Ghosh S, Jennissen J D, Zheng Y, Uckun F M
Department of Structural Biology (Drug Discovery Program), Parker Hughes Institute, 2665 Long Lake Road, Suite 330, St Paul, MN 55113, USA.
Acta Crystallogr C. 2000 Oct;56 ( Pt 10):1254-7. doi: 10.1107/s0108270100009768.
The title compounds, 1-cyano-2-hydroxy-N-[4-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI492, 1-cyano-2-hydroxy-N-[3-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI493, and N-[3-bromo-4-(trifluoromethoxy)phenyl]-1-cyano-2-hydroxybut-2-e namide , C(12)H(8)BrF(3)N(2)O(3), PHI495, are potent inhibitors of Bruton's tyrosine kinase (BTK). The molecular structures of these compounds are similar and they display similar hydrogen-bonding networks and crystal packing. Examination of the crystal-packing interaction in the three compounds reveals an alternating direction of adjacent molecules in the crystalline lattice due to intermolecular cyano-amide hydrogen bonding. PHI492, a positional isomer of PHI493, does not form intermolecular O-H.O hydrogen bonds between molecules and crystallizes in a space group different from that of PHI493 and PHI495. The aromatic ring and the amide group of each molecule form a conjugated pi-system which ensures planarity, with further stabilization gained from intramolecular O-H.O hydrogen bonds.
标题化合物1-氰基-2-羟基-N-[4-(甲基磺酰基)苯基]丁-2-烯酰胺（C₁₂H₁₂N₂O₄S，PHI492）、1-氰基-2-羟基-N-[3-(甲基磺酰基)苯基]丁-2-烯酰胺（C₁₂H₁₂N₂O₄S，PHI493）和N-[3-溴-4-(三氟甲氧基)苯基]-1-氰基-2-羟基丁-2-烯酰胺（C₁₂H₈BrF₃N₂O₃，PHI495）是布鲁顿酪氨酸激酶（BTK）的有效抑制剂。这些化合物的分子结构相似，并且它们展现出相似的氢键网络和晶体堆积。对这三种化合物中晶体堆积相互作用的研究表明，由于分子间氰基-酰胺氢键的存在，晶格中相邻分子的方向交替排列。PHI492是PHI493的位置异构体，分子间不形成O-H…O氢键，且其结晶的空间群与PHI493和PHI495不同。每个分子的芳环和酰胺基团形成一个共轭π体系，确保了平面性，分子内O-H…O氢键进一步增强了稳定性。
