Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 1, 2008, Pages 39-43

  Ly, Kiev S ^a   Letavic, Michael A ^a   Keith, John M ^a   Miller, Jennifer M ^a   Stocking, Emily M ^a   Barbier, Ann J ^a   Bonaventure, Pascal ^a   Lord, Brian ^a   Jiang, Xiaohui ^a   Boggs, Jamin D ^a   Dvorak, Lisa ^a   Miller, Kirsten L ^a   Nepomuceno, Diane ^a   Wilson, Sandy J ^a   Carruthers, Nicholas I ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Histamine; Histamine H3 antagonist; Serotonin; Serotonin reuptake inhibitor

Indexed keywords

HISTAMINE H3 RECEPTOR ANTAGONIST; PIPERAZINE DERIVATIVE; SEROTONIN UPTAKE INHIBITOR;

ARTICLE; CHEMICAL REACTION; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; NONHUMAN;

AMIDES; ANIMALS; AZEPINES; BRAIN; HISTAMINE H3 ANTAGONISTS; HUMANS; PIPERAZINES; RATS; SEROTONIN UPTAKE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 37549047997     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.016     Document Type: Article

References (20)

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18. Representative procedure for the synthesis of compounds 9 and 10. 6c: 5-bromo-2-fluorobenzaldehyde (5.13 g, 25.2 mmol) was dissolved in N,N-dimethylformamide (25 mL) and treated with 4-(methylthio)-m-cresol (4.42 g, 28.7 mmol) and potassium carbonate (7.40 g, 53.5 mmol). The mixture was heated to 90 °C for 48 h and then cooled and diluted with water and extracted into diethyl ether and concentrated. Chromatography on silica gel (EtOAc/hex) gave 6c (6.07 g, 71%). 7c: Compound 6c (6.07 g, 18.0 mmol) was dissolved in methanol (250 mL) and treated with 40% aqueous methylamine (30 mL, 387 mmol). The mixture was stirred at 23 °C for 20 min until homogeneous then was cooled to 0 °C prior to the addition of sodium borohydride (in portions, 1.048 g, 27.7 mmol). The reaction mixture was then allowed to warm to 23 °C and was stirred at that temperature for 25 h. The mixture was diluted with 1 N NaOH and was extracted with dichloromethane (3×). The organic layers were dried over sodium sulfate and concentrated to give 7c (5.76 g, 91%) as an oil. 8c: Compound 7c (5.76 g, 17.1 mmol) was dissolved in dichloromethane (250 mL) and was treated with triethylamine (4.8 mL, 34.4 mmol) and di-tert-butyl dicarbonate (4.51 g, 20.6 mmol). The mixture was stirred at 23 °C for 1 h, then was added to 1 N NaOH and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated to give crude 8c (8.18 g, 106%) containing a small amount of triethylamine as an oil. The material was used as it is for the next step. 9c: 8c (0.292 g, 0.646 mmol) was dissolved in tetrahydrofuran (2 mL) and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (0.3 mL), isopropylpiperazine (0.3 mL), trans-di-μ-acetatobis[2-(di-o-tolyl-phosphino)benzyl]di-palladium(II) (Hermann's catalyst) (28.7 mg), tri-tert-butylphosphonium tetrafluoroborate (26.9 mg), and molybdenum hexacarbonyl (177.4 mg) were then sequentially added to the vial. The vial was sealed and heated to 125 °C in a microwave reactor for 6 min. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting oil was applied directly to a silica gel column and chromatographed using a mixture of dichloromethane and 10% methanol containing 0.1% ammonium hydroxide as eluent to give the Boc protected amine, which was directly treated with dichloromethane (2 mL) and TFA (1 mL), stirred for 1 h at 23 °C, then concentrated and chromatographed using the above eluent to give 9c (0.0958 g, 35% over 2 steps).
19. 3 functional assay can be found in Ref. 12. A detailed description of the SERT, NET, and DAT assays can be found in Ref. 13.
20. Compound 9a had 73% inhibition of the μ-opiate receptor at 1 μM and compound 10h had 66% inhibition of the μ-opiate receptor at 1 μM and 64% inhibition of the muscarinic-3 receptor at 1 μM.