1-substituted 4-arylpiperazine as kappa opioid receptor antagonists
Provided are compounds represented by the formula: where R, Y.sub.3, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, G, R.sub.7, E.sub.1, E.sub.2, A, B, W, X, Y and Z are as defined herein.
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to arylpiperazine compounds which function as opioid receptor antagonists and can be used to treat a variety of disease states.
Description of the Background
The opioid receptors, .mu., .delta., .kappa., and the opioid-like receptor ORL-1 belong to the super family of G-protein coupled receptors (GPCRs) that possess seven helical trans-membrane spanning domains in their architecture..sup.1 The majority of research efforts focused upon this group of proteins has been directed toward the .mu. receptor since it mediates the actions of both the opiate and opioid analgesics such as morphine and fentanyl, respectively..sup.2 However, over the years it has become increasingly clear that the entire family of proteins is actively involved in a host of biological processes..sup.2 Furthermore, the advent of selective antagonists has demonstrated that pharmacotherapeutic opportunities exist via both negative and positive modulation of this receptor family..sup.3-8
The opioid receptor system has been extensively studied, and thousands of compounds have been synthesized and evaluated by in vitro binding and functional assays as well as by animal models..sup.2 An integral part of the effort to characterize the opioid receptor system has been the discovery of potent, pure antagonists. Naloxone (1a) and naltrexone (1b), both competitive antagonists at .mu., .delta., and .kappa. opioid receptors,.sup.9 have been extensively used as pharmacological tools to identify and characterize opioid systems. Additionally, naloxone is approved to treat heroin overdose and to reverse respiratory depression caused by morphine..sup.9 Naltrexone is used to treat heroin and alcohol abuse.
In 1978, Zimmerman and co-workers reported the discovery of a structurally unique series of opioid receptor pure antagonists based on N-substituted analogues of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (2a, LY272922)..sup.10 Unlike naloxone (1a) and naltrexone (1b) where the antagonist activity is dependent on the N-allyl or N-cyclopropylmethyl substituent, all N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2) including the N-methyl analogue 2b are opioid receptor pure antagonists..sup.10-14 A few of the more interesting analogues include alvimopan (3), which is an FDA-approved drug for GI motility disorder,.sup.15 LY255,582 (2d),.sup.13,16 which was developed to treat obesity, and the selective .kappa. opioid receptor antagonist JDTic (4),.sup.6-8,17 which shows activity in rat models of depression,.sup.18 anxiety,.sup.19 and stress-induced cocaine relapse..sup.18 All preclinical studies for JDTic have been completed, and phase 1 clinical studies are underway.
Previous work led to the discovery of 3-(4-substituted piperazin-1-yl)phenols (5) as a new class of opioid receptor antagonists and submitted two patent applications to cover this class of novel opioid receptor antagonist. These studies are presented in a recent publication..sup.20 These compounds are relatively nonselective opioid receptor antagonists. Thus, their opioid receptor properties are more like those of naloxone (1a), naltrexone (1b), and the originally reported N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines..sup.13
Previously, the opiate class, represented by naloxone (1a), naltrexone (1b), and the N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, represented by alvimopan, LY255,582, and JDTic, were the only two classes of nonpeptide pure opioid receptor antagonists known. The discovery that 3-(4-substituted piperazin-1-yl)phenols (5) are pure opioid receptor antagonists added a third example of this important class of compounds.
More recently, AZ-MTAB,.sup.21,22 PF-4455242,.sup.23 and LY2456302.sup.23 have been reported as selective .kappa. opioid receptor antagonists. These compounds have a very different structure as compared to the compounds discussed above.
Carroll, F., Thomas, J., Navarro, H., Mascarella, S., Runyon, S., Jin, C., & Kormos, C. (2016). 1-substituted 4-arylpiperazine as kappa opioid receptor antagonists. (Patent No. 9,512,105).