Wise L D, Butler D E, DeWald H A, Lustgarten D M, Pattison I C, Schweiss D N, Coughenour L L, Downs D A, Heffner T G, Pugsley T A
Department of Chemistry, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105.
J Med Chem. 1987 Oct;30(10):1807-12. doi: 10.1021/jm00393a021.
2-(Diethylamino)-N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl] acetamide (1) was recently found to have an antipsychotic-like profile in behavioral animal tests but, unlike clinically available antipsychotic agents, did not interact with dopamine receptors. Compound 1 was apparently metabolized to (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (2), which was both active in the behavioral animal tests and toxic. The synthesis and pharmacological evaluation of a series of 1,3-dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols are described in which the hydroxy and imine functionalities were selected as possible isosteric replacements for the amino and ketone groups of the earlier series. The initial target, 1,3-dimethyl-4-(iminophenylmethyl)-1H-pyrazol-5-ol (28), like known antipsychotics, reduced spontaneous locomotion in mice at doses that did not cause ataxia, and unlike known agents, it did not bind to D2 dopamine receptors in vitro. An examination of the SAR of related compounds indicated that maximal activity was obtained with analogues containing methyl groups at the 1- and 3-positions on the pyrazole ring and with a 3-chloro substituent on the phenyl ring. Replacement of the hydrogen atom of the imine moiety with various substituents led to loss of activity. Attempts to synthesize the 2-fluorophenyl compound analogous to 2 resulted in ring-closure to 1,3-dimethyl[1]benzopyrano[2,3-c]pyrazol-4-(1H)-one (65). 4-[(3-Chlorophenyl)iminomethyl]-1,3-dimethyl-1H-pyrazol-5-ol (41) was evaluated in additional tests. It inhibited conditioned avoidance responding in both rats and monkeys but, unlike available antipsychotic drugs, did not elicit dystonic movements in a primate model of antipsychotic-induced extrapyramidal side effects.
2-(二乙氨基)-N-[4-(2-氟苯甲酰基)-1,3-二甲基-1H-吡唑-5-基]乙酰胺(1)最近在动物行为试验中被发现具有类抗精神病药物的特征，但与临床可用的抗精神病药物不同，它不与多巴胺受体相互作用。化合物1显然代谢为(5-氨基-1,3-二甲基-1H-吡唑-4-基)(2-氟苯基)甲酮(2)，该化合物在动物行为试验中具有活性且有毒性。本文描述了一系列1,3-二烷基-4-(亚氨基芳基甲基)-1H-吡唑-5-醇的合成及药理学评价，其中羟基和亚胺官能团被选为早期系列中氨基和酮基可能的等排取代基。最初的目标化合物1,3-二甲基-4-(亚氨基苯基甲基)-1H-吡唑-5-醇(28)，与已知抗精神病药物一样，在不引起共济失调的剂量下能降低小鼠的自发活动，且与已知药物不同的是，它在体外不与D2多巴胺受体结合。对相关化合物的构效关系研究表明，吡唑环1位和3位含有甲基且苯环上有3-氯取代基的类似物具有最大活性。用各种取代基取代亚胺部分的氢原子会导致活性丧失。尝试合成与2类似的2-氟苯基化合物时，得到的是闭环产物1,3-二甲基[1]苯并吡喃并[2,3-c]吡唑-4-(1H)-酮(65)。4-[(3-氯苯基)亚氨基甲基]-1,3-二甲基-1H-吡唑-5-醇(41)在其他试验中进行了评价。它能抑制大鼠和猴子的条件性回避反应，但与现有的抗精神病药物不同的是，在抗精神病药物诱导的锥体外系副作用的灵长类动物模型中，它不会引起肌张力障碍性运动。
