Positive allosteric modulators of the muscarinic acetylcholine receptor M4
A C1-C4, C1-C4- technology, applied in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve problems such as limiting clinical utility
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example 1
[0472] Example 1. General Amine Synthesis
[0473] The following is an exemplary synthesis of one of the amines used to prepare the compounds disclosed herein.
[0474]
[0475]4-(2-Hydroxypropan-2-yl)benzonitrile. To a solution of 4-iodobenzonitrile (10.0 g, 43.7 mmol, 1.0 equiv) in THF (218 mL) was added n-butyllithium (2.5 M in hexane, 22.7 mL) dropwise at -78 °C. 56.8 mmol, 1.3 eq) to keep the temperature below -70 °C. After 1 hour, acetone (32.0 mL, 436.6 mmol, 10.0 equiv) was added while maintaining the temperature below -70 °C. Remove the dry ice bath. After 16 h at room temperature, add saturated NH 4 Cl solution (100 mL), then EtOAc (250 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0-60% EtOAc / hexanes) to afford the title compound (4.8...
example 2
[0477] Example 2. 2-(4-(((7,9-Dimethylthieno[2,3-d:4,5-d']dipyrimidin-4-yl)amino)methyl)phenyl)propane -2-alcohol (2-(4-(((7,9-Dimethylthieno[2,3-d:4,5-d']dipyrimidin-4-yl)amino)methyl)phenyl)propan-2-ol) (Compound 1)
[0478]
[0479] 5-Amino-2,4-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (ii). 5-Amino-2,4-dimethyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (compound i; CAS#930395-93-0) (320mg, 1.43mmol, 1.0eq) and HATU (1.09 g, 2.87 mmol, 2.0 equiv) in NMP (10.5 mL, 0.14M) was stirred at room temperature for 10 min. Ammonium chloride (537 mg, 10.0 mmol, 7.0 equiv) was added followed by DIEA (1.25 mL, 7.17 mmol, 5.0 equiv). After 3 hours at room temperature, the reaction mixture was diluted with DMSO and analyzed using reverse-phase HPLC (H 2 CH in O 3 CN (0.05% v / v NH 4 OH); Gradient: 0%-45%) purification. The desired fractions were concentrated to afford the title compound (220 mg, 69% yield) as an off-white powder. (400MHz, DMSO-d 6 )δ7.27(bs,2H),6.97(s,2H),...
example 3
[0483] Example 3. 7,9-Dimethyl-4-(pyrrolidin-1-yl)thieno[2,3-d:4,5-d']dipyrimidine (Compound 2)
[0484]
[0485] 4-Chloro-7,9-dimethylthieno[2,3-d:4,5-d']dipyrimidine (compound iv, prepared as described in Example 1) (6.0 mg, 0.021 mmol, 1.0 equiv ), pyrrolidine (50 μL, 0.60 mmol, 29.0 equiv), and NMP (1.0 mL) were charged in a microwave vial. The vial was subjected to a microwave reactor at 100°C for 10 min. The crude material was subjected to reverse phase HPLC (H 2 CH in O 3 CN (0.05% v / v NH 4 OH); Gradient: 20%-60%) was purified to afford the title compound (4.6 mg, 77%) as a white powder. 1 H NMR (400MHz, CDCl 3 )δ8.67(s,1H),3.95-3.92(m,4H),3.20(s,3H),2.85(s,3H),2.12-2.08(m,4H); ES-MS[M+1] + :286.4.
[0486] Compounds shown in Table 1 were prepared in a similar manner to compounds 1 and 2 using appropriate starting materials.
[0487] Table 1
[0488]
[0489]
[0490]
PUM
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