JP2005525293A - Analgesics and methods of use - Google Patents

Abstract

A method of inducing analgesia and / or a method of deterring abuse of an abused substance, comprising the step of administering a d-methadone metabolite or a structural analog thereof. The d-methadone metabolites, EMPD and EDDP, and their structural analogs can be incorporated into suitable pharmaceutical compositions for administration to patients. The present invention encompasses the method itself, specific structural analogs for use according to the method, as well as pharmaceutical compositions for use according to the method.

Description

(Cross-reference of related applications)
This application claims the benefit of priority of US Provisional Application No. 60 / 315,530, filed Aug. 29, 2001. This application is incorporated herein by reference in its entirety.

(Field of Invention)
The present invention relates to d-methadone metabolites and analogs thereof, and to their methods of use to cause analgesia and / or deter abuse of substances of abuse (eg, opioids, cocaine, nicotine, etc.).

(Description of related technology)
Pain and pain relief studies reveal that pain relief development is not a single route. A number of different pain sources and their alleviation are known and suspected. For this reason, scientists are continually searching for different and better pain treatment methods and associated side effect relief methods.

  Nicotine-like acetylcholine receptors are distributed throughout the central and peripheral nervous systems and they mediate the actions of endogenous acetylcholine, as well as nicotine and other nicotine-like agonists. They are often associated with cell bodies and major neurotransmitter system axons, and nicotine-like agonists are found in many neurotransmitters (eg, dopamine, norepinephrine, γ-aminobutyric acid, acetylcholine, and glutamate (reviews). (See Wonnacott, 1997), and to release one pituitary hormone (Andersson et al., 1983; Sharp et al., 1987; Flores et al., 1989; Hulihian-Giblin et al., 1990)). It is thought to act through the receptor. This extensive neurotransmitter and hormone release probably contributes to the effects of various and sometimes inverse nicotine. For example, norepinephrine release is usually associated with wakefulness, while stimulation of the gamma-aminobutyric acid system is associated with sedation.

  Nicotine was first examined for its potential as an analgesic almost 70 years ago (Davis et al., 1932), but its dose-response relationship to analgesia leads to poor therapeutic indices, Did not help with its development. More recently, after the discovery of the analgesic properties of epibatidine, an effective nicotinic agonist isolated from Ecuador frog skin, by Dary and colleagues (Spande et al., 1992), the potential for analgesia acting at nicotinic receptors Some drugs are again attracting new interest (Bannon et al., 1998; Flores and Hargreaves, 1998; Flores, 2000).

  Perhaps one or more neurotransmitter systems play an important role in analgesia. For example, methadone (a synthetic μ-opioid agonist) has an effect similar to that of morphine (Kristensen et al., 1995), which is also useful in the treatment of opium addiction. Because the (+)-enantiomer has rather weak analgesic properties (Scott et al., 1948; Smiths and Myers, 1974; Horng et al., 1976), most of the (±) -methadone morphine-like analgesic properties are (- )-Due to the enantiomer. However, (+)-methadone exhibits analgesic activity in several experimental models (Shimoyayama et al., 1997; Davis and Inturrisi, 1999) and also appears to attenuate the development of morphine tolerance (Davis and Inturrisi, 1999) .

In addition to the agonistic action at the opiate receptor, methadone competes with the [ ³ H] MK801 binding site in the NMDA receptor channel and blocks NMDA receptor-mediated reactions (Ebert et al., 1995); The two enantiomers are approximately potently equivalent at the [ ³ H] MK801 binding site (Gorman et al., 1997). Some drugs that block the NMDA receptor (eg, MK801, phencyclidine, dextromethorphan, and dextrophan) also block neuronal nicotinic receptors (Ramoa et al., 1990; Amador and Dani, 1991; Hernandez) Et al., 2000). Both nicotinic and NMDA receptors are involved in the pain pathways and possible mechanisms underlying pain perception. We therefore investigated the effects of methadone, its metabolites, and structural analogs (FIG. 1) on neuronal nicotinic receptors.

  In addition to its involvement in pain relief, it has recently been discovered that certain nicotine-like receptors can play a role in limiting abuse behavior.

  Substances that can be abused include opioids, methamphetamines, hallucinogens, psychotropic drugs, cocaine and the like. Some abused substances are sensitive and easy to spread. Perhaps one of the most widespread is nicotine found in tobacco. The term “substance of abuse” as used herein refers to any substance that can lead to abuse by causing dependence or otherwise causing drug-seeking behavior.

  During the study of d-methadone and its metabolites, EMDP and EDDP, we have found that EMDP and EDDP and novel analogs thereof can cause analgesia and one or more abused substances as described above Has been found to be useful to stop the abuse of the subject independently or voluntarily.

(Summary of the Invention)
Methods for causing analgesia and / or deter abuse of a substance of abuse include administration of EMDP, EDDP, and novel analogs thereof. The compounds of the present invention can be incorporated into pharmaceutical compositions suitable for administration to a patient. The present invention encompasses novel compounds, methods of causing analgesia and / or preventing abuse of abused substances, and pharmaceutical compositions used in the methods.

(Detailed explanation)
(Definition)
Throughout this specification, unless otherwise indicated, what is simply referred to as "metabolite" or "d-methadone metabolite" is EDDP and EMDP as defined below, and pharmaceutically acceptable Means salt.

The term “(+)-methadone” means S-(+)-methadone hydrochloride;
The term “(−)-methadone” means R-(−)-methadone hydrochloride;
The term “LAAM” means (−)-α-acetylmethadol hydrochloride;
The term “(+)-EDDP” means R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolium perchlorate;
The term “(−)-EDDP” means S-(−)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolium perchlorate;
The term “(+)-EMDP” means R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride;
The term “(−)-EMDP” means S-(−)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride;
The term “EMDP” means (+)-EMDP, (−)-EMDP, or a mixture thereof;
The term “EDDP” means (+)-EDDP, (−)-EDDP, or a mixture thereof.

Despite a structure similar to d-methadone, EMDP and EDDP, and their analogs, have different properties than d-methadone. FIGS. 13 and 14 illustrate this by comparing the effects of MK-801, d-methadone and (+)-EDDP on glutamate-induced catecholamine release in rat brain sections from hippocampus and striatum. . The hippocampus and striatum are both important and anatomically well-studied areas of the brain. The hippocampus is related to learning and memory function, while the streak is related to motor function. Sections were supplemented with [ ³ H] norepinephrine or [ ³ H] dopamine and then impregnated with 1 mM glutamate for 2 minutes in the presence or absence of MK-801, d-methadone or (+)-EDDP. . Base strain release was measured in the presence of glutamate. These results indicate that (+)-EDDP is physiologically different from d-methadone, opioid blockers, and MK-801, an NMDA blocker. As can be seen together in FIGS. 13 and 14, this difference is evident from the shift of dose to the right. With only 10 μM d-methadone or MK-801, partial blockade of catecholamine release is achieved, while (+)-EDDP has no effect up to 100 μM.

  Although we are not limited to the following theory, the success of the compounds of the invention in causing analgesia and / or deter abuse is in their ability to block their nicotinic receptors. Think. However, it should be noted that the binding and blocking of other sites can also contribute to the effect.

  The effects of d-methadone and the compounds of the present invention on α3β4 neuronal nicotinic receptors stably expressed in human embryonic kidney 293 cells were measured. These compounds are effective nicotinic receptor blockers. One of the compounds disclosed herein is one of the most effective nicotinic receptor blockers reported.

(Effects of methadone and related drugs on nAChR)
(Experimental procedure)
(Substances and drugs)
Tissue culture medium, antibiotics, and serum were obtained from Invitrogen (Carlsbad, CA). [ ³ H] (±) -epibatidine and [ ⁸⁶ Rb] rubidium chloride ( ⁸⁶ Rb ⁺ ) were obtained from PerkinElmer Life Science Products (Boston, Mass.). Unless otherwise stated, all chemicals are from Sigma Chemical Co. (St. Louis, MO). (±) -methadone hydrochloride (methadone), S-(+)-methadone hydrochloride [(+)-methadone], and R-(−)-methadone hydrochloride [(−)-methadone] are Sigma / RBI (Natick, MA). The following compounds were obtained from Research Triangle Institute (Research Triangle Park, NC) through National Institute on Drug Abuse: (−)-α-acetylmethadol hydrochloride (LAAM, methadone analog); R-(+)- 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate [(+)-EDDP, methadone metabolite]; S-(−)-2-ethyl-1,5-dimethyl-3 , 3-Diphenylpyrrolium perchlorate [(−)-EDDP, methadone metabolite]; R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride [(+) -EMDP, methadone metabolite]; S-(-)-2-ethyl-5-methyl-3,3-diph hydrochloride Enyl-1-pyrroline [(−)-EMDP, methadone metabolite]; hydrochloric acid (+)-α-propoxyphene (methadone analog); and maleic acid (+)-α-N-norpropoxyphene (propoxyphene metabolism) product). The structures of methadone, EMDP, EDDP, and some analogs used herein are shown in FIG. 1 along with mecamylamine (a well-known nicotinic channel blocker).

(Cell culture)
The cell line KXα3β4R2 was previously established by stably co-transfecting human embryonic kidney 293 cells with the rat α3 and β4 nAChR subunit genes (Xiao et al., 1998). The cells were placed in a humidified incubator in the minimum required medium supplemented with 10% fetal bovine serum, 100 units / ml penicillin G, 100 mg / ml streptomycin, and 0.7 mg / ml geneticin (G418). Maintained at 37 ° C. with 5% CO ₂ .

( ⁸⁶ Rb ⁺ efflux assay)
The function of nAChR expressed in transfected cells was measured using the ⁸⁶ Rb ⁺ efflux assay as previously described (Xiao et al., 1998). Briefly, cells in selective growth media were placed in 24-well plates coated with poly (D-lysine). Plated cells were grown at 37 ° C. for 18-24 hours to 70-95% confluence. The cells were then incubated for 4 hours at 37 ° C. in growth medium (0.5 ml / well) containing ⁸⁶ Rb ⁺ (2 μCi / ml). The loaded mixture was then aspirated and the cells were washed 3 times with buffer (15 mM HEPES, 140 mM NaCl, 2 mM KCl, 1 mM MgSO ₄ , 1.8 mM CaCl, 11 mM glucose, pH 7.4; 1 ml / well), Washed for 30 seconds, 5 minutes, and 30 seconds, respectively. 1 ml of buffer with or without the compound to be tested was then added to each well. After a 2 minute incubation, assay buffer was collected for measurement of ⁸⁶ Rb ⁺ released from the cells. The cells were then lysed by adding 1 ml of 100 mM NaOH to each well and the lysate was collected to determine the amount of ⁸⁶ Rb ⁺ present in the cells at the end of the efflux assay. The radioactivity of the assay samples and lysates was measured by liquid scintillation counting. Total loading (cpm) was calculated as the sum of assay sample and lysate for each cell. The amount of ⁸⁶ Rb ⁺ efflux assay was expressed as a percentage of ⁸⁶ Rb ⁺ loaded. Induced ⁸⁶ Rb ⁺ efflux was defined as the difference between efflux in the presence and absence of nicotine.

Experiments with antagonists were performed in two different ways. To determine IC ₅₀ values, inhibition curves were generated such that different concentrations of antagonist were included in the assay to inhibit efflux induced by 100 mM nicotine. To determine the mechanism of antagonist blockade, a concentration response curve of receptor activation by nicotine was generated in the presence or absence of agonist. Maximum nicotine-induced ⁸⁶ Rb ⁺ efflux (E _max ) was defined as the difference between maximal and basal efflux in the presence of nicotine. EC ₅₀ , E _max , and IC ₅₀ values were determined by nonlinear least squares regression analysis (GraphPad, San Diego, CA).

(Ligand binding test)
The ability of a compound to compete for the agonist recognition site of nAChR was determined in a ligand binding test as previously described (Houghling et al., 1995; Xiao et al., 1998). Briefly, membrane preparations were incubated with [ ³ H] EB for 4 hours at 24 ° C. Bound and free ligands were separated by vacuum filtration through Whatman GF / C filters treated with 0.5% polyethyleneimine. The radioactivity retained on the filter was measured by liquid scintillation counting. Total binding and non-specific binding were determined in the absence and presence of (−)-nicotine (300 μM), respectively. Specific binding was defined as the difference between total binding and non-specific binding. Binding curves were generated by incubating a series of concentrations of each compound with a single concentration of [ ³ H] EB. Binding inhibition curve IC ₅₀ and K _i values were determined by non-linear least squares regression analysis.

(result)
(Effect of methadone on ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells)
FIG. 2 shows the effect of methadone versus nicotine on ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells. ⁸⁶ Rb ⁺ efflux was measured as described in the experimental procedure section. Cells were loaded with ⁸⁶ Rb ⁺ and then buffer alone (to measure basal release) or buffer containing methadone at the indicated concentrations (100 μM nicotine or 100 μM nicotine plus 200 μM methadone). The solution was exposed for 2 minutes. ⁸⁶ Rb ⁺ efflux response was expressed as a percentage of ⁸⁶ Rb ⁺ loaded. The data shown in FIG. 2 is the mean ± standard error of 4 independent measurements. As shown in FIG. 2, at concentrations up to 1 mM, methadone did not increase ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells. However, in parallel assays, 100 μM nicotine induced ⁸⁶ Rb ⁺ efflux about 10 times the basal level, and this induction was completely blocked by 200 μM methadone. Therefore, blocking of α3β4 by methadone was shown.

(Potency of methadone and its enantiomers in inhibiting nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells)
The potential of racemic methadone and its enantiomers as antagonists of nAChR was investigated by measuring ⁸⁶ Rb ⁺ efflux induced by 100 μM nicotine in the presence of increasing concentrations of the compound. Cells are loaded with ⁸⁶ Rb ⁺ and then buffer alone (basal release) or buffer containing 100 μM nicotine in the presence or absence of racemic methadone or methadone enantiomer at the indicated concentrations. For 2 minutes. ⁸⁶ Rb ⁺ efflux was expressed as% of loaded ⁸⁶ Rb ⁺ and the control value was defined as ⁸⁶ Rb ⁺ efflux elicited by 100 μM nicotine in the absence of methadone. The inhibition curve shown in FIG. 3 is from quadruplicate, single experiments. Table 1 shows the mean and standard error of IC ₅₀ values. As shown in FIG. 3, racemic methadone potentially inhibited nicotine-induced ⁸⁶ Rb ⁺ efflux in a concentration-dependent manner with an IC ₅₀ of about 2 μM. Furthermore, (+)-methadone and (−)-methadone inhibited the function of these receptors with similar potential (FIG. 3; Table 1).

Table 1 lists the inhibitory properties of methadone and the enantiomers of the compounds of the invention in nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells. IC ₅₀ values were calculated against an inhibition curve in which ⁸⁶ Rb ⁺ efflux is induced by 100 μM nicotine as described in the experimental procedure section. Mecamylamine, a standard nAChR antagonist, was added as a comparison. The data shown is the mean ± standard error of 3-6 independent measurements.

(Low affinity of methadone for nAChR agonist binding site)
In the membrane derived from KXα3β4R2 cells, the ability of methadone to compete with the α3β4 receptor agonist recognition site labeled with [ ³ H] EB was examined. The binding assay was performed as described in the experimental procedure section using 323 pM [ ³ H] EB. The nicotine K _i value was 559 nM. The K _i values for methadone and mecamylamine cannot be estimated because even high concentrations of use (1 mM) were below 50% inhibition. As shown in FIG. 4, methadone does not compete effectively for [ ³ H] EB binding sites. Mecamylamine is shown as a comparison. Thus, even at high concentrations (1 mM), methadone inhibited [ ³ H] EB binding to the α3β4 receptor by less than 50%. This demonstrated the weak binding potential of mecamylamine. In a parallel assay performed as a positive control, nicotine effectively competed for the agonist binding site of the α3β4 receptor, resulting in a dissociation constant (K _i ) of 560 nM. This is equivalent to that previously reported in these cells (Xiao et al., 1998). The very low affinity of methadone for the agonist recognition site of the α3β4 receptor is in contrast to its high potential in blocking receptor function (IC _{50 of} about 2 μM), suggesting a non-competitive mechanism for receptor antagonists.

^ａ（−）−ＥＤＤＰのＩＣ_５０値はメカミラミンのＩＣ_５０値よりも有意に低い（ｐ＜０．０２）。

^a (-) - _{IC 50} value of EDDP is significantly lower than _{an IC 50} value of mecamylamine (p <0.02).

(Non-competitive blocking of nAChR function by methadone)
To finally identify the type of receptor blockade by methadone, we examined its effect on the concentration response curve for receptor activation by nicotine. ⁸⁶ Rb ⁺ efflux was measured as described in the experimental procedure section. Cells were loaded with ⁸⁶ Rb ⁺ and then exposed to a buffer containing increasing concentrations of nicotine for 2 minutes in the presence (control) or absence of 1 μM methadone. ⁸⁶ Rb ⁺ efflux was calculated as the percent of ⁸⁶ Rb ⁺ loaded, and E _max was defined as the maximum response in the absence of methadone. The curve shown is from a single experiment measured in quadruplicate. EC ₅₀ values in the presence and absence of methadone were 28.8 ± 1.2 and 21.3 ± 2.1 μM, respectively (mean ± standard error from 4 independent experiments). The value E _max (mean ± standard error) in the presence of 1 μM methadone was 63 ± 2% of the control value. Both EC _max values (p <0.05) and E _max values (p <0.01) in the presence of methadone are significantly different from the control values as shown in FIG. In the presence, the maximum ⁸⁶ Rb ⁺ efflux (E _max ) elicited by nicotine was markedly reduced, however, the EC ₅₀ of nicotine was only slightly altered. This result in fact shows that methadone blocks α3β4 nAChR function primarily by a non-competitive mechanism.

(Inhibitory effect of methadone metabolites and structural analogs on ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells)
We tested seven compounds related to methadone (including its metabolites and structural analogs) for agonist and antagonist effects on ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells. None of these compounds increased ⁸⁶ Rb ⁺ efflux up to a concentration of 100 μM (data not shown).

(Effects of methadone and related drugs on nAChR)
However, all compounds tested here were relatively effective blockers of nicotine-induced ⁸⁶ Rb ⁺ efflux (see Table 1). Thus, the long acting methadone analogs LAAM and propoxyphene and norpropoxyphene were almost as effective as methadone in blocking this α3β4 receptor-mediated response. The methadone metabolite, EDDP, is even more effective; in fact, EDDP appears to be one of the most effective nAChR antagonists reported, with an efficacy about 5 times higher than methadone and about mecamylamine's Two times more effective (Figure 6; Table 1). Furthermore, these studies indicate that the difference in IC ₅₀ values between (−)-EDDP and mecamylamine is substantially significant (p <0.02), while (+)-EDDP is not significant (0 .05 <p <0.1), but the two enantiomers of the metabolite, like methadone, are equally effective in blocking α3β4 nAChR (Table 1).

FIG. 6 shows a comparison of the inhibition of nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells by methadone, (+)-EDDP, LAAM and mecamylamine. ⁸⁶ Rb ⁺ efflux was measured as described in the experimental procedure section. Cells were loaded with ⁸⁶ Rb ⁺ and then 100 μM in buffer alone (basal release) or in the presence or absence of indicated concentrations of racemic methadone, (+)-EDDP, LAAM or mecamylamine. Was exposed to a buffer containing nicotine for 2 minutes. ⁸⁶ Rb ⁺ efflux was expressed as a percentage of ⁸⁶ Rb ⁺ loaded and the control value was defined as ⁸⁶ Rb ⁺ efflux elicited by 100 μM nicotine in the absence of methadone.

(Non-competitive blockade of nAChR function by methadone metabolites and structural analogs)
None of the compounds examined here competed effectively for [ ³ H] EB binding sites, which, like methadone, indicated that they blocked receptor function by a non-competitive mechanism. Suggest. To examine this more directly, the effect of (+)-EDDP and LAAM on the concentration response curve for receptor activation by nicotine was examined. ⁸⁶ Rb ⁺ efflux was measured as described in the experimental procedure section. Cells were loaded with ⁸⁶ Rb ⁺ and then exposed to a buffer containing increasing concentrations of nicotine in the presence or absence of 0.5 μM EDDP, 3 μM LAAM (control) for 2 minutes. ⁸⁶ Rb ⁺ efflux was calculated as% of loaded ⁸⁶ Rb ⁺ and EC ₅₀ was defined as the maximum response in the absence of antagonist. The curve shown is from a single experiment measured in quadruplicate. The EC ₅₀ values for nicotine-induced ⁸⁶ Rb ⁺ efflux in control cells were 28.2 ± 1.5 and 25.5 ± 1.5 in the presence of 0.5 μM (+) EDDP and 3 μM LAAM, respectively. And 18.8 ± 1.4 μM ^* . The E _max values in the presence of 0.5 μM (+) EDDP and 3 μM LAAM were 60 ± 3% ^** and 44 ± 5% ^** of the control, respectively. Values are mean ± standard error from three independent experiments. Values markedly different from control values are specified as ^* p <0.05 and ^** p <0.01, respectively. As shown in FIG. 7, both of these compounds acted as non-competitive blockers of the α3β4 nicotinic receptor.

(Discussion)
We investigated the effect of the methadone enantiomer and its metabolites and the three structural analogs of methadone on the function of rat α3β4 nAChR stably expressed in KXα3β4R2 cells. All of these compounds inhibited nicotine-induced ⁸⁶ Rb ⁺ efflux in a concentration-dependent manner and with a relatively high potency compared to mecamylamine. In particular, EDDP, the major oxidative metabolite of methadone, exhibits an IC ₅₀ of about 0.4 μM and is one of the most effective nicotinic antagonists reported.

The non-competitive mechanism of nAChR blockade by methadone, EDDP and LAAM is a significant decrease in maximal receptor-mediated responses in the presence of these compounds, without substantial changes in EC ₅₀ values of nicotine-induced ⁸⁶ Rb ⁺ efflux. Clearly shown by The non-competitive mechanism is also consistent with the observation that neither methadone, its metabolites, or its structural analogs are effectively comparable to the [ ³ H] EB binding site that represents the agonist recognition site of the receptor. Taken together, these data demonstrate that all these compounds can block most within the α3β4nAChR channel. Also, in the presence of methadone and LAAM, there appears to be a slight but substantially significant decrease in the EC ₅₀ value of nicotine-induced ⁸⁶ Rb ⁺ efflux, and these drugs have the potential of nicotine at the receptor. Suggests that this can actually be increased. There is a high possibility that small differences in The EC ₅₀ values of the nicotine is a statistical artifact, we can not exclude the allosteric effect.

  The (+)-enantiomer and (-)-enantiomer of methadone and its metabolites are equally competent in blocking nChR. This is in contrast to the agonistic action of methadone at the sedation receptor, almost entirely due to the (−)-enantiomer. Therefore, the high potential of the (+)-enantiomer of methadone and its metabolites allows for the blockade of nicotine-like receptors without having to induce sedative receptors. This in turn allows these (+)-enantiomers to be used in conditions where blockade of neuronal nicotinic receptors may be beneficial. For example, receptor blockade by mecamylamine has been reported to aid smoking cessation (Rose et al., 1994, 1998), and the most effective methadone metabolite is about twice as effective as mecamylamine. In addition, nicotinic receptors are thought to play an important role in several analgesia pathways (Flores, 2000). Analgesia is most associated with nicotinic agonists, but these effects are not fully understood, and nicotinic antagonists may also contribute to analgesia (Hamann and Martin, 1992). If this is the case of methadone and its metabolites, their analgesic effects through nicotine-like mechanisms are probably additional to the analgesia mechanism mediated by sedative receptors. This is particularly useful where tolerance to sedatives and / or upper limit effects are a problem. In fact, dextromethorphan, which blocks NMDA and nicotinic receptors, and (+)-methadone have been reported to weaken the development of resistance to morphine analgesia (Eliot et al., 1994; Davis and Inturrisi, 1999).

  The plasma concentration of methadone following a single dose is about 0.25 μM (Inturrisi and Verebelly, 1972), and steady state concentrations in patients taking methadone can chronically exceed 1 μM (de Vos et al., 1995; Alburges et al., 1996; Dyer et al., 1999). At these concentrations, methadone can be expected to produce significant blockade of the α3β4 nicotinic receptor. More effective EDDP steady-state plasma concentrations are usually lower, but the peak concentration following administration of methadone can reach up to 0.2 μM (de Vos et al., 1995).

  It should also be noted that (+)-methadone blocks the NMDA receptor channel with the same (but slightly lower) ability as the nicotine-like receptor found herein (Gorman 1997; Stringer et al., 2000). Blockade of the NMDA receptor methadone is also associated with its analgesia (Shimoyama et al., 1997; Davis and Inturrisi, 1999) and its potential to treat chronic pain and / or neuropathic pain. Of particular relevance to utility (Elliot et al., 1995; Hewitt, 2000; Stringer et al., 2000). Furthermore, the potential of methadone to attenuate morphine resistance may include NMDA receptors (Gorman et al., 1997; Davis and Inturrisi, 1999). In this regard, however, blockade of nicotine-like receptors by EDDP and (+)-methadone can also contribute directly to analgesia and can even contribute to attenuation of morphine tolerance. Thus, methadone and its metabolites may potentially affect three different neurotransmission systems associated with analgesia pathway and sedation resistance.

  Thus, the compounds of the present invention block α3β4 nicotinic cholinergic receptors by a non-competitive mechanism consistent with channel blockade. Both the (+)-enantiomer and the (-)-enantiomer of methadone and their metabolites are active; therefore, the (+)-enantiomer of these compounds in blocking the nicotinic receptor. The body, especially the high potential of EDDP, can be used as a probe for nicotinic receptors without affecting the sedative receptors.

(Compound)
In describing the compounds, the following definitions are used, each including all possible geometric isomers, racemic isomers, diastereoisomers, and their enantiomers:
The term “alkyl” includes branched and straight chain, saturated and unsaturated, substituted and unsubstituted alkyl groups. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.

  The term “alkenyl” refers to an ethylenically unsaturated hydrocarbon group and can be straight and branched chain, saturated or unsaturated.

  The term “alkynyl” refers to a straight or branched hydrocarbon group having one or two acetylene bonds that can be saturated or unsaturated.

  The term “aryl” refers to phenyl that may be substituted with 1 to 5 substituents.

  The term “azaaromatic” refers to an aromatic ring containing 1-3 nitrogen atoms that can be substituted with 1-5 substituents.

  The general structures of these compounds are shown below as Formula I and Formula II, and include all possible geometric isomers, racemates, diastereoisomers, and their enantiomers:

ここで、
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Ｒ^３は水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_３〜Ｃ_６）シクロアルキル、（Ｃ_２〜Ｃ_６）アルケニル、アリール、およびアリール（Ｃ_１〜Ｃ_６）アルキルより選択され；
好ましくは、Ｒ^３はメチルまたはエチルであり；
Ｒ^４はＣ_１〜Ｃ_６アルキルおよび（Ｃ_３〜Ｃ_６）シクロアルキルであり；そして
Ｒ^５は、以下からなる群より独立して選択される１〜５個の置換基を有するアリールまたはアザ芳香族であり、そしてＲ^１と結合して結合体化環系を生じる：水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_３〜Ｃ_６）シクロアルキル、（Ｃ_２〜Ｃ_６）アルケニル、アリール、およびアリール（Ｃ_１〜Ｃ_６）アルキル、Ｎ−メチルアミノ、Ｎ，Ｎ−ジメチルアミノ、カルボキシレート、（Ｃ_１〜Ｃ_３）アルキルカルボキシレート、カルボキシアルデヒド、アセトキシ、プロピオニルオキシ、イソプロピオニルオキシ、シアノ、アミノメチル、Ｎ−メチルアミノメチル、Ｎ，Ｎ−ジメチルアミノメチル、カルボキサミド、Ｎ−メチルカルボキサミド、Ｎ，Ｎ−ジメチルカルボキサミド、アセチル、プロピオニル、ホルミル、ベンゾイル、スルフェート、メチルスルフェート、ヒドロキシル、メトキシ、エトキシ、プロポキシ、イソプロポキシ、チオール、メチルチオ、エチルチオ、プロピオチオ−ル、フルオロ、クロロ、ブロモ、ヨード、トリフルオロメチル、プロパルギル、ニトロ、カルバモイル、ウレイド、アジド、イソシアネート、チオイソシアネート、ヒドロキシルアミノ、およびニトロソ。

here,
R ¹ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) Alkenyl and aryl or azaaromatic having 1 to 5 substituents independently selected from the group consisting of: hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cyclo _{alkyl, (C} 2 _{~C 6)} alkenyl, aryl, and aryl _(C 1 _{~C 6)} alkyl, N- methylamino, N, N- dimethylamino, _{carboxylate, (C} 1 _{~C 3)} alkyl carboxylate, Carboxaldehyde, acetoxy, propionyloxy, isopropionyloxy, cyano, aminomethyl, N-methylaminomethyl, N, N-dimethylaminomethyl, carboxyl Mido, N-methylcarboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate, methylsulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothiol, fluoro , Chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thioisocyanate, hydroxylamino, and nitroso;
R ² is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkene, or (C ₂ -C ₆ ) alkenyl, and in formula I, R ² is also O═ or HN═ More can be selected;
R ³ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl;
Preferably R ³ is methyl or ethyl;
R ⁴ is C ₁ -C ₆ alkyl and (C ₃ -C ₆ ) cycloalkyl; and R ⁵ is aryl or aza having 1 to 5 substituents independently selected from the group consisting of Is aromatic and combines with R ¹ to give a conjugated ring system: hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl _(C 1 _{~C 6)} alkyl, N- methylamino, N, N- dimethylamino, _{carboxylate, (C} 1 _{~C 3)} alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy , Cyano, aminomethyl, N-methylaminomethyl, N, N-dimethylaminomethyl, carboxamide, N-methylcarboxamide, N , N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate, methyl sulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothiol, fluoro, chloro, bromo, iodo, tri Fluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thioisocyanate, hydroxylamino, and nitroso.

  The compounds can be in the form of pharmaceutically acceptable salts, including but not limited to: inorganic acid addition salts (eg, hydrogen chloride, hydrogen bromide, sulfate, phosphate and Nitrates); organic acid addition salts (eg acetate, galactate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate Methanesulfate, salicylate, p-toluenesulfonate, benzenesulfonate, and ascorbate); salts with acid amino acids (eg, aspartate and glutamate); It may be a hydrate or solvate with alcohol and other solvents. Salt forms may be prepared by mixing the acid and the appropriate amine in a conventional solvent with or without alcohol or water.

  More specifically, the following compounds are contemplated:

^＊＝Ｎは、Ｒ^３と炭素を有するＲ^２との間で、５員環において二重結合が存在することを示す。

^* = N indicates that there is a double bond in the 5-membered ring between R ³ and R ² having carbon.

As the compounds shown below, compounds in which R ⁵ is bound to R ¹ can also be used; and can be prepared through simple modifications to the synthesis of the above compounds.

ここで、
ＸおよびＹは、ＣおよびＮからなる群より独立して選択され；
Ｒ^３は上記の通りであり；
Ｒ^６は、水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_３〜Ｃ_６）シクロアルキル、（Ｃ_２〜Ｃ_６）アルケニル、アリール、およびアリール（Ｃ_１〜Ｃ_６）アルキル、Ｎ−メチルアミノ、Ｎ，Ｎ−ジメチルアミノ、カルボキシレート、（Ｃ_１〜Ｃ_３）アルキルカルボキシレート、カルボキシアルデヒド、アセトキシ、プロピオニルオキシ、イソプロピオニルオキシ、シアノ、アミノメチル、Ｎ−メチルアミノメチル、Ｎ，Ｎ−ジメチルアミノメチル、カルボキサミド、Ｎ−メチルカルボキサミド、Ｎ，Ｎ−ジメチルカルボキサミド、アセチル、プロピオニル、ホルミル、ベンゾイル、スルフェート、メチルスルフェート、ヒドロキシル、メトキシ、エトキシ、プロポキシ、イソプロポキシ、チオール、メチルチオ、エチルチオ、プロピオチオ−ル、フルオロ、クロロ、ブロモ、ヨード、トリフルオロメチル、プロパルギル、ニトロ、カルバモイル、ウレイド、アジド、イソシアネート、チオイソシアネート、ヒドロキシルアミノからなる群より独立して選択される。

here,
X and Y are independently selected from the group consisting of C and N;
R ³ is as described above;
R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl, N-methyl amino, N, N- dimethylamino, _{carboxylate, (C} 1 _{~C 3)} alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- Dimethylaminomethyl, carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate, methyl sulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propi Thio - le, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azido, isocyanate, thioisocyanate, is independently selected from the group consisting of hydroxylamino.

(Exemplary synthesis)
Figures 8 and 9 show some exemplary synthetic reactions that can be used to produce these compounds. Unless otherwise noted, the compounds disclosed in this synthesis include all possible geometric isomers, racemic forms, diastereoisomeric forms, and enantiomeric forms. The structures listed in parentheses correspond to those listed in the table above. Those skilled in the art will recognize that these compounds are formed by other synthetic reactions and that simple modifications to these synthetic systems produce similar products, all of which are within the scope of the present invention. Recognize what is considered to be.

(Series 1)
FIG. 8 shows the basic synthetic reaction to produce compound (f) (structures 9 and 10). First, bromobenzene (a) or a bromoheterocycle in which X is a heteroatom at any position is mixed with CH ₃ CN and KNH ₂ in liquid ammonia to produce (b). This is then mixed with a second bromobenzene, or heterocycle (Y is a heteroatom, selected at any position independently of X) with Br ₂ at 105-110 ° C .; Diphenyl cyanide (c) is produced. Subsequently, this product is reacted with t-butylene methoxylate in a basic solution to produce compound (d). Compound (d) is reacted with SOCl ₂ and ammonia to produce compound (f), an amidino analog. One skilled in the art will appreciate that in view of this synthesis, compounds 11 and 12 and other variations can be readily produced by similar methods.

(Synthesis of compounds (g) and (j))
Compound (f) is further reacted with 1.2 N HCl with NaNO ₂ for about 1 hour to produce compound (g) (structures 5 and 6). Reaction of this mixture with LAH / THF produces compound (j). This can also be used in the methods disclosed herein.

(Synthesis of compounds (h) and (k))
Starting with the reaction stopped with compound (g) above, further reaction with CH ₃ I replaces the methyl group with a 5-membered ring nitrogen to produce compound (h) (structures 7 and 8). . Compound (k) is achieved by reacting this mixture with LAH / THF.

(Synthesis of compounds (i), (l), (m), (n), (o), and (p))
The reaction product is picked up during the formation of compound (h), and the reaction with EtLi opens the double-bonded oxygen to produce compound (i) (structures 33 and 34). Subsequently, compound (i) serves as the basis for three other reaction systems.

Compound (l) is formed by reacting compound (i) with MCPBA and CHCl ₃ at 0 ° C. for 12 hours. Subsequently, compound (m) (structures 1 and 2) is formed by reacting it with NaBH ₄ .

Compound (n) (structures 3 and 4) is produced by reacting compound (i) with NaBH ₄ .

Compound (i) is reacted with HCHO and CH ₃ OH to produce compound (o) (structure 14). This is then reacted with H ₂ and Pd—C to produce compound (p) (structures 16, 18).

(Series 2)
The series 2 synthesis reaction is the same as the series 1 synthesis reaction except that the second step of mixing the second bromobenzene (b ₂ ) or bromoheterocycle is omitted. Accordingly, similar mono-phenyl compounds are produced. FIG. 9 shows a series 2 synthesis reaction. Compounds similar to Series 1 compounds are indicated by a reference symbol using the subscript 2.

(Analgesic and abuse deterrence)
In order to confirm these suspicions that the compounds of the present invention actually have analgesic effects, we experimented with mice. FIG. 10 shows the results of experiments performed on native adult Swiss-Webster mice. Each enantiomer of EDDP (40 μg) was administered to the mouse cerebrum. These animals were monitored for baseline sensitivity using a warm-water tail-withdrawal nocturny assay, and the response time to tail withdrawal was monitored as an analgesic measure. It was. The results demonstrate that administration of either enantiomer of EDDP increased tail withdrawal reaction time. Therefore, it is clear that EDDP, which is a metabolite of d-methadone, has a remarkable analgesic effect. Similarly, the metabolite EMDP and structural analogs of EDDP and EMDP are expected to have similar effects. Figures 11 and 12 show the effect of EDDP concentration on the inhibition of currents activated by nicotine. This is explained as one of the analgesic effects.

  As discussed in detail above, we believe that d-methadone metabolites and their analogs block the nicotine α3β4 receptor. Recently, it was reported that dextromethorphan and dextrophan, which are α3β4 blockers, actually deter abuse of abused substances. Glick et al. Report reduced self-administration of each of morphine, methamphetamine, and nicotine in rats when exposed to 5-30 mg / kg of these specific α3β4 blockers. (Glick SD, Maisonneuve IM, Dickinson HA, Kitchen BA; 87-90). With the discovery that d-methadone metabolites and their structural analogs are α3β4 blockers, we now believe that d-methadone metabolites and their analogs also have such inhibitory effects.

  Although we do not want to be bound by this theory, we believe that d-methadone metabolites or structural analogs interfere with the rewarding component of the abused substance. This rewarding component is often considered as an euphoric effect and induces the act of seeking drugs. Administration of d-methadone metabolites or structural analogs interferes with these effects and consequently deters abuse. Such administration aids smoking cessation and deters abuse of more hardcore materials.

  Thus, administration of d-methadone metabolites or their structural analogs can actually deter abuse of abuse substances from opioids to nicotine.

(Administration)
The compounds of the present invention may be administered to a patient in an amount effective or effective dose to reduce pain and / or deter abuse of the substance of abuse. In another embodiment, the compound is administered in a single pharmaceutical composition in combination with an abuse substance, particularly an opioid or other analgesic. In this scenario, the compounds of the invention contribute to the analgesic effect while also deterring abuse of related compounds. Thus, patients benefit from the analgesic effect conferred by this compound while gaining the additional benefit of reducing the potential for abuse. In another embodiment, the compounds of the invention are administered independently of the substance of abuse to induce an analgesic effect. In yet another example, independent administration of the compound serves to deter abuse of individually administered abuse substances.

  An “effective amount”, “therapeutic amount”, or “effective dose” is an amount sufficient to elicit the desired pharmacological or therapeutic effect and thus provide effective prevention or treatment for the condition or disorder. Means. Thus, when treating a CNS disorder, an effective amount of a compound is an amount sufficient to cross the subject's blood brain barrier and interact with the relevant receptor site in the subject's brain. Prevention of a condition or disorder is manifested by delaying the appearance of the condition or disorder symptoms. Treatment of a condition or disorder is manifested by a decrease in symptoms associated with the condition or disorder, or an improvement in the recurrence of symptoms of the condition or disorder.

  Effective doses may vary depending on factors such as the condition of the patient, the severity of the symptoms of the disorder, age, weight, metabolic status, the drug currently being taken, the manner in which the pharmaceutical composition is administered. Typically, an effective dose of a compound will generally require administration of the compound in an amount of about 0.1-500 mg / kg body weight of the subject. In embodiments of the invention, a dose of about 0.1 to about 300 mg / kg per day is administered indefinitely or until symptoms associated with discontinuation of the condition or disorder appear. Preferably, about 1.0-50 mg / kg body weight is administered per day. When administered parenterally, less dosage is required.

  One skilled in the art will recognize that the compounds of the present invention can be combined with agents suitable for making pharmaceutical compositions for proper administration. Such compositions limit the active ingredients for the compounds of the invention, or may contain other active ingredients, or multiple compounds of the invention, as appropriate.

(Pharmaceutical composition)
The compounds of the present invention may be used as a single agent or as a primary or ancillary agent using any other pharmaceutical treatment, chemical treatment, drug treatment or non-drug treatment, or a combination thereof. Useful in pharmaceutical compositions for systemic administration to mammals, including humans. In addition to the compound, a pharmaceutical composition according to the present invention may include one or more agents including carriers, excipients, active agents, fillers and the like.

  Administration of the compound, or a pharmaceutically acceptable salt, or a complex thereof can be oral, buccal, nasal, pulmonary, transdermal, rectal, vaginal, intradermal, intrathecal, intravenous Depending on the accepted route of administration, including but not limited to, the intramuscular route, the intramuscular route, and / or the subcutaneous route, it can be used rapidly, as a single dose, or intermittently or not It is administered on a regular schedule at specific intervals or by continuous dosing at unspecified intervals.

  Pharmaceutical preparations are tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile parenteral solutions or sterile parenteral suspensions containing an appropriate amount of the active ingredient. It can be used in unit dosage forms such as suspensions, oral solutions or suspensions, oil-in-water emulsions or water-in-oil emulsions, and the like. Topical applications can be in the form of ointments, creams, lotions, jellies, sprays, water dispensers and the like. For oral administration, solid or liquid unit dosage forms can be prepared with the compounds in this invention.

  Either liquid or solid unit dosage forms can be readily prepared for oral administration. For example, the compounds include dicalcium phosphate, magnesium magnesium silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and substances that are functionally similar as pharmaceutical excipients or pharmaceutical carriers. Such as conventional ingredients. Sustained release formulations can be used as needed. Capsules can be formulated by mixing the compound and an inert pharmaceutical diluent and inserting the mixture into hard gelatin capsules of appropriate size. If soft capsules are desired, a slurry (or other dispersion) of the compound can be encapsulated by machine into gelatin capsules with an acceptable vegetable oil, light oil, or other inert oil.

  Suspensions, syrups and elixirs can be used for oral dosage in liquid unit dosage forms. Liquid preparations containing oil can be used in oil-soluble form. Vegetable oils such as corn oil, peanut oil, safflower oil, together with flavors, sweeteners, and optional preservatives, for example, produce acceptable liquid preparations. A surfactant can be added to the water to make a syrup for liquid dosing. Hydro-alcoholic pharmaceutical preparations can be used to have sugars, saccharin, acceptable sweeteners such as biological sweeteners, and flavors in the form of elixirs.

  Pharmaceutical compositions for parenteral and suppository administration can also be obtained using techniques standard in the art. Another preferred use of these compounds is in transdermal parenteral pharmaceutical preparations in mammals such as humans.

  The above and other compounds may be present alone in the reservoir or are present in a form combined with a pharmaceutical carrier. An acceptable pharmaceutical carrier for the purposes of the present invention is a known carrier that does not adversely affect the substance, including the drug, host, drug delivery device. Suitable pharmaceutical carriers include: sterile water, saline, dextrose, dextrose in water or saline, castor oil, and about 30 to about 35 moles of ethylene oxide bound per mole of castor oil. Emulsifiers such as condensation products with ethylene oxide, liquid acids, lower alkanols, oils (eg corn oil, peanut oil, sesame oil etc.) and fatty acids mono- or diglycerides, or phosphatides (eg lecithin), glycols, polyalkylenes Glycols, aqueous media in the presence of suspending agents (eg, sodium carboxymethyl cellulose), sodium alginate, poly (vinyl pyrrolidone), etc. (alone or with a suitable dispersing agent such as lecithin), or polyoxyethylene stearate Such as emissions. The carrier may also contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and the like with the penetration enhancers of the invention.

  Although the invention has been described with reference to specific forms thereof, those skilled in the art will recognize that a wide variety of equivalents can be used without departing from the scope and spirit of the invention as set forth in the appended claims. It is understood that certain elements disclosed in the specification may be substituted.

FIG. 1 shows the chemical structures of methadone, EDMP, EDDP, analogs, and mecamylamine. FIG. 2 is a graph showing the effect of methadone versus nicotine on ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells. FIG. 3 is a graph showing inhibition of: nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells by methadone and its two enantiomers. FIG. 4 is a graph showing competition by methadone for [ ³ H] EB binding sites in membrane homogenates from KXα3β4R2 cells. FIG. 5 is a graph showing non-competitive inhibition of nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells by methadone. FIG. 6 is a graph showing competition for inhibition of nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells by methadone, (+)-EDDP, LAAM and mecamylamine. FIG. 7 is a graph showing non-competitive inhibition of nicotine-induced ⁸⁶ Rb ⁺ efflux from KXα3β4R2 cells by (+)-EDDP and LAAM. FIG. 8 is a schematic diagram of a synthetic reaction scheme for producing various compounds according to the present invention. FIG. 8 is a schematic diagram of a synthetic reaction scheme for producing various compounds according to the present invention. FIG. 9 is another schematic diagram of a synthetic reaction scheme for producing various compounds in accordance with the present invention. FIG. 10 is a graph showing the analgesic effect of EDDP. FIG. 11 shows sample flow inhibition by EDDP. FIG. 12 shows a concentration response curve. FIG. 13 is a graph comparing glutamate-induced catecholamine release by treatment with MK-801, d-methadone, and R (+) EDDP in the hippocampus. FIG. 14 is a graph comparing glutamate-induced catecholamine release by treatment with MK-801, d-methadone, and R (+) EDDP in the striatum.

Claims (32)

A method for inducing analgesia, wherein the method is selected from the following formulas I and II, and one of its pharmaceutically acceptable salts, in an amount that induces analgesia. A method comprising administering to a patient a composition containing the compound:

Here, Formula I and Formula II include all possible geometric isomers, racemic isomers, diastereoisomers, and enantiomers, and where:
R ¹ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C _6). ) Selected from alkenyl, aryl, and azaaromatic;
R ² is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkene, and (C ₂ -C ₆ ) alkynyl, and in formula I, R ² is also O═ Or may be selected from HN =;
R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl. Selected;
R ⁴ is selected from (C ₁ -C ₆ ) alkyl, and (C ₃ -C ₆ ) cycloalkyl; and R ⁵ is aryl or azaaromatic and results in a conjugated ring system For R ¹ may be included. The method according to claim 1, wherein said R ¹ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfe Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A process having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. The method according to claim 1, wherein said R ⁵ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfe Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A process having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. The method of claim 1, wherein R ³ is methyl or ethyl. 2. The method of claim 1, wherein the compound is selected from the following group:

. 2. The method of claim 1, wherein the amount of the composition that induces analgesia is sufficient to block the nicotine receptor and thereby induce analgesia. . A method of deterring abuse of a substance of abuse, said method comprising deterring abuse of a composition comprising a compound selected from the following formulas I and II and one of its pharmaceutically acceptable salts: A method comprising administering an amount to a patient:

Here, Formula I and Formula II include all possible geometric isomers, racemic isomers, diastereoisomers, and enantiomers, and where:
R ¹ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C _6). ) Selected from alkenyl, aryl, and azaaromatic;
R ² is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkene, and (C ₂ -C ₆ ) alkynyl, and in formula I, R ² further represents O═ Or may be selected from HN =;
R ³ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl;
R ⁴ is (C ₁ -C ₆ ) alkyl, and (C ₃ -C ₆ ) cycloalkyl; and R ⁵ is aryl or azaaromatic and results in a conjugated ring system Can include a bond to R ¹ . The method according to claim 7, wherein said R ¹ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfe Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A process having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. The method according to claim 7, wherein said R ⁵ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfe Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A process having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. R ³ is methyl or ethyl, A method according to claim 7. 8. The method of claim 7, wherein the compound is selected from the following group:

. 8. The method of claim 7, wherein the amount of the compound selected from Formula I and Formula II and one of the pharmaceutically acceptable salts blocks the nicotine receptor, Is sufficient to deter abuse of the substance of abuse. A compound selected from the group consisting of Formula I and Formula II below, and pharmaceutically acceptable salts thereof:

Here, Formula I and Formula II include all possible geometric isomers, racemic isomers, diastereoisomers, and enantiomers, and where:
R ¹ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C _6). ) Selected from alkenyl, aryl, and azaaromatic;
R ² is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkene, and (C ₂ -C ₆ ) alkynyl, and in formula I, R ² is O═ or May be further selected from HN =;
R ³ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl;
R ⁴ is (C ₁ -C ₆ ) alkyl, and (C ₃ -C ₆ ) cycloalkyl; and R ⁵ is aryl or azaaromatic and forms a bond to R ¹ to form a bond A compound of formula II wherein R ⁵ = R ¹ = phenyl, R ² is ethyl, R ⁴ is H, and R ³ is H or CH ₃ except. A compound according to claim 13, wherein said R ¹ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfo , Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A compound having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. A compound according to claim 13, wherein said R ⁵ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently hydrogen, (C ₁ - C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxylate , _(C 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide, N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfo , Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A compound having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. R ³ is methyl or ethyl A compound according to claim 13. 14. A compound according to claim 13, wherein the compound is selected from the following group:

. 14. A compound according to claim 13, wherein the analog is in a pharmaceutically acceptable form. The pharmaceutically acceptable salts are inorganic acid addition salts, organic acid addition salts, salts with acidic amino acids, and hydrates or solvates of these salts with alcohols and other solvents. 18. A compound according to 18. 20. A compound according to claim 19, wherein the analog is an inorganic acid addition salt selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, and nitrate. The analog is acetate, mucolate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, 20. The compound of claim 19, which is an organic acid addition salt selected from the group consisting of salicylate, p-toluenesulfonate, benzenesulfonate, and ascorbate. 20. The compound of claim 19, wherein the analog is a salt having an acidic amino acid selected from the group consisting of aspartic acid and glutamic acid. A pharmaceutical composition comprising:
A pharmaceutically acceptable agent; and a compound selected from one of the following formulas I and II, and pharmaceutically acceptable salts thereof:

Here, Formula I and Formula II include all possible geometric isomers, racemic isomers, diastereoisomers, and enantiomers, and where:
R ¹ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C _6). ) Selected from alkenyl, aryl, and azaaromatic;
R ² is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkene, and (C ₂ -C ₆ ) alkynyl, and in formula I, R ² is O═ or May be further selected from HN =;
R ³ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, aryl, and aryl (C ₁ -C ₆ ) alkyl;
R ⁴ is (C ₁ -C ₆ ) alkyl, and (C ₃ -C ₆ ) cycloalkyl; and R ⁵ is aryl or azaaromatic and forms a bond to R ¹ to form a bond An amount that is sufficient to induce induction of analgesia and / or deter abuse of the substance of abuse. A composition according to claim 23, wherein said R ¹ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently group consisting of hydrogen, (C ₁ -C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxy _{rate, (C} 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfo , Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A composition having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. A composition according to claim 23, wherein said R ⁵ is selected from the group consisting of aryl and aza aromatic, said aryl and azaaromatic are each independently group consisting of hydrogen, (C ₁ -C _{6) alkyl, (C} 3 -C _{6) cycloalkyl, (C} 2 -C ₆₎ alkenyl, aryl, aryl _(C 1 -C ₆₎ alkyl, N- methylamino, N, N- dimethylamino, carboxy _{rate, (C} 1 -C ₃₎ alkyl carboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyl oxy, cyano, aminomethyl, N- methylaminomethyl, N, N- dimethylaminomethyl, carboxamide, N- methyl-carboxamide N, N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfo , Methyl sulfate, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothio, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azide, isocyanate, thio A composition having 1 to 5 substituents selected from the group consisting of isocyanate, hydroxyamino, and nitroso. R ³ is methyl or ethyl, A composition according to claim 23. 24. The composition of claim 23, wherein the compound is selected from the following group:

. 24. The pharmaceutical composition according to claim 23, wherein the analog is in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts are inorganic acid addition salts, organic acid addition salts, salts with acidic amino acids, and hydrates or solvates of these salts with alcohols and other solvents. 28. The pharmaceutical composition according to 28. 30. The pharmaceutical composition of claim 29, wherein the analog is an inorganic acid addition salt selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, and nitrate. The analog is acetate, mucolate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is an organic acid addition salt selected from the group consisting of salicylate, p-toluenesulfonate, benzenesulfonate, and ascorbate. 30. The pharmaceutical composition of claim 29, wherein the analog is a salt having an acidic amino acid selected from the group consisting of aspartic acid and glutamic acid.

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