DIMDAZENIL

CAS 308239-86-3

WeightAverage: 372.81
Monoisotopic: 372.1101515

Chemical FormulaC₁₇H₁₇ClN₆O₂

EVT-201, 308239-86-3, EVT201, 6J8AF7CLE4, EVT 201

7-Chloro-3-[5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a]

[1,4]benzodiazepin-6-one

7-chloro-3-[5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl]-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one

EVT 201 is a novel partial positive allosteric modulator of the GABAA receptor complex which is being developed as a treatment for insomnia. It is being developed by Evotec Inc.

• OriginatorRoche
• DeveloperEvotec SE; Zhejiang Jingxin Pharmaceutical
• ClassBenzodiazepines; Chlorobenzenes; Dimethylamines; Imidazoles; Ketones; Oxadiazoles; Sleep disorder therapies; Small molecules
• Mechanism of ActionGABA A receptor modulators
• RegisteredInsomnia
• 29 Nov 2023Registered for Insomnia in China (PO) – First global approval
• 24 Oct 2023Efficacy and adverse events data from a phase III trial in Insomnia released by Zhejiang Jingxin Pharmaceutical
• 21 Oct 2023Efficacy and adverse events data from a phase II trial in Insomnia released by Zhejiang Jingxin Pharmaceutical

Dimdazenil, sold under the brand name Junoenil, is a medication used in the treatment of insomnia in China.^[1] It is a benzodiazepine derivative and a partial positive allosteric modulator of the GABA_A receptor^[2] with two- to four-fold higher functional affinity for the α₁ subunit relative to the α₂, α₃, and α₅ subunits.

Medical use

Dimdazenil shows effectiveness in the treatment of insomnia, but has less intrinsic activity in comparison to currently-marketed benzodiazepines and the Z-drugs;^[3] however, it is thought that the lower efficacy may result in fewer side effects, such as motor incoordination.^[3] In China, dimdazenil is approved for short-term treatment of insomnia.^[4]

History

Dimdazenil was originally developed by Roche, based on preclinical data, as a non-sedating anxiolytic, but was found to produce sedation in humans in phase I clinical trials. For this reason, it was subsequently licensed to Evotec, which is now developing it for the treatment of insomnia.^[3] By 2007, dimdazenil completed phase II clinical trials for this indication, with positive findings reported.^[5] In China, the drug was developed by Zhejiang Jingxin Pharmaceutical.

SCHEME

PATENT

CN111620834

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN306317338&_cid=P10-MAWAJX-84923-1

PATENT

WO2000069858

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2000069858&_cid=P10-MAWAOS-90001-1

EXAMPLE

a) 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione (III).

25.0 g 6-chloro-isatoic anhydride (II) and 12.4 g sarcosine were suspended under stirring and argon atmosphere in 100 ml p-xylene and heated at reflux for two hours. The suspension was cooled to room temperature and further stirred 1 hour, then filtered off. The precipitate was washed with 25 ml p-xylene twice and dried at 50°C under vacuum. The solid so obtained (6-chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5( lH)-dione (II)) was digested in 75 ml deionized water at 0°C for 1 hour, filtered off, washed with 25 ml deionized water and dried under vacuum 18 hours at 80°C. Crude product: 25.2 g as a beige powder, m.p. 230-232°C

b) Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[ l,5-a] [ 1,4] benzodiazepine- 3-carboxylate (V).

25.0 g 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5( lH)-dione (III) were suspended under stirring and argon atmosphere in 200 ml toluene and 32.1 ml N,N-dimethyl-p-toluidine. The suspension was heated to 100°C and 11.2 ml phosphorus oxychloride were added over 30 minutes and stirring was pursued two and an half hours at 100°C. The dark-orange solution was cooled to 40°C and toluene was removed under reduced pressure to give 82 g of a dark-orange oil.

Meanwhile, 81.2 ml hexamethyldisilazane and 265 ml tetrahydrofuran were mixed and cooled to -35°C. 229.5 ml Butyllithium were added over 45 minutes and, after stirring 30 minutes at -35°C, a solution of 35.2 g ethyl(dimethylamino-methylenamino)acetate in 70.4 ml tetrahydrofuran was added over 30 minutes. The orange solution obtained was stirred one more hour at -35°C and a solution of the crude iminochloride in 100 ml
tetrahydrofuran was added over 1 hour at -15°C. The dark red solution was stirred one hour at -15°C, then 18 hours at room temperature (r.t.). 75 ml Acetic acid were added in 10 minutes, then 75 ml deionized water were added in one portion and the orange suspension was heated at reflux for two hours. Tetrahydrofuran was removed under reduced pressure and the residue was partitioned between 200 ml dichloromethane and 100 ml deionized water. The phases were separated and the organic phase was washed with 100 ml aqueous HC1 IN twice and with 100 ml deionized water. The aqueous phases were extracted twice with 100 ml dichloromethane. The combined organic extracts were dried (Na₂S0₄) and evaporated. The residue was digested in 200 ml n-heptane 30 minutes at r.t. and filtered off. The sticky crystals obtained were digested at reflux for 30 minutes in 213.5 ml ethanol, then stirred 3 hours to r.t. and 2 hours at -20°C. The precipitate (ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ l,5-a] [ l,4]benzodiazepine-3-carboxylate (V)) was filtered off, washed three times with 20 ml ethanol and dried under reduced pressure 16 hours at 60°C. Crude product: 23.4 g as a beige powder, m.p. 225.5-226.5 °C c) 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [ 1 ,5-a] [ 1 ,4]benzodiazepine-3- carboxamide (VI).

22.8 g Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ l,5-a] [l,4]- benzodiazepine-3-carboxylate (V)were suspended under stirring and argon atmosphere in 91.2 ml 1 ,4-dioxane. 14.1 ml Formamide and 13.9 ml sodium methanolate were successively added to yield a clear light-orange solution, which turned to a white suspension after 10 minutes. This suspension was stirred two hours at 30°C. 200 ml deionized water were added in one portion and 1,4-dioxane was distilled off at 40°C under reduced pressure. The remaining white suspension was stirred two hours at 0°C and filtered. The precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[ l,5-a] [ l,4]benzodiazepine-3-carboxamide (VI)) was washed with 50 ml deionized water three times and dried under reduced pressure for 18 hours at 80°C. Crude product: 19.43 g as a white powder. m.p.>250°C

d) 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a] [l,4]benzodiazepine-3- carbonitrile (VII).

19.0 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ l,5-a] [ l,4]benzodiazepine-3- carboxamide (VI) were suspended under stirring and argon atmosphere in 95 ml 1,4- dioxane and 6.58 phosphorous oxychloride were added in one portion. The reaction mixture was heated to reflux for one hour giving a yellow solution, which was concentrated at 50°C under reduced pressure. The residue was digested in 100 ml deionized water for two hours at r.t.. The precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5- a] [ l ,4]benzodiazepine-3-carbonitrile (VII)) was filtered off, washed three times with 30 ml deionized water and dried under vacuum at 80°C for 18 hours. Crude product: 17.3 g as a light yellow powder, m.p. 238.5-239.5°C

_ e) 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a] [l,4]benzodiazepine-3- carboxamidoxime (VIII).

16.8 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ l,5-a] [ l,4]benzodiazepine-3- carbonitrile (VIII) were suspended under stirring and argon atmosphere in 101 ml N,N- dimethylformamide and 13.48 g hydroxylamine hydrochloride was added in one portion. 34.2 ml Sodium methanolate were then added over 60 minutes to the yellow suspension, which turned to a colorless suspension. It was stirred one more hour at r.t., then cooled to 0-2°C and 202 ml deionized water were added over 30 minutes. After stirring one more hour at 0°C, the precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[l,5-a] [l,4]benzodiazepine-3-carboxamidoxime (VIII) was filtered off, washed twice with 40 ml deionized water and dried under vacuum at 70°C for 18 hours Crude product 17.84 g as a white powder m.p.>250°C

f) 7-Chloro-3- (5-chloromethyl- [ 1 ,2,4] oxadiazol-3-yl)-5-methyl-4,5-dihydro- imidazo [ 1 ,5-a] [ 1 ,4] benzodiazepin-6-one (IX).

8.0 g 7-chloro-5,6-dιhydro-5-methyl-6-oxo-4H-ιmιdazo[ 1,5-a] [ l,4]benzodιazepιne-3-carboxamidoxime (VIII) and 1.0 g magnesium oxide were suspended under stirring and argon atmosphere in 160 ml 1,4-dioxane. 2 7 ml Chloracetyl chloride were added in one portion and the white thick gel obtained was stirred 4 hours at r.t. and then 17 hours at reflux to give a lightly orange fluid suspension 100 ml Dioxane were distilled off and the reaction mixture was cooled to room temperature. 180 ml Deionized water were added within 15 minutes and the suspension was stirred 1 hour at r.t . The precipitate was filtered off, washed with 50 ml deionized water twice and dried under vacuum at 80°C for 18 hours Crude product: 8.3 g as a light pink powder. This crude product was dissolved in 120 ml tetrahydrofuran at reflux and 0.83 g active charcoal Darco G 60 were added. The system was refluxed 1 hour, then filtered on 25 g Dicaht-Speedex and the filter cake was washed with three portions of 50 ml warm tetrahydrofuran. The filtrate was concentrated at 40°C under reduced pressure The residue was digested in 80 ml ethanol 1 hour at reflux, then stirred 16 hours at r.t. and finally 2 hours at 2°C. The precipitate (7-chloro-3-(5-chloromethyl- [ l,2,4]oxadιazol-3-yl)-5-methyl-4,5-dιhydro-ιmιdazo [ 1,5-a] [ l,4]benzo-dιazepιn-6-one (IX)) was filtered off, washed with 2 portions of 25 ml cold tert-butyl ethvl- ether and dried under vacuum 5 hours at 80°C Crude product: 7.6 g as a light beige powder, m p. 234-238°C

g) 7-Chloro-3-(5-dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5- dιhydro-imidazo[l,5-a] [l,4]benzodιazepin-6-one (I).

7.0 g 7-Chloro-3-(5-chloromethyl- [ l,2,4]oxadιazol-3-yl)-5-methyl-4,5-dιhydro-ιmιdazo-[ 1,5-a] [ l,4]benzodιazepιn-6-one (IX) were suspended under stirring and argon
atmosphere in 70 ml 1,4-dioxane and 25.7 ml dimethylamine (33% in ethanol) were added over 60 minutes The reaction mixture was stirred one more hour at r.t. and then the solvents were removed under reduced pressure at 35°C. The residue was partitioned between 50 ml dichloromethane and 20 ml deionized water. The phases were separated and the organic phase was washed twice with 20 ml deionized water. The aqueous phases were extracted separately with the same portion of 25 ml dichloromethane, twice. The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure Crude product: 8.0 g as a light yellow foam Purification
The crude product was dissolved in 40 ml ethanol at reflux and 400 mg active charcoal Darco G 60 were added. The system was stirred 1 hour at reflux, then filtered on a hot pad of Dicalit Speedex, which was washed with two portions of 40 ml hot ethanol. The filtrate was concentrated to 14 g under reduced pressure, heated to reflux and at this temperature and 40 ml terf-butyl-methylether were added over 5 minutes. The suspension was cooled slowly to r.t., stirred 16 hours, further cooled to 2°C. After stirring 1 hour at 2°C, the precipitate was filtered off, washed with 20 ml tert-butyl-methylether and dried 1 hour at 60°C under vacuum. The so obtained powder was dissolved at reflux in 26 ml ethyl acetate. 6.5 ml Ethyl acetate were then distilled off and the turbid solution obtained was slowly cooled to r.t., then to 0°C. After 1 hour stirring at 0°C, the precipitate was filtered off, washed with 10 ml cold tert-butyl-methylether and dried under vacuum at 60°C for 16 hours. The so obtained powder (7-chloro-3-(5-dimethylaminomethyl-[ 1,2,4] oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1,5-a] [l,4]benzodiazepin-6-one (I)) was crystallized a second time in 24.3 ml ethyl acetate according to the procedure described above. Product: 5.5 g as a white powder, m.p. 151.5-153°C

7-Chloro-3-(5-dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo [ 1 ,5-a] [ 1 ,4] benzodiazepin-6-one maleate (1:1)

373 mg 7-Chloro-3-(5-dimethylaminomethyl-[ l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1,5-a] [ l,4]benzodiazepin-6-one (I) and 116 mg maleic acid were dissloved in 3 ml hot ethanol. The salt crystalized on cooling. The suspension was stirred for 10 min at 0°C. Filtration and drying afforded 460 mg 7-Chloro-3-(5-dimethylaminomethyl-[ l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[l,5-a] [ l,4]benzodiazepin-6-one maleate (1:1) as a white solid, m.p. 182-184°C

References

1. ^ Huang Z, Zhan S, Chen C, Zhang R, Zhou Y, He J, et al. (February 2024). “Efficacy and safety of Dimdazenil in adults with insomnia disorder: results from a multicenter, randomized, double-blind, placebo-controlled phase III trials”. Sleep. 47 (2). doi:10.1093/sleep/zsad272. PMC 10851846. PMID 37875349.
2. ^ Guilleminault C (2010). Sleep Medicine. Elsevier Health Sciences. pp. 574–. ISBN 978-1-4377-1836-2.
3. ^ Jump up to:^a b c Monti JM, Pandi-Perumal SR, Möhler H (28 September 2010). GABA and Sleep: Molecular, Functional and Clinical Aspects. Springer Science & Business Media. pp. 50–51. ISBN 978-3-0346-0226-6.
4. ^ Syed YY (March 2024). “Dimdazenil: First Approval”. Drugs. doi:10.1007/s40265-024-02020-9. PMID 38546956.
5. ^ Plunkett JW (September 2007). Plunkett’s Biotech & Genetics Industry Almanac 2008: Biotech & Genetics Industry Market Research, Statistics, Trends & Leading Companies. Plunkett Research, Ltd. pp. 311–. ISBN 978-1-59392-087-6.

External links

• Dimdazenil – AdisInsight

//////////DIMDAZENIL, EVT-201, 308239-86-3, EVT201, 6J8AF7CLE4, EVT 201, CHINA 2023, INSOMNIA