Structure of 19869-42-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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AI Derived Therapeutic Development for the Treatment of Opioid Use Disorder
Valeria Lallai ; A.C. Martin ; J.P. Fowler ; Malia Bautista ; Allison S. Mogul ; Jinjutha E. Cheepluesak , et al.
Abstract: The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, especially fentanyl given its high potency and speed of onset. Here, we developed a novel theraputic based on a newly developed artificial intelligence (AI)-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. The GATC-021 compound was synthesized and validated with in vitro screening for target specificity. Thereafter, GATC-021 was examined for its effectiveness in modulating opioid dependence with an animal model of addiction. We found that GATC-021 substantially reduced fentanyl intake in both male and female rats, as assessed with intravenous self-administration. However, given drug soluability challenges, additional studies are needed to better develop drug formulations to permit translation into clinical populations more effectively. Taken together, these findings validate our AI-based platform for novel therapeutic development with a polypharmacy approach and further support the effectiveness of such target modulation as a promising therapeutic approach for those suffering from opioid use disorder.
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Keywords: Opioid ; Addiction ; Fentanyl ; Therapeutic Development
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CAS No. : | 19869-42-2 |
Formula : | C7H14ClNO |
M.W : | 163.65 |
SMILES Code : | Cl.CN1CCCC(CC1)=O |
MDL No. : | MFCD07779465 |
InChI Key : | BHSJZGRGJYULPA-UHFFFAOYSA-N |
Pubchem ID : | 10197846 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1 A side stream of 245.3 g of ethyl 4-(2-carbethoxyethyl-methylamino)butyrate is charged evenly under nitrogen over a period of 2 hours into a solution of 123.4 g of potassium tert-butylate in 1.3 l of boiling xylene pumped round a loop reactor and the mixture is allowed to react for a further 0.5 hours. 750 ml of azeotrope is distilled off. The reaction mixture is hydrolyzed at 50° to 80° C. by rapid addition to a mixture of 300 ml of concentrated (37percent) hydrochloric acid and 500 g of crushed ice. The organic layer separated off is washed twice, each time with 150 ml of semi-concentrated hydrochloric acid. The combined aqueous extracts are heated for 2 hours under vigorous reflux and then evaporated to dryness in vacuo. The residue is dissolved in 700 ml of isopropanol, filtered off hot from the undissolved potassium chloride and crystallized at 0° to -5° C. The residue filtered off is dried to constant weight in vacuo at elevated temperature. A second fraction can be obtained by concentrating the mother liquor to a volume of approximately 100 ml. 141.6 g (86.6percent) of 1-methyl-perhydroazepin-4-one HCl is obtained. Melting point: 167° C. (decomposition) | ||
Example 4 90.0 kg of ethyl 4-(2-carbethoxyethylmethylamino)butyrate is charged evenly under nitrogen over a period of 2 to 3 hours at the top of the column into a solution of 50.0 kg of potassium tert-butylate in 400 ml of boiling xylene and the mixture is allowed to react for a further 1 to 1.5 hours. Approximately 160 l of azeotrope is distilled off. The reaction mixture is hydrolyzed at 50° to 80° C. by rapid addition to a mixture of 80 l of concentrated (37percent) hydrochloric acid and 100 g of crushed ice. The organic phase separated off is washed twice, each time with 50 l of semi-concentrated hydrochloric acid. The combined aqueous extracts are heated for 2 hours under vigorous reflux and then evaporated to dryness in vacuo. The residue is dissolved in 400 l of isopropanol, filtered off hot from the undissolved potassium chloride and crystallized at 0° to -5° C. The residue filtered off is dried to constant weight in vacuo at elevated temperature. 43.2 kg (72.0percent) of 1-methylperhydroazepin-4-one HCl is obtained. Melting point: 162°-165° C. (decomposition) | ||
Example 8 34.0 kg of ethyl 4-(2-carbethoxyethylmethylamino)butyrate dissolved in 400 l of xylene is charged evenly under nitrogen over a period of 2 to 3 hours into a suspension of 5.0 kg of sodium hydride (80percent in mineral oil) in 200 l of boiling xylene and allowed to react for a further 0.5 hours. Approximately 400 l of azeotrope is distilled off. The reaction mixture is hydrolyzed at 50° to 80° C. by rapid addition to a mixture of 35 l of concentrated (37percent) hydrochloric acid and 60 g of crushed ice. The organic layer separated off is washed twice, each time with 30 l of semi-concentrated hydrochloric acid. The combined aqueous extracts are heated for 2 hours under vigorous reflux and then evaporated to dryness in vacuo. The residue is dissolved in 100 l of isopropanol, filtered off hot from the undissolved potassium chloride and crystallized at 0° to -5° C. The residue filtered off is dried to constant weight in vacuo at elevated temperature. 11.7 kg (52.0percent) of 1-methyl-perhydroazepin-4-one HCl is obtained. Melting point: 162°-164° C. |
Example 9 245.3 g of ethyl 4-(2-carbethoxyethylmethylamino)butyrate is charged evenly, under nitrogen, over a period of 1.75 hours into a solution of 39.0 g of sodium hydride (80percent in white mineral oil) and 75 ml of ethanol in 1.3 l of boiling xylene and allowed to react for a further 0.5 hours. Approximately 700 of azeotrope is distilled off. The reaction mixture is hydrolyzed at 80° to 100° C. by rapid addition to a mixture of 300 ml of concentrated (37percent) hydrochloric acid and 500 g of crushed ice. The organic layer separated off is washed twice, each time with 150 ml of semi-concentrated hydrochloric acid. The combined aqueous extracts are heated for 2 hours under vigorous reflux and then evaporated to dryness in vacuo. The residue is extracted hot from 600 ml of isopropanol and crystallized. The residue filtered off is dried to constant weight in vacuo at elevated temperature. A second crop of material can be obtained by concentrating the mother liquor to a volume of approximately 100 ml. 44.3 g (27.1percent) of 1-methyl-perhydroazepin-4-one HCl is obtained. Melting point: 159°-161° C. (decomposition) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium borohydrid; In water; isopropyl alcohol; | Example 7 100 ml of 1N sodium hydroxide solution is added to a solution of 18.9 g of sodium borohydride in 100 ml of water. A solution of 163.6 g of 1-methylperhydroazepin-4-one HCl in 100 ml of water is added dropwise at an internal temperature of 0° to 5° C. The mixture is stirred for 2 hours at 0° to 5° C. and then for 2 hours at room temperature. The pH is adjusted to 2 to 3 by addition of semi-concentrated hydrochloric acid. The mixture is evaporated to dryness in vacuo, the residue is taken up in 600 ml of isopropanol, the inorganic salts are separated off at 60° to 75° C. and the product is crystallized in an ice bath. The product is filtered and dried to constant weight in vacuo at elevated temperature. 149 g (90percent) of 1-methylperhydroazepin-4-ol HCl is obtained. Melting point: 156°-158° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
208 g of benzoyl hydrazine (1.0 eq), 9.4 ml of water, and 174 g of potassium hydroxide 50percent (1.00 eq) were mixed. Then, a solution of 250 g of <strong>[19869-42-2]4H-azepine-4-one, hexahydro-1-methyl hydrochloride</strong> in 415 ml of water was added at room temperature. A solution of 43.35 g of sodium borohydride (0.75 eq.) in 312 ml of water was also added. Once the reaction was completed 1200 ml of ethyl acetate were added. A two layer solution was formed. After 20 minutes of stirring at room temperature, the organic layer was separated. The aqueous solution was extracted with 575 ml of ethyl acetate. The organic layers were combined and the solution was filtered off. Then, 204 g hydrochloric acid 36percent (1.3 eq) at room temperature were added. A two layer solution was formed. The outcome aqueous solution was diluted with 250 ml of water, it was heated at reflux temperature and distilled until the temperature of the mixture was over 100 °C. Then, 400 g of hydrochloric acid were added (36percent) (3 eq) and the mixture refluxed during 4 hours. The mixture was cooled down to 60 °C and 925 ml of xylene were added. The organic layer was separated and washed once with 465 ml of xylene at the same temperature. The aqueous phase was kept as a solution of 1H-azepine, 4-hydrazinohexahydro-1-methyl dihydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Example 1 Preparation of 9-chloro-l,2,3,4,5,6-hexahvdro-3-methylazepmor4,5-b1mdole[0366] The title compound was prepared by following general procedure 1 1-Methylazepan- 4-one hydrochloride (164 mg, 1 mmol) and 4-chlorophenylhydrazme hydrochloride (179 mg, 1 mmol) were heated in a mixture of 7percent sulfuric acid in 1,4-dioxane (2-3 mL) overnight under nitrogen Two liquid layers persisted throughout the reaction The mixture was poured on to ice and basified with 50percent aq NaOH The resulting precipitate was filtered, washed well with water, and dried in air to give 9-chloro-l,2,3,4,5,6-hexahydro-3-methylazepmo[4,5-b]mdole as a dark brown solid (183 mg 78percent yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2 Preparation of 1.2.3.4.5.6-hexahvdro-3.9-dimethylazepmor4.5-b1mdole[0367] The title compound was prepared by following general procedure 1 p-Tolyl hydrazine hydrochloride (15 g, 94 55 mmol) was taken into 7percent H2SO4 in 1,4-dioxane (650 mL), 1- methylazepan-4-one HCl (15 4 g, 94 55 mmol) was added and stirred at RT for 10 mm The reaction mixture was stirred at 800C for 14 h After completion of the reaction, reaction mass was slowly basified with 50percent NaOH solution, extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness and purified by column chromatography (silica gel 100-200 mesh, eluent 10percent methanol-DCM) to afford 3,9-dimethyl- l,2,3,4,5,6-hexahydroazepmo[4,5-b]mdole (5 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In acetic acid; at 20℃; | (3E,5E)-l-methyl-3,5-bis[(4-nitrophenyl)methylidene]azepan-4-one (compound No. 1563). N-methylazepan-4-one HCI (50 mg, 0.30 mmol) and 4-nitrobenzaldehyde were dissolved in acetic acid (5 mL) and stirred for 10 min, then cone. H2S04 (50 mu?) was added slowly and the mixture was stirred at rt overnight. More concentrated H2S04 (100 mu?) was added and stirring was continued at rt for 6 h. Additional 500 mu? of concentrated H2S04 was added and the reaction stirred overnight. A further 350 mu? of cone. H2S04 was added and stirring continued for additional 5 h, during which period further H2S04 was added in two portions (500 mu? and 250 mu?). Then water ( 3 x reaction volume) was added and the mixture was stirred until rt was reached. The reaction mixture was extracted with ethyl acetate (3 x reaction volume). The phases were separated and the organic phase concentrated to yield a dark yellow viscous oil. The crude product was purified by preparative HPLC, (XBridge column; eluents 50 mM ammonium carbonate buffer at pH 10 and methanol) giving the title product as a yellow solid (26.3 mg). LCMS System A: Rt 1.87 m/z [M+H]+ 394.1, System B: Rt 2.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In acetic acid; at 20℃; for 192.0h; | (3E,5E)-5-[(4-chlorophenyl)methylidene]-3-[(4-nitrophenyl)methylidene]azepan-4-one (compound No. 1583). <strong>[19869-42-2]N-methylazepan-4-one hydrochloride</strong> (75 mg, 0.46 mmol) and4-chlorobenzaldehyde (64 mg, 0.46 mmol) were dissolved in acetic acid (7 mL) and stirred for 10 min, then cone. H2S04 (350 mu?) was added slowly and the mixture was stirred at rt for 8 days. More cone. H2S04 was added during days 2-4 (0.175 mL, 0.35 mL, 0.25 mL respectively). Water (2 x reaction volume) was added and the solution extracted with ethyl acetate (2 x reaction volume). The organic phase was concentrated to give Intermediate 8. A portion of the intermediate (35 mg, 0.14 mmol) and 4-nitrobenzaldehyde (69.5 mg, 0.46 mmol) were dissolved in acetic acid (2.5 mL) and stirred for 10 min, then cone. H2S04 (200 mu?) was added slowly and the mixture was stirred at rt for 5 days. More cone. H2S04 (0.2 mL) was added, and stirring continued for 5 more days. Water (2 x reaction volume) was added and the solution extracted with ethyl acetate (2 x reaction volume). The organic phase was concentrated and the residue purified by preparative LC to give the title compound (1.8 mg) as a yellow solid of 94percent purity. LCMS System A: Rt 1.98/2.04 m/z[M+H]+ 383.1, System B: Rt 2.82/2.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In acetic acid; at 20℃; | (3E,5E)-5-[(4-fluorophenyl)methylidene]-3-[(4-methoxyphenyl)methylidene]-l- methylazepan-4-one (compound No. 1577). <strong>[19869-42-2]N-methylazepan-4-one hydrochloride</strong> (75 mg, 0.46 mmol) and 4-fluorobenzaldehyde were dissolved in acetic acid (7 mL) and stirred for 10 min, then cone. H2S04 (350 iL) was added slowly and the mixture was stirred at rt for 8 days. More cone. H2S04 was added during days 2-4 (0.175 mL, 0.35 mL, 0.25 mL respectively). Water was added and the solution extracted with ethyl acetate (twice the volume of reaction mixture). The organic phase was concentrated to give Intermediate 5. A portion of this intermediate (35 mg, 0.15 mmol) and 4-methoxybenzaldehyde (17 mu?, 0.15 mmol) were dissolved in acetic acid (2.5 mL) and stirred for 10 min, then cone. H2S04 (0.20 mL) was added slowly and the reaction stirred for five days. Water (2 x reation volume) was added and the reaction mixture extracted with ethyl acetate (2 x reaction volume). The organic layer was concentrated and water was added. A precipitate was formed and filtered off to give the title product (11.2 mg) in 91percent purity as a yellow solid. LCMS System A: Rt 1.86 m/z [M+H]+ 352.1, System B: Rt 2.79. |
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