Positive allosteric modulators of the muscarinic acetylcholine receptor m4
A C1-C4, C1-C4- technology, applied in the field of positive allosteric regulators of muscarinic acetylcholine receptor M4, can solve problems such as limiting clinical utility and the like
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example 17
[0294] Example 1.7,9-Dimethyl-4-(tetrahydro-2H-pyran-4-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (compound 1 )Synthesis
[0295] (3-Amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanone. In isopropanol (2mL ) to a mixture of 2-mercapto-4,6-dimethylnicotinecarbonitrile (50 mg, 0.30 mmol, 1 equiv) was added 2-bromo-1-(tetrahydro-2H-pyran-4-yl) Ethan-1-one (0.045 mL, 0.37 mmol, 1.2 equiv) and 10% potassium hydroxide (0.28 mL). After 10 minutes, the reaction was concentrated in vacuo. Purification by reverse phase HPLC gave 32 mg (37%) of the title compound. 1 H NMR (400MHz, DMSO-d 6 )δ7.76 (s, 2H), 7.08 (s, 1H), 3.92 (d, J = 11.1Hz, 2H), 3.45 (ddd, J = 11.0, 11.2, 3.0Hz, 2H), 2.97-2.91 (m ,1H),2.72(s,3H),2.52(s,3H),1.72-1.66(m,4H); ES-MS[M+1] + :291.2.
[0296] 7,9-Dimethyl-4-(tetrahydro-2H-pyran-4-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (Compound 1) To a mixture of Intermediate 1 (31 mg, 0.107 mmol, 1 equiv) and formamide (0.564 mL) in a v...
example 2
[0301] Example 2.8-Cyclohexyl-3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazine (Compound 16)
[0302](5-Amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)(cyclohexyl)methanone. To 3-mercapto-5 in isopropanol (8 mL) , to a mixture of 6-dimethylpyridazine-4-carbonitrile (200 mg, 1.21 mmol, 1 eq) was added 2-bromo-1-cyclohexylethan-1-one (0.175 mL, 1.45 mmol, 1.2 eq) and 10% potassium hydroxide (solution) (1.12 mL). After one hour, the reaction was concentrated in vacuo and used without further purification. ES-MS[M+1] + :290.2.
[0303] 8-cyclohexyl-3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazine (16). Open to air heated to 150°C (5-Amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)(cyclohexyl)methanone (350 mg, 1.21 mmol, 1 equivalent) and formamide in vials of (6.4 mL) was added formamidine acetate (1.26 g, 12.1 mmol, 10 equiv) in six equal portions over three hours. After an additional three hours, more formamidine acetate (1.26 g, 12.1 mmol, 10 equiv) was added. ...
example 3
[0309] Example 3. Biological Activity
[0310] A. Cell lines expressing muscarinic acetylcholine receptors
[0311] Use Lipofectamine2000 to human M 4 cDNA together with chimeric protein G qi5 Transfected into Chinese Hamster Ovary (CHO-K1) cells purchased from American Type Culture Collection. Will M 4 / G qi5 / CHO cells were cultured in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, 500 μg / mL G418 sulfate and 200 μg / mL hygromycin B.
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