Velagliflozin
- 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 | |
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- 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,