CN101675926A - Analgesics and methods of use - Google Patents

Analgesics and methods of use Download PDF

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CN101675926A
CN101675926A CN200910168311A CN200910168311A CN101675926A CN 101675926 A CN101675926 A CN 101675926A CN 200910168311 A CN200910168311 A CN 200910168311A CN 200910168311 A CN200910168311 A CN 200910168311A CN 101675926 A CN101675926 A CN 101675926A
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phenyl
group
pyridine radicals
chloro
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R·史密斯-卡里斯
F·S·卡鲁索
P·克鲁克斯
K·J·凯拉
校迎宪
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Endo Pharmaceuticals Inc
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

A method for inducing analgesia and/or inhibiting abuse of abusive substances includes administration of d-methadone metabolites or their structural analogs. The d-methadone metabolites, EMDP and EDDP, and their structural analogs may be incorporated into a suitable pharmaceutical composition for administration to patients. The invention includes the method itself, certain structural analogs, andpharmaceutical compositions for use in accordance with the method.

Description

Analgesic and using method
The cross reference of related application
The U.S. Provisional Application No.60/315 that the application submits on August claimed calendar year 2001 29,530 priority, it quotes in full at this as a reference.
Invention field
The present invention relates to the analog of d-methadone metabolite and they and they and be used to the method for inducing pain relieving and/or being used to suppress the property abused substance abuse, for example opiates, ***e, nicotine etc.
The explanation of association area
The research of pain and pain relief clearly reveals, and the development of pain relief is not single approach.A lot of different pain are originated and alleviated all is known and suspicious.For this reason, scientist constantly seeks the approach of more, the different side effect relevant with it with minimizing with better treating pain.
Nicotine-like acetylcholinergic receptor is distributed widely in maincenter and peripheral nervous system, there the effect of their mediation endogenous acetylcholine and nicotine and other nicotine sample agonist.They often associate with the cyton and the aixs cylinder of main neurotransmitter system, nicotine sample agonist is considered to play a role by these receptors, promote the release of a large amount of neurotransmitteies, for example dopamine, norepinephrine, γ-An Jidingsuan, acetylcholine and glutamate, Glu are (about comment, referring to Wonnacott, 1997), and the release of some pituitary hormone (Andersson et al., 1983; Sharpet al., 1987; Flores et al., 1989; Hulihian-Giblin et al., 1990).The release of various neurotransmitters and hormone helps the different effect of nicotine probably, is opposed effect sometimes.For example, the release of norepinephrine is usually with excited relevant, and the stimulation of γ-An Jidingsuan system is with calm relevant.
For the first time checked the probability (Davis etal., 1932) of nicotine as analgesic before about 70 years, but it draws relatively poor therapeutic index to analgesic dosage-response relation, this is unfavorable for its exploitation.Recent findings the pain relieving character of epibatidine, it is a kind of strong nicotine sample agonist, be by Daly and colleague (Spande et al. isolating from Ecuador's Rana nigromaculata skin, 1992), interest (Bannon et al., 1998 of people have been caused again to the pain relieving probability of the medicine that acts on nicotine receptor; Flores andHargreaves, 1998; Flores, 2000).
Might more than one neurotransmitter system in pain relieving, play an important role.For example, methadone is a kind of synthetic μ-opiate agonist, has the pain relieving character similar to morphine (Kristensen et al., 1995), also can be used for the treatment of opiate addiction.Most of morphine sample pain relieving character of (±)-methadone is owing to (-)-enantiomer, because the opium character of (+)-enantiomer is wanted much weak (Scott et al., 1948; Smits and Myers.1974; Hornget al., 1976).But, (+)-methadone shows pain relieving effectiveness (Shimoyama et al., 1997 really in some experimental model; Davis and Inturrisi, 1999), as if this also weakened morphine tolerance development (Davis and Inturrisi, 1999).
Except agonism to opiate receptor, in the methadone competition nmda receptor channel [ 3H] the MK801 binding site, the reaction (Ebert et al., 1995) of retardance nmda receptor mediation; In addition, two of methadone kinds of enantiomer to [ 3H] the MK801 binding site almost is (Gorman et al., 1997) of equal authenticity.The medicine of some retardance nmda receptors, for example MK801, phencyclidine, dextro-methorphan and dextrorphan also block neuronal nicotinic receptor (Ramoa et al., 1990; Amador and Dani, 1991; Hernandez et al., 2000).Nicotine receptor and nmda receptor be all implications in pain pathways, and are the possible mechanism of experience pain perception.Therefore, the inventor has checked methadone, its metabolite and analog (Fig. 1) effect to neuronal nicotinic receptor.
Except participating in pain relief, have been found that recently some nicotine receptor can be in the restriction abuse figure.
The material that may be abused comprises opiates, dexoxyn, hallucinogen, psychotropic agents, ***e and other.Some abuse property material is sharp on general.Perhaps one of the most general is nicotine, sees in the tobacco product.Term used herein " abuse property material " any material that may cause abuse of expression produces dependency or brings out the behavior of seeking medicine.
During the research at d-methadone and metabolite EMDP and EDDP, the inventor finds that EMDP and EDDP and novel analog thereof induce pain relieving, can be independently or be used to prevent the abuse of one or more above-mentioned abuse materials simultaneously.
Summary of the invention
The method of inducing pain relieving and/or inhibition to abuse the property substance abuse comprises the administration of EMDP, EDDP and its novel analog.Chemical compound of the present invention can mix in the suitable pharmaceutical composition, is used for the administration to the patient.The present invention includes novel chemical compound, induce pain relieving and/or suppress the method for abuse property substance abuse and with in the method pharmaceutical composition.
Brief description of drawings
Fig. 1 describes the chemical constitution of methadone, EMDP, EDDP, analog and mecamylamine.
Fig. 2 describes methadone and nicotine is right 86Rb +The influence of from KX α 3 β 4R2 cells, overflowing.
Fig. 3 describes that methadone and two kinds of enantiomer thereof stimulate nicotine 86Rb +The inhibitory action of from KX α 3 β 4R2 cells, overflowing.
Fig. 4 describe methadone in the KX α 3 β 4R2 cell membrane homogenate products [ 3H] the competition effect of EB binding site.
Fig. 5 describes that methadone stimulates nicotine 86Rb +The noncompetitive inhibitory action of from KX α 3 β 4R2 cells, overflowing.
Fig. 6 describes that methadone, (+)-EDDP, LAAM and mecamylamine stimulate nicotine 86Rb +The inhibitory action contrast of from KX α 3 β 4R2 cells, overflowing.
Fig. 7 describes that (+)-EDDP and LAAM stimulate nicotine 86Rb +The noncompetitive inhibitory action of from KX α 3 β 4R2 cells, overflowing.
Fig. 8 is the synthetic reaction flow chart of preparation according to all cpds of the present invention.
Fig. 9 is preparation another synthetic reaction flow chart according to all cpds of the present invention.
Figure 10 shows the analgesic effect of EDDP.
Figure 11 describes the sample current inhibitory action of EDDP.
Figure 12 describes the concentration-response curve.
Figure 13 relatively uses MK-801, d-methadone and R (+) EDDP to handle the catecholamine release that glutamate, Glu stimulates in the hippocampus of back.
Figure 14 relatively uses MK-801, d-methadone and R (+) EDDP to handle the catecholamine release that glutamate, Glu stimulates in the striatum of back.
Describe in detail
Definition
In this description, the abbreviation of " metabolite " or " d-methadone metabolite " is expressed as follows defined EDDP and EMDP and pharmaceutically acceptable salt thereof, other has except the indication.
Term " (+)-methadone " expression S-(+)-methadone hydrochloride; Term " (-)-methadone " expression R-(-)-methadone hydrochloride; Term " LAAM " expression (-)-α-acetyl group methadone hydrochloride; Term " (+)-EDDP " expression R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolin perchlorate; Term " (-)-EDDP " expression S-(-)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolin perchlorate; Term " (+)-EMDP " expression R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolin hydrochlorate; Term " (-)-EMDP " expression S-(-)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolin hydrochlorate; Term " EMDP " expression (+)-EMDP, (-)-EMDP or its mixture; Term " EDDP " expression (+)-EDDP, (-)-EDDP or its mixture.
Although with the d-methadone structural similarity is arranged, EMDP and EDDP and analog thereof have the character that is different from the d-methadone.The influence that catecholamine discharges in rat hippocampal body that Figure 13 and 14 stimulates glutamate, Glu by relatively MK-801, d-methadone and (+)-EDDP and the striatum section has proved this point.Hippocampus and striatum all are important and brain anatomic region that be well studied.Hippocampus is relevant with the learning and memory function, and striatum and motor function are related.The tangential section loading [ 3H] norepinephrine or [ 3H] dopamine, then be with or without MK-801, d-methadone or (+)-EDDP in the presence of be exposed to the 1mM glutamate, Glu and reach 2 minutes.Do not have glutamate, Glu in the presence of measure baseline and discharge.These results show that (+)-EDDP is different from the d-methadone, is opium blocker and MK-801, is the NMDA blocker on the physiology.The present dosage of this difference table is offset to the right, as what arrive seen in Figure 13 and 14.Only 10 μ Md-methadones or MK-801 promptly realize the part retardance that catecholamine discharges, and (+)-EDDP does not see effect until 100 μ M yet.
The inventor believes, but is not limited to this theory, and The compounds of this invention is being induced pain relieving and/or suppressed the ability that success on the abuse is their retardance nicotine receptors.But should be noted that the combination in other sites or block also to have and help this effect.
Measured the effect of d-methadone and The compounds of this invention to α 3 β 4 neuronal nicotinic receptors of stably express in the human embryonic kidney 293 cell.These chemical compounds are strong nicotine receptor blocker.Chemical compound disclosed herein has a kind of the strongest nicotine receptor blocker that belongs to existing report.
Methadone and related drugs are to the influence of nAChRs
Experimental technique
Material and medicine.Tissue culture medium (TCM), antibiotic and serum from Invitrogen (Carlsbad, CA).[ 3H] (±)-epibatidine and [ 86Rb] Rubinorm (Ifi). ( 86Rb +) from PerkinElmer Life Science Products (Boston, MA).All (St.Louis, MO), other has except the regulation every other chemicals available from Sigma Chemical Co..(±)-methadone hydrochloride (methadone), S-(+)-methadone hydrochloride ((+)-methadone) and R-(-)-methadone hydrochloride ((-)-methadone) from Sigma/RBI (Natick, MA).Following compounds by National Institute on Drug Abuse from ResearchTriangle Institute (Research Triangle Park, NC): (-)-α-acetyl group methadone hydrochloride (LAAM, methadone analog); R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolin perchlorate ((+)-EDDP, methadone metabolite); S-(-)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolin perchlorate ((-)-EDDP, methadone metabolite); R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolin hydrochlorate ((+)-EMDP, methadone metabolite); S-(-)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolin hydrochlorate ((-)-EMDP, methadone metabolite); (+)-α-propoxyphene hydrochloride (methadone analog); The fragrant maleate of nor-third oxygen of (+)-α-N-(the fragrant metabolite of third oxygen).The structure of employed here methadone, EMDP, EDDP and some analog and mecamylamine as shown in Figure 1, mecamylamine is a kind of nicotine channel blocker of knowing.
Cell culture.In advance the human embryonic kidney 293 cell is used the stably common transfection of rat α 3 and β 4nAChR subunit gene, set up KX α 3 β 4R2 cell lines (Xiao et al., 1998).In the humidification calorstat, at 37 ℃ and 5%CO 2Down, support cell in minimal essential medium, culture media supplemented has 10% hyclone, 100 units/ml benzylpenicillin, 100mg/ml streptomycin and 0.7mg/ml Geneticin (G418).
86Rb +Overflow mensuration.Utilize 86Rb +Overflow algoscopy and measure the function of the nAChRs in transfectional cell, express, as (Xiao et al., 1998) as described in the forefathers.In brief, will select cell plating in the growth substrate in scribbling the 24 hole flat boards of poly-(D-lysine).Make cell behind the plating 37 ℃ of growths 18 to 24 hours down, reach 70 to 95% fusion rate.Containing then 86Rb +In the growth substrate of (2 μ Ci/ml) cell is cultivated 4 hours (0.5ml/ hole) down at 37 ℃.Aspirate the load mixture then, with cell buffer (15mM HEPES, 140mM NaCl, 2mM KCl, 1mM MgSO 4, 1.8mM CaCl, the 11mM glucose, pH 7.4; The 1ml/ hole) washing is three times, is respectively 30 seconds, 5 minutes and 30 seconds.Add the 1ml buffer to every hole then, contain or do not have a test compound.Cultivate after 2 minutes, collect and measure buffer, measurement discharges from cell 86Rb +Add 1ml 100mM NaOH to every hole then, make cytolysis, collect lysate, be determined to overflow and measure when finishing in the cell 86Rb +Amount.Measure the radioactivity of measuring sample and lysate by liquid scintillation counting.Calculate total load (cpm), measure the summation of sample and lysate for every hole. 86Rb +Spill-out is with institute's load 86Rb +Percentage ratio is represented.Irriate 86Rb +Overflow and be defined in and do not have the poor of nicotine overflowing under existing.
Utilize antagonist to experimentize in two different ways.In order to obtain IC 50Value makes up and suppresses curve, wherein comprises the antagonist of variable concentrations in algoscopy, to suppress to be subjected to overflowing of 100mM nicotine stimulation.With regard to the mensuration of antagonist retardance mechanism, be with or without antagonist in the presence of make up receptor by the activatory concentration-response curve of nicotine.Maximum nicotine stimulates 86Rb +Overflow (E Max) be defined in the maximum of nicotine under existing overflow with the basis overflow poor.Measure EC by the nonlinear least square regression analysis 50, E MaxAnd IC 50Value (GraphPad, San Diego, CA).
Part is in conjunction with research.Measure the ability of the agonist recognition site of chemical compound competitive n AChRs in conjunction with research at part, as (Houghtling et at., 1995 as described in the forefathers; Xiao etal., 1998).In brief, with the film preparation thing with [ 3H] EB cultivated 4 hours down at 24 ℃.By the vacuum filtration of the Whatman GF/C filter of handling with 0.5% polyethylene imine, separate bonded and free part.Measurement is retained in the radioactivity on the filter by liquid scintillation counting.Respectively do not have and have (-)-nicotine (300 μ M) in the presence of measure total combination and non-specific binding.Specificity is in conjunction with being defined as the poor of total binding and non-specific binding.Every kind of chemical compound by cultivating a series of concentration and single concentration [ 3H] EB, generate binding curve.Measure in conjunction with the IC that suppresses curve by the nonlinear least square regression analysis 50And K iValue.
The result
Methadone is right 86Rb +The influence of from KX α 3 β 4R2 cells, overflowing.Fig. 2.Methadone and nicotine are right 86Rb +The influence of from KX α 3 β 4R2 cells, overflowing.As measurement as described in testing under the technology 86Rb +Overflow.Load to cell 86Rb +, be exposed to independent buffer (Fundamentals of Measurement release) then or contain shown in the buffer of concentration methadone reach 2 minutes.100 μ M nicotine or 100 μ M nicotine add 200 μ M methadones. 86Rb +Overflow reaction with institute's load 86Rb +Percentage ratio is represented.Data shown in Figure 2 are four independent Mean +/-SEs of measuring.As shown in Figure 2, under the concentration up to 1mM, methadone does not increase 86Rb +From KX α 3 β 4R2 cells, overflow.But in parallel mensuration, 100 μ M nicotine stimulated about 10 times to foundation level 86Rb +Overflow, this stimulation is blocked by 200 μ M methadones fully.Thereby proved the retardance of methadone to α 3 β 4.
Methadone and enantiomer thereof stimulate at inhibition nicotine 86Rb +The effectiveness of from KX α 3 β 4R2 cells, overflowing.Stimulated by 100 μ M nicotine by in the presence of the progressive concentration chemical compound, measuring 86Rb +Overflow, check raceme methadone and enantiomer thereof effectiveness as the nAChRs antagonist.Load to cell 86RbW, the buffer that is exposed to independent buffer (basis discharge) then or contains 100 μ M nicotine in the presence of one of the raceme methadone of concentration shown in being with or without or methadone enantiomer reaches 2 minutes. 86Rb +Overflow with institute's load 86Rb +Percentage ratio represents that control value is defined in and stimulated by 100 μ M nicotine 86Rb +Overflow.Inhibition curve shown in Figure 3 is measured quadruplicate from single experiment.Referring to table 1 about IC 50Average and the standard error of value.As described in Figure 3, the raceme methadone may suppress that nicotine stimulates in the concentration dependent mode 86Rb +Overflow IC 50About 2 μ M.And (+)-methadone is similar (Fig. 3, table 1) with the effectiveness that (-)-methadone suppresses these function of receptors.
Table 1 has enumerated that methadone enantiomer and The compounds of this invention stimulate nicotine 86Rb +The inhibition activity that from KX α 3 β 4R2 cells, overflows.From suppressing curve calculation IC 50Value wherein utilizes 100 μ M nicotine to stimulate 86Rb +Overflow, as described under the experiment technology.Comprise mecamylamine for contrast, it is the nAChR antagonist of standard.Shown in data are Mean +/-SEs of three to six independent measurements.
Methadone is to the low affinity of nAChR agonist binding site.Checked in the methadone competition KX α 3 β 4R2 cell membrane by [ 3H] ability of α 3 β 4 receptor stimulating agent recognition sites of EB labelling.As described in testing under the technology, use 323pM[ 3H] EB carries out combination and measures.The K of nicotine iValue is 559nM.Can not estimate the K of methadone and mecamylamine iValue, even because use the highest concentration (1mM), suppression ratio is still less than 50%.As shown in Figure 4, methadone can not compete effectively [ 3H] the EB binding site.Show that mecamylamine is for contrast.Thereby, even use the highest concentration (1mM), methadone also suppress to be less than 50% [ 3H] EB and α 3 β 4 receptors bind.This is equivalent to the weak in conjunction with rendeing a service of mecamylamine.In the parallel assay that carries out as positive control, nicotine is competed the agonist binding site of α 3 β 4 receptors effectively, obtains dissociation constant (K i) be 560nM, to the numerical value of being reported in the past in these cells similar (Xiao et al., 1998).Methadone is very low to the affinity of α 3 β 4 receptor stimulating agent recognition sites, with the high (IC of the effectiveness of its retardance function of receptors 50About 2 μ M) present a contrast, this has pointed out the noncompetitive mechanism of receptor antagonism.
Table 1
Figure G2009101683118D00081
The IC of α (-)-EDDP 50Value significantly is lower than mecamylamine (p＜0.02).
Methadone is to the noncompetitive retardance of nAChR function.For the final receptor retardance type of identifying methadone, we have checked that it is to being subjected to the influence of nicotine activated receptors concentration-response curve.As measurement as described in testing under the technology 86Rb +Overflow.Load to cell 86Rb +, then be with or without (contrast) 1 μ M methadone in the presence of be exposed to the buffer that contains progressive concentration nicotine and reach 2 minutes.Calculate 86Rb +Overflow, for institute's load 86Rb +Percentage ratio, E MaxBe defined in the peak response that does not have under the methadone existence.Shown in curve from single experiment, measure quadruplicate.There is not and having EC in the presence of the methadone 50Value is respectively 28.8 ± 1.2 and 21.3 ± 2.1 μ M (from the Mean +/-SE of four independent experiments).E in the presence of 1 μ M methadone MaxValue (Mean +/-SE) is 63 ± 2% of a control value.EC in the presence of methadone Max(p＜0.05) and E Max(p＜0.01) all significantly is different from control value.As shown in Figure 5, in the presence of 1 μ M methadone, the maximum that stimulated by nicotine 86Rb +Overflow (E Msx) significantly reduced, but the EC of nicotine 50Minor alteration is only arranged, if any.This result shows that in fact methadone is really mainly by noncompetitive mechanism retardance α 3 β 4nAChR functions.
Methadone metabolite and analog are right 86Rb +The depression effect of from KX α 3 β 4R2 cells, overflowing.We have tested seven kinds of chemical compounds relevant with methadone, comprise its metabolite and analog, test that they are right 86Rb +The agonist effect and the antagonist effects of from KX α 3 β 4R2 cells, overflowing.Under the concentration up to 100 μ M, these chemical compound neither ones increase 86Rb +Overflow (data not shown).
Methadone and related drugs are to the influence of nAChRs
But, all chemical compounds of being tested here all are that strong relatively nicotine stimulates 86Rb +Overflow blocker (seeing Table 1).Thereby, the fragrant and nor-third oxygen sweet smell of long-acting methadone analog LAAM and third oxygen in blocking this α 3 β 4 receptor-mediated reactions approximately with the methadone equivalence.Methadone metabolite EDDP or even stronger; In fact, EDDP is one of existing the strongest nAChR antagonist of reporting seemingly, approximately is five times in methadone, approximately doubles mecamylamine (Fig. 6, table 1).In addition, as methadone, two kinds of enantiomer of metabolite are equivalent (tables 1) on retardance α 3 β 4nAChR, but in these researchs, the IC between (-)-EDDP and the mecamylamine 50Value difference is different to be significant (p＜0.02) on the statistics, and (+)-EDDP quite different (0.05＜p＜0.1).
Fig. 6 shows what methadone, (+)-EDDP, LAAM and mecamylamine stimulated nicotine 86Rb +The inhibitory action contrast of from KX α 3 β 4R2 cells, overflowing.As measurement as described in testing under the technology 86Rb +Overflow.Load to cell 86Rb +, the buffer that is exposed to independent buffer (basis discharge) then or contains 100 μ M nicotine in the presence of the raceme of concentration shown in being with or without methadone, (+)-EDDP, LAAM or mecamylamine reaches 2 minutes. 86Rb +Overflow with institute's load 86Rb +Percentage ratio represents that control value is defined in and stimulated by 100 μ M nicotine 86Rb +Overflow.
Methadone metabolite and analog are to the noncompetitive retardance of nAChR function.Here the chemical compound neither one of being checked compete effectively [ 3H] the EB binding site, to have pointed out as methadone, they are via noncompetitive mechanism retardance function of receptors.In order more directly to check this point, checked that (+)-EDDP and LAAM are to being subjected to the influence of nicotine activated receptors concentration-response curve.As measurement as described in testing under the technology 86Rb +Overflow.Load to cell 86Rb +, then be with or without (contrast) 0.5 μ M EDDP or 3 μ M LAAM in the presence of be exposed to the buffer that contains progressive concentration nicotine and reach 2 minutes.Calculate 86Rb +Overflow, for institute's load 86Rb +Percentage ratio, EC 50Be defined in the peak response that does not have under the antagonist existence.Shown in curve from single experiment, measure quadruplicate.In the presence of 0.5 μ M (+)-EDDP and in the presence of 3 μ M LAAM, nicotine stimulated control cell 86Rb +The EC that overflows 50Value is respectively 28.2 ± 1.5,25.5 ± 1.5 and 18.8 ± 1.4 μ M* of contrast.In the presence of 0.5 μ M (+)-EDDP and 3 μ M LAAM, E MaxValue is respectively the 60 ± 3%** and the 44 ± 5%** of contrast.Numerical value is Mean +/-SE, from three independently experiments.The resin that significantly is different from control value is used * p＜0.05 and * * p＜0.01 expression respectively.As shown in Figure 7, these chemical compounds all serve as the noncompetitive blocker of α 3 β 4 nicotine receptors.
Discuss
We have studied the influence of three kinds of analogs of methadone and metabolite and methadone to the rat α 3 β 4nAChRs functions of stably express in KX α 3 β 4R2 cells.All these chemical compounds suppress in the concentration dependent mode all that nicotine stimulates 86Rb +Overflow, compare with mecamylamine, effectiveness is quite high.Definite, the main oxidative metabolism product EDDP of methadone is one of the strongest nicotinic antagonists of existing report, IC 50About 0.4 μ M.
In the presence of methadone, EDDP and LAMM, receptor-mediated peak response has obvious reduction, and nicotine stimulates 86Rb +The EC that overflows 50Value does not have material alterations, and this has clearly illustrated that the noncompetitive mechanism of these chemical compound retardances nAChR.The all not competitions effectively of methadone, its metabolite and its analog [ 3H] the EB binding site, the latter represents the agonist recognition site of this receptor, and this observed result is consistent with noncompetitive mechanism also.In a word, these data show that all these chemical compounds are most likely at retardance in the α 3 β 4nAChR passages.In the presence of methadone and LAAM, nicotine stimulates 86Rb +The EC that overflows 50As if value also has reduction significantly on the slight still statistics, has hinted that in fact these medicines may increase the effectiveness of nicotine to this receptor.Although nicotine EC 50The fine difference of value has very likely been represented the artefact on the statistics, but we can not get rid of allosteric effect.
(+) of methadone and metabolite thereof-and (-)-enantiomer be equivalent in retardance on the nAChR.This is opposite to the agonism of opiate receptor with methadone, and the latter is almost completely owing to its (-)-enantiomer.Therefore, the efficient of (+) of methadone and metabolite thereof-enantiomer should block nicotine receptor, and there is no need to stimulate opiate receptor.This can allow these (+)-enantiomer to be used in such situation then, and it may be useful wherein blocking neuronal nicotinic receptor.For example, receptor be it is reported that by the mecamylamine retardance helping smoking cessation (Rose et al., 1994,1998), the strongest methadone metabolite approximately is the twice that mecamylamine is renderd a service.In addition, nicotine receptor be considered in some pain relieving approach, to play the part of may be very important role (Flores, 2000).Although pain relieving is often relevant with nicotinic agonist, these effects are not familiar with completely yet, might can help pain relieving (Hamann and Martin, 1992) by nicotinic antagonists yet.If this also is so for methadone and metabolite thereof, perhaps their analgesic effects by nicotine mechanism will be the replenishing of pain relieving mechanism that is subjected to opioid receptors.When facing the problem of opium toleration and/or ceiling effect, this point will be useful especially.In fact, the dextro-methorphan of retardance NMDA and nicotine receptor and (+)-methadone it is reported and all weakened morphine pain relieving tolerance development (Elliott et al., 1994; Davis and Inturrisi, 1999).
Blood plasma methadone concentration after the single dose approximately is 0.25 μ M (Inturrisi andVerebely, 1972), and the Css of taking the patient of methadone for a long time can surpass 1 μ M (de Vos et al., 1995; Alburges et al., 1996; Dyer et al., 1999).Under these concentration, can expect that methadone produces significant α 3 β 4 nicotine receptors retardance.The Cpss of stronger EDDP is much lower usually, but the peak concentration after the methadone administration can reach 0.2 μ M (de Vos et al., 1995).
Shall also be noted that (+)-effectiveness of methadone retardance nmda receptor channel is similar to the effect to nicotine receptor, but lower slightly (Gorman et al., 1997; Stringer et al., 2000).Methadone retardance nmda receptor also with its analgesic effect be related (Shimoyama etal., 1997; Davis and Inturrisi, 1999), particularly with its treatment potentially useful chronic and/or neuropathic pain be related (Elliott et al., 1995; Hewitt, 2000; Stringer et al., 2000).In addition, methadone may involve nmda receptor (Gorman et al., 1997 to the possible attenuation of morphine toleration; Davis andInturrisi, 1999).But in this, EDDP and (+)-methadone also may directly help analgesic effect to the retardance of nicotine receptor, even directly help the attenuation of morphine toleration.Thereby, might methadone and metabolite influence three kinds of different neurotransmission systems relevant with the opium toleration with the pain relieving approach.
Therefore, chemical compound of the present invention is by the noncompetitive mechanism retardance α 3 βs 4 nicotine cholinoceptors consistent with channel blocking.(+) of methadone and metabolite thereof-and (-)-enantiomer all be activated; Therefore, the efficient of (+) of these chemical compounds, particularly EDDP-enantiomer in the retardance nicotine receptor should make them be used as the probe of nicotine receptor, and can not influence opiate receptor.
Chemical compound
When describing chemical compound, use following definition, they comprise its all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form separately.
That the term alkyl comprises is side chain and straight chain, saturated and undersaturated, replacement and unsubstituted alkyl.The example of alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.
The term thiazolinyl is represented the ethylenically unsaturated hydrocarbons base, straight or branched, it can be that replace or unsubstituted.
The term alkynyl represents to have the straight or branched alkyl of 1 or 2 acetylene bond, and it can be that replace or unsubstituted.
Term aryl is represented phenyl, and it can be replaced by 1-5 substituent group.
Term azepine aromatic group represents to contain the aromatic ring of 1-3 nitrogen-atoms, and it can be replaced by 1-5 substituent group.
The universal architecture of these chemical compounds comprises its all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form as shown in the formula shown in I and the II:
Wherein:
R 1Be 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) thiazolinyl and have 1-5 substituent aryl or azepine aromatic group, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root, aldehyde, acetoxyl group, propionyloxy, different propionyloxy, cyano group, aminomethyl, N-methylamino methyl, N, the N-dimethylamino methyl, Methanamide, the N-methylformamide, N, dinethylformamide, acetyl group, propiono, formoxyl, benzoyl, sulfate radical, methylsulfate, hydroxyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, sulfydryl, methyl mercapto, ethylmercapto group, the rosickyite base, fluorine, chlorine, bromine, iodine, trifluoromethyl, propargyl, nitro, carbamyl, urea groups, azido, isocyano, the isothiocyanic acid root, the group that hydroxyl amino and nitroso-group are formed;
R 2Be hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl or (C 2-C 6) alkynyl, among the formula I, R 2Can also be selected from O=or HN=;
R 3Be selected from hydrogen, (C 1-C 6) alkyl, (C 6-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl and aryl-(C 1-C 6) alkyl; Preferably, R 3Be methyl or ethyl;
R 4Be (C 1-C 6) alkyl and (C 3-C 6) cycloalkyl;
R 5Be to have 1-5 substituent aryl or azepine aromatic group, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; Methanamide; the N-methylformamide; N; dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed, and can constitute and R 1The key that connects obtains conjugated ring system.
Chemical compound can be the form of pharmaceutically acceptable salt, includes but not limited to inorganic acid addition salt, for example hydrochlorate, hydrobromate, sulfate, phosphate and nitrate; Organic acid addition salt, for example acetate, mutate, propionate, succinate, lactate, oxyacetate, malate, tartrate, citrate, maleate, fumarate, mesylate, Salicylate, right-toluene fulfonate, benzene sulfonate and Ascorbate; The salt of acidic amino acid, for example aspartate and glutamate, Glu; Salt can be in some cases hydrate or with the solvate of pure and mild other solvents.Salt form can prepare like this, and suitable amine and acid are blended in the conventional solvent, contains in the solvent or does not have alcohol or water.
More specifically, contain following compounds:
Figure G2009101683118D00151
Figure G2009101683118D00161
Figure G2009101683118D00171
Figure G2009101683118D00181
Figure G2009101683118D00201
Figure G2009101683118D00211
*=N represents in the five-membered ring at R 3With carry R 2Carbon atom between have two keys.
Can also use wherein R 5With R 1The chemical compound of bonding, for example following those, can prepare by the synthetic simple change of above-claimed cpd.
Wherein
X and Y are independently selected from the group of being made up of C and N;
R 3Be aforesaid;
R 6Be independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; Methanamide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino is formed.
Exemplary synthetic
Fig. 8 and 9 shows some exemplary synthetic reactions, can be used to prepare these chemical compounds.Disclosed chemical compound comprises all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form in synthetic, other have indicate except.Cited structure is corresponding to cited those in the last table in the bracket.Those skilled in the art will recognize that these chemical compounds can generate by other synthetic reactions, will make similar product to these synthetic simple changes, all these all are regarded as belonging to scope of the present invention.
Series 1
Fig. 8 shows basic synthetic reaction, makes chemical compound (f) ( structure 9 and 10).At first,---wherein X is the hetero atom of optional position---is with CH with bromobenzene (a) or broma ring 3CN and KNH 2Be blended in the liquefied ammonia, obtain (b).Descending with second kind of bromobenzene or heterocycle---wherein Y is the hetero atom of optional position at 105-110 ℃ then, is independently to select with X---and Br 2Mix, obtain diphenyl cyanide (c).This product is reacted with inferior tert-butyl group methoxylation thing in alkaline solution, obtain chemical compound (d).Make chemical compound (d) and SOCl 2And ammonia react, generate chemical compound (f), be the amidino groups analog.Those skilled in the art will recognize that, according to this synthetic, by similar methods can prepare simply chemical compound 11 and 12 and other.
Chemical compound (g) and (j) synthetic
Make chemical compound (f) further with 1.2N HCl and NaNO 2Reacted about 1 hour, and obtained chemical compound (g) ( structure 5 and 6).This mixture and LAH/THF reaction obtain chemical compound (j), and they also can be used in the method disclosed herein.
Chemical compound (h) and (k) synthetic
Start from the above-mentioned reaction that ends at chemical compound (g), further with CH 3The reaction of I obtains chemical compound (h) (structure 7 and 8) with the pentacyclic nitrogen of methyl substituted.Make this mixture and LAH/THF reaction obtain chemical compound (k).
Chemical compound (i), (l), (m), (n), (o) and (p) synthetic
Continue to generate the reaction of chemical compound (h), further, open two key oxygen, obtain chemical compound (i) (structure 33 and 34) with the EtLi reaction.Chemical compound (i) is the basis of other three reaction chains.
Make chemical compound (i) and MCPBA and CHCl 3Reacted 12 hours down at 0 ℃, generate chemical compound (l).Make itself and NaBH then 4Reaction generates chemical compound (m) (structure 1 and 2).
Make chemical compound (i) and NaBH 4Reaction generates chemical compound (n) (structure 3 and 4).
Make chemical compound (i) and HCHO and CH 3The OH reaction generates chemical compound (o) (structure 14), then with H 2With the Pd-C reaction, obtain chemical compound (p) (structure 16 and 18).
Series 2
The synthetic reaction of second series is equal to first series, mixes second kind of bromobenzene (b but omit 2) or heterocyclic second step of bromine.Thereby prepare similar single phenyl compound.Fig. 9 sets forth the synthetic reaction of second series.The chemical compound that is parallel to series 1 is represented with subscript 2.
The prevention of pain relieving and abuse
In order to confirm in fact to have really about The compounds of this invention the suspection of analgesic effect, the inventor utilizes mice to test.Figure 10 shows being sheerly the result of experiment that the Swiss-Webster mice that grows up is carried out.In mouse brain, give every kind of enantiomer of EDDP, dosage 40 μ g.Utilize warm water to remove the baseline sensitivity of tail nociception algoscopy monitoring animal, monitoring is removed tail and is measured as analgesic incubation period.The result proves, removes tail and has prolonged because of the administration of EDDP enantiomer incubation period.Thereby obviously d-methadone metabolite EDDP has significant analgesic effect.Equally, the analog of desired metabolites EMDP and EDDP and EMDP is not always the case.Figure 11 and 12 sets forth EDDP concentration to suppressing the influence of nicotine activation electric current, and this is one of explanation of analgesic effect.
Go through as top, the inventor believes d-methadone metabolite and their analog retardance nicotine α 3 β 4 receptors.Recently, reported that in fact α 3 β, 4 blocker dextro-methorphans and dextrorphan prevent the abuse of abuse property material.Glick etc. have reported that the rat oneself takes morphine, dexoxyn and nicotine and reduced when being exposed to these specificitys of 5-30mg/kg α 3 β 4 blocker.Glick?SD，Maisonneuve?IM，Dickinson?HA，Kitchen?BA；Comparative?effects?of?dextromethorphan?anddextrorphan?on?morphine，methamphetamine，and?nicotineself-administration?in?rats；Eur?J?Pharmacol.2001?Jun?22；422(1-3)：87-90。Owing to found that d-methadone metabolite and their analog are α 3 β 4 blocker, the inventor thinks that d-methadone metabolite and their analog also have this class and prevent effect.
The inventor does not wish to be subjected to this theoretical limit, but believes that d-methadone metabolite or analog disturb the award component (reward component) of abuse property material.The award component often is considered to have euphoric effect, brings out the behavior of seeking medicine.These effects are disturbed in the administration of d-methadone metabolite or analog, consequently prevent abuse.This class administration will help to give up smoking and prevent the more abuse of multinuclear heart material.
Therefore, in fact the administration of d-methadone metabolite or their analog can stop the abuse of the property abused material, from the opiates to nicotine.
Administration
Chemical compound of the present invention can be by effective dose or effective dose to patient's administration, to ease the pain and/or to prevent the abuse of abuse property material.In another embodiment, in single pharmaceutical composition with chemical compound and abuse property material administering drug combinations, particularly opiates or other analgesic.In this scheme, chemical compound of the present invention helps analgesic effect, also prevents the abuse of chemical compound together.Thereby the patient benefits from adding of chemical compound and analgesic effect, obtains simultaneously to reduce adding and benefit of abuse potential.In another embodiment, chemical compound of the present invention is independent of the administration of abuse property material, to induce pain relieving.In another embodiment, the effect of the abuse of preventing individually dosed abuse material is played in the independent administration of chemical compound.
" effective dose ", " therapeutic dose " or " effective dose " expression are enough to cause the amount of required pharmacological action or therapeutic effect, thereby cause the effective prevention or the treatment of disease or obstacle.Thereby when treatment CNS obstacle, the effective dose of chemical compound is to be enough to pass curee's blood brain barrier to disturb the amount of relevant acceptor site in curee's brain.Disease or prevention of disorder show as the generation that postpones this disease or obstacle symptom.The treatment of disease or obstacle shows as and reduces and this disease or the relevant symptom of obstacle, perhaps improves the recurrence of this disease or obstacle symptom.
Effective dose can be different because of various factors, for example the administering mode of the seriousness of patient's situation, obstacle symptom, age, body weight, metabolism state, the Drug therapy of following and pharmaceutical composition.Usually, the general requirement of the effective dose of chemical compound given chemical compound by about 0.1 to the amount of 500mg/kg curee's body weight.In one embodiment of the invention, give about dosage of 0.1 to about 300mg/kg every day, do not have the time limit or stop until the symptom relevant with this disease or obstacle.Preferably, give about 1.0 to 50mg/kg body weight every day.When parenteral, required dosage is less.
Those skilled in the art will recognize that chemical compound of the present invention can combine with the medicinal ingredient that is fit to and constitute pharmaceutical composition, is used for suitable administration.This based composition can only limit to chemical compound of the present invention to active component, perhaps can comprise other active component or multiple The compounds of this invention alternatively.
Pharmaceutical composition
Chemical compound of the present invention can be used in the pharmaceutical composition, be used for the administration of mammal whole body is comprised the mankind, as single composition or as main or accessory composition, associating is other Drug therapy, chemistry, medicine or non-drug therapy arbitrarily, or their combination.Except chemical compound, can also comprise one or more medicinal ingredients according to pharmaceutical composition of the present invention, comprise carrier, excipient, activating agent, filler etc.
The administration of chemical compound or its pharmaceutically acceptable salt or coordination compound can be carried out immediately, perhaps as single dosage, perhaps administration off and on, perhaps press mode clocklike, time limit is uncertain, perhaps continuous infusion, the time limit is uncertain, that acceptable route of administration includes but not limited to is oral, in the cheek, intranasal, lung, transdermal, rectum, vagina, Intradermal, sheath, intravenous, intramuscular and/or subcutaneous route.
Pharmaceutical preparation can be adopted unit dosage form, for example tablet, capsule, pill, powder, granule, suppository, aseptic parenteral solution or suspension, the aseptic outer solution of parenteral or suspension, oral administration solution or suspension, oil-in-water type or water-in-oil emulsion etc. contain an amount of active component.Local application can be the form of ointment, cream, lotion, gel, spray, irrigating etc.With regard to oral administration, can utilize compound solid of the present invention or liquid unit dosage form.
Fluid or solid unit dosage form are made oral administration easily.For example, chemical compound can be mixed with conventional composition, for example dicalcium phosphate, Magnesiumaluminumsilicate, magnesium stearate, calcium sulfate, starch, Talcum, lactose, arabic gum, methylcellulose and play drug excipient or the analog material of carrier function.Can use slow releasing preparation alternatively.Capsule can be prepared like this, and chemical compound is mixed with inert pharmaceutical diluent, this mixture is filled in the hard gelatin capsule of suitable size.Soft capsule can be encapsulated in chemical compound serosity (or other dispersions) and the vegetable oil, light petroleum or other inert oils that are fit in the gelatine capsule by machine if desired.
Suspension, syrup and elixir can be used for the oral administration of element of fluid dosage form.The fluid preparation that comprises oil can use the oil-soluble form.Prepare acceptable fluid preparation from vegetable oil, for example Semen Maydis oil, Oleum Arachidis hypogaeae semen or safflower oil and correctives, sweeting agent and any antiseptic.Can add surfactant to water, be formed for the syrup of fluid dosage form.Can make water-alcohol pharmaceutical preparation, it has acceptable sweeting agent, and for example sugar, glucide or biological sweet agent, and correctives are the form of elixir.
Can also utilize this area standard technique to obtain being used for the pharmaceutical composition of parenteral and suppository administration.Another preferable use of these chemical compounds is the transdermal parenteral pharmaceutical formulations, is used for mammal, and is for example human.
Above-mentioned and other chemical compounds can separately exist in the Drug Storage, or with the form of pharmaceutical carrier combination.The acceptable drug carrier is a carrier known in the art for purposes of the present invention, and they can influence medicine, host sharply or comprise the material of drug release device.The pharmaceutical carrier that is fit to comprises aseptic water, saline, glucose, the water of glucose or saline solution, Oleum Ricini---combines and has an appointment 30 to the every mole of castor oil of about 35 moles of ethylene oxide---with the condensation product of oxirane, liquid acid, low-level chain triacontanol, oil (Semen Maydis oil for example, Oleum Arachidis hypogaeae semen, the Semen Sesami wet goods), emulsifying agent---for example fatty acid one-or two-glyceride or phospholipid (for example lecithin etc.), glycol, poly alkylene glycol, aqueous medium in the presence of suspending agent (for example sodium carboxymethyl cellulose), sodium alginate, poly-(vinylpyrrolidone) or the like (separately or with the dispersant coupling that is fit to, lecithin for example), perhaps Myrj 45 etc.Carrier of the present invention can also contain auxiliary agent, for example antiseptic, stabilizing agent, wetting agent, emulsifying agent etc., and penetration enhancers.
Although described the present invention about its concrete mode, but those skilled in the art will figure out, and multiple equivalents can replace appointment key element as herein described, and does not deviate from following claims of the present invention scope and spirit.

Claims (32)

1, induce the analgesic method, comprise the compositions of the patient being given the pain relieving amount of inducing, said composition comprises chemical compound and its pharmaceutically acceptable salt that is selected from one of formula I and formula II:
Figure A2009101683110002C1
Formula I formula II
Its Chinese style I and II comprise all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form, wherein:
R 1Be selected from 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) thiazolinyl, aryl and azepine aromatic group;
R 2Be selected from hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl or (C 2-C 6) alkynyl, among the formula I, R 2Can also be selected from O=or HN=;
R 3Be selected from hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl and aryl-(C 1-C 6) alkyl;
R 4Be selected from (C 1-C 6) alkyl and (C 3-C 6) cycloalkyl;
R 5Be aryl or azepine aromatic group, and can comprise and R 1The key that connects obtains conjugated ring system.
2, the process of claim 1 wherein R 1Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
3, the process of claim 1 wherein R 5Be selected from the group of being made up of aryl and ammonia heteroaromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
4, the process of claim 1 wherein R 3Be methyl or ethyl.
5, the process of claim 1 wherein that described chemical compound is selected from down group:
?X ??R 1 ??R 2 ?R 3 ?R 4 ??R 5 Formula ?C Phenyl ??CH 2CH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??＝NH ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝NH ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??-CCH 3CH 2 ?H ?CH 3 Phenyl ??II ?C Phenyl ??-CCH 3CH 2 ?CH 3 ?CH 3 Phenyl ??II
?C Phenyl ??-CH(CH 3) 2 ?H ?CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?CH 3 ?CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?H ?CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?CH 3 ?CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?H ?CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?H ?CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??II ?N ??H ??-CH 2CH 3 ?H ?CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ?CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ?CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ?CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?H ?CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?H ?CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?CH 3 ?CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?CH 3 ?CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II
6, the process of claim 1 wherein that the compositions of the described pain relieving amount of inducing is enough to block nicotine receptor, thereby induce pain relieving.
7, prevent the method for abuse property substance abuse, comprise the compositions of the patient being given to abuse the prevention amount, said composition comprises chemical compound and its pharmaceutically acceptable salt that is selected from one of formula I and formula II:
Figure A2009101683110005C1
Formula I formula II
Its Chinese style I and II comprise all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form, wherein:
R 1Be selected from 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) thiazolinyl, aryl and azepine aromatic group;
R 2Be selected from hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl or (C 2-C 6) alkynyl, among the formula I, R 2Can also be selected from O=or HN=;
R 3Be selected from hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl and aryl-(C 1-C 6) alkyl;
R 4Be selected from (C 1-C 6) alkyl and (C 3-C 6) cycloalkyl;
R 5Be aryl or azepine aromatic group, and can comprise and R 1The key that connects obtains conjugated ring system.
8, the method for claim 7, wherein R 1Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; Methanamide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
9, the method for claim 7, wherein R 5Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; Methanamide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
10, the method for claim 7, wherein R 3Be methyl or ethyl.
11, the method for claim 7, wherein said chemical compound is selected from down group:
?X ??R 1 ??R 2 ??R 3 ??R 4 ??R 5 Formula ?C Phenyl ??CH 2CH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝NH ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NH ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??-CCH 3CH 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CCH 3CH 2 ??CH 3 ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??CH 3 ??CH 3 Phenyl ??II
?C Phenyl ??-CH(CH 3) 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??CH 3 ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ??H ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ??H ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??II ?N ??H ??-CH 2CH 3 ??H ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??H ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??CH 3 ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??CH 3 ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??H ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??H ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ??CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ??H ??CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ??H ??CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ??CH 3 ??CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ??CH 3 ??CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ??H ??CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ??H ??CH 3 4-chloro-3-pyridine radicals ??II ?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ??H ??CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ??CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ??CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ??CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II
12, the method for claim 7 wherein saidly is selected from the chemical compound of one of formula I and formula II and the amount of pharmaceutically acceptable salt is enough to block nicotine receptor, thereby prevents the abuse of abuse property material.
13, select chemical compound and its pharmaceutically acceptable salt of the group of free style I and formula II composition:
Formula I formula II
Its Chinese style I and II comprise all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form, wherein:
R 1Be selected from 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) thiazolinyl, aryl and azepine aromatic group;
R 2Be selected from hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl or (C 2-C 6) alkynyl, among the formula I, R 2Can also be selected from O=or HN=;
R 3Be selected from hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl and aryl-(C 1-C 6) alkyl;
R 4Be selected from (C 1-C 6) alkyl and (C 3-C 6) cycloalkyl; With
R 5Be aryl or azepine aromatic group, and can constitute and R 1The key that connects obtains conjugated ring system, except that formula II chemical compound, and R wherein 5=R 1=phenyl, R 2Be ethyl, R 4Be H, and R 3Be H or CH 3
14, the chemical compound of claim 13, wherein R 1Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
15, the chemical compound of claim 13, wherein R 5Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
16, the chemical compound of claim 13, wherein R 3Be methyl or ethyl.
17, the chemical compound of claim 13, wherein said chemical compound is selected from down group:
?X ??R 1 ??R 2 ??R 3 ??R 4 ??R 5 Formula ?C Phenyl ??CH 2CH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝O ??CH 3 ??CH 3 Phenyl ??I ?C Phenyl ??＝NH ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NH ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ??H ??CH 3 Phenyl ??I ?C Phenyl ??-CCH 3CH 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CCH 3CH 2 ??CH 3 ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??CH 3 ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ??CH 3 ??CH 3 Phenyl ??II
??C ??H ??-CH 2CH 3 ?H ??CH 3 Phenyl ??II ??C ??H ??-CH 2CH 3 ?H ??CH 3 Phenyl ??II ??C ??H ??-CH 2CH 3 ?CH 3 ??CH 3 Phenyl ??II ??C ??H ??-CH 2CH 3 ?CH 3 ??CH 3 Phenyl ??II ??N ??H ??-CH 2CH 3 ?H ??CH 3 The 3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?H ??CH 3 The 3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 The 3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 The 3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ??N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ??N Phenyl ??-CH 2CH 3 ?H ??CH 3 Pyridine radicals ??II ??N Pyridine radicals ??-CH 2CH 3 ?H ??CH 3 Pyridine radicals ??II ??N Phenyl ??-CH 2CH 3 ?CH 3 ??CH 3 Pyridine radicals ??II ??N Pyridine radicals ??-CH 2CH 3 ?CH 3 ??CH 3 Pyridine radicals ??II ??N Phenyl ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ??N Pyridine radicals ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ??N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ??N Phenyl ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ??N Pyridine radicals ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ??N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II
18, according to the chemical compound of claim 13, wherein said analog is the form of pharmaceutically acceptable salt.
19, the chemical compound of claim 18, wherein said pharmaceutically acceptable salt are the solvates of the salt of inorganic acid addition salt, organic acid addition salt, acidic amino acid and hydrate or itself and pure and mild other solvents.
20, the chemical compound of claim 19, wherein said analog is an inorganic acid addition salt, is selected from the group of being made up of hydrochlorate, hydrobromate, sulfate, phosphate and nitrate.
21, the chemical compound of claim 19, wherein said analog is an organic acid addition salt, is selected from the group of being made up of acetate, mutate, propionate, succinate, lactate, oxyacetate, malate, tartrate, citrate, maleate, fumarate, mesylate, Salicylate, right-toluene fulfonate, benzene sulfonate and Ascorbate.
22, the chemical compound of claim 19, wherein said analog is the salt of acidic amino acid, is selected from the group of being made up of aspartate and glutamate, Glu.
23, pharmaceutical composition comprises:
Pharmaceutically acceptable reagent; With
Be selected from chemical compound and its pharmaceutically acceptable salt of one of formula I and formula II:
Figure A2009101683110011C1
Formula I formula II
Its Chinese style I and II comprise all possible geometrical isomerism form, racemic form, diastereo-isomerism form and enantiomerism form, wherein:
R 1Be selected from 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) thiazolinyl, aryl and azepine aromatic group;
R 2Be selected from hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl or (C 2-C 6) alkynyl, among the formula I, R 2Can also be selected from O=or HN=;
R 3Be selected from hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl and aryl-(C 1-C 6) alkyl;
R 4Be selected from (C 1-C 6) alkyl and (C 3-C 6) cycloalkyl;
R 5Be aryl or azepine aromatic group, and can constitute and R 1The key that connects obtains conjugated ring system;
The abuse that wherein said amount is enough to induce pain relieving and/or prevents abuse property material.
24, the compositions of claim 23, wherein R 1Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
25, the compositions of claim 23, wherein R 5Be selected from the group of being made up of aryl and azepine aromatic group, have 1-5 substituent group separately, substituent group is independently selected from by hydrogen, (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl, (C 2-C 6) thiazolinyl, aryl, aryl-(C 1-C 6) alkyl, N-methylamino, N, N-dimethylamino, carboxylate radical, (C 1-C 3) the alkyl carboxylic acid root; aldehyde; acetoxyl group; propionyloxy; different propionyloxy; cyano group; aminomethyl; N-methylamino methyl; N; the N-dimethylamino methyl; amide; the N-methylformamide; N, dinethylformamide; acetyl group; propiono; formoxyl; benzoyl; sulfate radical; methylsulfate; hydroxyl; methoxyl group; ethyoxyl; propoxyl group; isopropoxy; sulfydryl; methyl mercapto; ethylmercapto group; the rosickyite base; fluorine; chlorine; bromine; iodine; trifluoromethyl; propargyl; nitro; carbamyl; urea groups; azido; isocyano; the isothiocyanic acid root; the group that hydroxyl amino and nitroso-group are formed.
26, the compositions of claim 23, wherein R 3Be methyl or ethyl.
27, the compositions of claim 23, wherein said chemical compound is selected from down group:
?X ??R 1 ??R 2 ?R 3 ?R 4 ??R 5 Formula ?C Phenyl ??CH 2CH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?H ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??CH 2CH 3 ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?H ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?CH 3 ?CH 3 Phenyl ??I ?C Phenyl ??＝O ?CH 3 ?CH 3 Phenyl ??I
?C Phenyl ??＝NH ?H ??CH 3 Phenyl ??I ?C Phenyl ??＝NH ?H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ?H ??CH 3 Phenyl ??I ?C Phenyl ??＝NCH 3 ?H ??CH 3 Phenyl ??I ?C Phenyl ??-CCH 3CH 2 ?H ??CH 3 Phenyl ??II ?C Phenyl ??-CCH 3CH 2 ?CH 3 ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?CH 3 ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?H ??CH 3 Phenyl ??II ?C Phenyl ??-CH(CH 3) 2 ?CH 3 ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?H ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?H ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?CH 3 ??CH 3 Phenyl ??II ?C ??H ??-CH 2CH 3 ?CH 3 ??CH 3 Phenyl ??II ?N ??H ??-CH 2CH 3 ?H ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 The 3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N ??H ??-CH 2CH 3 ?CH 3 ??CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?H ??CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?H ??CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?CH 3 ??CH 3 Pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?CH 3 ??CH 3 Pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?H ??CH 3 4-chloro-3-pyridine radicals ??II
?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?H ?CH 3 4-chloro-3-pyridine radicals ??II ?N Phenyl ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N Pyridine radicals ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II ?N 4-chloro-3-pyridine radicals ??-CH 2CH 3 ?CH 3 ?CH 3 4-chloro-3-pyridine radicals ??II
28, according to the pharmaceutical composition of claim 23, wherein said analog is the form of pharmaceutically acceptable salt.
29, the pharmaceutical composition of claim 28, wherein said pharmaceutically acceptable salt are the solvates of the salt of inorganic acid addition salt, organic acid addition salt, acidic amino acid and hydrate or itself and pure and mild other solvents.
30, the pharmaceutical composition of claim 29, wherein said analog is an inorganic acid addition salt, is selected from the group of being made up of hydrochlorate, hydrobromate, sulfate, phosphate and nitrate.
31, the pharmaceutical composition of claim 29, wherein said analog is an organic acid addition salt, is selected from the group of being made up of acetate, mutate, propionate, succinate, lactate, oxyacetate, malate, tartrate, citrate, maleate, fumarate, mesylate, Salicylate, right-toluene fulfonate, benzene sulfonate and Ascorbate.
32, the pharmaceutical composition of claim 29, wherein said analog is the salt of acidic amino acid, is selected from the group of being made up of aspartate and glutamate, Glu.
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