -1 and 5 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was
monitored by HPLC.15 Water (200 mL) was added drop-wise, maintaining the temperature below 30 °C,
and then EtOAc (220 mL) was added to the mixture. The biphasic solution was transferred to a
separating funnel for phase separation. The aqueous layer was extracted with EtOAc (140 mL). The
EtOAc layers were combined, washed successively with an aqueous solution of 10% citric acid (180 mL
× 2), an aqueous solution of 10% NaCl (66 g), an aqueous solution of 5% NaHCO3 (65 g × 2), and an aqueous solution of 10% NaCl (100 g), and then dried over Na2SO4 (65 g). After acetic acid (10 g,
0.167 mol) was added to the filtrate, the mixture was concentrated under reduced pressure. The residue
was dissolved in EtOH (660 mL) at 65 °C. The solution was concentrated under reduced pressure until
more than 330 mL distillate had been collected. EtOH was added to the residue, and the weight was
adjusted to 370 g. n-Heptane (120 mL) was added, and the resulting slurry was heated to 65 °C to
dissolve solids. The solution was cooled to 55 °C and seeded with 1. The solution was aged for 1 h at
50 °C, during which time the product began to crystallize. n-Heptane (480 mL) was added drop-wise to
the slurry, maintaining the temperature between 50 and 60 °C, and the slurry was stirred for 0.5 h at 55 °C.
The slurry was allowed to cool slowly over 2.5 h to 30 °C, then cooled to 3 °C, and then stirred for 1.5 h
at 3 °C. The slurry was filtered, and the wet cake was washed with a mixed solvent of EtOH (80 mL)
and n-heptane (180 mL). The precipitate was dried in vacuo at 70 °C to give 63.6 g (82% yield) of 1 as
a white solid.
REFERENCES (AND NOTES)
- W. N. Washburn, Expert Opin. Ther. Patents, 2009, 19, 1485.
- A. M. Pajor and E. M. Wright, J. Biol. Chem., 1992, 267, 3557.
- E. M. Wright, Am. J. Physiol. Renal Physiol., 2001, 280, F10.
- Y. Kanai, W. S. Lee, G. You, D. Brown, and M. A. Hediger, J. Clin. Invest., 1994, 93, 397.
- H. Fujikura, N. Fushimi, T. Nishimura, K. Tatani, and M. Isaji, PCT, WO 02/28872 (2002).
- H. Fujikura, N. Fushimi, T. Nishimura, K. Tatani, K. Katsuno, M. Hiratochi, Y. Tokutake, and M.
Isaji, PCT, WO 01/688660 (2001). - K. Katsuno, Y. Fujimori, Y. Takemura, M. Hiratochi, F. Itoh, Y. Komatsu, H. Fujikura, and M. Isaji,
J. Pharmacol. Exp. Ther., 2007, 320, 323. - M. Isaji, Curr. Opin. Investig. Drugs, 2007, 8, 285.
- S. Y. Lee, S. E. Rho, K. Y. Min, T. B. Kim, and H. K. Kim, J. Carbohydr. Chem., 2001, 20, 503.
- M. Yamaguchi, A. Horiguchi, A. Fukuda, and T. Minami, J. Chem. Soc., Perkin Trans. 1, 1990,
1079. - K. Ishihara, H. Kurihara, and H. Yamamoto, J. Org. Chem., 1993, 58, 3791.
- I. T. Akimova, A. V. Kaminsky, and V. I. Svistunova, Chem. Heterocycl. Compd., 2005, 41, 1374.
- B. N. Cook, S. Bhakta, T. Biegel, K. G. Bowman, J. I. Armstrong, S. Hemmerich, and C. R. Bertozzi,
J. Am. Chem. Soc., 2000, 122, 8612. - HPLC conditions: column, Inertsil ODS-3 (5 µm) 4.6 mm × 250 mm (GL Science Inc.); mobile
phase, isocratic elution with acetonitrile / 0.02 M KH2PO4, pH 3 = 6/4; flow rate, 1.0 mL/min;
column oven temperature, 40 °C; wave length, 225 nm; retention times, 5 = 16 min, α-anomer of 5 =18 min. - HPLC conditions: column, Inertsil ODS-3 (5 µm) 4.6 mm × 250 mm (GL Science Inc.); mobile
phase, gradient elution with 5 min 4/6 → 15 min 6/4 → 30 min 6/4 of acetonitrile/0.02 M KH2PO4,
pH 3; flow rate, 1.0 mL/min; column oven temperature, 40 °C; wavelength, 225 nm; retention times,
1 = 17 min, 2,6- and 4,6-bis-O-ethoxycarbonyl derivatives = 24 min, 3,6-bis-O-ethoxycarbonyl
derivative = 25 min.
SYN
Synthesis 2024, 56, 906–943
Sergliflozin etabonate (16), also known as GW869682X, was developed collaboratively by GlaxoSmithKline and Kissei Pharmaceutical (Japan). Unfortunately, it did not pass phase III trials. It belongs to the class of sodium–glucose linked transporter 2 (SGLT2) inhibitors and acts as a prodrug of sergliflozin, with the ethyl carbonate group referred to as etabonate. When compared to phlorizin, sergliflozin etabonate demonstrated significantly higher activity against SGLT2 than SGLT1. The initial synthetic route for the preparation of sergliflozin was described and patented by Kissei Pharmaceutical Co., Ltd. This particular route for Oaryl-glycoside-type derivatives was registered in the United States under patent application number US6872706B2.73 The first reported synthesis of sergliflozin etabonate
(16), which involves six steps, can be found in the patents US6872706B2 73a and WO2001068660A1 (Scheme 48).73b Compound 271 was prepared in a high yield of 96% follow ing a literature procedure. The selective monodeacetylationof penta-O-acetyl-b-D-glucopyranose, compound 269, was
achieved using N,N-dimethylethylenediamine in THF, resulting in the formation of compound 270. Subsequently, a reaction with trichloroacetonitrile and potassium carbonate led to the synthesis of intermediate 271 in excellent yield. To prepare the aglycone intermediate 268, phenol (235) was condensed with 4-methoxybenzyl chloride (267) using LiOH under reflux conditions. Further,O-glycosyla
tion of compound 268 with 271 was accomplished using boron trifluoride–diethyl etherate (BF3·OEt2), yielding intermediate 272. Removal of the acetyl groups from intermediate 272 was carried out using NaOMe in methanol to obtain sergliflozin (16a) in a yield of 73%. Finally, sergliflozin etabonate (16) was obtained by reacting compound 16a with ethyl chloroformate and 2,6-lutidine, resulting in a yield of
66%. The overall yield of sergliflozin etabonate (16a) was calculated to be 11%. It is important to note that the trichloroimidation reaction used in the synthesis of trichloroacetimidate 271 is considered hazardous and is not recommended for commercial use due to the highly toxic reagent, trichloroaceto
nitrile. Additionally, the process poses challenges in effectively removing the unwanted by-product, trichloroacetamide, formed during the preparation.A recently published approach presents an alternative synthesis of sergliflozin etabonate (16) that avoids the use of a trichloroacetimidate intermediate (Scheme 49).74a The five-step synthesis of compound 16a commenced from
readily available anisole (273a). An efficient Friedel–Crafts reaction was performed on anisole (273a) using the acid chloride 273 in the presence of aluminum chloride in chlorobenzene, leading to formation of benzophenone 274. Notably, demethylation of 274 was also observed under these
conditions. Next, ketone group reduction was achieved us ing 10% Pd/C and ethanol under 0.3–0.4 MPa of H2, providing compound 268 in 88% yield and high purity. Subsequently, O-glycosylation of 268 with penta-acetylated com pound 269 was carried out using BF3·Et2O and triethylamine, resulting in the formation of 272 in 90% yield with a high b-selectivity (99:1).74b Deacetylation of compound 272 was performed using NaOMe in methanol, affording sergliflozin (16a) in 80% yield. Further reaction with
ethyl chloroformate in the presence of 2,6-lutidine resulted in sergliflozin etabonate (16). The overall yield of compound 16 was calculated to be 41%. This novel synthetic route offers a promising alternative to the traditional method and demonstrates improved efficiency in the preparation of sergliflozin etabonate (16)
(73) (a) Fujikura, H.; Fushimi, N. US6872706B2, 2005. (b) Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K.; Hiratochi, M.; Tokutake, Y.; Isaji, M. WO2001068660A1, 2001.
(74) (a) Kobayashi, M.; Isawa, H.; Sonehara, J.; Kubota, M. Heterocycles 2016, 92, 1599. (b) Lee, Y. S.; Rho, S. E.; Min, K. Y.; Kim, T. B.; Kim, H. K. J. Carbohydr. Chem. 2001, 20, 503.
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| Progression Inhibitor For Disease Attributed To Abnormal Accumulation Of Liver Fat [US2008045466] | 2008-02-21 | |
| NOVEL SUBSTITUTED TETRAHYDRONAPHTHALENES, PROCESS FOR THE PREPARATION THEREOF AND THE USE THEREOF AS MEDICAMENTS [US2010249097] | 2010-09-30 | |
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| Systematic (IUPAC) name | |
|---|---|
| 2-(4-methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside | |
| Clinical data | |
| Routes of administration | Oral |
| Identifiers | |
| CAS Number | 408504-26-7 |
| ATC code | None |
| PubChem | CID: 9824918 |
| IUPHAR/BPS | 4587 |
| ChemSpider | 21234810 |
| ChEMBL | CHEMBL450044 |
| Chemical data | |
| Formula | C23H28O9 |
| Molecular mass | 448.463 g/mol |
References
- World Health Organization (2008). “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 59” (PDF). WHO Drug Information. 22 (1): 66. Archived from the original (PDF) on February 19, 2009.
- “Statement on a nonproprietary name adopted by the USAN council: Sergliflozin etabonate” (PDF). American Medical Association. Retrieved 2008-08-10.
- Katsuno K, Fujimori Y, Takemura Y, et al. (January 2007). “Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level”. J Pharmacol Exp Ther. 320 (1): 323–30. doi:10.1124/jpet.106.110296. PMID 17050778. S2CID 8306408.
- “Prous Science: Molecule of the Month November 2007”. Archived from the original on 2007-11-05. Retrieved 2008-10-28.
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////////// etabonate, Sergliflozin etabonate, Sergliflozin, PHASE 3, GW869682X, GSK, KISSEI, GW-869682; GW-869682X; KGT-1251
CCOC(=O)OCC1C(C(C(C(O1)OC2=CC=CC=C2CC3=CC=C(C=C3)OC)O)O)O
CCOC(=O)OCC1C(C(C(C(O1)Oc2ccccc2Cc3ccc(cc3)OC)O)O)O
Donidalorsen
Donidalorsen
CAS 2304692-48-4
| 분자량 Mw | 8672.64 |
|---|---|
| 화학식Mf | C296H435N83O151P20S15 |
ISIS 721744, ISIS-721744
FDA 8/21/2025, Dawnzera, To prevent attacks of hereditary angioedema
DNA, D((2′-O-(2-METHOXYETHYL))M5RU-SP-(2′-O-(2-METHOXYETHYL))RG-SP-(2′-O-(2-METHOXYETHYL))M5RC-(2′-O-(2-METHOXYETHYL))RA-(2′-O-(2-METHOXYETHYL))RA-SP-G-SP-T-SP-M5C-SP-T-SP-M5C-SP-T-SP-T-SP-G-SP-G-SP-M5C-SP-(2′-O-(2-METHOXYETHYL))RA-(2′-O-(2-METHOXYETHYL)
- WHO 11653
- DNA, d((2′-O-(2-methoxyethyl))m5rU-sp-(2′-O-(2-methoxyethyl)(rG-sp-(2′-O-(2- methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxyethyl))rA-spG-sp-T-sp-m5C-sp-T-sp-m5C-sp-T-sp-T-sp-G-sp-G-sp-m5C-sp-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxyethyl))rA-sp-(2′-O-(2-methoxyethyl))m5rC-sp-(2′-O-(2-methoxyethyl))rA), 5′-(26-((2-(acetylamino)-2-deoxy-beta-D-galactopyranosyl)oxy)-14,14-bis((3-((6-((2-(acetylamino)-2-deoxybeta-D-galactopyranosyl)oxy)hexyl)amino)-3-oxopropoxy)methyl)-8,12,19-trioxo16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate)
- UNII-ZD4D8M32TL
| Ingredient | UNII | CAS | . |
|---|---|---|---|
| Donidalorsen sodium | Y30VEG5PH1 | 2304701-45-7 |
Donidalorsen, sold under the brand name Dawnzera, is a medication used to prevent attacks of hereditary angioedema.[1] Donidalorsen is a prekallikrein-directed antisense oligonucleotide.[1] It is given by injection under the skin (subcutaneous).[1]
Donidalorsen was approved for medical use in the United States in August 2025.[2]
Donidalorsen is under investigation in clinical trial NCT05392114 to assess the long-term safety and efficacy of donidalorsen in the prophylactic treatment of hereditary angioedema (HAE)
Donidalorsen is an antisense oligonucleotide designed to reduce the production of prekallikrein (PKK). PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of Hereditary angioedema (HAE).
AWNZERA™ (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema
August 21, 2025
– DAWNZERA demonstrated significant and sustained HAE attack rate reduction and long-term disease control –
– Offers longest dosing option for HAE, with dosing every 4 or 8 weeks –
– Compelling profile supported by recently published switch data –
– Ionis’ second independent launch in just nine months, with potential for two additional launches next year –
– Ionis to host webcast today at 12:15pm ET –
CARLSBAD, Calif.–(BUSINESS WIRE)–Aug. 21, 2025– Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) announced today that the U.S. Food and Drug Administration (FDA) has approved DAWNZERA™ (donidalorsen) for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. DAWNZERA is the first and only RNA-targeted medicine approved for HAE, designed to target plasma prekallikrein (PKK), a key protein that activates inflammatory mediators associated with acute attacks of HAE. DAWNZERA 80mg is self-administered via subcutaneous autoinjector once every four (Q4W) or eight weeks (Q8W).
This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20250818615141/en/
DAWNZERA (donidalorsen) logo
HAE is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face and/or throat. HAE is estimated to affect approximately 7,000 people in the U.S.
“DAWNZERA represents a significant advance for people living with HAE who need improved treatment options. With strong and durable efficacy, convenient administration and the longest dosing option available, we believe DAWNZERA will be the prophylactic treatment of choice for many people living with HAE. Importantly, the recently published switch data empowers patients and physicians with a roadmap for switching to DAWNZERA from other prophylactic therapies,” said Brett P. Monia, Ph.D., chief executive officer, Ionis. “At Ionis, we are dedicated to turning groundbreaking science into life-changing medicines. With the early success of our first independent launch of TRYNGOLZA® for familial chylomicronemia syndrome (FCS), and now with DAWNZERA, our second independent medicine approved in less than nine months, we are proudly delivering on that vision. To the patients, families, advocacy partners and investigators who helped make this moment a reality, we express our deepest gratitude.”
The approval of DAWNZERA was based on positive results from the Phase 3 global, multicenter, randomized, double-blind, placebo-controlled OASIS-HAE study in patients with HAE. The study met its primary endpoint, with DAWNZERA Q4W significantly reducing monthly HAE attack rate by 81% compared to placebo over 24 weeks. Mean attack rate reduction increased to 87% when measured from the second dose, a key secondary endpoint. Additionally, DAWNZERA Q4W reduced moderate-to-severe HAE attacks by ~90% over 24 weeks when measured from the second dose.
These results are bolstered by the ongoing OASISplus open-label extension (OLE) study, in which DAWNZERA Q8W had a similar effect as Q4W over time. DAWNZERA demonstrated 94% total mean attack rate reduction from baseline across both dosing groups after one year in the OLE.
The OASISplus study also includes a switch cohort evaluating DAWNZERA Q4W in patients previously treated with lanadelumab, C1-esterase inhibitor or berotralstat for at least 12 weeks. Switching to DAWNZERA reduced mean HAE attack rate by 62% from prior prophylactic treatment over 16 weeks, with no mean increase in breakthrough attacks observed during the switch. A total of 84% of patients surveyed preferred DAWNZERA over their prior prophylactic treatment, citing better disease control, less time to administer and less injection site pain or reactions.
Across clinical studies, DAWNZERA demonstrated a favorable safety and tolerability profile. The most common adverse reactions (incidence ≥ 5%) were injection site reactions, upper respiratory tract infection, urinary tract infection and abdominal discomfort.
“As the first FDA-approved RNA-targeted therapy for HAE, DAWNZERA represents a welcome advance in therapeutic options for preventing attacks. Today’s approval gives people living with HAE and their physicians another important choice for aligning treatment with individual needs,” said Anthony J. Castaldo, CEO & chairman of the board, U.S. Hereditary Angioedema Association (HAEA) and Hereditary Angioedema International (HAEi).
“People living with HAE manage this condition for all their lives, and many continue to face unpredictable, painful and dangerous breakthrough attacks even with current treatments. Durable efficacy is essential in maintaining long-term disease control,” said Marc Riedl, M.D., M.S., clinical director, U.S. HAEA Angioedema Center; University of California, San Diego; OASIS-HAE and OASISplus trial investigator. “DAWNZERA is positioned to help meet patient needs, providing substantial and sustained reduction of HAE attacks, continued improvement over time and reduced burden of treatment.”
DAWNZERA will be available in the U.S. in the coming days.
Ionis is committed to helping people access the medicines they are prescribed and will offer a suite of services designed to meet the unique needs of the HAE community through Ionis Every Step™. As part of Ionis Every Step, patients and healthcare providers will have access to a wide range of support and resources including dedicated support from a Patient Education Manager, assistance with the insurance approval process, information on affordability programs, access to the DAWNZERA Direct digital companion and other ongoing services and resources to help patients stay on track. Visit DAWNZERA.com for more information.
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References
- “DAWNZERA (donidalorsen) injection, for subcutaneous use” (PDF). Highlights of Prescribing Information. Ionis Pharmaceuticals, Inc.
- “Dawnzera (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema” (Press release). Ionis Pharmaceuticals, Inc. 21 August 2025. Retrieved 22 August 2025 – via Business Wire.
- “Donidalorsen: An Investigational RNA-targeted Medicine” (PDF). Ionis Pharmaceuticals, Inc.
- Farkas H, Balla Z (March 2024). “Kallikrein inhibitors for angioedema: the progress of preclinical and early phase studies”. Expert Opinion on Investigational Drugs. 33 (3): 191–200. doi:10.1080/13543784.2024.2320700. PMID 38366937.
- “Dawnzera: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 22 August 2025.
- World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
Further reading
- Raja A, Shuja MH, Raja S, Qammar A, Kumar S, Khurram L, et al. (December 2024). “Efficacy and safety of Donidalorsen in Hereditary Angioedema with C1 inhibitor deficiency: a systematic review and a meta analysis”. Archives of Dermatological Research. 317 (1): 110. doi:10.1007/s00403-024-03652-3. PMID 39666085.
External links
- Clinical trial number NCT05139810 for “OASIS-HAE: A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants With Hereditary Angioedema (HAE)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Dawnzera |
| Other names | ISIS 721744, ISIS-721744 |
| AHFS/Drugs.com | Dawnzera |
| License data | US DailyMed: Donidalorsen |
| Routes of administration | Subcutaneous |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 2304692-48-42304701-45-7 |
| DrugBank | DB18751DBSALT003520 |
| UNII | ZD4D8M32TLY30VEG5PH1 |
- [1]. Fijen LM, Riedl MA, Bordone L, et al. Inhibition of Prekallikrein for Hereditary Angioedema. N Engl J Med. 2022;386(11):1026-1033. [Content Brief][2]. Valerieva A, Longhurst HJ. Treatment of hereditary angioedema-single or multiple pathways to the rescue. Front Allergy. 2022;3:952233. [Content Brief]
//////////Donidalorsen, FDA 2025, APPROVALS 2025, Dawnzera, ISIS-721744 FREE ACID, ISIS 721744
Baxdrostat
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
- (+)-(R)-N-(4-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide
- N-((8R)-5,6,7,8-Tetrahydro-4-(1,2,3,4-tetrahydro-1-methyl-2-oxo-6-quinolinyl)-8-isoquinolinyl)propanamide
- N-[(8R)-4-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide
- Propanamide, N-((8R)-5,6,7,8-tetrahydro-4-(1,2,3,4-tetrahydro-1-methyl-2-oxo-6-quinolinyl)-8-isoquinolinyl)-
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
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)Cl 2 (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 (SiO 2 ) 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)Cl 2 (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 (SiO 2 ) 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)Cl 2 (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 (SiO 2 ) 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
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 |
Example 2.1
Example 2.2
Example 2.3
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
Pradefovir
WeightAverage: 423.79
Monoisotopic: 423.0863188
Chemical FormulaC17H19ClN5O4P
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
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, N 2 Stir 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 N 2 Stir 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, N 2 Stir 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-NH 2 Preparation |
| (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), H 2 A mixed solution of O (10 ml) and TIS (10 ml) was introduced into 2 , 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-NH 2 , sealed and stored at -20℃. |
| 5: Linear crude peptide Mpr-X-Gly-Asp-Trp-Pro-Cys-NH 2 Cyclization |
| The crude linear peptide of batifiban and its analogues obtained in Example 4 was dissolved in water, and 1 mmol/ml of I 2 The 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-NH 2 (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
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
- (9R)-N-((1S,4S)-4-Ethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-9-(2-pyridinyl)-6-oxaspiro(4.5)decane-9-ethanamine
- (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
- (1S,4S)-4-Ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro(4.5)decane-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
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017063509&_cid=P20-METU6J-22458-1
[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).
[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).
[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
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)
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)
SYN
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.
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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
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
- 2-((4-CYCLOPROPYLPHENYL)METHYL)-4-.BETA.-D-GLUCOPYRANOSYLBENZONITRILE
- BENZONITRILE, 2-((4-CYCLOPROPYLPHENYL)METHYL)-4-.BETA.-D-GLUCOPYRANOSYL-
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
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
EXAMPLE 17
2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile
| The compound is obtained according to example 6 using 4-cyclopropyl-phenylboronic acid as the coupling partner. |
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 | FV2YU8SL0PEQE2P2T77I |
| 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
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
(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-α]pyrazine derivatives, preparation process and medicinal use thereofPublication Number: US-8207161-B2Priority Date: 2007-12-26Grant Date: 2012-06-26
SYN
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
5
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,
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
