STRUCTURES OF HISTAMINE H1-RECEPTOR ANTAGONISTS DERIVED FROM THE CIMETIDINE GROUP OF HISTAMINE-H2-RECEPTOR ANTAGONISTS

The crystal and molecular structures of ten compounds with strong stru ctural resemblances to the cimetidine group of histamine H2-receptor a ntagonists, but exhibiting selective H1-receptor antagonist activity, (1)-(7), or H1 and H2 activity (8)-(10), have been determined: (1) yla mino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrobromide (temal astine), C21H27BrN5O3+.3Br-, M(r) = 685.09, triclinic, P1BAR, a = 6.31 4 (2), b = 11.192 (2), c = 19.441 (5) angstrom, alpha = 102.47 (2), be ta = 92.77 (2), gamma = 103.28 (2)-degrees, V = 1298.51 angstrom3, Z = 2, D(x) = 1.75 g cm-3, mu = 61.6 cm-1, F(000) = 672, R = 2.93% for 32 08 independent rflexions. (2) Bromo-3-methyl-2-pyridyl)butylamino]-4-p yrimidone, C14H19BrN4O2, M(r) = 355.23, monoclinic, I2/a, a = 16.359 ( 3), b = 10.469 (6), c = 18.339 (4) angstrom, beta = 90.90 (2)-degrees, V = 3140.49 angstrom3, Z = 8, D(x) = 1.503 g cm-3, mu = 26.0 cm-1, F( 000) = 1176, R = 4.2% for 1872 independent reflexions. (3) dyl)butylam ino]-4-amino-1,2,5-thiadiazole-1-oxide, C12H16BrN5OS, M(r) = 358.26, t riclinic, P1BAR, a = 14.295 (2), b = 12.447 (2), c = 9.917 (2) angstro m, alpha = 95.77 (2), beta = 113.86 (2), gamma = 106.91 (1)-degree, V = 1495.18 angstrom3, Z = 4, D(x) = 1.59 g cm-3, mu = 50.96 cm-1, F(000 ) = 728, R = 5.98% for 5674 independent reflexions. (4) tylamino]-4-be nzylamino-1,2,5-thiadiazole-1-oxide, C19H22BrN5OS, M(r) = 448.38, mono clinic, P2(1)/c, a = 36.293 (7), b = 4.826 (2), c = 11.528 (3) angstro m, beta = 96.91 (2)-degrees, V = 2004.27 angstrom3, Z = 4, D(x) = 1.49 g cm-3, mu = 39.2 cm-1, F(000) = 920, R = 12.1% for 1945 independent reflexions. (5) Benzyl-N-2-pyridylamino)propylamino]-4-pyrimidone, C19 H21N5O, M(r) = 335.4, orthorhombic, Pbna, a = 7.082 (1), b = 19.889 (3 ), c = 24.899 (3) angstrom, V = 3507.16 angstrom3, Z = 8, D(x) = 1.27 g cm-3, mu = 6.24 cm-1, F(000) = 1424, R = 4.05% from 2470 independent reflexions. (6) opylamino]-4-ethylamino-1,2,5-thiadiazole-1-oxide, C1 9H23FN6OS, M(r) = 402.5, monoclinic, P2(1)/n, a = 6.686 (2), b = 14.71 7 (3), c = 20.850 (5) angstrom, beta = 97.83 (2)-degrees, V = 2032.47 angstrom3, Z = 4, D(x) = 1.32 g cm-3, mu = 16.41 cm-1, F(000) = 848, R = 8.5% from 2484 independent reflexions. (7) 8-tetrahydro-8-quinolyl) propylamino]-4-pyrimidone, C23H29N5O2, M(r) = 407.5, monoclinic, P2(1) /c, a = 14.966 (2), b = 16.075 (2), c = 9.1608 (9) angstrom, beta = 99 .158 (8)-degrees, V = 2175.83 angstrom3, Z = 4, D(x) = 1.24 g cm-3, mu = 6.19 cm-1, F(000) = 872, R = 5.3% from 2784 independent reflexions. (8) henylbutylamino)-5-(3-pyridylmethyl)-4-pyrimidone, C20H26N4O3, M( r) = 370.5, monoclinic, P2(1)/c, a = 8.040 (4), b = 21.279 (4), c = 11 .404 (2) angstrom, beta = 92.08 (5)-degrees, V = 1949.68 angstrom3, Z = 4, D(x) = 1.26 g cm-3, mu = 0.93 cm-1, F(000) = 792, R = 4.05% from 3816 independent reflexions. (9) thio)ethylamino]-5-(3-pyridylmethyl)- 4-pyrimidone, C18H19N5OS, M(r) = 353.4, triclinic, P1, a = 8.577 (3), b = 9.197 (2), c = 11.830 (2) angstrom, alpha = 86.57 (2), beta = 81.8 8 (2), gamma = 69.83 (2)-degrees, V = 867.2 angstrom3, Z = 2, D(x) = 1 .35 g cm-3, mu = 2.04 cm-1, F(000) = 372, R = 7.46% from 3673 independ ent reflexions. (10) idyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone , C21H25N5O2, M(r) = 379.5, monoclinic, P2(1)/c, a = 8.451 (2), b = 19 .522 (4), c = 12.564 angstrom, beta = 106.78 (3)-degrees, V = 1984.51 angstrom3, Z = 4, D(x) = 1.27 g cm-3, mu = 0.91 cm-1, F(000) = 808, R = 4.36% from 3908 independent reflexions. The relationship between act ivity as H1-receptor histamine antagonists and conformation has been e xamined and it has been found that a predominance of low-energy confor mations with distances between 'aromatic' N atoms and those in the iso cytosine or thiadiazole-1-oxide groups in the region 5.2-6.0 angstrom tend to correlate with H1 activity in agreement with work by others on established H1 antagonists.