Iminopyrimidine NMDA NR2B receptor antagonists

#1. Field of the Invention

#This invention relates to novel iminopyrimidine compounds. In particular, this invention relates to novel iminopyrimidine compounds effective as NMDA NR2B antagonists.

#2. Related Background

#The following Examples 1-29 are shown as trifluoroacetic acid (“TFA”) salts. The trifluoroacetic acid salt form arose from the HPLC procedure and not because the salt per se was desired. The free bases of the trifluoroacetic acid salts can be readily obtained by the following procedure. Dissolve the salt in a 1:1 mixture of ethyl acetate and saturated aqueous sodium bicarbonate, separate the layers, dry the organic part over Na2SO4 and concentrate. The resulting residue is the base of the starting trifluoroacetic acid salt.

#Example 1 was prepared by the following method, Procedure A: A solution of 2-iminopiperidine (60 mg, 0.61 mmol) was dissolved in 5% MeCN/THF (5 mL) at room temperature. 3-Phenyl-2-propynenitrile (77 mg, 0.61 mmol) was added in one portion and the resulting reaction mixture was stirred 2 h. The reaction mixture was poured into ethyl acetate and aqueous NaHCO3. The layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC to give Example 1 (134 mg, 65% yield as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.42 (br s, 1H), 7.58-7.50 (m, 3H), 7.38-7.35 (m 2H), 6.81 (s 1H), 6.73 (br s, 1H), 3.84 (t, J=5.8 Hz, 2H), 3.10 (t, J=6.6 Hz, 2H), 2.03-1.94 (m, 4H) ppm; 13C NMR (125 MHz), CDCl3) δ 163.5, 163.0, 157.4, 131.5, 130.6, 129.5, 128.3, 106.6, 50.3, 31.5, 21.8, 18.1, ppm; high resolution mass spectrum m/z 226.1353 [(M+H)+; calc'd for C14H16N3: 226.1339].

#Example 2 was prepared by the following method, Procedure B: A solution of 2-iminopiperidine (60 mg, 0.61 mmol) was dissolved in 5% MeCN/THF (5 mL) at room temperature. NaHMDS (1.0M/THF, 1.22 mL. 1.22 mmol) was added dropwise and the resulting solution was stirred at room temperature for 5 min. 3-Phenyl-2-propynenitrile (77 mg, 0.61 mmol) was then added in one portion, the reaction mixture turned dark red and was stirred for 5 min. The reaction mixture was poured onto ethyl acetate and aqueous NaHCO3 and the layers separated. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse HPLC to give Example 2 (107 mg, 52% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.74 (br s, 1H), 9.18 (br s, 1H), 8.04 (dd, J=7.8, 1.5 Hz, 2H), 7.56-7.43 (m, 4H), 4.10 (t, J=6.2 Hz, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.18-2.11 (m, 2H), 2.02-1.98 (m, 2H) ppm; 13C NMR (125 MHz), CDCl3) δ 161.2, 158.3, 157.7, 132.2, 129.1, 129.0, 127.5, 101.4, 47.0, 32.3, 21.4, 18.1, ppm; high resolution mass spectrum m/z 226.1351 [(M+H)+; calc'd for C14H16N3: 226.1339].