BENZGALANTAMINE

CAS 224169-27-1

Benzgalantamine gluconate, 1542321-58-3

• 6H-Benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, benzoate (ester), (4aS,6R,8aS)- (9CI)
• Alpha 1062
• GLN 1062
• Memogain

6h-benzofuro(3a,3,2-ef)(2)benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, benzoate (ester), (4as,6r,8as)-

Formula	C24H25NO4
Molar mass	391.467 g·mol−1

External IDs GLN-1062 gluconate

UNIILN7PMJ4P57

CAS Number1542321-58-3

WeightAverage: 587.622
Monoisotopic: 587.236661015

Chemical FormulaC₃₀H₃₇NO₁₁

Benzgalantamine, sold under the brand name Zunveyl, is a medication used for the treatment of mild to moderate dementia of the Alzheimer’s type.^[1] It is a cholinesterase inhibitor.^[1] Benzgalantamine is a prodrug of galantamine.^[1]

The most common side effects include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.^[1]

Benzgalantamine was approved for medical use in the United States in July 2024.^[1][2][3]

compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and to their agonists, of neuronal cholinergic receptors, and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g., Galantamine, Narwedine and Lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as “pro-drugs”, in the sense that after reaching their target regions in the body, they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this disclosure may be used as medicaments for the treatment of human brain diseases associated with a cholinergic deficit, including the neurodegenerative diseases Alzheimer’s and Parkinson’s disease and the neurological/psychiatric diseases vascular dementia, schizophrenia and epilepsy. Galantamine derivatives disclosed herein have higher efficacy and lower levels of adverse side effects in comparison to galantamine, in treatment of human brain diseases.

Benzgalantamine is a prodrug of galantamine. Gastrointestinal adverse effects are the most frequently reported side effects in patients undergoing treatment with cholinesterase inhibitors, including galantamine, and are often a reason for treatment discontinuation.² As a prodrug, benzagalantamine remains inert as it passes through the stomach, thereby avoiding many of the gastrointestinal effects associated with peripheral cholinesterase inhibition.⁴

Benzgalantamine was approved by the FDA in July 2024 for the treatment of mild-to-moderate dementia in Alzheimer’s patients.^3,4

SCHEME

US20090253654

https://patentscope.wipo.int/search/en/detail.jsf?docId=US42863485&_cid=P12-M8ZQT3-74791-1

O-Benzoyl-galantamine(=(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, benzoate (ester)); yield: 78%

O-3,4-Dichlorobenzoyl-galantamine(=(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 3,4-dichlorobenzoate (ester)); off-white solid; mp. 69-70° C.

1H NMR (200 MHz, CDCl 3) δ (ppm) 8.02 (d, J=1.88 Hz, 1H), 7.81 (dd, J=1.88 Hz, J=8.38 Hz, 1H), 7.38 (d, J=8.32 Hz, 1H), 6.62 (d, J=8.18 Hz, 1H), 6.52 (d, J=8.18 Hz, 1H), 6.32 (d, J=10.34 Hz, 1H), 5.89-5.97 (m, 1H), 5.51 (t, J=4.43 Hz, 1H), 4.58 (s, 1H), 4.07 (d, J=15.16 Hz, 1H), 3.18 (s, 3H), 3.61 (d, J=15.16 Hz, 1H), 3.21-3.45 (m, 1H), 2.96-3.05 (m, 1H), 2.66-2.76 (m, 1H), 2.34 (s, 3H), 2.0-2.19 (m, 2H), 1.51-1.59 (m, 1H).

WO2009127218

US20220220121

https://patentscope.wipo.int/search/en/detail.jsf?docId=US368470159&_cid=P12-M8ZR8V-88578-1

Experiment 1

The Alpha-1062 gluconate (CA19-0673) was re-slurried in MEK/H2O at 20° C. 5.6 g of Alpha-1062 gluconate was used in 19.3 g MEK+1.9 g H2O. The slurry was stirred for 30 min before washing of the filter cake with 4.1 g MEK, re-filtration and drying.

The reaction mixture was yellow to orange. The suspension was initially relatively thin, then became thicker upon longer stirring. After 30 min a very thick paste-like suspension was obtained that was difficult to stir and transfer to filter. The suspension was deemed too thick and therefore unsuitable for production. The isolated material was slightly yellowish (white to pale yellow).

AND

US20090253654

Medical uses

Benzgalantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type in adults.^[1][2]

Side effects

The most common side effects include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.^[1]

Society and culture

Legal status

Benzgalantamine was approved for medical use in the United States in July 2024.^[1][2]

Names

Benzgalantamine is the international nonproprietary name.^[4]

References

1. ^ Jump up to:^{a b c d e f g h i} “Zunveyl- benzgalantamine tablet, delayed release”. DailyMed. 8 August 2024. Retrieved 15 August 2024.
2. ^ Jump up to:^a b c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/218549Orig1s000ltr.pdf
3. ^ “Alpha Cognition’s Oral Therapy Zunveyl Receives FDA Approval to Treat Alzheimer’s Disease” (Press release). Alpha Cognition. 29 July 2024. Archived from the original on 4 August 2024. Retrieved 4 August 2024 – via Business Wire.
4. ^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

1. Baakman AC, ‘t Hart E, Kay DG, Stevens J, Klaassen ES, Maelicke A, Groeneveld GJ: First in human study with a prodrug of galantamine: Improved benefit-risk ratio? Alzheimers Dement (N Y). 2016 Jan 20;2(1):13-22. doi: 10.1016/j.trci.2015.12.003. eCollection 2016 Jan. [Article]
2. Bakker C, van der Aart J, Hart EP, Klaassen ES, Bergmann KR, van Esdonk MJ, Kay DG, Groeneveld GJ: Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine. Alzheimers Dement (N Y). 2020 Oct 13;6(1):e12093. doi: 10.1002/trc2.12093. eCollection 2020. [Article]
3. FDA Approved Drug Products: Zunveyl (benzgalantamine) delayed-release tablets for oral use [Link]
4. Fierce Pharma: Alpha Cognition’s delayed-release Alzheimer’s drug Zunveyl passes muster with FDA [Link]
5. Alpha Cognition: Corporate Presentation Oct 2024 [Link]

External links

• “Benzgalantamine (Code C188656)”. NCI Thesaurus.

Clinical data
Trade names	Zunveyl
Other names	ALPHA-1062
AHFS/Drugs.com	Zunveyl
License data	US DailyMed: Benzgalantamine
Routes of administration	By mouth
Drug class	Cholinesterase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only[1]
Identifiers
CAS Number	224169-27-11542321-58-3
DrugBank	DB19353
UNII	XOI2Q0ZF7GLN7PMJ4P57
KEGG	D12930D12931
ChEMBL	ChEMBL5095056
Chemical and physical data
Formula	C24H25NO4
Molar mass	391.467 g·mol−1
3D model (JSmol)	Interactive image
showSMILES

//////////BENZGALANTAMINE, Alpha 1062, GLN 1062, Memogain, FDA 2024, APPROVALS 2024, Zunveyl